Insulin resistance and heart failure

The prevalence of obesity and heart failure has been increasing. A report linking the 2 found an increased risk of heart failure of 5% for men and 7% for women for each increment of 1 in body mass index (BMI).¹ Obese patients had double the risk of heart failure compared with those of normal weight. Approximately 11% of the cases of heart failure in men and 14% in women were attributable to obesity alone. An accompanying editorial suggested that the findings were mediated by insulin resistance.² Insulin resistance and its surrogate, abdominal obesity, are thought to be the underlying cause of the metabolic syndrome, which is often the precursor to diabetes and cardiovascular disease.

A recent prospective community-based observational study in Uppsala, Sweden, evaluated whether insulin resistance could predict heart failure.³ Researchers used euglycemic insulin clamps to measure the glucose disposal rate, the gold standard measurement of insulin resistance. Heart failure developed in 104 of 1187 elderly men over a median follow-up period of 8.9 years. Multivariate analysis, adjusted for established heart failure risk factors, showed a 44% increased risk associated with a 1-standard-deviation in­crease in 2-hour plasma glucose on an oral glucose tolerance test, a 35% increased risk with increased BMI, and a 44% decreased risk with a 1-standard-deviation increase in glucose disposal rate. When adding glucose disposal rate to the models as a covariate, obesity markers were no longer significant pre­dictors of subsequent heart failure. The researchers concluded that insulin resistance predicted heart failure incidence independent of diabetes and other established risk factors, and the association between obesity and subsequent heart failure was mediated largely by insulin resistance.

Doehner and colleagues assessed insulin resistance measured during an intravenous glucose tolerance test using the minimal model technique in 105 men without diabetes but with heart failure. This technique gives an accurate estimate of insulin resistance and has been validated against the euglycemic insulin clamp in patients with heart failure. Patients in the lower half for insulin sensitivity had a 4-year survival rate of 37% vs 73% for those in the upper half, independent of body composition or weight. Worsening in­sulin resistance paralleled worsening measures of heart failure. The authors hypothesized that worsening insulin resistance was secondary to worsening heart failure itself, and was a potential treatment target. A retrospective study of 16,417 older patients with diabetes and heart failure supports that idea, showing that crude 1-year mortality rates were lower among the 2226 patients treated with a thiazolidinedione (30.1%) or the 1861 treated with metformin (24.7%), compared with the 12,069 treated with neither drug (36%).⁴ In multivariable models, treatment with either a thiazolidinedione or metformin was associated with significantly lower risks of death (hazard ratio [HR] = .87). There was a higher risk of readmission for heart failure with thiazolidinediones and a lower risk with metformin (HR = 1.06 and .92, respectively).

Questions arise, including could treatment of insulin resistance in patients with diabetes prevent the development of heart failure and could treatment of insulin resistance after the development of heart failure alter the morbidity and mortality of this devastating disease? Possible mechanisms for worsening insulin resistance in patients with heart failure include decreased tissue perfusion, impaired oxidative metabolism, and decreased physical activity. With diabetes, there is abnormal myocardial metabolism with elevations in free fatty acids and glucose, which can affect coronary flow reserve, vascular and myocardial compliance, and myocardial gene transcription. Potential therapies include exercise (particularly resistance training), weight loss for patients who are obese, and insulin-sensitizing drugs, such as thiazolidinediones and metformin. Careful pro­spective studies are needed to determine if treatment of insulin resistance can decrease the prevalence of heart failure in patients with diabetes or improve outcomes in patients with established heart failure.