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, US Adopted Name, rINN)

Adverse Effects and Precautions

Troglitazone has been associated with severe hepatic reactions, sometimes fatal, which has led to its withdrawal in most countries. Regular monitoring of liver function during therapy, and withdrawal of the drug in any patient who develops j aundice or signs of liver dysfunction, is required. It should not be given to patients with pre-existing moderate or severe elevations of liver enzyme values, or active liver disease. Increased plasma volume has been reported in healthy subjects given troglitazone: it should be used with caution in patients with heart failure. Other adverse effects reported in patients receiving troglitazone include dizziness, headache, fatigue, musculoskeletal pain, and nausea and vomiting. There is no evidence of hypoglycaemia associated with the use of troglitazone alone.

Effects on the liver. The UK CSM was aware of over 130 cases of hepatic reactions to troglitazone worldwide as of December 1997, although only 1 had been in the UK. There had been 6 deaths. The average time to the onset of the reaction was 3 months, but the frequency of these reactions, and the existence of risk factors predisposing to them, were unclear. The manufacturers had voluntarily withdrawn the drug in the UK. The US manufacturer and the FDA recommended a schedule for routine monitoring of liver function in November 1997 and revised this again in December 1997. It was estimated that 2% of patients treated with troglitazone would have elevated liver enzyme values necessitating discontinuation of the drug. The FDAhad received 560 reports of troglitazone-associated hepatotoxic-ity by June 1998. There were 24 cases of hepatic failure which were likely to have been caused by the drug 21 patients died and 3 patients received transplants. More intensive liver function monitoring recommendations were made by the US manufacturer again in July 1998 and in June 1999. Subsequently the manufacturer withdrew the drug in Australiaia, Japan, and the USA in March 2000. The clinical details of 94 cases of liver failure associated with troglitazone, which were reported to the FDA, have been reviewed.

Interactions

Troglitazone may enhance the hypoglycaemic effects of sulfonylureas dosage adjustment may be necessary. There is a possibility that troglitazone may enhance the metabolism of drugs metabolised by cytochrome P450 isoenzyme CYP3A4, including some oral contraceptives and terfenadine.

Ciclosporin. For the effect of troglitazone on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Colestyramine. Colestyramine markedly impaired the absorption of troglitazone.

Pharmacokinetics

Troglitazone is rapidly absorbed after oral doses, with peak plasma concentrations 1 to 3 hours after a dose. Bioavailability is about 53% absorption is markedly increased in the presence of food. In the body, troglitazone is more than 99% bound to plasma albumin. It is extensively metabolised in the liver and excreted largely in faeces as metabolites small amounts of metabolites are excreted in urine. Plasma elimination half-life ranges from 10 to 39 hours.

Uses and Administration

Troglitazone is a thiazolidinedione oral antidiabetic (see Rosiglitazone Maleate). It has been given orally for the treatment of type 2 diabetes mellitus although as mentioned above it has been withdrawn in most countries owing to hepato-toxicity.

Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Australia: Rezulin¤; Japan: Noscal¤; Mexico: Rezulin; United Kingdom: Romozin¤; United States: Rezulin¤

1

Troglitazone

Brand Name Drug: Rezulin, Resulin or Romozin

Troglitazone has been shown to improve peripheral insulin sensitivity (ie, increase peripheral glucose disposal) by an as yet undetermined mechanism. We do know that the drug binds to an intranuclear receptor (PPARgamma), and this complex has been found to function as a transcriptional activator. How PPARgamma activation by troglitazone results in improved insulin sensitivity is not clear.

Troglitazone comes in 200-mg and 400-mg tablets, and patients are started at 200 mg in the morning with food to aid in rapid absorption. Thereafter, the dose can be increased to 400 mg/day and eventually to the maximum of 600 mg/day. The tablets should be given once in the morning, as there is no advantage to dividing the dose.

Troglitazone was initially proven effective in type 2 diabetic patients who already were being treated with insulin. In 1998, troglitazone was approved by the FDA for use as monotherapy in the treatment of type 2 diabetes. Studies in patients already receiving insulin therapy have shown a significant improvement in HgbA₁C and a reduction in insulin requirements. A 1.5% reduction in HgbA₁C has been reported when troglitazone is added to conventional insulin therapy. Monotherapy has been less effective, with an average decrease in HgbA₁C of .9%. Whether used as single or combination therapy, there is a lag time of several weeks for troglitazone to have a glucose-lowering effect and a delay of several months for maximum glucose lowering effect. The drug is not effective in those patients with relative insulinopenia. It is important to use clinical judgment in determining which patients with type 2 diabetes have significant insulin resistance with hyperinsulinemia and therefore are better candidates for troglitazone therapy. Significant reduction in HgbA₁C recently has been shown when troglitazone is used in combination therapy with glyburide or metformin.

Adverse effects range from mild peripheral edema and weight gain to recendy reported cases of florid hepatic failure. Weight gain can be seen in many patients, likely secondary to increased insulin sensitivity and improved glycemic control. The cases of hepatotoxicity are more concerning and recendy were detailed in Annals of Internal Medicine. In the initial clinical studies, troglitazone was associated with mild increases in liver function tests (1.9% compared with .6% for placebo) and reversible jaundice. However, there have been at least five cases of troglitazone-induced hepatotoxicity and death in the United States since the drug’s release in 1997.

Despite these events, the incidence of liver disease is rare, and troglitazone remains a useful weapon against type 2 diabetes, particularly in those with significant insulin resistance. The FDA now recommends that patients undergo monitoring of their liver function tests (LFTs) on a monthly basis for the first eight months of use. Over the next four months, LFTs can be monitored every other month and then periodically thereafter. Troglitazone should be stopped with any evidence of significant hepatic impairment or a threefold rise in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels.

Recendy, two additional thiazolidinediones have become available. It is hoped that rosiglitazone and pioglitazone will have many of the same insulin-sensitizing effects as troglitazone without the risk of hepatic injury.

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.

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.

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.

Dosing: Rosiglitazone is available in 2-mg, 4-mg and 8-mg tablets. The usual dose is 4-8 mg/day. Peak concentrations occur ~1 hour after dosing and the half-life is 3-4 hours. The medication is somewhat more efficacious when dosed twice daily; this may be a result of its relatively short pharmacologic half-life. Bioavailability is not affected by meals. Rosiglitazone is extensively metabolized by the hepatic CYP450 2C8 system, with the 2C9 system contributing as a minor pathway. All metabolites are notably less potent than the parent compound. No dose adjustment is necessary in subjects with renal impairment or in those on hemodialysis.

Pioglitazone is available in 15-mg, 30-mg and 45-mg tablets. The usual dose is 15-30 mg administered once daily. Peak concentrations occur 1-2 hours after dosing. The compound is hepatically metabolized to three weakly active metabolites via the CYP450 2C8 and 3A4 systems. The mean half life is 3-7 hours for the parent compound and 16-24 hours for total pioglitazone including active metabolites. No dose adjustment is necessary in subjects with renal impairment.

Both compounds are contraindicated in the presence of active liver disease and if serum ALT levels are >2.5 times the upper limit of normal. Due to idiosyncratic liver disease with troglitazone, the FDA recommends that for the first year of therapy with either available compound, liver function be monitored every 2 months, and then periodically after the first year of treatment. Because of their potential to exacerbate fluid retention, the drugs are also not indicated in class III or IV congestive heart failure unless the benefit is judged to outweigh the risk in individual 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.