The Surge of GLP-1 Drugs Amid India's Obesity Crisis

Glucagon-like peptide-1 receptor agonists, commonly known as GLP-1 drugs, have revolutionized treatment for type 2 diabetes and obesity worldwide. Drugs like semaglutide, marketed as Ozempic for diabetes and Wegovy for weight management, mimic the GLP-1 hormone produced in the gut after eating. This hormone signals the brain to reduce appetite, slows gastric emptying, and boosts insulin release in a glucose-dependent manner, leading to significant weight loss—often 10-15% of body weight in clinical trials.

In India, where over 100 million people live with diabetes and obesity rates are climbing rapidly despite lower average body mass indices, these drugs represent hope. Known as the 'thin-fat' paradox, many Indians accumulate visceral fat around organs at seemingly normal weights, heightening risks for metabolic diseases. With semaglutide generics flooding the market at prices as low as ₹3,000-5,000 per month—down from ₹8,000-10,000—these therapies are becoming accessible. Yet, not everyone responds equally. Reports from clinicians indicate some patients see minimal weight loss or intolerable side effects like nausea, prompting questions about underlying factors, including genetics.

Understanding the 'Thin-Fat' Indian Phenotype

South Asians, including Indians, exhibit unique metabolic traits shaped by evolutionary adaptations to famine-prone environments—a 'thrifty genotype' that promoted fat storage but now backfires in calorie-abundant modern life. Studies show South Asians secrete up to 45% more endogenous GLP-1 during glucose challenges than Caucasians, yet display insulin resistance and beta-cell dysfunction, suggesting GLP-1 resistance. This phenotype contributes to higher diabetes prevalence at lower BMIs: 30-40% of urban Indians have fatty liver disease, and metabolic syndrome affects nearly half of adults over 40.

Pharmacological GLP-1 agonists bypass natural resistance by delivering supraphysiological doses, reducing liver fat by over 85% in some trials and improving inflammation. However, muscle loss—up to 40% of total weight shed—exacerbates sarcopenia common in Indians, underscoring the need for protein-rich diets and resistance training alongside therapy.

New Genetic Research Illuminates Response Variability

A landmark study published in Nature on April 8, 2026, by the 23andMe Research Institute analyzed self-reported data from 27,885 GLP-1 users, uncovering genetic predictors of efficacy and side effects. This genome-wide association study (GWAS) identified variants in the drug target genes GLP1R and GIPR, explaining part of the inter-individual differences where average semaglutide users lose 10% body weight, but some exceed 25% while others see almost none.

The research highlights pharmacogenomics—the study of how genes affect drug responses—as key to optimizing treatments, particularly relevant for diverse populations like India's 1.4 billion people with varied ancestries.

Key Discoveries: GLP1R and GIPR Variants

The star finding is a missense variant in GLP1R (rs10305420, p.Pro7Leu), altering the protein's signal peptide. Each copy of the effect allele correlates with an extra 0.76 kg weight loss over eight months, with homozygotes losing 1.5 kg more. This variant, present in 40% of Europeans but directionally consistent across ancestries including South Asians, also ties to gastrointestinal side effects—nausea and vomiting—suggesting better responders endure more discomfort.Full Nature study details here

• GLP1R rs10305420: Enhances drug binding, boosts efficacy (+weight loss), increases nausea/vomiting risk.
• GIPR rs1800437 (p.Glu354Gln): Raises vomiting odds 1.84-fold on tirzepatide (Mounjaro), absent in semaglutide users; 14.8-fold risk when combined with GLP1R risk alleles.

Models integrating genetics, age, sex, BMI, and diabetes status predict 25% of efficacy variance and side effect risks with 65-68% accuracy, paving the way for pre-treatment stratification.

Photo by Shubham Dhage on Unsplash

Ancestry-Specific Insights and South Asian Relevance

Though 78% European, the study included South Asians, East Asians, and others, showing consistent effect directions. The GLP1R variant is rarer in Africans (7%) but present in South Asians (~20-30% inferred), while GIPR frequencies are lower in South Asians (14%). East Asians showed slower weight loss rates, hinting at population differences.

For Indians, underrepresentation in trials—less than 5% in most GLP-1 studies—means extrapolations carry caution. Yet, the 'thrifty' genetics amplifying GLP-1 resistance may modulate responses, with some super-responders and a subset of non-responders observed clinically.

Perspectives from Indian Researchers and Clinicians

Dr. V. Mohan of Madras Diabetes Research Foundation (MDRF), affiliated with Sri Ramachandra Institute, notes four response categories to earlier GLP-1s like liraglutide among Indians: super-responders (dual benefits), partial responders, side effect-only, and rare non-responders. He advocates pharmacogenomics studies tailored to ethnicities.

Dr. Anoop Misra emphasizes genetic determination of variability in Indians, urging well-designed local studies. Dr. Ambrish Mithal from Max Healthcare sees DNA tests aiding non-responders by guiding switches to alternatives like DPP-4 inhibitors, more effective in Indians/Koreans.Indian Express coverage

Challenges in Indian Higher Education Research Landscape

Indian universities like AIIMS, IIT Madras, and CCMB lead diabetes genomics, identifying T2D variants in families and metformin pharmacogenetics where Indians carry more loss-of-response alleles. Yet, GLP-1 specific pharmacogenomics lags due to funding, cohort sizes, and trial diversity. Initiatives like ICMR's diabetes biobanks offer promise for GWAS mirroring the 23andMe effort.

Toward Personalized Obesity Treatment in India

Integrating genetics could transform care: test for GLP1R/GIPR before prescribing, escalate doses for poor binders, or switch to GIP/GLP-1 dual agonists for nausea-prone. Cost-effective generics amplify potential, but muscle preservation via exercise/nutrition is vital. Universities training pharmacogenomics specialists will drive adoption.

Photo by Ashraful Islam on Unsplash

Future Outlook: Research and Policy Horizons

With generics booming, India could pioneer affordable pharmacogenomics via public-private ties (e.g., Novo Nordisk with IITs). Longitudinal studies from JIPMER, PGIMER tracking real-world responses will refine models. Globally, polygenic risk scores may predict 30%+ variance, benefiting India's diverse genetics.

Stakeholders—from ICMR to startups—must prioritize inclusive trials. Actionable insights: Consult endocrinologists for non-responders, combine drugs with lifestyle, monitor muscle mass. This genetic era promises equitable, effective weight management.