Risk for HF Hospitalization in Type 2 Diabetes Lower with First-line SGLT-2 Inhibitor vs Metformin

Initiating treatment for type 2 diabetes (T2D) with a sodium-glucose cotransporter (SGLT2) inhibitor could offer greater protection from major heart failure events and associated mortality than first-line therapy with metformin, according to new research from Brigham and Women’s Hospital (BWH) and Harvard Medical School.

The risk for cardio- and cerebrovascular events and mortality after 12 months of treatment, the study found, was the same with either class of drugs.

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Writing in the Annals of Internal Medicine, a research team led by HoJin Shin, BPharm, PhD, a postdoctoral research fellow at BWH, points out that SGLT-2 inhibitors have been recommended as second-line therapy for T2D since 2018 and most recently endorsed as first-line treatment in clinical guidelines from the American Diabetes Association, regardless of A1c or metformin use. Initiation with an agent from the class is particularly recommended for individuals at increased risk for cardiovascular (CV) disease, heart failure, and chronic kidney disease.

To help build the real-world information base on comparative first-line T2D treatment, Shin and colleagues designed their population-based cohort study using claims data (April 2013 through March 2020) from 2 large commercial databases and Medicare fee-for-service to model a target trial comparing the risk for CV events associated with first-line SGLT-2 inhibitors versus metformin in patients with T2D.

Eligible participants diagnosed with T2D were aged ≥18 years (>65 years in the Medicare set), were diabetes treatment-naïve before April 2013, and had initiated treatment with a SGLT2 inhibitor (ie, canagliflozin, empagliflozin, or dapagliflozin) or metformin during the study period.

The study team’s primary outcomes of interest were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Investigators also assessed safety outcomes, including incidence of genital infections.

After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported.

Results

Shin and colleagues identified 8613 participants who initiated therapy with an SGLT2 inhibitor and matched those with 17 226 who were prescribed first-line metformin.

Analysis of the composite CV outcome found that SGLT-2 inhibitor initiators compared with metformin initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up period of 12 months. The latter finding, according to the researchers, was likely driven by a lower risk for HHF (below).

When they analyzed the components of the composite outcomes the researchers report that initiators who received an SGLT2 inhibitor compared with metformin showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality.

Safety outcomes, according to the team, were similar between the two sets of initiators but that those taking an SGLT2 inhibitor had an increased risk for genital yeast infections (HR, 2.19; CI, 1.91 to 2.51), a known class side effect and one that “may be less serious than other safety outcomes and can be appropriately managed.”

In conclusion Hojin and colleagues write, “Although our findings may support the use of SGLT-2i as first-line T2D treatment of cardiovascular outcomes, further research, that is, a randomized clinical trial, is warranted to establish more robust evidence.”

Reference: Shin H, Schneeweiss S, Glynn RJ, Patorno, E. Cardiovascular outcomes in patients initiating first-line treatment of type 2 diabetes with sodium-glucose cotransporter=2 inhibitors versus metformin: a cohort study. Ann Intern Med. Published online May 23, 2022. doi: doi:10.7326/M21-4012.