What does 'beyond short-term biomarkers' actually mean?
Short-term biomarkers are things like blood sugar (HbA1c), body weight, or blood pressure — numbers that change quickly and predict future disease risk. 'Beyond' means actual clinical outcomes: fewer heart attacks, less liver scarring, better survival, or reversal of disease. The dual and triple incretin drugs show strong effects on biomarkers, and some evidence they improve intermediate outcomes like fatty liver disease and prediabetes reversal, but proof of long-term hard outcomes is still emerging.
For instance, in the REDEFINE 1 trial of CagriSema (a dual GLP-1/amylin agonist), 87.7% of patients with prediabetes achieved normal blood sugar — that's a reversal of a pre-disease state, not just a biomarker change [1]. Similarly, in MASLD (fatty liver disease), dual and triple agonists have shown histological improvements in phase 2 trials, meaning actual liver tissue looks healthier, not just blood tests [2][4]. These are steps beyond simple biomarkers, but they are still intermediate endpoints.
How much improvement do these drugs deliver, and for whom?
The weight loss from dual and triple drugs can approach bariatric surgery levels. CagriSema produced mean weight reductions of 20.4-22.7% over 68 weeks, with 53.6% of patients losing at least 20% of their body weight and 34.7% losing at least 25% [1]. For context, 20% weight loss is typically only seen with surgery. In people with type 2 diabetes, the same drug achieved 15.7% weight loss and 73.5% reached an HbA1c of 6.5% or lower (a normal range) [1]. The triple agonist retatrutide showed dose-dependent weight loss and HbA1c reductions in phase 2 trials, though the active comparator was a low dose of dulaglutide (1.5 mg, not the highest approved 4.5 mg), so the comparison is not fully fair [6].
These benefits extend to liver health. A review of incretin-based therapies for MASLD/MASH found that dual GLP-1/GIP agonists (like tirzepatide) and triple GLP-1/GIP/glucagon agonists (like retatrutide) improved liver histology in phase 2 trials, with benefits on weight and insulin resistance likely driving the effect [2][4]. However, whether the drugs have a direct liver effect or work indirectly through weight loss is still debated [4].
What are the caveats and what don't we know yet?
The biggest caveat is the lack of long-term cardiovascular outcome trials (CVOTs) for the newer dual and triple drugs. Retatrutide, a triple agonist, caused a dose-dependent increase in heart rate and mild to moderate cardiac arrhythmias in phase 2 trials, raising cardiovascular safety concerns that require dedicated long-term studies [6]. For CagriSema, while the weight loss is impressive, the safety profile is consistent with GLP-1 drugs — mainly transient gastrointestinal side effects like nausea (55% of patients), though discontinuation rates were low at 6-8.4% [1].
Another unknown is the optimal ratio of receptor activation. For dual GLP-1/glucagon agonists, there is uncertainty about whether GIP agonism or antagonism is better, and the ideal balance of glucagon to GLP-1 activity [4]. Additionally, the cost and potential drug-drug interactions of combining multiple gut hormone agonists with other agents (like FGF21 or PPAR agonists) need evaluation [4]. Finally, while incretin drugs show promise for conditions like sleep apnea, cognitive decline, and bone disorders, the evidence is still emerging and not yet definitive [3].
About These Sources
This answer is built on 6 peer-reviewed studies — published from 2023 to 2025, 3 from 2024 or later, 3 in Q1 journals, collectively cited 346 times — selected as the most relevant from 7 studies that passed quality screening, drawn from 46 papers retrieved from a database of over 500 million.
Sources used in this answer
The next frontier in metabolic health: Cagrilintide-Semaglutide and the evolving landscape of therapies
In the REDEFINE 1 and 2 trials, the dual GLP-1/amylin agonist CagriSema achieved mean weight reductions of 20.4-22.7% (overweight/obesity without diabetes) and 15.7% (with type 2 diabetes), with 87.7% of prediabetic patients achieving normoglycemia, and improved blood pressure, lipids, and C-reactive protein.
Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists
A narrative review of incretin-based therapies for MASLD/MASH found that dual and triple agonists (GLP-1/GIP/glucagon) show histological improvements in phase 2 trials, with benefits on weight and insulin resistance, but direct hepatoprotective mechanisms remain unclear.
Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities
A review of multifunctional incretin peptides (2023-2025) confirms that tirzepatide and semaglutide reduce glucose and weight across diverse populations, and emerging evidence suggests benefits for fatty liver disease, chronic inflammation, sleep apnea, and possibly cognitive decline, though long-term data are limited.
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
A review of incretin drugs for MASH notes that GLP-1RAs improve liver histology in phase 2/3 trials, but whether effects are direct or via weight loss is debated; dual/triple agonists show promise but optimal receptor ratios and side-effect burdens need further study.
Incretin hormones and type 2 diabetes
A review of incretin hormones in type 2 diabetes explains that the reduced incretin effect in diabetes is due to impaired GIP insulinotropic activity, while GLP-1 retains potency; tirzepatide (GIP/GLP-1 co-agonist) reduces HbA1c and weight more than selective GLP-1RAs.
Retatrutide: a triple incretin receptor agonist for obesity management
In phase 2 trials, the triple agonist retatrutide produced dose-dependent weight loss and HbA1c reductions in type 2 diabetes, but dose-dependent heart rate increases and mild cardiac arrhythmias raise cardiovascular safety concerns, making long-term CVOTs critical.