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Aims: To explore the effect of background treatment with metformin on the efficacy of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes.Methods: We searched MEDLINE and EMBASE through May 5, 2021 for randomized, placebo-controlled, cardiovascular outcomes trials of GLP-1 RAs in patients with type 2 diabetes that reported cardiovascular or mortality outcomes by baseline metformin use. Main outcome was incidence of major adverse cardiovascular events (MACE). Other outcomes included the individual components of the primary composite outcome (myocardial infarction, stroke, cardiovascular death), all-cause mortality and hospitalization for heart failure. We pooled hazard ratios (HRs) with 95% confidence intervals (CIs) stratified by baseline use of metformin using random-effects meta-analysis.Results: We included 4 trials (43,456 patients) assessing albiglutide, dulaglutide, exenatide once weekly and liraglutide. GLP-1 RAs reduced MACE by 13% (HR 0.87, 95% CI 0.82-0.93), an effect which was consistent in both subgroups (HR 0.91, 95% CI 0.85-0.97 and HR 0.80, 95% CI 0.72-0.90 with and without metformin, respectively). Presence of metformin at baseline did not affect the overall favorable effect of GLP-1 RAs both on cardiovascular and all-cause mortality. Finally, subgroup meta-analyses suggested that GLP-1 RAs had a neutral effect on stroke, myocardial infarction and hospitalization for heart failure, irrespective of metformin use at baseline.Conclusions: Subgroup analyses suggested that treatment with GLP-1 RAs has a beneficial effect on cardiovascular outcomes irrespective of baseline use of metformin. However, given the exploratory nature of subgroup analyses, these findings should be treated as hypothesis-generating rather than conclusive evidence. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the associations of microvascular disease (MVD) with incident cardiovascular disease (CVD) in individuals with type 2 diabetes.Methods: A total of 4098 participants with type 2 diabetes and without CVD were assessed for MVD (diabetic kidney disease, retinopathy or neuropathy) in the Look AHEAD (Action for Health in Diabetes) study. Cox models were used to generate hazard ratios (HRs) for: (1) CVD composite (myocardial infarction, stroke, hospitalization for angina and/or death from cardiovascular causes), (2) coronary artery disease (CAD), (3) stroke, and (4) CVD-related deaths.Results: Of 4098 participants, 34.7% (n = 1424) had MVD at baseline. Over a median of 9.5 years, 487 developed the CVD composite, 410 CAD events, 100  stroke, and 54 CVD-related deaths. After adjusting for relevant confounders, MVD was associated with increased risks of CVD composite (HR 1.34, 95% CI 1.11-1.61), CAD (HR 1.24, 95% CI 1.01-1.52), stroke (HR 1.55, 95% CI 1.03-2.33), and cardiovascular mortality (HR 1.26, 95% CI 0.72-2.22). HRs for CVD composite by type of MVD were 1.11 (95% CI 0.89-1.38), 1.63 (95% CI 1.22-2.17) and 1.16 (95% CI 0.92-1.46) for diabetic kidney disease, retinopathy, and neuropathy, respectively.Conclusions: Our findings underscore the relevance of MVD in CVD risk assessment in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the risk of all-cause and cardiovascular mortality, acute myocardial infarction, and stroke associated with insulin treatment in patients with type 2 diabetes.Methods: A systematic review with meta-analysis of randomized clinical trials (RCTs) was performed. EMBASE, Cochrane, and PubMed databases were searched for RCTs reporting mortality or cardiovascular events and comparing basal insulin to any treatment in patients with type 2 diabetes. Data were summarized with Mantel-Haenzel relative risk (RR). Trial sequential analysis (TSA) was used to evaluate the reliability of the results considering a 20% relative risk difference between treatments. PROSPERO Registry: CRD42018087336.Results: In total, 2351 references were identified, and 26 studies (24348 patients) were included. Most studies evaluated glargine insulin (69%), compared insulin to GLP-1 analogs (57%), and evaluated add-on therapy with metformin (77%). Insulin was not associated with increased all-cause mortality (RR 0.99; 95% confidence interval (CI) 0.92-1.06), cardiovascular mortality (RR 1.01; 95% CI 0.91-1.13), myocardial infarction (RR 1.02; 95% CI 0.92-1.15), or stroke (RR 0.87; 95% CI 0.68-1.12). Insulin treatment increased severe hypoglycemia risk (RR 2.98; 95% CI 2.47-3.61). All analyses had low statistical heterogeneity. TSA confirmed these findings: optimal sample size (myocardial infarction), futility boundary (all-cause mortality, cardiovascular mortality, and stroke) and harm boundary (hypoglycemia) were reached.Conclusion: Treatment with basal insulin of patients with type 2 diabetes does not increase the risk of cardiovascular events or death. Despite the increased risk of hypoglycemia, these findings reinforce that insulin is a safe option in the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]