title: Vildagliptin reduces plasma stromal cell‐derived factor‐1α in patients with type 2 diabetes compared with glimepiride Effects of Vildagliptin or Pioglitazone on Glycemic Variability and Oxidative Stress in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy: A 16-Week, Randomised, Open Label, Pilot Study Effect of gemigliptin on glycaemic variability in patients with type 2 diabetes (STABLE study) Is HbA(1c) affected by glycemic instability? The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials The synergistic effects of saxagliptin and metformin on CD34+ endothelial progenitor cells in early type 2 diabetes patients: a randomized clinical trial Effects of sitagliptin as initial therapy in newly diagnosed elderly type 2 diabetics: A randomized controlled study Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Effect of short‐term treatment with sitagliptin or glibenclamide on daily glucose fluctuation in drug‐naïve Japanese patients with type 2 diabetes mellitus GRADE guidelines: 3. Rating the quality of evidence. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study The relative importance of vascular structure and function in predicting cardiovascular events. The efficacy and safety of adding either vildagliptin or glimepiride to ongoing metformin therapy in patients with type 2 diabetes mellitus Reduction of Oxidative Stress and Inflammation by Blunting Daily Acute Glucose Fluctuations in Patients With Type 2 Diabetes Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. A comparative study of the effects of a dipeptidyl peptidase-IV inhibitor and sulfonylurea on glucose variability in patients with type 2 diabetes with inadequate glycemic control on metformin.
abstract: Abstract Aims / Introduction Dipeptidyl peptidase‐4 inhibitors might have pleiotropic protective effects on cardiovascular disease ( CVD ) , in contrast to sulfonylureas . Therefore , we compared various CVD risk factors between vildagliptin and glimepiride . Material s and Methods We carried out a r and omized , prospect i ve and crossover trial . A total of 16 patients with type 2 diabetes whose glycated hemoglobin was > 7 % were r and omized to add vildagliptin or glimepiride .  After 12‐week treatment , each drug was replaced with the other for another 12 weeks . Before and after each treatment , glucose homeostasis and CVD risk factors were assessed , and the continuous glucose monitoring system was applied to calculate glycemic variability . Results The mean age of the participants was 60 years , 31 % were men , body mass index 25.5 kg/m2 and HbA1c 8.41 % .  Both vildagliptin and glimepiride significantly decreased glycated hemoglobin and glycemic variability indices . Despite the improved glucose homeostasis , favorable change of CVD markers was not prominent in both the arms , along with significant weight gain . Only plasma stromal cell‐derived factor (SDF)‐1α decreased by 30 % in the vildagliptin arm . According to regression analyses , the reduction of SDF‐1α was independently associated with vildagliptin usage and serum interleukin‐6 changes , but white blood cells were not related with the SDF‐1α changes . Conclusion Compared with glimepiride , vildagliptin arrestingly decreased plasma SDF‐1α , and its clinical implication s should be further investigated Background Glycemic variability is associated with the development of diabetic complications through the activation of oxidative stress . This study aim ed to evaluate the effects of a dipeptidyl peptidase 4 inhibitor , vildagliptin , or a thiazolidinedione , pioglitazone , on glycemic variability and oxidative stress in patients with type 2 diabetes . Methods In this open label , r and omised , active-controlled , pilot trial , individuals who were inadequately controlled with metformin monotherapy were assigned to either vildagliptin ( 50 mg twice daily , n=17 )  or pioglitazone ( 15 mg once daily , n=14 ) treatment groups for 16 weeks . Glycemic variability was assessed by calculating the mean amplitude of glycemic excursions ( MAGE ) , which was obtained from continuous glucose monitoring . Urinary 8-iso prostagl and in F2α , serum oxidised low density lipoprotein , and high-sensitivity C-reactive protein were used as markers of oxidative stress or inflammation . Results Both vildagliptin and pioglitazone significantly reduced glycated hemoglobin and mean plasma glucose levels during the 16-week treatment . Vildagliptin also significantly reduced the MAGE ( from 93.8±38.0 to 70.8±19.2 mg/dL , P=0.046 ) , and mean st and ard deviation of 24 hours glucose ( from 38±17.3 to 27.7±6.9 , P=0.026 ) ; however , pioglitazone did not , although the magnitude of decline was similar in both groups . Markers of oxidative stress or inflammation including urinary 8-iso prostagl and in F2α did not change after treatment in both groups . Conclusion In this 16-week treatment trial , vildagliptin , but not pioglitazone , reduced glycemic variability in individuals with type 2 diabetes who was inadequately controlled with metformin monotherapy , although a reduction of oxidative stress markers was not observed The aim of this study was to evaluate the effect of gemigliptin vs sitagliptin or glimepiride as initial combination therapy with metformin on glycaemic variability and to assess the correlation between glycaemic variability reduction and the dipeptidyl peptidase‐4 ( DPP‐4 ) inhibition in patients with type 2 diabetes . This multicentre , r and omized , active‐controlled , open‐label exploratory study included 69 patients with HbA1c > 7.5 % . Subjects were r and omized to receive gemigliptin 50 mg ( n = 24 ) , sitagliptin 100 mg ( n = 23 ) or glimepiride 2 mg ( n = 22 ) for 12 weeks . After 12 weeks , the change in mean amplitude of glycaemic excursion ( MAGE ) compared with baseline was significantly lower in the DPP‐4 inhibitor groups compared with that in patients who received glimepiride . Furthermore , the st and ard deviation ( SD ) of glucose was significantly lower in patients who received gemigliptin than that in patients who received sitagliptin or glimepiride . The DPP‐4 inhibition was significantly correlated with changes in MAGE and SD of glucose . In conclusion , gemigliptin and sitagliptin were more effective than glimepiride in reducing glycaemic variability as initial combination therapy with metformin in patients with type 2 diabetes , and the DPP‐4 inhibition was associated with a reduction in glycaemic variability OBJECTIVE HbA(1c ) is a st and ard clinical assessment of glycemia and the basis of most data relating glycemic control to complications . It remains unclear , however , whether HbA(1c ) is affected by glycemic variation and mean glycemia . RESEARCH DESIGN AND METHODS To test this question , we analyzed the statistical relationship between HbA(1c ) levels and glycemic variability as measured by self-monitoring of blood glucose ( SMBG ) .  The records of 256 subjects were studied .  SMBG data for the preceding 3 months were downloaded , and HbA(1c ) was measured by ion-exchange high-performance liquid chromatography . Simple- and r and om-effects linear regression models were used to assess the independent contributions of mean blood glucose ( BG ) and SD of BG to HbA(1c ) , after adjusting for the mean BG . RESULTS Mean + /- SD for HbA(1c ) was 7.66 + /- 1.11 % and for BG was 8.5 + /- 1.9 mmol/l ( 153.3 + /- 34.9 mg/dl ) ; SD of BG for individual subjects was 3.5 mmol/l ( 63.3 mg/dl ) , varying from 0.4 mmol/l ( 8.1 mg/dl ; very stable glycemia ) to 8.4 mmol/l ( 152.5 mg/dl ; very unstable glycemia ) . A close correlation between mean BG and HbA(1c ) was demonstrated ( r = 0.62 ) . Also , within-subject SD of BG correlated with HbA(1c ) ( r = 0.375 ) , indicating that people with poorer glycemic control had higher BG variance . After adjusting for mean BG in a linear regression model , however , the effect of the within-subject SD of BG on the HbA(1c ) was insignificant . Several further analyses confirmed the strength of the observation . CONCLUSIONS HbA(1c ) reflects mean glycemia and is not meaningfully affected by glycemic instability after adjusting for mean BG Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Aims Type 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease . CD34 + endothelial Progenitor Cells ( EPCs ) are responsible for endothelial repair and neo-angiogenesis and can be used as a cardiovascular disease risk biomarker . This study investigated whether the addition of saxagliptin , a DPP-IV inhibitor , to metformin , may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients . Methods In 12 week , double-blind , r and omized placebo-controlled trial , 42 subjects already taking metformin 1–2 grams/day were r and omized to placebo or saxagliptin 5 mg . Subjects aged 40–70 years with diabetes for < 10 years , with no known cardiovascular disease , BMI 25–39.9 , HbA1C 6–9 % were included . We evaluated EPCs number , function , surface markers and gene expression , in addition to arterial stiffness , blood biochemistries , resting energy expenditure , and body composition parameters . A mixed model regression to examine saxagliptin vs placebo , accounting for within-subject autocorrelation , was done with SAS ( p < 0.05 ) . Results Although there was no significant increase in CD34 + cell number , CD31 + cells percentage increased . Saxagliptin  increased migration ( in response to SDF1α ) with a trend of higher colony formation count . MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells , indicating a functional improvement . Gene expression analysis showed an upregulation in CD34 + cells for antioxidant SOD1 ( p < 0.05 ) and a downregulation in CD34− cells for IL-6 ( p < 0.01 ) . For arterial stiffness , both augmentation index and systolic blood pressure measures went down in saxagliptin subjects ( p < 0.05 ) . ConclusionS axagliptin , in combination with metformin , can help improve endothelial dysfunction in early diabetes before macrovascular complications appear . Trial registration Trial is registered under clinical trials.gov , The objective of this study was to investigate the characteristics of blood glycemic excursion , incretins and pancreatic hormone secretion in elderly people with newly diagnosed type 2 diabetes mellitus ( T2DM ) and to study the effects of sitagliptin on glycemic excursion in these subjects . A total of 129 newly diagnosed T2DM patients were enrolled in the study from March 2012 to August 2013 .  Clinical data , serum incretin , pancreatic hormone and continuous glucose monitoring data were collected . Among these subjects , elderly patients ( NEDM ) r and omly received metformin combined with sitagliptin phosphate or glimepiride for 24 weeks . The blood glucose , glycosylated hemoglobin A1c ( GHbA1c ) , serum incretins and pancreatic hormone levels were determined . During the oral glucose tolerance test ( OGTT ) , 30 min insulin and C-peptide levels , 120 min insulin levels and ratio of the increases of insulin and blood glucose levels after 30 min of sugar loading ( ∆Ins30/∆Glu30 ) were significantly lower in elderly patients than in middle-aged patients ( P<0.05 ) . In addition , the glucagon elevation at 30 min was higher and the glucagon-like peptide-1 ( GLP-1 ) at 30 min was lower in the elderly patients ( P<0.05 ) . Glucose excursion indices , including the st and ard deviation of the average blood glucose , intraday mean average glucose excursions ( MAGE ) , and mean of daily differences ( MODD ) , were significantly higher in the elderly patients ( P<0.05 ) . During the OGTT , insulin , C-peptide and ∆Ins30/∆Glu30 results at 30 min and GLP-1 levels at 120 min in NEDM subjects were significantly increased ( P<0.05 ) and glucagon levels at 30 min was significantly lower after sitagliptin treatment ( P<0.05 ) compared with glimepiride . Moreover , MAGE and MODD were significantly lower in the sitagliptin group after treatment compared to those in the glimepiride group ( P<0.05 ) . No severe hypoglycemia or cardiovascular diseases were observed . Strong blood glucose excursions occur in elderly patients with newly diagnosed T2DM . Sitagliptin phosphate combined with metformin effectively and safely improves glycemic excursion and carbohydrate metabolism in NEDM patients by promoting the first phase of insulin and incretin secretion and inhibiting glucagon secretion of BACKGROUND In patients with type 2 diabetes , intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks . This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage . METHODS Of 4075 patients recruited to UKPDS in 15 centres , 1704 overweight ( > 120 % ideal bodyweight ) patients with newly diagnosed type 2 diabetes , mean age 53 years , had raised fasting plasma glucose ( FPG ; 6.1 - 15.0 mmol/L ) without hyperglycaemic symptoms after 3 months ' initial diet . 753 were included in a r and omised controlled trial , median duration 10.7 years , of conventional policy , primarily with diet alone ( n=411 ) versus intensive blood-glucose control policy with metformin , aim ing for FPG below 6 mmol/L ( n=342 ) . A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated  intensive blood-glucose control with chlorpropamide ( n=265 ) , glibenclamide ( n=277 ) , or insulin ( n=409 ) . The primary outcome measures were aggregates of any diabetes-related clinical endpoint , diabetes-related death , and all-cause mortality . In a supplementary r and omised controlled trial , 537 non-overweight and overweight patients , mean age 59 years , who were already on maximum sulphonylurea therapy but had raised FPG ( 6.1 - 15.0 mmol/L ) were allocated continuing sulphonylurea therapy alone ( n=269 ) or addition of metformin ( n=268 ) . FINDINGS Median glycated haemoglobin ( HbA1c ) was 7.4 % in the metformin group compared with 8.0 % in the conventional group . Patients allocated metformin , compared with the conventional group , had risk reductions of 32 % ( 95 % CI 13 - 47 , p=0.002 ) for any diabetes-related endpoint , 42 % for diabetes-related death ( 9 - 63 , p=0.017 ) , and 36 % for all-cause mortality ( 9 - 55 , p=0.011 ) . Among patients allocated intensive blood-glucose control , metformin showed a greater effect than chlorpropamide , glibenclamide , or insulin for any diabetes-related endpoint ( p=0.0034 ) , all-cause mortality ( p=0.021 ) , and stroke ( p=0.032 ) . Early addition of metformin in sulphonylurea-treated patients was associated with an increased risk of diabetes-related death ( 96 % increased risk [ 95 % CI 2 - 275 ] , p=0.039 ) compared with continued sulphonylurea alone . A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints ( risk reduction 19 % [ 2 - 33 ] , p=0.033 ) . Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin  ( risk reduction 5 % [ -33 to 32 ] , p=0.78 ) . INTERPRETATION Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients , and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas , it may be the first-line pharmacological therapy of choice in these patients AIMS To compare the effect of a dipeptidyl peptidase-4 inhibitor ( DPP4-i ) and a sulfonylurea ( SU ) on daily glucose fluctuation in drug-naïve Japanese patients with type 2 diabetes mellitus ( T2DM ) . MATERIAL S AND METHODS A total of 53 drug-naïve Japanese patients with T2DM ( HbA1c , 7.0%-9.0 % ; fasting plasma glucose , 6.1 mmol/L or higher ) were r and omly assigned to either sitagliptin 50 mg qd or glibenclamide 2.5 mg per day ( given in divided doses ) in a 1:1 ratio . A continuous glucose monitoring ( CGM ) device was used to obtain 24-hour glucose profiles for each patient at baseline and at Week 2 . The primary study endpoint was change from baseline in mean amplitude of glucose excursion ( MAGE ) during a 24-hour period . A key secondary endpoint was change from baseline in the st and ard deviation ( SD ) of 24-hour glucose levels . RESULTS After 2 weeks of treatment , a numerically greater reduction in MAGE from baseline was observed in the sitagliptin group compared with the glibenclamide group , but the between-treatment difference was not statistically significant ( LS mean difference [ 95 % CI ] : -0.48 mmol/L [ -1.31 , 0.34 ] ; P = .245 ) . However , a significantly greater reduction in the change from baseline in SD was observed in the sitagliptin group compared with the glibenclamide group ( LS mean difference [ 95 % CI ] : -0.33 mmol/L [ -0.62 , -0.03 ] ; P = .029 ) . CONCLUSIONS This study suggests that the DPP4 inhibitor sitagliptin has a greater ability to reduce daily glucose fluctuation than the SU glibenclamide in drug-naïve Japanese patients with T2DM . Clinical Trials.gov : NCT02318693 This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence Abstract Objective : To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes . Design : Prospect i ve observational study . Setting : 23 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Participants : 4585 white , Asian Indian , and Afro-Caribbean UKPDS patients , whether r and omised or not to treatment , were included in analyses of incidence ; of these , 3642 were included in analyses of relative risk . Outcome measures : Primary predefined aggregate clinical outcomes : any end point or deaths related to diabetes and all cause mortality . Secondary aggregate outcomes : myocardial infa rct ion , stroke , amputation ( including death from peripheral vascular disease ) , and microvascular disease ( predominantly retinal photo-coagulation ) . Single end points : non-fatal heart failure and cataract extraction . Risk reduction associated with a 1 % reduction in up date d mean HbA1c adjusted for possible confounders at diagnosis of diabetes . Results : The incidence of clinical complications was significantly associated with glycaemia . Each 1 % reduction in up date d mean HbA1c was associated with reductions in risk of 21 % for any end point related to diabetes ( 95 % confidence interval 17 % to 24 % , P<0.0001 ) , 21 % for deaths related to diabetes ( 15 % to 27 % , P<0.0001 ) , 14 % for myocardial infa rct ion ( 8 % to 21 % , P<0.0001 ) , and 37 % for microvascular complications ( 33 % to 41 % , P<0.0001 ) . No threshold of risk was observed for any end point . Conclusions : In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia . Any reduction in HbA1c is likely to reduce the risk of complications , with the lowest risk being in those with HbA1c values in the normal range ( < 6.0 % ) OBJECTIVES We sought to assess the prognostic utility of brachial artery reactivity ( BAR ) in patients at risk of cardiovascular events . BACKGROUND Impaired flow-mediated vasodilation measured by BAR is a marker of endothelial dysfunction . Brachial artery reactivity is influenced by risk factors and is responsive to various pharmacological and other treatments . However , its prognostic importance is uncertain , especially relative to other predictors of outcome . METHODS A total of 444 patients were prospect ively enrolled to undergo BAR and follow-up .  These patients were at risk of cardiovascular events , based on the presence of risk factors or known or suspected cardiovascular disease . We took a full clinical history , performed BAR , and obtained carotid intima-media thickness ( IMT ) and left ventricular mass and ejection fraction . Patients were followed up for cardiovascular events and all-cause mortality . Multivariate Cox regression analysis was performed to assess the independent association of investigation variables on outcomes . RESULTS The patients exhibited abnormal BAR ( 5.2 + /- 6.1 % [ mean + /- SD ] ) but showed normal nitrate-mediated dilation ( 9.9 + /- 7.2 % ) and normal mean IMT ( 0.67 + /- 0.12 mm [ average ] ) . Forty-nine deaths occurred over the median follow-up period of 24 months ( interquartile range 10 to 34 ) . Patients in the lowest tertile group of BAR ( < 2 % ) had significantly more events than those in the combined group of highest and mid-tertiles ( p = 0.029 , log-rank test ) . However , mean IMT ( rather than flow-mediated dilation ) was the vascular factor independently associated with mortality , even in the subgroup ( n = 271 ) with no coronary artery disease and low risk . CONCLUSIONS Brachial artery reactivity is lower in patients with events , but is not an independent predictor of cardiovascular outcomes in this cohort of patients ABSTRACT Objective : To compare the effects of either vildagliptin or glimepiride on glycemic variability , oxidative stress , and endothelial parameters in patients with type 2 diabetes mellitus ( T2DM ) inadequately controlled with metformin alone . Methods : In this r and omized , open-label , parallel study , 34 patients with T2DM being treated with metformin having an HbA1c of 7.0–10.0 % were allocated into either the vildagliptin or glimepiride group . A mixed-meal tolerance test and 72-hour continuous glucose monitoring were conducted , and urinary 8-iso-prostagl and inF2α ( PGF2α ) and endothelial-dependent flow-mediated dilatation ( FMD ) were evaluated at baseline and after 12 weeks of treatment . Results : Similar significant improvements in HbA1c level were shown in both vildagliptin ( −0.8 % ) and glimepiride ( −0.9 % ) groups after treatment ( Ps<0.001 ) . The mean amplitude of glycemic excursions ( MAGE ) and the mean of daily differences ( MODD ) were significantly decreased by vildagliptin ( P = 0.044 and P = 0.031 , respectively ) but not by glimepiride . Glimepiride was significantly associated with a higher incidence of hypoglycemia than vildagliptin ( P = 0.005 ) . There were no significant differences in urinary 8-iso-PGF2α or FMD between the two groups . Conclusions : Vildagliptin effectively improved glucose level with a significantly greater reduction in glycemic variability and hypoglycemia than glimepiride in patients with T2DM ongoing metformin therapy . The two drugs showed no significant differences in urinary 8-iso-PGF2α and FMD . Trial registration : OBJECTIVE Evaluate the effects of two dipeptidyl peptidase-IV ( DPP-4 ) inhibitors , sitagliptin and vildagliptin , known to have different efficacy on mean amplitude of glycemic excursions ( MAGE ) , on oxidative stress , and on systemic inflammatory markers in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS A prospect i ve , r and omized , open-label PROBE design ( parallel group with a blinded end point ) study was performed in 90 patients with type 2 diabetes inadequately controlled by metformin . The study assigned 45 patients to receive sitagliptin ( 100 mg once daily ; sitagliptin group ) and 45 patients to receive vildagliptin ( 50 mg twice daily ; vildagliptin group ) for 12 weeks . MAGE , evaluated during 48 h of continuous subcutaneous glucose monitoring , allowed an assessment of daily glucose fluctuations at baseline and after 12 weeks in all patients . Assessment of oxidative stress ( nitrotyrosine ) and systemic levels of inflammatory markers interleukin (IL)-6 and IL-18 was performed at baseline and after 12 weeks in all patients . RESULTS HbA1c , fasting and postpr and ial glucose , MAGE , and inflammatory and oxidative stress markers were similar between the groups at baseline . After 12 weeks , MAGE ( P < 0.01 ) was lower in the vildagliptin group than in the sitagliptin group . After treatment , HbA1c and postpr and ial glucose evidence d similar changes between the groups ( P = NS ) . Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine ( P < 0.01 ) , IL-6 ( P < 0.05 ) , and IL-18 ( P < 0.05 ) than sitagliptin treatment . Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE but not in fasting glucose and HbA1c . CONCLUSIONS MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients . These effects were greater in the vildagliptin group than in the sitagliptin group BACKGROUND In patients with type 2 diabetes , the effects of intensive glucose control on vascular outcomes remain uncertain . METHODS We r and omly assigned 11,140 patients with type 2 diabetes to undergo either  st and ard 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 infa rct ion , or nonfatal stroke ) and major microvascular events ( new or worsening nephropathy or retinopathy ) , assessed both jointly and separately . RESULTS 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 st and ard-control group ( 7.3 % ) . Intensive control reduced the incidence of combined major macrovascular and microvascular events ( 18.1 % , vs. 20.0 % with st and ard 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 st and ard-control group ; hazard ratio , 1.86 ; 95 % CI , 1.42 to 2.40 ; P<0.001 ) . CONCLUSIONS 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 . ( Clinical Trials.gov number , NCT00145925 . BACKGROUND This study aim ed to compare the effects of sitagliptin on glycemic change and 24-h blood glucose variability with those of the sulfonylurea glimepiride . SUBJECTS AND METHODS A 4-week r and omized double blind-labeled prospect i ve design was used . We recruited 33 patients who had been treated with metformin for at least 2 months . Each participant prescribed with metformin was r and omly assigned to either the sitagliptin ( 100 mg ) or the glimepiride ( 2 mg ) group .  Continuous glucose monitoring ( CGM ) was used to monitor glycemic changes for 3 successive days in both groups at baseline and at the 4-week follow-up . Glycemic changes and glucose variability were obtained using CGM , and these data were averaged over all subjects . RESULTS The comparison of glycated hemoglobin ( HbA1c ) between baseline and the 4-week follow-up showed that HbA1c was significantly reduced in the sitagliptin group ( 7.0 ± 0.5 % to 6.6 ± 0.4 % , P<0.001 ) and the glimepiride group ( 7.3 ± 0.4 % to 6.9 ± 0.4 % , P<0.001 ) . The sitagliptin and glimepiride groups had similar HbA1c levels after 4 weeks , and there were no significant differences between the two groups . The mean amplitude of glycemic excursions ( MAGE ) decreased significantly in the sitagliptin group ( 4.9 ± 1.0 to 3.7 ± 0.9 mmol/L , P<0.001 ) , but no significant difference was observed in the glimepiride group ( 5.7 ± 1.5 to 5.0 ± 1.4 mmol/L , P=0.175 ) . The SD and oxidative stress markers did not differ significantly between the two groups . CONCLUSIONS When sitagliptin was combined with metformin , the patients showed much more efficient blood glucose controlling effects , not only the three indexes of fasting blood glucose , postpr and ial blood glucose , and glycated hemoglobin , but also MAGE
target: Initial combination therapy with DPP-IV inhibitors more effectively reduced MAGE than stepwise add-on therapies ( p = 0.006 ) , although no differences in MAGE were found based on HbA1c values .
  These findings indicate that DPP-IV inhibitors are promising alternatives for reducing GV in type 2 diabetes patients .
background: Glycemic variability ( GV ) has been an emerging target for preventing complications related to type 2 diabetes .
  For reducing GV , DPP-IV inhibitors have shown effectiveness compared to other oral anti-hyperglycemic drugs ( OADs ) , but systematic evaluation has yet to be existed .