GLP-1 receptor agonists-SGLT-2 inhibitors combination therapy and cardiovascular events after acute myocardial infarction: an observational study in patients with type 2 diabetes

Abstract

Background: Few studies explored the effect of the combination of glucose sodium-cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on the incidence of cardiovascular events in patients with type 2 diabetes (T2D) and acute myocardial infarction (AMI).

Methods: We recruited patients with T2D and AMI undergoing percutaneous coronary intervention, treated with either SGLT-2i or GLP-1RA for at least 3 months before hospitalization. Subjects with HbA1c < 7% at admission were considered in good glycemic control and maintained the same glucose-lowering regimen, while those with poor glycemic control (HbA1c ≥ 7%), at admission or during follow-up, were prescribed either a SGLT-2i or a GLP-1RA to obtain a SGLT-2i/GLP-1RA combination therapy. The primary outcome was the incidence of major adverse cardiovascular events (MACE) defined as cardiovascular death, re-acute coronary syndrome, and heart failure related to AMI during a 2-year follow-up. After 3 months, the myocardial salvage index (MSI) was assessed by single-photon emission computed tomography.

Findings: Of the 537 subjects screened, 443 completed the follow-up. Of these, 99 were treated with SGLT-2i, 130 with GLP-1RA, and 214 with their combination. The incidence of MACE was lower in the combination therapy group compared with both SGLT-2i and GLP-1RA treated patients, as assessed by multivariable Cox regression analysis adjusted for cardiovascular risk factors (HR = 0.154, 95% CI 0.038-0.622, P = 0.009 vs GLP-1RA and HR = 0.170, 95% CI 0.046-0.633, P = 0.008 vs SGLT-2i). The MSI and the proportion of patients with MSI > 50% was higher in the SGLT-2i/GLP-1RA group compared with both SGLT-2i and GLP-1RA groups.

Interpretation: The combination of SGLT-2i and GLP-1RA is associated with a reduced incidence of cardiovascular events in patients with T2D and AMI compared with either drug used alone, with a significant effect also on peri-infarcted myocardial rescue in patients without a second event. Trial registraition ClinicalTrials.gov ID: NCT06017544.

Keywords: Combination therapies; Diabetes algorithm; GLP-1 receptor agonists; Glucose-lowering drugs; Heart failure; MACE; Myocardial infarction; SGLT-2 inhibitors.

Fig. 1

STROBE diagram showing the patients included in the different phases of the study

Fig. 2

Trend of HbA1c, LDL-cholesterol, and BMI in the three groups during follow-up. Graphs showing the mean values of glycated haemoglobin (HbA1c) (A), LDL-cholesterol (C), and BMI (D), along with the mean cumulative HbA1c (B), in the three groups during the successive visits of the follow-up. Error bars are ± SE for panels A, C, and D. *P < 0.05 SGLT-2i/GLP-1RA vs SGLT-2i; ^†P < 0.05 SGLT-2i/GLP-1RA vs GLP-1RA; ^⁋P < 0.05 SGLT-2i vs SGLT-2i/GLP-1RA; ^§P < 0.05 SGLT-2i vs GLP-1RA; Kruskal–Wallis followed by Dunn’s test for all. Boxplots show the median, 25th, and 75th percentiles, range, and extreme values

Fig. 3

Primary endpoint and myocardial salvage index. Cumulative incidence of MACE in the groups on therapy with SGLT-2i (ref), GLP-1RA, and their combination with the relative hazard ratios (HR) and confidence intervals (CI) resulting from the relative Cox regression analysis (A); percentange of myocardial salvage index assessed thorugh SPECT after 3 months in the three groups (B). *P < 0.05 SGLT-2i/GLP-1RA vs SGLT-2i; ^†P < 0.05 SGLT-2i/GLP-1RA vs GLP-1RA; Kruskal–Wallis followed by Dunn’s test. Boxplots show the median, 25th, and 75th percentiles, range, and extreme values