What Are GLP-1 Receptor Agonists?
GLP-1 receptor agonists are a class of medications that mimic the natural gut hormone glucagon-like peptide-1. These drugs reduce appetite, slow gastric emptying, and improve insulin sensitivity, making them effective treatments for both Type 2 diabetes and obesity approved by the FDA.
Glucagon-like peptide-1 (GLP-1) is a hormone naturally produced in the small intestine after eating. It signals the brain to reduce hunger, tells the pancreas to release insulin, and slows the rate at which food leaves the stomach. In people with obesity or Type 2 diabetes, this signaling system often functions suboptimally. GLP-1 receptor agonists are synthetic versions of this hormone, engineered to resist breakdown in the body and last much longer than the natural hormone, which is degraded within minutes.
The first GLP-1 drug, exenatide (Byetta), was approved by the FDA in 2005 for Type 2 diabetes. Since then, the class has expanded dramatically. Semaglutide, developed by Novo Nordisk, became available as Ozempic for diabetes in 2017 and as Wegovy for weight management in 2021. Tirzepatide, made by Eli Lilly, is a dual GIP/GLP-1 receptor agonist approved as Mounjaro for diabetes in 2022 and as Zepbound for weight management in 2023. These newer agents produce substantially greater weight loss than earlier versions.
The mechanism of action involves multiple pathways. GLP-1 drugs act on receptors in the hypothalamus to reduce appetite and increase feelings of satiety. They slow gastric emptying, meaning food stays in the stomach longer, contributing to fullness. They also enhance glucose-dependent insulin secretion from pancreatic beta cells and suppress glucagon release, which improves blood sugar control. Tirzepatide additionally activates GIP receptors, which may explain its enhanced efficacy for weight loss compared to GLP-1-only drugs.
Semaglutide was first approved for Type 2 diabetes based on the SUSTAIN clinical trial program
How Effective Are GLP-1 Drugs for Weight Loss?
Clinical trials show GLP-1 drugs produce significant weight loss. Semaglutide 2.4 mg leads to approximately 15-17% body weight loss, while tirzepatide at the highest dose can achieve up to 22.5% weight loss over 72 weeks, far exceeding older weight loss medications.
The STEP 1 trial, published in the New England Journal of Medicine in 2021, enrolled 1,961 adults with obesity or overweight with at least one weight-related condition. Participants receiving semaglutide 2.4 mg weekly lost an average of 14.9% of their body weight over 68 weeks, compared to 2.4% in the placebo group. Approximately one-third of participants achieved weight loss of 20% or more, a threshold previously achievable only through bariatric surgery (Source: NEJM, Wilding et al., 2021).
Tirzepatide showed even more impressive results in the SURMOUNT-1 trial, also published in the New England Journal of Medicine. Among 2,539 adults with obesity, those receiving the highest dose (15 mg weekly) lost an average of 22.5% of their body weight over 72 weeks. More than one-third of participants on the highest dose lost 25% or more of their body weight, with some achieving weight loss comparable to gastric bypass surgery outcomes (Source: NEJM, Jastreboff et al., 2022).
Head-to-head comparison data is still emerging. The SURMOUNT-5 trial, which is currently expected to be fully reported, is the first randomized trial directly comparing tirzepatide with semaglutide for weight loss. Preliminary reports suggest tirzepatide may produce greater weight loss, but complete peer-reviewed data will provide more definitive answers. Both drugs represent a paradigm shift in obesity treatment, moving it from a lifestyle-only condition to one with effective pharmacological options.
It is important to note that these results come from clinical trial settings where participants also received lifestyle counseling including diet and exercise guidance. Real-world weight loss may be somewhat lower than trial results, as adherence and support structures differ outside of controlled research environments.
The STEP 1 trial demonstrated 14.9% mean body weight reduction with semaglutide
SURMOUNT-1 showed tirzepatide produced up to 22.5% weight loss
What Did the SELECT Trial Reveal About Heart Health?
The landmark SELECT trial demonstrated that semaglutide 2.4 mg reduced major adverse cardiovascular events by 20% in people with overweight or obesity and established cardiovascular disease, even independent of weight loss. This was the first obesity drug to show direct cardiovascular protection.
The SELECT trial (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity), published in the New England Journal of Medicine in 2023, was a game-changing study. It enrolled 17,604 adults aged 45 or older with a BMI of 27 or higher who had existing cardiovascular disease but not diabetes. Participants were randomized to receive semaglutide 2.4 mg or placebo weekly for a mean follow-up of 39.8 months. The primary endpoint was a composite of cardiovascular death, nonfatal heart attack, or nonfatal stroke (Source: NEJM, Lincoff et al., 2023).
The results were striking. Semaglutide reduced the primary composite endpoint by 20% compared to placebo (hazard ratio 0.80, 95% confidence interval 0.72-0.90, p<0.001). This cardiovascular benefit appeared to be at least partly independent of weight loss, suggesting that GLP-1 drugs may have direct anti-inflammatory and anti-atherosclerotic effects on blood vessels. The mean weight loss in the semaglutide group was 9.4% versus 0.9% in the placebo group.
Based on the SELECT trial results, the FDA approved a new indication for Wegovy in March 2024 to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight. This was a landmark regulatory decision, making semaglutide the first anti-obesity medication to receive a cardiovascular risk reduction indication, fundamentally changing how the medical community views the treatment of obesity.
The SELECT trial enrolled 17,604 participants and showed a 20% reduction in MACE
What Are the Side Effects of GLP-1 Drugs?
The most common side effects of GLP-1 drugs are gastrointestinal, including nausea, vomiting, diarrhea, and constipation. These typically occur during dose escalation and improve over time. Serious but rare risks include pancreatitis, gallbladder disease, and potential thyroid concerns.
Gastrointestinal side effects are the most frequently reported adverse events across all GLP-1 drug trials. In the STEP 1 trial, nausea occurred in 44% of semaglutide users versus 18% on placebo, diarrhea in 30% versus 16%, and vomiting in 25% versus 6%. These side effects are related to the drug's mechanism of slowing gastric emptying and are typically mild to moderate in severity. Most subside within the first 4-8 weeks, particularly when doses are escalated gradually as recommended.
More serious adverse events, while rare, require medical attention. Pancreatitis has been reported in approximately 0.2% of GLP-1 users. Gallbladder problems including gallstones and cholecystitis occur at higher rates in people losing weight rapidly, affecting roughly 2-3% of users in clinical trials. The FDA requires a boxed warning about the risk of thyroid C-cell tumors based on findings in rodent studies, though this risk has not been confirmed in humans after more than a decade of use.
There have been reports of rare but serious complications including gastroparesis (stomach paralysis), intestinal obstruction, and aspiration events related to delayed gastric emptying, particularly around surgical anesthesia. The American Society of Anesthesiologists has recommended that patients hold GLP-1 drugs before elective surgeries. Ongoing pharmacovigilance studies are monitoring for signals of suicidal ideation, though the FDA and EMA have not confirmed a causal link after reviewing available data.
- Nausea (40-44%): Most common; usually improves within 4-8 weeks
- Diarrhea (30%): Often transient during dose escalation
- Vomiting (25%): Managed by gradual dose titration
- Constipation (24%): Can be managed with dietary fiber and hydration
- Pancreatitis (<1%): Rare but serious; seek immediate medical attention for severe abdominal pain
- Gallbladder disease (2-3%): Higher risk with rapid weight loss
- Injection site reactions (5-10%): Mild redness, swelling, or itching
What Happens When You Stop Taking GLP-1 Drugs?
Research consistently shows that most people regain a substantial portion of lost weight after discontinuing GLP-1 drugs. The STEP 1 extension trial found that participants regained about two-thirds of their weight loss within one year of stopping semaglutide, supporting the view of obesity as a chronic disease.
The STEP 1 trial extension study, published in the journal Diabetes, Obesity and Metabolism in 2022, followed 327 participants for one year after they stopped taking semaglutide. During the initial 68-week treatment phase, participants had lost an average of 17.3% of their body weight. By one year after stopping, they had regained approximately two-thirds of that lost weight, returning to about 5.6% below their starting weight. Cardiometabolic improvements in blood pressure, lipids, and blood sugar also partially reversed.
This weight regain pattern is not unique to GLP-1 drugs. It reflects the biological reality that obesity involves persistent changes in appetite-regulating hormones, metabolic rate, and neural pathways. When the drug is removed, these biological drivers of weight regain reassert themselves. The American Medical Association, the Obesity Society, and the World Health Organization all classify obesity as a chronic disease requiring ongoing management, similar to how hypertension or Type 2 diabetes requires sustained treatment.
Researchers are investigating strategies to maintain weight loss after discontinuation, including transitioning to lower maintenance doses, combining medications, and intensive behavioral interventions. Some emerging data suggest that longer treatment duration before discontinuation may lead to less regain, but this has not been conclusively demonstrated in large trials. Currently, most clinical guidelines recommend continued treatment as long as the benefits outweigh the risks.
The STEP 1 extension showed participants regained two-thirds of lost weight within one year
How Do GLP-1 Drugs Compare to Bariatric Surgery?
Bariatric surgery still produces greater average weight loss (25-35%) compared to GLP-1 drugs (15-22%), but the gap is narrowing. GLP-1 drugs offer a less invasive alternative, though surgery provides more durable results and may be more cost-effective long-term for severe obesity.
Bariatric surgery, particularly gastric bypass and sleeve gastrectomy, has been the gold standard for treating severe obesity for decades, producing average total body weight loss of 25-35% that is largely maintained over 10-20 years. GLP-1 drugs represent the first pharmacological treatments to approach surgical-level weight loss, with tirzepatide achieving 22.5% in clinical trials. However, direct head-to-head randomized trials comparing these approaches are limited.
The advantages of GLP-1 drugs over surgery include non-invasiveness, reversibility, and lower immediate risk. They do not require hospitalization, general anesthesia, or permanent anatomical changes. However, the advantages of bariatric surgery include greater and more durable weight loss, potential diabetes remission rates exceeding 60-80%, and long-term cost-effectiveness since surgery is a one-time procedure while GLP-1 drugs require ongoing monthly costs of $1,000 or more.
Many obesity medicine specialists now view these treatments as complementary rather than competing options. Some patients may start with GLP-1 drugs and transition to surgery if needed, or vice versa. Some centers are exploring the combination of bariatric surgery and GLP-1 drugs for patients who experience insufficient weight loss or weight regain after surgery. The expanded treatment landscape means more patients can access effective obesity treatment tailored to their circumstances.
What New GLP-1 Drugs Are in Development?
Several next-generation GLP-1-based drugs are in clinical trials, including oral semaglutide for obesity, retatrutide (a triple-hormone agonist), and survodutide. Early trial data suggest these newer agents may produce even greater weight loss, potentially reaching 25-30% body weight reduction.
Novo Nordisk is developing an oral formulation of semaglutide for obesity (CagriSema combines semaglutide with cagrilintide, an amylin analog). The REDEFINE clinical trial program is testing this combination, with early results suggesting weight loss potentially exceeding that of injectable semaglutide alone. An effective oral alternative would remove the barrier of weekly injections and could dramatically expand the number of patients willing to use these medications.
Eli Lilly's retatrutide is a triple-hormone agonist that activates GLP-1, GIP, and glucagon receptors simultaneously. Phase 2 trial results published in the New England Journal of Medicine in 2023 showed remarkable efficacy, with participants on the highest dose losing an average of 24.2% of their body weight over 48 weeks, a rate that would likely exceed 30% at 72 weeks. Phase 3 trials are underway, and if confirmed, retatrutide could become the most effective anti-obesity medication ever developed (Source: NEJM, Jastreboff et al., 2023).
Other compounds in development include Boehringer Ingelheim's survodutide (a dual glucagon/GLP-1 agonist showing promise for fatty liver disease and obesity), Amgen's MariTide (a long-acting bispecific antibody requiring only monthly injections), and several companies developing small-molecule oral GLP-1 agonists that could be manufactured more cheaply than injectable peptides, potentially addressing the cost barrier.
Phase 2 data for retatrutide showed 24.2% weight loss at 48 weeks
Who Should Consider GLP-1 Drugs for Weight Management?
GLP-1 drugs for weight management are FDA-approved for adults with a BMI of 30 or higher, or 27 or higher with at least one weight-related condition such as Type 2 diabetes, hypertension, or high cholesterol. They should be combined with diet and exercise modifications.
The FDA's approved indications are based on BMI thresholds established by clinical trial enrollment criteria. Adults with a BMI of 30 or greater (classified as obesity) are eligible regardless of other conditions. Adults with a BMI of 27-29.9 (classified as overweight) qualify if they have at least one weight-related comorbidity such as Type 2 diabetes, hypertension, dyslipidemia, or obstructive sleep apnea. Following the SELECT trial, Wegovy also has an indication for cardiovascular risk reduction in adults with established cardiovascular disease and BMI over 27.
Not everyone who meets these criteria is an ideal candidate. GLP-1 drugs are contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN2 syndrome. They should be used with caution in patients with a history of pancreatitis, severe gastrointestinal disease, or gastroparesis. Women who are pregnant or planning to become pregnant should not use these medications, as there is insufficient safety data, and semaglutide should be stopped at least 2 months before a planned pregnancy.
The decision to start a GLP-1 drug should involve a thorough discussion between patient and provider about goals, expectations, side effects, cost, and the chronic nature of treatment. The American Association of Clinical Endocrinology (AACE) and the Obesity Society both recommend anti-obesity medications as part of a comprehensive treatment plan that includes nutritional counseling, physical activity, and behavioral support, not as a standalone solution.
What Are the Current Access and Cost Challenges?
GLP-1 drugs face significant access barriers including high costs ($1,000-1,300 monthly without insurance), insurance coverage variability, drug shortages, and global supply constraints. These challenges disproportionately affect lower-income patients and raise health equity concerns.
The list price for Wegovy in the United States is approximately $1,350 per month, and Zepbound costs roughly $1,060 per month without insurance. While many commercial insurance plans now cover these medications, coverage varies widely and often requires prior authorization, step therapy (trying cheaper options first), or documentation of failed lifestyle interventions. Medicare currently does not cover anti-obesity medications, excluding millions of older adults, though legislative efforts to change this are underway in Congress.
Global demand has far exceeded manufacturing capacity, leading to widespread drug shortages. The FDA maintained semaglutide on its drug shortage list through much of 2023 and 2024, and supply issues have affected patients who started treatment and then could not refill prescriptions. Both Novo Nordisk and Eli Lilly have invested billions in new manufacturing facilities, but scaling production of these complex peptide drugs takes years. Compounding pharmacies have stepped in to fill demand, though the FDA has raised quality concerns about compounded versions.
Health equity advocates point out that the high cost and access barriers mean these medications are disproportionately available to wealthier, commercially insured patients. Obesity disproportionately affects Black, Hispanic, and lower-income communities in the United States, yet these populations face the greatest barriers to accessing treatment. Efforts to address this include state-level mandates for insurance coverage, manufacturer patient assistance programs, and advocacy for Medicare coverage expansion.
What Does the Future Hold for GLP-1 Drugs in Medicine?
GLP-1 drugs are being investigated for applications far beyond weight loss, including Alzheimer's disease, addiction, non-alcoholic fatty liver disease, sleep apnea, and polycystic kidney disease. The class is poised to become one of the most broadly prescribed medication categories in history.
The potential applications of GLP-1 receptor agonists continue to expand as researchers discover GLP-1 receptors throughout the body, not just in the gut and pancreas. Active clinical trials are investigating semaglutide and other GLP-1 drugs for non-alcoholic steatohepatitis (MASH/NASH), where early results show significant liver fat reduction and potential reversal of fibrosis. The STEP-HFpEF trial demonstrated that semaglutide improved symptoms and physical function in patients with heart failure and obesity, opening another major therapeutic area.
Perhaps the most intriguing frontier is neurology. GLP-1 receptors are expressed in brain regions involved in neurodegeneration, and preclinical studies have shown anti-inflammatory and neuroprotective effects. Multiple clinical trials are now testing semaglutide and liraglutide for Alzheimer's disease and Parkinson's disease. Additionally, early research suggests GLP-1 drugs may reduce addictive behaviors related to alcohol, nicotine, and other substances by acting on reward pathways in the brain, though this remains in early investigational stages.
Goldman Sachs has estimated that the GLP-1 drug market could reach $100 billion in annual sales by 2030, making it one of the largest drug categories in pharmaceutical history. As manufacturing scales up, prices may decrease, and as patent protections expire in the 2030s, generic versions could dramatically improve access. The GLP-1 revolution represents a fundamental shift in how medicine approaches obesity, from a condition of willpower to a treatable chronic disease with biological underpinnings.
The STEP-HFpEF trial showed semaglutide benefits in heart failure with preserved ejection fraction
