Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. [Body mass index, blood lactate and therapeutic effectiveness of metformin in type II diabetes mellitus]. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. The hyperlactatemic effect of biguanides: a comparison between phenformin and metformin during a 6-month treatment. A retrospective chart review of uncontrolled use of metformin as an add-on therapy in type 2 diabetes. Metformin as secondary therapy in a defined population with type 2 diabetes. Combined metformin and insulin therapy for patients with type 2 diabetes mellitus. Irreversibility of the defect in glycogen synthase activity in skeletal muscle from obese patients with NIDDM treated with diet and metformin. Targeting hyperglycaemia with either metformin or repaglinide in non-obese patients with type 2 diabetes: results from a randomized crossover trial. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Effect of combination glipizide GITS/metformin on fibrinolytic and metabolic parameters in poorly controlled type 2 diabetic subjects. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Low dose metformin in the treatment of type II non-insulin-dependent diabetes: clinical and metabolic evaluations. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Efficacy of once- or twice-daily extended release metformin compared with thrice-daily immediate release metformin in type 2 diabetes mellitus. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Metformin-induced lacticacidemia in patients with type 2 diabetes mellitus. [The effect of metformin on fasting and postprandial insulin secretion in obese patients with diabetes mellitus type 2]. Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. Multicenter, randomized, double-masked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea. Intensive insulin therapy combined with metformin in obese type 2 diabetic patients. The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes. The effect of metformin on glycemic control, serum lipids and lipoproteins in diet alone and sulfonylurea-treated type 2 diabetic patients with sub-optimal metabolic control. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Metformin efficacy and tolerance in obese non-insulin dependent diabetics: a comparison of two dosage schedules. Effect on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM. Adding metformin versus insulin dose increase in insulin-treated but poorly controlled Type 2 diabetes mellitus: an open-label randomized trial. Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control. Both slow-release and regular-form metformin improve glycemic control without altering plasma visfatin level in patients with type 2 diabetes mellitus. A comparison of preconstituted, fixed combinations of low-dose glyburide plus metformin versus high-dose glyburide alone in the treatment of type 2 diabetic patients. The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes. Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. Metformin-pioglitazone and metformin-rosiglitazone effects on non-conventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndrome. Combination of insulin and metformin in the treatment of type 2 diabetes. Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: effect of metformin administration. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. [Effectiveness of treatment with metformin in patients with type 2 diabetes mellitus poorly controlled with insulin treatment]. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study. Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study. Mechanism of metformin action in non-insulin-dependent diabetes. Metabolic variations with oral antidiabetic drugs in patients with Type 2 diabetes: comparison between glimepiride and metformin. Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: a randomized controlled trial. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients. Effects of exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients. Prospective randomized two-years clinical study comparing additional metformin treatment with reducing diet in type 2 diabetes. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus. Metformin's effects on glucose and lipid metabolism in patients with secondary failure to sulfonylureas. Comparative three-month study of the efficacies of metformin and gliclazide in the treatment of NIDD. Metabolic and haemodynamic effects of metformin in patients with type 2 diabetes mellitus and hypertension. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Effects of metformin on the glycemic control, lipid profile, and arterial blood pressure of type 2 diabetic patients with metabolic syndrome already on insulin. Effect of metformin on intact proinsulin and des 31,32 proinsulin concentrations in subjects with non-insulin-dependent (type 2) diabetes mellitus. [Evaluation of the efficacy of metformin-glibenclamide treatment in overweight non-insulin dependent diabetics]. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Rosiglitazone therapy improves insulin resistance parameters in overweight and obese diabetic patients intolerant to metformin. Metformin as additional therapy in adolescents with poorly controlled type 1 diabetes: randomised placebo-controlled trial with aspects on insulin sensitivity. Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Effect of metformin on glycaemic control in type 2 diabetes in daily practice: a retrospective study. Type 2 diabetes in the elderly: an assessment of metformin (metformin in the elderly). Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Effect of metformin on serum lipoprotein lipase mass levels and LDL particle size in type 2 diabetes mellitus patients. Influence of phenformin and metformin on exercise induced lactataemia in patients with diabetes mellitus. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Effect of homocysteine-lowering therapy on arterial elasticity and metabolic parameters in metformin-treated diabetic patients. Effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the LANCET randomized trial. Effects of metformin on fibrinogen levels in obese patients with type 2 diabetes. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. A comparison of treatment with metformin and gliclazide in patients with non-insulin-dependent diabetes. Metformin-induced changes in serum lipids, lipoproteins, and apoproteins in non-insulin-dependent diabetes mellitus. Continuing metformin when starting insulin in patients with Type 2 diabetes: a double-blind randomized placebo-controlled trial. Metformin causes a reduction in basal and post-venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. Clinical, metabolic, and endocrine parameters in response to metformin and lifestyle intervention in women with polycystic ovary syndrome: a randomized, double-blind, and placebo control trial. Clinical, metabolic and endocrine parameters in response to metformin in obese women with polycystic ovary syndrome: a randomized, double-blind and placebo-controlled trial. The effects of metformin and diet on plasma testosterone and leptin levels in obese men. Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind, placebo-controlled, clinical trial. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial.
BACKGROUND: The strict limiting criteria for the use of metformin in diabetes mellitus stem largely from reports, in the 1970s, of mortality and lactic acidosis associated with phenformin. Data about metformin are less clear and are based mainly on case reports. The aim of this study was to evaluate the safety of continued use of metformin in patients with contraindications to this agent. PATIENTS: Some 393 patients with type 2 diabetes mellitus (serum creatinine 130-220 &mgr;mol/l) were studied. Among them were 266 patients with coronary heart disease (CHD), 94 with congestive heart failure (CHF), and 91 with chronic obstructive pulmonary disease (COPD), all of whom had been treated with metformin. The patients were randomized to either continue or to stop metformin and were then followed for 4 years. RESULTS: Analysis was by intention-to-treat. The patients who stopped taking metformin showed a rise in body mass index and in hemoglobin A1c significantly greater than those who continued the drug. There were no cases of lactic acidosis. Lactic acid values did not differ in the two groups and correlated only with serum creatinine and body mass index. Microvascular diabetic complications, cardiovascular events, and cardiovascular and total mortality were identical in the two groups. CONCLUSIONS: Diabetic patients who are treated with metformin and who tolerate the drug well may continue taking it, even when mild renal impairment develops, possibly up to serum creatinine levels of 220 &mgr;mol/l. There is also no apparent reason why patients with CHD, CHF, and COPD should discontinue metformin. Metformin was approved by the Food and Drug Administration in 1995 subject to the conduct of a randomized trial to evaluate the risk of lactic acidosis or other serious adverse events (SAEs) with this agent, under usual care conditions.
                The Comparative Outcomes Study of Metformin Intervention versus Conventional (COSMIC) Approach Study was a randomized, open-label, active-comparator, parallel-group, 1-year trial in type 2 diabetic patients suboptimally controlled on diet or sulfonylurea. Patients received metformin (n = 7,227) or other usual care treatments (n = 1,505). The primary end point was the incidence of SAEs, death, and hospitalization.
                SAEs occurred in 10.3% (95% CI 9.6-11.1%) of the metformin group and in 11.0% (9.5-12.7%) of the usual care group (P = 0.431). Lactic acidosis did not occur. All-cause mortality (1.1% [0.9-1.4%] vs. 1.3% [0.8-2.0%], P = 0.596) and hospitalization (9.4% [8.8-10.1%] vs. 10.4% [8.9-12.1%], P = 0.229) were similar between groups.
                The incidence of SAEs was similar between groups. Lactic acidosis was not observed. Metformin may be safely prescribed for type 2 diabetes if contraindications and warnings are respected. This study demonstrates the utility of large, simple trials for risk evaluation of treatments for common diseases. Obese type II diabetic patients are often treated with metformin after full doses of sulfonylureas or insulin fail to achieve a satisfactory metabolic control. Clinical practice has often indicated that metformin has little effect on normal weight type II diabetics. The effectiveness of metformin vs placebo was evaluated in a double blind cross-over study on 53 type II diabetic patients with unsatisfactory glycaemic control. The patients were divided into two groups-the sulfonylurea-treated (S) and the insulin treated (I). Each group was then subdivided into three classes: 1) normal weight [BMI less than 25], 2) overweight [BMI 25-30] and 3) obese [BMI greater than 30]. Metformin did not modify body weight, plasma lipids or insulin profiles. Blood lactate increased slightly but only occasionally reached statistical significance. Metformin's antidiabetic activity was not influenced by the basal treatment (S or I) of the diabetics but was strongly linked to the degree of adiposity. Indeed both plasma glucose and HbA1 remained almost unchanged in normal weight patients. In the overweight and in the obese metformin significantly improved glycaemic profiles and reduced HbA1 levels. These results confirm clinical experience indicating that some degree of adiposity is a necessary prerequisite for metformin efficacy in diabetics. Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS) Metformin is a biguanide that has been shown to effectively lower plasma glucose levels in subjects with noninsulin-dependent diabetes mellitus (NIDDM). However, its mechanism of action remains unknown. Studies that have examined the effect of metformin on hepatic glucose production (HGP) and muscle glucose utilization in NIDDM have yielded conflicting results, and little information is available about the action of metformin on lactate turnover and gluconeogenesis from lactate in humans. We studied 20 NIDDM subjects and 8 nondiabetic controls in a randomized, double blind, placebo-controlled trial to determine the effect of 15 weeks of treatment with metformin or placebo on glucose and lactate metabolism. Before and after treatment, all participants received a 7-h infusion of [6-3H]glucose and [3-14C]lactate in combination with indirect calorimetry and estimation of lactate central vein specific activity. A euglycemic insulin clamp (20 mU/m2.min) was performed during the last 3 h of the tracer infusions. The study design allowed us to evaluate the effects of metformin vs. placebo treatment on glycemic control, plasma lipid profile, HGP, insulin-mediated glucose uptake, oxidative and nonoxidative glucose metabolism, and lactate turnover. Metformin treatment significantly reduced fasting plasma glucose (196 +/- 18 vs. 152 +/- 12 mg/dL; P < 0.01), hemoglobin A1 (12.5 +/- 0.6 vs. 9.2 +/- 0.3%; P < 0.01), and plasma triglyceride and low density lipoprotein cholesterol concentrations. When diabetics were compared to nondiabetic controls, basal HGP was higher (12.9 +/- 1.0 vs. 9.8 +/- 1.2 mumol/kg.min; P < 0.01) despite the presence of fasting hyperinsulinemia and insulin-mediated total body glucose disposal (10.9 +/- 0.9 vs. 20.2 +/- 3.3 mumol/kg.min; P < 0.01) was decreased. Metformin significantly reduced fasting HGP (from 12.9 +/- 0.7 to 11.0 +/- 0.5 mumol/kg.min; P < 0.01), but did not enhance total body glucose disposal during insulin stimulation (10.9 +/- 0.9 vs. 11.0 +/- 0.5 mumol/kg.min; P = NS). Neither oxidative nor nonoxidative glucose disposal was improved by metformin treatment. The fasting plasma lactate concentration (1.1 +/- 0.1 vs. 0.6 +/- 0.1 mmol/L) and lactate turnover (14.0 +/- 0.8 vs. 10.3 +/- 0.6 mumol/kg.min) were significantly increased in diabetics and strongly correlated (r = 0.68; P < 0.001). The percent gluconeogenesis derived from lactate was similar in diabetic and control subjects (17 +/- 2% vs. 15 +/- 2%; P = NS), but the estimated rate of gluconeogenesis from lactate was increased in the diabetic group (P < 0.01). Despite the significant reduction in HGP after metformin treatment, the percentage of gluconeogenesis from lactate and the rate of lactate-derived gluconeogenesis were unchanged from baseline. Basal lactate turnover (15.4 +/- 1.4 vs. 14.8 +/- 1.4 mumol/kg.min) and lactate oxidation (7.9 +/- 0.7 vs. 8.1 +/- 0.9 mumol/ kg.min) as well as total lactate turnover and lactate oxidation during the insulin clamp were similar before and after metformin treatment. There were no changes in any of the above metabolic parameters in the placebo-treated group. In poorly controlled NIDDM subjects, the primary mechanism by which metformin improves glycemic control is related to the suppression of accelerated basal HGP, and this most likely is secondary to an inhibition of hepatic glycogenolysis. Metformin has no effect on the rate of lactate turnover or gluconeogenesis from lactate in either the basal or insulin-stimulated states. To compare the chronic hyperlactatemic effect of phenformin and metformin, we performed a double-blind study in 10 non insulin-dependent diabetics without any other known hyperlactatemic condition. After a pre-study period, each patient was allocated to a 6-month treatment with phenformin (50 mg bid) or metformin (850 mg bid) in random sequence. Body weight values were not significantly different between phenformin and metformin. Diabetic control was significantly (p less than 0.001) improved by both biguanides versus pre-study, but was the same during metformin and phenformin: HbAI = 13.8 +/- 0.3 SEM% during pre-study 9.7 +/- 0.2% during phenformin, 10.2 +/- 0.2% during metformin. Mean values of plasma lactate during metformin were significantly lower versus phenformin (1.30 +/- 0.05 vs 1.64 +/- 0.05 mmol/l, p less than 0.001). Mean values of plasma lactate/pyruvate ratio during metformin were significantly lower versus phenformin (16.92 +/- 0.59 vs 22.65 +/- 0.87, p less than 0.001), but not versus pre-study (16.19 +/- 0.51). These results indicate that: 1) during a 6-month treatment with a diabetic control of similar degree phenformin produces a significantly higher hyperlactatemic effect vs metformin; 2) metformin treatment is associated with less impairment of intracellular redox state versus phenformin, and therefore should be considered advantageous in the long-term treatment of non insulin-dependent diabetics. The hyperglycemia, hyperinsulinemia, insulin resistance, and obesity syndrome associated with type 2 diabetes can have debilitating consequences. The biguanide metformin has a mechanism of action that is complementary to those of insulin and the sulfonylureas, suggesting that combination therapy that includes metformin may result in improved glycemic control. The purpose of this retrospective chart review was to determine the effects of adding metformin in an uncontrolled fashion to existing therapy in obese patients with type 2 diabetes who had suboptimal glycemic control and insulin resistance. For the review, the records of 124 patients were divided into two groups: group 1 included 71 patients who were taking insulin with or without a sulfonylurea, and group 2 consisted of 53 patients who were taking a sulfonylurea alone. Metformin was added to patients' existing therapy in conjunction with downward titration of the sulfonylurea and insulin doses. A retrospective chart review was conducted at the end of 6 months for group 1 and at the end of 12 months for group 2 to determine the change from baseline in measures of diabetes control (ie, insulin and sulfonylurea dose, glycated hemoglobin [Hb A1c] value, body mass index [BMI], and lipid profiles). In group 1, the mean insulin dose decreased from 46.4 U/d at baseline to 6.1 U/d at the end of follow-up. Eighty-three percent of the patients were able to discontinue insulin therapy completely. Similarly, group 2 had statistically significant reductions in mean sulfonylurea dose. Both groups also achieved statistically significant reductions in Hb A1c, BMI, and total cholesterol level. The addition of metformin to treatment with insulin or sulfonylureas, either alone or in combination, significantly improved glycemic control and cholesterol levels and promoted weight loss in obese type 2 diabetic patients with insulin resistance. Less than 5% of patients reported mild, transient gastrointestinal side effects, none of which required cessation of metformin therapy. Five patients discontinued metformin due to lack of efficacy. This study was undertaken to assess the effect of metformin as a second-line oral antihyperglycemic agent in a defined population with type 2 diabetes mellitus. We measured the extent and circumstances of metformin use in the 15,000-person diabetes registry of a large, group-model health maintenance organization (HMO). Among subsets of patients in whom adequate glycemic control could not be maintained with sulfonylurea (SU) therapy, we compared glycemic control before and after metformin use to glycemic control during a similar interval before metformin was introduced. Metformin users were significantly more likely than nonusers to have had poor glycemic control at baseline. Nearly two thirds (63.8%) of patients with a glycosylated hemoglobin (Hb A1c) level >10% switched to metformin, as did 46.3% of those with an Hb A1c level of 8% to 10%. In all patients (metformin users and nonusers) in whom SU therapy failed to maintain glycemic control, Hb A1c levels decreased 0.9% after metformin was introduced, compared with a decrease of 0.4% during the control period. In a group-model HMO that promoted the use of metformin as second-line therapy in patients unable to maintain glycemic control with SU therapy, metformin reduced hyperglycemic levels. This study was undertaken to assess the effects of combined treatment with insulin and metformin in patients with type 2 diabetes mellitus in whom dietary measures, weight control, and oral antihyperglycemic therapy had failed.
                Insulin resistance in peripheral tissues, increased hepatic gluconeogenesis, and impaired insulin secretion are the underlying factors in the development of type 2 diabetes. Metformin is a biguanide antihyperglycemic agent that increases peripheral insulin sensitivity, reduces hepatic gluconeogenesis, and decreases intestinal glucose absorption.
                Thirty-one patients (24 women, 7 men; mean age, 61.8 years; mean body mass index [BMI], 28.0 kg/m2) were enrolled in this randomized, double-blind, 2-way, crossover, placebo-controlled study. Patients with type 2 diabetes who were treated previously with insulin or oral hypoglycemic agents and who had a glycosylated hemoglobin (HbA1c) level >9% or a fasting blood glucose level >8 mmol/L were included. Patients who were being treated with oral agents were switched to insulin therapy and required to maintain stable blood glucose control for 2 months prior to randomization. Patients received insulin plus either metformin 1,700 mg/d or placebo for 5 months, followed by a 2-month washout period, and were then crossed over to the other treatment arm for 5 months of additional treatment (total treatment period: 12 months).
                Thirty patients completed the study; 1 patient withdrew early because of hypoglycemia. Compared with placebo, metformin produced significant reductions from overall baseline in mean daily insulin dose requirement (-8.69 units (17.2%], P < 0.001), HbA1c level (-0.74 [9.9%], P = 0.005), serum fructosamine level (-44.40 micromol/L, P = 0.026), 24-hour blood glucose profile (P = 0.008), and total cholesterol level (-0.42 mmol/L, P = 0.005). No treatment effects were observed on body weight, blood pressure, serum high-density lipoprotein cholesterol levels, or serum triglyceride levels. There was no correlation between BMI and reduction in HbA1C. No major side effects were reported.
                Combination therapy with metformin and insulin improves glycemic control and reduces insulin requirements. with no major side effects, in patients with type 2 diabetes and may improve the risk profile in this patient population. To assess the reversibility of the defect in glycogen synthase (GS) activity in skeletal muscle from obese patients with NIDDM treated with a hypocaloric diet and metformin.
                Eighteen obese patients newly diagnosed with NIDDM were included in a randomized placebo-controlled double-blind parallel group trial and followed for 3 months. Euglycemic-hyperinsulinemic clamp including indirect calorimetry and biopsy of m. vastus lateralis was performed before and after treatment with a hypocaloric diet plus metformin or placebo. The patients were studied at basal, low, and high insulin concentrations.
                The impaired GS activity in muscle biopsies was not reversed either by acute normalization of glycemia (for 8 h) or by chronic reduction of hyperglycemia by diet plus metformin. In both treatment groups, comparable effects on glycemic control and weight loss were found together with marked insulin suppression of nonesterified fatty acids and increased glucose oxidation. Total glucose disposal at euglycemic-hyperinsulinemic clamp increased significantly in the metformin group by 25% at high insulin level (259 +/- 31 vs. 207 +/- 21 mg x m(-2) x min(-1), P < 0.05). An insignificant increase by 13% was found in the placebo group. There were no significant changes in nonoxidative glucose metabolism. GS activity and glucose utilization showed no significant differences between the two treatment groups when regression coefficients, expressed as incremental changes by increments of insulin, were compared.
                Defective GS activity in obese NIDDM patients is not secondary to hyperglycemia. Metformin and diet had no significant influence on GS activity. The added effect of metformin to that of a hypocaloric diet in improving insulin-stimulated glucose utilization is marginal when blood glucose reduction is obtained by weight loss. Metformin is the 'drug-of-first-choice' in obese patients with type 2 diabetes mellitus (T2DM) due to its antihyperglycaemic and cardiovascular protective potentials. In non-obese patients with T2DM, insulin secretagogues are empirically used as first choice. In this investigator-initiated trial, we evaluated the effect of metformin vs. an insulin secretagogue, repaglinide on glycaemic regulation and markers of inflammation and insulin sensitivity in non-obese patients with T2DM.
                A single-centre, double-masked, double-dummy, crossover study during 2 x 4 months involved 96 non-obese (body mass index < or = 27 kg/m(2)) insulin-naïve patients with T2DM. At enrolment, previous oral hypoglycaemic agents (OHA) were stopped and patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either repaglinide 2 mg thrice daily followed by metformin 1 g twice daily or vice versa each during 4 months with 1-month washout between interventions.
                End-of-treatment levels of haemoglobin A(1c) (HbA(1c)), fasting plasma glucose, mean of seven-point home-monitored plasma glucose and fasting levels of high-sensitivity C-reactive protein and adiponectin were not significantly different between treatments. However, body weight, waist circumference, fasting serum levels of insulin and C-peptide were lower and less number of patients experienced hypoglycaemia during treatment with metformin vs. repaglinide. Both drugs were well tolerated.
                In non-obese patients with T2DM, overall glycaemic regulation was equivalent with less hypoglycaemia during metformin vs. repaglinide treatment for 2 x 4 months. Metformin was more effective targeting non-glycaemic cardiovascular risk markers related to total and abdominal body fat stores as well as fasting insulinaemia. These findings may suggest the use of metformin as the preferred OHA also in non-obese patients with T2DM. The metabolic effects and mechanism of action of metformin are still poorly understood, despite the fact that it has been used to treat patients with non-insulin-dependent diabetes mellitus (NIDDM) for more than 30 years.
                In 10 obese patients with NIDDM, we used a combination of isotope dilution, indirect calorimetry, bioimpedance, and tissue-balance techniques to assess the effects of metformin on systemic lactate, glucose, and free-fatty-acid turnover; lactate oxidation and the conversion of lactate to glucose; skeletal-muscle glucose and lactate metabolism; body composition; and energy expenditure before and after four months of treatment.
                Metformin treatment decreased the mean (+/- SD) glycosylated hemoglobin value from 13.2 +/- 2.2 percent to 10.5 +/- 1.6 percent (P < 0.001) and reduced fasting plasma glucose concentrations from 220 +/- 41 to 155 +/- 28 mg per deciliter (12.2 +/- 0.7 to 8.6 +/- 0.5 mmol per liter) (P < 0.001). Although resting energy expenditure did not change, the patients lost 2.7 +/- 1.3 kg of weight (P < 0.001), 88 percent of which was adipose tissue. The mean (+/- SE) rate of plasma glucose turnover (hepatic glucose output and systemic glucose disposal) decreased from 2.8 +/- 0.2 to 2.0 +/- 0.2 mg per kilogram of body weight per minute (15.3 +/- 0.9 to 10.8 +/- 0.9 mumol per kilogram per minute) (P < 0.001), as a result of a decrease in hepatic glucose output; systemic glucose clearance did not change. The rate of conversion of lactate to glucose (gluconeogenesis) decreased by 37 percent (P < 0.001), whereas lactate oxidation increased by 25 percent (P < 0.001). There were no changes in the plasma lactate concentration, plasma lactate turnover, muscle lactate release, plasma free-fatty-acid turnover, or uptake of glucose by muscle.
                Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis. It also seems to induce weight loss, preferentially involving adipose tissue. Metformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes.
                This study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10-16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels > or =7.0 and < or =13.3 mmol/l (> or =126 and < or =240 mg/dl), HbA(1c) > or =7.0%, stimulated C-peptide > or =0.5 nmol/l (> or =1.5 ng/ml), and a BMI > 50th percentile for age.
                Metformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was -2.4 mmol/l (-42.9 mg/dl) for metformin compared with +1.2 mmol/l (+21.4 mg/dl) for placebo (P < 0.001). Mean HbA(1c) values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P < 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin.
                Metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients. Forty-eight diabetic subjects with diet-failed Type 2 mellitus, aged 40-69 years, were randomised to metformin (24 patients) or glipizide (24 patients) therapy, and followed prospectively for 12 months. Most subjects were obese. Metformin gave better fasting plasma glucose control compared to glipizide at 24 (p < 0.01), 36 (p < 0.05) and 52 weeks (p < 0.05) with a lower HbA1 concentration at 52 weeks (p < 0.05). Metformin treated patients lost weight whereas glipizide treated subjects gained weight. The weight change between the treatment groups reached significance at 4 weeks (p < 0.05) and was highly significant (p < 0.001) at 8, 12, 24, 36 and 52 weeks. There were no significant changes in either fasting plasma lipid or blood lactate levels in either the metformin or glipizide treated groups. Both drugs caused a similar reduction in albumin excretion rates. In conclusion, metformin gave better glycaemic control than glipizide, with weight loss rather than weight gain in obese Type 2 patients. Epidemiological studies have implicated increased plasminogen-activated inhibitor 1 (PAI-1) as a marker or predictor of accelerated coronary atherosclerotic disease in type 2 diabetes. We sought to determine whether metabolic control, independent of its oral mode of implementation, affects PAI-1 in patients with marked hyperglycemia.
                A total of 91 subjects were screened, subjected to a 4-week drug washout, and randomized to daily treatment with glipizide GITS (maximum 20 mg, n = 46) or metformin (maximum 2,550 mg, n = 45) as monotherapy. After monotherapy, combination therapy was initiated by adding the second agent to the regimen. Plasma glucose (fasting and postprandial), HbA(1c), fructosamine, and PAI-1 were assayed before and after randomization and sequentially thereafter in all subjects; hepatic glucose output (HGO) and abdominal fat distribution were each measured in a subset of subjects.
                Glycemic control was markedly impaired at baseline (mean HbA(1c) 10.4 +/- 0.2% glipizide GITS; 10.0 +/- 0.2% metformin) but improved comparably with each agent as monotherapy and in combination (P < 0.0001 vs. baseline), as assessed with meal tolerance studies, fructosamine values, and HGO. Body weight and abdominal fat distribution did not change significantly in either group. PAI-1 concentrations were extraordinarily high (5- to 10-fold more than normal) at baseline (202 +/- 12 ng/ml glipizide GITS; 201 +/- 13 ng/ml metformin) but declined comparably, and significantly, after treatment with either agent as monotherapy and decreased further with combination therapy.
                When hyperglycemia is profound, increases in PAI-1 are also profound. Control of hyperglycemia with either glipizide GITS, an insulin secretagogue, or metformin as monotherapy comparably ameliorates elevated PAI-1. Methylglyoxal (MG) is a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications either as a direct toxin or as a precursor for advanced glycation end products. It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway. Because guanidino compounds can block dicarbonyl groups, we have investigated the effects of the diamino biguanide compound metformin and of hyperglycemia on MG and its detoxification products in type 2 diabetes. MG and DL were measured by high-performance liquid chromatography in plasma from 57 subjects with type 2 diabetes. Of these subjects, 27 were treated with diet, sulfonylureas, or insulin (nonmetformin), and 30 were treated with metformin; 28 normal control subjects were also studied. Glycemic control was determined by HbA1c. MG was significantly elevated in diabetic subjects versus the normal control subjects (189.3 +/- 38.7 vs. 123.0 +/- 37 nmol/l, P = 0.0001). MG levels were significantly reduced by high-dosage (1,500-2,500 mg/day) metformin (158.4 +/- 44.2 nmol/l) compared with nonmetformin (189.3 +/- 38.7 nmol/l, P = 0.03) or low-dosage (< or = 1,000 mg/day) metformin (210.98 +/- 51.0 nmol/l, P = 0.001), even though the groups had similar glycemic control. Conversely, DL levels were significantly elevated in both the low- and high-dosage metformin groups relative to the nonmetformin group (13.8 +/- 7.7 and 13.4 +/- 4.6 vs. 10.4 +/- 3.9 micromol/l, P = 0.03 and 0.06, respectively). MG correlated with rising HbA1c levels (R = 0.4, P = 0.03, slope = 13.2) in the nonmetformin subjects but showed no increase with worsening glycemic control in the high-dosage metformin group (R = 0.0004, P = 0.99, slope = 0.02). In conclusion, MG is elevated in diabetes and relates to glycemic control. Metformin reduces MG in a dose-dependent fashion and minimizes the effect of worsening glycemic control on MG levels. To the extent that elevated MG levels lead to their development, metformin treatment may protect against diabetic complications by mechanisms independent of its antihyperglycemic effect. The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin. At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose -4.1 mmol.l-1; glycosylated haemoglobin A1 decrease -1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These positive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile < 10 mmol.l-1), and were less marked but still significant in the remaining 13 diabetics, whose response to therapy was not so good (glucose profile > 10 mmol.l-1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (-21.6 U/day). Metformin was well tolerated by all diabetics.(ABSTRACT TRUNCATED AT 250 WORDS) The purpose of this study was to determine the efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes.
                Adults with type 2 diabetes (newly diagnosed, treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial.
                Significant decreases (P < 0.001) in mean HbA(1c) (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (-0.73 and -0.74%) were not significantly different from the change in the immediate-release metformin group (-0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (-1.06%; mean difference [2,000 mg extended-release metformin - immediate-release metformin]: -0.36 [98.4% CI -0.65 to -0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group.
                Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment. Low doses of metformin (500 mg twice daily) were administered to 20 diabetic patients, combined with the original sulfonylurea treatment which had become ineffective even at full dosage. After 1 and 5 weeks, the effects of the drug on glycemic control, blood intermediate metabolites and monocyte insulin receptors were monitored. Metformin clearly improved glycemic control by reducing both fasting blood glucose from 189.88 +/- 21.11 mg/dl to 131.12 +/- 16.02 mg/dl after 1 week and to 130.11 +/- 13.29 mg/dl after 5 weeks (p less than 0.025 both after 1 and 5 weeks); the diurnal blood glucose average fell from 235.33 +/- 24.11 mg/dl to 174.66 +/- 23.45 mg/dl (p less than 0.0025) after 1 week and to 177.65 +/- 21.71 mg/dl (p less than 0.0005) after 5 weeks. Consequently both blood glycosylated hemoglobin (p = n.s. after 1 week, p less than 0.025 after 5 weeks) and serum fructosamine (p less than 0.0025 after both 1 and 5 weeks) also decreased after metformin treatment. No change in plasma insulin and C-peptide levels was reported and no modification in diurnal rhythms of blood lactate, pyruvate, alanine glycerol and beta-OH-butyrate was detected at any time during metformin treatment. All the changes documented in the binding values were already complete at the end of the first week; insulin binding to monocytes increased slightly but significantly (p less than 0.05) and the number of receptors per cell rose (p less than 0.05) but could not be correlated to any index of glycemic control. These data suggest that the antidiabetic action of metformin is neither related to its lactate-increasing activity nor does it depend upon its inducing an increase in insulin binding values. This metformin-related hypoglycemic effect might be the result, at least in part, of a reduced oxidative phosphorylation without inhibition of hepatic gluconeogenesis and/or of decreased hepatic glucose output. Moreover, our data are also consistent with the hypothesis that metformin might affect insulin action at a post-receptor level. To study the dose response to metformin in type II diabetic patients.
                Type II diabetic patients with a BMI > 25 were treated with 3,000 mg/day (n = 27), 1,500 mg/day (n = 25), or placebo (n = 23) for 6 months. Venous blood samples were taken at each visit for plasma glucose and insulin, HbA1c, triglyceride and cholesterol, plasminogen activator inhibitor-1 (PAI-1) antigen and activity, tissue plasminogen activator (tPA), and euglobulin clot lysis time (ECLT). Blood pressure was recorded at each visit.
                There were no changes in BMI or blood pressure. Blood glucose fell (mean) by 3.6 mmol/l in the high-dose and 0.5 mmol/l in the low-dose group over the 6-month study (P < 0.001 and NS compared with placebo). HbA1c and plasma insulin fell in both treatment groups (HbA1c, P < 0.001; insulin, P < 0.003 and 0.03). There was a fall in triglyceride (P < 0.05) and cholesterol (P < 0.008) with high-dose metformin. PAI-1 antigen and activity fell by approximately 20% of baseline in both treatment groups (PAI-1 antigen high dose, P < 0.01; PAI-1 antigen low dose, P < 0.002: PAI-1 activity high and low dose, P < 0.003). There were significant falls in total tPA in both groups (P < 0.004), but the overall effect was a fall in ECLT (P < 0.03).
                The results indicate that metformin has favorable effects on cardiovascular risk factors associated with type II diabetes. The effects on glycemic control and lipids are dose-dependent, while the enhanced fibrinolytic response is independent of the doses used. Metformin proved useful in the treatment of nonalcoholic fatty liver disease (NAFLD), but its superiority over nutritional treatment and antioxidants has never been demonstrated. We aimed to compare the usefulness of metformin versus prescriptive diet or vitamin E.
                In an open label, randomized trial, nondiabetic NAFLD patients were given metformin (2 g/day; n = 55) for 12 months. The control cases were given either vitamin E (800 IU/day; n = 28) or were treated by a prescriptive, weight-reducing diet (n = 27). Outcome measures were liver enzymes, insulin resistance (homeostasis model assessment), parameters of the metabolic syndrome, and histology.
                Aminotransferase levels improved in all groups, in association with weight loss. The effects in the metformin arm were larger (p < 0.0001), and alanine aminotransferase normalized in 56% of cases (odds ratio (OR) versus. controls, 3.11; 95% confidence interval (CI), 1.56-6.20; p= 0.0013). In multivariate analysis, metformin treatment was associated with higher rates of aminotransferase normalization, after correction for age, gender, basal aminotransferases, and change in body mass index (OR, 5.98; 95% CI, 2.05-17.45). Differences were maintained when the two control groups were separately analyzed. The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm (p= 0.001, signed rank test). A control biopsy in 17 metformin-treated cases (14 nonresponders) showed a significant decrease in liver fat (p= 0.0004), necroinflammation, and fibrosis (p= 0.012 for both). No side effects were observed during metformin treatment.
                Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling. Limited histological data support an association between improved aminotransferases and biopsy findings, which require confirmation in a double-blind trial with appropriate statistical power based on liver histology. The extended-release formulation of metformin (MXR) prolongs drug absorption in the upper gastrointestinal tract and permits once-daily dosing in patients with type 2 diabetes mellitus (T2DM). This newer formulation may enhance patient compliance with oral therapy compared to conventional immediate-release metformin (MIR) in T2DM.
                To analyse whether a switch from thrice daily MIR to once or twice daily MXR wouldachieve comparable degrees of glycemic control in patients with type 2 diabetes mellitus (T2DM).
                We conducted an open study of the efficacy and tolerability of MXR in 40 patients with T2DM who had achieved moderate or good glycemic control with MIR alone or in combination with other antihyperglycemic agents. After a lead in period of 3 months patients were switched over to a specific brand of MIR at baseline (Visit 0). Patients were subsequently followed for 4 more visits. These visits were done monthly, after taking MIR in a dose of 1-2 g/day (Visit 1); MXR as a single dose at dinner but 0.5 g less than baseline dose of MIR (Visit 2); MXR, 1-2 g/day as a single dose at bedtime, with strength same as that of baseline dose of MIR (Visit 3); and MXR, 1-2 g/day in two divided doses keeping dose same as baseline MIR (Visit 4). Glycemic control was assessed by a four-point glucose profile (fasting and three postprandial levels) at each visit.
                At visit 2, when patients had been on 500 mg lesser dose of MXR for 1 month, glucose profile worsened. However, glycemic control, at visit 3, returned to earlier levels when dose of MXR was increased back to original dose. Overall the MXR formulation was well tolerated with minor gastrointestinal adverse effects, reported by only 3 patients.
                Patients with T2DM who had been receiving thrice-daily MIR achieved comparable glycemic control when therapy was switched to once- or twice-daily MXR at the same total daily dose. We investigated whether metformin hydrochloride has sustained beneficial metabolic and (cardio) vascular effects in patients with type 2 diabetes mellitus (DM2).
                We studied 390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy. The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality, as separate aggregate scores. In addition, effects on hemoglobin A(1c) (HbA(1c)), insulin requirement, lipid levels, blood pressure, body weight, and body mass index were analyzed.
                Metformin treatment prevented weight gain (mean weight gain, -3.07 kg [range, -3.85 to -2.28 kg]; P < .001), improved glycemic control (mean reduction in HbA(1c) level, 0.4% percentage point [95% CI, 0.55-0.25]; P < .001) (where CI indicates confidence interval), despite the aim of similar glycemic control in both groups, and reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P < .001). Metformin was not associated with an improvement in the primary end point. It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P = .02), which was partly explained by the difference in weight. The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6).
                Metformin, added to insulin in patients with DM2, improved body weight, glycemic control, and insulin requirements but did not improve the primary end point. Metformin did, however, reduce the risk of macrovascular disease after a follow-up period of 4.3 years. These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated. Trial Registration ClinicalTrials.gov Identifier: NCT00375388. To determine whether metformin therapy can predispose patients with type 2 diabetes and normal renal function to lactic acidosis when certain conditions are present.
                We undertook this prospective cohort study in 110 consecutive patients (age range, 27 to 85 years) with normal serum creatinine levels (<1.5 mg/dL in men; <1.4 mg/dL in women), receiving metformin as monotherapy or in combination with sulfonylurea or insulin, who were undergoing assessment on a regular basis for diabetes care. Clinical evaluations were performed at 4- to 12-week intervals for up to 2 years. Serum electrolytes and creatinine as well as plasma lactic acid determinations were done in all patients, regardless of symptoms. The anion gap was calculated.
                Plasma lactic acid concentrations were normal in 47 patients (mean, 9.4 +/- 18.0 mg/dL or 1.053 +/- 0.194 mmol/L) and high in 63 patients (19.63 +/- 5.11 mg/dL or 2.208 +/- 0.569 mmol/L; P<0.001). The anion gap was increased in the high lactic acid group in comparison with the normal group (P<0.001). Comorbid conditions (for example, cardiovascular or respiratory disease) that may predispose to hypoxemia or compromise tissue perfusion were significantly more prevalent in patients in the high lactic acid group than in those with normal lactic acid values.
                Lacticacidemia may occur in metformin-treated patients with type 2 diabetes mellitus who have normal renal function. An increased anion gap and certain clinical symptoms may serve as clues for the presence of lacticacidemia. Progression from lacticacidemia to clinical lactic acidosis, under certain hemodynamic or respiratory adverse conditions, remains conjectural and needs further evaluation. The main causes of reduced glucose levels during metformin therapy appear to be an increase in insulin action in peripheral tissues and reduced hepatic glucose output due to inhibition gluconeogenesis.
                The purpose of the study was to establish the effect of metformin on fasting and postprandial insulin secretion.
                The study carried out was double blind, controlled, comparative, randomized, multicentric, including two groups of out-patient department (OPD) patients. 43 patients were administered metformin (Tefor ICN Canada), and 46 patients were given placebo. Patients enrolled in the study were newly diagnosed with diabetes mellitus (DM) type 2, glycaemia < 12 mmol/l, and had the Body Mass Index (BMI) > 30 kg/m2. Before treatment, blood biochemistry was done: fasting and postprandial glycaemia, glycosylated haemoglobin (HbA1c) value, fasting and postprandial insulinaemia, blood lipids (total cholesterol, total triglycerides, HDL cholesterol, and LDL cholesterol), and gamma glutaryl transferase (GGT) level. BMI was also established. After 42 days of treatment, fasting and postprandial insulinaemia were tested again. Analysis of the effects of therapy, and identification of co-variants for fasting and postprandial insulinaemia, were done by ANOVA two way and ANCOVA method.
                It was shown that metformin accompanied by diet, as compared to placebo accompanied by diet, lowered the fasting insulinaemia value during six weeks of therapy in obese patients with DM type 2 (24.392 mU/l vs. 25.667 mU/l), interacting both with BMI pre-therapy, and interacting with fasting insulinaemia pre-therapy (p < 0.001). A significant effect of the interaction of covariants BMI and GGT was defined. As for the effect of therapy on postprandial insulinaemia, it was found that there was a high statistical significance of the effect of BMI interacting with initial values for postprandial insulinaemia before therapy, and interacting with therapy (p < 0.01). Adjusted mean values for postprandial insulinaemia after therapy in the placebo group were lower as compared to the metformin group (44.807 mU/l vs. 47.114 mU/l).
                It can be concluded that, as compared to place- bo, metformin is more efficient in reducing insulin resistance in obese patients with DM type 2. In addition, as compared to placebo, metformin maintains more efficient productive insulin secretion, indicating that metformin protects the pancreas from beta cell depletion. In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients.
                Single-centre, double-masked, double-dummy, crossover study during 2x4 months involving 96 non-obese (body mass index< or =27 kg/m(2)) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions.
                Levels of tumour necrosis factor-alpha, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects.
                In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments. The UK Prospective Diabetes Study (UKPDS) showed that treatment with metformin decreases macrovascular morbidity and mortality independent of glycaemic control. We hypothesized that metformin may achieve this by improving endothelial function and chronic, low-grade inflammation. Data on this issue are scarce and we therefore tested, in the setting of a randomized, placebo-controlled trial, whether metformin can affect endothelial function and low-grade inflammation.
                The Hyperinsulinaemia the Outcome of its Metabolic Effects (HOME) trial is a double-blind trial, in which all patients were randomized to receive either metformin or placebo in addition to insulin therapy. At the beginning and the end of a 16-week treatment period fasting blood samples were drawn and a physical examination was carried out.
                The trial was conducted in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden; the Netherlands).
                Patients were included if they were between 30 and 80 years of age; had received a diagnosis of diabetes after the age of 25; had never had an episode of ketoacidosis; and their blood glucose-lowering treatment previously consisted of oral agents but now only consisted of either insulin (n = 345) or insulin and metformin (n = 45). We excluded pregnant women and women trying to become pregnant, patients with a Cockroft-Gault-estimated creatinine clearance <50 mL min(-1), or low plasma cholinesterase (reference value <3.5 units L(-1)), patients with congestive heart failure (New York Heart Association class III/IV), or patients with other serious medical or psychiatric disease. A total of 745 eligible patients were approached; 390 gave informed consent and were randomized (196 metformin, 194 placebo). About 353 patients completed 16 weeks of treatment (171 metformin, 182 placebo).
                The HOME trial was designed to study the metabolic and cardiovascular effects of metformin during a follow-up of 4 years. Presented here are the results of an interim analysis after 16 weeks of treatment.
                When compared with placebo, metformin treatment was associated with an increase in urinary albumin excretion of 21% (-1 to +48; P = 0.06); a decrease in plasma von Willebrand factor of 6% (-10 to -2; P = 0.0007); a decrease in soluble vascular cell adhesion molecule-1 of 4% (-7 to -2; P = 0.0002); a decrease in soluble E-selectin of 6% (-10 to -2; P = 0.008); a decrease in tissue-type plasminogen activator of 16% (-20 to -12; P < 0.0001); and a decrease in plasminogen activator inhibitor-1 of 20% (-27 to -10; P = 0.0001). These changes could not be explained by metformin-associated changes in glycaemic control, body weight or insulin dose. Markers of inflammation, i.e. C-reactive protein and soluble intercellular adhesion molecule-1, did not change with metformin treatment.
                In patients with type 2 diabetes treated with insulin, metformin treatment was associated with improvement of endothelial function, which was largely unrelated to changes in glycaemic control, but not with improvement of chronic, low-grade inflammation. Patients with type 2 diabetes are often obese and require large doses of insulin to achieve glycemic control. Weight gain often accompanies insulin therapy and results in increasing insulin requirements.
                To evaluate the efficacy of metformin in combination with insulin in patients with type 2 diabetes poorly controlled with insulin therapy alone.
                Randomized, double-blind, placebo-controlled trial.
                Outpatient diabetes clinic at a university medical center.
                43 patients with poorly controlled type 2 diabetes who were receiving insulin therapy.
                Patients were randomly assigned to receive placebo or metformin in combination with insulin for 24 weeks.
                Hemoglobin A1c levels decreased by 2.5 percentage points (95% CI, 1.8 to 3.1 percentage points) in the metformin group, a significantly greater change (P = 0.04) than the decrease of 1.6 percentage points in the placebo group. Average final hemoglobin A1c levels were 6.5% in the metformin group and 7.6% in the placebo group (difference, 11%). For patients who received placebo, the insulin dose increased 22.8 units (CI, 11 to 44 units) or 29% more than did the dose for patients who received metformin (P = 0.002); for these patients, the insulin dose decreased slightly. Patients in the placebo group gained an average of 3.2 kg of body weight (CI, 1.2 to 5.1 kg); patients in the metformin group gained an average of 0.5 kg of body weight (P = 0.07). Total cholesterol and low-density lipoprotein cholesterol levels decreased in both groups. High-density lipoprotein cholesterol and triglyceride levels did not change.
                The addition of metformin to insulin therapy resulted in hemoglobin A1c concentrations that were 10% lower than those achieved by insulin therapy alone. This improvement in glycemic control occurred with the use of 29% less insulin and without significant weight gain. Metformin is an effective adjunct to insulin therapy in patients with type 2 diabetes. In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin. Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus (NIDDM) in the United States. Recently, however, metformin has been approved for the treatment of NIDDM.
                We performed two large, randomized, parallel-group, double-blind, controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet (protocol 1: metformin vs. placebo; 289 patients), or diet plus glyburide (protocol 2: metformin and glyburide vs. metformin vs. glyburide; 632 patients). To determine efficacy we measured plasma glucose (while the patients were fasting and after the oral administration of glucose), lactate, lipids, insulin, and glycosylated hemoglobin before, during, and at the end of the study.
                In protocol 1, at the end of the study the 143 patients in the metformin group, as compared with the 146 patients in the placebo group, had lower mean (+/- SE) fasting plasma glucose concentrations (189 +/- 5 vs. 244 +/- 6 mg per deciliter [10.6 +/- 0.3 vs. 13.7 +/- 0.3 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.6 +/- 0.2 percent, P < 0.001). In protocol 2, the 213 patients given metformin and glyburide, as compared with the 210 patients treated with glyburide alone, had lower mean fasting plasma glucose concentrations (187 +/- 4 vs. 261 +/- 4 mg per deciliter [10.5 +/- 0.2 vs. 14.6 +/- 0.2 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.7 +/- 0.1 percent, P < 0.001). The effect of metformin alone was similar to that of glyburide alone. Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia, as compared with 3 percent in the glyburide group and 2 percent in the metformin group. In both protocols the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations, whereas the values in the respective control groups did not change. There were no significant changes in fasting plasma lactate concentrations in any of the groups.
                Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone. Many patients with type 2 diabetes mellitus (DM) with inadequate long-term blood glucose control with sulfonylurea or metformin monotherapy require additional treatment. The synergistic effects of combining glipizide with metformin on glucose control may be realized by treating the primary effects of type 2 DM, impaired insulin secretion, and insulin resistance.
                This study assessed therapy with glipizide/metformin combination tablets in patients with type 2 DM that is uncontrolled by at least half the maximum labeled daily dose of a sulfonylurea.
                In this multicenter, double-masked, parallel-group, active-controlled study, patients were randomized to receive glipizide 30-mg, metformin 500-mg, or glipizide/metformin 5/500 mg tablets for 18 weeks (metformin and glipizide/metformin doses were titrated to achieve blood glucose control). Maximum total daily doses were glipizide 30 mg, metformin 2000 mg, and glipizide/ metformin 20/2000 mg.
                A total of 247 patients were included in the study. The mean (SD) age was 56.2 (10.1) years; 61.5% of patients were male; 70.0% were white, 15.8% were Hispanic/Latino, 13.0% were black, and 1.2% were Asian/Pacific Islanders. Patients were, on average, obese (mean [SD] body mass index, 31.3 [4.7] kg/m2), had moderate to severe hyperglycemia (mean [SD] glycated hemoglobin [HbA1c], 8.7% [1.1]), and had a mean (SD) DM duration of 6.5 (4.9) years. Glipizide/ metformin tablets controlled the HbA1c level more effectively than did either glipizide or metformin monotherapies (mean treatment differences, in favor of glipizide/ metformin, of -1.06% and -0.98%, respectively, P < 0.001). At study end, an HbA1c level < 7.0% was achieved in approximately 4-fold more patients who were treated with glipizide/metformin (36.3%) compared with glipizide (8.9%) or metformin (9.9%) monotherapies. Glipizide/metformin tablets also reduced the fasting plasma glucose (FPG) level and the 3-hour postprandial glucose area under the concentration-time curve more effectively than did either monotherapy, without increasing the fasting insulin level. The greater blood glucose control with glipizide/ metformin tablets was achieved at a mean daily dose of glipizide/metformin 17.5/1747 mg, compared with mean doses of glipizide 30.0 mg or metformin 1927 mg. Treatments were well tolerated, with a low incidence of symptoms of hypoglycemia evidenced by a fingerstick blood glucose measurement < or = 50 mg/dL in the combination group (12.6%); 1 patient discontinued the study treatment for this reason. No patient required medical assistance for hypoglycemia.
                Glipizide/metformin tablets were more effective than either glipizide or metformin monotherapy in controlling HbA1c and in reducing FPG compared with baseline in patients with blood glucose that was uncontrolled with previous sulfonylurea treatment. In addition, patients receiving glipizide/ metformin were more likely to achieve an HbA1c level < 7.0%. These results were consistent with the synergistic effects on insulin resistance and beta cell dysfunction. Glipizide/metformin was well tolerated, with a low incidence of hypoglycemia. Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 +/- 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 +/- 0.4 to 7.6 +/- 0.3%) and metformin (from 8.5 +/- 0.4 to 7.4 +/- 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 +/- 0.7 to 9.5 +/- 0.7 mM) and metformin (from 10.3 +/- 0.5 to 9.5 +/- 0.6 mM, p = 0.44 vs. placebo). Total exogenous insulin requirements decreased from 53 +/- 10 to 35 +/- 7 units during metformin treatment (p = 0.02 vs. placebo). Changes in fasting insulin levels during placebo and metformin treatments were not different (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 +/- 18 to 211 +/- 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patients improves glycemia but not hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, approximately 30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selected obese patients with type 2 diabetes already on intensive insulin therapy. To test the hypothesis that metformin therapy, given as an adjunct to insulin therapy, improves metabolic control in insulin-treated NIDDM patients with suboptimal glycemic control.
                A total of 33 subjects with insulin-treated NIDDM were investigated; all had commenced insulin after secondary failure of antihyperglycemic agents. Two randomized double-blind placebo-controlled crossover studies were run. In study 1 (n = 19), insulin-treated subjects with suboptimal glycemic control received 12 weeks of metformin 1 g b.i.d. and 12 weeks of placebo. In study 2 (n = 14), subjects already established on adjunctive metformin/insulin therapy stopped the metformin component and received 12 weeks of metformin at their baseline dosage (range 1-2.5 g) and 12 weeks of equivalent placebo. Fasting plasma glucose, HbA1c, and serum lipids were measured at baseline and midway through and at the end of each treatment phase. The effect of 12 weeks of metformin treatment was compared with the effect of 12 weeks of placebo in each study and in both studies combined.
                In study 1, metformin treatment was associated with significant improvements in fasting plasma glucose (mean 12-week difference from placebo [95% CI]: 5.8 mmol/l [3.5-8.1], P < 0.001) and HbA1c (1.6% [0.9-2.4], P < 0.001). In study 2, metformin treatment was associated with significantly lower fasting plasma glucose (5.3 mmol/l [0.6-9.9], P = 0.029) and lower HbA1c (2.4% [1.0-3.8], P = 0.003) compared with those for placebo. Study 2 also showed metformin treatment to be associated with significantly lower total cholesterol than that for placebo (1.0 mmol/l [0.1-1.9], P = 0.032) and lower LDL cholesterol (1.0 mmol/l [0.1-1.9], P = 0.028). This significant difference in serum lipids seen in study 2 was not seen in study 1, but was present when both sets of data were combined (n = 33, mean total cholesterol difference at 12 weeks [95% CI]: 0.6 mmol/l [0.1-1.1], P = 0.015). Metformin had no significant effect on triglyceride, HDL cholesterol, weight, or blood pressure. Two subjects on metformin withdrew because of side effects.
                Metformin, when given as adjunctive therapy, was well tolerated and improved glycemic control and lipid concentrations in patients with insulin-treated NIDDM whose diabetes was poorly controlled. These improvements could be maintained over the long term. To investigate the mechanisms of action of metformin, insulin receptor binding and the activity of several insulin-controlled metabolic pathways were measured in adipocytes taken from 10 obese Type 2 diabetic patients treated for 4 weeks with either metformin (0.5 g x 3 daily) or matching placebo using a double-blind crossover design. Metformin therapy was associated with a significant fall in serum fructosamine levels (3.1 +/- 0.4 vs 2.8 +/- 0.4 mmol l-1, p less than 0.02) as well as fasting (10.8 +/- 2.4 vs 9.4 +/- 2.1 mmol l-1) and daytime (11.5 +/- 2.4 vs 10.0 +/- 2.2 mmol l-1) plasma glucose concentrations (p less than 0.05). Fasting and postprandial plasma levels of C-peptide and insulin were unchanged. While fasting plasma lactate concentrations remained unaltered after metformin, a rise was noted in response to meals (from 1.4 +/- 0.1 to 1.8 +/- 0.2 mmol l-1, p less than 0.05). Adipocyte insulin receptor binding was unaffected by drug treatment. Moreover, no insulin-like effects or post-binding potentiation of insulin action could be found on adipocyte glucose transport, glucose oxidation, lipogenesis, glycolysis or antilipolysis. A complementary in vitro study using adipocytes from non-obese healthy volunteers failed to show any direct effect of metformin on adipocyte insulin binding or glucose transport and metabolism, at media drug concentrations corresponding to therapeutic plasma levels. To see if Metformin Monotherapy affects glycemic control, serum lipid or lipoprotein levels in the treatment of type 2 diabetes who were poorly controlled with diet alone or despite maximal doses of (sulfonylurea) oral glucose lowering agents.
                A prospective, clinical intervention trial conducted between 1996-1997.
                Two out patient diabetic clinics of Karachi.
                A 12-week prospective clinical intervention trial. A total of 30 type 2 diabetic subjects were enrolled, of Whom 21 (12 men and 9 women) completed the study period. Their ages ranged between 35 and 70 years, (mean +/- SD 53.3 +/- 9.31) years, with a mean duration since diagnosis of diabetes was 4.5 +/- 2.3 years, body mass index (mean +/- SD) 26.8 +/- 3.53 kg/m2. They were previously treated with diet alone or had already been taking maximum doses of sulfonylurea monotherapy with suboptimal glycemic control, i.e., raised fasting blood glucose concentrations of 6-15 mmol/L or (108-270 mg/dL) on two occasions, with significant hyperglycemic symptoms. The patients were treated with metformin monotherapy with a follow up of 12 weeks. The initial dosage was 500 mg twice daily, and the dosage was increased to two or three tablets depending on the patient's metabolic changes. By comparing before and after 12 weeks therapy with metformin we assessed the importance of baseline parameters (glycemic control, serum lipid and lipoprotein concentrations, and measures of change in body weight and body mass index).
                Metformin therapy significantly decreased fasting blood glucose levels in all patients [(mean +/- SD) 227.2 +/- 37.5 to 168.6 +/- 20.5 mg/dl, p < 0.001)]. Serum total cholesterol decreased marginally [(mean +/- SD) 200.3 +/- 18.7 to 181.4 +/- 19.4 mg/dl, p < 0.01)]. Serum total triglycerides concentration also decreased [(mean +/- SD) 195.9 +/- 31.9 to 174.2 +/- 26.6 mg/dl, P < 0.01)]. Low-density lipoproteins declined [(mean +/- SD) 123.5 +/- 16.9 to 105.5 +/- 19.1 mg/dl, P < 0.01)], and very-low density lipoprotein cholesterol also decreased [(mean +/- SD) 39.2 +/- 6.4 to 34.8 +/- to 5.3 mg/dl, P < 0.01)]. Whereas, high-density lipoprotein cholesterol tended to increase [(mean +/- SD) 37.7 +/- 5.1 to 39.5 +/- 4.9 mg/dl, P < 0.01)], while no significant changes occurred in body weight and body mass index.
                Metformin treatment was effective, safe, and generally well tolerated. Insulin resistance is a major feature of type 2 diabetes mellitus, obesity and nonalcoholic fatty liver disease (NAFLD). Several studies pointed out the possible role of increased leptin in NAFLD in humans. The aim of this study is to determine the effect of metformin on plasma leptin levels in obese patients with type 2 diabetes mellitus and NAFLD compared with lifestyle interventions. Thirty-four obese patients with newly diagnosed type 2 diabetes mellitus were prospectively followed for 6 months. All patients had ultrasonographic evidence of NAFLD at baseline. The patients were randomized into two groups: group 1 (n = 15) followed lifestyle changes only and group 2 (n = 19) received metformin (1,700 mg/day). At the end of treatment, BMI, WHR, HbA1c, fasting glucose, leptin, HOMA-IR, alanine aminotransferase values decreased in both groups. No significant difference in the end-points was observed between two groups. Only in group 2, LDL decreased and HDL increased significantly. Liver echogenity decreased significantly at the end of study in both groups. The percentage of patients who no longer had evidence of NAFLD was not significantly different between the groups (20% of patients on lifestyle intervention vs. 16% of patients on metformin). The data demonstrate that, metformin and lifestyle interventions equally affected the plasma leptin levels, BMI and degree of NAFLD in obese patients with type 2 diabetes mellitus. In addition, the effects of metformin on the variables were not found to be mediated by leptin. To study the efficacy and safety of various dosages of metformin as compared with placebo in patients with type II diabetes mellitus.
                A 14-week, multicenter, double-blind, dose-response study was conducted. After a 3-week, single-blind, placebo-controlled washout, 451 patients with fasting plasma glucose levels of at least 180 mg/dL were randomized to receive an 11-week course of placebo or metformin given at 500, 1000, 1500, 2000, or 2500 mg daily.
                Metformin improved glucose variables as compared with placebo. The adjusted mean changes in fasting plasma glucose from baseline associated with each metformin group at week 7, 11, or at endpoint exceeded those associated with placebo by 19 to 84 mg/dL at dosages of 500 to 2000 mg daily, respectively. The corresponding between-group differences in glycated hemoglobin (HbA1c) ranged from 0.6% to 2.0% at dosages of 500 to 2000 mg daily, respectively. All between-group differences were significant (P < 0.05) for both fasting plasma glucose and HbA1c at week 7, week 11, and endpoint, except for the difference between placebo and metformin 500 mg in fasting plasma glucose at endpoint (P = 0.054). Treatment-related adverse events occurred in 15% of patients in the placebo group and in 28% in the metformin group (P = 0.02); these were primarily manifested as digestive disturbances, such as diarrhea.
                Metformin lowered fasting plasma glucose and HbA1c generally in a dose-related manner. Benefits were observed with as little as 500 mg of metformin; maximal benefits were observed at the upper limits of the recommended daily dosage. All dosages were well tolerated. Metformin appears to be a useful therapeutic option for physicians who wish to titrate drug therapy to achieve target glucose concentrations. A comparative open study of metformin unit doses of 500 mg and 850 mg was carried out in 64 obese, non-insulin dependent diabetics on 1.5 to 3 g metformin daily. Glycaemic response, blood lactate, plasma metformin concentrations and tolerance for metformin were assessed. On changing from a 500 mg unit dose to an equivalent total dose of metformin using the 850 mg preparation, there were no significant changes in the random blood glucose, glycated haemoglobin, or blood lactate concentrations. Metformin plasma concentrations remained unchanged except for patients transferred from 1.5 to 2.0 g daily to 850 mg twice daily; in these patients plasma concentrations increased from 1.83 +/- 0.87 to 2.50 +/- 0.89 micrograms/l (p less than 0.01). Seven patients (3 asymptomatic and 4 with background symptoms) became intolerant of the 850 mg regimen and required to return to the 500 mg dose regimen. After exclusion of patients intolerant of the 850 mg dose regimen (11%), the remaining patients noted no significant change in symptoms and 28% of all patients transferred to the 850 mg dose unit indicated an overall preference for this regimen. This study evaluated the effects on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with mild-to-moderate, but suboptimally controlled type 2 diabetes.
                In this multicenter, double-blind, placebo-controlled study, 122 patients with type 2 diabetes inadequately controlled (A1c 7-8.5%) on metformin (> or =1000 mg/day for > or =3 months) were randomized to 16 weeks treatment with 2.5 mg/day glipizide GITS (n=61) or placebo (n=61), in addition to their current metformin dose. The primary efficacy variable was the change in A1c from baseline to endpoint. Changes in fasting plasma glucose (FPG), insulin concentrations, lipid profile and safety variables were also measured.
                The addition of glipizide GITS to metformin gave significantly greater improvements in mean A1c and FPG from baseline to endpoint than placebo addition (p<0.0002). Significantly more patients in the glipizide GITS group than in the placebo group achieved the target A1c level of A1c<7.0% (p<0.0001) and an A1c<6.5% (p<0.0033). Fasting insulin concentrations were similar in both groups and unchanged by treatment. Addition of glipizide GITS to metformin did not produce any significant or clinically relevant weight gain or changes in BMI. Both treatment regimens were well tolerated.
                This study showed that the addition of 2.5 mg glipizide GITS to metformin significantly improved glucose control in patients with type 2 diabetes inadequately controlled by metformin monotherapy. To compare the effect of adding metformin to insulin therapy with a moderate increase in insulin dose alone in insulin-treated, poorly controlled Type 2 diabetic patients, 47 consecutive such patients (baseline daily dose >0.5 IU kg(-1) and HbA1c >8%) were openly randomized either to a combination of their previous insulin schedule plus metformin (2.55 g daily in three divided doses, n = 24) or to a moderate insulin dose increase (20% of baseline, n = 23). The patient status/biochemical profile was assessed at entry and at 4 months. Among those assigned to insulin + metformin, 18 took the drug. Upon an intention-to-treat basis, patients assigned to insulin dose increase had a statistically significant weight gain (1.16+/-1.9 vs 0.3+/-4.5 kg, p < 0.05). Patients assigned to the insulin + metformin regimen experienced a significantly greater fall in HbA1c (-1.87+/-2.16 vs 0.03+/-1.68%, p < 0.01), total cholesterol (-0.56+/-0.89 vs 0.14+/-0.72 mmol l(-1), p < 0.05) and LDL-cholesterol (-0.51+/-0.73 vs 0.19+/-0.6 mmol l(-1), p < 0.01). These data suggest that adding metformin to insulin in poorly controlled Type 2 DM patients offers an advantage in terms of glycaemic control and lipid plasma profile. The effect of metformin treatment was studied in 13 patients with noninsulin-dependent diabetes mellitus (NIDDM), whose fasting plasma glucose concentration was greater than 10 mmol/L with maximal sulfonylurea doses. Patients were studied before and 3 months after receiving 2.5 g/day metformin. The fasting plasma glucose concentration (12.4 +/- 0.8 vs. 8.8 +/- 0.7 mmol/L), mean hourly postprandial plasma glucose concentration from 0800-1600 h (14.0 +/- 1 vs. 9.4 +/- 0.9 mmol/L), and glycosylated hemoglobin level (12.3 +/- 0.6% vs. 9.0 +/- 0.6%) were all significantly (P less than 0.005-0.001) lower after the administration of metformin. The improvement in glycemic control was associated with a 24% increase (P less than 0.05) in insulin-stimulated glucose uptake during glucose clamp studies and a 16% decrease in basal hepatic glucose production (P less than 0.05). Mean hourly concentrations of plasma insulin (411 +/- 73 vs. 364 +/- 73 pmol/L) and FFA concentrations (440 +/- 31 vs. 390 +/- 40 mumol/L) were also lower after 3 months of metformin treatment. However, neither insulin binding nor insulin internalization by isolated monocytes changed in response to metformin. Finally, plasma triglyceride, very low density lipoprotein triglyceride, and very low density lipoprotein cholesterol were significantly decreased (P less than 0.01-0.001), and high density lipoprotein cholesterol was significantly increased (P less than 0.001) after metformin treatment. Thus, the addition of metformin to sulfonylurea-treated patients with NIDDM not in good glycemic control significantly lowered fasting and postprandial plasma glucose concentrations, presumably due to the combination of enhanced glucose uptake and decreased hepatic glucose production. Since the dyslipidemia present in these patients also improved, the results suggest that metformin may be of significant clinical utility in patients with NIDDM not well controlled with sulfonylurea compounds. Both slow-release (SR) and regular-release (RR) metformin were effective in the treatment of type 2 diabetes mellitus. We compare the efficacy, safety, and effects on serum adipocytokines and inflammatory markers of both regimens in patients with type 2 diabetes mellitus. A prospective, randomized, double-blind study enrolled 55 patients with type 2 diabetes mellitus, which were randomly assigned to receive either metformin SR or RR (at a maximal dosage of 2000 mg/d for 12 weeks). Glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, adipocytokines, C-reactive protein, and insulin resistance and pancreatic beta-cell function were measured before and after treatment. Significant decreases (P<.001) in mean HbA1c and fasting plasma glucose levels were observed in each group. However, the mean changes in HbA1c from baseline to end point in the 2 groups were not significantly different. Changes in metabolic parameters were similar except that a decreased total cholesterol level was observed in the metformin RR group. Neither regimen treatment had any influence on insulin resistance, but metformin RR improved beta-cell function. Neither regimen had an effect on serum adipocytokines or inflammatory markers. Once-daily metformin SR was as safe and effective as metformin RR in type 2 diabetic patients. Neither dosage form affected serum adipocytokines and inflammatory markers. In the present study we assessed and compared the effectiveness and safety of preconstituted, fixed, combinations of low-dose glyburide plus metformin with higher-dose glyburide monotherapy in patients with type 2 diabetes. This randomized, double-blind, cross-over study comprised 40 patients. After a 30-day run-in period of dietary treatment, patients received combined glyburide (5, 7.5 or 10 mg/day) and metformin (800, 1,200 or 1,600 mg/day) as preconstitued, fixed combinations, or glyburide alone (5, 10 or 15 mg/day). The dose was increased stepwise so as to have 1 (T1), 2 (T2) and 3 (T3) months of treatment for any given regimen (6 months in total). After 2 weeks of washout (T4), the groups were then crossed over (T5, T6, T7 periods). Body weight, fasting plasma glucose, HbA(1c), blood lactate, total cholesterol and HDL-cholesterol, and triglycerides were measured at the beginning and end of T1 and T5, and end of T2, T3, T6 and T7; postprandial plasma glucose, fasting and postprandial plasma insulin and C-peptide were evaluated at the beginning of T1 and T5, and end of T3 and T7. At these latter time points additional assessments included routine clinical chemistry measurements, ECG, and ophthalmoscopic examination. Statistical analysis was performed by the paired Student's t-test and analysis of variance for cross-over studies. Thirty-three patients completed the study. Fasting plasma glucose, postprandial plasma glucose and HbA(1c) levels improved significantly during combined treatment with glyburide at lower doses plus metformin. This effect was achieved without any major change of insulin and C-peptide concentrations. Circulating lactate concentrations increased during the regimen including metformin, but they remained well within the reference values for normal subjects. Plasma total cholesterol and triglycerides levels remained substantielly unchanged throughout the study, whereas HDL-cholesterol concentrations increased slightly, but significantly, with glyburide plus metformin therapy. Routine clinical chemistry measurements, ECG and ophthalmoscopic examinations did not change during the study. These results demonstrate that improved metabolic control can be achieved with preconstituted, fixed combinations of low-dose glyburide plus metformin in patients with type 2 diabetes, compared to higher doses of the sulphonylurea alone. The aim of the study was to evaluate the effect of metformin on markers of endothelial function, vascular inflammation and factors of thrombosis in obese type 2 diabetic patients. Twenty-four type 2 diabetic patients (15 female, 9 male) previously under medical nutrition treatment (MNT)+regular exercise programme (REP) without chronic micro or macrovascular complications with the mean age of 50.5+/-1.5 years, diabetes duration of 17.9+/-6.3 months and body mass index (BMI) of 31.7+/-0.8 kg/m(2) were enrolled in the study. In the first 4 weeks, all the patients continued MNT+REP. In the following 12 weeks, metformin (mean daily dosage of 1381+/-85 mg) was added. After the first period with MNT+REP, BMI, waist circumference, fat percentage, blood pressure and HDL cholesterol decreased significantly. After metformin addition, there was a significant decrement in BMI, waist circumference, fat percentage, fasting and postprandial plasma glucose, hemoglobin A1C, plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF) and increment in beta cell reserve values of the patients. Our results indicated that, metformin addition had beneficial effect on VEGF and PAI-1 levels in obese type 2 diabetic patients under MNT+REP, independent from its' favourable effects on BMI and glycemic control. To evaluate further the relative roles played by liver and adipose tissue in the therapeutic response to metformin in patients with type 2 diabetes.
                A total of 11 patients with diet-treated type 2 diabetes were given metformin for approximately 3 months. Measurements were made before and after treatment of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance (Ra) and disappearance (Rd) rates measured overnight with 3-[3H]glucose; and 3) plasma FFA concentrations during a 195-min infusion period at relatively low insulin (approximately 12-24 microU/ml) concentrations.
                Mean +/- SEM fasting plasma glucose concentration was significantly lower (175 +/- 11 vs. 224 +/- 15 mg/dl; P < 0.01) after treatment with metformin. Mean +/- SEM insulin concentrations measured from 8:00 A.M. to 5:00 P.M. did not change with treatment. However, both glucose and FFA concentrations were significantly lower (P < 0.01) when measured over the same time period, and the decreases in plasma FFA and glucose concentration were highly correlated (r = 0.81; P = 0.03). Overnight glucose turnover studies indicated that neither Ra (hepatic glucose production [HGP]) nor Rd changed significantly with treatment in association with metformin treatment. Since plasma glucose concentration was much lower after metformin treatment, the overnight glucose metabolic clearance rate (MCR) was significantly lower (P < 0.01). Finally, the ability of insulin to inhibit isoproterenol-stimulated increases in plasma FFA concentration was enhanced in metformin-treated patients (P < 0.05).
                Metformin treatment was associated with significantly lower fasting plasma glucose concentrations and lower day-long plasma glucose and FFA concentrations. Although overnight HGP was unchanged after treatment with metformin, the overnight glucose MCR was significantly increased, and the antilipolytic activity of insulin was also enhanced. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to a decrease in release of FFA from adipose tissue, leading to lower circulating FFA concentrations and an increase in glucose uptake. To investigate the effect of metformin plus roziglitazione (RSGMET) compared with metformin alone (MET) on glycaemic control in well-controlled Type 2 diabetes.
                Subjects (drug naïve or those on glucose-lowering monotherapy) were randomized (n = 526), following a 4-week placebo run-in period, to RSGMET [4 mg rosiglitazone (RSG)/500 mg MET] or MET 500 mg. From weeks 2-18, medication was escalated every 4 weeks (based on gastrointestinal tolerability), then remained at RSGMET 8 mg/2 g or MET 3 g for 14 weeks.
                RSGMET reduced HbA(1c) from 7.2 +/- 0.6 to 6.7 +/- 0.8% at week 32, compared with a reduction from 7.2 +/- 0.6 to 6.8 +/- 0.9% with MET (treatment difference -0.13%; P = 0.0357). More subjects achieved an HbA(1c) value of </= 6.5% at week 32 with RSGMET (51.6 vs. 43.7%), but the treatment difference was not significant (odds ratio 1.37, P = 0.0949). RSGMET produced larger reductions from baseline in mean fasting plasma glucose (adjusted difference -0.62 mmol/l, P < 0.0001), with the odds ratio of achieving a target of < 7.0 mmol/l being 2.33 (P < 0.0001). Statistically significant differences in favour of RSGMET relative to MET were seen for homeostatic model assessment (HOMA)-derived estimates of insulin sensitivity and pancreatic B-cell function, C-reactive protein (CRP), and systolic blood pressure. Overall rates of gastrointestinal adverse events (relevant to the known profile of MET) were comparable, but with a lower incidence of diarrhoea (8 vs. 18%) with RSGMET. Hypoglycaemia was reported in </= 7% subjects per group.
                RSGMET provided similar short-term glycaemic control to MET with greater improvements in estimates of insulin sensitivity, B-cell function and CRP, with less diarrhoea and low risk of biochemical hypoglycaemia, suggesting that early use of combination therapy may be appropriate. Mortality rates are considerably higher in chronic ischemic heart disease (IHD) patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those who are nondiabetics. The relationship between different types of antihyperglycemic pharmacological therapy and mortality rate in this NIDDM population is uncertain. We aimed to examine the survival in NIDDM patients with IHD using various types of oral antidiabetic treatments over a 5-year follow-up period. The study sample comprised 11,440 patients with a previous myocardial infarction and/or stable anginal syndrome, aged 45-74 years, who were screened, but not included in the Bezafibrate Infarction Prevention study. Among them, 9,045 were nondiabetics and 2,395 diabetics. The diabetic patients were divided into four groups on the basis of their therapeutic regimen at screening: diet alone (n = 990), sulfonylureas (n = 1,041), metformin (n = 78) and a combination of a sulfonylurea and metformin (n = 266). All NIDDM groups were similar with regard to age, gender, hypertension, smoking, heart failure, angina and prior myocardial infarction. Crude mortality rate was lower in the nondiabetic group (11.21 vs. 21.8%; p < 0.001). In the diabetic group, mortality was 18.5% for patients on diet alone, 22.5% for those on sulfonylureas, 25.6% for patients on metformin, and 31.6% for the combined sulfonylurea/metformin group (p < 0.01). When analyzing age-adjusted mortality rate and actuarial survival curves, the lowest mortality was found in patients on diet alone and the highest in patients on metformin (alone or in combination with sulfonylureas). After adjustment for variables connected with long-term prognosis, the use of metformin was associated with increased relative risk (RR) for all-cause mortality of 1.42 (95% CI 1.10-1.85), whereas the use of sulfonylureas alone was not [RR 1.11 (95% CI 0.90-1.36)]. NIDDM patients with IHD using metformin, alone or in combination with sulfonylureas, exhibited a significantly increased mortality. Until the results of problem-oriented prospective studies on oral control of NIDDM will be available, alternative therapeutic approaches should be investigated in these patients. The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion. Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin. The combination of metformin with thiazolidinediones is less well studied. The aim of the present study was to assess the differential effect, and tolerability, of metformin combined with pioglitazone or rosiglitazone on glucose, coagulation and fibrinolysis parameters in patients with type 2 diabetes mellitus and metabolic syndrome.
                This 12-month, multicentre, double-blind, randomized, controlled, parallel-group trial was conducted at three study sites in Italy. We assessed patients with type 2 diabetes mellitus (duration >or=6 months) and with metabolic syndrome. All patients were required to have poor glycaemic control with diet, or experienced adverse effects with diet and metformin, administered up to the maximum tolerated dose. Patients were randomized to receive either pioglitazone or rosiglitazone self-administered for 12 months. We assessed body mass index (BMI), glycaemic control [glycosylated haemoglobin (HbA(1c)), fasting and postprandial plasma glucose and insulin levels (FPG, PPG, FPI, and PPI respectively), homeostasis model assessment (HOMA) index], lipid profile [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG)], lipoprotein (a) [Lp(a)] and homocysteine (HCT) at baseline and at 3, 6, 9 and 12 months of treatment.
                No BMI change was observed at 3, 6, 9 and 12 months in either group. Significant HbA(1c) decreases were observed at 9 and 12 months in both groups. After 9 and 12 months, mean FPG and PPG levels decreased in both groups. Decreases in FPI and PPI were observed at 9 and 12 months compared with the baseline in both groups. Furthermore, in both groups, the HOMA index improved but only at 12 months. Significant TC, LDL-C, HDL-C, TG improvement was present in the pioglitazone group at 12 months compared with the baseline values, and these variations were significantly different between groups. No TC, LDL-C, TG improvement was present in the rosiglitazone group after 12 months. Significant Lp(a) and HCT improvement was present in the pioglitazone group at 12 months compared with the baseline values, and Lp(a) change was significant compared with the rosiglitazone group. Significant HCT decrease was observed in the rosiglitazone group at the end of the study. In our type 2 diabetic patients, both drugs were safe and effective for glycaemic control and improving HCT plasma levels. However, long-term treatment with metformin plus pioglitazone significantly reduced Lp(a) plasma levels, whereas metformin + rosiglitazone did not.
                For patients with type 2 diabetes mellitus and metabolic syndrome, combined treatment with metformin and rosiglitazone or pioglitazone is safe and effective, However, the pioglitazone combination also reduced the plasma Lp(a) levels whereas the rosiglitazone combination did not. To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin.
                Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment. The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured.
                Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P = 0.006; mean GHb 6.9 vs. 7.6%, P < 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P < 0.0001); reduced weight gain (-0.4 vs. +1.2 kg, P < 0.01); and decreased plasma LDL cholesterol (-0.21 vs. -0.02 mmol/l, P < 0.01). Risk of hypoglycemia was similar in both groups. CONCLUSIONS-In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less. Hyperinsulinemia/insulin resistance and elevated plasma free fatty acids (FFA) levels are involved in the hypertension and cardiac sympathetic overactivity. Metformin improves insulin action and lower plasma FFA concentrations. We investigate the possible effect of metformin on arterial blood pressure (BP) and cardiac sympathetic nervous system.
                One hundred twenty overweight type 2 diabetic patients were treated by placebo (n = 60) + diet or metformin (850 mg twice daily) (n = 60) + diet for 4 months, to evaluate the effect of metformin treatment on the cardiac autonomic nervous system. Insulin resistance was measured by the Homeostasis Model Assessment (HOMA) index. Heart rate variability (HRV) assessed cardiac sympathovagal balance.
                Metformin treatment, but not placebo treatment, was associated with a decrease in fasting plasma glucose (P <.05), insulin (P <.05), triglyceride (P <.05), and FFA (P <.03) concentrations and HOMA index (P <.03). Metformin treatment was also associated with a significant improvement in cardiac sympathovagal balance but not in mean arterial BP. Furthermore, in a multivariate analysis, delta change in sympathovagal balance index (LF/HF ratio) were associated with delta change in plasma FFA concentrations and HOMA index independently of gender and delta change in plasma triglyceride and HbA1c concentrations.
                Our study demonstrated that metformin treatment might be useful for improving cardiac sympathovagal balance in obese type 2 diabetic patients. To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM).
                Of 165 patients (fasting blood glucose [FBG] > or = 6.7 mmol/l) initially treated with diet alone, 144 (FBG still > or = 6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, with FBG < 6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration.
                The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG +/- SE was reduced (P = 0.001) from 9.1 +/- 0.4 to 7.0 +/- 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 +/- 0.8 to 7.8 +/- 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 +/- 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups.
                Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM. Combined treatment with insulin plus metformin could be a good alternative to improve the glycemic control in patients with type 2 diabetes mellitus poorly controlled with insulin therapy. We retrospectively studied 21 obese insulin-treated type 2 diabetic patients with deficient metabolic control (HbA1c 9.2 +/- 1.2%) who were treated with metformin for a minimum of 8 months. After 4 months of treatment, a significant decrease in the percentage of HbA1c was observed (delta HbA1c -1.07 +/- 1.12%; p < 0.01), with maintained values since then. Non changes in body weight or insulin requirement were noted. Our results suggest that the addition of metformin to insulin treatment is a safe and effective strategy for the improvement of glycemic control among obese type 2 diabetic patients. To compare the efficacy and safety of glimepiride versus metformin in pediatric subjects with type 2 diabetes inadequately controlled with diet and exercise alone or oral monotherapy.
                This 26-week, single-blind, active-controlled, multinational study randomized 285 subjects to receive glimepiride (1-8 mg once daily) or metformin (500-1000 mg twice daily) for 24 weeks. The primary end point was mean change in A1C from baseline to week 24. Safety was assessed by incidence of hypoglycemia and other adverse events.
                Significant reductions from baseline A1C were seen in both the glimepiride (-0.54%, P = 0.001) and metformin (-0.71%, P = 0.0002) groups. A total of 42.4% (56 of 132) and 48.1% (63 of 131) of subjects in the glimepiride and metformin groups, respectively, in the intent-to-treat population achieved A1C <7.0% at week 24. No significant differences were observed between groups in reductions in A1C and self-monitored blood glucose levels, changes in serum lipid concentrations, or hypoglycemia incidence. Significant differences were observed in mean changes from baseline in BMI between groups (0.26 kg/m(2) for glimepiride and -0.33 kg/m(2) for metformin; P = 0.003). The adjusted mean body weight increase was 1.97 kg for glimepiride and 0.55 kg for metformin (P = 0.005). A hypoglycemic episode with blood glucose <50 mg/dl (<2.8 mmol/l) was experienced by 4.9 and 4.2% of glimepiride- and metformin-treated subjects, respectively. A single severe hypoglycemic event occurred in each group.
                Glimepiride reduced A1C similarly to metformin with greater weight gain, and there was comparable safety over 24 weeks in the treatment of pediatric subjects with type 2 diabetes. This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus.
                Patients with poorly controlled type 2 diabetes (HbA1c > or = 7.5% to < or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured.
                There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated.
                Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.
                Copyright 2004 John Wiley & Sons, Ltd. The mechanism of action of metformin was studied by comparing glucose turnover before and after a 75-g oral glucose load in 10 nonobese men with non-insulin-dependent diabetes mellitus (NIDDM) during metformin and placebo therapy by the combined application of the forearm and double-isotope techniques. During the study, 9 of the 10 patients were regularly receiving glibenclamide therapy. In 5 of the men, the first study was performed during metformin therapy, and the second study was done during placebo administration; in the other 5 subjects, the order was reversed. The interval between the studies was at least 3 mo. The metformin dosage was 1 g twice daily in 9 of the patients and 850 mg thrice daily in the 10th subject. In the basal state, metformin administration reduced plasma glucose levels from 172 +/- 14 to 103 +/- 9 mg/dl (P less than .005), hepatic glucose output (HGO) from 2.67 +/- 0.15 to 2.20 +/- 0.20 mg X kg-1 X min-1 (P less than .02), and forearm glucose uptake (FGU) from 0.106 +/- 0.18 to 0.039 +/- 0.016 mg X 100 ml-1 forearm X min-1 (P less than .005), whereas insulin (23 +/- 6 microU/ml) and lactate (1.56 +/- 0.18 mM) levels were unchanged. Although the oral glucose tolerance curve (OGTC) was significantly lowered by metformin, the incremental area under the curve and the insulin response were unchanged. The systemic appearance of ingested glucose was unaffected by metformin; 64 +/- 2% of the load was recovered peripherally in 3 h.(ABSTRACT TRUNCATED AT 250 WORDS) Patients with Type 2 diabetes (T2DM) are at high risk of morbidity and mortality from cardiovascular complications, and hypoglycaemia increases this risk. Furthermore, other metabolic parameters exacerbate cardiovascular risk in these patients. The aim of the study was to compare the metabolic effects of glimepiride and metformin in patients with T2DM. We evaluated 164 patients with T2DM (80 males, 84 females) in a multicentre, randomised, controlled, open, parallel group study comparing glimepiride with metformin. Eighty-one patients (aged 56+/-10 yr) received glimepiride (3+/-1 mg/d); 83 patients (aged 58+/-9 yr) received metformin (2500+/-500 mg/d). Patients had been diagnosed for < or = 6 months; they were non-smokers; had no hypertension or coronary heart disease; were not taking hypolipidaemic drugs, diuretics, beta-blockers or thyroxin; and had normal renal function. Metabolic parameters were measured after 6 and 12 months of treatment. Glimepiride significantly lowered lipoprotein(a) [Lp(a)] and homocysteine levels (HCT) at 6 and 12 months. Both glimepiride and metformin lowered plasminogen activator inhibitor Type 1 (PAI-1) at 12 months and significantly improved levels of glycosylated haemoglobin, fasting plasma glucose and post-prandial plasma glucose after 6 and 12 months. Metformin significantly lowered fasting plasma insulin and postprandial plasma insulin. Glimepiride and metformin also reduced levels of other metabolic parameters in patients with T2DM. In particular, glimepiride significantly reduced HCT, Lp(a), and PAI-1 levels, important metabolic risk factors for atherosclerotic vascular disease. These reductions may be owing to improved glucose metabolism, but it cannot be excluded that these drugs have a direct effect on additional metabolic parameters. To evaluate whether, in adolescents with type 1 diabetes, the addition of metformin to insulin and standard diabetes management results in 1) higher insulin sensitivity and 2) lower HbA1c, fasting glucose, insulin dosage (units per kilogram per day) and BMI.
                This was a randomized, placebo-controlled 3-month trial of metformin therapy in 27 adolescents with type 1 diabetes, high insulin dosage (>1 unit. kg(-1). day(-1)), and HbA1c >8%, with measurements of insulin sensitivity (by frequently sampled intravenous glucose tolerance test [FSIGT]), HbA1c, insulin dosage, and BMI at the onset and end of treatment.
                At t = 0, HbA1c was 9.2 +/- 0.9%, insulin dosage was 1.2 +/- 0.2 units. kg(-1). day(-1), fasting glucose was 10.6 +/- 2.4 mmol/l, and BMI was 24.2 +/- 3.9 kg/m2 (means +/- SD), with no difference between the metformin and placebo groups. At the end of the study, HbA1c was 0.6% lower in the metformin group than in the placebo group (P < 0.05). This was achieved at lower daily insulin dosages (metformin group -0.14 +/- 0.1 vs. placebo group 0.02 +/- 0.2 units. kg(-1). day(-1); P < 0.05), with no significant change in BMI. Fasting glucose levels improved significantly in the metformin group (P < 0.05). Change in insulin sensitivity, measured by FSIGT, was not significantly different between the two groups at study end. Mild hypoglycemia occurred more frequently in the metformin-treated than in the placebo subjects (1.75 +/- 0.8 vs. 0.9 +/- 0.4 events. patient(-1). week(-1); P = 0.03). There were no differences in frequency of severe hypoglycemic episodes or gastrointestinal complaints between the two groups.
                Metformin treatment lowered HbA1c and decreased insulin dosage with no weight gain in teens with type 1 diabetes in poor metabolic control. Changes in insulin sensitivity were not documented in this study using the FSIGT. Long-term studies will determine whether these improvements are sustained and whether certain subgroups accrue greater benefit from this therapy. The prevalence of type 2 diabetes in American adolescents has increased markedly during the past generation. Although the factors that contribute to the development of type 2 diabetes are complex and not wholly elucidated, the triad of severe obesity, hyperinsulinemia, and a family history of type 2 diabetes places a child at an increased risk for development of the disease. Current approaches to the prevention of type 2 diabetes, including dietary counseling and exercise, have had limited success. We reasoned that drugs that increase glucose tolerance in diabetic patients might prove useful in preventing the progression to glucose intolerance in high-risk patients. To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index (BMI), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.
                The study population consisted of 29 white and black adolescents aged 12 to 19 years. All had BMIs exceeding 30 kg/m(2). Criteria for enrollment included: 1) a fasting insulin concentration exceeding 15 microU/mL; and 2) at least 1 first- or second-degree relative with type 2 diabetes. All patients had fasting plasma glucose concentrations <110 mg% and hemoglobin A1c concentrations </=6.0%. All had normal linear growth and sexual development for age, with no marked hirsutism, severe acne, or menstrual irregularities characteristic of polycystic ovary syndrome. Eight participants had acanthosis nigricans. After baseline laboratory studies including a rapidly sampled intravenous glucose tolerance test, patients were randomized to receive metformin (500 mg twice daily) or a placebo for a total of 6 months. The effects of metformin on BMI standard deviation score, serum leptin, glucose tolerance, and serum lipids were analyzed. The study was double-blinded and included no specific dietary restrictions.
                Metformin caused a decline of 0.12 standard deviation in BMI in study participants (-1.3% from baseline), and a 5.5% reduction in serum leptin in girls. In contrast, BMI and serum leptin rose 0.23 standard deviation (2.3%) and 16.2%, respectively, in the placebo group during the treatment period. Metformin caused a progressive decline in fasting blood glucose (from a mean of 84.9 to 75.1 mg%) and a reduction in fasting insulin levels (from 31.3 to 19.3 microU/mL). In contrast, fasting glucose levels in the placebo group rose slightly from 77.2 to 82.3 mg%, and fasting insulin levels did not change. Insulin sensitivity, as assessed by the ratio of fasting insulin to glucose concentrations and the quantitative insulin sensitivity check index (1/[log fasting insulin + log fasting glucose]) and homeostasis model assessment insulin resistance index (fasting insulin x fasting glucose/22.5) indices, increased slightly in the metformin-treated participants. However, the insulin sensitivity measured using Bergman's minimal model did not change. There were also no significant changes in glucose effectiveness, hemoglobin A1c, serum lipids, or serum lactate in the metformin or placebo groups. Metformin was tolerated well by the majority of patients. Transient abdominal discomfort or diarrhea occurred in 40% of treated participants; there were no episodes of vomiting or lactic acidosis.
                The treatment of obesity and insulin resistance in adults often proves ineffective because the vicious cycle leading to type 2 diabetes may have become entrenched and, to some extent, may be irreversible. Early detection and therapy of the obese adolescent with a family history of type 2 diabetes may interrupt the cycle of weight gain and insulin resistance that leads to glucose intolerance in adulthood. Through its ability to reduce fasting blood glucose and insulin concentrations and to moderate weight gain, metformin might complement the effects of dietary and exercise counseling and reduce the risk of type 2 diabetes in selected patients. To compare the effect of glimepiride in combination with metformin with monotherapy of each drug on glycaemic control in Type 2 diabetic patients.
                Randomized, double-blind, double-dummy, parallel-group multicentre study conducted in France. Type 2 diabetic patients aged 35-70 years inadequately controlled by metformin monotherapy 2550 mg daily for at least 4 weeks were randomized to either metformin, glimepiride or metformin and glimepiride.
                Three hundred and seventy-two patients aged 56 +/- 8 years were treated for 5 months. Combination treatment was significantly more efficient in controlling HbA1c (% change + 0.07 +/- 1.20 for metformin, + 0.27 +/- 1.10 for glimepiride, -0.74 +/- 0.96 for combination treatment, P < 0.001), fasting blood glucose (FBG) (mmol/l change + 0.8 +/- 0.4 for metformin, + 0.7 +/- 3.1 for glimepiride and -1.8 +/- 2.2 for combination treatment, P < 0.001) and post-prandial blood glucose (PPBG) (mmol/l change + 1.1 +/- 5.9 for metformin, + 0.1 +/- 5.1 for glimepiride and -2.6 +/- 3.9 for combination treatment, P < 0.001) than either glimepiride or metformin alone. There was no significant difference between metformin or glimepiride monotherapy with respect to the change in HbA1c or FBG; however, glimepiride was significantly more effective than metformin in reducing PPBG. The incidence of symptomatic hypoglycaemia was higher in the combination group than in either monotherapy group (P = 0.039).
                Addition of glimepiride to metformin in Type 2 diabetic patients inadequately controlled by metformin alone resulted in superior glycaemic control compared with glimepiride or metformin monotherapy. To determine whether exercise training in combination with metformin improves cardiovascular risk indices and insulin in comparison to metformin alone among HIV-infected patients.
                We conducted a prospective, randomized, 3-month study of HIV patients on stable antiretroviral therapy with hyperinsulinemia and fat redistribution. Subjects received metformin alone or metformin and exercise training consisting of 1 h of aerobic and resistance training three times a week. Cardiovascular parameters, including blood pressure and endurance during sub-maximal stress testing, body composition, strength, insulin and other biochemical parameters were determined.
                Thirty-seven patients were randomized and 25 subjects completed the study. Subjects receiving exercise training and metformin demonstrated significant decreases in median waist-to-hip ratio [-0.02 (-0.06, -0.01) (median (interquartile range) versus -0.01 (0.03, 0.02), P = 0.026], resting systolic [-12 (-20, -4) versus 0 (-11, 11), P = 0.012] and diastolic blood pressures [-10 (-14, -8) versus 0 (-7, 8), P = 0.001], increased thigh muscle cross-sectional area [3 (-3, 12) versus -7 (-11, 0), P = 0.015], and improved exercise time [3 (0, 4) versus 0 (-1, 1), P = 0.045] compared with subjects receiving metformin alone. Fasting insulin and insulin area under the curve decreased significantly more in the exercise and metformin group (P < 0.05). Lipids and resting lactate did not change significantly between treatment groups.
                These data demonstrate that exercise training in combination with metformin significantly improves cardiovascular and biochemical parameters more than metformin alone in HIV-infected patients with fat redistribution and hyperinsulinemia. Combined treatment was safe, well tolerated and may be a useful strategy to decrease cardiovascular risk in this population. After a 2 weeks hospital treatment with a strong dietary regime 100 patients not sufficiently controlled (blood glucose fasting 120-180, pp 180-250 mg/100 ml), were randomly allocated to a purely dietary therapy or to a diet-metformin-combination for a duration of 2 years. After 1 and 2 years the patients were rehospitalized for an accurate evaluation. Additionally, HbA1 was controlled every 3 months, in case of problems after shorter periods. If HbA1 exceeded 10% for more than 4 weeks the patients were hospitalized for 5 days in order to decide whether the deterioration of metabolic control was due to the patients' non-compliance to treatment or to treatment failure. During 2 years of observation 30 patients were withdrawn from the treatment for external reasons. 13 patients (6 diet, 7 metformin + diet) were non-compliant with diet, 3 further patients were not metformin-compliant. Therapeutic failures were confirmed in 4 diet patients, none of the metformin + diet patients failed to respond to treatment. After excluding all these patients there was a group of 29 diet and 25 metformin + diet patients with a similar development of criteria of metabolic control during 2 years. Lipid levels deteriorated in the dietary group more noticeably than during additional metformin treatment although without reaching a statistically significant level, though. The stimulated C-peptide was significantly reduced by metformin in comparison to diet only, which supports former findings of an insulin-lowering effect of the drug. Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3x3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity. Renal hyperfiltration and albuminuria have a deleterious effect on kidney function. Therefore, we studied the effect of metformin on blood pressure, renal hemodynamics, and microalbuminuria in type 2 diabetic patients.
                A clinical trial was designed in type 2 diabetic patients with incipient nephropathy. All patients were below the age of 65, normotensive, and without evidence of malignant, hepatic, or cardiovascular disorders. They were randomly allocated to receive glibenclamide or metformin. At baseline and 12 weeks thereafter we measured body mass index (BMI), serum insulin, blood glucose, lipid profile, glycosylated hemoglobin, blood pressure, glomerular filtration rate, renal plasma flow, and urine albumin.
                We studied 23 patients in the glibenclamide group and 28 in the metformin group. There was no difference in baseline variables between the groups. Metabolic control was obtained in both groups. In the metformin group, all the following variables decreased: microalbuminuria was reduced by a mean of 24.2 mg/day (p = 0.008); systolic and diastolic blood pressure by a mean of 5.3 mmHg (p = 0.002) and 3.93 mmHg (p = 0.009), respectively; insulin levels by an average of 11.8 microIU/mL (p = 0.001), and total cholesterol levels and triglycerides by an average of 0.45 and 0.18 mmol/L, respectively. Insulin resistance measured by the homeostasis model decreased more in the metformin group than in the glibenclamide group. Patients treated with glibenclamide had an increase in HDL cholesterol of 0.082 mmol/L (p = 0.01).
                Metformin significantly decreased the urine albumin excretion rate with none of the expected changes in renal hemodynamics, probably due to its favorable effects on blood pressure, lipid profile, metabolic control, and insulin resistance. To compare results obtained with metformin versus those obtained with DNA-recombinant insulin in obese patients with NIDDM suffering from secondary failure to sulfonylureas.
                We conducted an open, prospective, randomized, and comparative study comprising a total of 60 patients selected and placed in two parallel groups. We had previously confirmed that the subjects had secondary failure to high doses of sulfonylureas. The initial metformin dosage was a single 850 mg tablet, and the dosage was increased to two or three tablets depending on the patient's metabolic changes. The initial dosage of DNA-recombinant insulin was 24 U, subcutaneously administered and divided into two portions: two-thirds at around 8:00 A.M., before breakfast, and the remaining third at 8:00 P.M., before dinner. The dosage was adjusted based on the patient's clinical and metabolic response.
                The initial average glucose value for the metformin group was 269.1 +/- 32.2 mg/dl, decreasing by the end of the study to 159.7 +/- 30.5 mg/dl. For the insulin group, these figures went from 270.7 +/- 24.0 mg/dl at the beginning of the study to 134.8 +/- 26.7 mg/dl. This decrease correlates with the reduction in glycosylated hemoglobin from 12.8 to 8.9% for the first group and from 12.3 to 8.2% for the second, as well as with the reduction in triglyceride values from 230.3 to 183.1 mg/dl and from 218.4 to 186.3 mg/dl, respectively. The BMI (27.5-26.4), blood pressure (systolic from 145.7-132.1 mmHg, diastolic from 90.3-84.8 mmHg), and total cholesterol levels (235-202 mg/dl) decreased in only the metformin group.
                Metformin is an effective, safe, and well-tolerated treatment that improves metabolic control and favorably modifies secondary clinical alterations due to insulin resistance, such as arterial hypertension, overweight, and hyperlipidemia, in obese patients with NIDDM suffering from secondary failure to sulfonylureas. In order to compare the effects of metformin and gliclazide on fasting serum insulin, 60 non-insulin dependent diabetics were included in a multi-centre study. Patients on a diabetic diet alone or a diabetic diet together with a sulphonylurea hypoglycaemic agent, with a fasting glucose greater than 1.4 g/l, on two measurements were included in the study. They were randomly allocated to two parallel groups and received either gliclazide or metformin. They were treated for three months and attended for consultation at one month and three months. The fasting serum insulin level decreased significantly in the group receiving metformin (26.2 +/- 3.2 mlU/L at entry versus 19.8 +/- 2.3 mlU/L after three months: less than 0.01), and increased in a non-significant way in the group receiving gliclazide (21.6 +/- 3 mlU/L versus 26.5 +/- 5 mlU/L after three months: NS). The difference between the two groups was significant (p less than 0.01). There was a comparable significant improvement in blood sugar levels during the three months in both patients receiving gliclazide and metformin. However, significant weight loss (p less than 0.05) occurred only in patients receiving metformin. There was an identical improvement in blood sugar control in both patients receiving gliclazide and metformin over the three months. On the other hand, fasting serum insulin levels decreased significantly in patients receiving metformin compared to gliclazide. The effect of metformin on serum insulin levels is probably due to its action on insulin resistance and its lack of effect on insulin secretion, in contrast to sulphonylurea hypoglycaemic agents like gliclazide. Since metformin improves insulin sensitivity, it has been indicated for patients with diabetes and hypertension, which are insulin-resistant conditions. In contrast to its well-known effects on carbohydrate metabolism, its potential for reducing blood pressure (BP) and its effect on leptin levels have been investigated less frequently.
                A double-blind, randomized, placebo-controlled trial was carried out with 26 overweight diabetic subjects with mild-to-moderate hypertension to assess the effects of metformin-induced glycaemic control on BP and metabolic parameters. After a 4-week placebo period, when BP was stabilized by calcium channel blockers, they received either metformin (MG) or placebo (PG) for 12 weeks.
                Neither group showed any change in weight throughout the study. Only metformin-treated patients reduced fasting plasma glucose (8.54 + 1.72 to 7.54 + 1.33 mmol/l, p < 0.05), although HbA(1c) had decreased in both groups (PG: 6.7+/-3.0 to 5.9+/-2.6%; MG: 5.3+/-1.5 to 4.6+/-0.9%; p < 0.05). The initial office mean BPs were similar and decreased at the end of the treatment period in both groups, reaching statistical significance only in MG (105.7+/-8.0 to 99.2+/-9.3 mmHg, p < 0.05). No difference was observed when comparing baseline and final values obtained by 24-h ambulatory BP monitoring. Metformin induced a reduction in both insulinaemia (71.0+/-62.4 to 38.0+/-23.0 pmol/l, p < 0.05) and the insulin resistance index (3.5+/-2.7 to 1.8+/-1.0, p < 0.05). The two groups had similar baseline leptin levels which remained unchanged after treatment (PG: 16.8+/-7.9 to 21.4+/-14.6 microg/l; MG: 18.5+/-10.3 to 18.4+/-8.9 microg/l). Dopamine levels increased significantly only in metformin-treated subjects.
                Reductions in both the insulin levels and the resistance index reinforced metformin capacity to improve peripheral sensitivity. Moreover, such benefits were not accompanied by any hypotensive effects. Since leptin levels were affected neither by metformin per se nor by the induced insulinaemia reduction, our data support the role of body weight as the major determinant of circulating leptin levels. To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes.
                A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period.
                In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05).
                Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy. Fifty-seven type 2 diabetic patients with metabolic syndrome and on insulin were assessed by a paired analysis before and 6 months after addition of metformin as combination therapy to evaluate the impact of the association on glycemic control, blood pressure, and lipid profile. This was a historical cohort study in which the files of type 2 diabetic patients with metabolic syndrome on insulin were reviewed. The body mass index (BMI), waist circumference, lipid profile, A1C level, fasting blood glucose level, daily dose of NPH insulin, systolic blood pressure, and diastolic blood pressure were assessed in each patient before the start of metformin and 6 months after the initiation of combination therapy. Glycemic control significantly improved (P < 0.001) after the addition of metformin (1404.4 +/- 565.5 mg/day), with 14% of the 57 patients reaching A1C levels up to 7%, and 53% reaching values up to 8%. There was a statistically significant reduction (P < 0.05) of total cholesterol (229.0 +/- 29.5 to 214.2 +/- 25.0 mg/dL), BMI (30.7 +/- 5.4 to 29.0 +/- 4.0 kg/m2), waist circumference (124.6 +/- 11.7 to 117.3 +/- 9.3 cm), and daily necessity of insulin. The reduction of total cholesterol occurred independently of the reductions of A1C (9.65 +/- 1.03 to 8.18 +/- 1.01%) and BMI and the reduction of BMI and WC did not interfere with the improvement of A1C. In conclusion, our study showed the efficacy of the administration of metformin and insulin simultaneously without negative effects. No changes were detected in HDL-cholesterol or blood pressure. We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 +/- 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 +/- 2.5 vs placebo: 12.0 +/- 2.3 mmol l-1, p r2 0.001;). Concentrations of intact (median change -2.9 (range -28.4 to +2.5 pmol l-1), p = 0.02) and des 31,32 proinsulin (median change -1.6 (range -14.1 to +5.4 pmol l-1), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change -6% (range -16% to +6%), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r1 = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed. The authors evaluated the efficacy of treatment with the metformin-glibenclamide combination in 30 non-insulin dependent overweight diabetic patients in poor metabolic control during sulfonylurea treatment. After three months' therapy, a significant reduction of glycaemia, insulinaemia and fructosamine were found. Therefore, the addition of biguanides in those patients, was able to reduce blood glucose levels and to improve insulin resistance. In addition the metformin glibenclamide combination never produced relevant side effects of lactic acidosis, which is the most dangerous event during biguanide treatment. The effect of metformin therapy on glucose metabolism was examined in eight overweight newly presenting untreated type II diabetic patients (five males, three females). Patients were treated for 12 weeks with either metformin (850 mg x 3) or matching placebo using a double-blind crossover study design; patients were studied at presentation and at the end of each treatment period. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) before and during a 4-hour hyperinsulinemic euglycemic clamp (100 mU.kg-1 x h-1). Metformin therapy was associated with a significant decrease in fasting blood glucose (6.8 +/- 0.6 v 8.3 +/- 0.9 mmol.L-1, P < .01) and glycosylated hemoglobin ([HbA1] 7.7% +/- 0.4% v 8.5% +/- 0.5%, P < .01) levels. Fasting hepatic glucose production (HGP) was also significantly decreased following metformin therapy (1.98 +/- 0.13 v 2.41 +/- 0.20 mg.kg-1 x min-1, P < .02), whereas fasting insulin and C-peptide concentrations remained unaltered. The decrease in basal HGP correlated closely with the decrease in fasting blood glucose concentration (r = .92, P < .001). Insulin-stimulated glucose uptake was assessed using the hyperinsulinemic euglycemic clamp technique and was increased post-metformin (3.8 +/- 0.6 v 3.1 +/- 0.7 mg.kg-1 x min-1, P < .05). This was primarily the result of increased nonoxidative glucose metabolism (1.1 +/- 0.6 v 0.4 +/- 0.6 mg.kg-1 x min-1, P < .05); oxidative glucose metabolism did not change. Metformin had no measurable effect on insulin activation of skeletal muscle GS, the rate-limiting enzyme controlling muscle glucose storage.(ABSTRACT TRUNCATED AT 250 WORDS) The effects of metformin on glycaemia, insulin and c-peptide levels, hepatic glucose production and insulin sensitivity (using the euglycaemic, hyperinsulinaemic clamp) were evaluated at fortnightly intervals in 9 Type 2 diabetic patients using a stepwise dosing protocol: Stage 1--no metformin for four weeks; stage 2--metformin 500mg mane; stage 3--metformin 500mg thrice daily; stage 4--metformin 1000mg thrice daily. Results are expressed as Mean +/- SEM. Fasting blood glucose decreased from basal values (9.7 +/- 1.0 mmol/L) by 13% at stage 2, 34% at stage 3 and 41% at stage 4 (p less than 0.02 vs basal for all stages; p less than 0.02 stage 2 vs stage 3). Post-prandial glycaemia was significantly improved only with metformin 3000mg/day (p less than 0.05). Fasting, meal-stimulated and total insulin and c-peptide levels showed no change. Hepatic glucose output did not change significantly with metformin. Insulin sensitivity, measured as total glucose utilisation during hyperinsulinaemia, increased from stage 1 (10.3 +/- 2.1 mumoL/kg/min) by 23% at stage 3 (p less than 0.05) and by 29% at stage 4 (p less than 0.02). Basal metabolic clearance of glucose increased compared to stage 1 (1.69 +/- 0.16 mL/kg/min) by 30% at stage 2, 53% at stage 3 and 44% at stage 4 (all p less than 0.02). This study demonstrates that improved efficiency of glucose utilisation, both basally and under conditions of euglycaemic hyperinsulinaemia, is the basis of metformin's antihyperglycaemic action. Few studies have directly compared rosiglitazone and metformin effects on adipocytokines. The aim was to observe the possible effects of rosiglitazone and metformin on glycemic control, insulin sensitivity, plasma leptin (pL), adiponectin (ADN), tumor necrosis factor-alpha (TNF-alpha), and resistin (R) in overweight and obese diabetic patients intolerant to metformin.
                Six hundred and ninety-four consecutive overweight and obese type 2 diabetic patients were evaluated and 56 patients were intolerant to metformin at maximum dosage. We added rosiglitazone to metformin in these intolerant patients (RM) and we compared them with 61 patients treated with metformin (M) in a single-blind placebo-controlled trial. We evaluated body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), pL, ADN, TNF-alpha, and R at baseline and after 3 and 6 months. Furthermore, we calculated insulin resistance index (HOMA-index) using FPG and FPI.
                Glycated hemoglobin, FPG, FPI, and HOMA-index results were lower than baseline values in RM and M groups. Glycated hemoglobin and HOMA-index values were significantly lower in RM group compared to M group at 6 months. Plasma leptin, ADN, TNF-alpha, and R were significantly improved in RM group compared to M group at 6 months.
                No BMI change was observed, probably because rosiglitazone was added to metformin, that could mitigate the body increase of rosiglitazone. Rosiglitazone improved glycemic control and insulin resistance-correlated parameters when added to intolerant metformin patients. These data suggest that rosiglitazone may be the drug of choice for the treatment of overweight and obese type 2 diabetic patients. Metabolic control often deteriorates during puberty in children with type 1 diabetes. The aim of the present study was to investigate whether addition of metformin for 3 Months improves metabolic control and insulin sensitivity.
                Twenty-six of 30 randomised adolescents with type 1 diabetes (18 females, eight males) completed a double-blind placebo-controlled trial. Their mean age was 16.9+/-1.6 (s.d.) Years, mean glycated haemoglobin (HbA(1c)) 9.5+/-1.1% and daily insulin dosage 1.2+/-0.3 U/kg. The participants were randomised to receive oral metformin or placebo for 3 Months. HbA(1c) was measured Monthly, and peripheral insulin sensitivity was assessed by a euglycaemic hyperinsulinaemic clamp at baseline and at the end of the study.
                HbA(1c) decreased significantly in the group treated with metformin, from 9.6 to 8.7% (P<0.05), but was unchanged in the placebo group (9.5 vs 9.2%). Peripheral glucose uptake divided by mean plasma insulin concentration was increased in the metformin group (P<0.05) but not in the placebo group. Initial insulin sensitivity was inversely correlated to changes in HbA(1c) (r=-0.62; P<0.05) and positively correlated to changes in insulin sensitivity (r=0.77; P<0.01).
                In this double-blind placebo-controlled study we found that metformin improves metabolic control in adolescents with type 1 diabetes. The effect seems to be associated with an increased insulin-induced glucose uptake. The effect of metformin treatment was studied in nine patients with mild (fasting plasma glucose concentration less than 7.5 mmol.l-1) non-insulin-dependent diabetes mellitus (NIDDM) and fasting plasma triglyceride (TG) concentration greater than 2.0 mmol.l-1. Individuals were studied before and three months after receiving 2.5 g/day of metformin. Mean hourly plasma glucose concentration from 8 AM to 4 PM (7.5 +/- 0.5 vs 6.5 +/- 0.4 mmol.l-1, p less than 0.001), as well as glycosylated hemoglobin levels (7.0 +/- 0.5 vs 6.2 +/- 0.2%, p less than 0.02) were significantly lower following metformin treatment. The improvement in glycaemic control was not associated with an improvement in insulin stimulated glucose disposal as measured by the glucose clamp technique. Mean hourly day-long concentrations of plasma insulin (519 +/- 81 vs 364 +/- 64 pmol.l-1, p less than 0.001), FFA (502 +/- 45 vs 460 +/- 35 mu mol.l-1, p less than 0.01), and triglyceride (3.60 +/- 0.33 vs 3.02 +/- 0.31 mmol.l-1, p less than 0.001) concentrations were significantly lower following three months of metformin treatment. Finally, fasting plasma TG concentration, very low density lipoprotein (VLDL)-TG, and VLDL-cholesterol concentrations were significantly decreased, while high density lipoprotein (HDL)-cholesterol concentration was significantly increased following metformin therapy. Thus, metformin administration to individuals with NIDDM, who did not have significant fasting hyperglycaemia, led to a decrease in plasma glucose, insulin, FFA, and TG concentration, and an increase in plasma HDL-cholesterol concentration.(ABSTRACT TRUNCATED AT 250 WORDS) The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, added to ongoing metformin therapy, were assessed in patients with type 2 diabetes who had inadequate glycemic control (HbA(1c) [A1C] >or=7 and <or=10%) with metformin alone.
                After a screening diet/exercise run-in period, a metformin dose titration/stabilization period, and a 2-week, single-blind, placebo run-in period, 701 patients, aged 19-78 years, with mild to moderate hyperglycemia (mean A1C 8.0%) receiving ongoing metformin (>or=1,500 mg/day) were randomly assigned to receive the addition of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. The efficacy analyses were based on an all-patients-treated population using an ANCOVA and excluded data obtained after glycemic rescue.
                At week 24, sitagliptin treatment led to significant reductions compared with placebo in A1C (-0.65%), fasting plasma glucose, and 2-h postmeal glucose. Fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas under the curve (AUCs), postmeal insulin AUC-to-glucose AUC ratio, homeostasis model assessment of beta-cell function, and quantitative insulin sensitivity check index were significantly improved with sitagliptin relative to placebo. A significantly greater proportion of patients achieved an A1C <7% with sitagliptin (47.0%) than with placebo (18.3%). There was no increased risk of hypoglycemia or gastrointestinal adverse experiences with sitagliptin compared with placebo. Body weight decreased similarly with sitagliptin and placebo.
                Sitagliptin 100 mg once-daily added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. Recently the UKPDS study revealed the potency of metformin therapy in obese type 2 diabetic patients. A retrospective study was performed to assess the efficacy of metformin therapy in improving metabolic control in everyday practice.
                Type 2 diabetic patients were included if they met the following criteria: metformin had been added when the previous treatment failed to optimise glycaemic control expressed in HbA1c level; duration of metformin therapy had to be at least six months. Efficacy of metformin therapy, expressed as a decrease in HbA1c, was measured with a median follow-up of 32 (range 6-60) months. Variables were analysed using a paired t-test.
                One hundred and sixty-three patients were treated with metformin. 98 patients were excluded, because of absence of an HbA1c value prior to treatment with metformin mainly (n = 78). The mean HbA1c of included patients had decreased 1.4% (p < 0.001) after 6 months (n = 65), 1.6% (p < 0.001) after 24 months (n = 45) and 1.5 (p < 0.001) after 36 months (n = 28). During follow-up there was no significant weight gain or loss.
                Metformin can be considered an effective treatment to improve glycaemic control in obese type 2 diabetic patients. Metformin efficacy and safety in type 2 diabetes has not been studied in the elderly patient under conditions pertaining to clinical practice. We have therefore, studied prospectively over two months 24 patients aged between 70-88 years with 115% mean ideal body wt and glycemic control greater than 10 mol.l-1 fasting and/or greater than 14 mol.l-1 postprandial, and/or an HbA1 value greater than 10%. At entry into the study, patients were on metformin + sulfonylurea (n = 15), sulfonylurea (n = 3), metformin (n = 2), insulin (n = 1) or diet alone (n = 3). They received metformin as the sole therapy when possible (sulfonylureas were discontinued in 9 cases) at a dosage of either 850 mg or 1,700 mg/day dependent on creatinine clearance values of 30-60 ml.min-1 (n = 11) and greater than 60 ml.min-1 (n = 13), respectively. Compared to pretreatment values, glycemic control at 1 and 2 months were unchanged, with metformin blood levels remaining within expected values for both dosage groups. Blood lactate levels remained unchanged in the high dosage group but were reduced (p less than 0.05) on 850 mg/day probably because of the reduction of metformin dosage in patients already treated prior to the study. It is concluded that provided the dosage is adjusted to renal function, the metabolic tolerance of metformin therapy is satisfactory in the elderly type 2 diabetic patient. With regard to efficacy, longer observations are needed to know whether this therapy may offer on a long-term basis equivalent glycemic control compared to other treatment modalities. To test the efficacy and tolerability of metformin.
                An 8-mo double-blind placebo-controlled parallel-group trial was performed at University hospital diabetic clinics on 60 patients with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone. Metformin was administered and built up to a maximum dosage of 1 g three times daily.
                Mean HbA1 fell from 11.7 +/- 0.4 to 10.3 +/- 0.4% (means +/- SE) on metformin but rose from 11.8 +/- 0.4 to 13.3 +/- 0.4% on placebo (P less than 0.001). Final mean fasting blood glucose was 5.1 mM lower with metformin than placebo (P less than 0.001). No other biochemical variable differed significantly, and weight did not change. A favorable glycemic response was not restricted to the obese. The mean final dosage of metformin was 1.7 +/- 0.1 g and was well tolerated.
                Metformin achieved a 23% lower mean HbA1 than placebo without weight gain or significant unwanted effects. We previously reported that lipoprotein lipase mass levels in preheparin serum (preheparin LPL mass) was significantly lower in type 2 diabetes mellitus compared to healthy subjects and that low preheparin LPL mass may be a high-risk factor of coronary atherosclerosis. The aim of this study was to clarify the effects of metformin on serum lipoprotein lipase mass levels (preheparin LPL mass), adiponectin and lipid metabolism in patients with type 2 diabetes mellitus. Twenty-eight patients with type 2 diabetes mellitus (HbAlc>7.0%), who were already receiving sulfonylurea agents, took metformin 500 mg orally twice daily for 3 months. Fasting blood glucose (FBG), immunoreactive insulin (basal IRI) and HbAlc decreased significantly after metformin treatment. LDL-Rm ratio decreased significantly (from 0.3521+/-0.046 to 0.3339+/-0.030, P<0.05) and preheparin LPL mass increased significantly (from 42.5+/-3.2 to 50.6+/-3.5 ng/ml, P<0.0005), but adiponectin was unchanged. The correlation of a change of LDL-Rm ratio and a change of preheparin LPL mass showed a negative correlation tendency. The changes in LDL-Rm ratio and preheparin LPL mass were independent of the hypoglycemic effect of metformin. These results suggest that metformin may increase LPL production, thereby increasing LDL particle size. These effects might be independent of the hypoglycemic effect of metformin. The effect of long-term treatment with phenformin and metformin respectively on blood lactate concentrations in relation to submaximal muscular exercise has been examined in 21 maturity-onset diabetics, using a cross-over method. At similar degrees of diabetic control the mean blood lactate concentration during exercise and shortly thereafter was significantly higher when the patients had received phenformin. The mean fasting lactate concentration was 1.07 mmol/l with phenformin and 1.03 mmol/l with metformin and the peak concentration was 2.56 mmol/l and 2.19 mmol/l respectively. The mean fasting blood glucose concentration before the exercise was 11.2 mmol/l with phenformin and 11.3 mmol/l with metformin; the glucose output in the urine during the preceding 24 hours was 93 mmol and 105 mmol respectively. The mean work load during exercise was 60 watts. It has been reported that women with polycystic ovary syndrome (PCOS) benefit from metformin therapy.
                A randomized, placebo-controlled, double-blind study of obese (body mass index >30 kg/m2), oligo-/amenorrhoeic women with PCOS. Metformin (850 mg) twice daily was compared with placebo over 6 months. All received the same advice from a dietitian. The primary outcome measures were: (i) change in menstrual cycle; (ii) change in arthropometric measurements; and (iii) changes in the endocrine parameters, insulin sensitivity and lipid profile.
                A total of 143 subjects was randomized [metformin (MET) = 69; placebo (PL) = 74]. Both groups showed significant improvements in menstrual frequency [median increase (MET = 1, P < 0.001; PL = 1, P < 0.001)] and weight loss [mean (kg) (MET = 2.84; P < 0.001 and PL = 1.46; P = 0.011)]. However, there were no significant differences between the groups. Logistic regression analysis was used to analyse the independent variables (metformin, percentage of weight loss, initial BMI and age) in order to predict the improvement of menses. Only the percentage weight loss correlated with an improvement in menses (regression coefficient = 0.199, P = 0.047, odds ratio = 1.126, 95% CI 1.001, 1.266). There were no significant changes in insulin sensitivity or lipid profiles in either of the groups. Those who received metformin achieved a significant reduction in waist circumference and free androgen index.
                Metformin does not improve weight loss or menstrual frequency in obese patients with PCOS. Weight loss alone through lifestyle changes improves menstrual frequency. Metformin may affect the risk of atherothrombotic disease. However, metformin increases levels of homocysteine (Hcy), considered an independent risk factor for atherosclerosis. We evaluate whether homocysteine-lowering has a beneficial effect on arterial elasticity and metabolic parameters in metformin-treated diabetic patients. In double-blind, placebo-controlled study, 60 diabetic patients treated with high dose of metformin were randomly assigned to receive daily oral supplementation with folate (1000 mcg), vitamins B12 (400 mcg) and B6 (10mg) (group 1) or placebo (group 2). Lipid profile, HbA1C, insulin, C-peptide, hs-CRP, vitamin B12, folic acid, homocysteine, endothelin, homeostasis model assessment-insulin resistance (HOMA-IR) were measured. Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, MN). The two groups were similar at baseline in terms of hemodynamic and arterial elasticity parameters. After a 4-month small artery elasticity index (SAEI) was significantly greater in patients who received Hcy-lowering agents than in the placebo group: 4.3+/-2.04 ml/mm Hg x 100 versus 3.2+/-1.1 ml/mm Hg x 100, p=0.01. Post-treatment vitamin B12 and folic acid levels were greater in group 1 versus group 2: 738.1+/-279.9 pg/ml versus 566.1+/-167.4 pg/ml, p=0.007 and 14.9+/-4.8 ng/ml versus 8.3+/-2.9 ng/ml, p<0.0001, respectively. Hcy level decreased significantly in the treatment group from 10.0+/-4.4 to 7.6+/-2.5 micromol/l, p=0.002 and did not change in placebo group (p=0.9). Hcy-lowering therapy improved small arterial elasticity in diabetic patients treated with high dose of metformin. The improvement was associated with a decrease in Hcy as well as an increase in folic acid and vitamin B12. These findings suggest that Hcy-lowering may have beneficial vascular effect in metformin-treated diabetic patients. As diabetes is in part an inflammatory condition, the initiation of insulin and/or metformin may beneficially reduce levels of inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP).
                To determine whether insulin alone or combined with metformin lowers levels of hsCRP, IL-6, and soluble tumor necrosis factor receptor 2 (sTNFr2) in patients with recent-onset type 2 diabetes mellitus.
                Randomized 2 x 2 factorial trial of open-label insulin glargine and placebo-controlled metformin in 500 adults with type 2 diabetes (median time from diagnosis, 2.0 years), suboptimal glycemic control, and elevated hsCRP levels. Patients were recruited from US office-based practices between October 2006 and December 2008.
                Random allocation to 1 of 4 treatments (placebo metformin only, placebo metformin and insulin glargine, active metformin only, or active metformin and insulin glargine) with dose titration targeting fasting blood glucose less than 110 mg/dL.
                Change in hsCRP level (primary end point) and change in IL-6 and sTNFr2 levels (secondary end points) from baseline to 14 weeks.
                Levels of glucose and glycated hemoglobin (HbA(1c)) were significantly reduced with active treatment vs placebo (all P values <.001). Levels of hsCRP were reduced in all 4 groups. There was no significant difference in hsCRP reduction among those allocated to insulin (-11.8%; 95% CI, -18.7% to -4.4%) or to no insulin (-17.5%; 95% CI, -23.9% to -10.5%) (P for difference = .25), or among those allocated to active metformin (-18.1%; 95% CI, -24.4% to -11.1%) or placebo metformin (-11.2%; 95% CI, -18.1% to -3.7%) (P for difference = .17). In the individual treatment groups, despite a differential impact on glucose control, reductions in hsCRP in the metformin (-16.1%; 95% CI, -25.1% to -6.1%) and metformin plus insulin (-20.1%; 95% CI, -28.8% to -10.4%) groups were no different than reductions with placebo alone (-19.0%; 95% CI, -27.8% to -9.1%; P = .67 and .87 vs placebo, respectively). By contrast, hsCRP reduction was attenuated with insulin alone (-2.9%, 95% CI, -13.2% to 8.6%; P = .03 vs placebo). Similar findings were noted for levels of IL-6 and sTNFr2.
                In patients with recent-onset type 2 diabetes, treatment with insulin or metformin compared with placebo did not reduce inflammatory biomarker levels despite improving glucose control.
                clinicaltrials.gov Identifier: NCT00366301. To determine fibrinogen levels in obese patients with type 2 diabetes and assess its changes with the use of metformin.
                60 obese patients (BMI > 27) with type 2 diabetes were studied in an open, two phase, prospective, randomized and comparative study. The pre-treatment phase was a period of four weeks of a controlled diet. In the treatment phase they were divided in two subgroups of 30. One received metformin as a daily single tablet of 850 mg and increasing the dosage to two or three tablets depending on their metabolic control. The second subgroup received 24 units of DNA-recombinant insulin subcutaneously (two thirds of dose before breakfast, and the remaining third before dinner). The insulin dosage was adjusted according to the metabolic response. A control group was formed by 60 non diabetic obese patients with only the controlled diet.
                The mean values of plasma glucose, fibrinogen levels and body mass index did not change in the pretreatment phase in controls and diabetics. These parameters decreased significantly in the metformin subgroup in the treatment phase (p < 0.001). Only glucose decreased in the insulin subgroup. There were no changes in the controls.
                In addition to improving metabolic control, metformin showed to be a good therapeutic alternative in modifying fibrinogen levels in type 2 diabetic patients. To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment.
                We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n=51) or LAF237 (50 mg once daily, n=56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52.
                In patients randomized to LAF237, baseline HbA1c averaged 7.7 +/- 0.1% and decreased at week 12 (Delta=-0.6 +/- 0.1%), whereas HbA1c did not change from a baseline of 7.9 +/- 0.1% in patients given placebo (between-group difference in DeltaHbA1c=-0.7 +/- 0.1%, P <0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 +/- 0.4 mmol/l (P <0.0001) and 1.2 +/- 0.4 mmol/l (P=0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 +/- 0.6 mmol/l (P=0.0001), 40 +/- 16 pmol/l (P=0.0153), and -1.1 +/- 0.5 mmol/l (P=0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n=42) but increased in participants given placebo (n=29). The between-group difference in DeltaHbA1c after 1 year was -1.1 +/- 0.2% (P <0.0001).
                Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes. Twenty-seven obese non-insulin-dependent diabetic patients, treated with dietary carbohydrate restriction and metformin, were recruited from the diabetic outpatient clinic and entered into an open crossover study with gliclazide. Twenty-one patients completed the study. During three months observation on metformin, the mean weight of the group fell by 1.0 kg with 14 patients losing a mean of 1.8 kg with 14 patients losing a mean of 1.8 kg, 3 remaining unchanged and 4 gaining a mean weight of 1.1 kg. Over the subsequent three months on gliclazide, the mean weight of the group rose by 1.4 kg with 16 patients gaining a mean of 2.2 kg, two remaining unchanged and 3 losing a mean of 2.0 kg. In addition, 10 patients were heavier after gliclazide than at the time of recruitment (mean 2.6 kg), 3 were unchanged and 8 had lost weight since commencing the trial (mean 2.1 kg), mostly due to greater loss on metformin than gain on gliclazide. Glycaemic control did not improve significantly during the observed period on metformin but lower concentrations of fasting glucose and total glycosylated haemoglobin were achieved with gliclazide. Mean plasma insulin concentration was significantly higher and mean serum lactate was significantly lower during treatment with gliclazide. In conclusion, gliclazide does not support weight loss in obese non-insulin-dependent diabetic patients to the same extent as metformin but the difference between the two drugs is small. Gliclazide is a suitable oral hypoglycaemic agent for use in the obese diabetic who cannot be controlled by diet alone. Forty patients with NIDDM and hyperlipoproteinemia were selected for a 12-week double-blind placebo-controlled trial to study the effects of metformin on lipoprotein concentration and composition. A significant decrease occurred in VLDL-apo B and all lipid components of VLDL, indicating a decreased number of circulating VLDL, while LDL-apo B was unchanged. Moreover in VLDL the relative TG content increased, the cholesterol content decreased, while in LDL the TG content decreased and the cholesterol content increased, indicating a change in the particle distribution over the spectrum VLDL-IDL-LDL. The initially enhanced TG-content in HDL was reduced. While a reduction in VLDL is observed together with improving glucose control irrespective of the applied method, the observed compositional changes in VLDL and LDL have not been described before and seem to be metformin-specific. To test the effect of continuing metformin on weight gain and glycaemic control in patients with poorly controlled Type 2 diabetes who need to start insulin.
                Patients with Type 2 diabetes on maximum tolerated oral agents referred for insulin conversion were recruited from hospital diabetes clinics into a double-blind randomized placebo-controlled trial. The 183 participants received metformin or placebo, titrated up to 2 g a day or maximum tolerated dose, with insulin started according to local practice. The main outcome measures were weight change over 12 months, HbA1c, insulin dose, frequency of hypoglycaemia, treatment satisfaction, and well-being.
                Over 12 months, metformin was associated with less weight gain than placebo [mean 6.1 kg vs. 7.6 kg; adjusted difference 1.5 kg (95% confidence interval 0.2-2.9); P=0.02], a greater reduction in HbA1c[1.5% vs. 1.3%; adjusted difference 0.5% (0.1-0.9); P=0.02] and a lower insulin requirement [62 units vs. 86; adjusted difference 25 units (15-34); P<0.001], but also more hypoglycaemia [relative risk of any episode 1.24 (1.02-1.1); P=0.03]. Treatment satisfaction improved more in patients on metformin than on placebo (P<0.001), as did the positive well-being score (P=0.02).
                Metformin decreases weight gain, lowers insulin requirement, and improves glycaemic control, and should be continued in patients with Type 2 diabetes who transfer to insulin. The effects of metformin on the fibrinolytic system were studied pre- and post-venous occlusion in 38 Type 2 diabetic patients in a double-blind, placebo-controlled trial. After a 3-week run-in period, 21 patients received metformin and 17 placebo, for 6 weeks. In the metformin-treated patients basal plasminogen activator inhibitor-1 antigen (PAI-1Ag) fell from 57.4 micrograms l-1 before treatment to 36.1 (p less than 0.05) and 41.0 micrograms l-1 (p less than 0.01) after 3 and 6 weeks therapy. In this group post-venous occlusion PAI-1Ag also fell after 3 weeks (p less than 0.002) and 6 weeks (p less than 0.05) treatment. There were no changes in either basal or post-venous occlusion concentrations of PAI-1Ag in the placebo treated group. The fall in PAI-1Ag was not associated with an increase in basal plasminogen activator activity (PAA) which remained unchanged in both groups. Post-venous occlusion values for PAA in the metformin treated patients were increased at 3 weeks (p less than 0.05) although there was no difference at 6 weeks. This double-blind study evaluated the efficacy and safety of metformin-glibenclamide tablets vs. metformin plus rosiglitazone therapy in patients with type 2 diabetes inadequately controlled on metformin monotherapy.
                After an open-label, metformin lead-in phase, 318 patients were randomly assigned to treatment based on metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg) or metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks. Doses were titrated to achieve the therapeutic glycaemic target. The primary efficacy variable was the change in HbA1C.
                At week 24, metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C (-1.5%) and fasting plasma glucose [-2.6 mmol/l (-46 mg/dl)] than metformin plus rosiglitazone [-1.1%, p < 0.001; -2 mmol/l (-36 mg/dl), p = 0.03]. More patients receiving metformin-glibenclamide attained HbA1C <7.0% than did those in the metformin plus rosiglitazone group (60 vs. 47%) and had fasting plasma glucose levels <7 mmol/l (<126 mg/dl) by week 24 (34 vs. 25%). Both treatments were well tolerated. Frequency of adverse gastrointestinal events was comparable between groups. Four per cent of patients receiving metformin-glibenclamide withdrew because of symptomatic hypoglycaemia contrasted with 3% of patients receiving metformin plus rosiglitazone who withdrew because of persistent hyperglycaemia. Hypoglycaemic events were mild or moderate in intensity and were easily self-managed.
                Metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C and fasting plasma glucose compared with metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m(2)) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 microg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 +/- 5.1 (SE) to 29.8 +/- 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 +/- 0.01 to 0.75 +/- 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 +/- 0.3 to 2.0 +/- 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 +/- 0.2 to 1.4 +/- 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment. The aim of this study was to evaluate the effects of metformin in addition to diet and exercise on endocrine and metabolic disturbances in women with polycystic ovary syndrome (PCOS) in a prospective, double-blind, randomized, placebo (PBO) control trial. Thirty women with insulin resistance and PCOS received lifestyle modification and 1500 mg of metformin or placebo for 4 months. Before and after treatment, body mass index, waist/hip ratio, blood pressure, hirsutism, and menstrual patterns were evaluated. Serum concentrations of gonadotropins, androgens, progesterone, glucose, insulin, and lipids were measured. Lifestyle interventions resulted in similar weight and menstrual cycle's improvements in both groups. A significant reduction in serum fasting insulin, HOMA index, waist and testosterone levels was only observed with metformin. There were no significant changes in androstenedione, dehydroepiandrosterone sulfate, gonadotropins, and lipids levels. No other changes were observed in hirsutism or blood pressure. These findings suggest that metformin has an additive effect to diet and exercise to improve parameters of hyperandrogenism and insulin resistance. Although, a small decrease in body weight trough lifestyle changes could be enough to improve menstrual cycles in insulin-resistant women with PCOS. There is still some controversy concerning the effects of metformin in the treatment of Polycystic Ovary Syndrome (PCOS). The aim of this study was to asses the effect of metformin on clinical, metabolic and hormone parameters in obese women with PCOS. Thirty obese, non-diabetic women with PCOS received 500 mg of metformin or placebo, TID, over 90 days. Assessed parameters included body mass index, waist-to-hip ratio, blood pressure, FSH, LH, total testosterone, SHBG, fasting insulinemia, insulin-to-glucose ratio, total, HDL and LDL cholesterol, triglycerides, and menstrual cycles before and after the use of the drugs. Before treatment, patients did not differ in the two groups. After 90 days of metformin use, PCOS women presented significantly lower levels of total testosterone (p = 0.030) and total cholesterol (p = 0.023) compared to the women that used placebo. The other parameters did not differ between the groups. In conclusion, obese women with PCOS may benefit from the use of metformin through the reduction of hyperandrogenemia, total cholesterol, and possibly by restoration of regular menstrual cycles. Further studies with longer follow-ups are necessary to determine cardiovascular and endometrial metformin benefits and insulin-resistance decrease in women with polycystic ovary syndrome. The aim of this study was to investigate the effects of combined hypocaloric diet and metformin on circulating testosterone and leptin levels in obese men with or without type 2 diabetes.
                Twenty obese men with type 2 diabetes (mean body mass index [BMI]: 35.5 +/- 1.1 kg/m(2)) and 20 nondiabetic obese men were enrolled in the study. We measured serum follicle-stimulating hormone, luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), sex-hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and plasma leptin levels before and 3 months after metformin treatment. Both groups were placed on a hypocaloric diet and 850 mg of metformin taken orally twice daily for 3 months.
                Metformin and hypocaloric diets led to decreases in BMI and waist and hip circumferences in both groups. A significant decrease in TT levels in the diabetic group and FT levels in the control group was found, whereas follicle-stimulating hormone, LH, and DHEAS levels were not changed significantly. A significant increase in SHBG levels was observed in the control group but not in the patient group. Leptin levels also decreased after treatment in both groups. Decreased testosterone levels were not correlated to changes in waist and hip circumference, waist-to-hip ratio, BMI, and levels of fasting blood glucose, leptin, SHBG, or DHEAS in the diabetic group. However, a decrease in FT was correlated to changes in the levels of SHBG (r = -0.71, p = 0.001) and LH (r = 0.80, p = 0.001) but not to other parameters.
                We conclude that metformin treatment combined with a hypocaloric diet leads to reduced FT levels in obese nondiabetic men and to reduced TT levels in obese men with type 2 diabetes. Increased SHBG levels may account for the decrease in FT levels in the former group. To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.
                During a 12-week observation period 236 patients were treated with metformin 500 or 750 mg/day. 169 patients with a confirmed HbA(1c) level >or= 6.5% were randomized (stratified according to metformin dosage) to receive pioglitazone 15 mg/day for 12 weeks then increased to 30 mg/day for a further 16 weeks (n = 83), or placebo (n = 86). Outcome measures included HbA(1c), fasting blood glucose (FBG), percentage of patients achieving HbA(1c) < 6.5%, lipid profile, and other metabolic parameters.
                Mean HbA(1c) was reduced by 0.67% in patients receiving pioglitazone plus metformin versus an increase of 0.25% in those receiving metformin alone (p < 0.0001). After 8 weeks' treatment and until the end of the study, HbA(1c) was significantly lower with pioglitazone plus metformin and more patients in this group achieved an HbA(1c) < 6.5% (38.6% vs. 8.1%; p < 0.0001). FBG was also reduced by a significantly greater amount in patients receiving pioglitazone plus metformin compared with metformin monotherapy (-20.5 vs. 1.9 mg/dl; p < 0.0001). Combination therapy was associated with significantly increased HDL-cholesterol, total cholesterol, and adiponectin, and significantly decreased levels of fasting insulin, free fatty acids, and homeostasis model assessment insulin resistance (HOMA-R) compared with metformin monotherapy. Overall, combination therapy and monotherapy were equally well tolerated and the incidence of adverse effects 'possibly' related to therapy was 15.7% and 11.6% (p = 0.505), respectively. Edema occurred slightly more often in the combination group (6.0 vs. 1.2%).
                Pioglitazone plus metformin significantly improved glycemic control (HbA(1c) and FBG), and markers associated with increased insulin resistance and cardiovascular risk compared with metformin monotherapy.
                UMIN 000001110. The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known.
                We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function.
                Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons).
                The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).
                Copyright 2006 Massachusetts Medical Society. Twenty-two NIDDM patients completed an open randomized cross-over study comparing metformin and glibenclamide over 1 year. The drugs had an equivalent effect on glycaemic control, but, in contrast to glibenclamide, metformin reduced body weight. Neither drug affected triglycerides, total- and LDL-cholesterol or C-peptide. Metformin caused a slight elevation of HDL-cholesterol (P less than 0.05). No serious adverse effects were observed. The results show that oral hypoglycaemic agents are not associated with undesirable effects on lipids and lipoproteins. Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs.
                To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea.
                26-week multicenter, open-label, randomized, controlled trial.
                82 outpatient study centers in 13 countries.
                551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy.
                Exenatide, 10 microg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL).
                Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability.
                Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [CI, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/patient-year; difference, -1.6 events/patient-year [CI, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%).
                The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL).
                Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.
There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.