Relevance of Pioglitazone in Indian T2DM Care Continuum

India is experiencing a rising burden of type 2 diabetes (T2D), affecting 11.4% of adults. Hypertension (35.5%), generalized obesity (28.6%), abdominal obesity (39.5%), and dyslipidemia (81.2%) are widespread cardiometabolic risk factors among Indian people living with diabetes, low HDL-C (66.9%), high LDL-C (20.9%), and hypercholesterolemia (24%) further contribute to cardiovascular (CV) risk. This clustering of metabolic issues—even among those with normal BMI (1), as seen in “thin-fat/metabolically unhealthy non-obese (MUNO)” Indians—calls for early, comprehensive use of insulin-sensitizing therapies in the diabetes care continuum. (2)

Role of Pioglitazone in MUNO T2DM Patients: Pioglitazone is effective in managing MUNO individuals with T2DM by enhancing insulin sensitivity and restoring first-phase insulin secretion, a key defect in this phenotype. Despite normal BMI, these patients often show marked insulin resistance and β-cell dysfunction. Pioglitazone enhances glucose uptake and lowers HbA1c by over 1%, providing both metabolic and CV benefits. (3)

Pioglitazone in T2DM - Application in T2DM Beyond MUNO Phenotypes

Pioglitazone offers significant benefits in early-stage, treatment-naïve T2DM by reducing insulin resistance and increasing muscle glucose uptake by 30% over six months while enhancing β-cell function. It is particularly effective in insulin-resistant(IR) patients with metabolic syndrome (Met-S), even without obesity, due to its action on adipose tissue, muscle, and liver. (4) In uncontrolled or treatment-experienced T2D patients, pioglitazone lowers HbA1c by up to 1.26% and reduces insulin dose requirements. (5) In T2DM patients with prior stroke, it reduces the risk of recurrent stroke by 47% and improves CV outcomes. (4)

Pioglitazone: Clinical Evidence Review: Pioglitazone offers substantial benefits across multiple metabolic and CV domains, making it highly relevant for Indian patients with T2DM.

Pioglitazone lowers FBG, PPG & HbA1c in Indian T2D: In a double-blind RCT conducted in India at PGIMER, Chandigarh (n=90), T2DM patients received pioglitazone in varied doses, including 7.5 & 15 mg. Both 7.5 mg and 15 mg significantly reduced HbA1c (−0.5%, −0.6%), FPG (−30.6, −40.3 mg/dL), and PPG (−48.3, −53.3 mg/dL) with statistical significance (p < 0.001). The 7.5 mg dose demonstrated a safer profile, with significantly less weight gain & increase in body fat. (6)

Pioglitazone Benefits T2D with MASLD: Pioglitazone activates PPARγ with modest effects on PPAR-α, improving insulin sensitivity, lipid metabolism, and hepatic inflammation. (7) In a 5-year follow-up of MASLD patients treated with pioglitazone (n = 34), the liver-to-spleen attenuation ratio improved by +0.26, while serum adiponectin levels significantly increased by +6.11 μg/mL (P = 0.012). (8) Pioglitazone benefits all four parameters – liver enzymes, hepatic steatosis, liver stiffness, and MASH; reportedly, showing an edge over Metformin, DPP4i, Sulphonylureas, and SGLT2i. (9)

Pioglitazone BP Lowering Effects: Pioglitazone has been consistently associated with a modest yet steady reduction in systolic blood pressure (SBP), typically by 3–5 mmHg. In individuals with T2D, it has also been shown to restore the normal circadian variation in blood pressure, shifting from a “non-dipper” to a “dipper” pattern, coinciding with improved insulin sensitivity as reflected by reductions in the homeostatic model assessment (HOMA) index. (10)

Pioglitazone Improves CV Outcomes: The PROactive trial demonstrated that pioglitazone reduced the combined risk of all-cause mortality, non-fatal myocardial infarction (MI), and stroke by 16% in individuals with T2D at high macrovascular risk (HR = 0.84; 95% CI: 0.72–0.98). Additionally, a meta-analysis of nine randomized controlled trials (RCTs) (n = 12,026) found a 17% reduction in MACE with pioglitazone use in T2D patients (HR = 0.83; 95% CI: 0.72–0.97). (11)

Pioglitazone Improves Inflammatory & Atherosclerosis Markers: In a 28-day RCT (n=92) among T2D patients with coronary artery disease(CAD), pioglitazone significantly reduced MMP-9 (−12%) and hs-CRP (−18%) within 3 days (p < 0.05) and MCP-1 by 14% at 10 days (p < 0.0001). sCD40 dropped 32.5% (p < 0.05). These changes occurred independent of glycemic control, highlighting pioglitazone’s vascular anti-inflammatory effects. (11)

Pioglitazone and Fat Redistribution in T2D: In a 24-week study including T2D patients (n=12) compared to individuals with normal glucose tolerance (NGT) subjects (n=12), pioglitazone reduced epicardial adipose tissue by 9% (p = 0.03). Left ventricular diastolic function, measured by E/A ratio and peak LV filling rate, improved significantly as reported in the study. (p = 0.01–0.05). (12)

Pioglitazone is cost-effective (13), accessible, and safe in liver disease and chronic kidney disease (CKD), including End-stage kidney disease(ESRD), without dose adjustment. (14) In a real-world Taiwanese study (n=6,727), pioglitazone reduced MACCEs (HR 0.85 vs. 1.00) and all-cause mortality (HR 0.88 vs. 1.00) compared to DPP-4 inhibitors. (15)

Pioglitazone – Guideline Recommendations Review

Pioglitazone is US FDA-approved as an adjunct to diet and exercise in T2DM. (16) The European Medicines Agency supports its use in overweight adults, either alone or with metformin, sulfonylureas, or insulin. (17)

The American Diabetes Association suggests it for T2D patients with biopsy-proven MASH or high fibrosis risk. (18) RSSDI supports its use in elderly patients, during prolonged fasting, and for secondary stroke prevention. (19) The American Association for the Study of Liver Diseases (AASLD) supports its role in improving NASH, particularly in patients with coexisting T2D. (20) Furthermore, the American Association of Clinical Endocrinology (AACE) consensus statement notes that pioglitazone may reduce the risk of recurrent stroke and could be considered in patients with insulin resistance, prediabetes, or T2D with prior stroke or transient ischemic attack(TIA). (21)

Take Home Messages

• Pioglitazone is highly relevant in the Indian T2DM care continuum, including metabolically unhealthy, thin-fat/MUNO, and beyond MUNO phenotypes due to its insulin-sensitizing & metabolic effects.
• Pioglitazone improves glycemic control, β-cell function, adiponectin levels, inflammatory markers, and CV outcomes across newly diagnosed, early, uncontrolled, or treatment-experienced T2D patients.
• Evidence supports the role of Pioglitazone in MASLD, with added benefits in liver enzymes, steatosis, inflammation, and cardiac fat reduction.
• Cost-effective, guideline-supported, and safe in CKD and liver disease, pioglitazone remains relevant as a practical long-term consideration among Indian T2D patients.

Abbreviations: MMP-9; matrix metalloproteinase 9, MCP-1; Monocyte Chemoattractant Protein-1, hs-CRP;high-sensitivity C-reactive protein, s-CD40; soluble cluster of differentiation 40, LFE; Liver Fat Equation, HSI; Hepatic Steatosis Index, ION; Index of NASH, MACE; major adverse cardiovascular events, MACCEs; major adverse cardiac cerebrovascular events, PPARγ; Peroxisome proliferator-activated receptor gamma, PPAR-α; Peroxisome Proliferator-Activated Receptor alpha, TOSCA.IT; Thiazolidinediones or Sulfonylureas and Cardiovascular Accidents Intervention Trial, FPG;fasting plasma glucose, PPG; postprandial glucose.

References:
1. Anjana, Ranjit Mohan et al. “Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17).” The lancet. Diabetes & endocrinology vol. 11,7 (2023): 474-489. doi:10.1016/S2213-8587(23)00119-5

2. Kapoor, Nitin et al. “Normal Weight Obesity: An Underrecognized Problem in Individuals of South Asian Descent.” Clinical therapeutics vol. 41,8 (2019): 1638-1642. doi:10.1016/j.clinthera.2019.05.016

3. Qian, Xin et al. “Pioglitazone Improved Insulin Sensitivity and First Phase Insulin Secretion Among Obese and Lean People with Diabetes: A Multicenter Clamp Study.” Diabetes therapy : research, treatment and education of diabetes and related disorders vol. 9,2 (2018): 815-826. doi:10.1007/s13300-018-0401-9

4. Stempa, Oded. Pioglitazone: Lessons and Learnings 15 Years Since Launch and Beyond. Diabetes Management, vol. 5, no. 6, 2015, pp. 415–429. Future Medicine Ltd, doi:10.2217/dmt.15.38.

5. Sourij, Harald, and Thomas C. Wascher. "Pioglitazone in the Management of Type 2 Diabetes and Beyond." Drug Evaluation, Medical University of Graz, Austria, pp. 1–17.

6. Rajagopalan, Sujit et al. “Effect of low dose pioglitazone on glycemic control and insulin resistance in Type 2 diabetes: A randomized, double blind, clinical trial.” Diabetes research and clinical practice vol. 109,3 (2015): e32-5. doi:10.1016/j.diabres.2015.05.030

7. Stefano Ciardullo, Emanuele Muraca, Michela Vergani, Pietro Invernizzi, Gianluca Perseghin, Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions, Gastroenterology Report, Volume 12, 2024, goae029, https://doi.org/10.1093/gastro/goae029

8. Ito, Daisuke et al. “Long-term effects of ipragliflozin and pioglitazone on metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: 5 year observational follow-up of a randomized, 24 week, active-controlled trial: Effect of ipragliflozin in MASLD.” Journal of diabetes investigation vol. 15,9 (2024): 1220-1230. doi:10.1111/jdi.14246

9. Isaacs SD, Farrelly FV, Brennan PNRole of anti-diabetic medications in the management of MASLDFrontline Gastroenterology Published Online First: 19 February 2025. doi: 10.1136/flgastro-2024-102856

10. Forst, T et al. "Pleiotropic and anti-inflammatory effects of pioglitazone precede the metabolic activity in type 2 diabetic patients with coronary artery disease.” Atherosclerosis vol. 197,1 (2008): 311-7. doi:10.1016/j.atherosclerosis.2007.05.006

11. Nesti, L., Tricò, D., Mengozzi, A. et al. Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug. Cardiovasc Diabetol 20, 109 (2021). https://doi.org/10.1186/s12933-021-01294-7

12. Moody AJ, Molina-Wilkins M, Clarke GD, et al. Pioglitazone reduces epicardial fat and improves diastolic function in patients with type 2 diabetes. Diabetes Obes Metab. 2023;25(2):426-434. doi:10.1111/dom.14885

13. DeFronzo, Ralph A et al. “Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes.” Diabetes & vascular disease research vol. 16,2 (2019): 133-143. doi:10.1177/1479164118825376

14. Yen CL, Wu CY, See LC, et al. Pioglitazone Reduces Mortality and Adverse Events in Patients With Type 2 Diabetes and With Advanced Chronic Kidney Disease: National Cohort Study. Diabetes Care. 2020;43(10):e152-e153. doi:10.2337/dc20-1584

15. Lin, Min-Hao et al. “Pioglitazone Is Associated with Lower Major Adverse Cardiovascular and Cerebrovascular Events than DPP4-Inhibitors in Diabetic Patients with End-Stage Renal Disease: A Taiwan Nationwide Cohort Study, 2006-2016.” Journal of clinical medicine vol. 9,11 3578. 6 Nov. 2020, doi:10.3390/jcm9113578

16. Singh G, Can AS, Correa R. Pioglitazone. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544287/

17. European Medicines Agency. Pioglitazone Actavis. European Union, https://www.ema.europa.eu/en/medicines/human/EPAR/pioglitazone-actavis. Accessed 24 Mar. 2025.

18. American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S181–S206. https://doi.org/10.2337/dc25-S009

19. Research Society for the Study of Diabetes in India (RSSDI). RSSDI Clinical Practice Recommendations 2022: Summary Document for Training. RSSDI, 2022.

20. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi:10.1097/HEP.0000000000000323a

21. Samson, Susan L et al. “American Association of Clinical Endocrinology Consensus Statement: Comprehensive Type 2 Diabetes Management Algorithm - 2023 Update.” Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists vol. 29,5 (2023): 305-340. doi:10.1016/j.eprac.2023.02.001