Incretin-based therapies for the treatment of type 2 diabetes: Evaluation of the risks and benefits

Incretin-based therapies provide new options for the treatment of type 2 diabetes and enable intensification of therapy while controlling body weight through mechanisms associated with a low rate of hypoglycemia. Investigational longacting GLP-1R agonists require less frequent administration and appear to be more potent with respect to A1C reduction than twice-daily exenatide or oncedaily sitagliptin with respect to A1C reduction. These long-acting GLP-1R agonists have considerable potential as antidiabetic therapies as they not only lower glucose as or more effectively than other noninsulin antihyperglycemic therapies, they do so in concert with weight loss, improvement in cardiovascular disease risk factors, and with very low risk of hypoglycemia. However, two safety issues have been raised-pancreatitis and medullary carcinoma of the thyroid. The relationship between the use of incretin therapy and the development of pancreatitis remains unclear. These agents may not substantially increase the risk of acute pancreatitis in humans and might not affect the risk at all. The relevance to humans of the pancreatic metaplasia observed with these agents in two of the rodent studies is unknown. Continued clinical monitoring and more research are required to clarify the actions of GLP-1R agonists and DPP-4i on the normal and diabetic exocrine pancreas. GLP-1R activation stimulates calcitonin secretion and promotes the development of C-cell hyperplasia and medullary thyroid cancer in rodents but not in monkeys, and the actions of GLP-1R agonists on human C-cells remain uncertain. Because of the rarity of medullary carcinoma of the thyroid and the lack of specificity of clinical markers, screening strategies, except in the setting of familial syndromes, almost certainly would be associated with an increase in morbidity and perhaps mortality as a result of false positives. Taken together, the available evidence supports the use of incretin-based therapies for patients requiring effective control of glycemia and body weight while minimizing the risk of hypoglycemia. Ongoing scrutiny and further studies are required to clarify the potential significance of reports of pancreatic injury, including pancreatitis and metaplasia, and rodent medullary thyroid cancer for human subjects treated with GLP-1R agonists and DPP-4i.