Unveiling an Uncommon Complication: Pleural Effusion Secondary to Pioglitazone Use

Abstract

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is used in the treatment of Type 2 diabetes mellitus by reducing insulin resistance. While peripheral edema and fluid retention are well-documented adverse effects, isolated pleural effusion in the absence of heart failure is rare. We present the fourth reported case of a woman in her 60s with Type 2 diabetes who developed recurrent left-sided pleural effusion after the initiation and dose escalation of pioglitazone. The effusion resolved completely following discontinuation of the drug. This case underscores the importance of early recognition of drug-induced pleural effusion and timely cessation of the offending agent to prevent morbidity.

1. Introduction

Pioglitazone, a member of the thiazolidinedione (TZD) class of antidiabetic agents, has been widely used in the management of Type 2 diabetes mellitus (T2DM) due to its ability to reduce insulin resistance and improve glycemic control.1 Its mechanism of action involves binding to the peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear transcription regulator that modulates the expression of various genes involved in glucose and lipid metabolism.1,10

Through PPAR-γ activation, pioglitazone promotes adipocyte differentiation, fatty acid storage, and increased insulin sensitivity, particularly in adipose tissue, skeletal muscle, and liver. However, this same receptor activation in the distal nephron and the epithelial sodium channels (ENaC) of the collecting tubules—a site also regulated by aldosterone—can lead to fluid retention, especially at higher doses.1

Common adverse effects associated with this fluid retention include weight gain, bone loss, and congestive heart failure (CHF), all of which are well-documented. 2 While peripheral edema is relatively common, pleural effusion is rarely reported, particularly in patients with preserved cardiac function.2 This is the fourth reported case of pioglitazone-induced pleural effusion and highlights it as an important, underrecognized adverse effect, with resolution following drug discontinuation and diuretic therapy.

2. Case report

A woman in her late 60s with a history of hypertension (controlled with losartan-hydrochlorothiazide), hyperlipidemia (on rosuvastatin), and newly diagnosed type 2 diabetes mellitus presented with progressive shortness of breath. She was initially started on metformin, which was discontinued due to gastrointestinal side effects, and switched to pioglitazone 15 mg daily. Pioglitazone was chosen for its benefits in MASLD (Metabolic dysfunction-Associated Steatotic Liver Disease), likely present given the patient’s diabetes, hypertension, and hyperlipidemia. The dose was later increased to 30 mg due to suboptimal glycemic control (glucose levels ranging from 160 to 180 mg/dL).

Approximately one month after the dose increase, she developed exertional dyspnea. Chest X-ray revealed a moderate left-sided pleural effusion (Fig. 1). She was started on bumetanide 2 mg daily. A repeat chest X-ray one month later showed worsening effusion without signs of peripheral volume overload. Thoracentesis yielded 500 mL of fluid, characterized as a pseudo-exudate, consistent with diuretic-associated effusions.13

Fig. 1.

Initial posteroanterior chest radiograph demonstrating a moderate left-sided pleural effusion.

She continued pioglitazone and re-presented six months later with worsening dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and lower extremity edema. She reported a 15-lb weight gain in one month. CT imaging revealed a large left-sided pleural effusion and a new minimal right-sided effusion (Figs. 2 and 3). Her bumetanide dose was increased to 2 mg twice daily, but symptoms persisted.

Fig. 2.

Non-contrast computed tomography (CT) scan of the chest obtained six months later showing increased left-sided pleural effusion.

Fig. 3.

Axial non-contrast CT chest image confirming a large left pleural effusion and minimal right pleural effusion.

A left-sided chest tube was placed, draining 1.5 L of serous fluid. Pleural fluid analysis once again demonstrated a pseudo-exudative effuision.

A transthoracic echocardiogram revealed a normal left ventricular ejection fraction (60–64 %), normal right ventricular function, and no evidence of pulmonary hypertension. She was diuresed to a net negative fluid balance of 15 liters, and pioglitaone was discontinued. Her symptoms improved significantly, and she was discharged on a revised diabetic regimen that included dulaglutide and empagliflozin.

Given the absence of cardiac dysfunction, the temporal relationship with pioglitazone initiation and dose escalation, and the resolution after drug withdrawal, and diuresis, pioglitazone induced pleural effusion was diagnosed.

On follow-up two months later, the patient was asymptomatic. Chest X-ray showed resolution of the left-sided pleural effusion and only minimal right-sided effusion. A follow-up chest X-ray a year later confirmed no recurrence.

3. Discussion

Thiazolidinediones like pioglitazone act by activating PPAR-γ, which is expressed in adipose tissue, skeletal muscle, and liver.1,10 Activation of this receptor regulates genes such as lipoprotein lipase, glucokinase, and fatty acyl-CoA synthase, enhancing glucose utilization, fatty acid storage, and adipocyte differentiation. It also increases adiponectin and GLUT4 expression, while antagonizing TNF-α, thereby improving insulin sensitivity.1,10

However, pioglitazone has also been shown to cause dose-related fluid retention. This is mediated by its effect on PPAR-γ receptors in the distal nephron and insulin-activated ENaC channels in the collecting tubules, overlapping with aldosterone-sensitive pathways.1,3,12 These changes promote sodium and water retention, leading to peripheral edema, weight gain, and in some cases, congestive heart failure.2,3,9

The PROactive trial and subsequent studies confirmed a dose-dependent increase in edema and weight gain in patients on pioglitazone, especially those concurrently on insulin.9 Fluid retention can also occur through increased vascular permeability, the mechanism of which is thought to involve vascular endothelial growth factor (VEGF) and protein kinase C pathways.4,5 Emoto et al. reported significantly elevated VEGF levels in patients developing edema while on troglitazone, suggesting a similar mechanism may underlie fluid accumulation in pioglitazone users.5 This leads to transudative fluid accumulation; however, concurrent use of diuretics can increase pleural fluid protein and LDH concentrations through hemoconcentration or fluid shifts. As a result, the effusion may meet Light’s criteria for an exudate despite its transudative origin-a phenomenon referred to as a pseudoexudate.¹⁵

Although peripheral edema is well-known, pleural effusion has only been infrequently reported. To date, three additional cases of pioglitazone-induced pleural effusion have been reported in the literature that have all resolved with discontinuation of the drug and appropriate diuretic therapy.2,11,14 In these cases, the pleural fluid was transudative.

Another important differential diagnosis is insulin-induced edema, which though rare, has been reported with generalized edema, pleural, and pericardial effusions soon after initiating insulin therapy.6,7 Kalambokis et al. highlighted both sodium retention and increased capillary permeability in such cases,7 while experimental evidence by Kouritas et al. demonstrated pleural permeability changes under insulin exposure in sheep models.8 However, in our case, insulin therapy was not a contributing factor.

Our patient had no evidence of heart failure, renal dysfunction, hepatic disease, or vascular pathology, and was not on insulin therapy. The development of pleural effusion occurred shortly after an increase in pioglitazone dose to 30 mg, and symptoms resolved promptly upon drug cessation and diuretic use, strongly supporting a diagnosis of pioglitazone-induced pleural effusion.

This consistent clinical course supports a causal association and underscores the need to consider pioglitazone as a potential etiology in patients presenting with unexplained pleural effusions.

4. Conclusion

This case underscores pleural effusion as a rare but potentially serious adverse effect of pioglitazone. Clinicians should consider this possibility even in patients with preserved ejection fraction and no overt signs of heart failure. Timely recognition and appropriate management—including drug discontinuation and diuresis—can lead to complete resolution. Care should be taken, particularly in those also receiving insulin, due to potential for compounded fluid retention.

Learning Points.

• Pioglitazone, a PPAR-γ agonist used for glycemic control in type 2 diabetes, may cause significant fluid retention including pleural effusion.

• Pleural effusion associated with pioglitazone can occur in the absence of heart failure and may present unilaterally.

• Discontinuation of pioglitazone, along with diuretic therapy, can result in complete resolution of symptoms and effusion.

• Clinicians should be vigilant for respiratory symptoms in patients on pioglitazone, even those with preserved ejection fraction.

Funding Statement

This work was supported by MedStar Health Georgetown University (Baltimore) Program, which provided reimbursement for the article processing charge.