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Introduction: the Role of the Thiazolidinediones in the Cardiovascular Risk Management of Type 2 Diabetes

Posted on: Wednesday, 11 May 2005, 03:00 CDT

Key words: Atherosclerosis - Cardiovascular disease - Diabetic dyslipidaemia - Glitazones - Metabolic syndrome - Thiazolidinediones - Type 2 diabetes management

ABSTRACT

Scope: This article serves as an introductory overview to this supplement which covers type 2 diabetes as an atherosclerotic disease, the evidence base for treatment of the various vascular risk factors, and provides a detailed appraisal of the potential for thiazolidinediones to play a major role in overall diabetes management, not just for glycaemia, but also from the point of view of cardiovascular disease.

Conclusion: We are clearly entering into an extremely interesting time in the management of type 2 diabetes. The thiazolidinediones have the potential to target a fundamental defect in type 2 diabetes as well as to improve CV risk in this extremely high risk group of patients. Time will tell whether the obvious potential of these agents will result in dramatically improved clinical outcomes.

The first isolation of insulin in 1921 was hailed as a therapeutic miracle, lifesaving for many thousands of diabetic patients and health preserving for many more. A further 30 years elapsed before oral agents for the management of type 2 diabetes came on the scene with the first sulphonylurea in the mid-1950s, followed soon after by the first biguanide. There was then a gap of a further 30 years before we saw the alpha-glucosidase inhibitors, followed in the late 1990s by the rapidacting insulin secretagogues from the meglitinide class. In this new millennium, we have now also seen the advent of the peroxisome proliferator activated receptor gamma (PPARγ) agonists, also called thiazolidinediones (glitazones), which look potentially very exciting.

Not only do we now have a much greater choice of agents for the management of type 2 diabetes, but two other major developments have enabled us to approach management in a rather different way. The first of these is our greater knowledge of the pathogenesis and pathophysiology of type 2 diabetes. This has stimulated development of new drugs that more directly target the basic defects of type 2 diabetes. The second, and probably even more important, advance has been the realization that type 2 diabetes is a cardiovascular disease and must be managed aggressively from this point of view.

The two fundamental defects in the development and progression of type 2 diabetes are insulin resistance (resistance of the body to the biological actions of insulin) and pancreatic beta-cell dysfunction. Insulin resistance appears also to be a fundamental feature, and is perhaps the primary defect, in the metabolic syndrome. This latter describes the co-occurrence of a range of major cardiovascular risk factors in the same patient at a frequency greater than expected by chance. The majority of patients with type 2 diabetes have at least one other major cardiovascular risk factor and most will suffer from the metabolic syndrome. This is a major reason for the massively increased cardiovascular risk seen in patients with type 2 diabetes.

It is of particular interest, therefore, that agents have been developed, which not only target a single defect of type 2 diabetes itself, but also target what may be the primary underlying abnormality of the metabolic syndrome, i.e. insulin resistance. Apart from the fact that the thiazolidinediones are of interest because they represent the first in a new class of agents, they also, by targeting insulin resistance, offer the potential both to improve glycaemia and cardiovascular risk. It is particularly exciting, therefore, that these agents are now being studied in the context of major hard endpoint clinical trials to try and answer two fundamental questions: firstly, can these agents provoke sustained glycaemic control, and secondly, can they reduce the risk of cardiovascular endpoints and mortality.

For the above reasons, it is my pleasure to act as Guest Editor for this supplement, which covers type 2 diabetes as an atherosclerotic disease, the evidence base for treatment of the various vascular risk factors and provides a detailed appraisal of the potential for thiazolidinediones to play a major role in overall diabetes management, not just for glycaemia, but also from the point of view of cardiovascular disease.

Each article is written by an expert in his field. The first gives a detailed appraisal of type 2 diabetes as an atherosclerotic disease1. It is written by Professor Peter Grant, who has a major interest in this area, and he emphasizes the strong link between diabetes, atherosclerosis and cardiovascular disease, and points out that its development is dependent upon complex interactions between a number of metabolic pathways. In addition to discussing the links with hypertension, hyperglycaemia and dyslipidaemia (all associated with insulin resistance), he also describes processes of inflammation and coagulation, which are intimately linked with each other, and the development of atherosclerosis and its consequences. He contends that these inflammatory, atherothrombotic aspects of type 2 diabetes may be in part responsible for the accelerated development of vascular disease in this population.

This is followed by a paper from Professor Bart Staels who discusses PPARs and vascular insulin resistance2. He makes the point that PPARγ regulates a whole range of cellular processes that affect glucose homeostasis, endothelial function and vessel wall inflammation, thereby potentially protecting against cardiovascular complications, which may occur in diabetes. He discusses the fact that thiazolidinediones may exert cardioprotective effects during the atherogenic process, and this is supported by animal models and human studies, which show improvement in surrogate markers of atherogenesis. He believes, therefore, that these agents may produce benefits long-term by reducing cardiovascular risk related to atherosclerosis as well as improving glycaemia in patients with type 2 diabetes.

The third chapter, written by Erland Erdmann, covers diabetes and cardiovascular risk markers3. These include the co-occurrences of a range of major traditional risk factors for cardiovascular disease, but he also further discusses the importance of inflammatory mediators and coagulation/thrombolytic parameters. He correctly points out that there is little evidence that targeting raised glucose alone reduces excess risk of cardiovascular disease in diabetes, and highlights the need for aggressive treatment of other risk factors. He also points out that, although statins are very effective at reducing low-density lipoprotein cholesterol (LDL-C), a residual risk remains, which may be accounted for by other independent lipid and non-lipid factors. The thiazolidinediones display a number of potential antiatherogenic properties and may benefit the typical dyslipidaemia of type 2 diabetes, i.e. low high- density lipoprotein cholesterol (HDL-C) and raised triglycrides, as well as having other potentially beneficial non-lipid effects, such as regulating the levels of mediators involved in inflammation and endothelial dysfunction. He discusses the possibility of combining thiazolidinediones with statins and provides hope that studies currently underway will provide insights into the value of using these agents in reducing the excess cardiovascular risk in type 2 diabetes.

This is followed by a specific chapter on diabetic dyslipidaemia by Bruno Verges4. He details the lipid abnormalities that may be commonly associated with type 2 diabetes, covers various National and International Guidelines for the management of diabetic dyslipidaemia, and points out that statins are the normal first choice pharmacological therapy. He also covers the possible role of fibrates, which lower triglycerides and raise HDL-C. He then discusses the potential role for thiazolidinediones through their actions on lipid metabolism. He points out that one of these agents, pioglitazone, has consistently been shown to decrease plasma triglycerides while increasing HDL-C and decreasing the number of small dense atherogenic LDL particles. He discusses the possible use of thiazolidinediones in the overall management of type 2 diabetes and suggests that new strategies involving drug combinations that achieve good glycaemic and lipid control could potentially reduce the morbidity and mortality associated with type 2 diabetes.

The final chapter, written by Professor Markolf Hanefeld, discusses 'outcome' studies in type 2 diabetes5. These are clearly extremely important and have helped to transform our approach to diabetes management in recent years. He covers a range of clinical trials, including the United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT), both of which proved beyond reasonable doubt the value of tightened diabetic control in reducing the risk of long-term (particularly microvascular) complications.

He also cites studies looking at the value of lipid-lowering therapy, mostly with statins and mostly related to LDL-C reduction. Other studies in both incipient and overt diabetic nephropathy are covered, as well as a range of outcome trials using fibrates. The evidence base for blood-pressure lowering and use of antiplatelet agents is also discussed, together with multiple-risk-factor interv\ention trials.

He then goes on to discuss new outcome trials, specifically the prospective pioglitazone clinical trial in macrovascular events (PROactive) in patients with type 2 diabetes with clinical evidence of macrovascular disease. The study is due to report in 2005 and is based on the fact that pioglitazone not only improves glycaemic control, but also possesses additional properties, which may have an impact on risk of vascular events and mortality. This is because pioglitazone therapy has been associated with improvements in the lipid profile, reduction in blood pressure, improvement in other risk markers and reductions in carotid intima media thickness. The hypothesis is that pioglitazone will thus reduce total mortality and macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. The study also examines the effects of pioglitazone on individual risk factors for vascular complications. The study design involves over 5000 patients with type 2 diabetes at high cardiovascular risk, who are randomized to receive 'add-on' therapy with pioglitazone or placebo in addition to their existing medications for the management of hyperglycaemia, dyslipidaemia, thrombosis and hypertension. The primary endpoint is the time from randomization to occurrence of a new cardiovascular event or death.

The PROactive study has recently closed as sufficient endpoints have been met and the results will be presented at the European Association for the Study of Diabetes in Athens in September 2005. The strength of this study is that the patients enrolled are typical of the type 2 diabetic population at high risk for further cardiac events. PROactive will, it is to be hoped, provide an answer to the potential use of thiazolidinediones in the overall management of type 2 diabetes beyond the effect of these agents on glycaemia.

Other studies are planned and one with rosiglitazone, which will not report for some time, is also discussed.

We are clearly entering into an extremely interesting time in the management of type 2 diabetes. A whole range of new agents have either been introduced or are in the pipeline. The thiazolidinediones have the potential to target a fundamental defect in type 2 diabetes as well as to improve cardiovascular risk in this extremely high-risk group of patients. Time will tell whether the obvious potential of these agents will result in dramatically improved clinical outcomes. This series of articles provides a wealth of information and experience from recognized experts in the field. I hope that our readers find this supplement both interesting and instructive.

References

1. Grant PJ. Inflammatory, atherothrombotic aspects of type 2 diabetes. Curr Med Res Opin 2005;21(Suppl 1): S5-S12

2. Staels B. PPARγ and atherosclerosis. Curr Med Res Opin 2005;21(Suppl 1):S13-S20

3. Erdmann E. Diabetes and cardiovascular risk markers. Curr Med Res Opin 2005;21(Suppl 1):S21-S28

4. Verges B. Diabetic dyslipidemia: insights for optimizing patient management. Curr Med Res Opin 2005;21(Suppl 1):S29-S40

5. Hanefeld M. Outcome studies in type 2 diabetes. Curr Med Res Opin 2005;21(Suppl 1):S41-S48

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2863F_4, Accepted for publication: 11 February 2005

Published Online: 07 March 2005

doi:10.1185/030079905X36422

A. H. Barnett

Professor of Medicine and Honorary Consultant Physician, University of Birmingham and Birmingham Heartlands and Solihull NHS Trust (Teaching), Birmingham, UK

Address for correspondence: Professor Anthony Barnett, Department of Medicine, Undergraduate Centre, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK. email: anthony.barnett@heartsol.wmids.nhs.uk. Tl.: +44 (0)121-424 3587; Fax: +44(0)121-4240593

Copyright Librapharm 2005

Source: Current Medical Research and Opinion

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