SGLT2 inhibitors may protect against some major cardiovascular events

Sodium-glucose cotransporter-2 (SGLT2) inhibitors may protect against major cardiovascular events, cardiovascular death, heart failure, and death from any cause, an Australian study found.

To establish the effects of SGLT2 inhibitors, researchers included data from 6 regulatory submissions (37,525 participants) and 57 published trials (33,385 participants), from Jan. 1, 1950, to Sept. 30, 2015, which provided data for 7 different SGLT2 inhibitors. The primary outcome was major adverse cardiovascular events. Secondary outcomes were cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, admission for unstable angina, heart failure, and all-cause mortality. Results were published online March 18 by The Lancet: Diabetes & Endocrinology.

SGLT2 inhibitors were associated with lower risk of major adverse cardiovascular events (relative risk [RR], 0.84; 95% CI, 0.75 to 0.95; P=0.006), cardiovascular death (RR, 0.63; 95% CI, 0.51 to 0.77; P<0.0001), heart failure (RR, 0.65; 95% CI, 0.50 to 0.85; P=0.002), and death from any cause (RR, 0.71; 95% CI, 0.61 to 0.83; P<0.0001). There was no clear effect for nonfatal myocardial infarction (RR, 0.88; 95% CI, 0.72 to 1.07; P=0.18) or angina (RR, 0.95; 95% CI, 0.73 to 1.23; P=0.70), but researchers noted an adverse effect for nonfatal stroke (RR, 1.30; 95% CI, 1.00 to 1.68; P=0.049).

Researchers noted that the efficacy results were driven by findings for empagliflozin, the only SGLT2 inhibitor with data from a dedicated long-term cardiovascular safety trial. There was no clear evidence that individual drugs had different effects on cardiovascular outcomes or death.

Safety analyses showed consistent increased risks of genital infections (regulatory submissions: RR, 4.75; 95% CI, 4.00 to 5.63; scientific reports: RR, 2.88; 95% CI, 2.48 to 3.34). However, researchers noted, findings for other safety outcomes varied depending on whether analyses were based on data extracted from regulatory submissions or trials reported in the scientific literature.

Results from ongoing studies will be crucial to substantiate all the findings, the researchers said. “Although treatment with SGLT2 inhibitors does cause important adverse effects, protection against vascular events and death will probably override the risk of harm in many patients with type 2 diabetes,” the researchers wrote. “However, since our results were driven substantively by data for empagliflozin, results from ongoing trials of other SGLT2 inhibitors will be necessary to substantiate these findings across the drug class.”

An accompanying editorial stated that clinicians should probably not yet embrace use of SGLT2 inhibitors for any potential cardiovascular benefit. Much of the benefit related to heart failure, yet the effects seen are too rapid to be due to a reduction in atherosclerotic disease. Mechanistic studies are needed to fully understand the effects of SGLT2 inhibitors on the heart, the editorialist wrote. “SGLT2 inhibitors could represent the start of a new era for diabetes treatment, but we should await the results of these ongoing trials before adopting widespread use in the expectation of cardiovascular benefit, despite the encouraging data from this latest meta-analysis,” the editorial said.