Clinical Geriatrics

This article is the third in a continuing series on diabetes in the elderly. The second article in the series, “Quality Improvement in the Diagnosis and Management of Diabetes Mellitus in Older Adults,” was published in the May issue of the Journal. The remaining articles in the series will discuss such topics as insulin in the management of elderly patients with diabetes, the role of exercise and dietary supplements in the management of diabetes, and microvascular and macrovascular complications of diabetes.

Introduction
Individuals 65 years and older currently account for 12.4% of the U.S. population.¹ By 2040, this percentage is predicted to exceed 20%.² In the United States, diabetes affects 23.6 million people, or 7.8% of the population. In those over age 60 years, it affects 12.2 million, or 23.1% of people in this age group. Estimated direct and indirect diabetes costs in the United States are more than $174 billion annually.³ Despite the multiple classes of available diabetes medications, the majority of persons with type 2 diabetes are unable to maintain long-term glycemic control.⁴ Fewer than half of U.S. adults with type 2 diabetes mellitus reach an HbA1c level of less than 7%.⁵ With the morbidity and mortality related to diabetes and diabetes-related complications well established, having a better understanding of these in the elderly becomes increasingly important.

Recent years have brought many new classes of diabetic medications. The objective of this review is to delineate the safety and efficacy of those medications in the elderly, as well as to review the established medications. The data in the elderly are limited depending on the drug studied. This article will focus on the new and established oral agents, as well as new noninsulin injectable medications. An upcoming article in the next issue of Clinical Geriatrics will focus on the new insulin treatment options.

New Classes of Diabetes Medications

Incretin Mimetics
Incretins are gastrointestinal (GI) hormones that increase the amount of insulin released from the beta cells of the pancreas after eating, even before blood glucose levels become elevated. The two main incretin molecules are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (also known as glucose-dependent insulinotropic peptide [GIP]). Additionally, incretins slow the rate of absorption of nutrients into the bloodstream by reducing gastric emptying and may directly reduce food intake. By doing so, they also inhibit glucagon release from the alpha cells of the pancreas.^5-7

Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4.^6,8,9 Incretin action depends on glucose concentration, and its function ceases when the serum glucose level is less than 55 mg/dL.⁵ This is an inherent benefit of the drug, in that it facilitates a glucose-mediated insulin release with less risk of hypoglycemia. GLP-1 is secreted from the L cells of the intestinal mucosa, in response to ingestion of mixed meals or glucose.^6,8,9 Actions of GLP-1 include stimulating insulin secretion, inhibiting glucagon secretion and hepatic glucose output, decreasing gastric emptying and motility, and decreasing appetite and food intake.^8,9

In terms of appetite, GLP-1 agonists increase serotonin release in the hypothalamus, and their central anorectic effects could be partially mediated by this.¹⁰ In addition, GLP-1 receptor has anorexigenic and fat-reducing properties, as opposed to ghrelin, which is a potent orexigenic and adipogenic hormone, and strongly influences fat deposition and generation of hunger. Incretins reduce the levels of ghrelin by up to 74% in fasted rats, which may explain reduced food intake.¹¹

The first drug in this class on the market was exenatide.