Tirzepatide: Dual GIP/GLP-1 Agonist Profile

Most weight-loss drugs target a single hormone pathway. Tirzepatide targets two. As the first FDA-approved dual GIP/GLP-1 receptor agonist, tirzepatide represents a fundamentally different approach to treating obesity and type 2 diabetes -- one that produced the largest weight reductions ever recorded in clinical trials for a pharmaceutical drug. In the landmark SURMOUNT-1 trial, participants on the highest dose lost an average of 22.5% of their body weight over 72 weeks, or roughly 52 pounds.

Tirzepatide is a synthetic peptide developed by Eli Lilly and Company that simultaneously activates receptors for two gut hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). While GLP-1-only drugs like semaglutide had already changed the treatment of obesity, tirzepatide's dual mechanism pushed results further. Researchers refer to it as a "twincretin" -- a single molecule that does the work of two incretins.

The drug holds three FDA approvals as of early 2026. It launched as Mounjaro for type 2 diabetes in May 2022, received approval as Zepbound for chronic weight management in November 2023, and then became the first medication ever approved for obstructive sleep apnea in December 2024. Meanwhile, the clinical trial pipeline stretches into heart failure, MASH (formerly NASH), and cardiovascular outcomes -- areas where data has arrived quickly and with force.

Quick Facts
What Is Tirzepatide?
Development History
How Tirzepatide Works: Mechanisms of Action
Clinical Research
Administration and Dosing
Safety Profile and Side Effects
Legal and Regulatory Status
Frequently Asked Questions
The Bottom Line

Quick Facts

Property	Detail
Generic Name	Tirzepatide
Brand Names	Mounjaro (type 2 diabetes), Zepbound (weight management/OSA)
Drug Class	Dual GIP/GLP-1 receptor agonist (twincretin)
Manufacturer	Eli Lilly and Company
Structure	39-amino acid synthetic peptide with C20 fatty diacid moiety
Molecular Weight	~4,813.45 Da
Route of Administration	Subcutaneous injection (once weekly)
Available Doses	2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg
FDA Approval (Mounjaro)	May 13, 2022 (type 2 diabetes)
FDA Approval (Zepbound)	November 8, 2023 (chronic weight management)
FDA Approval (Zepbound OSA)	December 20, 2024 (obstructive sleep apnea)
Half-Life	~5 days (supports once-weekly dosing)
ClinicalTrials.gov	NCT04184622 (SURMOUNT-1)
Prescription Status	Prescription only (US)

What Is Tirzepatide?

Tirzepatide is a 39-amino acid synthetic peptide designed to activate two distinct hormone receptors in the body: the GIP receptor and the GLP-1 receptor. Both hormones belong to the incretin family -- peptides released by the gut after eating that help regulate blood sugar, appetite, and energy metabolism.

The molecule was engineered from the GIP sequence but modified to also bind and activate GLP-1 receptors. A C20 fatty diacid chain attached to the peptide extends its half-life to approximately five days, allowing once-weekly subcutaneous injection. This structural design gives tirzepatide a unique pharmacological identity that separates it from single-target GLP-1 receptor agonists such as semaglutide, liraglutide, exenatide, and dulaglutide.

In plain terms, tirzepatide turns on two natural appetite and metabolism switches at the same time. The GLP-1 part suppresses hunger, slows stomach emptying, and increases insulin release. The GIP part -- historically overlooked in drug development -- appears to improve fat metabolism and may amplify the effects of GLP-1 signaling on the brain's appetite centers. The result is greater weight loss and better blood sugar control than GLP-1-only drugs have achieved.

Development History

Tirzepatide's path from lab to pharmacy reflects a long-running scientific debate about GIP's role in metabolism and Eli Lilly's bet that dual receptor activation would outperform single targets.

Early Research (2010s). For decades, scientists questioned whether GIP signaling was helpful or harmful in metabolic disease. Some researchers argued that blocking GIP would improve diabetes outcomes; others believed activating it alongside GLP-1 would produce synergistic effects. Eli Lilly's preclinical work on dual agonists, which began in the early 2010s, eventually supported the activation hypothesis. The company advanced tirzepatide (then known as LY3298176) into clinical trials.

Phase 1 and Phase 2 Trials (2018-2019). Early-phase studies demonstrated that tirzepatide produced dose-dependent reductions in HbA1c and body weight in people with type 2 diabetes. A phase 2 study published in The Lancet in 2018 showed HbA1c reductions of up to 2.4 percentage points and body weight loss up to 11.3 kg at 26 weeks -- results that immediately attracted attention from the endocrinology community.

SURPASS Program Launches (2020-2022). Lilly initiated the SURPASS clinical trial program -- a series of five phase 3 trials in type 2 diabetes involving over 6,000 patients. The results across all five trials were consistently strong, and the FDA approved Mounjaro for type 2 diabetes on May 13, 2022.

SURMOUNT Program and Obesity Approval (2022-2023). Concurrent with the diabetes program, Lilly launched SURMOUNT -- a set of phase 3 trials studying tirzepatide in people with obesity or overweight (without diabetes for most trials). SURMOUNT-1 results, published in The New England Journal of Medicine, showed up to 22.5% weight loss at 72 weeks. The FDA approved Zepbound for chronic weight management on November 8, 2023.

Expanded Indications (2024-2025). The FDA approved Zepbound for moderate-to-severe obstructive sleep apnea on December 20, 2024 -- the first drug ever approved for that condition. The SUMMIT trial for heart failure with preserved ejection fraction reported positive results in November 2024. The SURPASS-CVOT trial, comparing tirzepatide to dulaglutide on cardiovascular outcomes, published results in late 2025.

How Tirzepatide Works: Mechanisms of Action

Understanding tirzepatide requires understanding the two hormones it mimics and why activating both matters more than activating either one alone.

GLP-1 Receptor Agonism

GLP-1 (glucagon-like peptide-1) is a hormone released by L-cells in the small intestine after meals. It acts on several systems:

Pancreas: Stimulates glucose-dependent insulin secretion and suppresses glucagon release, lowering blood sugar without causing hypoglycemia when used alone.
Brain: Activates appetite-suppressing centers in the hypothalamus and brainstem, reducing hunger and food intake.
Stomach: Slows gastric emptying, which extends the feeling of fullness after eating and blunts post-meal blood glucose spikes.

GLP-1 receptor agonists like semaglutide and liraglutide have been available since the mid-2000s (with exenatide being the first, approved in 2005). Tirzepatide shares all of these GLP-1 effects.

GIP Receptor Agonism

GIP (glucose-dependent insulinotropic polypeptide) is released by K-cells in the upper small intestine after meals. Its role in metabolism was historically controversial, but recent research supports several functions:

Insulin release: Like GLP-1, GIP stimulates glucose-dependent insulin secretion from pancreatic beta cells.
Fat tissue: GIP receptors are found on adipocytes (fat cells), where GIP signaling appears to influence fat storage, fat breakdown, and adipose tissue blood flow.
Brain: GIP receptors exist in brain regions involved in appetite control. Animal studies suggest GIP agonism may amplify the appetite-suppressing effects of GLP-1.
Bone: GIP has been linked to bone formation and mineral metabolism, though the clinical significance in the context of tirzepatide treatment remains unclear.

The Dual Agonist Advantage

The critical question that tirzepatide answered is whether activating both receptors simultaneously produces better outcomes than activating GLP-1 alone. The clinical trial data says yes.

In SURPASS-2, tirzepatide was compared head-to-head against semaglutide 1 mg (the diabetes dose) in patients with type 2 diabetes. All three tirzepatide doses (5 mg, 10 mg, 15 mg) produced superior HbA1c reductions compared to semaglutide 1 mg, and the two higher tirzepatide doses also produced significantly greater weight loss.

The SURMOUNT-5 trial compared tirzepatide directly to semaglutide for weight loss in adults with obesity but without diabetes. At their maximum tolerated doses over 72 weeks, tirzepatide produced 20.2% mean body weight loss compared to 13.7% with semaglutide -- an average difference of 50.3 pounds lost versus 33.1 pounds. That translates to roughly 47% greater weight loss with tirzepatide.

The exact mechanism behind this advantage is still being studied. One hypothesis: GIP signaling in the brain amplifies GLP-1's appetite suppression in ways that neither hormone can achieve alone. Another possibility is that GIP's effects on fat tissue promote more efficient lipid metabolism during weight loss. The answer is likely a combination of both, plus interactions between the two receptor systems that researchers are still working to characterize.

Clinical Research

Tirzepatide's clinical evidence comes from two major trial programs (SURPASS for diabetes, SURMOUNT for obesity) along with standalone trials in heart failure, liver disease, and cardiovascular outcomes.

SURPASS Program (Type 2 Diabetes)

The SURPASS program included five phase 3 trials testing tirzepatide in different diabetes treatment contexts. All were published in major peer-reviewed journals:

SURPASS-1 (NCT03954834): Tirzepatide monotherapy vs. placebo in treatment-naive patients. At 40 weeks, tirzepatide 15 mg reduced HbA1c by 2.07 percentage points (vs. 0.04 for placebo) and body weight by 9.5 kg (vs. 0.7 kg for placebo). Nearly 52% of patients on the 15 mg dose achieved an HbA1c below 5.7% -- the normal, non-diabetic range.

SURPASS-2 (NCT03987919): Tirzepatide vs. semaglutide 1 mg in patients on metformin. Tirzepatide was noninferior and superior to semaglutide for HbA1c reduction at 40 weeks across all three doses. The 15 mg dose reduced HbA1c by 2.46 points vs. 1.86 for semaglutide. Weight loss was 12.4 kg for tirzepatide 15 mg vs. 6.2 kg for semaglutide 1 mg.

SURPASS-3 (NCT03882970): Tirzepatide vs. insulin degludec in patients on metformin. Tirzepatide outperformed long-acting insulin on both HbA1c and weight.

SURPASS-4 (NCT03730662): Tirzepatide vs. insulin glargine in patients with cardiovascular risk. Tirzepatide was superior on HbA1c and weight with a comparable cardiovascular safety profile.

SURPASS-5 (NCT04039503): Tirzepatide added to insulin glargine. All three tirzepatide doses provided additional HbA1c and weight reductions.

SURMOUNT Program (Obesity/Overweight)

The SURMOUNT trials studied tirzepatide specifically for weight management:

SURMOUNT-1 (NCT04184622): The flagship obesity trial. 2,539 adults with obesity (or overweight with at least one weight-related condition), without diabetes. At 72 weeks:

Tirzepatide 5 mg: 16.0% mean weight loss (35.5 lbs / 16.1 kg)
Tirzepatide 10 mg: 21.4% mean weight loss (48.9 lbs / 22.0 kg)
Tirzepatide 15 mg: 22.5% mean weight loss (52.0 lbs / 23.6 kg)
Placebo: 2.4% mean weight loss (5.3 lbs / 2.4 kg)

Over one-third of participants on the highest dose lost more than 25% of their body weight -- a threshold once considered achievable only through bariatric surgery.

SURMOUNT-2 (NCT04657003): 938 adults with obesity/overweight and type 2 diabetes. At 72 weeks, tirzepatide 15 mg produced 14.7% weight loss (vs. 3.2% for placebo) and HbA1c reductions of 2.1 percentage points.

SURMOUNT-3 (NCT04657016): Tested tirzepatide after an initial 12-week intensive lifestyle intervention. Participants who switched to tirzepatide achieved an additional 21.1% weight loss beyond what the lifestyle changes produced.

SURMOUNT-4 (NCT04660643): A withdrawal design. Participants received tirzepatide for 36 weeks (losing ~21% of body weight), then were randomized to continue or switch to placebo. Those who continued lost another 5.5%; those who switched to placebo regained 14% over the following year. The trial demonstrated that stopping the drug leads to substantial weight regain -- an observation consistent across the GLP-1 class.

SURMOUNT-5 (NCT05822830): The first head-to-head comparison of tirzepatide vs. semaglutide (at maximum tolerated doses, 15 mg vs. 2.4 mg) for weight loss. Over 72 weeks, tirzepatide produced 20.2% mean weight loss vs. 13.7% for semaglutide. The average absolute difference was about 17 pounds more lost with tirzepatide.

SUMMIT Trial (Heart Failure)

The SUMMIT trial (NCT04847557), published in November 2024, tested tirzepatide in 731 patients with heart failure with preserved ejection fraction (HFpEF) and obesity. Over a median follow-up of about 2 years:

The primary composite endpoint (cardiovascular death or worsening heart failure) occurred in 36 tirzepatide patients vs. 56 placebo patients -- a 38% relative risk reduction (hazard ratio 0.62, 95% CI 0.41-0.95, p=0.026).
Participants lost an average of 11.6% of their body weight.
Exercise capacity (6-minute walk distance) and quality of life scores (Kansas City Cardiomyopathy Questionnaire) both improved more with tirzepatide.
C-reactive protein levels, a marker of systemic inflammation, decreased.

This trial matters because HFpEF -- the most common form of heart failure -- has had very few effective treatments. The connection between obesity, systemic inflammation, and HFpEF makes tirzepatide's mechanism particularly relevant.

SYNERGY-NASH Trial (Liver Disease)

The SYNERGY-NASH trial, published in June 2024, was a phase 2 study of tirzepatide in patients with metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) and moderate-to-severe liver fibrosis. At 52 weeks:

44% of patients on tirzepatide 5 mg and 62% on tirzepatide 80 mg achieved MASH resolution without worsening fibrosis, compared to 10% on placebo.
Fibrosis improved by at least one stage in approximately 51% of patients on the 80 mg dose vs. 30% on placebo.

These results position tirzepatide as a potential therapy for MASH, a liver condition affecting an estimated 5% of U.S. adults that currently has very limited treatment options. Phase 3 trials are ongoing.

SURPASS-CVOT (Cardiovascular Outcomes)

The SURPASS-CVOT trial (NCT04255433), one of the largest cardiovascular outcomes trials ever conducted for a diabetes drug, enrolled 13,299 patients with type 2 diabetes and established atherosclerotic cardiovascular disease. It compared tirzepatide to dulaglutide (Trulicity), another GLP-1 receptor agonist.

Over a median 4-year follow-up:

The primary composite endpoint (cardiovascular death, myocardial infarction, or stroke) occurred in 12.2% of tirzepatide patients vs. 13.1% of dulaglutide patients.
Tirzepatide met the noninferiority threshold (hazard ratio 0.92, p=0.003 for noninferiority) but did not reach statistical superiority (p=0.09).
Tirzepatide produced greater weight loss (-11.6% vs. -4.5%) and HbA1c reduction (-1.66% vs. -0.88%) than dulaglutide.
The expanded MACE endpoint (including revascularization) favored tirzepatide (HR 0.88).

This trial confirmed that tirzepatide's cardiovascular safety is at least as good as a proven cardioprotective GLP-1 drug, with suggestions of potential superiority that did not reach the prespecified statistical bar.

Administration and Dosing

Tirzepatide is administered as a once-weekly subcutaneous injection. It comes in prefilled single-dose pens (autoinjectors) and single-dose vials.

Dose Escalation Schedule

The standard titration schedule starts low to minimize gastrointestinal side effects:

Week	Dose	Purpose
Weeks 1-4	2.5 mg weekly	Initiation (not a therapeutic dose)
Weeks 5-8	5 mg weekly	First therapeutic dose
Weeks 9-12	7.5 mg weekly (optional)	Intermediate step if tolerated
Weeks 13-16	10 mg weekly	Higher therapeutic dose
Weeks 17-20	12.5 mg weekly (optional)	Intermediate step if tolerated
Week 21+	15 mg weekly	Maximum dose

Dose increases should occur no more frequently than every 4 weeks. Clinicians may keep patients at any tolerated dose (5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg) based on individual response and tolerability. The maximum recommended dose is 15 mg weekly.

Injection Details

Sites: Abdomen, thigh, or upper arm.
Rotation: Rotate injection sites with each dose.
Timing: Any time of day, with or without food. The day of the week can be changed as long as at least 3 days separate consecutive doses.
Missed dose: If within 4 days of the missed dose, take it as soon as possible. If more than 4 days have passed, skip and resume the regular schedule.
Storage: Refrigerate at 36-46F (2-8C). Pens can be kept at room temperature (up to 86F / 30C) for up to 21 days if needed. Do not freeze.

Safety Profile and Side Effects

Tirzepatide's safety profile is well-documented across thousands of clinical trial participants. Like all GLP-1 receptor agonists, gastrointestinal symptoms are the most common adverse effects.

Common Side Effects

The following affected 5% or more of participants in clinical trials:

Nausea (most common; often occurs during dose escalation and tends to diminish over time)
Diarrhea
Vomiting
Constipation
Abdominal pain
Dyspepsia (indigestion)
Injection site reactions
Fatigue
Gastroesophageal reflux disease (GERD)
Hair loss (reported in weight-loss trials, consistent with rapid weight reduction)
Hypersensitivity reactions
Burping

These side effects are typically mild to moderate and often improve with continued use. The dose escalation schedule is specifically designed to reduce gastrointestinal intolerance.

Serious Warnings

Boxed Warning -- Thyroid C-Cell Tumors: Tirzepatide carries a boxed warning (the FDA's most serious warning level) based on rodent studies showing that GLP-1 receptor agonists cause thyroid C-cell tumors in rats and mice. It is unknown whether tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Tirzepatide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Pancreatitis: Cases of acute pancreatitis have been reported with GLP-1 receptor agonists. Patients should be monitored for signs of pancreatitis (severe abdominal pain, sometimes radiating to the back).

Gallbladder disease: Cholelithiasis and cholecystitis have been reported at higher rates than placebo.

Hypoglycemia: When used with insulin or sulfonylureas, tirzepatide may increase the risk of low blood sugar. Used alone, hypoglycemia risk is low because its insulin-stimulating effect is glucose-dependent.

Kidney injury: Dehydration from gastrointestinal side effects (vomiting, diarrhea) can lead to acute kidney injury, particularly in patients with pre-existing kidney disease.

Diabetic retinopathy: Rapid improvements in blood sugar control have been associated with temporary worsening of diabetic retinopathy in some patients.

Anesthesia risk: Tirzepatide slows gastric emptying, which may increase aspiration risk during procedures requiring anesthesia or sedation. Patients should inform all healthcare providers that they are taking the medication before scheduled procedures.

Suicidality: Post-marketing reports have led to monitoring for depression and suicidal ideation, though a causal link has not been established in controlled trials.

Contraindications

Personal or family history of medullary thyroid carcinoma (MTC)
Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
Known hypersensitivity to tirzepatide or any component of the formulation

Comparison to Other GLP-1 Drugs

The side effect profile of tirzepatide is broadly similar to that of other GLP-1 receptor agonists like semaglutide and liraglutide. In the SURPASS-CVOT trial, the discontinuation rate due to adverse events was 13.2% for tirzepatide vs. 10.1% for dulaglutide, primarily driven by gastrointestinal side effects. The gradual dose titration schedule helps most patients manage these symptoms.

Legal and Regulatory Status

FDA-Approved Indications

As of February 2026, tirzepatide holds FDA approval for three distinct indications:

Mounjaro (type 2 diabetes): Approved May 13, 2022 for improving glycemic control in adults with type 2 diabetes, as an adjunct to diet and exercise. FDA approval letter.
Zepbound (chronic weight management): Approved November 8, 2023 for chronic weight management in adults with obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) with at least one weight-related comorbidity, as an adjunct to reduced-calorie diet and increased physical activity.
Zepbound (obstructive sleep apnea): Approved December 20, 2024 for moderate-to-severe obstructive sleep apnea in adults with obesity. This made tirzepatide the first medication ever approved specifically for sleep apnea.

The Compounding Controversy

Tirzepatide's story includes a significant chapter about compounding pharmacies. During 2023-2024, demand for Mounjaro and Zepbound far exceeded supply, and the FDA placed tirzepatide on its drug shortage list. Under the Federal Food, Drug, and Cosmetic Act, when an FDA-approved drug is in shortage, compounding pharmacies and outsourcing facilities can legally produce copies of that drug.

Dozens of compounding pharmacies began producing tirzepatide at significantly lower prices. This created access for patients who could not afford or obtain the brand-name products.

In October 2024, the FDA removed tirzepatide from the shortage list, determining that supply had stabilized. This meant compounding pharmacies could no longer legally produce the drug. Eli Lilly and the FDA moved to enforce the end of compounding, while compounding pharmacies and patient advocacy groups filed legal challenges.

A federal court initially remanded the shortage determination back to the FDA for reevaluation, but the FDA upheld its decision in December 2024. As of early 2026, compounded tirzepatide is no longer legally available from U.S. pharmacies, and patients must obtain the brand-name versions.

International Approvals

Tirzepatide has received regulatory approval in multiple countries and regions beyond the United States, including the European Union (EMA), United Kingdom (MHRA), Japan, and numerous other markets for type 2 diabetes and/or weight management indications.

Pipeline and Future Indications

Several regulatory submissions and ongoing trials could expand tirzepatide's approved uses:

Heart failure with preserved ejection fraction (HFpEF): Following positive SUMMIT trial results, a regulatory filing is anticipated.
MASH/NASH: Phase 3 trials are ongoing following strong SYNERGY-NASH phase 2 data.
Pediatric obesity: Studies are evaluating tirzepatide in adolescents.
Chronic kidney disease: Early-stage investigation.

Next-generation multi-agonists are also in development from multiple companies. Retatrutide, also from Eli Lilly, adds glucagon receptor activation to the GIP/GLP-1 dual mechanism, forming a triple agonist. Survodutide from Boehringer Ingelheim combines GLP-1 and glucagon agonism. CagriSema from Novo Nordisk pairs semaglutide with the amylin analog cagrilintide. And orforglipron from Eli Lilly is an oral small-molecule GLP-1 agonist that would eliminate the need for injections entirely. Meanwhile, pemvidutide is being studied as a dual GLP-1/glucagon agonist for NASH.

Frequently Asked Questions

How does tirzepatide compare to semaglutide (Ozempic/Wegovy)?

Both are injectable GLP-1-based therapies given once weekly, but they differ in their mechanism. Semaglutide activates only the GLP-1 receptor. Tirzepatide activates both GLP-1 and GIP receptors. In head-to-head trials, tirzepatide produced greater weight loss (20.2% vs. 13.7% in SURMOUNT-5) and larger HbA1c reductions (in SURPASS-2). Semaglutide has more long-term cardiovascular outcomes data (the SELECT trial showed a 20% reduction in major cardiovascular events in patients with obesity), while tirzepatide's SURPASS-CVOT trial met noninferiority but not superiority against dulaglutide. Both drugs share similar GI side effect profiles. The choice between them should be made with a healthcare provider based on individual needs, insurance coverage, and treatment goals. For a deeper comparison, see our profile of semaglutide.

How much weight can you lose on tirzepatide?

In the SURMOUNT-1 trial, average weight loss at 72 weeks ranged from 35.5 pounds (5 mg dose) to 52 pounds (15 mg dose). Over one-third of participants on the highest dose lost more than 25% of their body weight. Individual results vary widely based on starting weight, dose, diet, exercise, genetics, and other factors. People with type 2 diabetes tend to lose less weight than those without diabetes, as demonstrated by the lower (but still substantial) results in SURMOUNT-2.

What happens if you stop taking tirzepatide?

Weight regain is expected. The SURMOUNT-4 trial showed that participants who stopped tirzepatide after 36 weeks regained an average of 14% of their body weight over the following year, while those who continued the drug lost an additional 5.5%. This pattern is consistent across all GLP-1 and dual agonist therapies and reflects the biological reality that these drugs manage -- rather than cure -- the underlying metabolic condition. Current treatment guidelines recommend long-term use for sustained benefit.

Can you still get compounded tirzepatide?

As of early 2026, compounded tirzepatide is no longer legally available from U.S. pharmacies. The FDA removed tirzepatide from its drug shortage list in October 2024 and upheld that decision in December 2024. When a drug is no longer in shortage, compounding pharmacies lose the legal basis to produce copies of FDA-approved drugs. Patients seeking tirzepatide must obtain brand-name Mounjaro or Zepbound through a prescription.

What are the approved indications for tirzepatide?

Tirzepatide is FDA-approved as Mounjaro for type 2 diabetes (May 2022), as Zepbound for chronic weight management in adults with obesity or overweight with comorbidities (November 2023), and as Zepbound for moderate-to-severe obstructive sleep apnea in adults with obesity (December 2024). Off-label use for other conditions occurs but is not supported by the same level of regulatory review.

Does tirzepatide protect the heart?

The SURPASS-CVOT trial showed tirzepatide was noninferior to dulaglutide (an established cardioprotective GLP-1 drug) for major cardiovascular events over 4 years in patients with type 2 diabetes and cardiovascular disease. The SUMMIT trial demonstrated a 38% relative risk reduction in cardiovascular death or worsening heart failure in patients with HFpEF and obesity. While these results are positive, tirzepatide does not yet have a specific FDA-approved cardiovascular indication.

Tirzepatide belongs to the incretin-based therapy class. It shares the GLP-1 receptor activation mechanism with semaglutide, liraglutide, dulaglutide, and exenatide, but adds GIP receptor agonism. It is distinct from growth-hormone-related peptides like tesamorelin or MK-677, fat-loss research peptides like AOD-9604, and regenerative peptides like BPC-157 or GHK-Cu.

The Bottom Line

Tirzepatide changed the treatment of obesity and type 2 diabetes by proving that dual incretin receptor activation produces results beyond what GLP-1-only drugs can achieve. The numbers from clinical trials are hard to argue with: 22.5% average body weight loss in SURMOUNT-1, superior HbA1c reductions vs. semaglutide in SURPASS-2, and 47% more weight loss than semaglutide in the head-to-head SURMOUNT-5 trial.

The story has expanded beyond metabolic disease. Positive data in heart failure (SUMMIT), liver disease (SYNERGY-NASH), and sleep apnea (leading to the first-ever FDA approval for that condition) suggest tirzepatide's effects reach far beyond appetite suppression. The SURPASS-CVOT trial confirmed cardiovascular safety at a minimum, with hints of benefit that may sharpen with further analysis.

But context matters. Tirzepatide requires lifelong use to maintain its effects; stopping leads to weight regain. The drug costs roughly $1,000 per month without insurance, and access remains a barrier for many patients despite the end of the shortage. GI side effects are real and cause some patients to discontinue. And the thyroid C-cell tumor warning, while based on rodent data without confirmed human cases, remains a mandatory label element.

For patients with obesity, type 2 diabetes, or both, tirzepatide represents the most effective pharmaceutical tool currently available. It is a prescription medication that should be discussed with and monitored by a healthcare provider. It is not a replacement for healthy eating, physical activity, or comprehensive medical care -- it is a tool that, in the right hands, can produce outcomes that were not possible five years ago.

This article is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare provider before starting, stopping, or changing any medication. PeptideJournal.org has no financial relationship with Eli Lilly or any pharmaceutical manufacturer.

References

Jastreboff AM, et al. "Tirzepatide Once Weekly for the Treatment of Obesity." N Engl J Med. 2022;387(3):205-216. NEJM
Frias JP, et al. "Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes." N Engl J Med. 2021;385(6):503-515. NEJM
Aroda VR, et al. "SURMOUNT-5: Tirzepatide versus Semaglutide for Weight Loss." N Engl J Med. 2024. NEJM
Packer M, et al. "Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity." N Engl J Med. 2024. NEJM
Loomba R, et al. "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis." N Engl J Med. 2024;391(4):299-310. NEJM
Nicholls SJ, et al. "Cardiovascular Outcomes with Tirzepatide versus Dulaglutide." N Engl J Med. 2025. NEJM
Rosenstock J, et al. "Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1)." N Engl J Med. 2021;385(6):497-510. NEJM
Jastreboff AM, et al. "Continued Treatment With Tirzepatide for Maintenance of Weight Reduction (SURMOUNT-4)." JAMA. 2024;331(1):38-48. JAMA
U.S. FDA. "FDA Approves First Medication for Obstructive Sleep Apnea." December 20, 2024. FDA.gov
U.S. FDA. "FDA Clarifies Policies for Compounders as National GLP-1 Supply Begins to Stabilize." FDA.gov
Hamza M, Papamargaritis D, et al. "Tirzepatide for overweight and obesity management." Expert Opin Pharmacother. 2025. Taylor & Francis
Qin W, et al. "Efficacy and safety of tirzepatide for weight management: updated meta-analysis including SURMOUNT-2." Endocrine. 2024. Springer
Zepbound Prescribing Information. Eli Lilly and Company. FDA Label
Eli Lilly Investor Relations. "SURPASS-2 Results Published in NEJM." June 25, 2021. Lilly.com

Table of Contents