Dapagliflozin reduced cardiorenal outcomes but not MACE in T2 diabetes with or at risk for atherosclerotic CVD

Baseline kidney disease, albuminuria, and cardiovascular disease (CVD) status may help determine which patients will benefit most from sodium-glucose cotransporter-2 inhibitors, according to an ACP Journal Club commentary.


The multinational, industry-funded DECLARE-TIMI 58 trial randomized more than 17,000 patients with type 2 diabetes and either established cardiovascular disease (CVD) or high CVD risk to dapagliflozin or placebo. After a median follow-up of 4.2 years, rates of major adverse cardiovascular events (MACEs) were similar in the two groups, but hospitalizations for heart failure (HF) were reduced in the intervention group. A separate secondary analysis found a significant reduction in the risk of declining renal function in the intervention group compared to the placebo group.

The trial's results were published on Jan. 24 by the New England Journal of Medicine. The secondary analysis of renal outcomes was published June 10 by The Lancet Diabetes & Endocrinology. The following commentary by Louise Moist, MD, was published in the ACP Journal Club section of the Oct. 15 Annals of Internal Medicine.

The beneficial effects of sodium–glucose cotransporter 2 (SGLT-2) inhibitors on CV outcomes may differ in patients without vs with previous CVD. In the DECLARE–TIMI 58 trial (CVD prevalence 41%), dapagliflozin did not reduce MACE, CV mortality, or all-cause mortality. This differs from other large SGLT-2 inhibitor CV trials, which showed that MACE and other CV outcomes were reduced in patients with and without CVD.

DECLARE-TIMI 58 supports previous evidence that SGLT-2 inhibitors reduce hospitalizations for HF. That this benefit occurred in patients without a history of CVD or HF is clinically important, as it expands the benefit of dapagliflozin to a broader population than previously identified in other large SGLT-2 inhibitor trials.

A secondary analysis of DECLARE-TIMI 58 by Mosenzon and colleagues showed that, in patients with mostly preserved kidney function with minimal proteinuria, dapagliflozin reduced risk for a cardiorenal composite outcome in patients with and without CVD and baseline kidney dysfunction. The results are only hypothesis-generating but are consistent with previous studies of SGLT-2 inhibitors.

Baseline kidney disease, albuminuria, and established CVD are the most important indicators of risk for both CV and kidney events and, thus, may also indicate which patients will benefit most from SGLT-2 inhibitors. Studies with definitive kidney outcomes in patients with and without these risk factors are currently under way (ClinicalTrials.gov NCT03036150, NCT03594110).