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Troglitazone

A Review of its Use in the Management of Type 2 Diabetes Mellitus

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Summary

Abstract

Troglitazone is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is indicated for the treatment of patients with type 2 (non-insulin-dependent) diabetes mellitus. Troglitazone acts by enhancing the effects of insulin at peripheral target sites and, unlike the sulphonylurea drugs, is not associated with hypoglycaemia when administered as monotherapy.

Clinical trials with troglitazone (usually 200 to 600 mg/day) in patients with type 2 diabetes mellitus consistently showed marked improvement in glycaemic control, as well as reductions in fasting serum insulin, C-peptide and triglyceride levels. Comparative studies with either glibenclamide (glyburide) or metformin indicated similar glycaemic control with troglitazone or these agents. Serum insulin levels were lower with troglitazone than with glibenclamide. Clinical trials of up to approximately 2 years’ duration showed that glycaemic control is maintained with troglitazone on a long term basis.

In general, troglitazone is well tolerated by the majority of patients. However, discontinuation of troglitazone because of elevated liver enzyme levels occurs in approximately 2% of patients receiving the drug, and frequent monitoring of liver enzymes is required (e.g. at least 11 times during the first year of therapy). Among patients who started troglitazone therapy in 1998 (after the incorporation of a boxed warning and increased monitoring requirements in the product labelling), the estimated risk of liver-related death is approximately 1 in 100 000.

Conclusions: Troglitazone improves the ability of target cells to respond to insulin. The drug has been shown to improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other oral antidiabetic drugs or insulin, and its efficacy is similar to that of glibenclamide or metformin. Although troglitazone is generally well tolerated, close monitoring of liver enzyme function is required to minimise the rare occurrence of serious hepatic dysfunction. Drug acquisition and liver function monitoring costs, as well as potential adverse effects, are important factors that may ultimately determine the precise place of troglitazone in the management of type 2 diabetes mellitus. Nevertheless, as the first member of a new class of oral antidiabetic agents, the thiazolidinediones, troglitazone offers an effective treatment option in patients with type 2 diabetes mellitus through its action of improving insulin sensitivity.

Overview of Type 2 Diabetes Mellitus

The prevalence of type 2 diabetes mellitus is approximately 5% in North America and Europe, and increases with age. Diabetes mellitus is even more common among certain populations, such as Native North Americans and African Americans. Multiple mechanisms appear to be involved in the pathogenesis of type 2 diabetes mellitus, including impaired insulin secretion by pancreatic β cells, increased hepatic gluconeogenesis, and reduced glucose uptake by skeletal muscle and adipose tissue (peripheral insulin resistance). These effects lead to hyperglycaemia in the short term, and to micro- and macrovascular complications in the long term. Available evidence suggests that improving glycaemic control reduces the risk of diabetic complications, although this relationship is more clear for microvascular complications such as retinopathy and nephropathy than for macrovascular complications such as coronary heart disease.

Pharmacodynamic Properties and Mechanism of Action

Troglitazone enhances the effects of insulin at peripheral tissue sites (skeletal muscle and adipose tissue), thereby increasing insulin-dependent glucose disposal. Some studies have also shown that troglitazone moderately reduces hepatic glucose production, although this effect has not been consistently demonstrated. Unlike sulphonylurea agents, troglitazone does not directly stimulate the release of insulin from pancreatic β cells. The improved insulin sensitivity demonstrated with troglitazone in patients with type 2 diabetes mellitus was accompanied by improvements in glycaemic control and reduced serum insulin levels. Troglitazone has a significant antihyperglycaemic effect in animal models of both genetic and non-genetic insulin resistance, but not in animal models of insulin deficiency. The mechanism of action of troglitazone at the cellular level has not been fully elucidated. One hypothesis is that binding of troglitazone to peroxisome proliferator-activated receptor-γ (PPARγ) may lead to regulation of the transcription of a number of insulin-responsive genes intimately involved in the control of glucose and lipid metabolism. Other actions may also be involved in the cellular mechanism of troglitazone.

Pharmacokinetic Properties

In healthy volunteers, troglitazone 200 to 600 mg/day achieves peak plasma drug concentrations of 0.9 to 2.8 mg/L approximately 2 to 3 hours after oral administration. It is extensively bound to plasma protein (>99%) and has a steady-state volume of distribution of 2.5 L/kg. The elimination half-life of troglitazone is 9 to 34 hours, allowing for once daily administration of the drug. Troglitazone is extensively metabolised by the liver to 3 main metabolites: the sulphate conjugate (present at a plasma concentration approximately 7 to 10 times that of the parent drug), the quinone metabolite (plasma concentration approximately equal to that of troglitazone) and the glucuronide metabolite (low or negligible plasma concentrations). Animal data indicate that the quinone metabolite has modest pharmacological activity, although the clinical relevance of this finding is unclear. Almost none of an administered dose of troglitazone is eliminated unchanged in the urine.

Therapeutic Use

In clinical trials of patients with type 2 diabetes mellitus, administration of troglitazone, alone or in combination with other antidiabetic agents, was consistently associated with improved glycaemic control compared with placebo or baseline. Statistically and clinically significant reductions were achieved in fasting serum or plasma glucose (FSG or FPG) levels and glycosylated haemoglobin (HbA1c) values. Fasting serum insulin, C-peptide and triglyceride levels were also typically reduced (by 13 to 26% from baseline in the case of triglyceride levels).

In large (n > 100) clinical trials conducted in North America in which troglitazone was administered as monotherapy (typically 200 to 800 mg/day for 12 to 26 weeks), FSG was reduced by approximately 11 to 33% and HbA1c by about 5 to 15% (relative reduction) compared with placebo or baseline values. Although a clear overall dose-response pattern was not evident, troglitazone was consistently effective over its recommended dosage range (200 to 600 mg/day in the US). The effects of troglitazone on glycaemic control were maintained for ≥1 year in a trial in which dosage adjustments were allowed after a 6-month fixed dosage interval. Results of a large study in elderly patients (mean age 75 years) with type 2 diabetes mellitus were similar to those of studies conducted in patients not selected by age. In comparative trials, troglitazone 600 or 800 mg/day had similar efficacy to glibenclamide (glyburide) titrated to response, in terms of glycaemic control, although only troglitazone was associated with reductions in serum insulin levels. Comparisons between troglitazone and metformin in commonly used dosage regimens also showed similar effects on glycaemic control. Results of studies with troglitazone monotherapy conducted in Japan were very similar to those conducted in Europe and North America.

Concomitant treatment with troglitazone 200 to 600 mg/day, plus either glibenclamide 12 mg/day (n = 545) or metformin 1000mg twice daily (n = 28) was more effective at achieving glycaemic control than monotherapy with these drugs. An open-label extension of troglitazone plus glibenclamide therapy demonstrated that glycaemic control was maintained with combined therapy on a long term basis (116 weeks). Other trials of up to 1 year’s duration also showed significantly greater reductions in FPG and HbA1c when troglitazone was added to sulphonylurea therapy compared with sulphonylurea monotherapy.

The addition of troglitazone 200 to 600 mg/day to insulin therapy (≥30 U/day) in patients with type 2 diabetes mellitus reduced FSG levels, insulin dosage requirements and HbAic values, with glycaemic control maintained for up to 23 months in an extension of the largest study (n = 286 for the long term extension).

Tolerability

In clinical trials, the incidence and type of adverse events associated with troglitazone were broadly similar to those observed with placebo. Tolerability data have been pooled from studies conducted in North American patients with type 2 diabetes mellitus receiving troglitazone (n = 1450) or placebo (n = 492). The most frequently reported adverse events with both troglitazone and placebo were infection (18 vs 22%), headache (11 vs 11%) and pain (10 vs 14%). Other adverse events included accidental injury, asthenia, dizziness, back pain, nausea, rhinitis, diarrhoea, urinary tract infection, peripheral oedema and pharyngitis; these were reported in 5 to 8% of troglitazone recipients and 4 to 7% of placebo recipients. The rate of treatment withdrawal during clinical trials was approximately 4% for both troglitazone and placebo. Unlike sulphonylurea drugs, troglitazone is not associated with hypoglycaemic reactions when administered as monotherapy.

Reversible elevations in serum liver enzymes (ALT levels >3 times the upper limit of normal) were noted in 1.9% of patients receiving troglitazone and 0.6% of placebo recipients in North American trials. Since its market launch, troglitazone has been associated with a number of reports of idiosyncratic liver dysfunction which, in a small number of cases, has led to death or the need for liver transplantation. Thus, although approximately 2% of patients receiving troglitazone can be expected to discontinue therapy because of elevated liver enzymes, the overall incidence of permanent liver damage leading to death or liver transplantation is estimated to be about 1 case in every 50 000 to 60 000 patients treated with troglitazone in the US. The manufacturer has introduced a series of labelling changes for the drug, requiring frequent monitoring of liver enzymes (e.g. at least 11 times during the first year of therapy) as well as careful monitoring of clinical signs of liver dysfunction. This appears to have reduced the risk of permanent liver damage: recent estimates focusing specifically on the risk of death related to liver dysfunction among patients who started troglitazone therapy in the US in 1998 indicate a risk of approximately 1 in 100 000.

Drug Interactions

Troglitazone appears to induce drug metabolism by the cytochrome P450 (CYP) 3A isoenzyme pathway, and concomitant administration with a variety of CYP3A substrates has resulted in decreased plasma concentrations of these drugs. Such substrates include terfenadine, cyclosporin and components of oral contraceptives (ethinylestradiol and norethindrone; potentially leading to loss of contraceptive efficacy). Concurrent administration of troglitazone and cholestyramine is not recommended because cholestyramine markedly reduces the absorption of troglitazone.

Dosage and Administration

Troglitazone is administered orally and should be taken with a meal, since this enhances absorption of the drug. The recommended dosage regimen of troglitazone in the US is 200 to 600mg once daily, with the usual dosage being 400mg once daily. If there is no response to the maximum dosage after 1 month, the drug should be discontinued in favour of alternative therapy. In Japan, the recommended dosage regimen of troglitazone is 200mg twice daily (after meals in the morning and evening).

When troglitazone is added to insulin therapy, it should be initiated at a dosage of 200mg once daily and the current insulin dosage should be continued (but may subsequently need to be reduced depending on glucose-lowering response). The dosage of troglitazone may be increased after 2 to 4 weeks for patients not responding adequately to this combined therapy. Dosage adjustment of troglitazone in patients with renal insufficiency is not necessary. Troglitazone is not recommended in patients with hepatic impairment. All patients receiving troglitazone should be monitored closely for laboratory and clinical signs of liver damage.

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Correspondence to Greg L. Plosker.

Additional information

Various sections of the manuscript reviewed by: A. Anwar, Department of Medicine, Birmingham Heartlands Hospital, Birmingham, England; R. Bressler, College of Medicine, University of Arizona, Tucson, Arizona, USA; L. Cominacini, Istituto di Semeiotica e Nefrologia Medica, Università di Verona, Ospedale Policlinico, Verona, Italy; J.C.N. Corrêa, Serviço de Endocrinologia, Hospital Curry Cabral, Lisbon, Portugal; C. Fürnsinn, Department of Medicine III, Division of Endocrinology and Metabolism, University of Vienna, Vienna, Austria; I. Inoue, Fourth Department of Internal Medicine, Saitama Medical School, Saitama, Japan; S.E. Inzucchi, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA; S. Kumar, Department of Medicine, Birmingham Heartlands Hospital, Birmingham, England; M. Leutenegger, Clinique Médicale, Hôpital Robert Debré, Reims, France; J.R. Petrie, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland; M. Tominaga, Department of Laboratory Medicine, Yamagata University School of Medicine, Yamagata, Japan.

Data Selection

Sources: Medical literature published in any language since 1966 on troglitazone, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘troglitazone’, ‘CI-991’, ‘CS-045’, ‘GR-92132’ and ‘GR-92132X’. Medline and EMBASE search terms were ‘troglitazone’, ‘CI-991’, ‘CS-045’, ‘GR-92132’, ‘GR-92132X’ and ‘97322-887-7’. Searches were last updated 11 February 1999.

Selection: Studies in patients with type 2 diabetes mellitus or impaired glucose tolerance who received troglitazone. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Troglitazone, thiazolidinediones, diabetes mellitus, insulin resistance, pharmacodynamics, pharmacokinetics, therapeutic use.

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Plosker, G.L., Faulds, D. Troglitazone. Drugs 57, 409–438 (1999). https://doi.org/10.2165/00003495-199957030-00014

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