Triple Threat-Triple Benefit: The Rise of GLP1-GCG-FGF21 Tritagonists in Tomorrow’s Metabolic Medicine

Abstract

Abstract

The global burden of metabolic disease—encompassing type 2 diabetes, obesity, severe hypertriglyceridemia, metabolic dysfunction–associated steatotic liver disease (MASLD), and premature atherosclerotic cardiovascular disease—continues to rise at an alarming pace, particularly in India and South Asia. These disorders rarely exist in isolation; rather, they represent interlinked manifestations of disturbed metabolic signalling, for which traditional mono-targeted therapies have delivered only incremental benefit. Although GLP-1 receptor agonists have transformed glycaemic and weight management, significant therapeutic gaps persist in patients with mixed dyslipidaemia, advanced MASLD, and overlapping diabetes–obesity phenotypes.

GLP-1–glucagon–FGF21 tritagonists represent a new paradigm designed to address this complexity through simultaneous, synergistic activation of three key metabolic axes. By integrating GLP-1–mediated glycaemic control and appetite suppression, glucagon-driven energy expenditure and lipid oxidation, and FGF21-induced hepatic fat clearance and insulin sensitization, tritagonists aim to reproduce the breadth of metabolic benefits previously achievable only with bariatric surgery—within a once-weekly injectable therapy.

Among emerging agents, the Fc-fusion tritagonist DR10624 has demonstrated unprecedented efficacy in Phase 2 trials, with profound reductions in fasting triglycerides, marked reversal of hepatic steatosis, meaningful improvements in glycaemic control, and clinically relevant weight loss, all within an acceptable safety profile. Importantly, these benefits appear preserved in Indian and South Asian populations, where metabolic disease presents earlier, progresses more aggressively, and clusters across multiple pathways.

This chapter reviews the scientific rationale, mechanistic integration, and clinical evidence supporting GLP-1–glucagon–FGF21 tritagonists, with particular emphasis on their relevance to the Indian cardio-metabolic landscape. Tritagonist therapy heralds a shift from sequential, siloed treatment to integrated disease modification, offering a promising foundation for the next era of comprehensive, patient-centred metabolic care.