How well do these drugs work in the short term, and what safety questions remain unanswered?
The short-term data is very encouraging. A 2025 network meta-analysis of 24 randomized trials involving 9,165 participants found that the dual agonist tirzepatide produced an average weight loss of 12.78 kg (about 28 pounds) and lowered HbA1c by 1.87 percentage points in people with type 2 diabetes [1]. The triple agonist retatrutide also showed strong dose-dependent weight loss and HbA1c reductions in phase 2 trials [4]. These are large, clinically meaningful effects.
But the safety picture is incomplete. Retatrutide caused a dose-dependent increase in heart rate and some cases of mild to moderate cardiac arrhythmias [4]. The authors of that paper explicitly state that long-term cardiovascular outcome trials (CVOTs) are 'critical' before we can be confident these drugs are safe for widespread, long-term use [4]. The meta-analysis found no increase in serious adverse events versus placebo, but it only included trials of at least 12 weeks—not years [1]. So we have good short-term safety data but almost no long-term cardiovascular safety evidence, which is a major gap.
What is the right balance of GLP-1, GIP, and glucagon activity, and do these drugs directly help the liver?
A key uncertainty is the optimal ratio of the three receptor activities. One review notes that it is still unclear whether GIP agonism or antagonism is the better approach, and what the ideal ratio of glucagon to GLP-1 agonism should be [2]. Different drug candidates use different ratios, and we don't yet have head-to-head trials that directly compare them to find the best one. This is a fundamental design gap.
Another big unknown is whether these drugs directly improve liver health in metabolic dysfunction-associated steatohepatitis (MASH) or simply work indirectly through weight loss and better blood sugar control. Two reviews highlight this debate: GLP-1 receptor agonists have shown improvements in liver enzymes and some histological markers in phase 2 trials, but whether they have a direct anti-fibrotic effect on the liver is still 'a matter of debate' [2][3]. The likely dominant mode of action is through weight loss, but if that's the case, then combining these drugs with agents that more directly target liver fibrosis (like FGF21 or pan-PPAR agonists) might be more effective [2]. That hypothesis remains untested in large trials.
Beyond the science, what practical gaps exist in getting these drugs to the people who need them?
Even if the scientific evidence gaps were closed, a major practical gap remains: supply and fair allocation. A 2024 perspective in the New England Journal of Medicine points out that shortages of GLP-1 receptor agonists and dual agonists are already happening, and there is no agreed-upon framework for how to allocate limited supplies [5]. This is not a biological evidence gap, but it is a real-world gap that holds back patient access. The authors propose a framework for governments and professional societies, but no such system is in place yet. So even when the drugs work, many patients cannot get them.
About These Sources
This answer is built on 5 peer-reviewed studies — published from 2023 to 2025, 3 from 2024 or later, 4 in Q1 journals, collectively cited 228 times — selected as the most relevant from 5 studies that passed quality screening, drawn from 40 papers retrieved from a database of over 500 million.
Sources used in this answer
Comparative efficacy of incretin drugs on glycemic control, body weight, and blood pressure in adults with overweight or obesity and with/without type 2 diabetes: a systematic review and network meta-analysis
In a network meta-analysis of 24 RCTs (9,165 participants), tirzepatide produced the largest weight loss (12.78 kg) and HbA1c reduction (1.87%) among dual/triple agonists, but long-term safety data beyond 12 weeks was not assessed.
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
This review highlights that it remains unclear whether GLP-1 receptor agonists have direct anti-fibrotic effects on the liver or work only indirectly through weight loss, and that the optimal ratio of glucagon to GLP-1 agonism in combination drugs is unknown.
Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists
This narrative review confirms that phase 2 trials of dual and triple incretin agonists show histological improvements in MASH, but the direct hepatoprotective mechanism versus indirect weight-loss-driven effects is still debated.
Retatrutide: a triple incretin receptor agonist for obesity management
Phase 2 data for retatrutide (triple agonist) shows dose-dependent weight loss and HbA1c reductions, but also dose-dependent heart rate increases and arrhythmias, making long-term cardiovascular outcome trials critical before widespread use.
Fair Allocation of GLP-1 and Dual GLP-1–GIP Receptor Agonists
This perspective article identifies a practical gap: shortages of GLP-1 and dual agonists are occurring, and no fair allocation framework exists to guide distribution of limited supplies.