Efficacy and safety of dapagliflozin according to baseline blood pressure – observations from DECLARE-TIMI 58 Trlial

Abstract

Abstract Background Type 2 diabetes mellitus (T2DM) is associated with heightened risk of cardio-renal complications. In DECLARE-TIMI 58, dapagliflozin, compared to placebo, reduced hospitalization for heart failure (HHF) and renal events (the composite of sustained decrease in glomerular filtration rate of at least 40%, progression to end-stage renal disease or death due to renal causes) in a broad range of patients with T2DM, without increase in volume depletion or amputations (two adverse events potentially related to blood pressure lowering). It is uncertain whether the cardio-renal effects of dapagliflozin are partially mediated by an anti-hypertensive effect and whether patients with normal blood pressure can be safely treated with this drug class. In this pre-specified analysis, we report the interaction of those results with baseline systolic blood pressure (SBP). Purpose To analyze efficacy and safety of dapagliflozin stratified according to baseline SBP. Methods DECLARE-TIMI 58 enrolled 17,160 patients with T2DM with either prior atherosclerotic disease or risk factors. Following the most recent guidelines, patients were categorized according to the following baseline SBP levels: <120, 120–129, 130–139, 140–159 and ≥160 mmHg (respectively, optimal, normal, high normal, grade 1 hypertension and grade 2–3 or severe hypertension). Additionally, spline models were developed to explore the association between SBP and the incidence rates of HHF and renal events. Models were adjusted for: diastolic blood pressure, prior coronary artery disease, prior stroke, peripheral artery disease, dyslipidemia, history of hypertension, prior HF, glomerular filtration rate <60 ml/min/1.73 m2, urinary albumin to creatinin ratio >300 mg/g, age, race, body mass index, DM duration and region. Results From the overall trial population, 2557, 3686, 4385, 5501 and 1031 patients were categorized as optimal, normal, high normal, grade 1 hypertension and grade 2–3 or severe hypertension, respectively. After adjustment for clinical co-variates, there was an independent association between SBP and HHF or renal events in the placebo arm, with a “U”-shaped association for both events. Moreover, patients with severe hypertension were at the highest risk for HHF and renal events (Figure 1, Panels A and B). While the HHF benefit of dapagliflozin was amplified in patients with severe hypertension (p-int=0.041), the benefit of dapagliflozin did not differ by SBP category for renal events (p-int=0.15), (Figure 1, Panels C and D). There was no increase in symptoms of volume depletion or amputation at any level of SBP (p-int = 0.93 and 0.28, respectively). Conclusion In patients with T2DM, baseline SBP was independently associated with HHF and renal events with a “U”-shaped relationship. Patients with severe hypertension experienced a greater benefit with dapagliflozin for HHF, and renal events were consistently reduced with dapagliflozin across all levels of SBP. Figure 1. HHF and renal events according to SBP Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): AstraZeneca