Cardiovascular disease and mortality appear lower in patients on SGLT2 inhibitors

Sodium-glucose co-transporter-2 (SGLT2) inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with other glucose-lowering drugs in patients with type 2 diabetes, an industry-funded study found.

Using real-world data from clinical practice, researchers sought to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors with new users of other glucose-lowering drugs. The study was an observational analysis of individual, patient-level data from patient registries in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed until Dec. 31, 2015.

Results were published online Aug. 3 by The Lancet: Diabetes and Endocrinology. AstraZeneca funded the study.

Each patient taking an SGLT2 inhibitor was matched by propensity scores with three users of other glucose-lowering drugs. Cardiovascular outcomes included cardiovascular mortality, a composite of major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischemic or hemorrhagic stroke), heart failure events, nonfatal myocardial infarction, nonfatal stroke, and atrial fibrillation.

Matched SGLT2 inhibitor (n=22,830) and other glucose-lowering drug (n=68,490) groups were well balanced at baseline, with a mean follow-up of 0.9 (SD, 4.1) years (80,669 patient-years) and a mean age of 61 years, Forty percent were women and 25% had cardiovascular disease. In the study, 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, 5% was for empagliflozin, and 1% was for canagliflozin.

Compared with other glucose-lowering drugs, SGLT2 inhibitors were associated with decreased risk of cardiovascular mortality (hazard ratio [HR], 0.53; 95% CI, 0.40 to 0.71), major adverse cardiovascular events (HR, 0.78; 95% CI, 0.69 to 0.87), and heart failure events (HR, 0.70; 95% CI, 0.61 to 0.81) (P<0.0001 for all). There were no significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for nonfatal myocardial infarction, nonfatal stroke, or atrial fibrillation. Use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycemia (HR, 0.76; 95% CI, 0.65 to 0.90; P=0.001) compared with other glucose-lowering drugs.

The reductions in cardiovascular mortality were similar for the individuals with cardiovascular disease at baseline and those without (HR, 0.60 [95% CI, 0.42 to 0.85] and 0.55 [95% CI, 0.34 to 0.90], respectively). There were more significant reductions in major adverse cardiovascular events in the group with cardiovascular disease at baseline (HR, 0.70; 95% CI, 0.59 to 0.83) compared to the group without (HR, 0.90; 95% CI, 0.76 to 1.07).

The study's conclusion was consistent with the results of other clinical trials in patients at high cardiovascular risk, the study authors noted. This study showed the effects in patients with a broader cardiovascular risk profile than in other studies, with a lower proportion having established baseline cardiovascular disease and lower event rates.

An accompanying comment noted that the study offers some additional support for a class effect of SGLT2 inhibitors but is limited by its observational design and possible channeling bias. “Only with the results of the DECLARE-TIMI 58 study, due in 2019, will we have definitive evidence for the cardiovascular benefit and safety of dapagliflozin,” the comment said.