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Rosiglitazone

A Review of its Use in Type 2 Diabetes Mellitus

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Summary

Abstract

Rosiglitazone (Avandia®) is an antihyperglycaemic agent of the thiazolidinedione class that improves glycaemic control (as indicated by glycosylated haemoglobin [HbA1c] and fasting plasma glucose [FPG] levels) primarily by increasing hepatic and peripheral insulin sensitivity, and in addition may help to preserve pancreatic β-cell function.

In general, rosiglitazone as monotherapy or in combination with other antihyperglycaemic agents, including metformin or sulfonylureas, improves glycaemic control in adults with type 2 diabetes mellitus and may slow disease progression associated with pancreatic β-cell function decline. Rosiglitazone is generally well tolerated; however, additional long-term and comparative studies are required to further evaluate the effects of rosiglitazone on bone and the potential cardiovascular risk of the drug, including the risk relative to pioglitazone. Thus, in light of recent cardiovascular safety concerns and the need for further long-term data to clarify the potential risk of rosiglitazone in this regard, it would be prudent to use rosiglitazone in the treatment of type 2 diabetes on a case-by-case basis, taking into account individual patient cardiovascular risk factors.

Pharmacological Properties

Rosiglitazone, a member of the thiazolidinedione class of antihyperglycaemic agents, is a potent agonist of the peroxisome proliferator-activated receptor-γ through which many of its effects are mediated. The drug reduces hyperglycaemia primarily by improving the insulin sensitivity of the liver and peripheral tissues, and also appears to attenuate the decline in function of pancreatic β-cells. Rosiglitazone increases subcutaneous fat levels and is generally associated with bodyweight gain, although visceral and intra-hepatic fat is reduced. Rosiglitazone may have detrimental effects on bone.

Plasma concentrations of rosiglitazone increase proportionally with dose over the therapeutic range and the absolute bioavailability of the drug is ≈99% following an oral dose. Rosiglitazone is extensively metabolised via N-demethylation and hydroxylation predominantly via the cytochrome P450 (CYP) enzyme CYP2C8. The drug is excreted mainly via the urine and faeces, has a terminal elimination half-life of ≈3–4 hours and a total plasma clearance of ≈3 L/h. In the EU, caution is advised in patients with severe renal impairment receiving rosiglitazone.

Therapeutic Efficacy

In well designed monotherapy trials of 24 weeks’ to a median of 4 years’ duration, rosiglitazone was as effective as pioglitazone, superior to metformin and noninferior or superior to both the sulfonylurea glibenclamide (glyburide) and the dipeptidyl peptidase IV inhibitor vildagliptin in improving glycaemic control in patients with type 2 diabetes. Long term, rosiglitazone was also associated with a significantly lower incidence of treatment failure than metformin or glibenclamide in patients with type 2 diabetes previously untreated with pharmacotherapy.

Rosiglitazone used in combination with metformin provided better glycaemic control than metformin alone in short-term trials in patients with type 2 diabetes inadequately controlled with metformin alone or in combination with an oral insulin secretagogue or acarbose. In addition, long term, rosiglitazone plus metformin was noninferior to or as effective as metformin plus a sulfonylurea in improving glycaemic control in patients with type 2 diabetes inadequately controlled with metformin monotherapy.

In additional short-term studies, rosiglitazone in combination with a sulfonylurea was superior to sulfonylurea monotherapy and noninferior to or at least as effective as metformin plus sulfonylurea with regard to improving glycaemic control in patients with type 2 diabetes inadequately controlled with a sulfonylurea alone. Furthermore, in a 1.5-year interim analysis of a large, randomised, multicentre study, rosiglitazone plus sulfonylurea was shown to be noninferior to metformin plus sulfonylurea in terms of improving HbA1c levels, with both combination therapies demonstrating similar efficacy in improving levels of FPG.

In triple-therapy trials in patients with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea, the addition of rosiglitazone significantly improved glycaemic control compared with metformin plus sulfonylurea combination therapy alone and produced similar improvements in glycaemic control to the addition of insulin glargine in terms of HbA1c.

Patients with type 2 diabetes receiving rosiglitazone in combination with metformin or a sulfonylurea were more satisfied with treatment than patients receiving uptitrated metformin or sulfonylurea, in studies of 24 weeks’ and 2 years’ duration. Data from a short-term study suggest that adding rosiglitazone to metformin plus a sulfonylurea in patients with inadequate glycaemic control with this dual therapy is generally significantly less effective at improving health-related quality of life than the addition of insulin glargine.

Fully published pharmacoeconomic model analyses from a healthcare system or health insurance perspective have indicated that rosiglitazone combination therapies are generally cost-effective options compared with conventional therapies for the treatment of type 2 diabetes, although in combination with metformin, rosiglitazone appears to be less cost effective than pioglitazone in patients with inadequate glycaemic control with metformin monotherapy, according to one pharmacoeconomic model.

Tolerability

Rosiglitazone was generally well tolerated as monotherapy and in combination with other antidiabetic agents in adult patients with type 2 diabetes in clinical trials of up to a median of 4 years’ duration. In general, rosiglitazone therapy was associated with oedema and congestive heart failure, although the drug did not differ from pioglitazone with regard to these adverse events in a 24-week study. Rosiglitazone alone or in combination with other antidiabetic agents was associated with changes from baseline in bodyweight of +0.2 to +4.3kg in trials of 8 weeks’ to a median of 4 years’ duration. The drug was also associated with an increased incidence of bone fractures compared with metformin or glibenclamide in female patients with type 2 diabetes in one long-term study. Limited data from long-term clinical trials have not confirmed the findings of meta-analyses suggesting an increased risk of myocardial infarction with rosiglitazone.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Emma D. Deeks & Susan J. Keam

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Emma D. Deeks & Susan J. Keam

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  1. Emma D. Deeks
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Correspondence to Emma D. Deeks.

Additional information

Various sections of the manuscript reviewed by: D. Bishop-Bailey, St Bartholomew’s and the Royal London School of Medicine and Dentistry, William Harvey Research Institute, London, UK; J. Eriksson, Diabetes and Genetic Epidemiology Unit, National Public Health Institute, Helsinki, Finland; E. Ferrannini, Department of Internal Medicine, University of Pisa, Pisa, Italy; B.K. Irons, Department of Pharmacy Practice, School of Pharmacy, Texas Tech University Health Sciences Centre, Lubbock, Texas, USA; D. Severson, Pharmacology Department, University of Calgary, Calgary, Alberta, Canada.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘rosiglitazone’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). 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: MEDLINE, EMBASE and AdisBase search terms were ‘rosiglitazone’ and (‘diabetes mellitus type 2’ or ‘diabetes mellitus non-insulin-dependent’ or ‘type-2-diabetes-mellitus’). Searches were last updated 20 November 2007.

Selection: Studies in patients with type 2 diabetes who received rosiglitazone. 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: Rosiglitazone, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, pharmacoeconomics.

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Deeks, E.D., Keam, S.J. Rosiglitazone. Drugs 67, 2747–2779 (2007). https://doi.org/10.2165/00003495-200767180-00008

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