Search

Aims: To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes., Methods: A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow-up ≥52 weeks, in which glucose-lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All-cause mortality, 3-point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints., Results: We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha-glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl-peptidase-4 inhibitors (n = 67), glucagon-like peptide-1 receptor agonists (n = 45) or sodium-glucose co-transporter-2 inhibitors (SGLT-2i; n = 42) and insulin (n = 18). Glucagon-like peptide-1 receptor agonist and SGLT-2i were associated with a significant reduction in all-cause mortality [Mantel-Haenszel odds ratio (MH-OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH-OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT-2i was associated with a reduced risk of HHF [MH-OR 0.68 (0.62; 0.75)], worsening albuminuria [MH-OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH-OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH-OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH-OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all-cause mortality [MH-OR 1.12 (1.01; 1.24)] and MACE [MH-OR 1.19 (1.02; 1.39)]., Conclusions: The results of this updated meta-analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose-lowering drugs on long-term glycaemic control., (© 2022 John Wiley & Sons Ltd.)

Aim: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect., Data Synthesis: A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively)., Conclusions: This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF., Competing Interests: Declaration of competing interest MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. AG has received speaking fees and/or advisory board invitations from Abbott, Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, MSD, Mundipharma, Novo-Nordisk, Sanofi. BN was an employee of NovoNordisk. The other authors did not report any relevant conflicts of interest. All the authors approved the final version of this manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect., Data Synthesis: A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99)., Conclusions: This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF., Competing Interests: Declaration of competing interest MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. AG has received speaking fees and/or advisory board invitations from Abbott, Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, MSD, Mundipharma, Novo-Nordisk, Sanofi. The other authors did not report any relevant conflicts of interest. All the authors approved the final version of this manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE)., Data Synthesis: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05])., Conclusions: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions., Competing Interests: Declaration of competing interest MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. All the other authors have no conflict of interests to declare. All the authors approved the final version of the manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i., Data Synthesis: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure., Conclusions: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure., Competing Interests: Declaration of competing interest BN is presently an employee of Novo Nordisk; CM, MG, and AG have no conflicts of interest to declare; MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis, and research grants from Merck, Novartis, and Takeda. All the authors approved the final version of this manuscript. Dr. Matteo Monami is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: The Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes., Data Synthesis: A MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n = 13 RCTs; MH-OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH-OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n = 2 RCTs; MH-OR 0.52 [0.37, 0.73]), p < 0.001. Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH-OR: 0.57 [0.42, 0.76])., Conclusions: This updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs., Competing Interests: Declaration of competing interest MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; RC, BP, and GT has no relevant conflicts of interest to declare. EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. All the authors approved the final version of this manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aim: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs) and all-cause mortality as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin secretagogues (sulfonylureas and glinides) with this respect., Methods and Results: A MEDLINE database search was performed to identify all RCTs, up to January 1st, 2020, with duration≥52 weeks, in which insulin secretagogues (glibenclamide, gliclazide, glimepiride, glipizide, chlorpropamide, repaglinide, nateglinide) were compared with either placebo or active comparators. The principal endpoints were MACE (restricted for RCT reporting MACEs within their outcomes) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Fourteen RCTs were included in the analysis for MACEs (919 in insulin secretagogues and 1,087 in control group). Insulin secretagogues were not significantly associated with an increased risk of MACEs in comparison with controls (MH-OR 1.08 [95% CI 0.96, 1.22], p = 0.20). When considering the 48 RCTs fulfilling criteria for inclusion in the analysis on all-cause mortality, insulin secretagogues were associated with a significantly increased risk of all-cause mortality (MH-OR 1.11 [1.00, 1.23], p = 0.04)., Conclusions: This meta-analysis suggests that insulin secretagogues are associated with an increased risk of all-cause mortality when compared with placebo or other anti-hyperglycaemic drugs., Competing Interests: Declaration of Competing Interest EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; RC, BP, and GT has no relevant conflicts of interest to declare. All the authors approved the final version of this manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: To conduct a meta-analysis of cardiovascular outcome trials on the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major adverse cardiovascular events (MACE)., Methods: A search of MEDLINE, EMBASE, Cochrane database and clinicaltrials.gov was performed to identify controlled trials (up to 15 June 2019) of GLP-1RAs with a cardiovascular endpoint. The principal endpoint of the present meta-analysis was MACE; secondary endpoints included myocardial infarction, stroke, cardiovascular and all-cause mortality, and hospitalization for heart failure. Mantel-Haenszel odds ratios (MH-ORs) with 95% confidence intervals (CIs) were calculated for all outcomes., Results: In the seven trials included, all placebo-controlled, GLP-1RA treatment was associated with a reduction in MACE (MH-OR 0.87 [95% CI 0.81, 0.93]). Cardiovascular and all-cause mortality, myocardial infarction and stroke were also reduced (MH-OR 0.88 [95% CI 0.80, 0.96], MH-OR 0.90 [95% CI 0.82, 0.98], MH-OR 0.91 [95% CI 0.84, 0.98] and MH-OR 0.86 [95% CI 0.77, 0.97], respectively). Results for hospitalization for heart failure were not statistically significant (MH-OR 0.93 [95% CI 0.83, 1.04]). The meta-analyses of patient subgroups showed a significant reduction in MACE with GLP-1RAs, irrespective of gender, advanced age and obesity., Conclusions: GLP-1RAs are associated with a reduction in cardiovascular morbidity and mortality in high-risk patients with diabetes. This effect does not appear to be moderated by gender or body mass index. The possibility of different effects of GLP-1RAs between patients in primary and secondary prevention merits further investigation., (© 2019 John Wiley & Sons Ltd.)

Background and Aim: The interpretation of discrepancies across cardiovascular safety trials (CVOT) with SGLT-2 inhibitors in the incidence of major cardiovascular events (MACE) and mortality is complex, because of heterogeneity in trial protocols and baseline characteristics of patients enrolled. Aim of this analysis is the exploration of possible determinants of heterogeneity of relative risk reduction for major cardiovascular events (MACE) and all-cause mortality., Methods and Results: Incidence of events (MACE and mortality) in intervention and control groups and baseline characteristics of patients were extracted for each trial (EMPAREG, CANVAS, and DECLARE). For studies including both primary and secondary prevention cohorts, those two subgroups were considered separately. Metaregression analysis was used to assess the association of relative risk reduction with baseline characteristics of patients, including observed incidence of events with placebo. The estimated reduction in the incidence of MACE associated with SGLT-2 inhibitors showed a significant association with the incidence of MACE in the control group, suggesting that a greater effect was observed in trials enrolling patients at higher risk (Slope -0.008 [-0.023; 0.007], p = 0.31). A higher proportion of patients treated with statins, β-blockers and insulin at baseline was associated with a greater reduction of MACE, but not of mortality., Conclusions: In CVOT trials, the magnitude of the effect of SGLT-2 inhibitors on MACE is driven by absolute risk of enrolled patients; as a consequence, the estimated risk reduction is lower in primary prevention cohorts, which have a lower risk. This result supports the hypothesis of a class effect of SGLT-2 inhibitors on MACE., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors bring about a wide reduction in low-density lipoprotein (LDL) cholesterol, greater than that of other lipid-lowering agents. The aim of this metanalysis was assessment of the effects of PCSK9 inhibitors on glucose metabolism, LDL cholesterol, cardiovascular morbidity and mortality in individuals with and without diabetes., Materials and Methods: A Medline and Clinicaltrials.gov search for eligible studies published before 1 December 2017 was performed. All randomized trials comparing PCSK-9 inhibitors with placebo or active drugs were included. Primary endpoints included (a) incident diabetes, fasting glucose and HbA1c, (b) LDL cholesterol at endpoint in patients with diabetes and in the total sample, and (c) major cardiovascular events (MACE) and mortality in individuals with and without diabetes., Results: A total of 38 trials was identified. The risk of incident diabetes was not increased by PCSK-9 inhibitors, vs placebo or any comparator. The reduction in LDL cholesterol vs placebo in patients with diabetes was 52.6 [41.3;63.8] mg/dL; the corresponding figure for all patients was 66.9 [62.4;71.3] mg/dL. Meta-regression analysis showed an inverse correlation between proportion of patients with diabetes and drug effect on LDL cholesterol in trials vs ezetimibe, but not in those vs placebo. In studies reporting data on MACE and mortality separately for individuals with and without diabetes, the effect of PCSK-9 did not appear to be affected by diabetes., Conclusion: PCSK-9 inhibitors do not affect glucose metabolism. Their efficacy on LDL cholesterol and MACE in patients with diabetes does not seem to be very dissimilar to that observed in non-diabetic participants., (© 2018 John Wiley & Sons Ltd.)

Background: Mortality in patients with type 2 diabetes and diabetic foot osteomyelitis (DFO) have been explored in few small studies with a short follow-up. Aim of the present study is to assess all-cause and cardiovascular mortality and predictors of mortality in a consecutive series of patients with DFO., Research Design and Methods: Patients with a diagnosis of DFO, attending the Diabetic Foot Unit of San Donato Hospital in Arezzo between January 1st, 2012 and December 31st, 2013, were included in this retrospective study. Information on all-cause mortality up to December 1st, 2016, was obtained from the registry of the Local Health Unit of Arezzo, which contains updated records of all persons living in Tuscany., Results: One hundred ninety-four patients were included in the study. During a mean period of observation of 2.8±1.4years, 73 (37.6%) died, with a yearly rate of 13.2%. Of the 73 deaths, 59 were attributable to cardiovascular causes. After adjusting for possible confounders in a Cox analysis, site of osteomyelitis (hindfoot vs mid/forefoot) was associated with a higher mortality, and surgical treatment with a lower mortality., Conclusions: Mortality in patients with DFO appears to be much higher than that reported in clinical series of patients with diabetic foot ulcers, particularly when hindfoot is affected., (Copyright © 2017. Published by Elsevier B.V.)

Introduction: The publication of the results of LEADER and SUSTAIN-6 trials suggested a possible beneficial effect of the class of GLP-1 receptor agonists on cardiovascular morbidity and mortality. The aim of the present meta-analysis is to collect and synthetize all available evidence on the effect of GLP-1 receptor agonists on cardiovascular events and mortality., Methods: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration >11weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The principal outcome of this analysis was the effect of GLP-1 receptor agonists on all-cause and cardiovascular mortality, overall (fatal plus nonfatal) myocardial infarction, stroke, and heart failure., Results: Out of 113 trials fulfilling inclusion criteria (mean duration 41.7±38.2weeks), 32, 25, 48, 43 and 32 reported at least one event for all-cause and cardiovascular mortality, overall (fatal plus nonfatal) myocardial infarction, stroke, and heart failure, respectively. In GLP-1 receptor agonist-treated patients, all-cause mortality, cardiovascular mortality, and myocardial infarction were significantly lower than in comparators (MH-OR [95% CI] 0.88 [0.79-0.97], p=0.015, 0.84 [0.74-0.96], p=0.009, and 0.90 [0.80-1.00], p=0.050, respectively), whereas no beneficial effect was observed for stroke and heart failure (MH-OR [95% CI] 0.90 [0.81-1.00]. p=0.059. 0.89 [0.76-1.04]. p=0.15. and 0.92 [0.81-1.06]. p=0.25. respectively)., Conclusions: Overall, the agents of this class appear to reduce all-cause mortality, cardiovascular mortality, and the incidence of myocardial infarction at mid-term follow up., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: EMPAREG OUTCOME study showed a reduction in cardiovascular events in patients treated with the sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin, as compared to placebo. Other drugs of the same class are currently been investigated for cardiovascular outcomes. In the meanwhile, a re-analysis of data collected in available studies can add relevant insight., Methods: A MEDLINE search for SGLT-2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials up to November 16, 2015. All trials with a duration of treatment ≥12 weeks, enrolling patients with type 2 diabetes, comparing a SGLT2i with placebo or other comparators were included. The principal outcome was the effect of SGLT2i on all-cause and cardiovascular mortality. Secondary endpoints were myocardial infarction and stroke. Mantel-Haenszel odds ratio with 95 % confidence interval (MH-OR) was calculated., Results: A total of 71 trials were included (31,199 and 16,088 patients in SGLT2i and comparator groups). Treatment with SGLT2i was associated with a significant reduction in all-cause mortality (MH-OR 0.70 [0.59-0.83], p < 0.001), cardiovascular mortality (MH-OR 0.43 [0.36-0.53], p < 0.001), and myocardial infarction (MH-OR 0.77 [0.63-0.94], p < 0.01), but not stroke (MH-OR 1.09 [0.86-1.38], p = 0.50), with no apparent difference across molecules (after excluding cardiovascular outcome trials)., Conclusions: Available data suggest that the beneficial action observed with empagliflozin on all-cause and cardiovascular mortality in EMPAREG OUTCOME study is a class effect. The present meta-analysis showed a significantly reduction in myocardial infarction, with no increased risk of stroke.

Diabetes mellitus is one of the most important causes of cardiovascular morbidity and mortality; the incidence of chronic complications of diabetes appears to be closely related to the degree of hyperglycaemia. However, results of clinical trials showed that intensive treatment of hyperglycaemia prevents microvascular complications, but has little or no effect on the incidence of cardiovascular events. Different hypoglycaemic drugs show different effects on cardiovascular risk. However, those trials have shown a neutral effect on cardiovascular mortality. This paradoxical result could be explained with the frequent use, in the past, of glucose-lowering agents capable of increasing the risk of hypoglicemia, glycemic variability and weight gain. In conclusion, an adequate glycemic control, in particular in elderly patients, should be achieved, whenever possible, using agents not inducing hypogycemia, glucose fluctuations, and weight gain. In fact, hypoglycaemia and glucose variability should be considered as independent cardiovascular risk factors to a similar extent to hyperglycemia. In this article, the author will review literature supporting the hypothesis that hyperglycemia, hypoglycaemia and glycemic variability are a fatal triad capable of increasing morbidity and mortality in patients with diabetes mellitus.

Introduction: The Atherosclerosis Risk in Communities (ARIC) algorithm is one of the most efficient instruments for the prediction of incident type 2 diabetes. Recently, it has been shown to predict another relevant cardiovascular (CV) risk factor, such as chronic kidney disease., Aim: To verify whether, in patients with erectile dysfunction (ED), the use of ARIC diabetes risk score might improve the efficacy in predicting major CV events of other CV risk algorithms specifically developed for the assessment of CV risk., Methods: A consecutive series of 2,437 men (mean age 52.5 ± 12.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study (mean follow-up of 4.3 ± 2.6 years)., Main Outcome Measures: The assessment of metabolic risk was evaluated with the ARIC algorithm. The assessment of CV risk was evaluated using the Progetto Cuore risk engine., Results: In the cross-sectional study, ARIC score was inversely related with testosterone levels, sexual functioning, and penile blood flow. When longitudinal sample was analyzed, higher baseline ARIC score significantly predicted major adverse cardiovascular event (MACE) even when subjects with diabetes mellitus at baseline were excluded from the analysis (hazard ratio = 1.522 [1.086-2.135]; P = 0.015 for trend). In addition, among subjects classified as "low risk" (CV risk <20% at 10 years corresponding to <9% at 4.3 years) by Progetto Cuore, a receiving operating curve (ROC) analysis for ARIC (vs. MACE) allowed the identification of a threshold of 0.22, which had a positive predictive value for 4.3-year MACE of 9%. Applying the ARIC score (with a threshold of 0.22) to Progetto Cuore "low-risk" subjects, we could classify as "at high risk" 89.8% of subjects with incident MACE vs. 79.6% with Progetto Cuore only., Conclusions: In patients with ED, identifying prediabetes, even with algorithms, predicts long-term CV events., (© 2013 International Society for Sexual Medicine.)

Introduction: Previous cross-sectional and longitudinal studies reported a negative correlation between fatherhood and testosterone (T) levels, likely due to a centrally mediated downregulation of the hypothalamic-pituitary-gonadal axis. Moreover, epidemiological data indicate that fatherhood might affect metabolic and cardiovascular outcomes, although different results have been reported. Up to now, no studies have evaluated these associations in a population of men seeking treatment for sexual dysfunction (SD)., Aim: To explore biological and clinical correlates of number of children (NoC) and its possible associations with forthcoming major cardiovascular events (MACE) in a sample of men with SD., Methods: A consecutive series of 4,045 subjects (mean age 52 ± 13.1 years old) attending the Outpatient Clinic for SD was retrospectively studied. A subset of the previous sample (N = 1,687) was enrolled in a longitudinal study., Main Outcome Measures: Information on MACE was obtained through the City of Florence Registry Office., Results: Among patients studied, 31.6% had no children, while 26.3% reported having one child, 33.4% two, and 8.8% three or more children. Although fatherhood was negatively related with follicle-stimulating hormone levels and positively with testis volume, we found a NoC-dependent, stepwise decrease in T plasma levels, not compensated by a concomitant increase in luteinizing hormone. NoC was associated with a worse metabolic and cardiovascular profile, as well as worse penile blood flows and a higher prevalence of metabolic syndrome (MetS). In the longitudinal study, after adjusting for confounders, NoC was independently associated with a higher incidence of MACE. However, when the presence of MetS was introduced as a further covariate, the association was no longer significant., Conclusions: This study supports the hypothesis that bond maintenance contexts and fatherhood are associated with an adaptive downregulation of the gonadotropin-gonadal axis, even in a sample of men with SD. Moreover, our data suggest that NoC predicts MACE, most likely because of an unfavorable, lifestyle-dependent, parenthood-associated behavior., (© 2012 International Society for Sexual Medicine.)

Introduction: Definitions of unfaithfulness and its consequences vary across different cultures, religions, and legal jurisdictions; however, having extramarital affairs is associated in most societies with a stigma. Therefore, the study of this sensitive topic is extremely complex, and its prevalence is often underestimated., Aim: To offer a summary of available data in literature about unfaithfulness., Method: An extensive Medline search was performed including the following words "unfaithfulness,""extramarital affairs,""infidelity,""men." The search, up to December 4, 2011, was restricted to English-language articles., Main Outcome Measures: We reported literature data on the prevalence of unfaithfulness and on related psychobiological, sexual, and risk factors., Results: Some surveys reported that 1.5-4% of married men had extramarital coitus in any given year, others that 23.2% of men have cheated during their current relationship. Different studies reported a lifetime prevalence of unfaithfulness between 15% and 50%. With respect to factors related to unfaithfulness, several authors reported that men with extramarital affairs more frequently have a dysfunctional primary relationship, in both relational and sexual terms. In addition, parenthood, as well as conflicts within the family, seem to be associated with a higher risk of having an affair. Furthermore, unfaithful men display a higher androgenization, larger testis volume, lower prevalence of hypoactive sexual desire, and better sexual functioning. Only few studies have evaluated the correlation between infidelity and cardiovascular risk, reporting that having an extramarital affair could have a negative impact on cardiac morbidity and mortality., Conclusions: Several interpersonal, sexual, and biological factors are associated with having extramarital affairs. Unfaithfulness in men seems to be associated with a higher risk of major cardiovascular events., (© 2012 International Society for Sexual Medicine.)

Introduction: Lipid 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., Methods: An 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., Results: Although 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)., Conclusions: This meta-analysis suggests a possible beneficial effect of DPP-4 inhibitors on cholesterol, which, although small, could contribute to the reduction of cardiovascular risk.

Introduction: Intracavernous alprostadil injection (ICI) test has been considered useless in assessing the vascular status of subjects with erectile dysfunction (ED)., Aim: To analyze the clinical correlates of ICI test in patients with ED and to verify the value of this test in predicting major adverse cardiovascular events (MACE)., Methods: A consecutive series of 2,396 men (mean age 55.9 ± 11.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study., Main Outcome Measures: Several clinical, biochemical, and instrumental (penile color Doppler ultrasound; PCDU) factors were evaluated. All patients underwent an ICI test, and responses were recorded on a four-point scale ranging from 1 = no response to 4 = full erection., Results: Among the patients studied, 16.4%, 41.2%, 40.2% and 2.2% showed grade 4, 3, 2, and 1 ICI test response, respectively. After adjusting for confounders, subjects with grade 1 ICI test response showed reduced perceived sleep-related, masturbation-related, and sexual-related erections when compared with the rest of the sample. In addition, a worse response to ICI test was associated with a higher prevalence of hypogonadism-related symptoms and signs along with lower testosterone levels. The prevalence of both diabetes mellitus and metabolic syndrome was inversely related to ICI test response. Accordingly, dynamic and basal peak systolic velocity (PSV), as well as acceleration at PCDU, decreased as a function of ICI test response. In the longitudinal study, after adjusting for confounders, grade 1 response was independently associated with a higher incidence of MACE (hazard ratio = 2.745 [1.200-6.277]; P < 0.05). These data were confirmed even when only subjects with normal PSV (>25 cm/s) were considered., Conclusions: Our results demonstrate that poor ICI test response is associated with several metabolic disturbances and higher incidence of MACE. We strongly recommend performing ICI test with alprostadil in all ED subjects., (© 2011 International Society for Sexual Medicine.)

Objective: To verify whether hypogonadism represents a risk factor for cardiovascular (CV) morbidity and mortality and to verify whether testosterone replacement therapy (TRT) improves CV parameters in subjects with known CV diseases (CVDs)., Design: Meta-analysis., Methods: An extensive Medline search was performed using the following words 'testosterone, CVD, and males'. The search was restricted to data from January 1, 1969, up to January 1, 2011., Results: Of the 1178 retrieved articles, 70 were included in the study. Among cross-sectional studies, patients with CVD have significantly lower testosterone and higher 17-β estradiol (E(2)) levels. Conversely, no difference was observed for DHEAS. The association between low testosterone and high E(2) levels with CVD was confirmed in a logistic regression model, after adjusting for age and body mass index (hazard ratio (HR)=0.763 (0.744-0.783) and HR=1.015 (1.014-1.017), respectively, for each increment of total testosterone and E(2) levels; both P<0.0001). Longitudinal studies showed that baseline testosterone level was significantly lower among patients with incident overall- and CV-related mortality, in comparison with controls. Conversely, we did not observe any difference in the baseline testosterone and E(2) levels between case and controls for incident CVD. Finally, TRT was positively associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression., Conclusions: Lower testosterone and higher E(2) levels correlate with increased risk of CVD and CV mortality. TRT in hypogonadism moderates metabolic components associated with CV risk. Whether low testosterone is just an association with CV risk, or an actual cause-effect relationship, awaits further studies.

Introduction: Obesity is an independent cardiovascular (CV) risk factor. Testosterone (T) is inversely related to body mass index (BMI) in males. There is substantial evidence suggesting that low T could play a role as a moderator of CV mortality in men., Aim: This study is designed to assess the possible interaction between T and obesity in predicting major CV events (MACE) in a sample of subjects with erectile dysfunction., Methods: A consecutive series of 1,687 patients were studied. Different clinical, biochemical, and instrumental parameters were evaluated. According to BMI, subjects were divided into normal weight (BMI = 18.5-24.9 kg/m(2) ), overweight (BMI = 25.0-29.9 kg/m(2) ), and obese (BMI ≥ 30.0 kg/m(2) ). Hypogonadism was defined as total T below 10.4 nmol/L. Information on MACE was obtained through the City of Florence Registry Office., Main Outcome Measures: Information on MACE was obtained through the City of Florence Registry Office., Results: Among the patients studied, 39.8% had normal weight, whereas 44.1% and 16.1% were overweight and obese, respectively. Unadjusted analysis in the whole sample showed that while hypogonadism and obesity were significantly associated with an increased risk of MACE, their interaction term was associated with a protective effect. In a Cox regression model, adjusting for confounders, hypogonadism showed a significant increased risk of MACE in normal weight subjects, whereas it was associated with a reduced risk in obese patients., Conclusions: Hypogonadism-associated CV risk depends on the characteristics of subjects, being more evident in normal weight than in obese patients. Further studies are advisable to clarify if low T in obese patients is a (positive) consequence of a comorbid condition (i.e., to save energy) or if it represents a pathogenetic issue of the same illness. Hence, possible misuse/abuse of T treatment in obese subjects must be avoided., (© 2011 International Society for Sexual Medicine.)

Objective: Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists., Design and Methods: MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ≥12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events., Results: Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50-1.08), P = .12 (0.85 (0.50-1.45), P = .55, and 0.69 (0.40-1.22), P = .20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25-0.83), P = .009, and 1.05 (0.63-1.76), P = .84, respectively., Conclusions: To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect.

Introduction: Erectile dysfunction (ED) and mood depression are often associated and both are correlated with an increased risk of cardiovascular morbidity and mortality., Aim: The aim of the present study is to explore biological and clinical correlates of depressive symptomatology in a sample of men consulting for sexual dysfunction and to verify possible associations between depressive symptoms and incidence of major cardiovascular events (MACE)., Methods: A consecutive series of 2,303 male patients attending the Outpatient Clinic for sexual dysfunction was retrospectively studied. A subset of the previous sample (N= 1,687) was enrolled in a longitudinal study. All patients were investigated using a Structured Interview on Erectile Dysfunction (SIEDY), composed of 3 scales which explore organic, relational and intra-psychic components of ED. MHQ-D scoring from Middlesex Hospital Questionnaire (MHQ) was used as a putative marker of depressive symptoms., Main Outcome Measures: Information on MACE was obtained through the City of Florence Registry Office., Results: We found a positive relationship between MHQ-D score and a progressive impairment in obtaining an erection hard enough for penetration, even after adjusting for confounding factors. Moreover, we observed positive relationships between MHQ-D score and the three pathogenetic domains underlying ED. When the longitudinal subset was evaluated, during a mean follow-up of 4.3±2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was significantly associated with baseline depressive symptoms. When the presence of severe depressive symptoms were introduced in a Cox regression model, along with the arteriogenic ED and partner's hypoactive sexual desire, after adjusting for age, Chronic Diseases Score, and ΣMHQ (a broader index of psychopathology), severe depressive symptomatology was independently associated with a higher incidence of MACE., Conclusion: Depressive symptomatology constitutes an independent risk factor for cardiac morbidity and mortality in men with ED., (© 2010 International Society for Sexual Medicine.)

Introduction: The relationship between alcohol consumption and erectile function is still not completely clarified., Aim: Aims of the present study are to explore a number of biological and clinical correlates of alcohol consumption in a sample of men consulting for sexual dysfunction, and to verify possible associations with the incidence of major adverse cardiovascular events (MACEs)., Methods: A consecutive series of 1956 (mean age 55 ± 11.9 years old) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of the previous sample (N = 1687) was enrolled in a longitudinal study., Main Outcome Measures: Different clinical, biochemical, instrumental (penile Doppler ultrasound [PCDU]), and intrapsychic (Middlesex Hospital Questionnaire [MHQ]) were evaluated. We considered alcohol abuse more than three drinks per day., Results: Among the patients studied 81% reported no or mild (<4 drinks/day) alcohol consumption whereas 14.3% and 3.9% declared a moderate (4-6 drinks/day) or severe (>6 drinks/day) alcohol abuse, respectively. After adjustment for confounders, both moderate or severe alcohol abuse was associated with low perceived partner's sexual desire, worse couple relationship, and smoking abuse. Furthermore, moderate and severe alcohol abuse was associated with low prolactin and thyroid-stimulating hormone levels, as well as an increase in triglycerides and total cholesterol levels. Penile blood flow was reduced in moderate and severe alcohol drinkers even after adjustment for confounders. In the longitudinal study, after adjusting for confounding factors, any kind of alcohol abuse was independently associated with a higher incidence of MACE (hazard ratio = 2.043 [1.059-3.943]; P < 0.0001)., Conclusions: Our findings demonstrate that, in subjects consulting for erectile dysfunction, severe alcohol consumption is associated with a worse sexual function and a higher incidence of MACE., (© 2010 International Society for Sexual Medicine.)

Introduction: Erectile dysfunction (ED) and, in particular, arteriogenic ED have been proposed as new markers of risk for incident major adverse cardiovascular events (MACE). Reduced penile blood flow is more common in obese people than in leaner ED subjects., Aim: To explore the interaction of overweight/obesity and penile blood flow in the prediction of incident MACE., Methods: This is an observational prospective cohort study evaluating a consecutive series of 1,687 patients attending our andrological unit for ED. Different clinical, biochemical, and instrumental (penile flow at color Doppler ultrasound: PCDU) parameters were evaluated., Main Outcomes Measures: According to body mass index (BMI), subjects were divided into three groups: normal weight (BMI = 18.5-24.9 kg/m(2)), overweight (BMI = 25.0-29.9 kg/m(2)), and obese (BMI >or= 30.0 kg/m(2)). Information on MACE was obtained through the City of Florence Registry Office., Results: Among patients studied, 39.8% were normal weight, while 44.1% and 16.1% showed BMI 25-29.9 and 30 kg/m(2) or higher, respectively. During a mean follow-up of 4.3 +/- 2.6 years, 139 MACE, 15 of which were fatal, were observed. Cox regression model, after adjusting for age and Chronic Diseases Score, showed that obesity classes along with the presence of arteriogenic ED (peak systolic velocity at PCDU <25 cm/second) were significantly and independently associated with incident MACE (hazard ratio = 1.47 [1.1-1.95], P < 0.05 and 2.58 [1.28-5.09], P < 0.001, respectively). When a separate analysis was performed for classes of obesity, reduced peak systolic velocity at PCDU (<25 cm/second) was significantly associated with incident MACE in obese (BMI >or= 30 kg/m(2)), but not in leaner, subjects., Conclusions: In obese subjects, more than in leaner ED subjects, impaired penile blood flow is associated with an increased risk of incident cardiovascular disease. The interaction with concomitant risk factors, such as obesity, should be taken into account when assessing the predictive value of penile blood flow for cardiovascular diseases.

Introduction: Although penile blood flow (PBF) has been recommended as an additional diagnostic test in identifying erectile dysfunction (ED) patients at risk for latent cardiovascular disease, no study has ever assessed the possible association of PBF and the relational component of sexual function with incident major cardiovascular events (MACE)., Aim: The aim of this study is to investigate whether severity of ED, PBF, and other factors related to a couple's relationship predict incident MACE., Methods: A consecutive series of 1,687 patients was studied. Different clinical, biochemical, and instrumental (penile flow at color Doppler ultrasound) parameters were evaluated., Main Outcome Measures: Information on MACE was obtained through the City of Florence Registry Office., Results: During a mean follow-up of 4.3 +/- 2.6 years, 139 MACE, 15 of which were fatal, were observed. Cox regression analysis, after adjustment for age and Chronic Disease Score, showed that severe ED predicted MACE (hazard ratio [HR] 1.75; 95% confidence interval 1.10-2.78; P < 0.05). In addition, lower PBF, evaluated both in flaccid (before) and dynamic (after prostaglandin-E1 stimulation) conditions, was associated with an increased risk of MACE (HR = 2.67 [1.42-5.04] and 1.57 [1.01-2.47], respectively, for flaccid [<13 cm/second] and dynamic [<25 cm/second] peak systolic velocity; both P < 0.05). Reported high sexual interest in the partner and low sexual interest in the patient proved to have a protective effect against MACE., Conclusions: The investigation of male sexuality, and in particular PBF, and sexual desire, could provide insights not only into present cardiovascular status but also into prospective risk.

Introduction: Although testosterone (T) has been suggested to play a protective role against the development of atherosclerosis, studies demonstrating an association between low T and incident major adverse cardiovascular events (MACE) are scanty in the general population and absent in subjects with erectile dysfunction (ED)., Aim: To investigate whether low T in subjects with ED predict incident fatal or nonfatal MACE., Methods: This is an observational prospective cohort study evaluating a consecutive series of 1687 patients attending our andrological unit for ED. Patients were interviewed using the structured interview on erectile dysfunction (SIEDY) and ANDROTEST structured interviews measuring components relative to ED and hypogonadal-related symptoms, respectively., Main Outcome Measures: Total T was evaluated at baseline. Information on MACE was obtained through the City of Florence Registry Office., Results: Among the patients studied, 5.2, 13.8, and 22.4% were hypogonadal according to different thresholds (T < 8, 10.4 and 12 nmol/L or 230, 300 and 350 ng/dL, respectively). During a mean follow-up of 4.3 + or - 2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was not associated with T levels. Conversely, the proportion of lethal events among MACE was significantly higher in hypogonadal patients, using either 10.4 nmol/L (300 ng/dL) or 8 nmol/L (230 ng/dL) thresholds. However, after adjustment for age and Chronic Diseases Score in a Cox regression model, only the association between incident fatal MACE and T < 8 nmol/L (230 ng/dL) was confirmed (HR = 7.1 [1.8-28.6]; P < 0.001). Interestingly, measuring hypogonadal-related symptoms and signs through ANDROTEST, only fatal MACE were also associated with a higher score (HR = 1.2 [1.0-1.5] for each ANDROTEST score increment; P = 0.05 after adjustment for age and Chronic Diseases Score)., Conclusions: T levels are associated with a higher mortality of MACE. The identification of low T levels should alert the clinician thus identifying subjects with an increased cardiovascular risk.

Thiazolidinediones (TZDs), agonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma, induce the expression of many genes, including several enzymes and transporters involved in glucose and lipid metabolism. Although the efficacy of TZDs on blood glucose control in type 2 diabetes is not questionable, their cardiovascular effects have been debated, with beneficial or harmful actions suggested by different authors. This article reviews the available clinical evidence on the cardiovascular effects of TZDs, discussing possible mechanisms underlying the observed effects and suggesting some directions for future research.

The treatment with rosiglitazone could be associated with increased risk for myocardial infarction (MI). This meta-analysis is aimed at identifying moderators of the effect of rosiglitazone on the risk of MI and chronic heart failure (CHF) in type 2 diabetic patients. The risk ratio (RR) of MI and CHF was calculated for each trial as the ratio of incidence density in rosiglitazone and comparator groups. A total of 86 trials were included. After adjusting for trial duration, RR for MI showed a significant inverse correlation with mean baseline HbA1c, triglycerides, and LDL-cholesterol (r=-0.24, -0.45, and -0.33, respectively; all p<0.05). Conversely, rosiglitazone-associated risk of MI was increased in trials with higher mean BMI or greater proportion of insulin-treated patients (r=0.26 and 0.42, respectively; p<0.05). Lower triglyceride levels were also associated with a higher rosiglitazone-induced risk of CHF (r=-0.23, p<0.05). Treatment with rosiglitazone could have divergent effects on cardiovascular risk, depending on the characteristics of the patients. Benefits could outweigh harms in patients with poor glycemic control and worse lipid profile; conversely, the drug could increase the risk of MI in obese or insulin-treated patients.

Background: Although age does not seem to modify the association of the metabolic syndrome (MS) with cardiovascular risk in middle-aged individuals, no comparison of risks associated with MS between old and middle-aged persons has been reported so far., Methods: An observational study was performed on a consecutive series of 1716 type 2 diabetic outpatients (age range: 28-96 years). The diagnosis of MS was made following either the National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATPIII) or the International Diabetes Federation (IDF) criteria., Results: The difference in cardiovascular mortality between patients with and without MS was significant up to the age of 70 years. After adjusting for age and sex, hazard ratios of MS for cardiovascular mortality were 3.03 (95% confidence interval, 1.45-6.29), 1.56 (0.91-2.68), and 1.17 (0.42-3.22) in patients < or =70, 71-80, and >80 years old, respectively., Conclusions: MS is associated with increased cardiovascular risk in middle-aged type 2 diabetic patients, and the clinical utility of this category in older diabetic individuals is questionable.

The aim of the study was to assess gamma-glutamyl transpeptidase (gamma-GT), alanine aminotransferase, and aspartate aminotransferase (AST) in the prediction of diabetes and cardiovascular disease (CVD) in subjects free from hepatic diseases other than nonalcoholic fatty liver disease. The present analysis was performed on the cohort of subjects enrolled in the Firenze Bagno a Ripoli (FIBAR) study, a screening program for diabetes performed between 1 March 2001 and 31 December 2003 in the city of Florence on 3124 subjects who underwent an oral glucose tolerance test. Incident cases of diabetes in nondiabetic subjects (n = 2662) were obtained through databases of drug prescriptions, hospital admissions, and lists of subjects eligible for reimbursement. Incident CVD in subjects free of diabetes and CVD at enrollment (n = 2617) was identified through hospital admissions and through the register of causes of death. Mean follow-up was 39.6 +/- 12.0 months and 39.8 +/- 11.4 months for diabetes and CVD, respectively. Yearly incidence of diabetes and CVD was 0.4% and 0.2%, respectively. After adjustment for age and sex, gamma-GT >40 U/L was associated with increased incidence of diabetes and CVD (hazard ratio [95% confidence interval]: 2.54 [1.26-5.11], P < .05 and 2.21 [0.98-5.43], P < .10, respectively). Risk of diabetes, but not of CVD, was increased in patients with gamma-GT in the 25- to 40-U/L range. After adjustment for confounders, AST >40 U/L predicted CVD (hazard ratio, 6.5 [95% confidence interval, 1.5-28.1]), but not diabetes. Elevated gamma-GT or AST is an independent predictor of CVD. An increase of gamma-GT levels above the reference range, or also in the upper reference range, is an independent predictor of incident diabetes.

The present review is aimed at critically analyzing the available literature on the relationship between psycho-emotional disorders and cardiovascular disease, and the effects of antidepressant and antianxiety drugs on clinically relevant outcomes. An extensive Medline search has been conducted between January 1966 and December 2006 using "coronary artery disease", "cardiac disease", "depression", "anxiety", and "emotional disorders" in all their possible combinations as search terms. Among patients with cardiovascular disease, depression and/or anxiety are very common, with a prevalence ranging from 15% to 50%. Many epidemiological studies with extended periods of follow-up have shown that psycho-emotional disorders (in particular, depressive disorders) are associated with increased risk of incident cardiovascular events, rehospitalization, all-cause and cardiovascular mortality both in patients with overt cardiac disease and in the general population. Pathophysiologic reasons supporting this association are represented by unhealthy lifestyle (i.e. persistent smoking habits, inadequate adherence to medical prescriptions, etc.) associated with psycho-emotional disorders, and also by functional alterations of the hypothalamic-pituitary-adrenal axis, platelets, and autonomic nervous system. Some observational studies and clinical trials with small numbers of patients included suggest that these alterations are effectively antagonized by some antidepressant/antianxiety drugs. However, no randomized clinical trial has yet demonstrated that such drugs can reduce the increased risk of unfavorable clinical events associated with psycho-emotional disorders. Despite a proven association of psycho-emotional disorders with an increased cardiovascular risk, and the demonstration that several antidepressant/antianxiety pharmacological agents favorably affect the pathophysiologic alterations associated with such disorders, randomized clinical trials with adequately large sample size and prolonged follow-up are necessary to clarify whether drug treatments may reduce the increased cardiovascular risk of patients affected by depression and/or anxiety.

Introduction: Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.Methods: A systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.Results: Thirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.Conclusion: Overall, incretin therapy does not appear to increase risk for MACE in the short term. [ABSTRACT FROM AUTHOR]

Although several studies have demonstrated that MetS is associated with a two-fold increase in the risk of cardiovascular (CV) diseases, this risk does not appear to be greater than the sum of risks associated with each of its individual components. To determine the association of men with ED and individual components of MetS and their subsequent relationship to CV risk, and, more specifically whether the sum of the MetS components is greater than the individual components in predicting CV risk. We longitudinally studied a consecutive series of 1,687 (mean age 52.9 ± 12.8; range 17-88 years) patients attending our clinic for ED and evaluated different clinical and biochemical parameters. Information on major adverse CV event (MACE) was obtained through the City of Florence Registry Office. One hundred thirty-nine MACE, 15 of which were fatal, occurred during a mean follow-up of 4.3 ± 2.6 years. Subjects with MetS at baseline showed a higher incidence of MACE (hazard ratio [HR] = 1.77), after adjusting for age, however, the association disappeared in an alternative Cox model, adjusting both for age and for individual MetS components (HR = 1,525 [0,564-4,123]; P = 0.408). The two most predictive MetS components of CV risk were low high-density lipoprotein (HDL) cholesterol and high triglycerides. Exploring possible interactions between individual components of MetS and their effect on CV risk using two alternative approaches indicates that the effect of MetS components on CV risk is additive, but not synergistic. Among subjects with hypertension, after adjusting for age, elevated glycemia, and low HDL cholesterol confer relevant additional risk, while in subjects with high triglycerides, hyperglycemia increased the risk of incident MACE. With regards to CV risk, the MetS construct seems to add little or nothing to the careful assessment of its components. Thus, there is no reason to recommend the use of MetS as a diagnostic category in patients with ED. [ABSTRACT FROM AUTHOR]

Pulse pressure (PP; i.e., the arithmetic difference between systolic and diastolic blood pressure) has been suggested to be an independent cardiovascular risk (CV) factor in the general population. We previously also reported a negative association between PP and arteriogenic erectile dysfunction (ED). This finding has recently been questioned. To verify the association of PP with ED severity and to evaluate its role in predicting forthcoming CV events. This is an observational prospective cohort study evaluating a consecutive series of 1,687 patients attending our Andrological Unit for ED. Several hormonal and biochemical parameters were studied, along with SIEDY structured interviews and penile Doppler ultrasound. Subjects with PP in the lowest quartile (I: 20-45; II: 46-55; III: 56-62; IV: 63-115 mm Hg) had a significant reduction in the risk of severe ED (RR = 0.60[0.47-0.76]; P < 0.0001). When the same analysis was repeated as a function of age quartile (I = 17-44, II = 45-55, III = 56-62, and IV = 63-88 years old), after adjusting for testosterone levels, mean blood pressure, Chronic Disease Score, and body mass index, PP was inversely related to ED only in the youngest age group. During a mean follow up of 4.4 ± 2.6 years, 147 major cardiovascular events (MACE) were observed. In a Cox regression model, after adjusting for possible confounding factors, a lower PP was associated with a lower risk of MACE in the whole sample and in younger subjects, but not in the older ones. Checking for blood pressure in ED subjects and calculating PP should become a routine practice in sexual medicine. In younger individuals, low PP reflects not only sexual health (better erection) but also cardiovascular health (less prevalence of MACE). [ABSTRACT FROM AUTHOR]

A correction to the article "Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials," by Matteo Monami and colleagues published in the October 11, 2016 online issue of "Acta Diabetologica" is presented.