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Cardiovascular, Renal, and Metabolic Outcomes of Dapagliflozin Versus Placebo in a Primary Cardiovascular Prevention Cohort: Analyses From DECLARE-TIMI 58

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posted on 02.03.2021, 16:57 by Avivit Cahn, Itamar Raz, Lawrence A. Leiter, Ofri Mosenzon, Sabina A. Murphy, Erica L. Goodrich, Ilan Yanuv, Aliza Rozenberg, Deepak L. Bhatt, Darren K. McGuire, John P.H. Wilding, Ingrid A. M. Gause-Nilsson, Anna Maria Langkilde, Marc S. Sabatine, Stephen D. Wiviott
Aims: International guidelines propose prescribing SGLT-2 inhibitors to patients with type-2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT-2 inhibitors in MRF patients.

Methods: The DECLARE-TIMI 58 trial randomized 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) to dapagliflozin vs. placebo, followed for a median 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction.

Results: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF; HR 0.84, 95%CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95%CI 0.37-0.69) did not differ from patients with ASCVD (Pinteraction 0.99 and 0.72 respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95%CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood-pressure and urinary albumin:creatinine ratio were lower with dapagliflozin vs. placebo and eGFR was higher (p<0.001).

Conclusion: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin on important outcomes in a broad primary prevention population.

Funding

The sponsor of the DECLARE - TIMI 58 study was initially AstraZeneca and Bristol-Myers Squibb and AstraZeneca later became the sole sponsor of the study. The DECLARE–TIMI 58 trial was a collaboration between the funder and two academic research organizations (TIMI Study Group and Hadassah Medical Organization). The funder was involved in the study design, data collection, data analysis, interpretation, and writing of this report. IAMG-N and AML are employed by the study funder. Data analyses were done by the academic TIMI Study Group, which has access to the complete study database, allowing independent analyses of the results; any discrepancies were resolved by discussion. The DECLARE–TIMI 58 publication committee made the decision to submit for publication.

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