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.

(British Approved Name, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Acarbosa; Acarbosum; Akarboosi; Akarbos; Akarbosa; Akarboz; Akarboze; Bay-g-5421.

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Acarbose). A white or yellowish, amorphous, hygroscopic powder. Very soluble in water practically insoluble in dichloromethane soluble in methyl alcohol. A 5% solution in water has a pH of 5.5 to 7.5. Store in airtight containers.

The United States Pharmacopeia 31, 2008 (Acarbose). Produced by certain strains of Actinoplanes utahensis. Store in airtight containers.

Adverse Effects

Acarbose often causes gastrointestinal disturbances, particularly flatulence due to bacterial action on non-absorbed carbohydrate in the colon. Abdominal distension, diarrhoea, and pain may occur. Ileus has been rarely reported. A decrease in dosage and improved dietary habits may reduce these adverse effects. Hepatotoxicity may occur and may necessitate a reduction in dosage or withdrawal of the drug. Skin reactions have occurred rarely. Very rarely oedema has been reported.

Incidence of adverse effects. The manufacturers reported that adverse effects of acarbose were rarer in a postmarketing surveillance study than in previous clinical trials this was held to represent better tailoring of individual doses to patient tolerability.

Effects on the liver. Hepatocellular liver damage, with jaundice and elevated serum aminotransferases, have been reported in patients receiving acarbose. Symptoms resolved on stopping the drug.

Effects on the skin. Generalised erythema multiforme and eosinophilia occurred in a male diabetic patient 13 days after starting acarbose. The hypersensitivity reaction was confirmed by rechallenge.

Precautions

Acarbose is contra-indicated in inflammatory bowel disease, particularly where there is associated ulceration, and in gastrointestinal obstruction or patients predisposed to it. It should be avoided in patients with chronic intestinal diseases that significantly affect digestion or absorption, and in conditions which may deteriorate as a result of increased gas formation, such as hernia.

Acarbose is also contra-indicated in patients with hepatic impairment and liver enzyme values should be monitored, particularly at high doses. If hypoglycaemia should develop in a patient receiving acarbose it needs to be treated with glucose, since the action of acarbose inhibits the hydrolysis of disaccharides.

Breast feeding. In the absence of evidence, licensed product information recommends that acarbose should be avoided during breastfeeding.

Interactions

Acarbose may enhance the effects of other antidiabetics, including insulin, and a reduction in their dosage may be needed. Use with gastrointestinal adsorbents and digestive enzyme preparations can diminish the effects of acarbose and should be avoided. Neomycin and colestyramine may enhance the effects of acarbose and a reduction in its dosage may be required. Acarbose may inhibit the absorption of digoxin.

Pharmacokinetics

After ingestion of acarbose, the majority of active unchanged drug remains in the lumen of the gastrointestinal tract to exert its pharmacological activity and is metabolised by intestinal enzymes and by the microbial flora. Ultimately about 35% of a dose is absorbed in the form of metabolites. Acarbose is excreted in the urine and faeces.

Uses and Administration

Acarbose is an inhibitor of alpha glucosidases, especially sucrase. This slows the digestion and absorption of carbohydrates in the small intestine and hence reduces the increase in blood-glucose concentrations after a carbohydrate load. It is given in the treatment of type 2 diabetes mellitus either alone or with a sulfonylurea, biguanide, or insulin. Acarbose treatment may be started with a low oral dose of 25 or 50 mg daily to minimise gastrointestinal disturbance. It is then gradually increased to a usual dose of 25 or 50 mg three times daily, immediately before food. Doses up to 100 to 200 mg three times daily may be given if necessary. Some benefit has also been found when acarbose is used to supplement insulin therapy in type 1 diabetes mellitus.

Acarbose has also been studied for the treatment of reactive hypoglycaemia, the dumping syndrome, and certain types of hyperlipoproteinaemia.

Impaired glucose tolerance. A prospective study of patients with impaired glucose tolerance concluded that acarbose significantly reduced the incidence of cardiovascular disease and hypertension.

Preparations

Proprietary Preparations

Argentina: Glucobay

Australia: Glucobay

Austria: Glucobay

Belgium: Glucobay

Brazil: Aglucose Glucobay

Canada: Prandase

Chile: Glucobay

Czech Republic: Glucobay

Denmark: Glucobay

France: Glucor

Germany: Glucobay

Greece: Glucobay

Hong Kong: Glucobay

Hungary: Glucobay

India: Acarbay Asucrose Glubose Glucar Glucobay

Indonesia: Glucobay

Ireland: Glucobay

Israel: Prandase

Italy: Glicobase Glucobay

Malaysia: Dibose Glucar Glucobay Precose

Mexico: Glucobay Incardel Sincrosa

The Netherlands: Glucobay

Norway: Glucobay

New Zealand: Glucobay

Philippines: Glucobay Gluconase

Poland: Glucobay

Portugal: Glucobay

Russia: Glucobay (Глюкобай)

South Africa: Glucobay

Singapore: Glucobay

Spain: Glucobay Glumida

Sweden: Glucobay

Switzerland: Glucobay

Thailand: Glucobay

Turkey: Glucobay Glynose

UK: Glucobay

USA: Precose

Venezuela: Glucobay

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.

Metformin (Glucophage) is a biguanide antidiabetic agent that reduces basal hepatic glucose production by altering gluconeogenesis and/or glycogenolysis. Additionally, metformin decreases insulin resistance by promoting insulin-sensitive glucose uptake by muscle cells. Metformin can also reduce triglycerides and low-density lipoprotein (LDL) cholesterol, and increase high-density lipoprotein (HDL) cholesterol. Weight reductions of 0.6 to 0.8 kg have been noted in study subjects taking metformin.When metformin is combined with the sulfonylurea glyburide, however, average weight gains of 0.7 kg have been reported.

Acarbose (Precose) is an alpha-glucosidase inhibitor as well as an inhibitor of pancreatic alpha-amylase. These enzymes are responsible for the hydrolysis of oligosaccharides and related saccharides in the small intestine. Inhibition of these enzymes results in reductions in the rate and extent of carbohydrate digestion and absorption of glucose in the body. Patients treated with acarbose tend to experience no changes in weight or serum lipids.

Troglitazone (Rezulin) belongs to a new class of drugs called thiazolidinediones. It works by decreasing insulin resistance. Its primary actions involve increasing glucose disposal from the blood stream into muscle tissue and decreasing glucose production in the liver. No or very small weight changes in patients taking troglitazone are seen. Decreases in plasma triglyceride and free fatty acid levels have also been reported.

Approximately three-quarters of all the insulin used in the U.S. is taken by people with type 2 diabetes. Exogenous insulin reduces hepatic glucose production in type 2 diabetics. It also increases insulin-stimulated glucose utilization and endogenous insulin secretion. Weight gain is common in patients using insulin and may include gains up to 6.0 kg in a 12-month period.

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.

New antidiabetic agents were approved for the U.S. market. They are metformin, acarbose and glimepiride. Precautions associated with their use in the patient with renal insufficiency will now be described.

Metformin (Glucophage): The biguanide hypoglycemic agent metformin (Glucophage) is approved for use in the treatment of diabetes mellitus. Metformin is indicated for use as an adjunct to diet and/or a sulfonylurea agent when either of these treatment regimens does not control hyperglycemia. The mechanism of action for metformin differs from the sulfonylureas. Metformin decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and use and by decreasing hepatic glucose production. The primary concern with metformin is the development of lactic acidosis, especially in patients with renal insufficiency.

Metformin is a congener of phenformin, also a biguanide hypoglycemic agent, which was pulled off the market in the U.S. in 1977 due to concerns with phenformin causing lactic acidosis. Metformin has also been associated with causing lactic acidosis; however, the rate of metformin-associated lactic acidosis is one-tenth that of phenformin (one in 4,000 vs. one in 40,000 – 80,000). Cases of metformin-induced lactic acidosis have occurred primarily in patients with renal insufficiency and increased age.

The biguanides can induce lactic acidosis through an increase in cellular lactate production and a decrease in the hepatic metabolism of lactate. Diabetic patients are particularly at high risk for metformin-induced lactic acidosis due to their predisposition to renal dysfunction and impaired clearance of the drug, as well as their abnormal lactate metabolism. Due to the high risk of lactic acidosis in patients with renal dysfunction, metformin is contraindicated in patients with serum creatinine levels >1.5 mg/dL for males and >1.4 mg/dL for females.

The signs and symptoms of biguanide-induced lactic acidosis are nonspecific and include (in decreasing order of frequency) vomiting, somnolence, nausea, epigastric pain, anorexia, hyperpnea, lethargy, diarrhea and thirst. The hallmark of biguanide-associated lactic acidosis is severe lactic acidosis without evidence of hypoperfusion or hypoxia. The treatment of biguanide-induced lactic acidosis is support of the circulation and removal of the drug from the body.

Acarbose (Precose): Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. In patients with renal impairment, plasma concentrations of acarbose have been shown to be proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine >2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with acarbose is not recommended.

Glimepiride (Amaryl): Glimepiride is a new sulfonylurea blood glucose-lowering agent. Patients with renal impairment may be more sensitive to the glucose-lowering effect of glimepiride. Thus, in patients who have renal dysfunction, a starting dose of 1 mg once daily followed by appropriate dose titration is recommended. Pharmacist’s Involvement

With the provision of pharmaceutical care, the pharmacist should be closely involved with the diabetic patient in renal failure and can offer the patient assistance in several health-care areas, including the management of his/her diabetes. The pharmacist can educate the patient about diabetes, its complications and the importance of controlling blood glucose levels through proper diet, exercise and use of medications. The proper use of a blood glucose machine to monitor home blood glucose levels can also be taught by the pharmacist, as well as frequently measuring and monitoring the patient’s blood glucose. Since hypertension can worsen renal function, the pharmacist should also periodically monitor the patient’s blood pressure and teach the patient how to measure his or her blood pressure at home. In monitoring blood glucose and blood pressure, the pharmacist also needs to assess the patient’s diet, activity level and health status.

In addition, the pharmacist should evaluate the patient’s drug therapy — assessing not only the medication’s efficacy, but also the medication’s effect on blood glucose, blood pressure, electrolytes, lipids and renal function. The patient’s optimal drug therapy, lifestyle, blood glucose, blood pressure and renal function must be monitored to prevent further complications.Summary

Renal failure seriously impacts the quality of life and management of the diabetic patient. There are numerous patient considerations that the pharmacist must evaluate. Additionally, an understanding of the effect renal failure has on insulin greatly assists the pharmacist who is providing pharmaceutical care to the diabetic patient with renal insufficiency.

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.

Acarbose has 100,000 times the binding affinity of glucose for alpha-glucosidase. It binds to the enzyme competitively in the brush border within the small intestine. By slowing the conversion and absorption of glucose, the drug reduces blood concentrations of glycosylated hemoglobin (HbA1c) by 0.5% to 1.0%. (Although glycosylated hemoglobin concentrations of 10% to 11% are associated with rapid progression of retinopathy, reducing the concentrations to 7% to 9% slows this progression significantly.) Acarbose improves postprandial hyperglycemia and maintains or lowers secretion of insulin (which is stimulated by hyperglycemia). As monotherapy, acarbose causes no hypoglycemia.

The mechanism of action of acarbose differs from that of other oral drugs such as sulfonylureas and metformin, which appear to control hyperglycemia by stimulating surviving beta cells in the pancreas to produce more insulin. These drugs can cause hypoglycemia. Acarbose, which shows little or no systemic absorption, has not been linked to serious adverse events. The main complaints are gastrointestinal symptoms (eg, flatulence, diarrhea) resulting from carbohydrate malabsorption. These can be minimized by using a low starting dose. In early studies, increases in serum hepatic transaminases were a concern, but these increases have been dramatically reduced with the lower dosages currently recommended by the sponsor (150 to 300 mg a day).

The advisory committee’s recommendation was based, at least in part, on a National Institutes of Health Diabetes Control and Complications Trial that demonstrated improved control of blood glucose with acarbose. Although that trial involved patients with type I (insulin-dependent) diabetes, panel members believe the findings will also apply to patients with NIDDM. In support of this hypothesis, a recently reported study indeed demonstrated the safety and efficacy of acarbose in a non-insulin-dependent diabetes mellitus (NIDDM) patient population. In a multicenter, double-blind, randomized trial conducted by Coniff et al., 290 NIDDM patients were randomly assigned to receive 200 mg acarbose, 250 to 1000 mg tolbutamide, acarbose plus tolbutamide, or placebo three times a day for 24 weeks. All active treatments were superior to placebo in controlling postprandial hyperglycemia and HbA1c. The two-drug combination was most effective, followed by tolbutamide and acarbose.

Tolbutamide increased body weight and postprandial insulin levels, but these effects were ameliorated when acarbose was given with tolbutamide. Elevated hepatic enzymes were observed in three patients receiving acarbose alone and two receiving acarbose plus tolbutamide; transaminase levels returned to normal when treatment was discontinued. The researchers concluded that acarbose was effective and well-tolerated and produced significantly better results than dietary restriction.