Introduction to Medications for Diabetes Mellitus- ENDOCRINE SELF STUDY MODULE Pham

ENDOCRINE SELF STUDY MODULE Introduction to Medications for Diabetes Mellitus Diabetes has often been described as "starvation in the midst of plenty." The adverse health effects of increased blood glucose occur either because there is too little insulin synthesized and released from the beta cells of the pancreas (type 1 diabetes) or because insulin receptors become insensitive and glucose transport into the cell is impaired (type 2 diabetes). It is now known that this is a gross oversimplification of the disease process. Most people with type 2 diabetes also experience reduced insulin secretion over time. Hormones other than insulin, such as glucagon, cortisol, and growth hormone (the so-called counterregulatory hormones), are involved as well. Serum potassium levels also play a role, because adequate levels of extracellular potassium are key in the ability of insulin to drive glucose into the cell. Goals of Pharmacotherapy for Diabetes Mellitus The primary goal of pharmacotherapy for diabetes is to maintain "tight control" of plasma glucose levels. Maintaining the plasma glucose level as near normal as possible, in addition to treating hypertension and hyperlipidemia, helps postpone or even prevent both acute and long-term complications (sequelae). Treatment Targets for Patients with Diabetes Categories of Pharmacotherapeutic Agents for Diabetes Pharmacotherapeutic agents for diabetes can be divided into the following categories: • Agents that stimulate insulin release • Agents that stimulate insulin receptors • Agents that decrease/delay glucose absorption • Insulin replacement • Agents that suppress glucagon • Glucagon to counteract excess insulin • Agents to prevent complications of diabetes • Agents to treat complications of diabetes Type 2 diabetes accounts for more than 90% of patients with diabetes. Epidemiologists estimate that at the current rate of increase in disease incidence, 50% of Americans more than age 50 will have diabetes by 2050. Type 2 diabetes is now increasingly common, even among children as young as age 10. However, the American Diabetes Association estimates that more than 90% of cases of type 2 diabetes could be prevented with diet, exercise, and weight control. Researchers are studying whether pharmacotherapy can delay or prevent type 2 diabetes in individuals at high risk. Agents that Stimulate Insulin Release Individuals with type 2 diabetes are typically obese at the time of diagnosis. Usually they secrete sufficient insulin. In fact, development of type 2 diabetes is often preceded by years of hyperinsulinemia due to consumption of large, frequent meals. Over time, the insulin receptors downregulate, and eventually the individuals become insulin resistant. Drugs that stimulate insulin release were once the mainstay of pharmacotherapy for type 2 diabetes. Today, they are step 1 drugs only for individuals with type 2 who are lean, a small minority of these patients. Single-drug therapy is rarely effective over the long term, however, and many obese patients take an agent to stimulate insulin release in addition to other drugs. Agents that stimulate insulin release include: • Sulfonylureas: first and second generations • Meglitinides: repaglinide (Prandin) and nateglinide (Starlix) Categories of Pharmacotherapeutic Agents for Diabetes Agents that Stimulate Insulin Release Sulfonylureas Sulfonylureas are chemically related to sulfonamide antibiotics ("sulfa drugs"). They increase beta-cell insulin release and decrease glycogenolysis. When taken for a long time, they may also increase insulin receptor sensitivity. There are two generations of sulfonylureas. Although these two generations have equal therapeutic efficacy, the second-generation agents are more potent and have the following advantages: • Longer duration of action (once-daily dosing convenience) • Less likely to cause disulfiram-like reactions with alcohol • Less likely to be involved in cross-sensitivity in people allergic to sulfonamides • Less potential for fluid retention (they have diuretic properties) • Less risk of UVA/UVB photosensitivity All sulfonylureas share the following potential adverse effects and drug interactions: Hypoglycemia Hypoglycemia may develop in individuals who tend to eat sporadically or who miss meals when ill, because insulin will be released throughout the day, not just in response to food. Displacement from plasma proteins by other drugs Drugs such as warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfonamides compete to bind to plasma albumin. The resulting increased free levels of the sulfonylurea may result in hypoglycemia. Inhibition of hepatic metabolism by other drugs Drug inhibitors—such as cimetidine, omeprazole (Prilosec), and antifungal drugs—can reduce hepatic biotransformation of sulfonylureas. Increased free levels of the sulfonylurea may result in hypoglycemia. Decreased action from drugs that cause hypokalemia Drugs such as thiazide diuretics and oral corticosteroids deplete potassium, as do drugs and diets high in sodium. Hypokalemia impairs insulin release and insulin-receptor function. Decreased action from drugs that cause hyperglycemia