Diabetes is a potent risk factor for heart failure (HF), and at least 40% of HF patients concomitantly have diabetes (1). However, the extent of the associations of diabetes with exercise tolerance, functional status, and death among individuals with chronic HF largely remains undescribed.
We included individuals from five studies of chronic HF, including HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), IRONOUT HF (Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure), NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction), INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF), and RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure). Diabetes was defined based on self-report of physician diagnosis. Exercise capacity was assessed using VO2max (in milliliters/kilogram/minute), VO2 at ventilatory threshold (VO2AT) (in milliliters/kilogram/minute), heart rate peak (HRpeak) (in percentage of maximal heart rate), peak respiratory exchange ratio (RERpeak), and 6-min walking test distance (6MWT-D) (in meters). Functional status was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score. All-cause mortality was ascertained in all the included studies.
We used mixed linear regression models to examine cross-sectional associations of diabetes with exercise capacity (VO2max, VO2AT, HRpeak, RERpeak, and 6MWT-D) and quality of life (naturally log-transformed KCCQ overall summary score). We employed Cox regression models to assess the diabetes and all-cause mortality association. In all models, we accounted for the clustering effect on study and adjusted for age, sex, race, left ventricular ejection fraction, obesity, hyperlipidemia, hypertension, chronic kidney disease, myocardial infarction, stroke, peripheral vascular disease, chronic obstructive pulmonary disease, anemia, and depression.
Among the included 2,786 individuals with HF (mean age 60.4 ± 12.8 years, 67.5% men, 42% non-White individuals, 84% with heart failure with reduced ejection fraction [n = 2,345], and 16% with heart failure with preserved ejection fraction [n = 441]), 33.7% had diabetes. Individuals with diabetes were older and more likely to be men; they also exhibited a higher prevalence of obesity, hypertension, hyperlipidemia, chronic kidney disease, myocardial infarction, peripheral vascular disease, chronic obstructive pulmonary disease, and anemia.
Over a median follow-up of 31.12 months, the cumulative risk of death was higher among individuals with diabetes than those without diabetes (Fig. 1A). In multivariable adjusted models, compared with no-diabetes status (Fig. 1B), diabetes was associated with a lower 6MWT-D (β coefficient [β] −20.18; 95% CI −30.85, −9.50), lower VO2max (β −1.27; 95% CI −1.67, −0.87), lower VO2AT (β −0.59; 95% CI −0.87, −0.31), lower HRpeak (β −2.89; 95% CI −5.05, −0.73), and higher risk of death (hazard ratio 1.31; 95% CI 1.01, 1.69). However, diabetes was not associated with RERpeak (β −0.00005; 95% CI −0.01, 0.01) or with quality of life (β for ln [KCCQ score] −0.03; 95% CI −0.07, 0.02).
Association of diabetes and heart failure outcomes. A: Cumulative incidence of death by diabetes status. B: β Coefficients of the association between diabetes and functional status parameters.
Association of diabetes and heart failure outcomes. A: Cumulative incidence of death by diabetes status. B: β Coefficients of the association between diabetes and functional status parameters.
Our findings confirm those from the few prior studies examining the connection of diabetes and exercise capacity or mortality in patients with HF (2–4). Our work complements these studies, which were relatively small in size, included a limited number of individuals with diabetes, lacked racial and ethnic diversity, examined single outcomes, and did not include all HF subtypes (2–4). Indeed, we pooled data from five well-characterized and clinical studies of the spectrum of chronic HF, thus providing a robust study size and several functional (including multiple aspects of exercise capacity) and mortality outcomes. However, definitive conclusions on causality are limited by the cross-sectional design of some analyses and possible residual confounding. We lacked data on direct glycemic assessment for a more accurate diagnosis of diabetes and assessment of the extent of its control; thus, we probably underestimated the burden of diabetes and the extent of its effects on HF outcomes. The study participants were predominantly patients with heart failure with reduced ejection fraction (>80%), precluding meaningful investigations by HF subtype. We also did not account for the effects of the drug interventions tested in the included clinical studies, given the lack of uniformity.
In summary, diabetes was associated with adverse functional capacity and mortality outcomes in patients with chronic HF. Our findings underscore the potential importance of optimizing metabolic health among individuals with chronic HF, ideally using sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists (5), which have glucose-lowering and cardioprotective effects. Additional studies that include a more comprehensive diabetes ascertainment and wider spectrum of HF subtypes are needed to further characterize the connection between diabetes and HF outcomes.
Article Information
Acknowledgments. J.B.E.-T. is an editor of Diabetes Care but was not involved in any of the decisions regarding review of the manuscript or its acceptance.
Funding. J.B.E.-T. was supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant K23 HL153774.
Duality of Interest. G.C.F. reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Boehinger Ingelheim, Cytokinetics, Eli Lilly Janssen, Medtronic, Merck, Novartis, and Pfizer. No other potential conflicts of interest relevant to this article were reported
Author Contributions. S.R.N. and J.B.E.-T. drafted the manuscript and performed statistical analysis. J.B.E.-T. conceived of and designed the study; obtained funding; provided administrative, technical, or material support; and supervised. All authors contributed to critical revision of the manuscript for important intellectual content. J.B.E.-T. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Frank B. Hu.