GLP-1 Drug Research Guide

Semaglutide, CagriSema, Tirzepatide & Retatrutide

Explore how GLP-1, GIP, glucagon, and amylin wiring combine into four different “personalities” of anti-obesity and cardiometabolic drugs.

Research compiled by Stephane Fourdrinier

GLP-1GLP-1

Core incretin axis: appetite down, gastric emptying slower, insulin up, glucagon down after meals.

GIPGIP

Synergistic incretin: supports β-cells, improves metabolic flexibility. In dual agonists, may contribute to tolerability at high efficacy (emerging evidence).

GCGGlucagon

Energy-expenditure lever: raises hepatic glucose output but can boost fat oxidation and resting burn when balanced. Tends to raise heart rate; long-term CV effects under study.

AMYAmylin

Powerful satiety hormone: shuts down meal initiation and strongly brakes gastric emptying.

Phenotype Map

X-axis = Satiety / GI brake. Y-axis = Metabolic activation / energy expenditure.

Baseline GLP-1+ Amylin+ GIP+ Glucagon

Lower satiety / lighter GIExtreme satiety / GI brake

Metabolic activation →

SSemaglutide

CCagriSema

TTirzepatide

RRetatrutide

Satiety / GI brake

How aggressively the drug suppresses hunger and slows the gut. GLP-1 + amylin lives at the extreme.

Metabolic activation

How much the biology shifts energy expenditure, nutrient partitioning, and metabolic flexibility.

Dot position

Schematic only – calibrated to match relative effects seen in published Phase 2/3 data, not an exact scale.

Receptor Map × Organs

How each hormone pathway behaves across organs, and which drugs light it up.

SemaglutideCagriSemaTirzepatideRetatrutide

Hormone	Brain (Appetite Circuits)	Stomach / GI	Pancreas / Islets	Liver	Adipose / Energy	Heart / CV	Drugs using this axis
GLP-1Core incretin axis: appetite down, gastric emptying slower, insulin up, glucagon down after meals.	Suppresses hunger, increases satiety via hypothalamic and brainstem targets.	Slows gastric emptying, flattening post-meal glucose spikes.	Boosts glucose-dependent insulin secretion and reduces inappropriate post-prandial glucagon.	Indirectly reduces liver fat and glucose production via weight loss and better insulin sensitivity.	Promotes weight loss; shifts body composition toward lower fat mass over time.	Improves CV risk factors (BP, weight, lipids); mild heart-rate increase as a class effect.	SemaglutideCagriSemaTirzepatideRetatrutide
GIPSynergistic incretin: supports β-cells, improves metabolic flexibility. In dual agonists, may contribute to tolerability at high efficacy (emerging evidence).	Modulates appetite and food reward; synergistic with GLP-1 for hunger control.	Modest GI impact; may mitigate some GLP-1‑related nausea in dual agonists.	Supports β-cells and amplifies meal-time insulin secretion when glucose is elevated.	Improves post-prandial handling of nutrients and contributes to lower hepatic fat over time.	Improves metabolic flexibility and nutrient partitioning, helping fat loss under caloric deficit.	Indirect CV benefits via weight, glycemia, and lipid improvements.	TirzepatideRetatrutide
GlucagonEnergy-expenditure lever: raises hepatic glucose output but can boost fat oxidation and resting burn when balanced. Tends to raise heart rate; long-term CV effects under study.	Minor direct appetite effects; systemic energy-signal more than a classic satiety hormone.	Little direct effect on gastric emptying.	Raises glucose and can provoke compensatory insulin responses when combined with GLP-1/GIP.	Increases hepatic glucose output and fat oxidation; when balanced, drives higher energy expenditure.	Promotes lipolysis and fat use as fuel when paired with appetite suppression and insulin support.	Tends to raise heart rate and may slightly increase blood pressure; needs careful long-term CV data.	Retatrutide
AmylinPowerful satiety hormone: shuts down meal initiation and strongly brakes gastric emptying.	Strong satiety signal in brainstem and hypothalamus; suppresses meal initiation and "food noise".	Potent gastric emptying brake, synergistic with GLP-1; small meals feel very filling.	Co-secreted with insulin in physiology; in analog form, blunts post-meal glucagon.	Flattens post-prandial glucose excursions via slower nutrient delivery and glucagon suppression.	Weight loss mainly via reduced intake rather than primary changes in energy expenditure.	Indirect cardio benefit via weight and glycemic control; GI intolerance can be dose-limiting.	CagriSema

The Four Core Axes: How Each Hormone Works

Think of these as the “control knobs” the drugs play with. Click a hormone to highlight which drugs use it.

Axis	Main Targets	Brain (Appetite)	Stomach / GI	Pancreas	Liver & Fat / Energy
GLP-1	GLP-1 receptor	↓ hunger, ↑ satiety	↓ gastric emptying	↑ insulin (glucose-dependent), ↓ glucagon after meals	↓ liver fat (via weight loss & insulin), improved cardiometabolic markers
GIP	GIP receptor	modest ↓ hunger, modulates reward	mild GI effects	↑ insulin, improves β-cell function	pushes fat/energy handling toward more 'metabolically flexible' state; synergistic with GLP-1
Glucagon	Glucagon receptor	little direct	none in gut motility	↑ insulin secondarily (via higher glucose)	↑ hepatic glucose output, ↑ energy expenditure & fat oxidation when balanced correctly
Amylin	Amylin receptors (CTR + RAMPs)	strong satiety signal, suppresses meal initiation	big GI brake (slows gastric emptying)	↓ post-meal glucagon	flattens post-prandial glucose peaks, adds to overall deficit via not eating / eating much less

Drug → Receptor Matrix: Who Hits What?

See which hormone pathways each drug activates. Hover for details, click drug names to explore.

GLP-1	GIP	GCG	AMY
✓	✕	✕	✕
✓	✕	✕	✓
✓	✓	✕	✕
✓	✓	✓	✕

Key✓Activates this pathway✕Does not activate

Semaglutide

Ozempic / Wegovy

Novo Nordisk • ~14.9% at 68 weeks in STEP-1 (obesity, no diabetes).

✓ Approved medicineType 2 diabetesObesity

GLP-1

Pure GLP-1 agonist that set the modern baseline for weight loss and CV benefit. First GLP-1 to show hard CV benefit in people with obesity but no diabetes (SELECT).

Who might choose this drug?

✓You have heart disease or high CV risk and want proven cardiovascular protection
✓You have (or are at risk for) MASH/fatty liver disease and want FDA-approved liver treatment
✓You have chronic kidney disease with diabetes and need kidney protection
✓You prefer a medication with the longest real-world safety data and widest clinical experience
✓You want a single-hormone approach that's been extensively studied

Health Outcomes Beyond Weight

•SELECT trial: 20% reduction in major adverse cardiovascular events (MACE)
•Studied in 17,604 adults with obesity and established CVD, no diabetes
•FDA approved Wegovy to reduce risk of heart attack and stroke in high-risk patients
•Benefits appear independent of weight loss magnitude

Key Trials:

SELECT – CV outcomes in obesity without diabetes(NEJM 2023)

•STEP-HFpEF: Significant improvements in HFpEF symptoms and physical function
•+20 meter improvement in six-minute walk distance
•Reduced inflammation markers and improved quality of life
•EMA endorsed Wegovy for obesity-related HFpEF

Key Trials:

STEP-HFpEF – Heart failure outcomes(NEJM 2023)

•FLOW trial: First dedicated kidney outcomes trial for GLP-1 RA in T2D + CKD
•Reduced kidney failure, >50% eGFR decline, and CV death
•FDA approved Ozempic to reduce risk of kidney disease progression
•Benefits seen across range of baseline kidney function

Key Trials:

FLOW – Kidney outcomes in T2D with CKD(NEJM 2024)

•ESSENCE trial: 63% achieved MASH resolution without fibrosis worsening
•~37% showed improvement in fibrosis stage
•August 2025: FDA accelerated approval for MASH with moderate-to-advanced fibrosis
•First GLP-1 class drug approved for liver disease treatment

Key Trials:

ESSENCE – MASH fibrosis resolution(NEJM 2025)

•STEP 9: Patients with obesity and knee OA had greater pain reduction vs placebo
•Studied over 68 weeks in people with BMI ≥30
•Mechanisms: Both mechanical load reduction and direct anti-inflammatory effects
•May be disease-modifying for obesity-related OA

Key Trials:

STEP 9 – Knee osteoarthritis outcomes(NEJM 2024)

•Consistent reductions in hsCRP (high-sensitivity C-reactive protein)
•Decreased IL-6, TNF-α, and other inflammatory markers
•Improvements in endothelial function and oxidative stress
•Inflammation reduction likely mediates many cardiometabolic benefits

Key Trials:

Anti-inflammatory mechanisms review(JCI 2025)

Evidence levels:✓ FDA-approved◐ Strong RCT○ Early phase

SELECT: ~20% reduction in major CV events (CV death, MI, stroke) in adults with obesity and established CVD, no diabetes.

STEP-HFpEF: symptom improvements and +20m six-minute walk distance in obesity-related heart failure with preserved ejection fraction.

FLOW: kidney and CV protection in T2D with chronic kidney disease.

ESSENCE: histologic improvements in metabolic dysfunction-associated steatohepatitis (MASH).

Long-term data show weight and CV benefit can persist for several years if treatment is continued; stopping tends to be followed by partial weight regain.

Still Being Studied

Long-term safety beyond ~5 years in very large real-world populations.
Best strategies to prevent weight regain if treatment is stopped.
Optimal use in diverse populations and special circumstances (pregnancy, adolescents, older adults).

CagriSema

Semaglutide + Cagrilintide

Novo Nordisk • ~22.7% at 68 weeks in REDEFINE-1 (obesity, no diabetes), ~15.7% in type 2 diabetes cohorts (REDEFINE-2).

Phase 3 – not yet approvedNot yet approved; available only in clinical trials

GLP-1Amylin

Fixed-dose combo of GLP-1 + amylin analogue designed to maximize satiety and GI braking for deeper weight loss and larger improvements in blood pressure and inflammatory markers than semaglutide alone in Phase 3 data.

Who might choose this drug?

✓You want the highest weight loss efficacy currently in Phase 3 trials (22.7%)
✓You have high blood pressure and want maximum BP reduction
✓You want strong anti-inflammatory effects (69% hsCRP reduction)
✓You're comfortable with higher GI side effects for maximum satiety control
✓You're interested in cutting-edge combination therapy (GLP-1 + amylin)

Health Outcomes Beyond Weight

•REDEFINE-1: ~10.9 mmHg systolic BP drop vs ~8.8 mmHg with semaglutide alone
•hsCRP (inflammation) fell ~69% vs ~55% with semaglutide and ~16% placebo
•REDEFINE-3 cardiovascular outcomes trial currently enrolling
•Stronger cardiometabolic risk factor improvements suggest potential CV benefit

Key Trials:

REDEFINE-1 – Phase 3 obesity outcomes(NEJM 2025)

•Combination GLP-1 + amylin showing strong liver fat reduction signals
•Being developed as potential MASLD/MASH therapy
•Weight loss magnitude correlates with liver fat improvements
•Phase 3 liver-specific trials expected

Key Trials:

REDEFINE program overview(Clinical trials registry)

•69% hsCRP reduction - largest seen in any GLP-1-based trial
•Amylin component may add anti-inflammatory effects beyond GLP-1
•Inflammation reduction likely contributes to BP and metabolic benefits
•May translate to broader cardiometabolic protection

Key Trials:

REDEFINE-1 – Inflammation outcomes(NEJM 2025)

Evidence levels:✓ FDA-approved◐ Strong RCT○ Early phase

Stacked satiety from GLP-1 and amylin nearly shuts down "food noise".

REDEFINE-1: 22.7% weight loss vs 16.1% with semaglutide 2.4 mg, 11.8% with cagrilintide alone, 2-3% with placebo.

~10.9 mmHg drop in systolic BP vs ~8.8 mmHg with semaglutide and ~2.1 mmHg with placebo.

hsCRP (inflammation marker) fell ~69% vs ~55% with sema and ~16% with placebo.

Phase 3 data show larger drops in blood pressure and hsCRP than semaglutide alone, hinting at extra cardio-protective potential.

Still Being Studied

Long-term cardiovascular outcomes and rare side effects at very high satiety and GI slowing.
Practical tolerability and dose strategies in the real world vs trial settings.
Whether the extra BP and inflammation benefits translate to hard CV outcome reductions.

Tirzepatide

Mounjaro / Zepbound

Eli Lilly • ~20.2% at 72 weeks in head-to-head trials vs semaglutide (~13.7%); SURMOUNT-1 showed dose-dependent losses up to 20.9%.

✓ Approved medicineType 2 diabetesObesityObstructive sleep apnea (US)

GLP-1GIP

Dual GLP-1/GIP agonist that pairs good satiety with strong metabolic finesse and better tolerability at high efficacy. Now FDA-approved for obstructive sleep apnea in adults with obesity.

Who might choose this drug?

✓You have sleep apnea and want the only FDA-approved drug for OSA treatment
✓You're at high risk for diabetes and want the strongest prevention data (94% reduction)
✓You want more weight loss than semaglutide (20% vs 15% head-to-head)
✓You prefer better tolerability at high efficacy (GIP's metabolic benefits)
✓You want a dual-agonist approach with strong metabolic optimization

Health Outcomes Beyond Weight

•SURMOUNT-OSA: ~60-63% reduction in apnea-hypopnea index (AHI)
•Two 52-week Phase 3 trials in moderate-severe OSA with obesity
•Lowered systolic BP, hsCRP, and hypoxic burden alongside OSA improvement
•December 2024: FDA approved Zepbound as first drug treatment for OSA in adults with obesity

Key Trials:

SURMOUNT-OSA – Sleep apnea outcomes(NEJM 2024)

•SURMOUNT-1 3-year extension: ~94% risk reduction for T2D progression
•~99% of participants with prediabetes remained diabetes-free at 3 years
•About half from weight loss, half from direct metabolic effects (insulin sensitivity, β-cell function)
•Most dramatic diabetes prevention data for any weight loss medication

Key Trials:

SURMOUNT-1 extension – Diabetes prevention(Lilly Investor Relations / PubMed 2024)

•Consistent improvements in BP, lipids, inflammatory markers, visceral fat across trials
•2025 ESC/JAMA analysis: 42-58% lower risk of hospitalization/death in obese HF patients with T2D
•Dedicated cardiovascular outcomes trial in progress
•Surrogate markers suggest CV benefit but awaiting hard endpoint data

Key Trials:

SURMOUNT program cardiometabolic outcomes(Multiple publications)

•Nature Medicine 2025: Reduced volume/pressure overload in obese HFpEF patients
•Decreased systemic inflammation and markers of CV-kidney injury
•Lilly plans regulatory submissions for HFpEF indication
•Mechanistic benefits beyond weight loss demonstrated

Key Trials:

HFpEF mechanistic study(Nature Medicine 2025)

•Mid-stage data showing substantial liver fat reductions
•Being explicitly developed as MASLD/MASH therapy
•Improvements in albuminuria and kidney stress markers seen
•Phase 3 liver trials expected to read out in coming years

Key Trials:

Tirzepatide cardiometabolic review(PMC 2024)

•Reductions in hsCRP, IL-6, TNF-α across SURMOUNT program
•GIP component may add metabolic and anti-inflammatory benefits beyond GLP-1
•Inflammation reduction correlates with CV and metabolic improvements
•Class effect enhanced by dual agonism

Key Trials:

Anti-inflammatory mechanisms(JCI 2025)

Evidence levels:✓ FDA-approved◐ Strong RCT○ Early phase

SURMOUNT-5 head-to-head: ~20.2% vs ~13.7% weight loss vs semaglutide at 72 weeks.

SURMOUNT-OSA: big reductions in apnea-hypopnea index, BP, hsCRP, and hypoxic burden.

Body composition: roughly one-third reduction in fat mass (~34%) with less lean mass loss vs placebo.

3-year SURMOUNT-1 extension shows most people maintain weight loss with minimal regain while staying on drug.

Acts as a high-efficacy 'metabolic optimizer' rather than a pure GI brake.

Still Being Studied

Whether future CV-outcome trials will show reductions in heart attacks and strokes similar to semaglutide.
How to best preserve lean mass while achieving large fat loss.
Real-world persistence and effectiveness patterns vs clinical trials.

Retatrutide

Triple G (GLP-1/GIP/Glucagon)

Eli Lilly • Up to ~24.2% mean weight loss at 48 weeks in Phase 2 obesity trials, with many participants losing ≥20% and some ≥30% of body weight.

Phase 2 – experimentalNot yet approved; early-phase obesity and liver-disease trials

GLP-1GIPGlucagon

Triple-agonist peptide that layers energy-expenditure and liver-fat effects on top of incretin biology. Most aggressive weight loss and liver-fat reductions; early-phase only.

Who might choose this drug?

✓You want maximum weight loss efficacy (up to 24% in Phase 2, some achieving 30%)
✓You have severe fatty liver disease and want the strongest liver fat reduction data
✓You're interested in cutting-edge triple-agonist therapy (GLP-1 + GIP + glucagon)
✓You want energy expenditure boost in addition to appetite suppression
✓You're comfortable with early-phase medication and close monitoring (heart rate effects)

Health Outcomes Beyond Weight

•Phase 2 MASLD trial: 82-86% relative liver fat reduction - highest reported to date
•At 8-12 mg doses: >90% of participants normalized liver fat to <5%
•~40% triglyceride reduction, ~38% ApoC-III reduction
•Glucagon-driven hepatic fat oxidation + VLDL-TG handling
•Being developed as potential breakthrough MASLD/MASH therapy

Key Trials:

Phase 2 MASLD – Liver fat outcomes(Nature Medicine 2024)

•Marked improvements in BP, lipids, CRP, and visceral fat in Phase 2
•Triple-agonist mechanism suggests potential CV benefit from multiple pathways
•Heart rate increases observed - clinical significance under study
•No long-term cardiovascular outcomes trial completed yet
•SELECT-style CVOT needed before CV claims can be made

Key Trials:

Phase 2 obesity trial – CV risk factors(NEJM 2023)

•Substantial hsCRP reductions in Phase 2 trials
•Triple-agonist approach may provide additive anti-inflammatory effects
•Glucagon's metabolic effects combined with GLP-1/GIP anti-inflammatory actions
•Inflammation reduction contributes to cardiometabolic remodeling

Key Trials:

Triple-agonist mechanisms review(Multiple sources)

Evidence levels:✓ FDA-approved◐ Strong RCT○ Early phase

🔬 Triple-Agonist Superpower: The Glucagon Difference

Glucagon receptor adds liver “defatting” and energy expenditure boost:

•82-86% liver fat reduction - unprecedented in any GLP-1 trial
•~40% triglyceride drop, ~38% ApoC-III reduction (liver lipid clearance)
•Increased resting energy expenditure and fat oxidation beyond GLP-1 alone
•Hepatic 'defatting' axis: Glucagon drives liver fat burning when balanced by GLP-1/GIP
•May enable highest weight losses (up to 30% in some Phase 2 participants)

⚠️Increases heart rate; long-term cardiovascular safety profile still under study. No completed CVOT yet.

Phase 2: ~22.8% and 24.2% weight loss with 8 and 12 mg doses; ~¼ participants achieved ≥30% loss at top dose.

Phase 2 liver studies show ~80% reductions in liver fat and many participants dropping below 5% liver fat, making it a strong MASLD candidate.

Glucagon agonism boosts fat oxidation and resting energy expenditure when balanced by GLP-1/GIP.

Triple agonism is potent but complex: trials report dose-dependent heart-rate increases and the long-term cardiovascular safety profile is still being worked out.

Still Being Studied

Long-term cardiovascular safety in the context of heart-rate increases.
Whether liver-fat and metabolic benefits translate into fewer hard liver/CV outcomes.
Optimal dosing strategies that balance efficacy and tolerability.

Glossary

Key terms and abbreviations used in this guide.

MACE

Major Adverse Cardiovascular Events: heart attack (MI), stroke, or cardiovascular death.

hsCRP

High-sensitivity C-Reactive Protein: a blood marker of systemic inflammation linked to cardiovascular risk.

MASH / MASLD

Metabolic dysfunction-Associated Steatohepatitis / Steatotic Liver Disease: liver fat accumulation with inflammation, formerly called NAFLD/NASH.

HFpEF

Heart Failure with preserved Ejection Fraction: a type of heart failure where the heart muscle stiffens but still pumps normally.

Metabolic flexibility

The body's ability to switch between burning carbohydrates and fats for energy based on availability and need.

Nutrient partitioning

How the body decides where to store or burn incoming calories (muscle, liver, fat tissue, etc.).

β-cells

Beta cells in the pancreas that produce and release insulin in response to glucose.

OSA

Obstructive Sleep Apnea: repeated breathing pauses during sleep due to airway blockage, strongly linked to obesity.

Apnea-hypopnea index (AHI)

Number of breathing pauses or shallow breaths per hour of sleep; used to measure OSA severity.

Gastric emptying

The rate at which food moves from the stomach into the small intestine; slower emptying increases satiety and reduces post-meal glucose spikes.

ITT

Intention-To-Treat: analysis including all enrolled participants regardless of whether they completed treatment, reflecting real-world effectiveness.

CKD

Chronic Kidney Disease: progressive loss of kidney function over time, often linked to diabetes and hypertension.

What's most important for your health?

Phenotype Map

Sleep Apnea (OSA)

Diabetes Prevention

Heart & Stroke (CV Events)

Heart Failure (HFpEF)

Liver Disease (MASLD/MASH)

Systemic Inflammation

The Four Core Axes: How Each Hormone Works

Drug → Receptor Matrix: Who Hits What?

Glossary

Phenotype Map

Receptor Map × Organs

The Four Core Axes: How Each Hormone Works

Drug → Receptor Matrix: Who Hits What?

Semaglutide

Who might choose this drug?

Health Outcomes Beyond Weight

Heart & Stroke (CV Events)

Heart Failure (HFpEF)

Kidney Protection (CKD)

Liver Disease (MASLD/MASH)

Joint Health (Osteoarthritis)

Systemic Inflammation

CagriSema

Who might choose this drug?

Health Outcomes Beyond Weight

Heart & Stroke (CV Events)

Liver Disease (MASLD/MASH)

Systemic Inflammation

Tirzepatide

Who might choose this drug?

Health Outcomes Beyond Weight

Sleep Apnea (OSA)

Diabetes Prevention

Heart & Stroke (CV Events)

Heart Failure (HFpEF)

Liver Disease (MASLD/MASH)

Systemic Inflammation

Retatrutide

Who might choose this drug?

Health Outcomes Beyond Weight

Liver Disease (MASLD/MASH)

Heart & Stroke (CV Events)

Systemic Inflammation

🔬 Triple-Agonist Superpower: The Glucagon Difference

Glossary