GLP-1–Based Therapy in Older Adults With Diabetes
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Aging is known to be associated with an increased prevalence of diabetes. In 2005, the Centers for Disease Control and Prevention reported an estimated prevalence of diabetes in the United States to be 2% in the 20-39 age group, 10% in the 40-59 age group, and 21% in the 60 or older age group.1
For type 2 diabetes, the mechanisms responsible can be broadly divided into insulin resistance in target tissues and impaired insulin secretion from beta cells in the pancreas. The pathogenesis of type 2 diabetes is multifactorial; however, hyperglycemia does not develop without beta cell failure. Glucagon-like peptide-1(GLP-1), a hormone secreted postprandially from enteroendocrine L cells, has potent insulinotropic effects. In addition, it suppresses glucagon secretion during hyperglycemia, delays gastric emptying, slows gut motility, and increases satiety; all work in synergy to normalize hyperglycemia in diabetes. Exenatide, a GLP-1 receptor agonist, was approved by the Food and Drug Administration (FDA) in April 2005 as the first of a new class of drugs for treating patients with type 2 diabetes.
In this review, we will summarize the biology of GLP-1, explore the latest development of GLP-1 analogs and GLP-1 receptor (GLP-1R) agonists for treatment of type 2 diabetes, and discuss how this new class of agents may be suitable for treating older patients with diabetes. An overview of the other pharmacotherapeutic options available for older adults with type 2 diabetes was reviewed by Rendell.2
Pathophysiology of Type 2 Diabetes in Older Adults
The pathogenesis of type 2 diabetes is characterized by two main defects: increase in insulin resistance in target tissues and impaired insulin secretion from beta cells. It is important to point out that type 2 diabetes does not develop without beta cell failure. Before the onset of diabetes, increased insulin secretion from beta cells maintains normal glucose tolerance (NGT) in subjects with insulin resistance. The progression from NGT to impaired glucose tolerance (IGT) and diabetes is due to the failure of beta cells to secrete adequate amounts of insulin.
Older individuals are noted to have increased prevalence of IGT and diabetes due to beta cell dysfunction. The average rise in fasting plasma glucose (FPG) is 1 mg/dL per decade compared to 5.3 mg/dL per decade for the 2-hour plasma glucose during oral glucose tolerance test (OGTT).3 The Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study4 evaluated the prevalence of diabetes in men and women age 60-79 years, and found that one-third of undiagnosed subjects with diabetes had isolated post-challenge hyperglycemia (FPG < 126 mg/dL, but 2-hr OGTT glucose > 200 mg/dL). Similarly, the Cardiovascular Health Study found that 52% of the newly screened subjects with diabetes age 65-80 years had isolated post-challenge hyperglycemia.5
Physioloogy of GLP-1
In 1964, Elrick et al6 observed an additional stimulus to insulin secretion during oral ingestion of glucose compared to intravenous infusion of glucose, so as to match the plasma glucose under both conditions.