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Rosiglitazone and pioglitazone: two new thiazolidinediones

2000; Wiley; Volume: 17; Issue: 5 Linguagem: Inglês

10.1002/1528-252x(200007/08)17

2047-2900

Clifford J. Bailey,

Drug Transport and Resistance Mechanisms

Copyright © 2000 John Wiley & Sons, Ltd. Two new oral antidiabetic agents, rosiglitazone Avandia and pioglitazone Actos were introduced in the USA in 1999. These agents are poised to become available in the UK. Rosiglitazone has been approved for use in Europe (March 2000) and pioglitazone is presently under review by the European Agency for the Evaluation of Medicinal Products. Both agents are thiazolidinediones (TZDs), which improve glycaemic control by enhancing insulin sensitivity1. TZDs require the presence of insulin, but they do not stimulate insulin secretion. They mainly activate a nuclear receptor called PPARγ (peroxisome proliferator-activated receptor gamma), which is most strongly expressed in adipose tissue. Activated PPARγ increases transcription of certain insulin-sensitive genes, including those that code for GLUT4 glucose transporters and enzymes for lipogenesis. Impaired insulin sensitivity (insulin resistance) underlies the pathogenesis of most forms of type 2 diabetes2. Initially this may be partially compensated by increased insulin secretion, eventually giving way to pancreatic β-cell failure. Type 2 diabetes is one of several independent and inter-related risk factors for coronary heart disease. All of these factors are commonly associated with insulin resistance and its initial accomplice hyperinsulinaemia, and they include obesity, dyslipidaemia, hypertension, atherosclerosis and a pro-coagulant state3. Selecting antidiabetic therapy for an individual patient will probably focus firstly upon glycaemic control. The message here is quite clear: the nearer to normality the glucose profile the greater the benefits against complications. However, as recent studies have emphasised, attention must be given to the other likely attendant risk factors contributing to cardiovascular morbidity and premature mortality. Any sustained reductions in obesity, correction of an atherogenic lipid profile and rigorous treatment of hypertension are proven to reduce cardiovascular complications4. Thus, targeting insulin resistance is a valuable approach to the treatment of type 2 diabetes5. To date metformin has been the agent to strike directly against insulin resistance. The introduction of TZDs provides a novel means of improving insulin sensitivity. Few full peer-reviewed accounts of clinical studies with rosiglitazone are available, and fewer with pioglitazone, but conference abstracts are abundant6-13. Both agents produce a gradual blood-glucose-lowering effect in type 2 patients, often taking up to 3 months to achieve maximum effect6, 7. When used as monotherapy, the initially slower reduction in glycaemia has suggested a little less effective antihyperglycaemic action than sulphonylureas or metformin14, 15 (although long-term comparative data are not yet available). The effectiveness of TZDs is usually more pronounced when given in combination with another class of antidiabetic agent (Table 1). Glycaemic control was substantially improved by addition of rosiglitazone or pioglitazone to patients who were poorly controlled with a high dosage of a sulphonylurea8, 9, 16. The blood-glucose-lowering effects of the TZDs were also additive with metformin, 10, 11, 17 and both TZDs improved glycaemic control and lowered the insulin requirement in insulin-treated type 2 patients12, 13. Insulin concentrations tend to fall during TZD therapy, but adequate insulin levels appear to be required for patients to achieve a worthwhile glucose-lowering effect. Serious hypoglycaemia is unlikely when TZDs are used as monotherapy, although hypoglycaemic episodes can be accentuated when TZDs are taken as part of a combination regimen. TZDs generally reduce free fatty acid concentrations, and their correctional influence on the glucose–fatty acid cycle appears to be an important means of lowering blood glucose. They sometimes reduce triglycerides in hypertriglyceridaemic patients and may decrease coagulant risk by down-regulation of plasminogen activator inhibitor-1 (PAI-1) expression in vascular endothelium. There have been preclinical accounts of islet regranulation, reduced albuminuria and possibly some lowering of blood pressure, although these findings have yet to be confirmed clinically. Less appealing is the prospect of TZD-induced weight gain, typically similar in magnitude to sulphonylurea or insulin therapy, although a redistribution of fat may leave proportionally less in visceral depots. Rosiglitazone appears to raise total cholesterol concentrations over the first few months of treatment, but values level out and may decline thereafter. The rise in cholesterol is mainly due to increased low-density-lipoprotein (LDL) cholesterol. High-density-lipoprotein (HDL) cholesterol is also raised, leaving the LDL:HDL ratio little changed. Pioglitazone apparently has little effect on LDL cholesterol. The first TZD, troglitazone, was introduced in Japan and the USA in 1997 and withdrawn in 2000 due to reports of fatal idiosyncratic hepatotoxicity18. Troglitazone was introduced briefly in the UK (Oct–Nov 1997), but was suspended and then withdrawn when reports of hepatotoxicity emerged from Japan and the USA. With the experience of more than 2 million prescriptions for rosiglitazone and pioglitazone in the USA, there has been little evidence of hepatotoxicity, except two non-fatal cases of hepatocellular damage observed with the initiation of rosiglitazone therapy19, 20. Thus monitoring of serum alanine transaminase should be a precaution before starting therapy with these agents and at intervals thereafter, and pre-existing liver disease should be a contraindication. Fluid retention and increased plasma volume associated with a lower haematocrit, an apparent decrease in haemoglobin and sometimes oedema have been noted with rosiglitazone and pioglitazone, but no adverse effects on blood pressure or cardiac function have been detected21, 22. However, it would be prudent to avoid use in patients with heart failure, congestive heart disease or anaemia. By improving insulin sensitivity, TZDs can cause ovulation to resume in some anovulatory premenospausal women (e.g. with polycystic ovarian syndrome). Pioglitazone might interfere with oral contraceptives and drugs metabolised by the P450 isoform CYP3A4, whereas rosiglitazone is metabolised predominantly by a different isoform CYP2C8. Isolated accounts of temporarily raised creatine phosphokinase (CPK) and myalgia have been associated with pioglitazone. PPARγ is widely distributed in the body, and it has a role in cellular differentiation, leaving some questions about the potential long-term effects of stimulating this nuclear receptor, and raising the possibility for other indications in the future23, 24. In theory, agents that improve insulin sensitivity could be used early during the development of glucose intolerance in anticipation that they would defer or prevent the progression into type 2 diabetes. In practice, most patients are diagnosed when type 2 diabetes (and therefore insulin resistance) is already well established. In the USA rosiglitazone and pioglitazone can be used as monotherapy, or in combination with other classes of oral antidiabetic agents. However in March 2000 the Committee for Proprietary Medical Products (CPMP) of the European Agency for the Evaluation of Medicinal Products recommended that the use of rosiglitazone in Europe should be restricted mainly to combination therapy with other oral antidiabetic agents in patients who are not adequately controlled by monotherapy with other oral agents. At the time of writing the final labelling for rosiglitazone and the outcome of the regulatory review of pioglitazone are not known. Thus in Europe the main use of TZDs will probably be in combination with other classes of oral antidiabetic agents. This will provide an additional therapeutic option, which can be used to increase the number of patients who achieve target values for glycaemic control. As the UKPDS has shown, more than half of type 2 patients are poorly controlled (fasting plasma glucose >7.8 mmol/L) by 6 years, even with intensive use of existing therapies, and most will require combination therapy to attain glycaemic targets in the longer term25. So clearly a large proportion of type 2 patients could benefit from the use of TZDs in combination with other classes of oral agents. In reality, much will depend upon price, acceptance of the drugs onto local formularies and the enthusiasm of diabetes care professionals to add this new opportunity to the pursuit of better metabolic control. What then do rosiglitazone and pioglitazone bring to the treatment of type 2 diabetes? Principally they provide a novel mechanism for improving insulin action, which is complementary to existing therapies and additive in antihyperglycaemic efficacy. They provide a convenient once or twice daily tablet regimen with minimal extra risk of hypoglycaemia, while offering the opportunity for combination with other classes of oral antidiabetic drugs to achieve better glycaemic control.