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.

Previous studies had “been divided as to [the receptor's] presence in the artery wall,” although they did show that it existed in other types of tissue, Dr. Law said.

By binding to the artery receptors, the medication may lower diabetics’ risk of clogged arteries, including restenosis (when an artery is blocked again after angioplasty), the team reports. Rosiglitazone treats type 2 diabetes, which begins in adulthood, and not type 1, which usually begins in childhood.

If an artery is damaged even slightly, such as from atherosclerosis or after angioplasty, the tissue increases production of growth factors that cause cells in the area to multiply and migrate. Such cell activity is dangerous, because it can lead to artery walls getting thicker. However, when the researchers exposed artery smooth muscle cells to the diabetes medication, the cells failed to multiply or migrate, the team reports. The drugs may slow the build-up of fatty substances along the artery wall.

What the PPAR gamma receptor normally does other than bind with diabetes drugs is unclear, Dr. Law told Mediconsult. “We don’t really understand what normally turns these receptors on, or what their role is in tissue other than…to make more fat cells, he said.

The team also tested another diabetes drug, troglitazone (Rezulin), but it was taken off the market in March 2000, because of possible dangerous side effects. Both drugs are part of the thiazolidinedione (TZD) class of drugs that control blood sugar levels in people with type 2 diabetes.

Commenting on the study, Dr. Andrew P. Levy, M.D., Ph.D, at the Technion Faculty of Medicine, and Medical Advisor for HeartInfo, says that, “The new TZD drugs described above will help patients with type 2 control their glucose levels. The precise mechanism as to how these drugs achieve their effect is not entirely clear. More research is required to fully understand their mode of action, but their efficacy is indisputable.”

(British Approved Name Modified, US Adopted Name, rINN)

Adverse Effects and Precautions

Rosiglitazone may cause hypoglycaemia, headache, weight gain, and anaemia. It may also cause dizziness, gastrointestinal disturbances, muscle cramps and myalgia, dyspnoea, paraesthesia, pruritus, and hypercho-1 esterolaemia. Very rarely angioedema and urticaria have been reported. Rosiglitazone can also increase the risk of bone fracture in women. Rosiglitazone can cause oedema, which may worsen or precipitate heart failure. It should therefore be used with caution in patients with oedema, and should not be used in those with a history of heart failure (see also below). Renal impairment may increase the risk of fluid retention and heart failure. There have been very rare reports of new onset and worsening diabetic macular oedema with decreased visual acuity (see Effects on the Eyes, below). There is some evidence to suggest that rosiglitazone might increase the risk of myocardial ischaemia until further data become available, UK licensed product information advises that rosiglitazone is not recommended in patients with ischaemic heart disease or peripheral arterial disease (see also below). Liver function should be monitored periodically as there have been isolated reports of liver dysfunction, and the drug should be used with caution in patients with hepatic impairment (see Effects on the Liver, below).

In women who are anovulatory because of insulin resistance, rosiglitazone therapy may result in a resumption of ovulation.

Effects on the bones. Use of thiazolidinediones such as pioglitazone or rosiglitazone has been associated with decreases in bone mineral density and increased risk of fractures in female patients. Analysis of data from a comparative study of glycaemic control with rosiglitazone, metformin, or glibenclamide involving 4360 randomised patients found that the risk of fracture in female patients in these 3 groups was 9.3%, 5.1%, and 3.5% respectively the risk in male patients was not significantly different in the 3 groups at around 3.4 to 3.95%. Analysis of data from another large ongoing study was also consistent with an increased fracture risk with rosiglitazone, and data from the manufacturer of pioglitazone involving over 8100 treated patients also revealed an increased risk of fracture in women given the drug the excess risk was calculated to be 0.8 per 100 patient years of use. The pattern of fractures seems to differ from that associated with postmenopausal osteoporosis, being mainly in the upper arm, hand, or foot, rather than hip or spine, but an observational study has suggested that thiazolidinedione use is associated with ongoing loss of whole-body bone mineral density.

Effects on the cardiovascular system. It has been suggested that, in addition to their hypoglycaemic effect, thiazolidinediones may have beneficial effects in the prevention of macrovascular diabetic complications, and there is some evidence that pioglitazone may improve some cardiovascular outcomes (see Diabetic Complications). However, a meta-analysis of 42 studies found that, compared with either placebo or other antidiabetic drugs, rosiglitazone was associated with a significant increase in the risk of myocardial infarction, and an increase of borderline significance in death from cardiovascular causes. There were limitations to this analysis as the studies were not primarily intended to examine cardiovascular outcomes, and many were small and short-term. Another meta-analysis that was restricted to 4 long-term studies (at least 12 months of treatment) that had specified an intention to evaluate cardiovascular adverse effects also found an increased risk of myocardial infarction with rosiglitazone use, without a significant increase in the risk of cardiovascular mortality.

Studies with no recorded cardiovascular events were excluded from the larger meta-analysis, and this has been questioned. An alternative analysis that incorporated these excluded studies, with appropriate analysis adjustment, found odds ratios for myocardial infarction and cardiovascular death that were not statistically significant, and concluded that neither increased nor decreased risk could be established.

In response to concerns raised by the initial meta-analysis, an unplanned interim analysis of an ongoing open-label study designed to assess cardiovascular outcomes has been published (rosiglitazone added to either metformin or a sulfonylurea compared with metformin plus a sulfonylurea) The data, however, were insufficient to determine whether there was an increased risk of myocardial infarction, and the findings were inconclusive regarding any effect on overall risks of hospitalisation or death from cardiovascular causes.

For the risks of heart failure associated with thiazolidinediones, see Effects on the Heart, below.

Effects on the eyes. The manufacturers in the USA and Canada (GSK) have received postmarketing reports of the development or worsening of diabetic macular oedema in patients treated with rosiglitazone-containing products in most cases the patients also reported peripheral oedema or fluid retention. In some cases visual impairment improved or resolved after stopping the drug. Rosiglitazone should be used with caution in patients with pre-existing diabetic retinopathy or macular oedema, and should be stopped, and ophthalmological consultation sought, if visual impairment develops while using the drug.

Effects on the heart. Both pioglitazone and rosiglitazone can cause peripheral and pulmonary oedema, which can worsen or precipitate heart failure a number of cases have been described. A large retrospective cohort study also found that the use of thiazolidinediones increased the risk of heart failure. The incidence of peripheral oedema with monotherapy has been reported to range from 3 to 5%, and this increases slightly when a thiazolidinedione is used with another oral antidiabetic. The incidence is about 15% when a thiazolidinedione is used with insulin. The incidence of heart failure is generally lower, but has been reported to be 2 to 3% when a thiazolidinedione is used with insulin however, a large prospective study, which was intended to examine the cardiovascular benefits of pioglitazone in preventing secondary macrovascular events in diabetic patients with pre-existing macrovascular disease, reported a 6% incidence of heart failure, compared with 4% in the placebo group. Mortality rates from heart failure did not differ between groups. These figures were confirmed on re-analysis.The American Heart Association and American Diabetes Association have recommended that patients with risk factors for heart disease or a depressed ejection fraction but without symptoms, and patients with NYHA class I or II heart failure, should start with a low dose of a thiazolidinedione that is only increased gradually as necessary and with careful monitoring. Patients with more severe heart failure (class III and IV) should not receive these drugs. These recommendations are reflected in US licensed product information. UK licensed product information contraindicates the use of pioglitazone or rosiglitazone in patients with heart failure or any history of heart failure, even of class I or II. For restrictions on combination therapy see Administration, below.

Effects on lipids. Rosiglitazone and pioglitazone have different effects on serum lipids.

Effects on the liver. Several cases of hepatotoxicity have been described in patients receiving rosiglitazone. Most of these occurred within a few weeks or months of starting rosiglitazone therapy. However, the causality of some of these cases has been debated’ because of coexisting disease and concomitant medication.

Licensed product information recommends that liver enzymes should be checked before starting therapy with rosiglitazone patients with aminotransferase (ALT) concentrations more than 2.5 times the upper limit of normal should not be given rosiglitazone. ALT concentrations should then be monitored periodically. If aminotransferase concentrations rise to more than 3 times the upper limit of normal and remain so after retesting then treatment with rosiglitazone should be stopped treatment should also be stopped if jaundice develops.

Fasting. For mention that glitazones can probably be used with low risk of hypoglycaemia in fasting Muslim patients during Ramadan see under Precautions of Insulin.

Interactions

Gemfibrozil, ketoconazole, and trimethoprim, can increase plasma concentrations of rosiglitazone. Conversely, rifampicin can reduce rosiglitazone concentrations. These drugs should be given with caution to patients taking rosiglitazone, and glycaemic control should be monitored.

Use of NSAIDs or insulin with rosiglitazone may increase the risk of oedema and heart failure (see also Effects on the Heart, above, and Administration, below).

Antibacterials. Rifampicin significantly reduced the plasma concentration and elimination half-life of rosiglitazone in studies’ of healthy subjects, probably by induction of the cytochrome P450 isoenzyme CYP2C8. Conversely, trimethoprim can inhibit CYP2C8, and was found to increase the concentration and half-life of rosiglitazone modestly.’

Antifungals. In a study of healthy subjects, ketoconazole increased the plasma concentration and elimination half-life of rosiglitazone, probably by inhibition of the cytochrome P450 isoenzyme CYP2C8 and to a lesser extent CYP2C9

Lipid regulating drugs. Gemfibrozil increased the plasma concentration and about doubled the half-life of rosiglitazone in a study of healthy subjects, probably by inhibiting its metabolism. The authors suggested that these drugs should not be used together, or that the dose of rosiglitazone should be at least halved if gemfibrozil treatment is started.

Pharmacokinetics

Rosiglitazone is well absorbed from the gastrointestinal tract after oral dosing. Peak plasma concentrations occur within 1 hour and the bioavailability is 99%. It is 99.8% bound to plasma proteins. Rosiglitazone is extensively metabolised, almost exclusively by the cytochrome P450 isoenzyme CYP2C8. It is excreted in the urine and faeces, and has a half-life of 3 to 4 hours.

Uses and Administration

Rosiglitazone is a thiazolidinedione oral antidiabetic that improves insulin sensitivity and is used for the treatment of type 2 diabetes mellitus. It is usually given as rosiglitazone maleate but doses are expressed in terms of the base rosiglitazone maleate 1.32 mg is equivalent to about 1 mg of rosiglitazone. The potassium salt is used in some countries. Rosiglitazone is given orally as monotherapy, particularly in patients who are overweight and for whom metformin is contra-indicated or not tolerated. It may also be added to metformin, a sulfonylurea (or a combination of the two), or to insulin, when such therapy is inadequate (but see Administration, below). The usual initial dose is 4 mg daily, given in a single dose or two divided doses. The dose may be increased to a maximum of 8 mg daily if necessary after 8 to 12 weeks in patients receiving monotherapy or combination oral therapy. Rosiglitazone may be taken with or without food.

Administration. Although rosiglitazone is licensed for use with other antidiabetic drugs the specifics of licensing and use may vary from country to country. In both the UK and USA, rosiglitazone (Avandia GSK) is licensed for use with metformin or a sulfonylurea, or both if necessary, in patients in whom single or dual agent therapy is inadequate. In the UK, however, NICE recommends dual therapy only in patients who cannot be given combination therapy with metformin plus a sulfonylurea.The combination of rosiglitazone with insulin is now generally avoided because of an increased risk of heart failure and other cardiac adverse events (see also Effects on the Heart, above), although licensed product information may not necessarily contra-indicate the combination. In the UK, licensed product information for rosiglitazone warns that insulin should only be added to established rosiglitazone therapy in exceptional cases and under close supervision. In the USA, the combination of rosiglitazone and insulin is not recommended.

Inflammatory bowel disease. There is some evidence to suggest that drugs such as rosiglitazone that act as ligands to peroxisome proliferator-activated receptor y (PPARy) may offer a novel therapeutic approach to management of inflammatory bowel disease.

Polycystic ovary syndrome. Insulin resistance is a feature of polycystic ovary syndrome and the use of rosiglitazone is under investigation.

Preparations

Proprietary Preparations

Argentina: Avandia Diaben Gaudil Glimide Gliximina Gludex Rosiglit

Australia: Avandia

Belgium: Avandia

Brazil: Avandia

Canada: Avandia

Chile: Avandia

Czech Republic: Avandia

Denmark: Avandia

Finland: Avandia

France: Avandia

Germany: Avandia

Greece: Avandia

Hong Kong: Avandia

Hungary: Avandia

India: Rezult † Roglin Rosicon

Indonesia: Avandia

Ireland: Avandia

Israel: Avandia

Italy: Avandia

Malaysia: Avandia

Mexico: Avandia

The Netherlands: Avandia

Norway: Avandia

New Zealand: Avandia

Philippines: Avandia

Poland: Avandia

Portugal: Avandia

Russia: Avandia Roglit

South Africa: Avandia

Singapore Avandia

Spain: Avandia

Sweden: Avandia

Switzerland: Avandia

Thailand: Avandia

Turkey: Avandia

UK: Avandia

USA: Avandia

Venezuela: Avandia

Multi-ingredient

Argentina: Avandamet Gludex Plus Rosiglit-Met

Australia: Avandamet

Belgium: Avandamet

Canada: Avandamet

Chile: Avandamet

Czech Republic: Avaglim Avandamet

Denmark: Avandamet

Finland: Avandamet

France: Avaglim Avandamet

Germany: Avandamet

Greece: Avaglim Avandamet

Hong Kong: Avandamet

Hungary: Avaglim Avandamet

India: Glyroz Roglin-M Rosicon M †

Indonesia: Avandamet Avandaryl

Ireland: Avandamet

Israel: Avandamet

Italy: Avandamet

Malaysia: Avandamet

Mexico: Avandamet

The Netherlands: Avandamet

Norway: Avandamet

Philippines: Avandamet

Poland: Avandamet

Portugal: Avaglim Avandamet

Singapore: Avandamet

Spain: Avandamet

Sweden: Avandamet

Switzerland: Avandamet

Thailand: Avandamet

UK: Avandamet

USA: Avandamet Avandaryl

Venezuela: Avandamet

Separately, SKB strengthened its hand by announcing it would copromote rosiglitazone – likely to be approved for treatment of patients with diabetes type 2 as either monotherapy or with metformin – with Bristol-Myers Squibb, which markets metformin (Glucophage). Since rosiglitazone will probably reach the U.S. market before pioglitazone, the collaboration could be critical in quickly penetrating the insulin-resistance market. Some experts project that pioglitazone will become the market leader in the glitazone class, and Takeda’s previously announced marketing collaboration with Lilly promises to make the competition fierce.

FDA approval was based on clinical studies involving more than 5,500 patients with type 2 diabetes. In these studies, rosiglitazone effectively lowered blood glucose levels of patients by an average of 76 mg/dL, compared with placebo, and maintained blood glucose control for up to 12 months. Patients achieved an average reduction in hemoglobin A1C levels up to 1.5 percentage points at a daily dose of 8 mg, demonstrating a statistically significant improvement in glycemic control relative to placebo and also in comparison to baseline.

Commonly reported side effects with rosiglitazone were upper respiratory tract infections, headaches, anemia, and edema. As with other members of this class, weight gain has been reported.

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.

Introduction

Despite a growing understanding of the pathophysiology of diabetes mellitus, the long-term management of the disease remains one of the greatest challenges for clinicians. As the number of persons in the US with Type 2 diabetes continues to grow, so does the search for novel, effective and well tolerated therapies. Among the newest forms of therapies are drugs that sensitize the insulin receptor to the action of insulin. The first drug in this class approved in the US was Rezulin (troglitazone). Despite its widespread use and generally good tolerability profile, concerns have been raised about the effect of Rezulin on the liver. Now, Avandia (rosiglitazone) promises to provide good effectiveness while improving on the safety profile of this class of drugs.

How It Works

Insulin exerts its effects by linking to a cellular receptor. Following this interaction, the metabolism of glucose is altered in the cell. Evidence indicates that persons with Type 2 diabetes (formerly known as noninsulin-dependent diabetes) have a defect in their cells that results in reduced responsiveness to insulin. As a class, the thiazolidinediones (also called the “glitazones”) act by “sensitizing” receptors, known as PPAR-gamma receptors, to the effects of insulin. Consequently, the depressed levels of insulin found in persons with Type 2 diabetes achieve a near-normal physiologic effect. Patients who have responded poorly to other traditional oral diabetes therapies, and who have not reached the point where they require insulin injections, appear to respond favorably to Avandia.

Clinical Study Results

Rosiglitazone is one of the most potent members of the thiazolidinediones. Several studies have demonstrated the effectiveness of the drug in persons with diabetes. In one study, 380 diabetics received 12 weeks of treatment with doses ranging from 0.1 mg to 4 mg (given as a twice daily dose). The drug significantly lowered blood glucose compared to placebo, without an accompanying rise in fasting insulin. One fourth of patients receiving the highest dose had complete normalization of their fasting glucose level. The magnitude of effect was considered to be similar to that observed with an 800 mg daily dose of troglitazone. Similar results were observed in a second study of 493 patients.

Some evidence suggests that Avandia’s activity is enhanced when it is given concomitantly with another oral diabetes drug, metformin. Also, Avandia may be slightly more effective in women than in men, although the reasons for this are unclear.

What The Patient Should Know

All antidiabetic drugs, including Avandia, have the potential to cause low blood sugar levels. The dose must be carefully adjusted to ensure adequate control of blood sugar levels but without the development of hypoglycemia.

Because of the development of severe liver damage in some patients who had been treated with troglitazone, the liver safety profile of Avandia remains a concern. However, there has been no indication of hepatotoxicity in controlled clinical trials with Avandia. Nevertheless, it is recognized that hepatic adverse events occur in a very small minority of patients, and that if these adverse events occur with Avandia, they will not be seen until the drug is used by hundreds of thousands of patients.

Mechanism of Action: The mechanism of action of the thiazolidinediones is still being investigated, but many of their actions seem to be mediated through binding and activation of PPARg (peroxisome proliferator-activated receptor g). PPARg is a nuclear receptor that has a regulatory role in cell differentiation, particularly fat cell differentiation. Although concentrations of PPARg tend to be highest in fat cells, the receptor is present in many other tissues, including skeletal muscle and pancreatic beta cells. The potencies of the thiazolidinediones as antihyperglycemic agents are also correlated with their binding affinities and functional agonist potencies at PPARg. Intriguingly, while some agents are virtually complete PPARg agonists, other agents, particularly pioglitazone, are partial agonists with mixed a- and g-activation. This property has been suggested as a mechanism underlying the differential effects of these agents on lipid parameters.

Available data indicate that the major effects of these agents in vivo are to increase peripheral glucose disposal, primarily by enhancing skeletal muscle uptake of glucose. Some studies have also shown an effect of the agents on endogenous glucose production. It also remains unclear whether the glucose-lowering effects of these agents are produced directly, via activation of PPARg in skeletal muscle, or indirectly, via their effects on PPARg in adipocytes and potentially mediated by reductions in free fatty acids (FFA). Reductions in FFA concentrations have been documented to improve insulin sensitivity, and all of the clinically available thiazolidinediones produce significant reductions in FFA, despite having apparently disparate effects on overall lipid profiles.