Fluid retention versus cardio protection: rethinking pioglitazone

Abstract

Pioglitazone, a thiazolidinedione, acts through peroxisome proliferator-activated receptor gamma (PPAR-gamma) and is an established insulin sensitizer used in type 2 diabetes. Many cardio-protective aspects of pioglitazone are being actively researched. The drug modulates neurohormonal pathways and improves diastolic dysfunction in hypertensive patients. In diabetic patients, pioglitazone has been shown to reduce hyperperfusion injury post-STEMI. It also exerts positive effects on cardiac and vascular remodeling. Despite its cardioprotective effects, studies have shown that weight gain and oedema are among the most serious implications of the drug, specifically limiting its role in patients with heart failure. Hence, further studies are required to demonstrate the effect of pioglitazone among patients with heart failure.

Dear Editor,

Pioglitazone, a thiazolidinedione, acts through peroxisome proliferator-activated receptor gamma (PPAR-gamma) and is an established insulin sensitizer used in type 2 diabetes. It enhances glycemic control by improving insulin resistance in hepatic and skeletal muscle tissues, which is the hallmark of type 2 diabetes. Although its use declined due to concerns about bladder cancer, emerging evidence highlights its beneficial effects on individual components of metabolic syndrome, including obesity, hypertension, and hypertriglyceridemia. These pleiotropic actions suggest a potential cardioprotective role for pioglitazone in patients with type 2 diabetes^[1].

Many cardio-protective aspects of pioglitazone are being actively researched. The drug modulates neurohormonal pathways, such as enhancing sympathetic response to oral glucose load in obese individuals, and improves diastolic dysfunction in hypertensive patients through adiponectin (an anti-inflammatory agent). In diabetic patients, pre-treatment with pioglitazone has been shown to reduce reperfusion injury post-STEMI, and decrease arrhythmias, while improving stroke volume and left ventricular ejection fraction. It also exerts a positive effect on cardiac and vascular remodeling, and potentially promotes atherosclerotic plaque stabilization. Collectively, its impact on insulin sensitivity, lipid profile, systemic inflammation, and vascular health underscore pioglitazone as a potential cardioprotective agent^[2].

In a recently conducted systematic review, Sheikh et al discussed that numerous mechanisms involved in cardiovascular risks are attacked by pioglitazone. It ameliorates insulin resistance and decreases systemic inflammation by decreasing adipocytokines, inflammatory markers, and procoagulants. It also decreases LDL particle size. All these changes play a pivotal role in decreasing cardiovascular and all-cause mortality that is being associated with pioglitazone use^[3].

Despite its potential cardio-protective affects, pioglitazone has certain limitations. A systematic review conducted by Alam et al highlighted its major dose-dependent side effects of weight gain and oedema. This can lead to serious implications in clinical utilization of the drug, as oedema and acute change in body weight can have detrimental effects on patients previously diagnosed with heart failure^[4]. Despite growing evidence of its cardiovascular benefits, pioglitazone use remains limited, especially in patients with heart failure and reduced ejection fraction, due to concerns that fluid retention may worsen cardiac function and increase hospitalization^[3].

Recent data showcase pioglitazone as a potential cardiovascular protective agent, particularly in type 2 diabetic patients; further research is required to confirm its clinical implications. Further studies are required to further confirm the safety profile of pioglitazone in patients with heart failure and whether it deserves renewed attention as a dual action agent targeting both metabolic and cardiovascular risk.

This letter to the editor adheres to the Transparency in the Reporting of Artificial Intelligence in Research (TITAN) guideline^[5].

Ethical approval

Not applicable – this article does not involve original research on human or animal subjects.

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Sources of funding

The authors received no financial support for the research, authorship, or publication of this article.

Author contributions

G.I.: conception of the topic, literature search, extraction of relevant data, and drafting of the initial manuscript; U.A.: literature review, critical revision of scientific content, and editing for intellectual accuracy and clarity; R.K.M.: manuscript supervision, refinement of clinical and methodological interpretation, final drafting, and approval of the version to be submitted. All authors meet the ICJME criteria for authorship, approve the final manuscript, and agree to be accountable for all aspects of the work.

Conflicts of interest disclosure

The authors declared no potential conflicts of interest with respect to the research, authorship, or publication of this article.

Research registration unique identifying number (UIN)

None.

Guarantor

Raghabendra Kumar Mahato.

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Not commissioned.

Data availability statement

Not applicable.