What Are GLP-1 Agonists? A Complete Guide

GLP-1 (glucagon-like peptide-1) is an incretin hormone produced by L-cells in the small intestine in response to food intake. It plays a central role in metabolic regulation through multiple pathways:

• Appetite regulation: GLP-1 activates receptors in the hypothalamus and brainstem to reduce hunger and increase feelings of fullness
• Insulin secretion: Stimulates glucose-dependent insulin release from pancreatic beta cells — meaning it enhances insulin only when blood sugar is elevated
• Glucagon suppression: Reduces inappropriate glucagon secretion from alpha cells, helping to lower blood glucose
• Gastric emptying: Slows the rate at which food leaves the stomach, prolonging satiety and reducing post-meal blood sugar spikes

The problem with native GLP-1 is that it is rapidly degraded by the enzyme DPP-4, giving it a half-life of only about 2 minutes. This makes it impractical as a medication. GLP-1 agonists are synthetic analogs engineered with structural modifications that resist DPP-4 degradation and extend the half-life from minutes to days — enabling once-weekly or once-daily dosing with sustained therapeutic effect.

GLP-1 agonists bind to and activate GLP-1 receptors throughout the body. Their therapeutic effects stem from receptor activation in three key areas:

Brain (Hypothalamus and Brainstem)

GLP-1 receptors in the arcuate nucleus and area postrema mediate appetite suppression. Activation of these receptors reduces hunger signals and increases satiety, leading to reduced caloric intake. Brain imaging studies show that GLP-1 agonists reduce activity in brain regions associated with food reward and craving.

Pancreas

GLP-1 receptor activation on beta cells enhances insulin secretion in a glucose-dependent manner — meaning insulin is released only when blood sugar is elevated. This reduces the risk of hypoglycemia compared to insulin or sulfonylureas. GLP-1 agonists also suppress inappropriate glucagon release from alpha cells.

Gastrointestinal Tract

GLP-1 agonists slow gastric emptying, which prolongs the sensation of fullness after meals and flattens post-meal glucose spikes. This delayed gastric emptying is also responsible for the most common side effect — nausea — particularly during the initial weeks of treatment.

The combination of reduced appetite, improved insulin sensitivity, and slower gastric emptying produces the substantial weight loss seen in clinical trials. Importantly, these effects work through the body's existing hormonal signaling pathways rather than through stimulant or thermogenic mechanisms.

Three GLP-1-based medications currently have FDA approval for weight management and/or type 2 diabetes:

Semaglutide (Ozempic, Wegovy, Rybelsus)

Semaglutide is the most widely prescribed GLP-1 agonist. Developed by Novo Nordisk, it is a GLP-1 receptor agonist with 94% homology to native human GLP-1 and an albumin-binding fatty acid chain that extends its half-life to approximately 7 days.

• Ozempic: Injectable, approved for type 2 diabetes (0.5–1 mg weekly)
• Wegovy: Injectable, approved for chronic weight management (2.4 mg weekly)
• Rybelsus: Oral tablet, approved for type 2 diabetes (7–14 mg daily)
• Wegovy pill: Oral tablet approved December 2025 for weight management (25 mg daily) — the first oral GLP-1 for obesity

In the landmark STEP 1 trial, semaglutide 2.4 mg produced mean weight loss of 14.9% over 68 weeks (Wilding et al., NEJM 2021). The SELECT trial demonstrated a 20% reduction in major adverse cardiovascular events in obese patients without diabetes — establishing benefits beyond weight loss.

The OASIS 1 trial showed that oral semaglutide 50 mg achieved 15.1% mean weight loss — approaching the efficacy of the injectable formulation and eliminating the need for injections (Knop et al., The Lancet 2023).

Tirzepatide (Mounjaro, Zepbound)

Tirzepatide is the first dual GLP-1/GIP receptor agonist. Developed by Eli Lilly, it simultaneously activates both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors, producing greater weight loss than GLP-1-only agonists.

• Mounjaro: Approved for type 2 diabetes (2.5–15 mg weekly)
• Zepbound: Approved for chronic weight management (2.5–15 mg weekly)

The SURMOUNT-1 trial demonstrated up to 22.5% mean weight loss at the 15 mg dose over 72 weeks — with 57% of participants losing more than 20% of their body weight (Jastreboff et al., NEJM 2022). In the head-to-head SURMOUNT-5 trial, tirzepatide 15 mg produced 20.2% weight loss versus 13.7% for semaglutide 2.4 mg, establishing tirzepatide as the more effective approved option.

Liraglutide (Victoza, Saxenda)

Liraglutide was the first GLP-1 agonist approved specifically for obesity (as Saxenda, 2014). Also developed by Novo Nordisk, it requires daily dosing due to its shorter ~13-hour half-life.

• Victoza: Approved for type 2 diabetes (1.2–1.8 mg daily)
• Saxenda: Approved for weight management (3.0 mg daily)

Clinical trials demonstrated approximately 8% mean body weight loss with Saxenda — effective but substantially less than semaglutide or tirzepatide. The LEADER trial showed a 13% reduction in major adverse cardiovascular events in type 2 diabetes patients (Marso et al., NEJM 2016). Liraglutide remains relevant for patients who prefer daily dosing or need faster dose titration.

Several next-generation compounds build on the GLP-1 mechanism by adding additional receptor targets:

Retatrutide — Triple Agonist (GLP-1/GIP/Glucagon)

Retatrutide (LY3437943) is the first triple receptor agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. Developed by Eli Lilly, it is currently in Phase 3 clinical trials.

In the Phase 2 obesity trial, retatrutide at 12 mg produced 24.2% mean body weight loss over 48 weeks — the highest weight loss ever recorded for any anti-obesity medication in controlled trials (Jastreboff et al., NEJM 2023). The added glucagon receptor activation increases energy expenditure and drives dramatic liver fat reduction (up to 82% in participants with NAFLD).

Survodutide — Dual Agonist (GLP-1/Glucagon)

Survodutide (BI 456906) is a dual GLP-1/glucagon receptor agonist developed by Boehringer Ingelheim. Phase 2 trials demonstrated up to 18.7% body weight loss and significant improvements in liver histology in patients with MASH (metabolic dysfunction-associated steatohepatitis).

A Phase 2 randomized trial in patients with biopsy-confirmed MASH showed that 62% of participants on the 4.8 mg dose achieved MASH improvement with no worsening of fibrosis, compared to 14% on placebo (Sanyal et al., NEJM 2024). Survodutide received FDA Breakthrough Therapy designation for MASH in September 2024.

Mazdutide — Dual Agonist (GLP-1/Glucagon)

Mazdutide (LY3305677/IBI362) is a dual GLP-1/glucagon receptor agonist developed by Eli Lilly and Innovent Biologics. Phase 3 trials, primarily conducted in China, have shown 10–15% body weight loss over 24–48 weeks. Like survodutide, the glucagon component promotes liver fat oxidation and increased energy expenditure.

Cagrilintide and CagriSema

Cagrilintide is a long-acting amylin analog developed by Novo Nordisk. While not a GLP-1 agonist itself, it is studied primarily in combination with semaglutide as CagriSema — a fixed-dose injection combining amylin and GLP-1 signaling.

The Phase 3 REDEFINE 1 trial demonstrated 22.7% mean weight loss with CagriSema in adults with obesity, with 40.4% of participants achieving 25% or greater weight loss. Novo Nordisk submitted an NDA to the FDA in 2025, with regulatory review expected in 2026.

The evolution of GLP-1-based therapies follows a clear trajectory — adding receptor targets for greater efficacy:

Generation	Targets	Examples	Max Trial Weight Loss
Single agonist	GLP-1	Semaglutide, liraglutide	~15–17%
Dual agonist (GLP-1/GIP)	GLP-1 + GIP	Tirzepatide	~22.5%
Dual agonist (GLP-1/glucagon)	GLP-1 + glucagon	Survodutide, mazdutide	~18.7%
Triple agonist	GLP-1 + GIP + glucagon	Retatrutide	~24.2%
Amylin + GLP-1 combo	Amylin + GLP-1	CagriSema	~22.7%

Each added receptor target contributes distinct metabolic benefits:

• GIP agonism (as in tirzepatide): Enhances insulin sensitivity in adipose tissue, improves fat metabolism, and may reduce GLP-1-related nausea
• Glucagon agonism (as in retatrutide, survodutide, mazdutide): Increases hepatic fat oxidation and resting energy expenditure — attacking obesity from the expenditure side of the energy equation
• Amylin agonism (as in cagrilintide/CagriSema): Activates distinct satiety pathways in the brainstem that complement GLP-1 signaling

The trend is clear: multi-target approaches produce greater weight loss. However, more targets also increase complexity — balancing efficacy with side effect management through dose optimization becomes increasingly important.

Historically, all GLP-1 agonists required subcutaneous injection because peptides are degraded in the GI tract. Novo Nordisk solved this problem with SNAC (sodium N-[8-(2-hydroxybenzoyl) amino] caprylate), an absorption enhancer that protects semaglutide from degradation and promotes its absorption through the gastric mucosa.

Current Oral Options

• Rybelsus (oral semaglutide 7–14 mg): FDA-approved for type 2 diabetes since 2019
• Wegovy pill (oral semaglutide 25 mg): FDA-approved December 2025 for chronic weight management — the first oral GLP-1 for obesity

Oral vs. Injectable Efficacy

The OASIS 1 trial demonstrated that oral semaglutide 50 mg achieved 15.1% mean weight loss — approaching the injectable Wegovy's 14.9% from the STEP 1 trial. The FDA-approved 25 mg oral dose achieved 16.6% weight loss in the OASIS 4 trial when taken as directed.

Practical Considerations

• Convenience: Daily pill vs. weekly injection. Some patients strongly prefer avoiding needles
• Absorption requirements: Oral semaglutide must be taken on an empty stomach with no more than 4 oz of water, 30 minutes before food or other medications — this can be inconvenient
• Cost: The Wegovy pill launched in January 2026 at $149/month for the starting dose (cash pay)
• Efficacy ceiling: Injectable tirzepatide and emerging triple agonists still produce greater weight loss than any oral option currently available

All GLP-1 agonists share a similar side effect profile, primarily gastrointestinal:

Common (affecting 10–30% of users)

• Nausea: The most frequently reported side effect (20–44% depending on compound and dose). Typically worst during dose escalation and improving significantly over 4–8 weeks
• Diarrhea: Affects 12–22% of users, usually transient
• Constipation: Occurs in 5–24% due to slowed gastric emptying
• Vomiting: 5–18%, more common at higher doses and during titration
• Decreased appetite: An intended pharmacological effect but can become excessive

Serious but Rare

• Pancreatitis: Rare (<0.5%) but requires immediate medical attention if severe abdominal pain occurs
• Gallbladder events: Gallstones and cholecystitis occur at higher rates, likely related to rapid weight loss rather than the drug directly
• Thyroid C-cell tumors: Observed in rodent studies with GLP-1 agonists. All GLP-1 drugs carry a boxed warning and are contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or MEN2

Managing Side Effects

Gradual dose titration is the primary strategy for minimizing GI side effects. Standard protocols escalate doses over 16–20 weeks, allowing the body to adapt. Eating smaller meals, avoiding high-fat foods, and staying hydrated also help. Most patients who experience initial nausea find it resolves or becomes manageable within the first 4–8 weeks of treatment.

For a comprehensive breakdown by compound, see the peptide side effects guide.

Research increasingly demonstrates that GLP-1 agonists produce systemic benefits extending well beyond the number on the scale:

• Cardiovascular protection: The SELECT trial showed semaglutide reduced major adverse cardiovascular events by 20% in obese patients without diabetes (Lincoff et al., NEJM 2023). The LEADER trial demonstrated similar benefits for liraglutide in type 2 diabetes
• Liver fat reduction: GLP-1 agonists reduce hepatic steatosis. Retatrutide demonstrated up to 82% liver fat reduction; survodutide showed significant MASH histological improvement. Even semaglutide alone reduces liver fat by approximately 30%
• Glycemic control: Beyond weight-dependent improvements, GLP-1 agonists directly improve insulin secretion and glucose homeostasis. Up to 34% of tirzepatide-treated patients achieved normal HbA1c levels (<5.7%)
• Inflammatory markers: Clinical trials demonstrate reductions in C-reactive protein and other inflammatory biomarkers
• Blood pressure and lipids: Improvements in blood pressure, triglycerides, and LDL cholesterol are consistently observed
• Emerging research areas: Clinical trials are investigating GLP-1 agonists for kidney disease, heart failure, sleep apnea, PCOS, and neurodegenerative conditions — areas where the anti-inflammatory and metabolic effects may provide benefit independent of weight loss

These findings suggest GLP-1 agonists are not simply weight loss drugs but metabolic modulators with broad therapeutic potential. For a detailed overview of weight loss applications, see the peptides for weight loss guide.

Choosing between GLP-1 agonists requires understanding the specific differences in mechanism, efficacy, and side effects. Our head-to-head comparison guides break down the clinical evidence:

• Tirzepatide vs Semaglutide — the most searched GLP-1 comparison, with SURMOUNT-5 head-to-head trial data
• Semaglutide vs Liraglutide — weekly vs daily dosing, first-gen vs current standard
• Retatrutide vs Tirzepatide — triple vs dual agonist, the next frontier
• Tirzepatide vs Retatrutide vs Semaglutide — three-way comparison of the top GLP-1 compounds
• Survodutide vs Tirzepatide — GLP-1/glucagon vs GLP-1/GIP dual agonists
• Tesofensine vs Semaglutide — monoamine reuptake inhibitor vs GLP-1 agonist

For a complete weight management protocol that pairs GLP-1 therapy with complementary peptides, see the Weight Loss Stack (semaglutide + tesamorelin) and the Fat Loss Stack (AOD-9604 + tesamorelin + MOTS-c).