What next for patients whose type 2 diabetes remains uncontrolled with monotherapy?
Type 2 diabetes mellitus is an epidemic with serious and fatal complications. Some predictions estimate that 440 million persons will have this disease by 2030.1 Current recommendations state that patients with type 2 diabetes who are receiving monotherapy and who have elevated hemoglobin A1c levels between 7.6% and 9.0% should receive a second agent.2
What are the choices? Recent evidence supports the efficacy of so-called incretin therapy. Two "Top Papers" are included for reference.1,2
WHAT ARE INCRETINS?
The key postprandial actions of insulin are mediated through the polypeptide glucagon-like peptide-1 (GLP-1), which is degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). One of the "Top Papers" provides more detail on the many effects of and target locations for GLP-1’s actions and its metabolism.1 Unfortunately, in persons with type 2 diabetes, the secretion of GLP-1 is impaired; in fact, the worse the insulin resistance, the lower the GLP-1 level.2
HOW INCRETINS WORK
Incretins are used as therapy for type 2 diabetes in 2 ways:
•By parenteral administration of GLP-1.
•As oral agents that decrease the breakdown of GLP-1 by DPP-4.
Both classes of agents lower fasting and postprandial glucose levels, but GLP-1 agents also decrease appetite and lower body weight (by 1 to 4 kg over 6 months). Since GLP-1 affects the satiety center in the hypothalamus and also slows gastric emptying, the weight loss has a definite physiological basis.
The incidence of hypoglycemia as an adverse effect is low in both groups of incretins. There has been some concern, however, that GLP-1 agents may increase the risk of acute pancreatitis. Because the vascular complications consequent to type 2 diabetes are multifactorial, it is relevant to note that incretins also lower blood pressure (reduction in systolic pressure of 2 to 7 mm Hg) and improve pancreatic beta cell function and lipid profile (decreases in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels of 5%, 6%, and 12%, respectively; increase in high-density lipoprotein cholesterol level of 24%).
The 2 available GLP-1 receptor agonists are exenatide and liraglutide. Exenatide is given subcutaneously twice daily; liraglutide, once daily. The group of DPP-4 inhibitors includes sitagliptin, vildagliptin (not available in the United States), and saxagliptin. These are administered orally. Both classes of incretins are renally excreted and require dose adjustments in the setting of kidney disease.
It appears that incretins—from the GLP-1 and DPP-4 classes—are attractive additions to the treatment of type 2 diabetes. They affect multiple disturbed limbs in the pathophysiology of type 2 diabetes and have a good safety profile.
1. Gallwitz B. The evolving place of incretin-based therapies in type 2 diabetes.
Pediatr Nephrol. 2010;25:1207-1217.
2. Unger J. Choosing among the incretin agents and why it matters. J Fam
Pract. 2010;59(5 suppl):S31-S35.