Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). Effect of blood glucose control on peripheral nerve function in diabetic patients. Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian Ponalrestat Trial. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. A multicentre trial of the aldose-reductase inhibitor tolrestat, in patients with symptomatic diabetic peripheral neuropathy. North European Tolrestat Study Group. Lipid modulation in insulin-dependent diabetes mellitus: effect on microvascular outcomes. Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes: the RealTrend study. Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. Autonomic and somatosensory nerve function after 2 years of continuous subcutaneous insulin infusion in type I diabetes. A 12-month randomized controlled study of the aldose reductase inhibitor ponalrestat in patients with chronic symptomatic diabetic neuropathy. Continuous subcutaneous insulin infusion (Mill-Hill Infuser) versus multiple injections (Medi-Jector) in the treatment of insulin-dependent diabetes mellitus and the effect of metabolic control on microangiopathy. Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Proactive case management of high-risk patients with type 2 diabetes mellitus by a clinical pharmacist: a randomized controlled trial. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, an 8-year prospective study of Japanese patients with type 2 diabetes was performed.
                A total of 110 patients with type 2 diabetes (55 with no retinopathy [the primary prevention cohort] and 55 with simple retinopathy [the secondary intervention cohort]) were randomly assigned to multiple insulin injection therapy (MIT) groups and administered three or more daily insulin injections or assigned to conventional insulin injection therapy (CIT) groups and administered one or two daily intermediate-acting insulin injections. Worsening of microvascular complications was regularly assessed during 8 years. Two or more steps up in the 19 stages of the modified Early Treatment of Diabetic Retinopathy Study classification in retinopathy and one or more stages up among three stages in nephropathy (normoalbuminuria, microalbuminuria, and albuminuria) were defined as worsening of complications.
                In both primary prevention and secondary intervention cohorts, the cumulative percentages of worsening in retinopathy and nephropathy were significantly lower (P < 0.05) in the MIT group than in the CIT group. In neurological tests after 8 years, the MIT group showed significant improvement (P < 0.05) in the median nerve conduction velocities (motor and sensory nerves), whereas the CIT group showed significant deterioration (P < 0.05) in the nerve conduction velocities and vibration threshold. From this study, the glycemic threshold to prevent the onset and progression of diabetic microvascular complications was as follows: HbA1c < 6.5%, fasting blood glucose concentration < 110 mg/dl, and 2-h postprandial blood glucose concentration < 180 mg/dl.
                Intensive glycemic control can delay the onset and progression of the early stages of diabetic microvascular complications in Japanese patients with type 2 diabetes. To determine whether a difference in HbA(1c) could be safely sustained between a standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining HbA(1c) levels in both arms within a range acceptable in community practice. The effects of intensive treatment on various parameters were studied in this feasibility trial. We report here the results of 24 months of INT on peripheral and autonomic neuropathy.A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: (1) an evening insulin injection, (2) the same injection adding daytime glipizide, (3) two injections of insulin alone, and (4) multiple daily injections. Peripheral neuropathy was diagnosed clinically by a history and physical examination, and by abnormal autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10). An average HbA(1c) separation of 2.07% was achieved with INT, having HbA(1c) at or below 7.3% (p = 0. 001 versus STD). Baseline prevalence of peripheral neuropathy was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in STD (p = 0.005 versus baseline), and to 64% in INT (p = 0. 008 versus baseline, but no different than STD). Though INT did not reverse all elements of peripheral neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053 versus STD) and more frequent preservation of touch sensation in the upper extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD, the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p = 0.012 versus baseline and no different from STD). The prevalence of erectile dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD, and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from STD. There was no change in the frequency of abnormal gastrointestinal or sweating symptoms. Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy. In fact, the prevalence rose equivalently and significantly in both treatment arms. There was some benefit, however, in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT. A prospective, stratified, randomized 3-year clinical trial was conducted on the effect of rigorous versus conventional glucose control on peripheral nerve function in 33 insulin-treated diabetic patients with a duration of diabetes of less than 2 years. The goals for conventional glucose control were the mean of fasting and 80-minute postprandial plasma glucose of 150 mg/dl for non-insulin-dependent diabetes and 200 mg/dl for insulin-dependent diabetes. The goal of rigorous glucose control was an approximation of nondiabetic glucose control. No significant difference in glucose control or peripheral nerve function was observed between the rigorously and the conventionally controlled groups. Eight patients in the conventional-control group spontaneously achieved glucose control in the range that was the objective for the rigorous-control group, and five patients in the rigorous-control group never achieved the desired glucose control. In the remaining 20 patients, with similar baseline glucose control and peripheral nerve function characteristics, observed over a median of 2 years, improved blood glucose control (P less than 0.01) was not associated with any significant improvement in peripheral nerve function. Nevertheless, a significant (P less than 0.05) correlation was found between the degree of abnormal nerve function at entry into the study and change in nerve function during the study. If control of hyperglycemia benefits peripheral nerve function of diabetic patients, its demonstration may require a closer approximation of normoglycemia, a larger difference in glucose control between the two study groups, a longer duration of treatment, and the use of patients with more advanced peripheral nerve function abnormalities than those in this study. The potential of the aldose reductase inhibitor ponalrestat (600 mg daily) to ameliorate diabetic neuropathy was evaluated in 259 diabetes mellitus patients with peripheral neuropathy (defined by abnormal vibration perception threshold and abnormal peroneal motor conduction velocity) in a double-blind placebo-controlled clinical trial running for 18 months. Overall, no beneficial effect of ponalrestat on vibration perception thresholds, nerve conduction velocities, and nerve action potential amplitudes was detected. Because vibration perception thresholds and conduction velocities in median, peroneal, and sural nerves did not deteriorate in the placebo group, the potential of ponalrestat to prevent the expected deterioration in peripheral nerve function that occurs with an increased duration of diabetes was not tested. Patients with an abnormal heart rate reaction to standing (abnormal 30:15 ratio; n = 84) on ponalrestat did not deteriorate in this autonomic nerve function test as shown in those on placebo. In conclusion, ponalrestat did not improve peripheral nerve function in diabetes mellitus patients with signs of peripheral neuropathy, although it did ameliorate a deterioration in autonomic nerve function in diabetic patients with signs of autonomic neuropathy. Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
                A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
                In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
                Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM. One hundred and ninety patients with symptomatic diabetic peripheral neuropathy took part in a double blind multicentre trial of either placebo or tolrestat 200 mg once daily for 6 months. Painful and paraesthetic symptoms, vibration sensory threshold, and nerve conduction velocity (NCV) were assessed as efficacy end-points during the trial. There was an equally marked improvement of painful symptoms during the trial in the tolrestat and placebo groups. A difference in the improvement of paraesthetic symptoms was found however in favour of the placebo group at 24 weeks (p less than 0.02). The deterioration in mean vibration threshold of the tolrestat group was less than placebo at 24 weeks at all 3 sites measured, and reached significance at the carpal site (p less than 0.05). Significant improvements in median motor NCV and in the mean NCV of the four motor nerves were also seen in tolrestat treated patients at 24 weeks compared to placebo (p less than 0.05). In addition, significant changes in favour of tolrestat were seen when the number of motor nerves per patient with NCV increased during the trial was analysed (p less than 0.001). Concordance analysis of patients with increased mean motor NCV and improvement in painful symptoms demonstrated a positive effect for tolrestat compared to placebo (p less than 0.02). Mild reversible elevations of hepatic transaminases were seen in a few patients treated with tolrestat, with no other significant adverse effects. Tolrestat may therefore be helpful in diabetic peripheral neuropathy, where there is little opportunity for therapeutic intervention apart from effort to achieve normoglycaemic control. Although hyperlipidemia is associated with the development of diabetes complications, the effect of lipid reduction on microvascular complications is unknown. We initiated a 2-year, randomized, double-blinded placebo-controlled pilot trial of simvastatin/diet vs. diet alone in Type 1 diabetic patients without overt nephropathy. Thirty-nine patients with LDL cholesterol 100-160 mg/dl, >10 year duration of diabetes and an albumin excretion rate (AER) <200 microg/min were recruited for study. The primary end-point was change in AER. Secondary end-points were change in ankle-brachial index, progression of retinopathy status, change in vibratory threshold, and development of new clinical neuropathy. Nineteen patients were treated with simvastatin and twenty with placebo. However, because of the lowering of drug initiation levels by the American Diabetes Association, the trial was terminated early with 2 subjects reaching 2 years, 17 reaching 18 months, 36 reaching 1 year, and all 6 months. Simvastatin significantly reduced total cholesterol (mean on treatment 173.4 vs. 191.4, P=.020) and LDL cholesterol (mean on treatment 105.0 vs. 127.7, P<.001). Simvastatin therapy was associated with a slower rise in AER compared to placebo, though the result was not statistically significant (median rate of change/month 0.004 vs. 0.029). There was a trend towards slower progression of neuropathy as measured by vibratory threshold (median change at 1 year 0.03 simvastatin vs. 0.94, P=.07). There was no difference in change in ankle-brachial index, clinical neuropathy status, or retinopathy status. In conclusion, treatment with simvastatin may have a beneficial effect on early nephropathy and diabetic neuropathy, justifying a fully powered trial. However, this would be difficult under current treatment guidelines. To compare the improvements in glycemic control associated with transitioning to insulin pump therapy in patients using continuous glucose monitoring versus standard blood glucose self-monitoring.
                The RealTrend study was a 6-month, randomized, parallel-group, two-arm, open-label study of 132 adults and children with uncontrolled type 1 diabetes (A1C >or=8%) being treated with multiple daily injections. One group was fitted with the Medtronic MiniMed Paradigm REAL-Time system (PRT group), an insulin pump with integrated continuous subcutaneous glucose monitoring (CGM) capability, with instructions to wear CGM sensors at least 70% of the time. Conventional insulin pump therapy was initiated in the other group (continuous subcutaneous insulin infusion [CSII] group). Outcome measures included A1C and glycemic variability.
                A total of 115 patients completed the study. Between baseline and trial end, A1C improved significantly in both groups (PRT group -0.81 +/- 1.09%, P < 0.001; CSII group -0.57 +/- 0.94%, P < 0.001), with no significant difference between groups. When the 91 patients who were fully protocol-compliant (including CGM sensor wear >or=70% of the time) were considered, A1C improvement was significantly greater in the PRT group (P = 0.004) (PRT group -0.96 +/- 0.93%, P < 0.001; CSII group -0.55 +/- 0.93%, P < 0.001). Hyperglycemia parameters decreased in line with improvements in A1C with no impact on hypoglycemia.
                CGM-enabled insulin pump therapy improves glycemia more than conventional pump therapy during the first 6 months of pump use in patients who wear CGM sensors at least 70% of the time. There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8 +/- 8.0 percent in nerve sorbitol content (P less than 0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P less than 0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy. Autonomic and somatosensory nerve function was studied in 24 insulin-dependent diabetic subjects (aged 29 +/- 7 yrs, diabetes duration 8 +/- 4 yr) randomly allocated to either continuous subcutaneous insulin infusion (CSII; n = 12) or unchanged conventional insulin therapy (CIT; n = 12). Measures of glycemic control and somatosensory and autonomic nerve function were comparable in the two groups at the start. Glycemic control was significantly improved in the CSII group throughout study, whereas it remained unchanged in the CIT group. In the CIT group, vibratory perception threshold (VPT) of the great toe and the medial malleolus deteriorated, as did heart rate variation (HRV) at rest, at deep breathing (.05 less than P less than .06), and at standing. In contrast, CSII patients retained their VPT and HRV. Comparison of nerve function alterations during the 2-yr trial showed better preservation in CSII than in CIT patients of VPT in the great toe (0.8 +/- 1.7 vs. -1.4 +/- 1.9 V, P less than .01) and the medial malleolus (1.5 +/- 2.9 vs. -1.4 +/- 1.8 V, P less than .05) and of HRV at rest (10 +/- 24 vs. -13 +/- 22 ms, P less than .05) and at standing (-0.01 +/- 0.13 vs. -0.15 +/- 0.16 ms, P less than .05). We conclude that intensified glycemic control can favorably influence parasympathetic and somatosensory nerve function in insulin-dependent diabetes mellitus. The effects of the aldose reductase inhibitor ponalrestat (600 mg day-1) on sensory, electrophysiological, and autonomic function were examined in 50 patients with chronic symptomatic, distal symmetrical diabetic neuropathy in a 52-week randomized, double-blind, parallel-group, placebo-controlled, single-centre study. In an endeavour to identify patients with a degree of neuropathy potentially amenable to pharmacological intervention, a minimum conduction velocity of 30 m s-1 was set for the peroneal motor nerve. At 52 weeks, no significant differences were observed between the ponalrestat and placebo groups in motor (ulnar, median, and peroneal) or sensory (ulnar and radial) nerve conduction velocities, vibration perception thresholds, adjectival symptom scores or tests of autonomic function (mean electrocardiographic R-R interval variability on deep breathing and orthostatic blood pressure response). Ponalrestat was clinically well tolerated and had no significant effect on glycaemic control. The lack of beneficial effects of ponalrestat may in part reflect the advanced stage of the neuropathic process in patients with established symptomatic disease, and the poor reproducibility of current neurophysiological techniques. Firmer knowledge of clinico-pathological correlates allied to improved non-invasive neurophysiological measurement techniques should facilitate the selection of patients for future therapeutic trials in diabetic neuropathy. The present study was designed to compare continuous subcutaneous insulin infusion (CSII) using the Mill-Hill Infuser (Muirhead Medical Products Ltd., London, England) with multiple injections (MI) using the Medi-Jector (Derata Corporation, Minneapolis, Minnesota) in the treatment of insulin-dependent diabetes mellitus (IDDM), and to assess the effect of glucose control on diabetes complications. Twelve diabetic subjects were treated 3 mo with CSII and 3 mo with MI (bedtime ultralente and premeal boluses of regular insulin) in a randomized fashion. Prestudy preprandial/postprandial glucose levels were 147-215 mg/dl and improved to 108-138 mg/dl during CSII, and to 115-139 mg/dl during MI with glycosylated hemoglobin of 12.9%, 9.1%, and 8.7%, respectively. This improved glucose control with either CSII or MI was associated with an increase in sural nerve conductivity from 42.9 to 45 m/s and a decrease in proteinuria from 1.9 to 0.5 g/24 h. The 24-h insulin dose consisted of 45 U before the study, 44 U during CSII, and 56 U during MI. After the study, seven patients opted to continue with the Mill-Hill Infuser, and five with the Medi-Jector. We conclude the following: (1) treatment with both the Mill-Hill Infuser and the Medi-Jector was well accepted by the patients and resulted in similar improvement in measured blood glucose and glycosylated hemoglobin; (2) this improved metabolic control was associated with an increased nerve conductivity and a decreased protein excretion; and (3) MI required 20% more insulin than CSII to achieve similar glycemic control. Thirty patients with insulin-dependent diabetes mellitus (IDDM) who had advanced background retinopathy were randomized to unchanged conventional treatment (UCT) or to continuous subcutaneous insulin infusion (CSII). They were followed prospectively for 2 yr. The mean blood glucose and hemoglobin A1C (HbA1C) were significantly lower in the CSII group than in the UCT group. The mean blood glucose and HbA1C did not change from the first to the second year in either of the treatment groups in spite of less frequent home-monitoring of blood glucose and less frequent outpatient visits during the second year. Four patients in the CSII group and five in the UCT group developed proliferative retinopathy. However, a marginally significant trend was found toward more frequent improvement of retinal morphology in the CSII group (47%) than in the UCT group (13%). Beat-to-beat variation was found to deteriorate significantly with UCT compared with a nonsignificant improvement with CSII therapy. Vibration sense was unchanged in both treatment groups. It is concluded that near-normal blood glucose levels can be maintained with CSII therapy in spite of less frequent home-monitoring of blood glucose and outpatient visits. Furthermore, established background retinopathy may progress to proliferative retinopathy in spite of 2 yr of near-normal blood glucose levels. However, a marginally significant trend toward more frequent improvement of retinal morphology was found among CSII-treated patients compared with conventionally treated patients. Large-scale, prospective, randomized studies are needed to confirm these results. To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows; HbA1c < 6.5%, FBG < 110 mg/dl, and 2-h post-prandial blood glucose concentration < 180 mg/dl. To evaluate the effect of case management by a clinical pharmacist on glycemic control and preventive measures in patients with type 2 diabetes mellitus.
                Randomized controlled trial in a university-affiliated primary care internal medicine clinic.
                We recruited 80 patients with poorly controlled type 2 diabetes mellitus. A clinical pharmacist provided evaluation and modification of pharmacotherapy, self-management diabetes education, and reinforcement of diabetes complications screening processes through clinic visits and telephone follow-up. The main clinical outcome was hemoglobin A1C (HbA1C) level; process measures included HbA1C and low-density lipoprotein measurement, retinal examination, urine microalbumin testing (or use of angiotensin-converting enzyme inhibitors), and monofilament screening for diabetic neuropathy.
                Patients in the intervention and control groups were similar in age, sex, mean HbA1C levels (10.1% and 10.2%, respectively; P = .65), and current treatment regimens at baseline. Patients who received case management by the clinical pharmacist achieved greater reduction in HbA1C levels than those in the control group (2.1% vs 0.9%, P = .03). Three of the 5 process measures were conducted more frequently in the intervention group than the control group, including low-density lipoprotein measurement (100.0% vs 85.7%, P = .02), retinal examination (97.3% vs 74.3%), and monofilament foot screening (92.3% vs 62.9%).
                Proactive diabetes case management by a pharmacist substantially improved glycemic control and diabetes process-of-care measures. This approach, integrated with and based in the primary care setting, was an effective and efficient approach to improving care, especially for those with poor glycemic control at baseline. In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain.
                We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately.
                After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001).
                A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)
                2008 Massachusetts Medical Society
According to high-quality evidence, enhanced glucose control significantly prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in type 1 diabetes mellitus. In type 2 diabetes mellitus, enhanced glucose control reduces the incidence of clinical neuropathy, although this was not formally statistically significant (P = 0.06). However, enhanced glucose control does significantly reduce nerve conduction and vibration threshold abnormalities. Importantly, enhanced glucose control significantly increases the risk of severe hypoglycemic episodes, which needs to be taken into account when evaluating its risk/benefit ratio.