SGLT2 Inhibitors Reduce CV, Kidney Event Risk Regardless of Metformin Use

Investigators evaluated whether the effects of SGLT2 inhibitors on cardiovascular, kidney and mortality outcomes are the same with and without concomitant metformin use.

Treatment with sodium-glucose cotransporter (SGLT2) inhibitors, a recommended second-line approach to type 2 diabetes (T2D), is associated with reductions in cardiovascular (CV), kidney, and mortality risks, according to study results in Diabetes, Obesity and Metabolism. These reductions were observed both with and without concomitant metformin therapy in patients with T2D who are at high risk for CV events.

In this study, investigators from Australia analyzed a total of 6 placebo-controlled SGLT2 inhibitor trials that reported CV, kidney, or mortality outcomes by baseline metformin use. They pooled the trials together in a meta-analysis that comprised an overall T2D population of 51,743. The primary outcomes of the meta-analysis included the incidence of major adverse cardiovascular events (MACE) and rates of hospitalized heart failure or CV death.

Across the analyzed trials, baseline metformin use ranged from 21.4% up to 82%. Treatment with SGLT2 inhibitors were associated with reductions in the risk for MACE with metformin use (hazard ratio [HR], 0.93; 95% CI, 0.87-1) and without metformin use (HR, 0.82; 95% CI, 0.71-0.86; P-heterogeneity =.14).

Investigators observed separate reductions in hospitalizations for heart failure or CV death with SGLT2 inhibitors in patients who were using metformin (HR, 0.79; 95% CI, 0.73-0.86) and patients who were not using metformin (HR, 0.74; 95% CI, 0.63-0.87; P-heterogeneity =.48).

In addition, the use of SGLT2 inhibitors was associated with reductions in the risk for major kidney outcomes in patients receiving metformin (HR 0.58; 95% CI, 0.48-0.69) and not receiving metformin (HR, 0.63, 95% CI, 0.48-0.83; P-heterogeneity =.62).

Treatment with SGLT2 inhibitors also reduced the risk for all-cause mortality irrespective of whether patients received metformin (HR 0.84; 95% CI, 0.75-0.95) or did not receive metformin (HR, 0.79; 95% CI, 0.66-0.94; P-heterogeneity =.57).

A limitation of this meta-analysis was the inclusion of trials that enrolled mostly patients with long-term T2D who were at high risk for CV events. This may limit the generalizability of the findings to patients with newly diagnosed T2D.

The study investigators suggested their “data call into question current clinical practice recommendations that recommend SGLT2 inhibitors be used as second-line treatment only in people who do not achieve satisfactory glucose control with metformin alone.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Neuen BL, Arnott C, Perkovic V, et al. Sodium-glucose co-transporter-2 inhibitors with and without metformin: a meta-analysis of cardiovascular, kidney and mortality outcomes. Published online October 11, 2020. Diabetes Obes Metab. doi:10.1111/dom.14226