Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial

Background: Clinical trials have shown the cardiovascular protective effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors and reduced hospitalization for heart failure. However, no study has investigated the association between SGLT2 inhibitors and the risk of arrhythmias. This study aimed to evaluate the risk of new-onset arrhythmias (NOA) and all-cause mortality with the use of SGLT2 inhibitors. Methods: This was a population-based cohort study utilizing Taiwan's National Health Insurance Research Database. Each patient aged 20 years and older who took SGLT2 inhibitors was assigned to the SGLT2 inhibitor group, whereas sex-, age-, diabetes mellitus duration-, drug index date-, and propensity score-matched randomly selected patients without SGLT2 inhibitors were assigned to the non-SGLT2 inhibitor group. The study outcome was all-cause mortality and NOA. Results: A total of 399,810 patients newly diagnosed with type 2 DM were enrolled. A 1:1 matching propensity method was used to match 79,150 patients to 79,150 controls in the non-SGLT2 inhibitors group for analysis. The SGLT2 inhibitor group was associated with a lower risk of all-cause mortality [adjusted hazard ratio (aHR) 0.547; 95% confidence interval (CI) 0.482-0.621; P = 0.0001] and NOA (aHR 0.830; 95% CI 0.751-0.916; P = 0.0002). Conclusions: Patients with type 2 DM prescribed with SGLT2 inhibitors were associated with a lower risk of all-cause mortality and NOA compared with those not taking SGLT2 inhibitors in real-world practice.

Section: Introductionmentioning

confidence: 99%

The association between SGLT2 inhibitors and new-onset arrhythmias: a nationwide population-based longitudinal cohort study

Chen

Huang

Siao

et al. 2020

“…This indicates that the CV protective effect for GLP1RA can be seen in most patients with T2DM; therefore, all patients that have established or at high risk of CVD would benefit from being initiated on GLP1RA regardless of their age, duration of diabetes, and HbA1c level. Moreover, when using one of the GLP1RAs, the addition of another agent with CV protective effect, such as one of the SGLT2i, can contribute to even better CV outcomes in these patients [37]. Therefore, in patients with established or at high risk of CVD when additional therapy is needed for better control of diabetes, agents with CV protective effect should be considered.…”

Section: Discussionmentioning

confidence: 99%

Indirect comparison of glucagon like peptide-1 receptor agonists regarding cardiovascular safety and mortality in patients with type 2 diabetes mellitus: network meta-analysis

Alfayez

Almohammed

Alkhezi

et al. 2020

Background: The cardiovascular outcome trials (CVOTs) have shown that glucagon like peptide-1 receptor agonists (GLP1RAs) have varying degrees of cardiovascular (CV) safety in patients with type 2 diabetes mellitus (T2DM.) The lack of any head-to-head comparative trials among GLP1RAs urged the need for an indirect comparison of these agents. Therefore, this study was conducted to indirectly compare the CV safety and mortality effects among different GLP1RAs in patients with T2DM using network meta-analysis (NMA). Methods: Medline was searched to identify GLP1RA CVOTs to date. The outcomes of interest were CV death, myocardial infarction (IM), stroke, and death from any cause. An NMA with binomial likelihood logit link model was used for the binary outcomes. We conducted both fixed effects and random effects models for each outcome, and selected the best model based on the deviance information and the average posterior residual deviance. This NMA was reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA-NMA). Results: A total of seven GLP1RA CVOTs were included having 56,004 patients. The NMA results showed that oral semaglutide was statistically better than exenatide (OR 0.47, 95% CI 0.21-0.99), dulaglutide (OR 0.46, 95% CI 0.20-0.97), albiglutide (OR 0.45, 95% CI 0.19-0.97), lixisenatide (OR 0.43, 95% CI 0.19-0.92) in reducing CV death events. No significant differences were detected between most of the treatments regarding reducing death from any cause, MI and stroke events. The ranking results showed that oral semaglutide had the highest probability to be ranked first (> 90%) in reducing CV death and death from any cause. Moreover, once weekly semaglutide had the highest probability to be ranked first in reducing MI and stroke events. Conclusion: The GLP1RAs have shown significant benefits in terms of CV safety. The indirect comparison and ranking probability results have shown that one weekly semaglutide and oral semaglutide seems to be the preferred option in patients with T2DM and established or at high risk of CVD. This result can aid health care providers, pharmacy and therapeutics committees in hospitals, and insurance companies when deciding which GLP1RA to start or add to their formulary.

“…In patients with T2D and a recent acute coronary event, no difference was observed in the rates of MACE between lixisenatide and placebo [38] and the trial testing once weekly exenatide showed non-significant reductions in 3P-MACE versus placebo [39]. With regards to the latter, it is of interest that the combination with SGLT-2 inhibitors may potentiate the cardiovascular protection exerted by once weekly exenatide [40]. Yet, it has been speculated that cardiovascular protection might be conveyed selectively by human-based GLP-1RA (liraglutide, semaglutide, dulaglutide, albiglutide) and not by exendin-based GLP-1RA (exenatide and lixisenatide).…”

Section: Human Versus Exendin-based Glp-1ramentioning

confidence: 99%

Better cardiovascular outcomes of type 2 diabetic patients treated with GLP-1 receptor agonists versus DPP-4 inhibitors in clinical practice

Longato

Camillo

Sparacino

et al. 2020

Background: Cardiovascular outcome trials in high-risk patients showed that some GLP-1 receptor agonists (GLP-1RA), but not dipeptidyl-peptidase-4 inhibitors (DPP-4i), can prevent cardiovascular events in type 2 diabetes (T2D). Since no trial has directly compared these two classes of drugs, we performed a comparative outcome analysis using real-world data. Methods: From a database of ~ 5 million people from NorthEast Italy, we retrospectively identified initiators of GLP-1RA or DPP-4i from 2011 to 2018. We obtained two balanced cohorts by 1:1 propensity score matching. The primary outcome was the 3-point major adverse cardiovascular events (3P-MACE; a composite of death, myocardial infarction, or stroke). 3P-MACE components and hospitalization for heart failure were secondary outcomes. Results: From 330,193 individuals with T2D, we extracted two matched cohorts of 2807 GLP-1RA and 2807 DPP-4i initiators, followed for a median of 18 months. On average, patients were 63 years old, 60% male; 15% had pre-existing cardiovascular disease. The rate of 3P-MACE was lower in patients treated with GLP-1RA compared to DPP4i (23.5 vs. 34.9 events per 1000 person-years; HR: 0.67; 95% C.I. 0.53-0.86; p = 0.002). Rates of myocardial infarction (HR 0.67; 95% C.I. 0.50-0.91; p = 0.011) and all-cause death (HR 0.58; 95% C.I. 0.35-0.96; p = 0.034) were lower among GLP-1RA initiators. The as-treated and intention-to-treat approaches yielded similar results. Conclusions: Patients initiating a GLP-1RA in clinical practice had better cardiovascular outcomes than similar patients who initiated a DPP-4i. These data strongly confirm findings from cardiovascular outcome trials in a lower risk population.