Non-glycemic effects of pioglitazone and incretin-based therapies

Abstract

Atherosclerosis and cardiovascular events are highly prevalent and represent the major cause of mortality in patients with type 2 diabetes. Therefore, there is significant interest in the non-glycemic properties of anti-diabetic agents, particularly on those that are effective on cardiovascular risk factors. Thiazolidinediones and incretin-based therapies (IBTs) represent some of the most recent treatment options approved for the management of type 2 diabetes; these agents have shown important glycemic effects, as well as a number of non-glycemic effects. The latter include those on body weight, inflammation, hypertension and dyslipidemia, thus impacting the different components of the metabolic syndrome. Pioglitazone has been shown to significantly reduce cardiovascular adverse outcomes, while preliminary data on IBTs are very encouraging as well. Although highlighting the non-glycemic effects of pioglitazone and incretin-based therapies is of potential significance, clinical practice and patient care must be based largely on evidence-based medicine. Therefore, definitive opinions will await additional data from ongoing studies evaluating the effects of both GLP-1 agonists and DPP-4 inhibitors on cardiovascular morbidity and mortality.

Keywords::

• cardiovascular risk
• incretin-based therapies
• pioglitazone
• type 2 diabetes

1. Introduction

Atherosclerosis and cardiovascular events are highly prevalent and represent the major cause of mortality in patients with type 2 diabetes [1]. Therefore, there is significant interest in the non-glycemic properties of anti-diabetic agents, particularly on those that are effective on cardiovascular risk factors. Thiazolidinediones and incretin-based therapies (IBTs) represent the most recent treatment options approved in the recent years for the management of type 2 diabetes; these agents have shown important glycemic effects, as well as a number of non-glycemic effects, including those on body weight, inflammation, hypertension and dyslipidemia.

2. Non-glycemic effects of pioglitazone

The thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-γ agonists, represent an important class of drugs for the management of diabetes, being able to significantly lower the levels of fasting glucose and glycated hemoglobin (HbA1c) [2]. Only one in this class – pioglitazone – is currently available, since rosiglitazone has been withdrawn from the market due to potentially increased cardiovascular risk [3]. Since thiazolidinediones, and PPARs in general, are primarily involved in regulation of metabolism and subsequently in inflammation and atherosclerosis, recent studies have focused on novel use of PPAR agonists as potential therapeutic agents in the treatment of atherosclerosis [4]. In this context, an Expert Panel of the European Society for Cardiovascular Prevention has highlighted that pioglitazone may provide benefits beyond its influence on glycemia: additional effects may include cardiovascular protection, and the drug might have anti-atherosclerotic properties [5].

Indeed, the possible beneficial pleiotropic effects of thiazolidinediones have been known for several years, and the article by Khan et al. published in the previous issue of Expert Opinion on Therapeutic Targets highlights the beneficial effects of pioglitazone on the coagulation cascade [6]. In addition, a comprehensive review article by Rizos et al. has previously shown that thiazolidinediones favorably alter fat distribution and improve cardiovascular risk factors, such as blood pressure, inflammation markers and uric acid, and may also delay the progression of atherosclerosis [7]. However, the effects on the lipid profile significantly differ between the two agents in this class, with pioglitazone overall having more positive effects compared with rosiglitazone; indeed, pioglitazone has been shown to be able to significantly reduce the atherogenicity of lipoproteins, including small, dense low-density lipoproteins (LDL) [8-10].

This latter finding is of great importance, since it can help to explain the adverse cardiovascular risk profile of rosiglitazone, and not of pioglitazone. Increasing evidence suggests that the quality, and not necessarily the quantity, of plasma lipids and lipoproteins is directly associated with cardiovascular risk, with the small dense LDL subfraction possessing a more adverse atherogenic profile. The “quantity–quality” aspect of lipoproteins has been investigated in over a hundred studies, including epidemiological and cross-sectional analyses, as well as clinical intervention trials [11]. In this context, a European panel of experts provided a comprehensive and up-to-date consensus statement on the pathophysiology, atherogenicity, and clinical significance of LDL subclasses [12], and the main findings are summarized in its executive summary [13].

Yet, since pioglitazone causes salt and water retention via PPAR-γ activity on the distal tubule of the kidney, a potential side-effect of such therapy is edema; however, edema is infrequently severe enough to lead to treatment cessation, and it is usually very manageable [5]. By contrast, a severe adverse event of pioglitazone therapy may be bladder cancer; indeed, in a French database study a small but significant increased risk of bladder cancer in patients treated with pioglitazone has been reported [14]. This has led to the regulatory authorities in France and Germany suspending the use of pioglitazone containing products for the treatment of type 2 diabetes in 2011, although the European Medicines Agency in a statement on June 9, 2011 did not recommend any changes to the use of pioglitazone-containing medicines [15].

3. Non-glycemic effects of incretin-based therapies

Incretins are hormones produced by the gastrointestinal tract in response to oral food ingestion and they help to maintain glucose homeostasis through their coordinated effects on islet α and β cells [16]. Since the ‘incretin effect’ is diminished or lost over time in people with type 2 diabetes, novel therapies have been developed to address hyperglycemia through either mimicking the action of the endogenous incretin glucagon-like polypeptide (GLP-1), e.g., the so-called GLP-1 receptor agonists, or by inhibiting the activity of the enzyme that degrades GLP-1, e.g., the so-called dipeptyl peptidase-4 (DPP-4) inhibitors. In April 2005, the Food and Drug Administration (FDA) approved the first GLP-1 receptor analog, exenatide, as adjunctive therapy for patients with type 2 diabetes; further, in October 2006, the FDA approved the first oral incretin enhancer, sitagliptin, a selective DPP-4-inhibitor, for use as monotherapy or in combination with metformin or thiazolidinediones. Since then, a large number of IBTs have been developed, some of which have been introduced in the market.

GLP-1 agonists and DPP-4 inhibitors have several beneficial non-glycemic effects, including lowering body weight, reducing systolic and diastolic blood pressure, improving endothelial dysfunction and reducing plasma C-reactive protein levels [16,17]. Incretin-based therapies can also favorably manage diabetic dyslipidemia, with a reduction in plasma levels of triglycerides, total cholesterol and LDL cholesterol, and a concomitant increase in plasma HDL cholesterol concentrations [16,17]. Yet, it should be highlighted that these actions are not uniform for all agents of this drug class.

We recently summarized the pleiotropic effects of liraglutide, the first human GLP-1 analog [17]: this agent is able to favorably modulate glucose and lipid metabolism, as well as inflammatory markers, body weight, subclinical atherosclerosis, and possibly even the infarct size in experimental myocardial infarction models. On this basis, it is likely that liraglutide would be able to show reductions in cardiovascular morbidity and mortality in future studies; however, such desirable clinical end-points remain currently unproven. It is hoped that the ongoing international LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) study will provide useful answers in this regard.

4. Conclusions

Pioglitazone and IBTs have shown important glycemic effects, as well as a number of non-glycemic effects, including those on body weight, hypertension, dyslipidemia and the metabolic syndrome. Nevertheless, there is more to predicting vascular disease than just established risk factors [18]. Non-traditional risk markers, such as lipoprotein subfractions and inflammatory cytokines, also appear to play a role in the genesis and progression of atherosclerosis. Along these lines, the effects of pioglitazone on these ‘emerging’ risk factors have been extensively investigated, while data on GLP-1 agonists and DPP-4 inhibitors are still inconclusive. Results of studies assessing the effects of IBTs on novel cardio-metabolic risk factors, as well as on cardiovascular morbidity and mortality, are eagerly awaited.

5. Expert opinion

The recent introduction in the market of the new anti-diabetic drugs modulating the incretin system has opened new horizons in the management of type 2 diabetes. These agents have important glycemic effects, as well as a number of non-glycemic effects, including those on body weight, hypertension, inflammation and dyslipidemia, thereby significantly impacting the different components of the metabolic syndrome. However, it currently remains unclear whether these agents are able to actually reduce cardiovascular morbidity and mortality beyond their positive effects on cardio-metabolic biomarkers. This is of great importance, since the modulation of cardio-metabolic biomarkers per se does not automatically translate into a reduction in the cardiovascular outcome.

We must keep in mind the cautionary tale of rosiglitazone, a previously approved anti-diabetic drug and TZD agent that significantly reduced hyperglycemia with apparent benefit on metabolic parameters, but which was subsequently found to increase cardiovascular risk. Data to date suggest that pioglitazone may significantly reduce cardiovascular outcomes, while preliminary findings with IBTs are very encouraging as well. However, as clinicians we need to remain cautiously optimistic and patiently await firm evidence for a “global cardiovascular risk reduction” action of these agents on clinically measurable end-points. Hopefully, results from long-term trials currently in progress will provide us with definitive answers to these important questions.

Declaration of interest

M Rizzo has given talks and participated in conferences sponsored by Novo-Nordisk. The authors state no conflict of interest and have received no payment in preparation of this manuscript.