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Prioritization of GLP1-RA and Dual Agonists in an Era of Shortages

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As expected, the American Diabetes Association (ADA)’s 84th Scientific Sessions included many sessions about glucagon-like peptide-1 receptor agonists (GLP1-RAs, like liraglutide, dulaglutide, and semaglutide) and dual agonists (like tirzepatide), including results from the much-anticipated SELECT and FLOW trials and reports on safety and effectiveness in new populations from a variety of observational and pharmacoepidemiologic studies.

However, the overarching GLP1-RA-related theme that emerged from the conference was a growing tension between the overwhelming efficacy of the drugs for a wide variety of indications and the cost- and supply-related limitations in their use. This was reflected in numerous conversations on the role of GLP1s, particularly in populations for whom older and more cost-effective medications are currently available. 

Regarding diabetes prevention, Drs. David Marrero and Ildiko Lingvay debated whether the Diabetes Prevention Program (DPP; an intensive lifestyle intervention proven to delay progression from impaired glucose tolerance to overt diabetes) or GLP1-RA should be the primary therapy to prevent diabetes in high-risk populations. Dr. Lingvay argued that GLP1-RA have growing evidence to support superior efficacy, durability (albeit comparing continuous medication use to a time-limited intervention), and secondary benefits related to cardiometabolic health compared to the DPP. Dr. Marrero agreed but highlighted the much longer outcomes observed during follow-up from the DPP and the many limitations to GP1-RA access at present, particularly in underserved populations. Ultimately, the speakers agreed that in an ideal world, all patients would have access to both highly effective therapies, as well as the option of bariatric surgery, but that current resource constraints do not support this level of care.

Regarding first-line therapy, or rather initial goals for the treatment of new-onset diabetes, panelists debated the relative merits of an obesity treatment-first approach versus more traditional strategies focused on glycemic control and prevention of complications. Drs. Ania Jastreboff and Roy Taylor provided the rationale for early treatment of obesity, focusing on the many systemic benefits of obesity treatment beyond improved diabetes management and the possibility of remission. Drs. Roopa Mehta and David Nathan then provided the counter-argument focused on early glycemic control, highlighting that the vast majority of the medical literature showing improvements in diabetes outcomes has occurred in studies prioritizing glycemic control and that early glycemic control, in particular, is associated with a legacy effect resulting in reduced diabetes complications over decades.

Regarding management of established diabetes, a debate between Drs. Elbert Huang and Deborah Wexler focused on whether sulfonylureas remain a relevant therapy and included a heavy focus on comparing efficacy, safety, secondary benefits, and side effects of sulfonylureas with novel medications, including GLP1-RAs and dual agonists. Dr. Huang highlighted the efficacy, safety, and cost-effectiveness of sulfonylureas, while Dr. Wexler highlighted results from the GRADE trial showing liraglutide, as compared to glimepiride, was associated with greater time to glycemic failure, reduced hypoglycemia, greater weight loss, and reduced cardiovascular events even in a low-risk population.

Regarding new populations who may benefit from these medications, an ePoster theater – which was notably packed, with a dozen people sitting along the edges and three rows of people standing in the back – presented “real-world” data for GLP1-RA and tirzepatide use in individuals not included in clinical trials. Two posters reported observational results of semaglutide and/or tirzepatide use in adults with type 1 diabetes and obesity, both finding positive effects on weight, glycemic control, and total daily dose of insulin. Another poster found that GLP1-RA improved healthcare utilization, renal outcomes, and mortality among individuals with advanced chronic kidney disease (eGFR <45 mL/min/1.73m2). Lastly, a presentation (notably from Eli Lilly) reported on real-world effects of tirzepatide, finding significant improvements in both A1c and weight in new-users as well as those transitioning from a GLP1-RA to tirzepatide, almost half of whom lost an additional 5% body weight. In a subsequent presentation from the Public Health and Epidemiology interest group, Drs. Megan Oberle Bensignor and Mary Ellen Vajravelu reviewed the growing data around GLP1-RA in youth-onset type 2 diabetes, highlighting similar short-term glycemic effects but as yet limited data regarding weight management compared to adult populations.

A formal debate addressed the topic of prioritizing patient populations for GLP1-RA use given the reality of limited medication supply. Dr. Deborah Horn argued that those who had previously experienced success with the medicine should be prioritized to continue, highlighting multiple studies showing regression not only of weight but also of cardiometabolic risk factors upon discontinuation of the medicine. Dr. Pam Taub argued the perspective that limited supplies should be directed towards those with overweight or obesity and cardiovascular disease, sharing data from the recent SELECT trial and presented an overall message of the need to rebrand GLP1-RA not as obesity medications but as treatments for cardiometabolic disease that address many health conditions aside from weight alone. Lastly, Dr. Neda Rasouli argued that limited GLP1-RA supply should be directed towards those with class 3 obesity, particularly younger individuals who stand to receive the greatest absolute improvement in life-years gained. Following rebuttals, Dr. William Herman presented the sobering cost-effectiveness perspective – compared to phentermine-topiramate, a relatively established and inexpensive weight loss medication, none of these novel therapies even approach cost effectiveness.

Finally, in the last session of the conference, the gross inequities with which these medications are used was confronted. Drs. Utibe Essien and Kristina Lewis shared the available data concerning pharmacoequity, or rather, pharmco-inequity, of GLP1-RA and other anti-obesity medication use, revealing significant underprescribing of these medications (1-5% of eligible individuals receive any anti-obesity prescription) as well as major racial, ethnic, socioeconomic, regional, and insurance-related disparities in their use. Dr. Lewis highlighted the need to improve education and reduce stigma among both patients and providers and to practice “anti-obesity medicine stewardship” (not necessarily jumping to the most powerful and expensive option when another option may be sufficient) while all agreed that major policy changes are needed to improve access to and equity of obesity care.

In sum, the zeitgeist of the 2024 ADA Scientific Sessions included a heavy focus on GLP1-RA and dual agonist use, mirroring the national conversation on growing indications, cost, and shortages of these medications. Throughout, presenters agreed that an ideal world would provide these medications for a wide range of individuals, in addition to previously effective and more cost-effective therapies such as lifestyle interventions, alternative medications for weight loss, and bariatric surgery. Until the time when these medications are both affordable and available, however, the conversation about their ideal place in medical care for diabetes, obesity, cardiovascular disease, renal disease, and a variety of other diseases remains in debate.

Dr. Cromer has received grants from the American Diabetes Association and consulting fees from Patient Square Capital and Alexion Pharmaceuticals. She has recieved fees for participation from Boston University and writing fees from Wolters-Kluwer. Her spouse is employed by Spouse employed by Depuy-Synthes.

Image by SDI Productions / Getty Images

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