Dapagliflozin for heart failure according to body mass index: the DELIVER trial

Abstract

Background and Aims Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in DELIVER. Methods BMI was analyzed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Results BMI ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (SD ± 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); class I obesity 1574 (25.2%); class II obesity 798 (12.8%); class III obesity 415 (6.6%). Compared to placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval) 0.89 (0.69-1.15), 0.87 (0.70-1.08), 0.74 (0.58-0.93), 0.78 (0.57-1.08), and 0.72 (0.47-1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (-1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (-0.1, 3.8), 2.7 (-0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: -0.88 (-1.28, -0.47), -0.65 (-1.04, -0.26), -1.42 (-1.89, -0.94), -1.17 (-1.94, -0.40), and -2.50 (-4.4, -0.64) kg (P-interaction = 0.002). Conclusions Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared to those without, and has the additional benefit of causing modest weight loss.

Sodium–glucose cotransporter 2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: time to deliver implementation

“…This is indeed supported by the current analysis from DELIVER, where the magnitude of KCCQ‐TSS improvement was largest among those with most severe NYHA class. A similar theme has emerged in analyses of patients with worse symptoms, obesity, and frailty, each a patient subset where efforts to improve patient quality of life may be a particularly important driver of healthcare decisions 6,10,11 . The amplified benefits on symptoms and quality of life in these more debilitated patients are coupled with consistently strong safety and tolerability.…”

“…The amplified benefits on symptoms and quality of life in these more debilitated patients are coupled with consistently strong safety and tolerability. For example, even in patients with severe NYHA class, active/recent hospitalization, obesity, older age, or substantial frailty, rates of adverse reactions and treatment discontinuation with SGLT2i are no different than placebo, thus further solidifying the net clinical benefit of initiating therapy in these patients who arguably need it the most 10–13 . Nevertheless, it should be noted that only 18 (0.3%) of patients enrolled in DELIVER were NYHA class IV at baseline and only 18 patients (0.3%) were NYHA class IV in EMPEROR‐Preserved 1,2 .…”

“…For example, even in patients with severe NYHA class, active/recent hospitalization, obesity, older age, or substantial frailty, rates of adverse reactions and treatment discontinuation with SGLT2i are no different than placebo, thus further solidifying the net clinical benefit of initiating therapy in these patients who arguably need it the most. [10][11][12][13] Nevertheless, it should be noted that only 18 (0.3%) of patients enrolled in DELIVER were NYHA class IV at baseline and only 18 patients (0.3%) were NYHA class IV in EMPEROR-Preserved. Whether the benefits and safety of SGLT2i can be generalized to NYHA class IV patients will require further study.…”

“…A similar theme has emerged in analyses of patients with worse symptoms, obesity, and frailty, each a patient subset where efforts to improve patient quality of life may be a particularly important driver of healthcare decisions. 6,10,11 The amplified benefits on symptoms and quality of life in these more debilitated patients are coupled with consistently strong safety and tolerability. For example, even in patients with severe NYHA class, active/recent hospitalization, obesity, older age, or substantial frailty, rates of adverse reactions and treatment discontinuation with SGLT2i are no different than placebo, thus further solidifying the net clinical benefit of initiating therapy in these patients who arguably need it the most.…”

Diabetes Mellitus and Heart Failure: Epidemiology, Pathophysiologic Mechanisms, and the Role of SGLT2 Inhibitors

“…In the DELIVER trial of dapagliflozin, individuals with HFmrEF or HFpEF receiving the intervention experienced lower endpoint rates compared to those receiving a placebo [ 157 ]. Dapagliflozin’s effect was evident as early as 2 weeks after initiation [ 158 ], was more pronounced in subjects with a worse baseline symptom burden [ 159 ], and was consistent irrespective of age, body mass index, frailty, baseline glycemic status, or MRA/ARNI use [ 160 , 161 , 162 , 163 , 164 ]. The expected addition of SGLT2i in the societal guidelines of HFpEF/HFmrEF management may result in a significant alleviation of HF burden, with a recent study indicating 250,000 fewer hospitalizations for worsening HF in this group of patients [ 165 ].…”