Acute effect of increasing glucocorticoid replacement dose on insulin sensitivity and cardiovascular risk in patients with adrenocorticotrophin deficiency (#121)
Adrenocorticotrophin (ACTH)-deficient patients taking ≥30 mg hydrocortisone/day have increased cardiovascular mortality. The mechanisms underlying this are unclear. Glucocorticoid excess causes insulin resistance and postprandial hyperglycaemia, which are independent cardiovascular risk factors. Resistance to insulin’s cardiovascular effects, especially postprandially, may underlie this association. The aim was to determine whether increasing hydrocortisone to 30 mg/day in ACTH-deficient patients reduced insulin sensitivity, and consequently, by attenuating insulin’s haemodynamic effects, increased cardiovascular risk.
Seventeen ACTH-deficient subjects, usually taking ≤20 (17±3) mg/day hydrocortisone, were studied before and after increasing hydrocortisone to 30 mg/day for 7 days. Insulin sensitivity was estimated by the Matsuda Index, calculated from a frequently-sampled 75g oral glucose tolerance test. Cardiovascular function was assessed pre- and post-glucose load. Measures of left ventricular afterload (augmentation index (AIx75)) and arterial stiffness (pulse wave velocity (PWV)) were estimated by pulse wave analysis. Reactive hyperaemia index (RHI), a marker of endothelial function, was quantified by peripheral arterial tonometry.
There were no significant changes in fasting (4.8±0.6 vs 4.9±0.7 mmol/L, p=0.23) or 2-hour (8.4±2.6 vs 8.2±3.2 mmol/L, p=0.79) glucose concentration, nor the Matsuda Index (9.4±3.4 vs 7.1±1.4, p=0.32), on the higher glucocorticoid dose. Fasting AIx75 (24.9±2.7 vs 22.6±2.6 %, p=0.04) and RHI (2.3±0.2 vs 2.0±0.2, p=0.04) were lower, and fasting PWV (9.4±1.0 vs 9.1±0.9 m/sec, p=0.24) unchanged, on the higher glucocorticoid dose. There were no significant differences in post-glucose load change in AIx75, PWV or RHI on the higher glucocorticoid dose.In summary, increasing hydrocortisone to 30mg/day did not alter insulin sensitivity and exerted variable effects on cardiovascular risk markers, reducing endothelial function but also a measure of left ventricular afterload. We conclude that endothelial dysfunction may contribute to the increased cardiovascular mortality with higher glucocorticoid doses. This is likely a direct glucocorticoid effect, not mediated by insulin resistance.