Type 2 Diabetes in Heart Failure with Preserved and Mildly-Reduced Ejection Fraction: Insights from the REDUCE-LAP-HF II trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and obesity are the archetypal components of cardiometabolic syndromes associated with heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). The specific contribution of T2DM, independent of obesity, to myocardial adaptations and outcomes remains uncertain. OBJECTIVES: We aimed to explore the obesity-independent contribution of T2DM to cardiac structure, function, central hemodynamics, and outcomes. METHODS: We leveraged the sham-control arm of the REDUCE LAP-HF II trial (n=312), a prospectively phenotyped cohort of patients with HFpEF/HFmrEF undergoing invasive hemodynamic assessment. Multivariable models were used to adjust for body mass index (BMI) and clinical covariates. Outcomes included cardiovascular death, and total heart failure events. RESULTS: T2DM was present in 37% of patients and was associated with higher BMI, chronic kidney disease, and prior heart failure hospitalization. Obesity was present in 62% of patients and was more prevalent in those with T2DM (70% vs 57%, p=0.032). After adjustment for BMI, T2DM remained independently associated with greater left ventricular mass, lower ejection fraction, impaired left ventricular global longitudinal strain, reduced right ventricular free-wall strain, and higher resting filling pressures. Over a median 4.0 year (2.5-5.0) follow-up, T2DM was independently associated with increased risk of HF events or CV death (adjusted HR 1.96, 95% CI 1.28-3.00), driven by heart failure events, whereas BMI was not independently prognostic. CONCLUSIONS: HFpEF/HFmrEF patients with T2DM experience adverse myocardial remodeling, impaired biventricular function, adverse central hemodynamics, and worse clinical outcomes independent of obesity. These findings indicate that T2DM confers additional metabolic burden to the myocardium, beyond that attributable to obesity alone.