Cardiorenal benefit with investigational GLP-1 RA independent of concurrent SGLT2 inhibitor

The glucagon-like peptide-1 receptor agonist (GLP-1 RA) efpeglenatide affords cardiovascular and renal protection that is not explained by concurrent use of a sodium-glucose co-transporter-2 (SGLT2) inhibitor in patients with type 2 diabetes (T2D), according to an exploratory analysis of AMPLITUDE-O.

Over a median follow-up of 1.81 years, the effect of efpeglenatide vs placebo on the outcomes examined did not differ by SGLT2 inhibitor use. The respective hazard estimates among patients with and without concurrent SGLT2 inhibitor treatment were 0.74 (95 percent confidence interval [CI], 0.58–0.94) and 0.70 (95 percent CI, 0.37–1.30) for major adverse cardiovascular events (MACE), 0.77 (95 percent CI, 0.62–0.96) and 0.87 (95 percent CI, 0.51–1.48) for expanded MACE, 0.70 (95 percent CI, 0.59–0.83) and 0.52 (95 percent CI, 0.33–0.83) for composite renal events, and 0.74 (95 percent CI, 0.59–0.93) and 0.65 (95 percent CI, 0.36–1.19) for MACE or death. [Circulation 2021;doi:10.1161/CIRCULATIONAHA.121.057934]

Likewise, the beneficial effect of efpeglenatide on blood pressure, body weight, low density lipoprotein cholesterol, and urinary albumin:creatinine ratio (UACR) appeared to be independent of concurrent SGLT2 inhibitor use. The results for safety were the same, with the incidence of adverse events being similar among patients using and not using an SGLT2 inhibitor concomitantly.

According to the investigators, their data indicate that combined treatment with SGLT2 inhibitors and GLP-1 RAs may be expected to be “well tolerated and to yield substantial benefits across a wide range of cardiovascular outcomes among patients with T2D.”

AMPLITUDE-O included 4,076 T2D patients (mean age 64.5 years, 33 percent women), among whom 618 (15.2 percent) were using an SGLT2 inhibitor at baseline. Compared with nonusers, SGLT2 inhibitor users had a longer duration of diabetes, lower levels of systolic blood pressure, HbA1c, cholesterol, and UACR, as well as lower prevalence of prior heart failure and albuminuria.

“Several lines of evidence provide a strong basis for the combined use of GLP-1 RAs and SGLT2 inhibitors in the treatment of T2D and potential additive effect on glucose-lowering and prevention of cardiorenal events,” the investigators noted.

For the most part, the two drug classes have distinct mechanisms of action and complementary cardiovascular benefits, as reported in previous clinical trials in diabetes, thus raising the possibility that combined therapy may produce more comprehensive beneficial effects than when either drug class is given alone, they added. [Lancet Diabetes Endocrinol 2019;7:776-785; Lancet Diabetes Endocrinol 2021;9:653-662; JAMA Cardiol 2021;6:148-158]

Indeed, current guidelines recommend the addition of SGLT2 inhibitors after a GLP-1 RA or vice versa for patients with diabetes who has or at high risk of atherosclerotic cardiovascular disease or chronic kidney disease. [Diabetes Care 2020;43:487-493; Eur Heart J 2020;41:255-323; Diabetes Care 2021;44:S125-S150; Diabetes Care 2021;44:S111-S124]

Despite the presence of several study limitations, the current findings are consistent with growing evidence in support of the efficacy and safety of combined therapy in T2D, the investigators said.

“Of course, a prospective, randomized, controlled study testing the combination of a GLP-1 RA with a SGLT2 inhibitor vs each individual component will provide definitive evidence, but that would be a huge undertaking that perhaps can only be accomplished with a pragmatic study design,” they added.