Peroxisome proliferator-activated receptor (PPAR α/γ) agonists as a potential target to reduce cardiovascular risk in diabetes

Abstract

The disappointing results of glucose lowering studies have highlighted the ongoing need to develop new therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes. The presence of a range of metabolic abnormalities in diabetic patients presents a number of potential targets for therapeutic intervention. While modulation of peroxisome proliferator activated receptors (PPARs) represents an attractive approach, the results of studies of pharmacological agonists have been variable. The findings of these studies and rationale for development of dual PPAR-α/γ agonists will be reviewed.

Introduction

The last three decades have witnessed major advances in the therapeutic approach to reduction of cardiovascular risk. This is paralleled by a profound increase in the global prevalence of atherosclerotic cardiovascular disease, largely due to an increase in abdominal adiposity and associated type 2 diabetes mellitus.^1–3 The presence of an elevated rate of cardiovascular events in diabetic individuals has prompted guideline committees to consider type 2 diabetes a coronary risk equivalent. ⁴ While clinical trials have demonstrated a favourable effect of lowering low-density lipoprotein cholesterol (LDL-C) and blood pressure, there remains a considerable residual risk of cardiovascular events. Accordingly, there is an ongoing need to develop additional therapeutic strategies to reduce cardiovascular risk.

Metabolic regulation by peroxisome proliferator activated receptors

Type 2 diabetes is associated with a range of metabolic abnormalities including impaired glycaemic homeostasis, hypertriglyceridaemia, low levels of high-density lipoprotein cholesterol (HDL-C), small dense LDL particles, hypertension and elevation of systemic biomarkers reflecting inflammatory, oxidative and thrombotic pathways.^3,5–9 The major factor underlying these abnormalities appears to be the development of insulin resistance in association with the presence of abdominal obesity. Accordingly, there is considerable interest in elucidating the pathways that lead to the development of these metabolic abnormalities, in order to develop therapies that will complement LDL-C and blood pressure lowering agents.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, structurally similar to steroid hormone receptors, which regulate lipid homeostasis, cellular differentiation, proliferation and the immune response. ¹⁰ Once activated by a ligand including endogenous fatty acids and fatty acid derivatives, the receptor forms a heterodimer with members of the retinoid X receptor family and can act as a transcription factor.^10,11 In particular, activation of PPAR pathways results in a favourable effect on lipid synthesis and oxidation, glucose uptake, inflammation and expression of immunoregulatory genes.^12–14

Three peroxisome proliferator-activated receptors (PPARs) have been identified: PPAR-α, PPAR-γ and PPAR-δ (also referred to as PPAR-ß). PPAR-α is highly expressed in tissues such as liver and skeletal muscle, in addition to the heart, kidney and vasculature, where it regulates the expression of genes involved in lipid uptake, catabolism and homeostasis.^15–17 Activation of PPAR-α results in a reduction in very low density-lipoprotein (VLDL) triglyceride levels, increasing levels of apolipoprotein A-I and HDL-C, upregulation of cellular transporters involved in the promotion of cholesterol efflux and reverse cholesterol transport, increase in fatty acid uptake and oxidation and anti-inflammatory effects.^18–20 PPAR-γ is highly expressed in adipocytes, in addition to skeletal muscle, liver and kidney, and has been shown to regulate expression of genes that mediate adipocyte differentiation, energy metabolism and insulin action.^15,16,21,22 Accordingly, PPAR-γ activation results in an increase in insulin sensitivity and glucose uptake, adiponectin and fatty acid uptake, in addition to anti-inflammatory effects.^12,23–27 Although less well studied, the primary effects of PPAR-ß/δ may be fatty acid oxidation and immunomodulation.^28,29

PPAR-α as a therapeutic target

There has been considerable interest in the development of PPAR-α agonists, largely due to a potential favourable effect on lipid homeostasis. Activation of lipoprotein lipase promotes lipoprotein remodelling, resulting in a reduction in VLDL and triglyceride levels.^30–33 Upregulation of expression of apolipoproteins A-I and A-II and factors involved in reverse cholesterol transport result in an increase in HDL-C levels.^30,34,35 Additional benefits include a redistribution of LDL particles from small, dense to larger, less atherogenic forms, increasing hepatic and muscular fatty acid oxidation and inhibition of inflammatory pathways.^18–20,30 Fibric acid derivatives are weak PPAR-α agonists and have been demonstrated to have variable effects in large scale clinical trials.^36–41 Early studies with gemfibrozil demonstrated favourable cardiovascular effects in primary and secondary prevention settings. ⁴¹ Subsequent analyses of these studies revealed that modest elevations in HDL-C levels were a major predictor of the observed benefits. Difficulties prescribing gemfibrozil with statin therapy has prompted increasing use of fenofibrate.^42,43 While use of fenofibrate slowed progression of obstructive disease on serial coronary angiography in diabetic patients, ³⁶ no benefit was observed in two large clinical trials that evaluated its impact on cardiovascular events.^37,44 A meta-analysis of all fibrate trials reported that the greatest clinical benefit was observed in patients with either hypertriglyceridaemia or low HDL-C. ⁴⁵ While there has been interest in development of more potent PPAR-α agonists, this has proved disappointing due to either lack of incremental lipid efficacy or safety issues.

PPAR-γ as a therapeutic target

Thiazolidinediones are pharmacological PPAR-γ agonists that increase insulin sensitivity, reduce blood pressure and circulating free fatty acid levels and inhibit inflammatory pathways.^12,25–27 While these agents have also been reported to decrease triglycerides, raise HDL-C and promote a shift from small to large LDL particles, this is likely to reflect some intrinsic PPAR-α activation. ⁴⁶ The cardiovascular impact of PPAR-γ agonists appears to vary according to the individual agent studied. Pioglitazone has been reported in large clinical trials that have employed arterial wall imaging to arrest progression of carotid intima-medial thickness and coronary atherosclerosis in patients with type 2 diabetes.^47,48 The major factors underlying these benefits were favourable effects on HDL-C and the triglyceride/HDL-C ratio in the two vascular beds, respectively.^49,50 This benefit did not translate to a robust clinical benefit in a large scale clinical trial, in which a non-significant 10% reduction in cardiovascular events was observed. ⁵¹ It has been postulated that the lack of clinical benefit may have reflected the inclusion of lower limb revascularisations, given that subsequent analyses revealed a significant 15% reduction in hard ischaemic endpoints (death, myocardial infarction, stroke) and 19% reduction in all cardiovascular endpoints in higher risk patients with a previous myocardial infarction. ⁵¹ Subsequent meta-analyses of all studies of pioglitazone confirmed a favourable effect on death, myocardial infarction and stroke. ⁵²

The cardiovascular impact of rosiglitazone is less clear. While it was previously used to improve insulin sensitivity and glycaemic control, rosiglitazone has less favourable lipid effects. ⁵³ Several small studies employing serial measurements of carotid intima-medial thickness demonstrated a beneficial effect,^54–56 while subsequent studies using intravascular ultrasound in native coronary arteries and venous bypass grafts reported no adverse or beneficial effect on progression of atherosclerosis.^57,58 As part of the clinical development programme, a number of small studies were performed in which the metabolic effects of rosiglitazone were directly compared with either placebo or other agents. Pooling of the studies performed for regulatory registration revealed a 1.8-fold higher rate of ischaemic cardiovascular events with rosiglitazone. ⁵⁹ While no individual study had statistical power to investigate the effect of rosiglitazone on cardiovascular effects, a potentially worrisome trend was consistently present. A subsequent formal meta-analysis revealed a 43% increase in risk of myocardial infarction with rosiglitazone. ⁶⁰

The findings of the rosiglitazone meta-analysis stimulated considerable debate within the medical community. An unplanned interim analysis was performed of the ongoing Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study, which was comparing rosiglitazone versus the combination of metformin and sulphonylurea in patients who had inadequate glycaemic control with metformin or sulphonylurea monotherapy. After a median follow-up of 3.75 years, a hazard ratio of 1.11 (95% confidence interval 0.93–1.32) was observed for rosiglitazone for the primary endpoint of death plus cardiovascular hospitalisation. ⁶¹ This was consistent with the treatment effect lying somewhere between a 7% benefit and 32% harm. For myocardial infarction, the hazard ratio was 1.23 (95% confidence interval 0.81–1.86) and heart failure, the hazard ratio was 2.15 (95% confidence interval 1.30–3.57). ⁶¹ While there was no evidence of an adverse effect on mortality, the analysis had less than 1% power to detect a difference between the groups. As a result, the findings were described as inconclusive. A similar finding was observed with the final report of the study, which demonstrated a hazard ratio of 0.99 (95% confidence interval 0.85–1.16) for the primary endpoint, 0.84 (95% confidence interval 0.59–1.18) for cardiovascular death, 1.14 (95% confidence interval 0.80–1.63) for myocardial infarction and 0.72 (95% confidence interval 0.49–1.06) for stroke, in association with increased rates of heart failure events and bone fractures with rosiglitazone. On the basis of additional analyses confirming a consistent trend for an increased risk of myocardial infarction with rosiglitazone, ⁶⁰ the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, which was directly comparing the cardiovascular effects of rosiglitazone and pioglitazone, was suspended and, ultimately, rosiglitazone was withdrawn from clinical use. ⁶²

The experience with the individual PPAR-γ agonists highlights the differences between the members of the class. The first agent, troglitazone, was withdrawn from the market due to severe liver toxicity. ⁶³ Pioglitazone was associated with potential cardiovascular benefit, while rosiglitazone was associated with potential harm.^47,48,59 Further exploration revealed considerable mechanistic differences that might underlie the divergent effects on vascular outcomes. Pioglitazone is associated with a more favourable effect on lipid profile. ⁶⁴ Rosiglitazone does not lower triglycerides, promotes a smaller increase in HDL cholesterol than pioglitazone and increases LDL cholesterol. ⁵³ Arterial wall gene expression profiles suggest considerable differences in gene activation with the different agents. In particular, rosiglitazone activated genes implicated in plaque rupture, including lipoprotein associated phospholipase A₂ (Lp-PLA₂) and matrix metalloproteinases. ⁶⁵ Additional differences between these agents may be reflected by their relative avidity for different PPAR receptors. Neither agent is a pure PPAR-γ agonist, with both demonstrating some activation of PPAR-α receptors. ¹⁰ Pioglitazone displays greater PPAR-α activation, which may provide some rationale for its favourable lipid changes. This may reflect the importance of more balanced PPAR activation. Other adverse effects, in particular plasma volume expansion, bone fractures, macular oedema,^66–73 and in the setting of pioglitazone an increased rate of bladder cancer diagnoses,^74,75 presents further challenges to their use.

Dual PPAR-α/γ

The potential benefits of activating both PPAR-α and PPAR-γ agonists has stimulated interest in development of pharmacological agents that stimulate both major PPAR subtypes. Such an agent would have the theoretical benefits of fibrate-type effects on plasma lipids, thiazolidinedione-type effects on insulin sensitivity and potential anti-inflammatory effects. A number of agents have proceeded to an advanced stage of clinical development. Tesaglitazar, the first dual PPAR-α/γ agonist, was relatively weak, requiring high dose administration, and resulted in nephrotoxicity. ⁷⁶ This observation led to cessation of its clinical development. Muraglitazar produced robust lipid changes with decreases in triglyceride by up to 27% and increases in HDL cholesterol by up to 16%. ⁷⁷ However, in a manner similar to the rosiglitazone experience, a disturbing increase in cardiovascular events was observed upon pooling of data from early studies. ⁷⁸ This resulted in withdrawal of muraglitazar from further development and clinical use.

Aleglitazar is the most recent PPAR-α/γ agonist to move forward in clinical development. Phase 2 studies of aleglitazar in patients with type 2 diabetes demonstrated a range of metabolic benefits. The SYNCHRONY study evaluated the effects of aleglitazar 50–600 µg and pioglitazone 45 mg for 16 weeks.^79,80 Aleglitazar produced dose-dependent metabolic benefits, including reductions in HbA1c by –0.85% (LS mean) –0.5%, triglycerides by up to –29.7%, LDL cholesterol by up to 10%, high-sensitivity c-reactive protein (CRP) by –0.14 mg/L (50 μg) to –1.73 mg/L (600 μg) and systolic blood pressure by –3.1 mmHg (50 μg) to –7.4 mmHg (300 μg). Increases in HDL cholesterol by up to 25.1% were also observed.^79,80 These metabolic changes were more robust than those observed with any of the individual PPAR-α and PPAR-γ agonists. Whether these benefits will result in a reduction in cardiovascular events is currently being evaluated in a large phase 3 study. The ALECARDIO study is comparing the effects of aleglitazar 150 µg or placebo in 7000 patients with type 2 diabetes and an acute coronary syndrome.^79,80 Patients will be followed for a minimum of 2.5 years and the study will determine whether aleglitazar reduces the time to first occurrence of any component of the composite endpoint of cardiovascular death, myocardial infarction or stroke. The study will also characterise the safety and tolerability of aleglitazar, with interest to what degree commonly observed adverse effects observed with PPAR-γ agonists, such as weight gain, fluid retention and bone fractures, are also demonstrated.

Summary

PPAR activation represents a novel approach to modifying metabolic risk factors associated with adverse cardiovascular outcomes in patients with type 2 diabetes. It remains to be determined whether a dual PPAR-α/γ agonist will be proven to be clinically efficacious and safe. The results of the ALECARDIO study may provide further insights to determine whether a dual PPAR-α/γ agonist will be integrated into the clinical approach to treatment of diabetic patients.