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Monami M.,Careggi Teaching Hospital | Dicembrini I.,Obesity Agency | Antenore A.,Careggi Teaching Hospital | Mannucci E.,Diabetes Agency
Diabetes Care | Year: 2011

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. © 2011 by the American Diabetes Association.


Monami M.,Careggi Teaching Hospital | Dicembrini I.,Obesity Agency | Mannucci E.,Diabetes Agency
Acta Diabetologica | Year: 2014

Recent epidemiological data have contributed to the formulation of the hypothesis about the long-term safety of pioglitazone, a thiazolidinedione (TZD), with respect to malignancies, in particular bladder cancer. The primary aim of this meta-analysis of randomized clinical trials, not designed a priori to test this hypothesis, was to explore whether TZDs affect the risk of cancer. A meta-analysis was performed including published and unpublished randomized trials with a duration of at least 52 weeks, enrolling patients with or without diabetes, comparing TZDs with either placebo or other drug therapies on various different outcomes. We found 22 trials reporting at least one cancer and enrolling 13,197 patients to TZD (pioglitazone: n = 3,710 and rosiglitazone: n = 9,487) and 12,359 to placebo or active comparator groups. The mean follow-up was 26.1 months. Overall, those assigned at random to TZDs had a significant reduction (MH-OR 0.85 [0.73-0.98]; p = 0.027) in the incidence of malignancies, with no significant difference in effect between pioglitazone and rosiglitazone. Specifically, subgroup analyses showed a significant reduction for rosiglitazone (MH-OR 0.82 [0.69-0.98]; p = 0.029), but not for pioglitazone (MH-OR 0.66 [0.34-1.28]; p = 0.22). In further subgroup analyses of site-specific malignancies based on the data from four trials, the risk of bladder cancer with pioglitazone (MH-OR) was 2.05 [0.84-5.02]; p = 0.12. Further, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk of bowel cancer. In contrast, pioglitazone, but not rosiglitazone, was associated with a significant reduction in breast cancer. The present meta-analysis of trials, not designed a priori to test the hypothesis, provides reassuring evidence that TZDs are not associated with risk of overall malignancies. In fact, they are compatible with the possibility of a decreased risk of cancer. In site-specific subgroup analyses, for rosiglitazone, there was a significant decreased risk of bowel cancer. Subgroup analyses for pioglitazone did not allow to exclude an increased risk of bladder cancer, while the risk of breast cancer was significantly decreased. While these data are also useful to formulate not test hypotheses, they provide somewhat more cogent evidence than the previously published epidemiological data. © 2013 Springer-Verlag Italia.


Monami M.,Careggi Teaching Hospital | Ahren B.,Lund University | Dicembrini I.,Obesity Agency | Mannucci E.,Diabetes Agency
Diabetes, Obesity and Metabolism | Year: 2013

Aims: Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major cardiovascular events (MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. Methods: A comprehensive search for published and unpublished trials with a duration ≥24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. Results: A total of 70 trials, enrolling 41959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MH-OR (95% Confidence Interval) was 0.71[0.59;0.86], 0.64[0.44;0.94], 0.77[0.48;1.24] and 0.60[0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. Conclusions: Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms. © 2012 Blackwell Publishing Ltd.


Monami M.,Careggi Teaching Hospital | Dicembrini I.,Obesity Agency | Dicembrini I.,Diabetes Agency | Mannucci E.,Diabetes Agency
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2014

Background & aims: Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus - Thrombolysis in Myocardial Infarction-53) reported a significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with placebo. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4. Methods & results: Data sources: An extensive Medline, Embase, and Cochrane Database search for "vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and "dutogliptin" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. Studies were included if they satisfied the following criteria: i) randomized trials, ii) duration ≥24 weeks; iii) on type 2 diabetes; iv) comparison of DPP4i with placebo or active drugs. The principal outcome was the effect of DPP4i on the incidence of acute heart failure. A total of 84 eligible trials was identified. The overall risk of acute heart failure was higher in patients treated with DPP4i in comparison with those treated with placebo/active comparators (MH-OR: 1.19[1.03; 1.37]; p=0.015). When trials with non-cardiovascular outcomes were analysed separately no signal of risk was detectable. Conclusion: Available data from RCTs suggest that DPP4i could be associated with an increased risk of heart failure, without any clear evidence of differences among drugs of the class. Although it is plausible that the risk is greater in some sub-populations of patients, current evidence is not yet sufficient to identify susceptible patients. © 2014 Elsevier B.V.


Monami M.,Careggi Teaching Hospital | Dicembrini I.,Obesity Agency | Dicembrini I.,Diabetes Agency | Mannucci E.,Diabetes Agency
Diabetes, Obesity and Metabolism | Year: 2014

Aim: Some observational studies reporting an increased risk of pancreatitis in association with Dipeptidyl Peptidase-4 inhibitors (DPP4i) have raised concerns on the overall safety of this class. Aim of the present meta-analysis is the systematic collection of information on pancreatitis in randomized clinical trials with DPP4i. Methods: Data Sources: an extensive Medline, Embase and Cochrane Database search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin' and 'dutogliptin' was performed up to 1 March 2013. Study Selection: studies were included if they satisfied the following criteria: (i) randomized trials, (ii) duration ≥12weeks, (iii) on type 2 diabetes and (iv) comparison of DPP4i with placebo or active drugs. The identification and the selection of studies, and the subsequent data extraction were performed independently by two authors. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all the adverse events defined below. The principal outcome was the effect of DPP4i on the incidence of pancreatitis. Results: A total of 134 eligible trials were identified. The overall risk of pancreatitis and pancreatic cancer was not different between DPP4i and comparators (MH-OR: 0.93[0.51-1.69]; p=0.82). Conclusions: It should be recognized that the number of observed cases of incident pancreatitis is small and the confidence intervals of risk estimates are wide. However, the present meta-analysis do not suggest any increase in the risk of pancreatitis with DPP4i. © 2013 John Wiley & Sons Ltd.


Monami M.,Careggi Teaching Hospital | Genovese S.,Diabetes and Metabolic Diseases Unit | Mannucci E.,Diabetes Agency
Diabetes, Obesity and Metabolism | Year: 2013

Aim: Cardiovascular safety of sulfonylurea has been questioned by some authors. This article aims at collecting all available data on this issue from randomized trials. Methods: A meta-analysis was performed including all trials with a duration of at least 6months, comparing a sulfonylurea with a non-sulfonylurea agent in type 2 diabetes. Major cardiovascular events (MACE) and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR). Results: Of the 115 selected trials, 62 reported information on MACE, and 30 reported at least one event. MH-OR for sulfonylurea was 1.08 [0.86-1.36], p=0.52 (1.85 [1.20-2.87], p=0.005, in the five trials vs. DPP4 inhibitors, no significant differences vs. other comparators). The MH-OR for myocardial infarction and stroke was 0.88 [0.75-1.04], p=0.13 and 1.28 [1.03-1.60], p=0.026, respectively. Mortality was significantly increased with sulfonylureas (MH-OR: 1.22 [1.01-1.49], p=0.047). Conclusions: In type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of MACE appears to be unaffected. Significant differences in cardiovascular risk could be present in direct comparisons with specific classes of glucose-lowering agents, such as DPP4 inhibitors, but this hypothesis needs to be confirmed in long-term cardiovascular outcomes trials. The results of this meta-analysis need to be interpreted with caution, mainly because of limitations in trial quality and under-reporting of information on cardiovascular events and mortality. However, the cardiovascular safety of sulfonylureas cannot be considered established unless it is evaluated in long-term cardiovascular outcomes trials. © 2013 John Wiley & Sons Ltd.


Monami M.,Careggi Teaching Hospital | Nardini C.,Careggi Teaching Hospital | Mannucci E.,Diabetes Agency
Diabetes, Obesity and Metabolism | Year: 2014

Aims: Sodium glucose co-transport-2 (SGLT-2) inhibitors, a new class of glucose-lowering agents, reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. The aim of the present meta-analysis is the assessment of the overall efficacy and safety profile of these drugs. Methods: A meta-analysis was performed including all trials with a duration of at least 12weeks, comparing a SGLT-2 inhibitor with a non-SGLT-2 inhibitor agent in type 2 diabetes. The principal outcome of this analysis was the effect of SGLT-2 inhibitors on HbA1c at 12, 24 and 52weeks. Hypoglycaemia, genital and urinary infections were retrieved and combined to calculate Mantel-Haenszel odds ratio (MH-OR). Furthermore, data on body mass index (BMI), endpoint fasting plasma glucose, systolic and diastolic blood pressure, creatinine, hematocrit and lipid profile were collected. Results: Among placebo-controlled trials, HbA1c reduction at 12, 24 and 52weeks was 0.5 [0.4; 0.6], 0.6 [0.6; 0.5] and 0.6 [0.7; 0.5]%. In placebo-controlled studies, 24-week reduction of HbA1c with SGLT-2 inhibitors was greater in trials enrolling patients with a lower mean age and duration of diabetes, and a higher baseline BMI, HbA1c and fasting glucose. In placebo-controlled trials, SGLT-2 inhibitors determined a weight loss during the first 24weeks, which was maintained up to 52weeks. Conclusions: SGLT-2 inhibitors are effective in the treatment of type 2 diabetes, providing additional benefits, such as weight loss, reduction of blood pressure and increase in high-density lipoprotein (HDL)-cholesterol. Apart from genital and urinary infections, rather frequent but usually mild, SGLT-2 inhibitors appear to be well tolerated. © 2013 John Wiley & Sons Ltd.


Rotella F.,Diabetes Agency | Mannucci E.,Diabetes Agency
Journal of Clinical Psychiatry | Year: 2013

Objective: The present meta-analysis aimed to assess the risk of incident diabetes associated with clinical depression, depressive symptoms, or both in nondiabetic subjects. Data Sources: We performed a MEDLINE search for studies published in the English language using the search string diabetes AND (depression OR antidepressant). The search included studies from any date to December 30, 2011. Study Selection: 1,898 studies were independently assessed for eligibility, and longitudinal studies that assessed the risk of incident diabetes in subjects with or without clinical depression were selected. Data Extraction: Study design and characteristics were verified for each study. A meta-analysis was performed for unadjusted and adjusted risk ratios of incident diabetes in subjects with depression by using a random-effects model. Additional analyses were performed to assess heterogeneity, publication bias, and specific hazard ratios for diabetes associated with antidepressant drug use. Results: The 23 studies included in the metaanalysis enrolled 424,557 subjects, with a mean follow-up of 8.3 years and 19,977 cases of incident diabetes. A higher incidence of diabetes was found in depressed versus nondepressed subjects (0.72% vs 0.47% yearly), with unadjusted and adjusted risk (95% CI) of 1.56 (1.37-1.77) and 1.38 (1.23-1.55), respectively (both P values < .001). The use of antidepressant drugs and untreated depression were associated with an adjusted risk of diabetes of 1.68 (1.17-2.40) (P = .005) and 1.56 (0.92-2.65) (P = .09). Conclusions: Depressive symptoms are associated with a significantly increased risk for incident diabetes. This association cannot be entirely explained by the use of antidepressant drugs or being overweight. Pathogenetic mechanisms connecting depression with diabetes deserve further exploration. Depression should be included among risk factors that indicate intensified screening for diabetes. © 2012 copyright physicians postgraduate press, Inc.


Deacon C.F.,Copenhagen University | Mannucci E.,Diabetes Agency | Ahren B.,Lund University
Diabetes, Obesity and Metabolism | Year: 2012

Aims: During recent years, two strategies of incretin-based therapy [glucagon-like peptide-1 (GLP-1) receptor agonism and dipeptidyl peptidase-4 (DPP-4) inhibition] have entered the market for pharmacological management of type 2 diabetes. A main indication for this therapy is as add-on to on-going metformin therapy in subjects with type 2 diabetes who have insufficient glycaemic control with metformin alone. The aim of this study was to compare improvements in glycaemic control and changes in body weight, as well as adverse events, in comparable studies with incretin-based therapy as add-on to metformin. Methods: Studies having a duration of 16-30 weeks were identified from PubMed. Results: A total of 27 study groups in 21 studies fulfilled the criteria of examining incretin-based therapy as add-on to metformin at clinically recommended doses in patients with type 2 diabetes for 16-30 weeks; 7 of these used a short-acting GLP-1 receptor agonist (exenatide BID), 7 used longer acting GLP-1 receptor agonists (liraglutide or exenatide LAR), whereas 14 studies examined DPP-4 inhibitors. In all studies, incretin-based therapy reduced HbA1c concentrations. The reduction in HbA1c was significantly greater in study groups with long-acting GLP-1 receptor agonists than with the other two groups (both p < 0.001), whereas there were no differences between exenatide BID and DPP-4 inhibitors. Across all study groups, there was a negative linear correlation between baseline HbA1c and change in HbA1c (r = -0.70; p < 0.001). Fasting glucose also fell significantly more in study groups given liraglutide or exenatide LAR than in those given exenatide BID or DPP-4 inhibitors (both p < 0.001). Furthermore, body weight was reduced by a similar extent in the two groups with GLP-1 receptor agonists and was not significantly altered in the groups with DPP-4 inhibitors. Lipids, blood pressure and heart rate were not reported consistently, which did not allow general conclusions. Adverse events were rare, apart from increased incidence of nausea and vomiting with GLP-1 receptor agonists. Conclusion: Incretin-based therapy efficiently improves glycaemia when added to metformin in patients with type 2 diabetes, and within 16-30 weeks there is a more pronounced reduction in HbA1c with long-acting GLP-1 receptor agonists (liraglutide and exenatide LAR) than with exenatide BID and DPP-4 inhibitors, although the magnitude of the effect is dependent on the baseline values. Both strategies appear to be associated with a very low risk of adverse events, including hypoglycaemia. Finally, the injectable GLP-1 receptor agonists also reduce body weight (whereas the DPP-4 inhibitors are weight neutral) but are also associated with a greater incidence of gastrointestinal side effects and a tendency to increase heart rate. © 2012 Blackwell Publishing Ltd.


Rotella F.,Diabetes Agency | Mannucci E.,Diabetes Agency
Diabetes Research and Clinical Practice | Year: 2013

Aim: The present meta-analysis is aimed at the assessment of the risk of incident clinical depression and/or depressive symptoms in patients with diabetes. Methods: A Medline search was performed on December 30th, 2011, using the search string: "diabetes AND (depression OR antidepressant)", selecting longitudinal studies that assessed the risk of incident depression in subjects with or without diabetes. Study design and characteristics were verified for each study. A meta-analysis was performed for unadjusted and adjusted risk ratios of incident depression in subjects with diabetes using a random effect model. Additional analyses were performed to assess heterogeneity, publication bias and specific hazard ratios for several possible confounders. Results: Of the 1898 retrieved studies, 16 were included in the meta-analysis, enrolling 497,223 subjects, with a mean follow-up of 5.8 years and 42,633 cases of incident depression. A higher incidence of depression was found in diabetic subjects (1.6% vs 1.4% yearly), with unadjusted and adjusted risk [95% confidence interval] of 1.29 [1.18-1.40] (p< 0.001) and 1.25 [1.10-1.44] (p= 0.001), respectively. Conclusions: Diabetes is associated with a significantly increased risk for depressive symptoms. Pathogenetic mechanisms connecting diabetes with depression deserve further exploration. © 2012 Elsevier Ireland Ltd.

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