Addition of Basal Insulin to Oral Antidiabetic Agents: A Goal-Directed Approach to Type 2 Diabetes Therapy

Louis Kuritzky, MD

Disclosures

November 15, 2006

Currently Available Oral Agents

Among the major classes of currently available oral agents, the therapeutic actions of insulin secretagogues and insulin sensitizers address the 2 core defects in type 2 diabetes: a deficit of endogenous insulin secretion and insulin resistance in the skeletal muscle and hepatic and adipose compartments. Additionally, the alpha-glucosidase inhibitors slow glucose uptake from many dietary sources. Notably, any combination of currently available agents is unlikely to reduce A1C levels by more than approximately 3.0% ( Table 1 ).[2] In addition, dosing and precaution information for currently available oral agents is listed in Table 2 .

Insulin Secretagogues

Sulfonylureas (eg, glyburide, glipizide, and glimepiride) lower blood glucose primarily by stimulating insulin release from the pancreas. These agents demonstrate similar efficacy for glucose control. With the exception of long-acting formulations, sulfonylureas are characterized by rapid onset. All secretagogues can produce hypoglycemia, particularly if caloric intake is inadequate or meals are not eaten regularly.[7,8,9] Although older, longer-acting sulfonylureas (eg, chlorpropamide) are used less commonly since a longer half-life can cause prolonged hypoglycemia, these agents may be considered for persons of marginal economic resources if hypoglycemia is a lesser concern.[9,10,11,12] Weight gain is a common side effect of sulfonylureas, but is seen less often with newer-generation agents (eg, glimepiride) than with traditional long-acting formulations.[13]

The meglitinides, repaglinide and nateglinide, also stimulate pancreatic insulin secretion. Meglitinides have a more rapid onset and shorter duration of action compared with sulfonylureas; therefore, they are indicated for control of postprandial serum glucose excursions. Meglitinides may also be associated with a lower risk of hypoglycemic events due to their limited duration of action.[14,15] Because of the potential for hypoglycemia when a meal is skipped, patients need careful instruction to use meglitinides only when a meal is imminent (ie, administer 15-30 minutes before a meal is begun).

Insulin Sensitizers

Metformin is the only biguanide currently approved for use in the United States. Metformin decreases hepatic glucose production, increases hepatic sensitivity to insulin, and may also have a mild effect on sensitivity to insulin in muscle.[16] Metformin is as effective as sulfonylureas in reducing A1C levels (approximately 1.0% to 2.0% [ Table 1 ]). Metformin is weight neutral and therefore may be useful in treating obese patients.[17]

Pioglitazone and rosiglitazone are the 2 thiazolidinediones currently approved for use in the United States. Thiazolidinediones enhance glucose uptake and disposal by increasing glucose transporters in peripheral tissues.[16] Weight gain and edema are the primary side effects of thiazolidinediones.[18,19] Edema may occur more frequently in patients treated with thiazolidinediones in combination with insulin[18,19] and should be used cautiously in patients with preexisting edema. These agents should be avoided in patients exhibiting signs and symptoms of heart failure (New York Heart Association Class III or IV), including orthopnea, dyspnea, unexplained cough or fatigue, or pedal edema.[20]

Alpha-Glucosidase Inhibitors

Acarbose and miglitol slow glucose uptake from many dietary sources by inhibiting the alpha-glucosidase-dependent breakdown of complex carbohydrates as well as simple sugars in the brush border of the proximal small intestine epithelium.[21,22] The mechanism of action is not glucose absorption blockade; indeed, long-term therapy is not associated with weight loss. Rather, simply by "spreading out" the digestion of carbohydrates through the small intestine, alpha-glucosidase inhibitors decrease postprandial as well as fasting glucose concentrations. Of interest, a recent meta-analysis of 7 randomized studies of patients with type 2 diabetes suggested a reduction in the risk of myocardial infarction (hazard ratio = 0.36 [95% CI, 0.16-0.80]; P = .0120) associated with acarbose compared with placebo.[23] Gastrointestinal symptoms are the most common side effects associated with alpha-glucosidase inhibitors, however, slow titration and careful instruction can help address these effects.

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