GLP-1 RA plus SGLT-2i better than monotherapy for CV, renal events prevention

Patients with type 2 diabetes (T2D) who received combined treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a much lower risk of major adverse cardiovascular events (MACE) and serious renal events than those treated with either drug class alone, suggests a recent study.

Moreover, adding an SGLT-2i to an existing GLP-1 RA use also contributes to a decreased risk of cardiovascular (CV) mortality and heart failure when compared with GLP-1 receptor agonists alone.

Lead author Nikita Simms-Williams, Institute of Applied Health Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK, and colleagues conducted this population-based cohort study using a prevalent new-user design, emulating a randomized controlled trial.

The researchers assembled two cohorts between January 2013 and December 2020, with follow-up until the end of March 2021. A total of 6,696 patients who initiated GLP-1 RAs and added on SGLT-2is comprised the first cohort. The second cohort included 8,942 patients who started SGLT-2is and added on GLP-1 RAs.

Simms-Williams and her team then matched the combination users in a 1:1 ratio to patients prescribed the same background drug, duration of background drug, and time conditional propensity score. They used Cox proportional hazard models to calculate the hazard ratios (HRs) and 95 percent confidence intervals (CIs) of MACE and serious renal events, separately.

Combined treatment with SGLT-2i and GLP-1 RA, compared with GLP-1 RA monotherapy, correlated with a 30-percent reduced risk of MACE (7.0 vs 10.3 events per 1,000 person-years; HR, 0.70, 95 percent CI, 0.49‒0.99) and a 57-percent lower risk of serious renal events (2.0 vs 4.6 events per 1,000 person-years; HR, 0.43, 95 percent CI, 0.23‒0.80). [BMJ 2024;385:e078242]

Likewise, combined use of GLP-1 RAs and SGLT-2is, compared with SGLT-2is, correlated with a 29-percent lower risk of MACE (7.6 vs 10.7 events per 1,000 person-years; HR, 0.71, 95 percent CI, 0.52‒0.98), while serious renal events generated a wide confidence interval (1.4 vs 2.0 events per 1,000 person-years; HR, 0.67, 95 percent CI, 0.32‒1.41).

Similar results were observed regarding associations with the individual components of MACE (ie, myocardial infarction, ischaemic stroke, CV mortality), heart failure, and all-cause mortality.

“These findings are concordant with those of observational studies that have also observed a decreased risk of MACE when comparing the GLP-1 RA-SGLT-2i combination with different types of comparators,” Simms-Williams said. [Circulation 2021;143:770-779; Circulation 2021;143:770-779; Diabetes Care 2022;45:909-918]

Mechanisms

The beneficial effects of the combination treatment appear to be driven by the additive effect arising from the different but complementary mechanisms of action. For instance, both drug classes provide clinical benefits such as glycaemic control, body mass reduction, and better systolic blood pressure and lipid profiles. [Can J Diabetes 2021;45:291-302]

“Additional studies, including randomized controlled trials, will be needed to corroborate our findings and to explore the full therapeutic potential of the GLP-1 RA-SGLT-2i combination among patients with T2D,” the researchers said.