Multi-pathway obesity drugs top weight loss charts

Clinical takeaway: Match agent to patient: efficacy, side-effect tolerance, and route of administration now differ meaningfully across the approved field. The upcoming pipeline is poised to offer even more effective and differentiated options. 

Obesity pharmacotherapy is moving faster than almost any other corner of primary care. Patients arrive asking about drugs they saw announced weeks earlier, and the gap between what is approved, what is coming, and what the evidence actually supports has become genuinely difficult to track in clinic. 

Two years ago the field rested on a handful of injectable GLP-1 receptor agonists with a well-worn efficacy ceiling. When the same team last mapped the evidence in early 2025, three drugs were commercially available and every one was an injectable. Since then, regulators have approved the first oral agents for weight loss, and drug developers have shifted from stimulating a single hormonal pathway toward compounds that pair GLP-1 action with amylin, GIP, or glucagon signaling. An updated systematic review now maps this widening field, and its most striking data belong to agents most clinicians cannot yet prescribe. 

The biggest weight loss, on the order of bariatric surgery, belongs to the upcoming candidates. Placebo-subtracted weight loss reached 23.9% with amycretin, a dual GLP-1 and amylin agonist, 22.1% with the triple agonist retatrutide (GLP-1, GIP, and glucagon), and 20.9% with the dual GLP-1 and glucagon agonist mazdutide, all in phase 1 or 2 trials running 20 to 48 weeks, shorter and earlier than the pivotal trials behind approved agents. 

In the one head-to-head trial reporting both arms, CagriSema cut body weight 20.4% against semaglutide's 14.9% at 68 weeks; tirzepatide also beat semaglutide at 72 weeks. Every agent that has beaten semaglutide in a randomized comparison works through more than one pathway. 

Among approved drugs, placebo-subtracted loss reached 19.0% with tirzepatide, 14.8% with the new 7.2 mg dose of subcutaneous semaglutide, and 14.3% with oral semaglutide 50 mg, while the newly approved oral orforglipron reached 9.1% at 72 weeks and liraglutide trailed at 5.8%. 

Gastrointestinal adverse events remained the tolerability story, affecting 76.0% of recipients of GLP-1-based drugs versus 40.1% on placebo, and discontinuation due to adverse events stayed low overall at 10.7% versus 3.4%. Discontinuation ran numerically higher with oral nonpeptide agents, and two of those, danuglipron and lotiglipron, have since been dropped from development over safety concerns. Across 25,816 participants, serious adverse events and deaths were rare and no new safety signal emerged. 

The review pooled 38 randomized controlled trials of GLP-1 receptor agonists and co-agonists in adults with overweight or obesity without diabetes, adding 14 trials since the authors' prior review. Trials ran at least 16 weeks; heterogeneity across designs and populations precluded meta-analysis, so cross-agent figures are indirect comparisons. 

Expect the comparisons to get more direct and more interesting. Mechanism innovation is running on two tracks: combining pathways within a single molecule, as the dual and triple agonists already do, and combining drugs across mechanisms, as the pairing that steered weight loss overwhelmingly toward fat mass has begun to show. That last result points at the field's next optimization target: preserving muscle while stripping fat. 

Source: Moiz A, et al. (2026 Sep 1) Ann Intern Med. Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists and Co-agonists for Weight Loss Among Adults Without Diabetes: An Updated Systematic Review