Although ORIGIN indicated that insulin is safe regarding the risk of incident heart failure, an observational study called CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) demonstrated a significantly increased risk of all-cause mortality (HR 1.25 (95% CI 1.03–1.51)), as well as a significantly increased risk of a composite outcome of cardiovascular death and hospitalisation for heart failure (HR 2.03 (95% CI 1.80–2.29)) associated with insulin in patients with established heart failure [16]. This evidence concerns the gene INS and heart failure.