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Pharmacologic Therapy for Type 2 Diabetes Mellitus

Ralph A. DeFronzo, MD
[+] Article, Author, and Disclosure Information

From the University of Texas Health Science Center, San Antonio, Texas.

Note: Over the past 3 years, the author has received funding from the following organizations and companies: American Diabetes Association, National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases), Veterans Administration System, Parke-Davis, Bristol-Myers Squibb, SmithKline Beecham, Takeda America, Hoechst Marion Roussel, Novo Nordisk Pharmaceuticals, Pfizer, ERGO Science, Bayer Corp., and Merck & Co. The information contained in this review represents an objective synthesis, which is based on published data in the literature and is not influenced by grant support from any of the preceding pharmaceutical companies.

Requests for Reprints: Ralph A. DeFronzo, MD, Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284.

Ann Intern Med. 1999;131(4):281-303. doi:10.7326/0003-4819-131-4-199908170-00008
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Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided.


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Figure 1.
Pathogenesis of type 2 diabetes mellitus.

Sites of action of oral agents are indicated. A negative sign indicates inhibition; a positive sign indicates stimulation.

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Figure 2.
Time-related change in median fasting plasma glucose level (left) and median hemoglobin A 1c (HbA 1c ) (right) in patients with type 2 diabetes treated with sulfonylureas (triangles), metformin (diamonds), insulin (squares), or conventional (diet) therapy (circles).2829

The number of patients followed for more than 11 years drops off markedly. The curves for chlorpropamide and glibenclamide have been combined into one sulfonylurea curve for ease of presentation. Redrawn from references and .

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Figure 3.
Effect of conventional treatment with diet (bold solid line), intensive treatment with sulfonylureas or insulin (solid line), and metformin therapy (dashed line) on any diabetes-related end point (top left), diabetes-related death (bottom left), microvascular complications (top right), and myocardial infarction (bottom right).P2829

values represent differences between metformin and other therapies. Redrawn from references and .

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Figure 4.
Pharmacologic algorithm for treatment of patients in whom type 2 diabetes is inadequately controlled with diet and exercise.1c1c

*Goals and therapies must be individualized. †Preferred if the patient is obese or dyslipidemic. FPG = fasting plasma glucose level; HbA = hemoglobin A value; HBGM = home blood glucose monitoring.

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