Insulin use and increased risk of mortality in type 2 diabetes: a cohort study

Aim: To compare population‐based rates of all‐cause and cardiovascular (CV) mortality in newly treated patients with type 2 diabetes according to levels of insulin exposure. Methods: Using the administrative databases of Saskatchewan Health, 12272 new users of oral antidiabetic therapy were identified between 1991 and 1996 and grouped according to cumulative insulin exposure based on total insulin dispensations per year: no exposure (reference group); low exposure (0 to <3); moderate exposure (3 to <12) and high exposure (≥12). Time‐varying multivariable Cox proportional hazards models were used to examine the relationship between insulin exposure and all‐cause, CV‐related and non‐vascular mortality after adjustment for demographics, medications and comorbidities. Results: Average age was 65 (s.d. 13.9) years, 45% were female, and mean follow‐up was 5.1 (s.d. 2.2) years. In total, 1443 (12%) subjects started insulin, and 2681 (22%) deaths occurred. The highest mortality rates were in the high exposure group; 95 deaths/1000 person‐years compared with 40 deaths/1000 person‐years in the no exposure group [unadjusted hazard ratio (HR): 2.32; 95% confidence interval (CI): 1.96–2.73]. After adjustment, we observed a graded risk of mortality associated with increasing exposure to insulin: low exposure [adjusted HR (aHR): 1.75; 95% CI: 1.24–2.47], moderate exposure (aHR: 2.18; 1.82–2.60) and high exposure (aHR: 2.79; 2.36–3.30); p = 0.005 for trend. Analyses restricted to CV‐related (p = 0.042 for trend) and non‐vascular (p = 0.004 for trend) mortality showed virtually identical results. Conclusions: We observed a significant and graded association between mortality risk and insulin exposure level in an inception cohort of patients with type 2 diabetes that persisted despite multivariable adjustment.     

Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes

Many patients with type 2 diabetes fail to achieve or maintain the American Diabetes Association's recommended treatment goal of glycosylated hemoglobin levels. This multicenter, double-blind trial enrolled patients with type 2 diabetes who had inadequate glycemic control [glycosylated hemoglobin A(1C) (A1C), >7% and <12%) with diet and exercise alone to compare the benefits of initial therapy with glyburide/metformin tablets vs. metformin or glyburide monotherapy. Patients (n = 486) were randomized to receive glyburide/metformin tablets (1.25/250 mg), metformin (500 mg), or glyburide (2.5 mg). Changes in A1C, fasting plasma glucose, fructosamine, serum lipids, body weight, and 2-h postprandial glucose after a standardized meal were assessed after 16 wk of treatment. Glyburide/metformin tablets caused a superior mean reduction in A1C from baseline (-2.27%) vs. metformin (-1.53%) and glyburide (-1.90%) monotherapy (P = 0.0003). Glyburide/metformin also significantly reduced fasting plasma glucose and 2-h postprandial glucose values compared with either monotherapy. The final mean doses of glyburide/metformin (3.7/735 mg) were lower than those of metformin (1796 mg) and glyburide (7.6 mg). First-line treatment with glyburide/metformin tablets provided superior glycemic control over component monotherapy, allowing more patients to achieve American Diabetes Association treatment goals with lower component doses in drug-naive patients with type 2 diabetes.     

Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study

Aims/hypothesis In type 2 diabetic patients we compared 9 months of combination therapy with insulin glargine and metformin with 9 months of NPH insulin combined with metformin. The primary focus was changes in HbA_1c; secondary focus was diurnal glucose profiles and symptomatic hypoglycaemia. Methods In this investigator-initiated open, parallel-group clinical trial involving seven centres, 110 insulin-naive type 2 diabetic patients with poor glycaemic control (HbA_1c ≥8.0%) on oral hypoglycaemic agents (90% using sulfonylurea plus metformin) were randomised to receive bedtime insulin glargine with metformin (G+MET) or bedtime NPH with metformin (NPH+MET) for 36 weeks. The patients were taught how to self-adjust their insulin dose and use a modem to send the results of home glucose monitoring to treatment centres. The goal was to achieve a fasting plasma glucose (FPG) of 4.0 to 5.5 mmol/l in both groups. Results During the last 12 weeks, FPGs averaged 5.75±0.02 and 5.96±0.03 mmol/l (p<0.001) and insulin doses were 68±5 and 70±6 IU/day (0.69±0.05 and 0.66±0.04 IU kg^–1 day^–1, NS) in the G+MET and NPH+MET groups, respectively. At 36 weeks, mean HbA_1c was 7.14±0.12 and 7.16±0.14%, respectively (NS). Symptomatic, but not confirmed symptomatic, hypoglycaemia was significantly lower during the first 12 weeks in the G+MET group (4.1±0.8 episodes/patient-year) than in the NPH+MET group (9.0±2.3 episodes/patient-year, p<0.05), but not significantly different thereafter. Glucose levels before dinner were higher in the NPH+MET group (10.1±0.3 mmol/l) than in the G+MET group (8.6±0.3 mmol/l, p=0.002) throughout the 36-week study. With regard to baseline characteristics such as initial glycaemia or C-peptide, there was no difference between patients who achieved good glycaemic control (HbA_1c <7.0%) and those who did not. Differences were seen in the following: between study centres, weight gain during the run-in period and insulin therapy, and FPG during the last 12 weeks (5.7±0.2 vs 6.7±0.3 mmol/l for patients reaching vs those not reaching target, p<0.01). Conclusions/interpretation Good glycaemic control can be achieved with both G+MET and NPH+MET. Use of G+MET reduces symptomatic hypoglycaemia during the first 12 weeks and dinnertime hyperglycaemia compared with NPH+MET.     

Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes

Aim: To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment‐naïve patients with type 2 diabetes. Methods: In a double‐blind study, 1050 treatment‐naïve patients (i.e. not taking an antihyperglycaemic agent for ≥16 weeks prior to study entry) with type 2 diabetes and an HbA_1c 6.5–9% were randomized (1:1) to treatment with once‐daily sitagliptin 100 mg (N = 528) or twice‐daily metformin 1000 mg (N = 522) for 24 weeks. Metformin was up‐titrated from 500 to 2000 mg per day (or maximum tolerated daily dose ≥1000 mg) over a period of 5 weeks. The primary analysis used a per‐protocol (PP) approach to assess whether sitagliptin was non‐inferior to metformin based on HbA_1c change from baseline at week 24. Non‐inferiority was to be declared if the upper boundary of the 95% confidence interval (CI) for the between‐group difference in this endpoint was <0.40%. Results: From a mean baseline HbA_1c of 7.2% in the PP population, HbA_1c change from baseline was ?0.43% with sitagliptin (n = 455) and ?0.57% with metformin (n = 439). The between‐group difference (95% CI) was 0.14% (0.06, 0.21), thus confirming non‐inferiority. Baseline HbA_1c influenced treatment response, with larger reductions in HbA_1c observed in patients with baseline HbA_1c≥8% in the sitagliptin (–1.13%; n = 74) and metformin (–1.24%; n = 73) groups. The proportions of patients at week 24 with HbA_1c values at the goals of <7 or <6.5% were 69 and 34% with sitagliptin and 76 and 39% with metformin, respectively. Fasting plasma glucose changes from baseline were ?11.5 mg/dL (–0.6 mmol/l) and ?19.4 mg/dl (–1.1 mmol/l) with sitagliptin and metformin, respectively (difference in LS mean change from baseline [95% CI] = 8.0 mg /dl [4.5,11.4]). Both treatments led to similar improvements from baseline in measures of homeostasis model assessment‐β cell function (HOMA‐β) and insulin resistance (HOMA‐IR). The incidence of hypoglycaemia was 1.7% with sitagliptin and 3.3% with metformin (p = 0.116). The incidence of gastrointestinal‐related adverse experiences was substantially lower with sitagliptin (11.6%) compared with metformin (20.7%) (difference in incidence [95% CI] = ?9.1% [?13.6,?4.7]), primarily because of significantly decreased incidences of diarrhoea (3.6 vs. 10.9%; p < 0.001) and nausea (1.1 vs. 3.1%; p = 0.032). Body weight was reduced from baseline with both sitagliptin (LS mean change [95% CI] = ?0.6 kg [?0.9,?0.4]) and metformin (–1.9 kg [–2.2, ?1.7]) (p < 0.001 for sitagliptin vs. metformin). Conclusions: In this 24‐week monotherapy study, sitagliptin was non‐inferior to metformin in improving HbA_1c in treatment‐naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal‐related adverse experiences was observed with sitagliptin.     

Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes.

AIM: Metformin therapy reduces microvascular complications in Type 2 diabetes; questions remain, however, regarding its impact on macrovascular events. This study examined metformin use in relation to risk of cardiovascular-related hospitalization and mortality. METHODS: We conducted a retrospective cohort analysis, using Saskatchewan Health administrative databases to identify new users of oral antidiabetic drugs. Subject groups were defined by medication use during 1991-1999: sulphonylurea monotherapy, metformin monotherapy, or combination therapy. Deaths and non-fatal hospitalizations recorded during the study period were identified as cardiovascular-related from ICD-9 codes. The main outcome was a composite of first non-fatal hospitalization or death. Standard multivariate techniques, including propensity scores, were used to adjust for potential confounding. Multivariate Cox proportional hazard models were used to examine the relationship between metformin use and the composite endpoint. RESULTS: Metformin monotherapy was associated with a lower risk of the composite endpoint (adjusted hazard ratio 0.81; 95% confidence interval 0.68, 0.97) compared with sulphonylurea monotherapy. Combination therapy with meformin and a sulphonylurea was associated with lower mortality, but had similar hospitalization rates, to sulphonylurea monotherapy. CONCLUSIONS: Metformin monotherapy was associated with a lower risk of cardiovascular-related morbidity and mortality, and combination metformin and sulphonylurea therapy was associated with a reduced risk of fatal cardiovascular events, when compared with sulphonylurea monotherapy.     

Insulin sensitivity in type 2 diabetes is closely associated with LDL particle size

PRINCIPLES: Small dense LDLs have been found to be associated with type 2 diabetes (T2DM). This association has been observed in the context of decreased HDL cholesterol and increased triglycerides. METHODS: In the present study the relationship between LDL particle size and insulin sensitivity was assessed in 46 patients with T2DM (mean age 60 (11) years, HbA1c 7.6 (0.8) %). 75 g oral glucose tolerance testing was performed and composite insulin sensitivity index was calculated by the method of Matsuda and de Fronzo (ISI(comp)). Additional parameters included BMI, waist circumference, blood pressure, HDL cholesterol, triglycerides and LDL cholesterol. LDL particle size was measured by gradient gel electrophoresis. RESULTS: Log ISI(comp) correlated most strongly with LDL particle size (R = 0.61), less closely with HDL cholesterol (R = 0.48) and plasma triglycerides (R = -0.45) and not at all with LDL cholesterol (R = 0.001), as supported by multiple regression analyses where log ISI(com) was associated with LDL particle size (p = 0.004) and HDL cholesterol (p = 0.027) but not with triglycerides and LDL cholesterol. CONCLUSION: Log ISI(comp) estimated by a formula using endogenous insulin levels is very closely associated with LDL particle size in patients with T2DM. Our data suggest that smaller LDL particle size reflects the impact of insulin resistance on lipoprotein metabolism more strictly than do the traditional lipid parameters.     

Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes

AIM: This study assessed the efficacy and safety of rosiglitazone and metformin (RSG/MET) fixed-dose combination (AVANDAMET) as initial therapy in patients with uncontrolled type 2 diabetes compared with monotherapy with either RSG or MET after 32 weeks of treatment. METHODS: A total of 468 drug-naive patients with uncontrolled type 2 diabetes were recruited for this multicentre, double-blind trial if their glycated haemoglobin (A1c) was greater than 7.5%, but less than or equal to 11%, and their fasting plasma glucose (FPG) was less than or equal to 15 mmol/l. Patients were randomized to 32 weeks of blinded treatment with either RSG/MET fixed-dose combination (n = 155), MET (n = 154) or RSG (n = 159). The groups were comparable at baseline, with mean A1c of 8.8% and FPG of 11 mmol/l. RSG/MET was initiated with a total daily dose of 2 mg/500 mg and could be increased up to 8 mg/2000 mg; MET therapy began with a total daily dose of 500 mg and could be increased up to 2000 mg; and RSG treatment began with a total daily dose of 4 mg and could be increased up to 8 mg. Medication was uptitrated during on-therapy visits based on failure to attain glycaemic target of mean daily glucose less than or equal to 6.1 mmol/l (unless at maximum tolerated dose). Patients were assessed for efficacy and safety at nine visits over a 32-week treatment period. This was a trial designed to show greater efficacy of RSG/MET combination therapy compared with MET or RSG monotherapy. The primary end point was change in A1c from baseline to week 32. Secondary end points included the proportion of patients achieving recommended A1c and FPG targets for glycaemic control and change from baseline in FPG, free fatty acid, lipids, insulin, insulin sensitivity, C-reactive protein and adiponectin. Safety evaluations included adverse-event (AE) monitoring, changes in weight and clinical laboratory evaluations. RESULTS: At week 32, RSG/MET showed significant improvements in A1c from a baseline of 8.9 +/- 1.1% to 6.6 +/- 1.0% at study end, and this 2.3% reduction was significantly greater than the reductions achieved individually with MET (-1.8%; p = 0.0008) and RSG (-1.6%; p < 0.0001). The greatest mean decrease in FPG was seen with RSG/MET (-4.1 mmol/l) and was significant compared with MET (-2.8 mmol/l; p < 0.0001) and RSG (-2.6 mmol/l; p < 0.0001). Target A1c of less than or equal to 6.5% and less than 7% were achieved in more patients in the RSG/MET group (60% and 77%) than with MET (39% and 57%) or RSG (35% and 58%) respectively. Treatment was well tolerated, with nausea, vomiting and diarrhoea as the most commonly reported AEs. Oedema was comparable between RSG/MET (6%) and RSG (7%) and lower in the MET group (3%). No new safety and tolerability issues were observed in the RSG/MET group. CONCLUSIONS: As first-line therapy in patients with uncontrolled type 2 diabetes, RSG/MET fixed-dose combination therapy achieved significant reductions in A1c and FPG compared with either RSG or MET monotherapy. RSG/MET was generally well tolerated as initial therapy, with no new tolerability issues identified with the fixed-dose combination.     

The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus

Aims: This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed‐dose combination of sitagliptin and metformin versus metformin monotherapy in drug‐naive patients with type 2 diabetes. Methods: This double‐blind study (18‐week Phase A and 26‐week Phase B) randomized 1250 drug‐naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. Results: At week 18, mean change from baseline HbA1c was ?2.4% for sitagliptin/metformin FDC and ?1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (?3.8 mmol/l) versus metformin monotherapy (?3.0 mmol/l; p < 0.001). Homeostasis model assessment of β‐cell function (HOMA‐β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. Conclusion: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea.     

Higher mortality of patients on haemodialysis with pancreatic diabetes compared to type 2-diabetes

ABSTRACT: In rare cases (1-8%) diabetic patients with end-stage renal disease (ESRD) suffer from diabetic nephropathy (dNP) due to pancreatic diabetes mellitus (PDM). Aim of this study was to investigate differences in the outcome of patients with PDM and those with type 2 diabetes.In a retrospective study we evaluated 96 diabetic patients, who started hemodialysis (HD) in our dialysis centre (1997-2005). In 12 patients PMD was diagnosed, and 84 patients had type 2 diabetes. In both groups we compared vascular risk factors and prevalence of vascular diseases at the start of dialysis. We also evaluated incidence of malnutrition, and 5-year survival in both patient groups.The vascular risk factors were similar in both patient groups, also the prevalence of vascular diseases at the initiation of HD was similar in both groups. In the patients with PDM the mean BMI (kg/m2) was lower (22 + 3 versus 25 + 3), and also their serum albumin was lower (2.7 + 0.3 versus 3.4 + 0.3 g/dl, p < 0.05). Four of these patients (33%) developed malnutrition (BMI < 18.5). In the patients with PDM the age adjusted 5-year survival was significantly lower (8% versus 27%, p < 0.05) than in the type 2 diabetic patients.Conclusions in HD-treated patients with type 2 diabetes or PDM the prevalence of vascular diseases was not significantly different. The lower survival of PDM patients can be related to poor nutrition status.     

2型糖尿病胰岛素治疗的时机

早期胰岛素强化治疗控制血糖,通过减轻糖毒性、脂毒性以及控制炎症,可以改变糖尿病并发症的自然病程,具有持久益处.因此,现在对于2型糖尿病胰岛素治疗的理念已经发生了很大变化,特别是对于诱导病情缓解和口服用药失效的2型糖尿病患者;为尽早和尽可能使血糖达标及恢复β细胞功能,应尽早启用胰岛素治疗.     

Improved endothelial function with metformin in type 2 diabetes mellitus

OBJECTIVES: This study was designed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus. BACKGROUND: Abnormalities in vascular endothelial function are well recognized among patients with type 2 (insulin-resistant) diabetes mellitus. Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction. The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported. METHODS: Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks. Before and after treatment, blood flow responses to intraarterial administration of endothelium-dependent (acetylcholine), endothelium-independent (sodium nitroprusside) and nitrate-independent (verapamil) vasodilators were measured using forearm plethysmography. Whole-body insulin resistance was assessed on both occasions using the homeostasis model (HOMA-IR). RESULTS: Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p = 0.0027 by 2-way analysis of variance), whereas no significant effect was seen on nitroprusside-stimulated (p = 0.27) or verapamil-stimulated (p = 0.40) flows. There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p = 0.01), and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment (r = -0.659, p = 0.0012). CONCLUSIONS: Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.