Our recent webinar on Drugs to Watch 2026: Navigating the next wave of GLP-1 evolution and beyond drew some excellent audience questions. Expert Clarivate analysts Carles Recasens and Shambhavi Shukla provide their answers here.
Retatrutide:
Efficacy vs. currently available medications
Q: How does the weight loss achieved with retatrutide compare with currently available medications in terms of lean mass loss as a proportion of total weight loss?
A: Retatrutide appears to cause a similar proportion of lean mass loss relative to total weight lost compared with current GLP-1 drugs. In a body composition substudy in people with type 2 diabetes and obesity (PMID: 40609566), retatrutide produced a lean mass loss of about 38% of total weight loss, which falls within the 20–40% range reported for other GLP‑1–based therapies such as semaglutide and tirzepatide (see PMID: 40609564; 39344838). These findings suggest that retatrutide’s greater weight loss efficacy does not come at the cost of a higher lean mass percentage.
From a clinical perspective, the main consideration with retatrutide—and potential concern—is therefore not the proportion of lean mass lost, but the absolute amount. Because overall weight reduction with retatrutide is greater than with other GLP-1 therapies, the absolute loss of lean mass may also be more substantial, which could have important implications in older, frail, and other high-risk patient populations.
Muscle maintenance
Q: Muscle maintenance is increasingly of concern in the GLP-1 era. How do you expect companies to adapt? Will muscle preservation or functional improvement become its own drug development category, or will it remain mostly an add-on to incretin therapy?
A: The approach to muscle preservation hinges on one key driver: determining whether the muscle loss observed with GLP-1 therapy is an expected physiological adaptation to any caloric deficit, or clinically significant and potentially pathological in certain cases. If pathological in specific settings, identifying the underlying causes and high-risk patient groups becomes essential.
Once these high-risk groups are clearly defined—for example, individuals with reduced mobility or sarcopenic obesity—clinical management will likely first focus on optimizing lifestyle measures such as resistance training and adequate protein intake, before introducing additional pharmacological interventions such as emerging muscle-sparing drugs.
Within this framework, muscle-sparing drugs would initially serve as add-ons to GLP-1 or amylin-based therapies to improve outcomes in high-risk patients, rather than standalone drugs. In the coming years, we expect clearer definitions and stratification of these patient groups and precise thresholds for pathological muscle loss and functional decline among GLP-1-treated patients. In parallel, drug developers running trials in frail and vulnerable cohorts with endpoints assessing muscle quality, strength, and functional performance will be valuable to position muscle preservation as an important differentiator in obesity therapy design.
Market potential for a triple agonist
Q: Retatrutide looks like it will be able to claim the greatest weight loss at launch. However, what proportion of the market do you think will realistically be treated with a triple agonist? Perhaps only those with severe obesity? And once there is greater availability, choice and access to simpler obesity drugs, will this segment be substantially diminished?
A: We expect retatrutide to primarily serve patients who do not achieve sufficient weight loss with current GLP-1–based therapies, particularly those with high cardiometabolic risk.
Even with tirzepatide, a substantial proportion of patients remain underserved. This includes individuals at the higher end of the BMI spectrum, such as those with class 2 or class 3 obesity, as well as patients with type 2 diabetes and obesity who tend to be more metabolically resistant to weight loss. This creates a clear opportunity for a step-up treatment approach. If retatrutide demonstrates clear superiority to tirzepatide in the right patients, it could become a natural intensification option for patients who do not meet their weight or metabolic goals.
The severe obesity segment is unlikely to shrink meaningfully over time. The population remains large, and lower-efficacy therapies will not be sufficient to meet the need for greater weight reduction. For example, in the United States, around 50% of obesity patients have class 2 or class 3 obesity. These individuals may require approximately 30–45% weight loss to achieve a normal BMI. Based on categorical weight loss data from the Phase 3 TRIUMPH-4 trial, even retatrutide may not fully address this unmet need in more severe populations. This indicates that highly efficacious therapies will remain relevant, even as simpler and more accessible obesity drugs become more widely available.
Orforglipron:
Trypanophobia
Q: When orforglipron becomes available, will we see increased use among patients who are uncomfortable with injections?
A: Yes, we expect increased use of orforglipron among patients who are uncomfortable with injections.
It is important to note that orforglipron’s use will not be driven solely by its oral formulation. Oral semaglutide (Rybelsus) has been on the market for a few years now; however, its use in type 2 diabetes remains limited, and patient share has not meaningfully shifted from injectable GLP-1 RAs to oral semaglutide. This limited adoption is largely due to the strict dosing requirements associated with oral semaglutide. These constraints—combined with the positive results from the head‑to‑head ACHIEVE‑3 study—are where orforglipron holds a clear advantage over oral semaglutide. In the obesity market, the approval of oral semaglutide (Wegovy pill) is relatively recent, and prescribing patterns are still evolving.
That said, orfrglipron’s market penetration will vary by indication. We expect its uptake will be stronger in the obesity market, which is an oral-centric indication, and where orforglipron’s formulation and dosing advantages position it favorably over injectable GLP‑1s as well as over oral semaglutide.
In contrast, injection phobia is not a major determinant of drug choice in the type 2 diabetes market. As the disease progresses, many patients eventually transition to insulin for long-term management. Moreover, injectable GLP-1 RA products have been used for many years, and both physicians and patients are comfortable with these therapies. This reduces the relative importance of injection avoidance. Consequently, while orforglipron may broaden the use of oral GLP-1-based drugs at earlier stages of treatment, the overall impact on the use of injectable GLP-1 RA products in diabetes is expected to be modest.
Over time, orforglipron use will broaden through selective switching from injectables—mainly among patients who struggle with adherence to injectable regimens or who are reluctant to continue long-term injections for weight maintenance purposes.
Impact on incumbent GLP-1s
Q: How is orforglipron likely to affect the market for first and second-generation treatments within the GLP-1 RA drug class?
A: First-generation GLP-1 RA products, such as exenatide and lixisenatide, have already experienced a sharp decline as physicians increasingly favor second-generation agents, like subcutaneous semaglutide and tirzepatide, with stronger efficacy and more convenient dosing. Launch of orforglipron will further reinforce this shift by drawing additional use away from older products, particularly among patients and clinicians seeking oral options over daily injectables that offer modest efficacy.
However, second-generation injectable GLP‑1-based therapies have strong clinical profiles and have penetrated very well across type 2 diabetes and obesity markets. Although oral options offer dosing convenience, newer and highly efficacious injectable formulations will remain dominant within the class in both markets.
Orals vs. generic GLP-1s
Q: Speaking strictly of the type 2 diabetes space, how do you foresee orals, especially orforglipron, faring once generics of semaglutide become available and retatrutide has established itself by 2031-2032?
A: In an efficacy-led market like type 2 diabetes, we expect orforglipron to hold a conservative position relative to injectables as generic semaglutide enters and retatrutide becomes established.
Prescribing in type 2 diabetes remains anchored to therapies that deliver strong outcomes across glycemic and non‑glycemic goals; accordingly, tirzepatide will continue to dominate, with retatrutide reinforcing injectable leadership after launch.
While orforglipron is likely to lead the oral segment in the type 2 diabetes market, owing to its fasting free dosing and head-to-head advantage over oral semaglutide, orals are expected to remain a minority of class use. Market developments, including the availability of generic semaglutide and a strong uptake of next-generation injectables such as retatrutide, will further constrain the expansion of oral GLP-1-based therapies.
Notably, the entry of liraglutide generics did not drive meaningful growth in that therapy’s use, indicating that lower price alone is unlikely to displace higher efficacy options in the type 2 diabetes market; similarly, generic semaglutide is expected to mainly offset its forecast decline by 2030–2031, while the class remains injectable centric—with tirzepatide leading near term and retatrutide gradually taking the top position a few years postlaunch.
Clarivate analysts Shambhavi Shukla, Lead Healthcare Research and Data Analyst (on orforglipron), and Carles Rescasens, Healthcare Research and Data Analyst (on retatrutide), contributed the answers to these audience questions and featured in this webinar.
This webinar was the first in a series on our 2026 Drugs to Watch. Learn more or register for on demand and future webinars in this series here.
To learn more about how Cortellis Competitive Intelligence helps life science innovators see around corners and beat competitors to early-stage assets, please visit: Cortellis Pharma Competitive Intelligence | Clarivate
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