Who benefits most from these drugs, and how much weight can they really lose?
People with type 2 diabetes and obesity stand to gain the most from dual and triple incretin drugs. In a network meta-analysis of randomized trials, tirzepatide (a GLP-1/GIP dual agonist) was the most effective at lowering blood sugar, reducing HbA1c by 1.88 percentage points and fasting glucose by 57.3 mg/dL [4]. For weight loss, retatrutide (a triple agonist) led the pack with an average of 8.6 kg (about 19 lbs) more weight loss than standard therapy, and in a separate phase 2 trial, patients lost up to 24.2% of their body weight over 48 weeks [2][4]. To put that in perspective, losing a quarter of your body weight is the kind of result usually only seen after bariatric surgery.
But these numbers come from clinical trials with careful monitoring and dose escalation. In the real world, results may vary, and the drugs are not a magic bullet — they require continued use to maintain weight loss, as one study noted that weight regain occurred after stopping retatrutide [3].
Do these drugs help with liver disease, heart health, or cancer?
Yes, early evidence suggests benefits beyond weight and blood sugar, but the data are strongest for liver and heart outcomes, and more preliminary for cancer. For liver disease, a 19-week trial of cotadutide (a GLP-1/glucagon dual agonist) in people with MASH (a type of fatty liver with scarring) showed a 5% absolute reduction in liver fat, along with significant drops in liver enzymes ALT (down 23.5 U/L) and AST (down 16.8 U/L) [1]. Another review concluded that GLP-1-based therapies improve non-invasive liver markers, though it remains unclear whether the effect is direct or simply due to weight loss [5].
For heart health, semaglutide reduced major cardiovascular events (heart attack, stroke, death) by 20-26% in large trials, and tirzepatide was projected to prevent up to 2 million cardiovascular events over a decade in eligible U.S. patients [2]. For cancer, a preclinical study found that retatrutide reduced pancreatic tumor volume by 14-fold and lung tumor volume by 17-fold in mice, and the anti-tumor effect persisted even after weight regain [3]. These are animal results, so they are promising but not yet proven in humans.
What are the catches — side effects, dropouts, and what we still don't know?
The main catch is that gastrointestinal side effects are very common and can be severe enough to make people stop treatment. In the cotadutide MASH trial, 91.7% of patients on the highest dose reported adverse events (mostly nausea, vomiting, diarrhea), and 16.7% dropped out because of them [1]. Across all the drugs, gastrointestinal issues are the most frequent side effect, though they are usually mild to moderate and improve with dose escalation [2].
Another catch is that long-term safety data for the newer triple agonists like retatrutide are still limited — the phase 2 trial was only 48 weeks long [2]. We also do not yet know the optimal balance of GLP-1, GIP, and glucagon activity in combination drugs, and whether GIP should be activated or blocked for best results [5]. Finally, the cancer benefits are only from animal studies [3], and the liver benefits, while promising, come from a small 74-patient trial [1]. So while the hype is grounded in real results, the full picture of risks and long-term outcomes is still emerging.
About These Sources
This answer is built on 5 peer-reviewed studies — published from 2023 to 2026, 4 from 2024 or later, 2 in Q1 journals, collectively cited 191 times — selected as the most relevant from 5 studies that passed quality screening, drawn from 49 papers retrieved from a database of over 500 million.
Sources used in this answer
Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Noncirrhotic MASH With Fibrosis
In a 19-week randomized trial of 74 patients with MASH and fibrosis, the dual agonist cotadutide (600 μg) reduced liver fat by 5%, ALT by 23.5 U/L, and AST by 16.8 U/L versus placebo, but 91.7% of patients had adverse events and 16.7% discontinued treatment.
Impact of GLP-1 Receptor Agonists and Dual/Triple Incretin Therapies on Cardiometabolic Outcomes Beyond Glycemic Control: Evidence from Recent Randomized Trials
This review of recent trials reports that semaglutide reduced major cardiovascular events by 20-26%, tirzepatide produced up to 20.2% weight loss, and retatrutide led to 24.2% weight loss at 48 weeks, though long-term safety data for triple agonists remain limited.
Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression
In preclinical mouse models, the triple agonist retatrutide reduced pancreatic tumor volume by 14-fold and lung tumor volume by 17-fold compared to controls, with anti-tumor immune effects persisting after weight regain.
Beyond GLP-1: efficacy and safety of dual and triple incretin agonists in personalized type 2 diabetes care—a systematic review and network meta-analysis
This network meta-analysis of randomized trials found retatrutide achieved the greatest weight reduction (mean difference -8.6 kg) and tirzepatide was most effective for lowering HbA1c (-1.88 percentage points) and fasting glucose (-57.3 mg/dL), though tirzepatide and cotadutide increased adverse events.
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
This review concludes that GLP-1 receptor agonists and dual/triple combinations improve weight, insulin resistance, and non-invasive liver markers in MASH, but it is unclear whether effects on the liver are direct or secondary to weight loss, and the optimal ratio of receptor activation is unknown.