Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial

Abstract

Objective: Anti-inflammatory glucocorticoid (GC) therapy often induces hyperglycemia due to insulin resistance and islet-cell dysfunction. Incretin-based therapies may preserve glucose tolerance and pancreatic islet-cell function. In this study, we hypothesized that concomitant administration of the dipeptidyl peptidase-4 inhibitor sitagliptin and prednisolone in men at high risk to develop type 2 diabetes could protect against the GC-induced diabetogenic effects. Design and methods: Men with the metabolic syndrome but without diabetes received prednisolone 30 mg once daily plus sitagliptin 100 mg once daily (nZ14), prednisolone (nZ12) or sitagliptin alone (nZ14) or placebo (nZ12) for 14 days in a double-blind 2!2 randomized-controlled study. Glucose, insulin, C-peptide, and glucagon were measured in the fasted state and following a standardized mixed-meal test. b-cell function parameters were assessed both from a hyperglycemic-arginine clamp procedure and from the meal test. Insulin sensitivity (M-value) was measured by euglycemic clamp. Results: Prednisolone increased postprandial area under the curve (AUC)-glucose by 17% (P!0.001 vs placebo) and postprandial AUC-glucagon by 50% (P!0.001). Prednisolone reduced 1st and 2nd phase glucose-stimulated-and combined hyperglycemia-arginine-stimulated C-peptide secretion (all P%0.001). When sitagliptin was added, both clamp-measured b-cell function (PZNS for 1st and 2nd phase vs placebo) and postprandial hyperglucagonemia (PZNS vs placebo) remained unaffected. However, administration of sitagliptin could not prevent prednisolone-induced increment in postprandial glucose concentrations (P!0.001 vs placebo). M-value was not altered by any treatment. Conclusion: Fourteen-day treatment with high-dose prednisolone impaired postprandial glucose metabolism in subjects with the metabolic syndrome. Concomitant treatment with sitagliptin improved various aspects of pancreatic islet-cell function, but did not prevent deterioration of glucose tolerance by GC treatment.

Glucocorticoid-Induced Diabetes Mellitus: An Important but Overlooked Problem

“…Drugs with incretin effects should probably be the drug of choice because of their immediate onset of action, their predominant effect on postprandial glycemia, and their low risk of hypoglycemia related to glucose-dependent effects [40]. A recent study found that concomitant treatment with a DPP-4 inhibitor improved various aspects of pancreatic islet-cell function in patients receiving high-dose prednisolone [41]. Furthermore, an intravenous infusion of exenatide prevented glucose intolerance induced by high doses of prednisolone in healthy patients and may be explored as a potential strategy to prevent GIDM [42].…”

Dapagliflozin for prednisone‐induced hyperglycaemia in acute exacerbation of chronic obstructive pulmonary disease

“…Glucagon-like peptide-1mediating agents have been suggested to be beneficial in preclinical studies but have not yet been studied in a clinical setting. 13,14 Thiazolidinediones were suggested to be effective in chronic glucocorticoidinduced hyperglycaemia in a pilot study, but the findings were never confirmed in a comparative study. Moreover, thiazolidinediones carry risks of heart failure and liver toxicity.…”

“…Despite our negative results, we are convinced that the present study is valuable given the scarcity of evidence on treatment of glucocorticoid‐induced hyperglycaemia. Glucagon‐like peptide‐1‐mediating agents have been suggested to be beneficial in preclinical studies but have not yet been studied in a clinical setting . Thiazolidinediones were suggested to be effective in chronic glucocorticoid‐induced hyperglycaemia in a pilot study, but the findings were never confirmed in a comparative study.…”

MANAGEMENT OF ENDOCRINE DISEASE: Critical review of the evidence underlying management of glucocorticoid-induced hyperglycaemia

“…In contrast, some data suggest exenatide may increase fracture risk (73). The DPP-4 inhibitor sitagliptin improved glycaemic control in a retrospective study of subjects on low-dose prednisolone (84), but did not attenuate the postprandial effects of a 30 mg daily prednisolone dose in a prospective randomized controlled trial (85). These contrasting results may reflect the difference in prednisolone dose in the two studies or could reflect potential selection bias in the retrospective study.…”