The Cardio-Metabolic Effects of Low Dose Glucocorticoids and the Treatment of Prednisolone-Induced Hyperglycaemia

Author: Anjana Radhakutty

Radhakutty, Anjana, 2019 The Cardio-Metabolic Effects of Low Dose Glucocorticoids and the Treatment of Prednisolone-Induced Hyperglycaemia, Flinders University, College of Medicine and Public Health

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Glucocorticoids are anti-inflammatory agents that are commonly prescribed in low doses (e.g prednisolone <10 mg/day) long-term to attenuate inflammatory disease progression and in higher doses (e.g prednisolone >20 mg/day) short-term to treat an acute inflammatory exacerbation. Low dose glucocorticoids can cause insulin resistance and postprandial hyperglycaemia. However, whether this translates into an increased cardiovascular risk is unclear. Although it is known that higher prednisolone doses can increase blood glucose, optimal treatment of prednisolone-induced hyperglycaemia has not been defined. This PhD project comprised three studies investigating the acute and chronic cardio-metabolic effects of low dose prednisolone in the same cohort and an open randomized-controlled trial comparing the efficacy and safety of two insulin regimens in hospitalized patients with prednisolone-induced hyperglycaemia.

In Study 1 acute, but not chronic, prednisolone was associated with a reduction in sympathetic nervous system activity and postprandial fall in augmentation index indicating reduced arterial stiffness. There was no change in fasting reactive hyperaemia index (RHI), a marker of endothelial function, with low dose prednisolone. Moreover, there was an attenuated postprandial fall in RHI in patients taking chronic prednisolone that almost reached statistical significance. To further investigate the effect of prednisolone on endothelial function, the effects of rheumatoid arthritis per se and low dose prednisolone on arginine metabolomics were assessed (Study 2). Patients with rheumatoid arthritis have higher plasma asymmetric dimethyl arginine (ADMA) than controls, a potent inhibitor of endothelial nitric oxide synthase (e-NOS). Chronic, but not acute, prednisolone reduced ADMA, which may contribute to better endothelial function in patients taking long-term prednisolone.

In study 3, prednisolone did not affect resting energy expenditure or diet-induced thermogenesis. However, acute and chronic prednisolone induced insulin resistance, which was associated with attenuated postprandial suppression of fat oxidation. Patients on long-term prednisolone had higher fasting non-esterified fatty acids (NEFA), but there was no difference in insulin-mediated suppression of NEFA. These results suggest that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes.

Finally, in Study 4 the efficacy and safety of isophane and glargine-based basal bolus insulin regimens were compared in hospitalized patients with prednisolone-induced hyperglycaemia. Glycaemic control was assessed using a continuous glucose monitoring system. There were no significant differences in the percentage time outside a target glucose range of 4-10 mmol/L or hypoglycaemia with the two insulin regimens.

In summary, acute and chronic low dose prednisolone causes greater insulin resistance in skeletal muscles than in adipocytes. However, this does not translate into increased arterial stiffness or endothelial dysfunction in patients with rheumatoid arthritis. A reduction in the elevated levels of inhibitors of e-NOS associated with rheumatoid arthritis could explain why patients on long-term prednisolone had better endothelial function. There was no difference in the efficacy or safety of isophane- and glargine-based insulin regimens in the treatment of prednisolone-induced hyperglycaemia. The study demonstrates that a starting daily insulin dose of 0.5 units/Kg is safe treatment of prednisolone-induced hyperglycaemia in patients who are not already taking insulin, but that a 30% increase in daily insulin dose is insufficient in insulin-treated patients.

Keywords: Glucocorticoids, vascular dysfunction, hyperglycaemia

Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2019
School: College of Medicine and Public Health
Supervisor: Morton Burt