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The liver X receptors α and β are orphan nuclear receptors that are key regulators in maintaining cholesterol homeostasis. Originally they were found to play an important role in reverse cholesterol transport, a pathway for the removal of excess cellular cholesterol. However several groups have now shown that the liver X receptors also functions in lipid and carbohydrate metabolism, cellular differentiation, apoptosis and many immune responses. Tissue distribution of the two paralogues differs with liver X receptor β ubiquitously expressed, while liver X receptor α is confined to the liver, kidney, intestine, spleen, adipose tissue, macrophages and skeletal muscle. The endogenous ligands for the liver X receptors are certain oxidized derivatives of cholesterol, the oxysterols. Upon activation by oxysterols, the receptors form obligate heterodimers with retinoid X receptors α, β and γ; and become competent to activate the transcription of target genes.

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Aims: Up to a third of patients with diabetes mellitus (DM) and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes. Methods and results: We examined two datasets: (1) 24,012 patients with HF from 4 large randomized trials and (2) an administrative database of 4 million individuals, 103857 with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine-Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter a case-control nested within a population-based cohort study was conducted with propensity score. Prevalence of DM at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with diabetes vs no-diabetes, and highest of all in patients prescribed insulin (propensity score pooled HR for all-cause mortality 1.27 [1.16-1.38], for HF hospitalization 1.23 [1.13-1.33]). In the administrative registry, insulin prescription was associated with a higher risk of all-cause death (OR 2.02 95% CI [1.87-2.19]) and re-hospitalization for HF (OR 1.42 95% CI [1.32-1.53]). Conclusions: Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose lowering treatments for patients with HF and T2DM.