Two key environmental factors that increase the risk for the development of type 2 diabetes and adversely affect glycemia include being overweight and having a sedentary lifestyle. Weight loss and exercise have been shown to effectively lower glycemia and may improve cardiovascular disease (CVD) risks, but the high frequency of weight regain substantially limits the effectiveness of these interventions in the treatment of diabetes. While lifestyle intervention programs that promote weight loss and increase activity levels should almost always be incorporated into diabetes management, the majority of patients with type 2 diabetes will also need medications over the course of their disease to maintain glycemic control.
The most recent glycemic goal recommended by the American Diabetes Association is to achieve an A1C level less than 7%, though clinical judgment should be exercised based on the potential risks and benefits for individual patients. Factors such as life expectancy, risk of hypoglycemia, and the presence of CVD should be considered before intensifying a therapeutic regimen. Currently recommended medications for the medical management of type 2 diabetes—metformin, sulfonylureas, and insulin—are recognized as the most effective and safe pharmacological interventions. However, newer classes of medications and combinations that have been recently approved or are still in development have also been shown to lower A1C levels, including glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors.
Relationship Between GLP-1 & DPP-4
DPP-4 is a widely distributed enzyme that rapidly degrades GLP-1, an incretin hormone that stimulates glucose-dependent insulin release. GLP-1 is released after meal ingestion and stimulates insulin secretion. Administering GLP-1 alone to increase insulin secretion is problematic in treating diabetes because it’s rapidly inactivated by DPP-4. However, GLP-1 drugs that resist inactivation by DPP-4 have been used effectively. They modestly lower A1C levels and may decrease appetite and weight. The GLP-1 analogues do not cause hypoglycemia when used as monotherapy, but are associated with gastrointestinal side effects such as nausea and vomiting.
Drugs that inhibit DPP-4 have been used to treat type 2 diabetes as well. The DPP-4 inhibitors have been shown to prevent the inactivation of GLP-1 and therefore enhance and prolong the action of the endogenously released incretin hormone. Clinical trials have shown that DPP-4 inhibitors only lower AIC levels by 0.6 to 0.9 percentage points, which is somewhat less than other traditional medical interventions. Recent literature has demonstrated that they’re relatively well tolerated, weight neutral, and, like the GLP-1 analogues, are not associated with hypoglycemia.
Although the GLP-analogues lower A1C more than the DPP-4 inhibitors and are associated with weight loss, they require injections and are associated with gastrointestinal side effects. DPP-4 inhibitors are weaker in their effect on A1C levels, but they are taken orally and don’t result in weight loss, nausea, or vomiting. Neither of these classes of medications is as powerful in reducing A1C levels as some of the older and less expensive generic medications.
Continuing Research Necessary
Benefits, risks, and costs of the available anti-diabetic medications must be considered in deciding which agents should be used. Further research is necessary to evaluate and compare the long-term durability and safety of anti-diabetic medications. In addition, determining which agents are best suited for specific groups of patients requires further research.
David M. Nathan, MD, has indicated to Physician’s Weekly that he has received research grants for investigator-initiated research from Sanofi-Aventise.
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