Learning from tesaglitazar

161 The development of glucose intolerance and type 2 diabetes is typically associated with multiple disturbances of endocrine, metabolic, cytokine and other factors. Many of these factors contribute to the heightened cardiovascular risk of ‘metabolic syndrome’ and may share in a communal aetiopathogenic process. Insulin resistance and dyslipidaemia are generally recognised as early offenders in this process that require therapeutic intervention. Against this background, the concept of the dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists (socalled ‘glitazars’) was born. These dual-action molecules combine the antihyperglycaemic and insulin-sensitising properties of PPARγ agonism with the triglyceride-lowering and high-density lipoprotein cholesterol (HDL)-raising effects of PPARα agonism. In essence, dual PPAR α/γ agonists amalgamate the PPARα-mediated effects of fibrates with the PPARγ-mediated effects of thiazolidinediones, offering the potential to address the insulin resistance and hyperglycaemia of type 2 diabetes as well as aspects of the associated dyslipidaemia with a single compound (figure 1). Dual PPAR α/γ agonism might also be expected to mitigate several atherothrombotic risk markers such as plasminogen activator inhibitor (PAI)-1 and fibrinogen, along with mediators of inflammation and lipid accumulation in liver and muscle. By the same token, the side effects associated with PPARα and γ agonism might also be expected. Two glitazars proceeded through phase III clinical trials: tesaglitazar (Galida, AstraZeneca) and muraglitazar (Pargluva, Bristol-Myers Squibb). Although each showed efficacy against the hyperglycaemia and hypertriglyceridaemic dyslipidaemia of type 2 diabetes, neither entered the market since both had side effects. For muraglitazar the US Food and Drug Administration required further safety studies due to the incidence of oedema, heart failure and cardiovascular deaths during the trials. For tesaglitazar there were concerns about elevated serum creatinine and decreased glomerular filtration. Nevertheless, a wealth of information was accumulated during the clinical trials with tesaglitazar and muraglitazar to instruct future research with PPAR agonists. This issue of Diabetes and Vascular Disease Research captures the experiences with tesaglitazar in non-diabetic hypertriglyceridaemic and diabetic subjects, including studies using tesaglitazar as monotherapy and in combination with other oral antidiabetic agents and insulin. So what lessons should we be looking to learn that are applicable to the class and to the tesaglitazar molecule? Dual PPARα/γ agonists were selected to provide a balance between the α and γ agonism. This takes into account their binding affinity with the α and γ PPARs such that desired efficacy via each PPAR is achieved at the same dose: tesaglitazar shows a relatively strong affinity for PPARα. Differences in the balance of binding affinities have contributed to the individuality of the dual PPARs. Size, shape and other physico-chemical features of the agonists affect conformational adjustments to PPARs during binding: this in turn will modify the effects on co-repressors and co-activators, adding to the diversity of actions by further modifying the range of genes affected. Hence, considerable diversity of efficacy and side effects can be achieved within the glitazar class, and in principle agents could be selected to reduce the unwanted effects. In addition to PPARα and γ there is a third PPAR – PPARδ, activation of which can improve the lipid profile and counter obesity with increased energy expenditure. Present research is focused on the use of selective PPAR modulators (SPPARMs), designed for activation of each PPAR to varying extents in order to accentuate the desired effects and obviate the undesired effects. Although the raised serum creatinine with tesaglitazar is unexplained, some fibrate PPARα agonists are also prone to this side effect. However, the creatinine effect is not seen with PPARγ-stimulating thiazolidinediones, suggesting that it may be predominantly an α-mediated effect. Conversely, weight gain, oedema, decreased haematocrit and cardiac issues appear to be more γ-related, although the mechanisms responsible for the cardiovascular side effects of γ stimulation are unresolved. So future research will be looking to SPPARMs that can obviate these side effects. Bringing a new class of therapy from concept to clinic EDITORIAL