Dapagliflozin Reduces Cardiovascular Risk in Diabetes Patients, Regardless of Baseline Kidney Function

Stephen Wiviott, MD

A new analysis of dapagliflozin use in patients with type 2 diabetes has returned evidence supporting use of the SGLT2 inhibitor for reducing cardiovascular risk in patients with diabetes across all eGFR and UACR groups included within the phase 3 trial.

Results of the DECLARE-TIMI 58 analysis suggest the reduced risk of cardiovascular events seen with dapagliflozin was consistent irrespective of baseline eGFR and UACR, with the greatest absolute benefit observed among those with both reduced eGFR and albuminuria.

“The results from the present analyses of the DECLARE-TIMI 58 trial showed largely consistent relative risk reductions with dapagliflozin in CV events irrespective of baseline eGFR and albuminuria status in a broad population of patients with type 2 diabetes who had or were at risk for ASCVD. However, patients with more markers of CKD derived a significantly greater absolute risk reduction for the composite of CV death or hospitalization for heart failure,” wrote investigators.

With an interest in further examining the cardiovascular efficacy of dapagliflozin beyond glucose control, the current study was designed as a prespecified secondary analysis of patients within DECLARE-TIMI 58. Using data from the 17,160 participants of the trial, investigators hoped to assess the efficacy and safety of dapagliflozin in patients based on baseline kidney function and albuminuria status.

For the purpose of analysis, eGFR groups were defined as an eGFR at or above 60 mL/min/1.73 m2 and less than 60 mL/min/1.73m2. For UACR, groups were defined as a UACR less than 30 mg/g and mg/g or greater. Investigators also noted analyses planned to use presence of these markers of chronic kidney disease to further categorize patients into subgroups (0, 1, or 2).

Overall, 10,958 patients had an eGFR at or above 60 mL/min/1.73 m2 and an UACR below 30 mg/g and 5336 patients with an eGFR below 60 mL/min/1.73 m2 or an UACR at or above 30 mg/g. This group included 1265 patients with an eGFR below 60 mL/min/1.73 m2, 5199 patients with UACR at or above 30 mg/g, and 548 patients with both.

The primary efficacy endpoints for the study were composites of CV death or hospitalization for heart failure and major adverse cardiovascular events (MACE). The primary safety endpoints included major hypoglycemia, amputation, diabetic ketoacidosis, and fracture.

Using a Kaplan-Meier approach, investigators found patients in the placebo groups with more chronic kidney disease markers had higher event rates at 4 years for the composite of cardiovascular death or hospitalization for heart failure (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and MACE (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers).

When estimating relative risk reductions for the primary efficacy endpoints, results indicated the effect of dapagliflozin was generally consistent across the subgroups (P > .24 for interaction. However, investigators pointed out greater absolute risk reductions were observed among those with more markers of chronic kidney disease. Additionally, in assessments of absolute risk difference, the greatest benefit was seen among patients with more markers of chronic kidney disease (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P=.02 for interaction).

In safety analyses, results indicated the number of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared to placebo therapy in patients with an eGFR lower than 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.

This study, “Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes,” was published in JAMA Cardiology.