SGLT-2 Inhibitors Reduce Cardiovascular Mortality, but Benefit Is Modest, Even in Patients With Established Heart Disease

What are the major cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in different patient populations?

A 14% reduction in cardiovascular death and a number needed to treat of 200 for 3 years to prevent one death was reported with SGLT-2 inhibitors. (Level of Evidence = 1a−)

The authors of the meta-analysis included studies that compared SGLT-2 inhibitors with placebo in at least 1,000 patients who were followed up for at least 6 months. They found a total of 11 studies with 78,607 patients; all studies were industry sponsored. The mean age ranged from 62 to 72 years, 34% were female, and 75% were White. Nearly 80% of patients had diabetes, and 37% had an estimated glomerular filtration rate of less than 60 mL/min/1.73 m². Follow-up ranged from 1.3 years to 4.2 years. The authors combined studies of different SGLT-2 inhibitors, such as empagliflozin (Jardiance), dapagliflozin (Farxiga), ertugliflozin (Steglatro), and canagliflozin (Invokana), and did not identify the specific medication used in the results tables.

In four studies of patients with diabetes and high risk of cardiovascular disease (CVD), there was a significant overall reduction in the composite endpoint of major adverse cardiovascular events (ie, nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) with SGLT-2 inhibitors (hazard ratio [HR] = 0.91; 95% CI, 0.86–0.97). A similar benefit was seen in three studies of patients with chronic kidney disease but not in studies of patients with heart failure (HR = 0.94; 95% CI, 0.86–1.01). It is important to point out that in the four trials with patients at high risk for CVD, two studies included only patients with established CVD, and the other two studies included 40% to 67% of patients with CVD. There was heterogeneity; for example, two of three trials that included patients with kidney disease produced negative results, and only one showed a significant benefit. There was no significant reduction in myocardial infarction or nonfatal stroke, although cardiovascular deaths were significantly reduced (HR = 0.86; 95% CI, 0.81–0.92).

The absolute reductions are less impressive. The authors make it difficult to calculate them, reporting only relative values such as HRs. For cardiovascular death in patients who mostly had established CVD, mortality in the placebo groups was 4.1% overall in a median 3-year study period. Applying an HR of 0.86, there is a mortality of 3.6% in the treatment group, for an absolute reduction in mortality of 0.5% and a number needed to treat of 200 for 3 years to prevent one cardiovascular death, with no impact on myocardial infarction or stroke.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Industry and government

Setting: Outpatient (any)

Reference: Patel SM, Kang YM, Im K, et al. Sodium-glucose cotransporter-2 inhibitors and major adverse cardiovascular outcomes: A SMART-C collaborative meta-analysis. Circulation. 2024;149(23):1789-1801.

Editor's Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.