We read the report by Tomova et al on the inverse association of hyperglycemia (glycosylated hemoglobin [HbA _1c ]) with outcomes in advanced heart failure (HF). The conclusion of the investigators, that HbA _1c may be an insufficient marker of hyperglycemia in these patients, falls short of the true question to be addressed here: in fact, HbA _1c , as a biochemical measure, seems beyond doubt to reflect long-term glycemic balance. The question, however, if hyperglycemia is indeed the appropriate target to look for is on the table. Indeed, the report adds to the emerging inconsistency if not confusion on the relevance of glycemia as suitable outcome predictor as well as therapeutic target in patients with HF and diabetes.

First, a profound discrepancy in the association between glycemia and mortality in HF populations has emerged as both linear positive (in the Candesartan in Heart Failure Assessment of Mortality and Morbidity [CHARM] trial) and inverse (Eshagian, Tomova) associations between HbA _1c and outcomes have been reported. Moreover, an U-shaped (Aguilar) relation has also been observed, and in a recent study, a J shape described a threshold characteristic of glycemia with an abrupt increase in mortality if HbA _1c levels > 6.6 were measured. On the basis of the discrepancies of these data, it seems safe to conclude that HbA _1c as a measure of hyperglycemia may not be a suitable tool to evaluate mortality in these patients. Moreover, substantial evidence has accumulated suggesting that glycemia is unsuitable as a therapeutic target, as well. In a number of large-scale clinical trials (the United Kingdom Prospective Diabetes Study [UKPDS], the Prospective Pioglitazone Clinical Trial in Macrovascular Events [PROactive], the Veterans Affairs Diabetes Trial [VADT], the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] trial, and the Action to Control Cardiovascular Risk in Diabetes [ACCORD] trial), targeting hyperglycemia has failed to translate into improved outcomes. Targeting hyperglycemia directly (therapy with insulin and sulfonylurea) in the UKPDS trial yielded better outcomes only at the 10-year follow-up analysis. In contrast, targeting insulin resistance (metformin), the underlying upstream pathophysiologic principle of hyperglycemia, resulted in early and sustained clinical benefit. Furthermore, it has been shown previously in patients with HF without diabetes that higher insulin resistance predicts higher mortality, independent of body composition and established prognosticators. Indeed, insulin resistance has been identified as an intrinsic metabolic feature within HF pathophysiology contributing to symptomatic status as to disease progression.

Taken together, the emerging data suggest that insulin sensitivity may be superior to hyperglycemia as a prognostic marker and as a therapeutic target in HF. Diagnostic tools (homeostasis model assessment) and therapeutic options to improve insulin resistance directly should be pursued to improve glycemic control in patients with HF.