Metformin - Eight Points on a Metabolic Anchor in T2D: World Diabetes Day Special

This World Diabetes Day, the focus on diabetes goes beyond rising numbers to the growing burden of managing the disease and its long-term complications. The challenge is particularly significant for India, which is home to an estimated 89.8 million adults aged 20-79 years living with diabetes—approximately one in seven adults with diabetes globally¹.

One medicine that has remained a constant through the changing landscape of diabetes & metabolic care is metformin. Reportedly used daily by around 150 million people worldwide² and the most prescribed glucose-lowering drug in Asia³.

Metformin continues to remain a foundational and relevant anchor in the diabetes and metabolic care continuum since its first introduction by Jean Sterne and colleagues in 1957⁴. It subsequently became the world’s most widely prescribed glucose-lowering agent, and more than six decades later, research continues to explore its potential beyond glycaemic control⁴.

Here, we look at the growing evidence on metformin and its continuously evolving role across the diabetes care continuum.

1. Physiologically friendly multi-modal mechanism of Metformin

Metformin’s role in diabetes care extends beyond glucose lowering, with emerging evidence pointing to broader effects on ageing biology, host-microbiome interactions, immune-metabolic regulation, and cancer. It may also influence the gut microbiome by altering bacterial composition, increasing short-chain fatty acid (SCFA) production and supporting intestinal barrier function⁵. Together, these effects may contribute to improved cellular stress response, metabolic function, and regulation of inflammation, relevant to vasculo-protection in T2D. Beyond glycaemic control, metformin has been associated with improvements in insulin sensitivity, dyslipidaemia, body weight and lipid profiles.

2. Metformin: Vascular health friendly in T2D – EASD 2026

The burden of macrovascular and microvascular complications remains substantial in India, with studies reporting complications in 5%–37% of people with diabetes⁶. Evidence presented at the EASD 2026 Annual Meeting highlighted the potential benefits of metformin across vascular outcomes. UKPDS data showed that early intensive glycaemic control with metformin was associated with a 20% lower risk of all-cause mortality and a 31% lower risk of myocardial infarction, with benefits persisting during long-term 24-year follow-up⁷. A meta-analysis reported a 33% reduction in stroke risk with metformin in people with T2D⁸. Renal outcomes were also favourable in a study of 316,693 people with diabetes, in which metformin use was associated with a lower incidence of doubling of serum creatinine by 29% (HR, 0.71; 95% CI, 0.65–0.77), eGFR ≤15 mL/min/1.73 m² by 39% (HR, 0.61; 95% CI, 0.53–0.71), and end-stage kidney disease (ESKD) by 45% (HR, 0.55; 95% CI, 0.47–0.66)⁹.

3. Liver friendly: Metformin improves MASLD parameters in T2D

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in India, with reported prevalence ranging from 9% to 53%¹⁰. Metformin may also have a role in MASLD and MASH through its effects on insulin sensitivity and hepatic glucose production. Studies have¹¹ found improvements in liver histology, while a meta-analysis reported that short-term metformin treatment improved ALT, AST, triglycerides, total cholesterol, and HOMA-IR in patients with NAFLD¹².

4. Metformin: Combination-comfortable for Use with Multiple Anti-hyperglycaemic Agents

Metformin is effective both as monotherapy and in combination with other glucose-lowering agents for type 2 diabetes. It can be safely and effectively combined with SGLT2 inhibitors, DPP-4 inhibitors, sulfonylureas, glinides, alpha-glucosidase inhibitors, insulin, and newer therapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists¹³. Reportedly, metformin is also approved for use in 12 internationally approved fixed-dose combination (FDC) formulations¹⁴.

5. Metformin SGLT2i equivalent in Preventing Macro-vascular & Micro-vascular Complications in T2D: SMARTEST Trial Presented at EASD 2026

Presented at the EASD 2026 Annual Meeting, the SMARTEST study (SGLT2 inhibitor or Metformin As standaRd Treatment of Early-Stage Type 2 diabetes) evaluated whether dapagliflozin 10 mg/day was superior to individually dosed metformin in preventing microvascular and macrovascular complications and premature death in people with early-stage T2D. There were 425 events with dapagliflozin and 421 with metformin, with no statistically significant difference between the groups, including across age, sex and diabetes-duration subgroups. Overall, neither treatment demonstrated superiority for the outcomes investigated¹⁵.

6. GLP-1 RA Supportive – New Milestone Potential for Metformin

Metformin may also complement GLP-1 receptor agonists (GLP-1 RAs) in weight management known to improve leptin sensitivity, making the brain more responsive to the anorexigenic effects of the adipokine¹⁶. In a 52-week prospective study of 194 adults with obesity and T2D, concomitant initiation of metformin with GLP-1 RA therapy was associated with greater weight-loss efficacy, suggesting a potential synergistic effect when both treatments are started together¹⁶. In another 2026 published retrospective cohort analysis using the global TriNetX database¹⁷ found that 36347 patients received dual metformin and GLP-1 RA therapy, which was associated with a 39% lower risk of adiposity-related cancer incidence and a 67% lower risk of all-cause mortality.

7. Synergy with Tirzepatide - Achieved Greater Weight Loss Success in T2D Patients

With overweight and obesity affecting around 45.2% of the population in India, excess weight remains an important risk factor for type 2 diabetes¹⁸. In 3,188 participants from SURPASS-1 to SURPASS-4, concurrent metformin use was associated with 1.77 times greater odds [(95% CI: 1.27–2.46), P < 0.001] of achieving ≥15% weight loss with tirzepatide. Higher tirzepatide doses, female sex, younger age and lower baseline HbA1c, fasting glucose and non-HDL cholesterol were also associated with greater weight loss¹⁹.

8. Metformin Could Be a Useful Option in Weight Optimizing Post-GLP-RA in T2D

While weight loss is achievable, maintaining that weight loss remains a long-term challenge. While GLP-1 RAs are effective for significant weight loss, maintaining it after discontinuation of these agents can be challenging due to cost, access barriers, and physiological tendencies of weight regain. In a prospective real-world study, patients transitioning to medications with weight lowering effect post GLP-1 RA discontinuation maintained a 25.1% ± 2.6% mean weight reduction through 24 months, with metformin used by 80% of the cohort, supporting its potential role in long-term weight maintenance²⁰.

Metformin: Physiologically Friendly, Person Friendly & Pocket Friendly

As we mark World Diabetes Day, it is an opportune moment to recognize metformin’s enduring contribution to the gluco-metabolic care continuum; a legacy further underscored by the Silver Jubilee of DCGI approval of metformin 500 mg sustained-release in India earlier this month. Twenty-five years since this regulatory milestone in India²¹ metformin continues to hold relevance, reaffirming its place as a potential anchor in the evolving landscape of diabetes management.

Abbreviations: T2D: Type 2 diabetes, SCFA: Short-chain fatty acid, FDC: Fixed Dose Combination, HR: Hazard Ratio, CI: Confidence Interval, GIP: Glucose-dependent insulinotropic polypeptide, DCGI: Drugs Controller General of India, DPP-4: Dipeptidyl peptidase-4, SGLT2: Sodium-glucose cotransporter-2, GLP-1 RA: Glucagon-like peptide-1 receptor agonist, MASLD: Metabolic dysfunction-associated steatotic liver disease, MASH: Metabolic dysfunction-associated steatohepatitis, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, HOMA-IR: Homeostatic model assessment of insulin resistance, NAFLD: Non-alcoholic fatty liver disease, EASD: European Association for the Study of Diabetes, UKPDS: UK Prospective Diabetes Study, eGFR: Estimated glomerular filtration rate, ESKD: End-stage kidney disease, TriNetX: TriNetX Research Network, HbA1c: Glycated haemoglobin, SGLT2i: Sodium-glucose cotransporter-2 inhibitor, non-HDL: Non-high-density lipoprotein.