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Hyperglycemia strongly affects endothelial function and activation, which in turn increases the risk of atherosclerotic cardiovascular disease. Among pharmacotherapies aimed at lowering blood glucose levels, glucagon-like peptide 1 receptor agonists (GLP-1RA) represent a class of drugs involved in the improvement of the endothelium damage and the progression of cardiovascular diseases. They show antihypertensive and antiatherosclerotic actions due at least in part to direct favorable actions on the coronary vascular endothelium, such as oxidative stress reduction and nitric oxide increase. However, cumulative peripheral indirect actions could also contribute to the antiatherosclerotic functions of GLP-1/GLP-1R agonists, including metabolism and gut microbiome regulation. Therefore, further research is necessary to clarify the specific role of this drug class in the management of cardiovascular disease and to identify specific cellular targets involved in the protective signal transduction. In the present review, we provide an overview of the effects of GLP-1RAs treatment on cardiovascular disease with particular attention on potential molecular mechanisms involving endothelium function on formation and progression of atherosclerotic plaque. [ABSTRACT FROM AUTHOR]

Aims: Previous observational studies on glucose-lowering drugs and risk of stroke in type 2 diabetes yielded conflicting results. The aim was to examine the association of glucose-lowering drugs with incident stroke and transient ischaemic attacks (TIA) in newly diagnosed type 2 diabetes. Methods: We conducted a retrospective cohort analysis of the disease analyzer, which comprises a representative panel of 1248 general and internal medicine practices throughout Germany (01/2000–12/2019: 9.8 million patients). Incident non-fatal stroke/TIA was defined based on ICD-10 codes (I63, I64; G45) in newly diagnosed type 2 diabetes. Cox regression models were fitted to obtain hazard ratios (HR; 95%CI) for stroke/TIA adjusting for potential confounders (age, sex, health insurance, coronary heart disease, myocardial infarction, heart failure, polyneuropathy, blood pressure, eGFR) and anthropometric and metabolic intermediators (BMI, HbA1c, HDL- and LDL-cholesterol, triglycerides, lipid-lowering drugs). Result: 312,368 persons with newly diagnosed type 2 diabetes without previous stroke/TIA (mean age: 64 years; 52% males) were included. There were 16,701 events of non-fatal stroke/TIA corresponding to an incidence rate of 9.3 (95%CI 9.1–9.4) per 1000 person-years. Using Cox regression, adjusted HR for stroke/TIA (per 1 year of treatment) of 0.59 (0.54–0.64) for SGLT2 inhibitors and of 0.79 (0.74–0.85) for GLP-1 receptor agonists were estimated. DPP-4 inhibitors (0.84; 0.82–0.86), metformin (0.90; 0.89–0.91), insulin (0.92; 0.91–0.93) and sulfonylureas (0.98; 0.96–0.99) also showed moderately reduced HR for stroke/TIA. Sex-specific regression analyses yielded similar results (HR). Conclusions: Treatment with SGLT2 inhibitors or GLP-1 receptor agonists might reduce non-fatal stroke/TIA in persons with newly diagnosed type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: Treatment effects from the large cardiovascular outcome trials (CVOTs) of new antidiabetic drugs are almost exclusively communicated as hazard ratios, although reporting guidelines recommend to report treatment effects also on an absolute scale, e.g. as numbers needed to treat (NNT). We aimed to analyse NNTs in CVOTs comparing dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or sodium–glucose cotransporter-2 (SGLT2) inhibitors to placebo. Methods: We digitalized individual time-to-event information for the primary outcome and all-cause mortality from 19 CVOTs that compared DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors to placebo. We estimated Weibull models for each trial and outcome and derived monthly NNTs. NNTs were summarized across all trials and within drug classes by random effects meta-analysis methods. Results: Treatment effects in the CVOTs appear smaller if they are reported as NNTs: Overall, 100 (95%-CI: 60, 303) patients have to be treated for 29 months (the median follow-up time across all trials) to avoid a single event of the primary outcome, and 128 (95%-CI: 85, 265) patients have to be treated for 39 months to avoid a single death. NNT time courses are very similar for GLP-1 receptor agonists and SGLT2 inhibitors, whereas treatment effects with DPP-4 inhibitors are smaller. Conclusions: We found that the respective treatment effects look less impressive when communicated on an absolute scale, as numbers needed to treat. For a valid overall picture of the benefit of new antidiabetic drugs, trial authors should also report treatment effects on an absolute scale. [ABSTRACT FROM AUTHOR]

Aims: Results with GLP1-receptor agonists (GLP-1RA) on microvascular complications of diabetes are contrasting. In trials designed for cardiovascular outcomes, both liraglutide and semaglutide were associated with a relevant reduction in the incidence and progression of nephropathy. On the other hand, in the same trials, semaglutide was associated with an increased progression of retinopathy, and a similar trend was observed for liraglutide. This meta-analysis is aimed at assessing the effects of GLP-1RA on retinopathy and nephropathy. 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 >11 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. Results: Of the 113 trials fulfilling the inclusion criteria, 78 and 62 did not report information on retinopathy and nephropathy, respectively. Treatment with GLP1-RA was not associated with a significant increase in the incidence of retinopathy (MH-OR [95% CI] 0.92 [0.74-1.16]. p = 0.49). In subgroup analyses, GLP1-RA were associated with a lower risk of retinopathy in comparison with sulfonylureas. Cases of macular edema were reported only in nine trials with no sign of increased risk. GLP1-RA reduced the incidence of nephropathy with respect to comparators (MH-OR [95% CI] 0.74 [0.60-0.92]. p = 0.005). This difference was significant versus placebo, but not versus any class of active comparators. Conclusions: GLP1-RA appear to reduce the incidence and/or progression of nephropathy and to have no specific effect on retinopathy-with the notable exception of semaglutide, which could have a negative impact on the retina. [ABSTRACT FROM AUTHOR]