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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 the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial. Methods and results Body mass index was analysed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Body mass index ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (standard deviation ± 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%); and Class III obesity 415 (6.6%). Compared with 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 with those without, and has the additional benefit of causing modest weight loss. [ABSTRACT FROM AUTHOR]

Aims: Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium–glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment. Methods and results: We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA‐HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end‐of‐study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N‐terminal pro‐B‐type natriuretic peptide [NT‐proBNP] and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT‐proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 [95% confidence interval 1.37–2.17], p < 0.001; and 1.52 [1.12–2.07], p = 0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow‐up, dapagliflozin had no effect on liver tests. Conclusion: Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests. Clinical Trial Registration: ClinicalTrials.gov NCT03036124. [ABSTRACT FROM AUTHOR]

Aims: In heart failure with reduced ejection fraction (HFrEF), there is an 'obesity paradox', where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a sodium-glucose co-transporter 2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).Methods and Results: Body mass index was examined using standard categories, i.e. underweight (<18.5 kg/m2 ); normal weight (18.5-24.9 kg/m2 ); overweight (25.0-29.9 kg/m2 ); obesity class I (30.0-34.9 kg/m2 ); obesity class II (35.0-39.9 kg/m2 ); and obesity class III (≥40 kg/m2 ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal-weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% confidence interval) for the primary outcome with obesity class 1, the lowest risk group, as reference was: under/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI, e.g. hazard ratio for primary outcome: under/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00) (P-value for interaction = 0.79). The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) kg (P < 0.001).Conclusion: We confirmed an 'obesity survival paradox' in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied.Clinical Trial Registration: ClinicalTrials.gov NCT03036124. [ABSTRACT FROM AUTHOR]