Matteo Monami

Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials

Aim: Some studies suggested that metformin could reduce cardiovascular risk to a greater extent than that determined by glucose reduction. Aim of the present meta‐analysis is to assess the effects of metformin on the incidence of cardiovascular events and mortality.

Safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of randomized clinical trials

Abstract Objective: Dipeptidyl peptidase-4 inhibitors (DPP4i) have been recently associated with increased risk of pancreatitis and cancer. The aim of the present meta-analysis of randomized clinical trials is the assessment of the effect of DPP4i on the incidence of major cardiovascular events (MACE), cancer, and pancreatitis. Research design and methods: An extensive Medline and Embase search for ‘vildagliptin’, ‘sitagliptin’, ‘saxagliptin’, ‘alogliptin’, ‘linagliptin’, and ‘dutogliptin’ was performed, collecting all randomized clinical trials on humans up to March 1, 2011. The present meta-analysis was therefore performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP4i with either placebo or active drugs. Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov, Food and Drug Administration, and European Medicines Agency website. Results: Fifty-three trials enrolling 20,312 and 13,569 patients for DPP4i and comparators, respectively, were included, reporting 176 malignancies, 257 MACE, and 22 pancreatitis. DPP4i, compared with placebo or other treatment, were associated with a similar risk of cancer (MH-OR 1.020 [0.742–1.402]; p = 0.90) and pancreatitis (0.786 [0.357–1.734], p = 0.55), and with a reduced risk of MACE (MH-OR 0.689 [0.528–0.899], p = 0.006). Conclusions: The present meta-analysis seems to exclude any relevant short term effect of DPP4i on the incidence of cancer and suggest a possible protection from cardiovascular events. This result should be interpreted with caution, as those events were not the principal endpoint, the trial duration was short, and the characteristics of patients included could be different from routine clinical practice.

Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials

BACKGROUND AND AIMS Randomized clinical trials (RCTs) aimed at the assessment of the efficacy of lowering blood glucose in the prevention of diabetic complications have always failed to detect a significant effect on cardiovascular events. Aim of this meta-analysis is the assessment of the effects of improvement of glycemic control on the incidence of cardiovascular diseases in patients with type 2 diabetes. METHODS The RCTs were included in this meta-analysis if: a) the between-group difference in mean HbA1c during the trial was at least 0.5%, b) they had a planned duration of treatment of at least 3 years, c) if they had a cardiovascular endpoint. Data for analysis were extracted independently by two observers and potential contrasts were resolved by a senior investigator. RESULTS Five studies (17,267 and 15,362 patients in the intensive and conventional therapy groups, respectively) were included. Intensive treatment, which reduced mean HbA1c by 0.9% on average, was associated with a significant reduction of incident cardiovascular events and myocardial infarction (OR 0.89 [0.83-0.95] and 0.86 [0.78-0.93], respectively), but not of stroke or cardiovascular mortality (OR 0.93 [0.81-1.07] and 0.98 [0.77-1.23], respectively). In meta-regression analysis, a higher BMI duration of diabetes, and incidence of severe hypoglycaemia were associated with greater risk for cardiovascular death in intensive treatment groups. CONCLUSION Intensified hypoglycaemic treatment in type 2 diabetic patients leads to a significant reduction of the incidence of myocardial infarction, while it does not affect the incidence of stroke and cardiovascular mortality. Hypoglycemia induced by intensified treatment could be associated with increased cardiovascular mortality.

Dipeptidyl Peptidase-4 Inhibitors and Bone Fractures A meta-analysis of randomized clinical trials

OBJECTIVE Thiazolidinediones and insulin are associated with a higher risk of fractures in type 2 diabetic patients. Incretin hormones increase bone density in experimental models, but the effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on bone fractures has not been reported so far. RESEARCH DESIGN AND METHODS A meta-analysis was performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 inhibitors with placebo or active drugs. RESULTS Twenty-eight trials enrolling 11,880 and 9,175 patients for DPP-4 inhibitors and comparators, respectively, were included, reporting 63 fractures. DPP-4 inhibitors, compared with placebo or other treatments, were associated with a reduced risk of fractures (Mantel–Haenszel odds ratio [MH-OR] 0.60, 95% CI 0.37–0.99, P = 0.045), even after the exclusion of comparisons with thiazolidinediones or sulfonylureas (MH-OR 0.56, 0.33–0.93, P = 0.026). CONCLUSIONS The present meta-analysis suggests that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures.

Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis.

Aim:  Basal insulin in type 1 diabetes can be provided using either NPH (Neutral Protamine Hagedorn) human insulin or long‐acting insulin analogues, which are supposed to warrant a better metabolic control with reduced hypoglycaemic risk. Aim of this meta‐analysis is the assessment of differences with respect to HbA1c (Glycated hemoglobin), incidence of hypoglycaemia, and weight gain, between NPH human insulin and each long‐acting analogue.

Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials.

BACKGROUND AND AIM The role of Dipeptidyl Peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information. METHODS AND RESULTS All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with DPP-4 inhibitors, with a duration >12 weeks were meta-analyzed for HbA1c, BMI, hypoglycemia, and other adverse events. A total of 41 RCTs (9 of which are unpublished) was retrieved and included in the analysis. Gliptins determine a significant improvement of HbA1c in comparison with a placebo (-0.7 [-0.8:-0.6]), with a low risk of hypoglycemia. DPP-4 inhibitors show a similar efficacy in monotherapy and in combination with other agents. The risk of cardiovascular events and all-cause death with DPP-4 inhibitors is 0.76 [0.46-1.28] and 0.78 [0.40-1.51], respectively. CONCLUSIONS DPP-4 inhibitors reduce HbA1c, although to a lesser extent than sulphonylureas, with no weight gain and no hypoglycemic risk; further data are needed to assess their long-term safety.

Cardiovascular safety of sulfonylureas: A meta-analysis of randomized clinical trials

Cardiovascular safety of sulfonylurea has been questioned by some authors. This article aims at collecting all available data on this issue from randomized trials.

Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: A meta-analysis

BACKGROUND Long-acting insulin analogues, in comparison with NPH insulin, should warrant a greater reproducibility of absorption after subcutaneous injection, providing better metabolic control with reduced hypoglycaemic risk. Aim of the present meta-analysis is the assessment of differences with respect to HbA1c, incidence of hypoglycaemia, weight gain, between NPH human insulin and each long-acting analogue. METHODS All randomized controlled trials (RCTs) with a duration >12 weeks comparing long-acting insulin analogues (detemir or glargine) with NPH insulin in type 2 diabetic patients were retrieved; data on HbA1c and BMI at endpoint, and incidence of any, symptomatic, nocturnal, and severe hypoglycaemia, were extracted and meta-analysed. RESULTS A total of 14 RCTs was retrieved and included in the analysis. Long-acting analogues did not produce any significant improvement of HbA1c, in comparison with NPH human insulin. When trials with different analogues were analysed separately, NPH showed a significant superiority (by 0.1%) over detemir, but not over glargine. When analysing the effect of long-acting analogues on body weight, detemir, but not glargine, was associated with a significantly smaller weight gain than human insulin Both analogues were associated with a reduced risk for nocturnal and symptomatic hypoglycaemia (OR: 0.46[0.38-0.55] and 0.69[0.60-0.80]; all p<0.01). CONCLUSIONS Long-acting insulin analogues in type 2 diabetic patients does not seem to provide a better glycemic control in comparison with NPH insulin, whereas it reduces the risk of nocturnal and symptomatic hypoglycemia. Detemir, but not glargine, could be associated with smaller weight gain than NPH insulin.

DPP-4 inhibitors and lipids: systematic review and meta-analysis.

IntroductionLipid profile is an important determinant of cardiovascular risk in type 2 diabetic patients. Available glucose-lowering agents can affect lipid levels. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to reduce total cholesterol, but results are inconsistent across trials. The present metaanalysis was designed to assess the effect of DPP-4 inhibitors on blood lipids, verifying possible differences across compounds of this class.MethodsAn extensive search of Medline and the Cochrane Library (any date up to December 31, 2010, restricted to randomized clinical trials, published in English) was performed for all trials containing, in any field, the words “sitagliptin,” “vildagliptin,” “saxagliptin,” “alogliptin,” “linagliptin,” and/or “dutogliptin.” Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website, using the same keywords as above. Differences in the endpoint levels and absolute or percent variations of lipids were assessed. A metaregression was performed on the trials specified above to assess the effect of putative moderators on the effect of DPP-4 inhibitors on plasma lipids, considering all drugs together and each one separately.ResultsAlthough the number of trials of appropriate size and duration was high (n=53), only a small fraction of those (n=17) reported data on endpoint total, high-density lipoprotein, and low-density lipoprotein cholesterol, and triglyceride. The difference-in-means for endpoint versus baseline total cholesterol in patients on DPP-4 inhibitors treatment was significantly higher in comparison with controls, meaning that treatment with DPP-4 inhibitors is associated with a significant reduction in total cholesterol (−0.18 [−0.29; −0.06] mmol/L (−7.0 [−11.2; −2.50] mg/dL); P=0.002).ConclusionsThis meta-analysis suggests a possible beneficial effect of DPP-4 inhibitors on cholesterol, which, although small, could contribute to the reduction of cardiovascular risk.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials.

New drugs for type 2 diabetes need to demonstrate their cardiovascular safety, due regulatory requirements from the Food and Drug Administration. For this reason, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) are currently undergoing large‐scale, long‐term randomized trials specifically designed for cardiovascular outcomes. Aim of the present meta‐analysis of randomized clinical trials is the assessment of the effects of GLP‐1 RA on major cardiovascular events (MACE), mortality and cardiovascular risk factors.