Edoardo Mannucci

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 Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov, Food and Drug Administration, and European Medicines Agency website.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.

Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases

Hypogonadism, erectile dysfunction (ED), visceral adiposity, insulin resistance and metabolic syndrome (MetS) often coexist in the same subjects. This cluster of abnormalities is associated with an increased risk of diabetes and cardiovascular diseases (CVD), affecting not only quality of life but also life expectancy. Longitudinal studies have also demonstrated that ED and male hypogonadism could be considered surrogate markers of incident CVD and MetS. However, how androgens signal fat depots and lessen them is still a matter of active research and whether or not low testosterone could play a pathogenetic role in CVD is still under debate. Hence, pathogenetic mechanisms linking hypogonadism with obesity and insulin resistance appear to be complex and often multi-directional. Visceral obesity can probably be considered a relevant cause of hypogonadism but at the same time, hypogonadism could be a cause of obesity and insulin resistance, consequently establishing a vicious cycle. To provide a critical analysis of these issues, a comprehensive literary search was carried out to discuss the relationship between insulin resistance ED, visceral adiposity, MetS and hypogonadism focusing on their possible involvement in the development of CVD.

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.

Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.

Introduction: Recent reports have significantly halted the enthusiasm regarding androgen-boosting; suggesting that testosterone supplementation (TS) increases cardiovascular (CV) events. Areas covered: In order to overcome some of the limitations of the current evidence, the authors performed an updated systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCTs) on the effect of TS on CV-related problems. Out of 2747 retrieved articles, 75 were analyzed, including 3016 and 2448 patients in TS and placebo groups, respectively, and a mean duration of 34 weeks. Our analyses, performed on the largest number of studies collected so far, indicate that TS is not related to any increase in CV risk, even when composite or single adverse events were considered. In RCTs performed in subjects with metabolic derangements a protective effect of TS on CV risk was observed. Expert opinion: The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease.

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.

Structured interview on erectile dysfunction (SIEDY © ): a new, multidimensional instrument for quantification of pathogenetic issues on erectile dysfunction

The aim of the present study is the definition of a brief structured interview (SI) providing scores useful for identification and quantification of pathogenetic factors of erectile dysfunction (ED). A SI was developed and applied to a consecutive series of 320 ED patients. A 13-item SI, with three-factor analysis-derived scales, was identified and applied for validation to an independent consecutive series of 194 ED patients. PGE1 (10 μg) intracavernosal injection, penile duplex ultrasound (PDU), blood hormones, PSA, glycemia, and lipids were used for the assessment of an organic component (OC), and Middlesex Hospital Questionnaire (MHQ) modified for psychological disturbances. Scale 1, dealing with OC, showed a positive correlation with age, BMI, blood pressure, glycemia, and inverse correlation, with testosterone, PGE1 and several parameters derived from PDU. Scale 2, related to partners relationship, was not correlated with organic parameters. Scale 3, which measures psychopathological traits was correlated with MHQ scales. Scale 1 (>3) had a sensitivity of 67.9% and a specificity of 67.6% for OC. SIEDY© provides information on ED pathogenesis and might assist physicians in diagnostic and therapeutic choices.

Quality of life and overweight: the obesity related well-being (Orwell 97) questionnaire.

The development and validation of a self-reported measure of obesity-related quality of life, the Obesity Related Well-Being (ORWELL 97), were undertaken to examine the intensity and the subjective relevance of physical and psychosocial distress. The questionnaire was validated in a sample of 147 obese patients (99 females, 48 males). The Eating Disorder Examination 12.0D interview, a structured diagnostic interview for DSM-III-R (DSM-IV criteria for binge eating disorder), Beck Depression Inventory, Binge Eating Scale, and the State-Trait Anxiety Inventory 1 and 2 scales were also applied. Internal consistency and test-retest reliability were satisfactory. Factor analysis allowed the identification of two subscales: ORWELL 97-1 related to psychological status and social adjustment, and ORWELL 97-2 related to physical symptoms impairment. Obese female patients showed a lower quality of life, and the severity of obesity appeared to interfere with physical functioning rather than psychological status and social adjustment. The ORWELL 97 questionnaire appears to be a simple and reliable measure of obesity-related quality of life, which can be used in current clinical practice.

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.