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, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Glibenclamida; Glibenclamidum; Glibenklamid; Glibenklamidas; Glibenklamidi; Glybenclamide; Glybenzcyclamide; Glyburide (US-AN); HB-419; U-26452

C₂₃H₂₈CIN₃0₅S = 494.0.

CAS — 10238-21-8.

ATC — A10BB01.

Note. The name glibornuride has frequently but erroneously been applied to glibenclamide.

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed. (Glibenclamide). A white or almost white, crystalline powder. Practically insoluble in water slightly soluble in alcohol and in methyl alcohol sparingly soluble in dichloromethane.

The United States Pharmacopeia 31, 2008 (Glyburide). Store in airtight containers.

Adverse Effects, Treatment, and Precautions

As for sulfonylureas in general.

For a suggestion that the failure rate in type 2 diabetics treated with glibenclamide may be higher than that for those treated with chlorpropamide, see Diabetes Mellitus under Uses and Administration of Chlorpropamide.

Hypoglycaemia. Severe hypoglycaemia may occur in any patient given any sulfonylurea glibenclamide which has a relatively prolonged duration of action, may cause severe hypoglycaemia more often than shorter-acting sulfonylureas. In a 1983 review of 57 instances of hypoglycaemia associated with glibenclamide the median age of patients affected was 70 years only one was less than 60 years old. Median daily dosage was 10 mg. Coma or disturbed consciousness was seen in 46 patients. Ten of these remained comatose despite alleviation of their hypoglycaemia and died up to 20 days after presentation. The authors noted that, including their series of 57 cases, there had been published reports on 101 cases of severe hypoglycaemia with glibenclamide, 14 with a fatal outcome. There has been a report of hypoglycaemic coma associated with the inhalation of glibenclamide by a worker at a pharmaceutical plant.

Porphyria. Glibenclamide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for sulfonylureas in general.

Pharmacokinetics

Glibenclamide is readily absorbed from the gastrointestinal tract, peak plasma concentrations usually occurring within 2 to 4 hours, and is extensively bound to plasma proteins. Absorption may be slower in hyper-glycaemic patients and may differ according to the particle size of the preparation used. It is metabolised, almost completely, in the liver, the principal metabolite being only very weakly active. About 50% of a dose is excreted in the urine and 50% via the bile into the faeces.

Uses and Administration

Glibenclamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus and has a duration of action of up to 24 hours.

The usual initial dose of conventional formulations in type 2 diabetes mellitus is 2.5 to 5 mg daily with breakfast, adjusted every 7 days in steps of 2.5 or 5 mg daily up to 15 mg daily. Although increasing the dose above 15 mg is unlikely to produce further benefit, doses of up to 20 mg daily have been given. Doses greater than 10 mg daily may be given in 2 divided doses. Because of the relatively long duration of action of glibenclamide, it is best avoided in the elderly. In some countries micronised preparations of glibenclamide are available, in which the drug is formulated with a smaller particle size, and which have enhanced bioavailability. The usual initial dose of one such preparation (Glynase PresTab; Pharmacia Upjohn, USA) is 1.5 to 3 mg daily, adjusted every 7 days in steps of 1.5 mg, up to a usual maximum of 12 mg daily. Doses greater than 6 mg daily may be given in 2 divided doses.

Action. Proceedings of a symposium on the mechanism of action of glibenclamide.

EFFECTS ON THE HEART. A reduced incidence of ventricular fibrillation has been reported in diabetics treated with glibenclamide who develop myocardial infarction, compared with those receiving other treatments or with nondiabetic patients with myocardial infarction. However, some evidence has also suggested that sulfonylureas may impair the adaptive responses of the heart to ischaemia.

Preparations

British Pharmacopoeia 2008: Glibenclamide Tablets

The United States Pharmacopeia 31, 2008: Glyburide and Metformin Hydrochloride Tablets Glyburide Tablet.

Proprietary Preparations

Argentina: Agobilina Benclamid Daonil Diabe Pass Diabemin Euglucon Gardoton Glentor Glibediab † Glibemida Glidanil Gliptid Glitral GON Pira Siruc

Australia: Daonil Glimel Semi-Daonil

Austria: Daonil Dia-Eptal Euglucon Gilemal Glucobene Glucostad Normoglucon Semi-Euglucon

Belgium: Bevoren Daonil Euglucon

Brazil: Aglucil Benclamin Clamiben Daonil Diaben Diabetty’s † Diabexil Euglucon Gliben † Glibenclamon Glibendiab Glibexil † Glicamin Glionil Lisaglucon Uni Gliben †

Canada: DiaBeta Euglucon Gen-Glybe

Chile: Daonil Euglusid Mezalit

Czech Republic: Betan-ase † Glibenhexal † Glucobene Humedia † Maninil

Denmark: Daonil Hexaglucon Regulin †

Finland: Daonil † Euglamin Euglucon Origlucon Semi-Euglucon

France: Daonil Euglucan Hemi-Daonil Miglucan

Germany: Azuglucon † Bastiverit † duraglucon N Euglucon N Glib Glib-ratiopharm Gliben Glib-en-Azu † Gliben-Puren N † Glibenbeta Glibendoc Glibenhexal Glimidstada † Glucoremed † Glukoreduct † Glukovital glycolande N † Humedia Jutaglucon † Maninil Praeciglucon † Semi-Euglucon N

Greece: Daonil Deroctyl Diabefar †

Hong Kong: Calabren † Clamide Daonil Euglucon Gliben Gliboral Glimel Glitisol Marglucon Semi-Daonil † Semi-Euglucon Xeltic

Hungary: Gilemal Glucobene Maninil

India: Daonil Euglucon Glinil Glybovin Semi-Daonil Semi-Euglucon

Indonesia: Condiabet Daonil Glidanil Glimel Gluconic Glulo Glyamid Libronil Prodiabet Prodiamel Renabetic Semi-Daonil Tiabet Trodeb

Ireland: Daonil Semi-Daonil

Israel: Daonil † Glibetic Gluben

Italy: Daonil Euglucon Gliben Gliboral

Japan: Euglucon

Malaysia: Claben † Daonil Debtan † Dibelet Gliben Glibesyn Glimide

Mexico: Abuglib Apogly Biostin Daonil Dibetid Diglexol Euglucon Gadinor Glemicid Glibenil Glibenval Glicavin Glicoxem Glifarcal Glihexal Glikeyer † Glipar Glucal Glucoven Insusym Mibeclag Nadib † Norboral Ocrix Reglusan

The Netherlands: Daonil Hemi-Daonil †

Norway: Daonil †

New Zealand: Gliben

Philippines: Ameciadin Daonil Diabitor Euglucon Eundin Gluban Glymod Insol Loduice Orabetic Semi-Euglucon Sentionyi Sucron

Poland: Euclamin

Portugal: Daonil Euglucon Semi-Daonil Semi-Euglucon †

Russia: Betanase Glibamide Glibex Glidanil Maninil

South Africa: Daonil Diacare Euglucon † Glycomin

Singapore: Clamide Daonil Dibelet GBN † Glibemid † Glibesyn Glimel Glimide

Spain: Daonil Euglucon Glucolon Norglicem

Sweden: Daonil Euglucon

Switzerland: Daonil Euglucon Glibasan Glibenorme Glibesifar Melix Semi-Daonil Semi-Euglucon †

Thailand: Benclamin BNIL Cytagon † Daonil Daono Debtan Diabenol Dibelet Diclanil Euglucon Glencamide † Gliben † Glibetic Glibic Gluconil Gluzo Locose Manoglucon Med-Glionil † Semi-Euglucon † Sugril Unil Xeltic

Turkey: Dianorm Diyalen Gliben

United Arab Emirates: Glynase Mini-Glynase

UK: Daonil Diabetamide † Euglucon † Semi-Daonil †

USA: DiaBeta Glynase Micronase

Venezuela: Daonil Euglucon Gliciron.

Multi-ingredient

Argentina: DBI Duo Glucovance Isloglib Medobis G Metformin Duo

Australia: Glucovance

Belgium: Glucovance

Brazil: Glucovance

Chile: Bi-Euglucon M Diaglitab Plus Glifortex-G Glimet Glucovance Glukaut Hipoglucin DA

Czech Republic: Glibomet Glucovance

France: Glucovance

Greece: Daopar † Normell

Hong Kong: Glucovance

India: Diaforte Glinil M

Indonesia: Glucovance

Italy: Bi-Euglucon M Bi-Euglucon † Gliben  † Glibomet Gliconorm Glicorest Gliformin Glucomide Suguan M Suguan †

Malaysia: Glucovance

Mexico: Apometglu Bi-Dizalon Bi-Euglucon M Bi-Pradia Duo-Anglucid Glinorboral Glucotec Glucovance Imalet Insusym-Forte Maviglin Midapharma Mifelar-C Nadib-M Norfaben M Sibet-C Sil-Norboral Wadil

The Netherlands: Glucovance

Philippines: Euglo Plus Glucovance

Portugal: Glucovance

Russia: Glibomet Glucovance

South Africa: Glucovance

Singapore: Glucovance

Switzerland: Glucovance

USA: Diofen Glucovance Glybofen

Venezuela: Bi-Euglucon Diaformina Plus Glucovance.

Sulfonylureas: First-Generation

Sulfonylureas consists of two groups or generations of agents. The first-generation agents are now less commonly used because second-generation agents are as effective and have fewer side effects. Two first-generation agents, chlorpropamide and tolbutamide are still popular with some physicians. This group also contains tolazamide and acetohexa-mide; both are rarely used today.

Chlorpropamide. Brand Name Drug: Diabinese. Chlorpropamide is administered once daily in a 100 mg or 250 mg tablet. Its half-life is extremely long, with effects lasting up to >48 hours. The principal disadvantage of this agent is that it is excreted almost entirely renally. Therefore, the risk of hypoglycemia makes this drug relatively contraindicated in the elderly and absolutely contraindicated in those with renal insufficiency. Chlorpropamide also enhances the effects of vasopressin, at times resulting in the syndrome of inappropriate antidiuretic hormone (SIADH). With the introduction of more potent agents that have a much shorter half-life and fewer side effects, today there is little reason to use chlorpropamide.

Tolbutamide. Brand Name Drug: Orinase. Tolbutamide has a much shorter duration of action (6-10 hours) and is metabolized primarily by the liver. It is a safer agent than chlorpropamide; however, it is relatively weak in its antidiabetic activity.

Sulfonylureas: Second-Generation

Second-generation sulfonylureas are the most commonly prescribed agents for treating type 2 diabetes. As a group, they are at least 100 times more potent than tolbutamide. They include glyburide, glipizide, and the newest agent, glimepiride. Glyburide and glipizide, when used as monotherapy, have proven effective in lowering HgbA₁C 1% to 2% in most studies.

Glyburide. Brand Names: Diabeta, Glycron, Glynase, Micronase. Glyburide is metabolized in the liver to metabolites with reduced hypoglycemic activity. These metabolites are then excreted renally. Therefore, in the elderly and patients with compromised renal function, glyburide is relatively contraindicated because of the risk of hypoglycemia. Even in normal subjects it is not unusual to see persistence of glyburide’s effects for up to 24 hours. In the United Kingdom Prospective Diabetes Study (UKPDS), a multicenter trial of >5000 patients with type 2 diabetes mellitus, the incidence of hypoglycemia with glyburide was similar to that seen with chlorpropamide. Patients usually are started on a 2.5-mg or 5-mg tablet in the morning before the first meal of the day. The dose can be escalated gradually to a maximum of 20 mg/day. However, it is rare to see further improvement in efficacy with doses > 10 mg/day. Again, this agent should be used with caution in the elderly population and in those with renal insufficiency.

There also is a micronized form of glyburide. However, it has been difficult to find exactly equivalent dosages between the two forms, which can lead to confusion for the patient and physician. The micronized agents have not been shown to have a higher bio availability or greater efficacy than regular glyburide.

Glipizide. Brand Name Drug: Glucotrol. Glipizide is completely metabolized in the liver and excreted primarily by the kidneys. However, it is not as potent as glyburide at raising basal insulin levels and therefore is the preferred sulfonylurea in elderly patients or those with renal insufficiency. It usually is started with 5 mg orally 30 minutes prior to breakfast. If the dose exceeds 15 mg/day, then it is best to divide the doses by giving it before breakfast and before dinner. The maximum recommended dose is 40 mg/day, although it is rare to see additional efficacy with doses >20 mg/day. There is also an extended release form of glipizide, which allows for once a day dosing.

Glimepiride. Brand Name Drug: Amaryl. In 1996, a new sulfonylurea, glimepiride, was approved for use in the treatment of type 2 diabetes. It is the most potent of the sulfonylureas to date, requiring a 1-, 2-, or 4-mg dose once daily. It is completely metabolized in the liver, making it safe in the elderly and in those with renal insufficiency. The maximal recommended dose is 6 mg/day, and this agent is of equal efficacy whether given once or twice daily. Like the other sulfonylureas, glimepiride acts as an insulin secretagogue, but in comparative trials, it caused fewer episodes of hypoglycemia. Other data from comparative trials show that glimepiride provides greater postprandial insulin secretion, but fasting glucose control and HgbA₁C lowering is similar to that of glyburide. Glimepiride has been shown to have extrapancreat-ic in vitro effects on glucose uptake, but the clinical significance of these effects is still to be determined.

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.