PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome
Introduction
The metabolic syndrome (MS) is diagnosed by a cluster of clinical parameters including central obesity, atherogenic dyslipidemia, raised blood pressure and hyperglycemia. Visceral obesity, hepatic steatosis and insulin resistance (IR) have been proposed as unifying mechanisms, yielding a prothrombotic and proinflammatory state [1]. Consequently, patients with MS are at increased risk of micro- and macro-vascular complications (e.g. coronary artery disease (CAD), stroke, renal failure, blindness and lower extremity amputation) and progression to type 2 diabetes (T2D). Although improved glycemic control translates into significant benefits against microvascular complications [2], global control of all metabolic parameters is necessary to decrease the risk of CAD [3]. Because CAD is the primary cause of mortality among patients with T2D and the MS [4], treatments normalizing both lipid and glucose metabolism have become increasingly important. The discovery of peroxisome proliferator-activated receptors (PPARs) as regulators of lipid and glucose metabolism has created interest in the development of compounds acting via these receptors as potential tools for therapeutic intervention in MS (and its components) [5]. Fibrates are PPARα activators used to improve the dyslipidemia component of MS, which is characterised by elevated triglyceride (TG) and low high-density lipoprotein (HDL) levels, whereas thiazolidinediones (TZDs) are PPARγ activators that improve IR in T2D patients, with less pronounced effects on plasma lipoproteins. Results of angiographic studies and CAD prevention trials in T2D patients indicate that fibrate treatment decreases the risk of CAD in patients with T2D without pre-existing CAD or MS [6, 7], and TZDs improve cardiovascular outcomes in secondary prevention [8]. Research programs to develop agonists that combine the therapeutic effects of both PPARα and PPARγ selective agonists, creating the expectation of synergy in the treatment of T2D and the MS, have therefore been undertaken. Among these dual PPARα/γ agonists, compounds belonging to the glitazar class have been advanced to clinical development (Phases II and III). These trials clearly demonstrate superior efficacy of these compounds in correcting abnormalities associated with T2D and the MS, improving both lipid and glucose homeostasis to a greater extent than did selective PPAR agonists. However, safety remains a critical issue for glitazars, as the development of several promising candidates was halted because of adverse toxicity profiles. This review discusses the scientific rationale behind the development of dual PPARα/γ agonists, and examines the contribution that new therapeutics acting via PPAR targets might make to the treatment of T2D and the MS.
Section snippets
PPARα and PPARγ are molecular targets in T2D and the MS
PPARs (PPARα, PPARγ, PPARβ/δ) are transcription factors that regulate gene transcription by binding to specific DNA response elements upon ligand activation and heterodimerization with the 9-cis retinoic acid receptor. Ligand-induced conformational changes induce the recruitment of coactivators that transmit transcription activation signals to basal transcriptional machinery. Depending upon the activating ligand, different receptor conformations are adopted, leading to differential coactivator
PPARα and PPARγ activators exert complementary activities
Simultaneous activation of PPARα and γ activators might, through a complementary mechanism of action, alter the tissue distribution of FAs by stimulating their uptake and utilization in adipose tissue, liver and skeletal muscle (Figure 2). TZDs increase FA uptake in adipose tissue, leading to the utilization of glucose instead of FAs as the energy source for the muscle. Because PPARα activators increase hepatic oxidation of FAs and reduce synthesis and secretion of TGs, this will increase the
Animal studies
Using animal models of diabetes and IR, beneficial metabolic effects of glitazars have been demonstrated. In young Zucker diabetic fatty (ZDF) rats that are not yet diabetic, ragaglitazar improved blood glucose and plasma HbA1c and TG levels to a greater extent than did rosiglitazone. However, in older overtly diabetic rats, ragaglitazar improved glycemic control more effectively than rosiglitazone without further affecting circulating insulin levels, suggesting that razaglitazar, in the long
Potential safety issues of dual PPARα/γ agonists
If (arguably) dual PPARα/γ agonists display potent and beneficial effects on metabolic abnormalities associated with T2D and the MS, preclinical carcinogenicity findings and the first clinical trial reports using glitazars raised questions on their safety. Indeed, before dual PPAR agonists are approved as long-term treatment for diabetes, the US FDA requires extended safety tests in preclinical animal models, even though precise patterns of toxicity can appear different compared with humans.
Perspectives and conclusions
Parallel to the glitazar development programs, research into other dual PPARα/γ agonists with an improved safety margin is ongoing [42, 43, 44]. Indeed, current strategies aim to reduce the side effects of PPARγ agonists through identification of partial agonists based on the SPPARM concept. This should lead to the controlled and differential regulation of genes that have beneficial effects on glucose homeostasis, avoiding the activation of those which lead to unwanted side effects (e.g. fat
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
A grant from the Fondation Coeur et Artères (FCAO5T5) is kindly acknowledged.
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