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Erik Ingelsson, MD; Johan Sundström, MD, PhD; Johan Ärnlöv, MD, PhD; Björn Zethelius, MD, PhD; Lars Lind, MD, PhD

JAMA. 2005;294:334-341.

Context  Diabetes and obesity are established risk factors for congestive heart failure (CHF) and are both associated with insulin resistance.

Objective  To explore if insulin resistance may predict CHF and may provide the link between obesity and CHF.

Design, Setting, and Participants  The Uppsala Longitudinal Study of Adult Men, a prospective, community-based, observational cohort in Uppsala, Sweden. We investigated 1187 elderly (70 years) men free from CHF and valvular disease at baseline between 1990 and 1995, with follow-up until the end of 2002. Variables reflecting insulin sensitivity (including euglycemic insulin clamp glucose disposal rate) and obesity were analyzed together with established risk factors (prior myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, and serum cholesterol level) as predictors of subsequent incidence of CHF, using Cox proportional hazards analyses.

Main Outcome Measure  First hospitalization for heart failure.

Results  One hundred four men developed CHF during a median follow-up of 8.9 (range, 0.01-11.4) years. In multivariable Cox proportional hazards models adjusted for established risk factors for CHF, increased risk of CHF was associated with a 1-SD increase in the 2-hour glucose value of an oral glucose tolerance test (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.08-1.93), fasting serum proinsulin level (HR, 1.29; 95% CI, 1.02-1.64), body mass index (HR, 1.35; 95% CI, 1.11-1.65), and waist circumference (HR, 1.36; 95% CI, 1.10-1.69), whereas a 1-SD increase in clamp glucose disposal rate decreased the risk (HR, 0.66; 95% CI, 0.51-0.86). When adding clamp glucose disposal rate to these models as a covariate, the obesity variables were no longer significant predictors of subsequent CHF.

Conclusions  Insulin resistance predicted CHF incidence independently of established risk factors including diabetes in our large community-based sample of elderly men. The previously described association between obesity and subsequent CHF may be mediated largely by insulin resistance.

Author Affiliations: Departments of Public Health and Caring Sciences (Drs Ingelsson, Sundström, Ärnlöv, and Zethelius) and Medical Sciences (Dr Lind), Uppsala University, Uppsala, Sweden; and Astra Zeneca R&D, Mölndal, Sweden (Dr Lind).

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