Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug

Abstract

Since 1985, the thiazolidinedione pioglitazone has been widely used as an insulin sensitizer drug for type 2 diabetes mellitus (T2DM). Although fluid retention was early recognized as a safety concern, data from clinical trials have not provided conclusive evidence for a benefit or a harm on cardiac function, leaving the question unanswered. We reviewed the available evidence encompassing both in vitro and in vivo studies in tissues, isolated organs, animals and humans, including the evidence generated by major clinical trials. Despite the increased risk of hospitalization for heart failure due to fluid retention, pioglitazone is consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention, without any proven direct harm on the myocardium. Moreover, it reduces atherosclerosis progression, in-stent restenosis after coronary stent implantation, progression rate from persistent to permanent atrial fibrillation, and reablation rate in diabetic patients with paroxysmal atrial fibrillation after catheter ablation. In fact, human and animal studies consistently report direct beneficial effects on cardiomyocytes electrophysiology, energetic metabolism, ischemia-reperfusion injury, cardiac remodeling, neurohormonal activation, pulmonary circulation and biventricular systo-diastolic functions. The mechanisms involved may rely either on anti-remodeling properties (endothelium protective, inflammation-modulating, anti-proliferative and anti-fibrotic properties) and/or on metabolic (adipose tissue metabolism, increased HDL cholesterol) and neurohormonal (renin-angiotensin-aldosterone system, sympathetic nervous system, and adiponectin) modulation of the cardiovascular system. With appropriate prescription and titration, pioglitazone remains a useful tool in the arsenal of the clinical diabetologist.

Keywords: Cardioprotection; Cardiovascular; Cardiovascular prevention; Cardiovascular risk factors; Clinical management; Heart failure; PPARs; Pharmacologic effects; Pioglitazone; Type 2 diabetes.

Fig. 1

Effects of pioglitazone on cardiovascular endpoints. Metanalysis subgroup analysis on pioglitazone trials on major adverse cardiovascular events (MACE) by primary and secondary prevention. Pioglitazone is associated with a reduction in overall MACE, non-fatal myocardial infarct, and non-fatal stroke, while having a neutral effect on cardiovascular death and all-cause mortality. In overt heart failure, conversely, it is associated with an increase in the risk of hospitalization. Modified with permission from Zhou Y et al. [18]. p* = p for heterogeneity between subgroups

Fig. 2

Effects of pioglitazone on the heart. Based on literature review, the effects of the treatment with pioglitazone on diverse cardiac functions are reported. The effects on electrophysiology and arrhythmias, ischemia, left ventricle functions, metabolism, cardiac remodeling, pulmonary vasculature and right ventricle, and on neurohormonal activation are reported. In each section, evidence is subdivided in in vitro, animal, and human studies. For more details, see main text

Fig. 3

Effects of pioglitazone on the vascular system and on cardiovascular risk factors. The effects of the treatment with pioglitazone on the vasculature and on modifiable risk factors are illustrated. The effects on atherosclerosis, endothelial function and blood pressure are reported, together with hydro-electrolyte homeostasis, the effects on the adipose tissue, and on blood lipids. For more details, see main text