Metabolically unhealthy non-obese individuals (MUNO) comprise around 20% of the normal-weight population and have a 3.14-fold higher risk of cardiovascular events and mortality compared with their metabolically healthy counterparts. Prevalence is highest in South Asians (43.6%) [1], and in India, the latest (June 2025) published ICMR–INDIAB-23 study reported it at 43.3%. [2] Visceral Fat as a Cardiometabolic Driver- Pathophysiological Interactions: Visceral fat deposition induces insulin resistance, leading to MASLD, increased cIMT, and a lipodystrophy-like phenotype that drives cardiometabolic risk. Impaired adipogenesis causes ectopic lipid deposition, while low adiponectin and chronic inflammation accelerate atherosclerosis. The "Asian Indian Phenotype" amplifies this risk through abdominal fat, insulin resistance, and dyslipidemia despite normal BMI. Eventually, β-cell exhaustion reduces insulin production, progressing to T2D and CVD.[1,2] Targeting Insulin Resistance in T2DM: Rationalistic Confluence of Pioglitazone, Metformin & Glimepiride Pioglitazone-Insulin Sensitizer with Effect on MASLD:Pioglitazone, a PPAR-γ agonist, improves hepatic and peripheral insulin sensitivity, targeting underlying insulin resistance. Clinical evidence shows durable glycemic control, MASLD/MASH improvement, and cardiovascular protection, including reduced CV events. [3] Metformin- Hepatic & Skeletal Insulin Sensitizer:Metformin reduces liver glucose production and improves tissue insulin sensitivity, thereby addressing insulin resistance [4], and remains the guideline-recommended therapy across global diabetes management guidelines. [5] Glimepiride- Insulin Secretagogue with Insulin Sensitizing Effects:Glimepiride blocks potassium channels in pancreatic beta cells, causing depolarization and calcium influx that stimulates insulin release. It also enhances tissue insulin sensitivity and reduces hepatic glucose production. Glimepiride's proven efficacy in glycemic control and high patient acceptance (51.7% preference) in India indicate its widespread use in India. [6] Glimepiride, Metformin, Pioglitazone: Indian Evidence in Dual & Triple Combination in 2025 Glimepiride-Metformin in Newly Diagnosed Indian T2D:A multicenter study across India (n=17,994) demonstrated the efficacy of glimepiride-metformin in newly diagnosed patients for 3-month outcomes: HbA1c decreased from 8.3% to 7.3% (p<0.001), while fasting and postprandial glucose levels showed substantial reductions of 38.6 mg/dL and 58.1 mg/dL, respectively. Clinicians rated treatment effectiveness as excellent in 50.28% and good in 44.93% of cases. [7] Glimepiride Metformin Pioglitazone-Based Treatment in Newly Diagnosed T2DM:Indian Experience: Another latest published Indian prospective study (n=137) conducted on newly diagnosed T2DM patients (mean BMI 24.8 kg/m²) assessed the safety of pioglitazone-containing triple-drug therapy, treated with metformin 1,000 mg BD + glimepiride 2 mg OD + pioglitazone 15 mg OD for 1 year. HbA1c improved from 10.5%→6.1%, LDL from 120→91 mg/dL, with no significant change in weight (+0.86 kg) or waist circumference (+0.62 cm). Pioglitazone in combination therapy provided significant metabolic benefits and improved insulin resistance markers. [8] Legacy Benefits with Insulin Sensitizer – Pioglitazone and Metformin Metformin's Legacy Protection:UKPDS Landmark Data (after 24 years) noted the CV safety of metformin, showed a 39% reduction in MI, 50% in coronary death, and 41% in stroke.[9] A retrospective, observation, multicenter cohort study (n=316,693 patients) indicated that metformin therapy reduced eGFR decline by 30%, decreased new CKD risk by 22% and significantly decreased end-stage kidney disease. [10] Pioglitazone Benefit in MASLD & Beyond: MASLD & Beyond:A decade-long retrospective analysis (n=65) revealed pioglitazone's sustained hepatic benefits. Liver enzymes normalized (ALT: 41→34 U/L), hepatic steatosis significantly improved (CAP: 330.5→299 dB/m, p=0.002), with 61.5% of patients showing reduced or stable liver stiffness. [11] Safety Considerations with Pioglitazone:Despite its therapeutic advantages, pioglitazone requires monitoring for weight gain and fluid retention, and should be avoided in patients with active bladder cancer. In postmenopausal women, its cardiovascular benefits should be balanced against the risk of fractures. Metformin needs monitoring for lactic acidosis risk and vitamin B12 levels. When using glimepiride, clinicians should be mindful of hypoglycemia and occasional gastrointestinal discomfort. Across all agents, individualized dosing tailored to patient profile and comorbidities ensures optimal outcomes. [12,13] Guideline & Consensus Perspectives on Pioglitazone Various guidelines recommend that triple combination therapy be considered when dual therapy fails to achieve target glycemic control. [14] Pioglitazone is recommended for T2DM with MASLD, with global guidelines (ADA, AASLD, Global MASH Council) supporting its role in T2DM with MASLD/MASH, though not as MASH-specific therapy. [15,16,17] The RSSDI-ESI recommended initiating metformin at the time of diagnosis, advocating for early or combination therapy. [18] ADA 2025 also favored metformin for diabetes and its prevention, further noted its beneficial effects on A1C, weight neutrality, lower risk of hypoglycemia, and CV risk, and is even safe to use in patients with CKD, estimated glomerular filtration rate ≥30 mL/min/ 1.73 m2. [15] The RSSDI-ESI also prioritized modern sulfonylureas such as glimepiride due to their proven CV safety [18] Final Takeaways Abbreviations: MUNO – Metabolically Unhealthy Non-Obese, MONO – Metabolically Obese Normal-Weight, T2DM – Type 2 Diabetes Mellitus, CVD – Cardiovascular Disease, MASLD – Metabolic Dysfunction-Associated Steatotic Liver Disease, MASH – Metabolic Dysfunction-Associated Steatohepatitis, cIMT – Carotid Intima-Media Thickness, PPAR-γ – Peroxisome Proliferator-Activated Receptor Gamma, AMPK – AMP-Activated Protein Kinase, ALT – Alanine Aminotransferase, GGT – Gamma-Glutamyl Transferase, CAP – Controlled Attenuation Parameter, HDL – High-Density Lipoprotein, LDL – Low-Density Lipoprotein, HOMA-R – Homeostatic Model Assessment of Insulin Resistance, GLP-1 RA – Glucagon-Like Peptide-1 Receptor Agonist, GIP – Glucose-Dependent Insulinotropic Polypeptide, AASLD – American Association for the Study of Liver Diseases, ADA – American Diabetes Association, AACE – American Association of Clinical Endocrinology, RSSDI – Research Society for the Study of Diabetes in India