Within two decades, glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications have become mainstays in type 2 diabetes (T2D) management, as well as disruptive forces in obesity treatment and cardiometabolic prevention. Also known as GLP-1 analogs or incretin memetics, GLP-1 RA medications—such as semaglutide (Ozempic, Wegovy, Rybelsus), dulaglutide (Trulicity), tirzepatide (Mounjaro), and liraglutide (Victoza, Saxenda)—mimic the metabolic effects of GLP-1, a natural human hormone that stimulates secretion of glucose and enhances feelings of satiety after ingestion (1). Some data estimate that around 4% of U.S. patients use GLP-1 RAs, but experts forecast that this proportion will change over the next 5 years due to upcoming changes in approved indications and adherence concerns (2, 3).
GLP-1 medication development began in the 1980s, after discoveries of the GLP-1 hormone inspired early T2D clinical trials (4). However, rapid renal clearance and dipeptidyl peptidase-4 (DPP-4) degradation restrain the half-life of endogenous GLP-1 to 1 to 2 minutes, which limited the success of early, wildtype therapeutic strategies (4, 5). Eventually, in the 1990s, AstraZeneca developed twice-daily, injectable exenatide (Byetta), averting the problem of low bioavailability by using a DPP-4-resistant GLP-1 receptor agonist derived from Gila monster saliva (4, 6). After its approval by the Food and Drug Administration (FDA) in 2006 as an adjunct T2D medication, exenatide’s comparatively variable efficacy and poor tolerability resulted in its discontinuation in 2025, yet its formulation motivated other manufacturers to pursue DPP-4-resistant or renal-avoidant GLP-1 strategies (6, 7).
Soon after exenatide entered the market, a wave of FDA-approved T2D bioengineered peptides emerged—including liraglutide (Victoza) in 2010, dulaglutide (Trulicity) in 2014, and semaglutide (Ozempic) in 2017—each of which boasted longer bioavailability, higher tolerability, and greater efficacy, with fewer injections per day (4, 6). By the late 2010s, clinical practice guidelines recommended several GLP-1 RAs as second-line T2D therapies, leading to gradual increase in annual users from around 3% of T2D patients in 2015 to nearly 10% in 2022 (8-10).
Amid the flurry to develop longer-acting GLP-1 medications in the 1990s and 2010s, drug manufacturers quietly uncovered an unexpected side effect: weight loss (11, 12). Initially deemed an off-target effect, significant dose-dependent weight loss occurred alongside improved glycemic control in the majority of diabetic GLP-1 clinical trial participants and post-market users (4, 11-13). Consequently, between 2014 and 2023, four GLP-1 medications—higher-dose liraglutide (Saxenda), semaglutides (Wegovy, Ozempic), and tirzepatide (Zepbound)—gained both FDA approval and off-label popularity for weight management (2, 10, 13, 14). A similar phenomenon occurred after observations of lower cardiovascular and renal events in clinical trials, leading to the approval of four GLP-1 RAs for cardiometabolic risk prevention and one for renal disease prevention (15). Other indications, such as polycystic ovarian syndrome (PCOS), Parkinson’s disease, and liver disease, drive off-label prescriptions, with promising preliminary results, despite representing small proportions of overall GLP-1 RA users (15).
However, patient adherence to GLP-1 RAs is an area of concern, primarily related to access and cost. First, concerns regarding appropriate treatment practices surfaced after obesity-related GLP-1 RA prescriptions surged, leading to a widespread shortage between 2022 and 2024 (16, 17). Currently, although T2D remains a primary indication for all GLP-1 RAs except Wegovy, T2D patients composed only 71% of total users in 2023, compared to 88% in 2019 (3). To avert future shortages and focus on high-risk patients, strategies recommend prioritizing GLP-1 RA prescriptions for T2D as the pharmaceutical supply chain recovers (16). Second, with average out-of-pocket monthly GLP-1 costs varying from roughly $375 to $900, financial constraints also limit adherence, often with significant consequences, such as hospitalizations and emergency department visits for T2D patients, as well as weight regain for overweight or obese patients (17, 18).
Upcoming generic GLP-1 RA medications, new therapeutic delivery strategies, and clinical study results lead to a forecast of decreased costs, increased adherence, and greater clarity for patients and providers (19, 20). Although most insurance plans have gradually increased coverage for GLP-1 RAs in recent years and one generic version entered the market in 2024, substantial cost decreases will remain delayed until the addition of two to three additional options, likely in 2026 (19, 20). Second, several drug manufacturers have begun developing oral GLP-1 RA options, which will likely appear at lower prices due to reduced production costs and increased competition, starting around 2026 (21, 22). Finally, the results of long-term follow-up studies in patients with cardiovascular, renal and other diseases will provide further insight into appropriate uses (22, 23). Overall, pending these changes, the forecast for GLP-1 RA medications is promising, with the potential to improve the health and quality of life for more patients.
References
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