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.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects and Precautions

As for alpha-glucosidase inhibitors in general (see Acarbose). Skin rash may occur. Miglitol should be used with caution in patients with renal impairment.

Interactions

As for alpha-glucosidase inhibitors in general (see Acarbose). Miglitol may reduce the bioavailability of propranolol and ranitidine.

Pharmacokinetics

Miglitol is completely absorbed at a dose of 25 mg, but only 50 to 70% is absorbed at a dose of 100 mg. It is not metabolised, and is excreted unchanged in the urine with a plasma elimination half-life of about 2 hours.

Uses and Administration

Miglitol is an alpha-glucosidase inhibitor similar in action to acarbose. It is given orally in the management of type 2 diabetes mellitus, alone or with a sulfonylurea. Usual initial doses are 25 mg three times daily with meals, increased if necessary to a maximum of 100 mg three times daily.

Proprietary Preparations

Austria: Diastabol

Czech Republic: Diastabol

France: Diastabol

Germany: Diastabol

Hungary: Diastabol

India: Diamig Mignar †

Mexico: Diastabol

Poland: Diastabol

Portugal: Diastabol Limarcan

Spain: Diastabol Plumarol

Sweden: Diastabol

Switzerland: Diastabol

USA: Glyset

Acarbose

Brand Name Drug: in Europe under the brand name Glucobay, in North America as Precose, and in Canada as Prandase

Acarbose and the other agents of this class have relatively weak antidiabetic activity, only reducing HgbA₁C by .5%-1% in most patients. Diarrhea and flatulence are the most common side effects, occurring in up to 40% of patients in most trials. Secondary to the high incidence of gastrointestinal distress, acarbose should be initiated slowly. It comes in 50-mg and 100-mg tablets, and it is currendy recommended that patients begin with 25 mg daily taken with a meal. Afterward, it can be advanced to 25 mg with two meals and slowly increased to a maximum of 300 mg/day. Acarbose should be taken with the first bite of the meal and the most benefit is achieved with doses > 150 mg/day. It is at these higher dosages that a recent study has shown reduction of HgbA₁C of 1%-2%. Unfortunately, the incidence of gastrointestinal side effects often precludes reaching these doses.

Miglitol

Brand Name Drug: Glyset

Recendy, miglitol, a new alpha-glucosidase inhibitor, was approved by the Food and Drug Administration. It reportedly has many of the gastrointestinal side effects that limit acarbose use. However, in preliminary studies, miglitol effectively lowered postprandial blood glucose and glycosylated hemoglobin levels.

Glyset: Introduction

Glyset (miglitol) is an oral alpha-glucosidase inhibitor that is similar to acarbose (Precose®). Glyset has not yet demonstrated hepatotoxicity, which has occurred with the use of Precose. Although Glyset was first approved by the FDA in 1996, Pharmacia & Upjohn recently acquired the rights to Glyset and launched its sale in the US.

Glyset: How It Works

Glyset is a reversible inhibitor of membrane-bound intestinal alpha-glucoside hydrolase enzymes. These enzymes hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the small intestine. In patients with diabetes, inhibition of this enzyme results in delayed glucose absorption and lowering of postprandial hyperglycemia. Glyset can be used in combination with sulfonylureas to enhance glycemic control.

Glyset: Clinical Study Results

Several controlled, fixed-dose studies have been conducted to demonstrate the efficacy of Glyset monotherapy. The first study was one year in duration and evaluated a combination of Glyset and a sulfonylurea, in addition to Glyset as monotherapy. The results indicated that there was a statistically smaller increase in mean glycosylated hemoglobin (HbA1c) over time in the Glyset 50 mg three times a day arm when compared to placebo. Mean fasting and postprandial plasma glucose levels as well as mean postprandial insulin levels were significantly reduced in the Glyset group in comparison to the placebo group. In a 14-week study, patients in the Glyset group had a significant decrease in HbA1c in comparison to those taking placebo. The dose of Glyset used in this study was either 50 mg 0or 100 mg three times a day. Significant decreases in postprandial plasma glucose levels and postprandial insulin levels were seen in the Glyset group.

Several studies have also examined the use of Glyset in combination with sulfonylureas. The first study was 14 weeks’ duration and enrolled patients already on maximal doses of sulfonylureas. The patients received either Glyset 50 mg or 100 mg three times a day or placebo. Patients in the Glyset group had significantly reduced HbA1c levels at the end of the study period. A second study enrolled patients on maximum doses of glyburide and added either Glyset 25 mg, 50 mg or 100 mg three times a day or placebo to the regimen. At the end of the study, patients in both of the Glyset groups had significantly reduced HbA1c levels.

Glyset: What The Patient Should Know

Glyset is contraindicated in patients with diabetic ketoacidosis, inflammatory bowel disease, colonic ulceration or partial intestinal obstruction, and in patients predisposed to intestinal obstruction. Glyset should also be avoided in patients who suffer from chronic intestinal diseases associated with marked disorders of digestion or absorption, or those with conditions that may deteriorate as a result of increased gas formation in the intestine.

Glyset should be taken three times a day at the start of each main meal with the first bite of food.

Glyset does not cause hypoglycemia when administered alone, even in the fasted state. However, sulfonylureas and insulin can lower blood sugar levels enough to cause hypoglycemia. When Glyset is given in combination with a sulfonylurea or insulin it may increase the hypoglycemic potential of these agents. It is important that the patient and other family members recognize and understand the symptoms, predisposing factors, and treatment of hypoglycemia. Because Glyset prevents the breakdown of table sugar, a source of glucose should be kept available to be administered if the patient is taking Glyset in addition to sulfonylureas and insulin.

The most common adverse effects of Glyset are primarily dose-related gastrointestinal effects including flatulence, soft stools, diarrhea, or abdominal discomfort. Side effects, if they occur, usually develop in the first few weeks of therapy and generally diminish in frequency and intensity with time.

Oral antidiabetic drugs fall into several classes (Table 5). Of particular interest are the insulin sensitizers because they specifically target insulin resistance. Other agents address different aspects of glycemic control.

Insulin secretion stimulators (secretagogues)

For more than 40 years, sulfonylureas have been the first line of therapy for individuals with type 2 diabetes. These agents directly stimulate pancreatic b-cells to produce insulin by increasing the influx of calcium. Sulfonylureas increase circulating insulin and reduce both fasting and postprandial glucose, but they are not insulin sensitizers and therefore do not address the problem of insulin resistance. Sulfonylureas lower A1C an average of 1% to 2% and offer effective glycemic control in up to 75% of patients; however, efficacy lapses over time, with about 5-10% of patients per year failing to maintain the initial glycemic control. Primary adverse effects include hypoglycemia and weight gain (typically 2-5 kg). Glimepiride (Amaryl) is emerging as the sulfonylurea of choice due to its once-a-day dosing, extrapancreatic effect, and the fact that it causes less weight gain and hypoglycemia and is priced as low as generic glyburide.

Another class of secretagogues, derivatives of meglitinide or phenylalanine, also stimulate insulin but act at a different site on pancreatic beta-cells than the sulfonylureas. Because these agents have a very short onset of action and short half-life, they must be taken immediately before every meal (compared to once-daily dosing for sulfonylureas), so treatment adherence may be an issue for some patients. They have a side effect profile similar to the sulfonylureas; however, because meglitinides are shorter-acting agents, they carry a lower risk of sustained hypoglycemia. Efficacy is similar to that of sulfonylureas. The two products currently available are nateglinide (Starlix) and repaglinide (Prandin).

Alpha-glucosidase inhibitors

Drugs in this group produce mild reductions in postprandial hyperglycemia by inhibiting the enzyme responsible for metabolizing complex carbohydrates in the small intestine. Taken right before a meal, these agents reduce glucose levels by slowing absorption of carbohydrates and delaying entry of glucose into liver and muscle tissue. Gastrointestinal side effects (ie, abdominal pain, diarrhea, and flatulence) are the most common reactions to alpha-glucosidase inhibitors (reported in up to 75% of patients), leading some patients to discontinue therapy with these drugs. Available agents include acarbose (Precose) and miglitol (Glyset). Gastrointestinal side effects can be greatly reduced if low doses are started and then gradually titrated over 10-12 weeks to the maximum and effective doses. At present, these agents are seldom used in the United States.

Thiazolidinediones

The thiazolidinediones (TZDs or glitazones) are a relatively new class of agents that reduce insulin resistance. TZDs do not stimulate the secretion of insulin but rather enhance the effects of circulating insulin by improving insulin sensitivity in muscle and adipose tissue and by inhibiting hepatic gluconeogenesis. TZDs work by stimulating certain receptors (peroxisome proliferator-activated receptor gamma, or PPAR-gamma) in the nucleus of the cells. Activation of PPAR-gamma modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism. In response to thiazolidinediones stimulation, the genes produce a protein called GLUT-4. Insulin works by recruiting GLUT-4 to the cell’s outer membrane. This partnership, in turn, promotes transport of glucose across the membrane and into the cell’s interior.

Examples of insulin sensitizers include pioglitazone hydrochloride (Actos) and rosiglitazone maleate (Avandia). Another drug in this class, troglitazone (Rezulin), was removed from the market because it was linked to idiosyncratic cases of hepatotoxicity. In clinical trials, there has been no evidence of drug-induced hepatotoxicity with pioglitazone or rosiglitazone, but there have been rare postmarketing case reports of liver damage in patients receiving rosiglitazone and pioglitazone (causality not established). The safe use of these agents, therefore, requires careful monitoring of liver function: ALT enzyme levels should be measured at baseline and monitored every 2 months for 1 year and periodically thereafter. Patients with hepatic impairment should not be treated with thiazolidinediones.

In large placebo-controlled trials lasting up to 26 weeks, monotherapy with pioglitazone or rosiglitazoneproduced significant improvements in A1C and fasting blood glucose concentrations (Table 6). Pioglitazone also led to significant improvements in A1C and improvements in FPG when combined with a sulfonylurea, metformin, or insulin. Rosiglitazone resulted in significant decreases in A1C and FPG levels when combined with metformin or a sulfonylurea.

In addition to reducing insulin resistance, thiazolidinediones also have effects on lipids (Table 6). In a 26-week placebo-controlled study, pioglitazone was associated with decreases in triglycerides of 9.0%, 9.6%, and 9.3% in patients treated with 15-, 30-, and 45-mg, respectively, compared with baseline. HDL (“good”) cholesterol increased by 14%, 12%, and 19% in the 15-, 30-, and 45-mg groups, respectively. No consistent differences were reported for LDL (“bad”) cholesterol and total cholesterol in patients treated with pioglitazone versus placebo.

In a similar 26-week pla-cebo-controlled study, rosiglitazone raised HDL cholesterol by 11.4% and 14.2% in doses of 4- and 8-mg per day, respectively, compared to baseline, but the drug also raised LDL cholesterol by 14.1% and 18.6%, respectively. Changes in triglycerides were variable and generally not statistically significant compared to placebo controls. A recent retrospective review of type 2 diabetes patients treated with either pioglitazone (n=525) or rosiglitazone (n=590) suggested that pioglitazone provides a greater benefit in terms of blood lipid profile than does rosiglitazone.

Because TZDs do not affect insulin secretion, they do not induce hypoglycemia. Dose-related weight gain is seen with both pioglitazone (average increase 0.5 kg to 2.8 kg) and rosiglitazone (median increase 1.0 kg to 3.1 kg). Also, a small number of patients experience mild to moderate edema and anemia. TZDs can cause fluid retention, which may lead to or exacerbate heart failure; thus, patients should be observed for signs and symptoms of congestive heart failure, and TZDs should not be used in patients with class III or IV cardiac status. Studies are currently underway to determine whether thiazolidinediones may be effective in preventing progression of insulin resistance to full-blown type 2 diabetes.