Dapagliflozin may reduce the risk for hospitalization for heart failure (HF) and adverse renal outcomes regardless of baseline characteristics in patients with type 2 diabetes (T2D) and multiple risk factors, according to study results published in Diabetes Care.

The Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58; ClinicalTrials.gov Identifier: NCT01730534) trial included 17,160 patients who were randomly assigned to receive dapagliflozin or placebo and were followed for a median of 4.2 years. Of the total cohort, 6974 patients had established atherosclerotic cardiovascular disease (ASCVD) and 10,186 had multiple risk factors but without ASCVD.

Participants with multiple risk factors had at least 1 additional cardiovascular (CV) risk factor, including dyslipidemia, hypertension, or current tobacco use. Investigators evaluated the CV and renal outcomes in the multiple risk factor cohort in the clinically relevant subgroups for treatment effect and subgroup-based treatment interaction.

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The cohort of 10,186 patients with multiple risk factors (56.1% men) was included in the current analysis. The mean age of the participants was 64.8±5.6 years, with body mass index of 32± 5.9 and baseline glycated hemoglobin (HbA1c) of 8.3%±1.2%. Researchers observed heart failure at baseline in 568 (5.6%) patients, and 622 (6.1%) had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2.

In the multiple risk factor cohort, the reduction with dapagliflozin in risk for CVD/HF hospitalization (hazard ratio [HR], 0.84; 95% CI, 0.67-1.04) was not different from that observed in patients with ASCVD (Pinteraction =.99). The effect on CVD/HF hospitalization was entirely driven by a decrease in hospitalization for HF (HR, 0.64; 95% CI, 0.46-0.88), noted the study authors.

At 48 months, the least squares mean for patients who received dapagliflozin vs placebo was lower for HbA1c (7.79%±0.04% vs 8.03%±0.04%), weight (85.76±0.14 vs 87.86±0.14 kg), systolic blood pressure (132.96±0.37 vs 135.32±0.37mm Hg), and urinary albumin-to-creatinine ratio (22.53±1.03 vs 27.42±1.03 mg/g), and higher for eGFR (77.21±0.31 vs 75.62±0.31 mL/min/1.73 m2).

The investigators observed a significant difference in the change from baseline for dapagliflozin compared with placebo for all measurements (P <.001).

The findings have several limitations, according to the researchers. The trial was not powered to detect all possible event reductions and treatment-by-subgroup interactions, and the analyses of subgroups within the patients with multiple risk factors are post hoc, and no adjustment was made for multiple comparisons.

“The current analyses highlight the benefits of dapagliflozin in the prevention of [HF hospitalization] and adverse renal outcomes across a broad risk continuum of a primary prevention population with T2D,” the study authors concluded. “Dapagliflozin’s overall favorable safety profile places it as an appropriate option early in the disease for patients with T2D.”

Disclosure: The sponsor of DECLARE-TIMI 58 was initially AstraZeneca Pharmaceuticals LP (AstraZeneca) and Bristol-Myers Squibb Company (BMS), and AstraZeneca later became the sole sponsor of the study. Some of the authors reported affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Cahn A, Raz I, Leiter LA, et al. Cardiovascular, renal, and metabolic outcomes of dapagliflozin versus placebo in a primary cardiovascular prevention cohort: analyses from DECLARE-TIMI 58. Diabetes Care. Published online March 2, 2021. doi: 10.2337/dc20-2492