In type 2 diabetes, SGLT2 inhibitors reduce all-cause, but not cardiovascular, mortality vs. GLP-1 RAs

A meta-analysis identified relative benefits of sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) based on individual cardiovascular and renal risks.

The benefits and harms of sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were compared in a meta-analysis of 764 trials. The trials all added SGLT2 inhibitors or GLP-1 RAs to existing diabetes treatments and followed patients for at least 24 weeks. The results, which found differing effects of the classes based on patients' renal and cardiovascular risks, were used to develop the BMJ Rapid Recommendations reported in the previous article in this issue.

The study was published by The BMJ on Jan. 13 and summarized in the February ACP Diabetes Monthly. The following commentary by Michael Tanner, MD, FACP, was published in the ACP Journal Club section of Annals of Internal Medicine on June 1.

No pharmacologic therapy for type 2 diabetes had been shown to improve mortality in clinical trials until 1998, when the UKPDS 34 reported that metformin reduced all-cause mortality by 34% at 11 years compared with lifestyle modification. In 2015, the EMPA-REG OUTCOME trial heralded a promising new era in diabetes pharmacology, showing a 31% reduction in all-cause mortality at just 3 years with the SGLT2 inhibitor, empagliflozin, vs. placebo (number needed to treat, 38). The following year, the LEADER trial showed a lesser, but still impressive, mortality benefit with the GLP-1 RA liraglutide. The question, then, was whether the results of these early studies would be replicable or whether they were too good to be true.

The large systematic review and network meta-analysis by Palmer and colleagues found mortality benefits with these drug classes when added to background diabetes treatment. SGLT2 inhibitors were better than GLP-1 RAs for treating heart failure and preventing all-cause mortality; GLP-1 RAs were better for reducing hemoglobin A1c levels and preventing nonfatal stroke. Surprisingly, SGLT2 inhibitors reduced body weight more than GLP-1 RAs, SGLT2 inhibitors did not reduce risk for nonfatal stroke, and the 2 drug classes did not differ for kidney failure.

Baseline level of risk played a large role in degree of benefit. Patients were stratified into 5 groups ranging from very low risk (no cardiovascular risk factors) to very high risk (cardiovascular disease and kidney disease). As expected, the higher the risk, the more adverse events prevented per 1000 persons over 5 years.

This review of 421,346 patients with a median hemoglobin A1c level of 8.1% and BMI of 30.1 kg/m2 confirms the impressive results of EMPA-REG OUTCOME and LEADER. With high certainty, SGLT2 inhibitors and GLP-1 RAs reduce all-cause mortality, cardiovascular mortality, kidney failure, and myocardial infarction.