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Five classes of oral pharmaceutical agents for the treatment of type 2 diabetes have been approved in the United States by the Food and Drug Administration (FDA). In general, there is no clinical evidence of superiority of a particular drug over another in elderly patients. Knowledge of pharmacokinetics, side effects, and potential interactions allow for a safe use of these drugs in older patients with diabetes. Two classes of drugs, the sulfonylureas and the meglitinides improve glucose levels by stimulating insulin secretion from pancreatic β-cells. Other agents target different mechanisms in the underlying pathogenesis of the disease, such as the reduction of carbohydrate absorption (a-glucosidase inhibitors) and improvement in insulin sensitivity (biguanides and thiazolidinediones). Any of these agents may be used as first-line monotherapy since most demonstrate equivalent efficacy in improving glycemic control. When monotherapy fails, the addition of a second oral agent from a different drug class is advised to achieve fasting or postprandial glycemic targets. In general, the use of triple therapy is safe but should be used with caution because of the high risk of polypharmacy in the elderly and higher associated costs.

TABLE Noninsulin Agents for Treatment of Type 2 Diabetes

TABLE Mechanisms to Lower Blood Glucose by Each Antidiabetic Agent

Note: X, main mechanism; (X) less-clear mechanism.

Sulfonylurea

Sulfonylurea preparations have a long record of safety and effectiveness. They work by stimulating insulin secretion by the pancreatic /3-cell, binding to an adenosine triphosphate-sensitive potassium channel, which results in its depolarization, a subsequent influx of intracellular calcium, and the release of insulin. Sulfonylureas are effective both as monotherapy and in combination with other agents that have different mechanisms of action. A significant percentage of patients (up to 10% per year) who are initially properly managed with sulfonylurea monotherapy lose glycemic control over time. Their main side effects include hypoglycemia and weight gain. Hypoglycemia is a serious adverse effect in the elderly and can trigger serious events such as myocardial infarction and stroke. These drugs must be used cautiously in patients with significant renal and hepatic insufficiency, since the liver is the primary site of metabolism and they are excreted by the kidneys. In these settings, the preferred option may be glipizide, whose metabolites are inactive, or glimepiride, which is substantially excreted through the bile.

A commonly used sulfonylurea in younger populations, glyburide, may have age-related impaired absorption and elimination, and elderly subjects appear to have enhanced insulin responses to the drug as well. This may explain, in part, the age-related exponential increase in the frequency of severe or fatal hypoglycemia with this drug.

TABLE Limiting Factors in the Use of Antidiabetic Agents in the Elderly

May impede ischemic preconditioning Frequent dosing may affect compliance; no long-term experience Risk of lactic acidosis; diarrhea Edema; expensive; no long-term experience Frequent dosing may affect compliance; intestinal gas; expensive Injection; expensive; no long-term experience

Note: X, main side effect; XX, pronounced side effect. Abbreviation: wt, weight.

In addition to the type of sulfonylurea, other potential risk factors for hypoglycemia with these drugs in elderly persons include black race, multiple medications, male sex, renal dysfunction, and ethanol consumption. Sulfonylureas should be considered as first-line therapy in lean elderly patients with diabetes. The result in hemoglobin Ale (HbAlc) lowering is approximately 1% to 2% as monotherapy.

Meglitinides

Meglitinides (repaglinide and nateglinide) are nonsulfonylurea drugs that have a distinct β-cell binding profile and stimulate insulin secretion from the β-cell by a mechanism similar to that of sulfonylureas. The potential advantage of this type of drug is that it has a rapid onset and very short duration of action. Meglitinides have been associated with lower frequency of hypoglycemic events when compared with conventional sulfonylureas, presumably because of their shorter duration of action and the fact that the kinetics are not altered with age. Repaglinide lowers HbAlc by 1% to 2%, a reduction similar to that of the sulfonylureas, whereas the glucose-lowering effect of nateglinide is somewhat less potent. Similar changes in fasting glucose and HbAlc values are seen in middle-aged and elderly subjects, suggesting that there is similar efficacy in each age group. Both repaglinide and nateglinide are extensively metabolized by the liver; therefore, they should be used cautiously in patients with hepatic dysfunction. Meglitinides may be considered as an appropriate strategy for elderly patients who have irregular eating habits or have frequent hypoglycemic events on conventional sulfonylureas. These potential benefits must be balanced against the cost of these newer drugs and the compliance problems that could result from a three-times-a-day dosing schedule, particularly in patients who have impaired memory or take may other drugs.

α-Glucosidase Inhibitors

α-glucosidase inhibitors (miglitol and acarbose) impair the breakdown and limit the absorption of carbohydrates from the gut; therefore their major effect is reduction in postprandial glucose excursions. These drugs are associated with less weight gain and a lower frequency of hypoglycemia than sulfonylureas. The residual carbohydrates in the intestinal lumen cause diarrhea in about 25% of patients taking these drugs. Gradual dose titration is crucial to minimize gastrointestinal side effects and achieve better compliance. Their overall effect on HbAlc concentration is a modest reduction of 0.5% to 1%. In a recent randomized multicenter trial of the a-glucosidase inhibitor acarbose in obese elderly patients with diabetes, acarbose reduced HbAlc by about 0.8% when compared with placebo and also resulted in an improvement in insulin sensitivity. α-glucosidase inhibitors are useful drugs as primary therapy for elderly patients with modest fasting hyperglycemia, especially if they are obese. They can also be used in patients taking other oral agents to enhance glycemic control. Hypoglycemia may occur if these agents are used in combination with sulfonylureas or insulin; consequently, only glucose should be used for prompt treatment of hypoglycemia because the absorption of other carbohydrates is delayed. Acarbose has minimal systemic absorption, yet some hepatic metabolism occurs and because of rare but possible hepatotoxicity, it is contraindicated in patients with advanced liver disease. In contrast, as much as 50% to 90% of the miglitol dose may be absorbed but is not metabolized in the liver but rather eliminated through the kidney. Therefore, miglitol should not be used in patients with renal failure.

Metformin

Metformin is currently the only biguanide available in North America. Its mechanism of action is to improve insulin sensitivity, chiefly by reducing insulin resistance in the liver, thereby decreasing hepatic glucose production. In addition, its glucose-lowering effect is accompanied by a reduction in plasma insulin concentration, and some experts refer to metformin as an insulin sensitizer. Metformin lowers HbAlc by 1% to 2%. Although, the most important side effect associated with biguanides is lactic acidosis, this is rare with metformin; and aging itself does not appear to be a risk factor provided that careful attention is paid to the contraindications for this drug (significant liver, renal, and cardiac disease). Clinical studies suggest that the drug is safe and effective as monotherapy in obese older people. In our view, metformin is an ideal drug for first-line therapy of obese older patients, because it increases insulin sensitivity, assists with weight loss, reduces lipid levels, and does not cause hypoglycemia. The recently published ADA management algorithm suggests the use of metformin, together with lifestyle intervention, as initial monotherapy.

In addition, metformin is a useful adjunct for patients who are inadequately controlled on maximum doses of sulfonylureas. Metformin is contraindicated in older subjects with renal insufficiency, in men with a serum creatinine level of 1.5 mg/dL or higher or women with a serum creatinine level of 1.4 mg/dL or higher. Serum creatinine should be measured at least annually and with any increase in dose of metformin. It should be noted, however, that serum creatinine does not adequately reflect the renal function in the elderly. For those aged 80 years or older or those suspected to have reduced muscle mass, a timed urine collection for creatinine clearance should be obtained. Metformin should be avoided if the value is less than 60 mL/ min. Metformin should be temporarily discontinued during radiographic studies that use iodinated contrast agents, during acute illness, and during most hospitalizations. Clinical situations where tissue perfusion is compromised (sepsis, dehydration, pulmonary disease with hypoxemia, and acute or advanced heart failure) also contraindicate the use of metformin.

Thiazolidinediones

Thiazolidinediones (rosiglitazone and pioglitazone) improve insulin sensitivity primarily in muscles and adipocytes, thereby increasing peripheral uptake and utilization of glucose. They are generally well tolerated and appear to be as effective in older patients as in younger patients, with an approximate 1.5% reduction in HbAlc and with a dose-dependent glucose-lowering effect, which may take four to eight weeks. In addition to benefits of these drugs on cardiovascular and metabolic markers, a recent randomized trial has shown the effect of pioglitazone on the reduction of cardiovascular outcomes in patients with type 2 diabetes. Thiazolidinediones do not lead to hypoglycemia unless they are used in conjunction with secretagogues or insulin. Hepatic toxicity has not been reported in elderly subjects, but liver function tests should be monitored regularly. The incidence of edema and anemia is higher in elderly patients than in middle-aged patients treated, and volume status and blood count need to be carefully monitored. Thiazolidinediones-related fluid retention is a major contributor to increased body weight, typically manifests as peripheral edema, and develops predominantly within the first months of treatment. Thiazolidinediones can be a useful first-line therapy in obese elderly patients, particularly for those patients who cannot tolerate metformin or those who have a contraindication to it. In fact, thiazolidinediones can be safely used in patients with renal impairment provided that the cardiac function is preserved. In addition, they may be a beneficial adjunct therapy in elderly patients who have suboptimal glycemic control, despite insulin requirements of 50 or more units per day.