Key points
- Mice lacking the GIP receptor and fed a high-fat diet were protected from obesity and insulin resistance, which made GIP a suspect [1].
- Chronic GIP receptor agonism desensitizes the receptor in adipocytes and can behave like functional antagonism, which helps explain why both agonists and antagonists lower weight in animal models [3].
- Tirzepatide is an imbalanced dual agonist: at clinical doses it engages the GIP receptor more than the GLP-1 receptor [4].
- Head to head, it has shown greater HbA1c reduction than semaglutide 1 mg (SURPASS-2) and greater weight reduction than semaglutide in obesity (SURMOUNT-5) [8][9].
- Versus dulaglutide, tirzepatide was noninferior for major adverse cardiovascular events, without reaching statistical superiority (SURPASS-CVOT) [11].
US status (October 2026): Approved as Mounjaro and Zepbound; the shortage ended December 19, 2024, so a 503A pharmacy may compound it only for a named patient inside the copy limits. See the tirzepatide status page.
Tirzepatide works even though mouse genetics once marked its GIP half as a cause of obesity. The best current explanation is that chronic GIP agonism desensitizes the receptor in fat, and that tirzepatide’s pharmacology is lopsided toward GIP. The clinical benefit is measured. The exact mechanism is still argued over by the two companies with drugs on either side.
GIP looked like a cause of obesity
Glucose-dependent insulinotropic polypeptide (GIP) is secreted in the duodenum mainly after fat absorption. In 2002 a Kyoto group reported in Nature Medicine that wild-type mice on a high-fat diet hypersecreted GIP and accumulated visceral and subcutaneous fat, while mice lacking the GIP receptor (Gipr-/-) were protected from both obesity and insulin resistance. They used fat as their preferred energy substrate. The authors concluded that GIP links overnutrition to obesity and was a target for anti-obesity drugs [1].
The logical reading was to block the receptor. So it was surprising that industry bet on the opposite: a peptide that activates both the GIP and GLP-1 receptors, tirzepatide.
Antagonist or agonist: the debate is still open
Amgen scientists developed antagonist antibodies against the GIP receptor. In diet-induced obese mice the antibody protected against weight gain and improved several metabolic parameters. In obese non-human primates weight loss was more pronounced, and it was enhanced when combined with GLP-1 agonists [2]. The same Amgen strategy gave rise to maridebart cafraglutide, an antibody conjugate that combines GIP receptor antagonism with GLP-1 receptor agonism [15], covered in After semaglutide.
In 2020 the same group proposed a reconciliation: in adipocytes, chronic GIP receptor agonism desensitizes the receptor so that it ends up functioning like an antagonist [3]. In the laboratory, both approaches can converge on a similar effect on adipose tissue.
Lilly scientists argue for another reading. GIP would be the primary incretin. In the central nervous system its receptor attenuates nausea and suppresses appetite, and in adipose tissue it would protect against ectopic fat [7]. In mice, a GIP receptor agonist reduced nausea-like behavior induced by a PYY analog without affecting hypophagia, and GIP and PYY receptors are expressed by the same neurons in the area postrema [6]. Both groups are employees of the companies developing each approach [3][7], and the debate is unresolved.
Tirzepatide is an imbalanced dual agonist
Tirzepatide (LY3298176) is a fatty-acid-modified peptide for once-weekly dosing. In its phase 1, with 142 participants exposed to tirzepatide, dulaglutide or placebo, the most frequent adverse effects were gastrointestinal, dose-dependent and mild to moderate in severity [5].
Its pharmacology is asymmetric. By calculating occupancy of each receptor at clinically effective doses, Willard and colleagues showed greater engagement of the GIP receptor than of the GLP-1 receptor. At the GIP receptor it mimics native GIP. At the GLP-1 receptor it is biased toward cAMP generation over β-arrestin recruitment, with less receptor internalization. In islets, that bias was associated with greater insulin secretion [4].
SURPASS-2 beat semaglutide 1 mg in type 2 diabetes
In SURPASS-2, a 40-week open-label trial in 1,879 patients with type 2 diabetes (mean baseline HbA1c 8.28%), tirzepatide 5, 10 and 15 mg lowered HbA1c by 2.01, 2.24 and 2.30 percentage points, versus 1.86 with semaglutide 1 mg. All three doses were noninferior and superior. The weight difference versus semaglutide was -1.9 kg, -3.6 kg and -5.5 kg [8].
Obesity trials: head to head and withdrawal
SURMOUNT-5 compared the two drugs directly in 751 adults with obesity without diabetes, using each one’s maximum tolerated dose (tirzepatide 10 or 15 mg; semaglutide 1.7 or 2.4 mg) for 72 weeks. Weight change was -20.2% with tirzepatide and -13.7% with semaglutide (P < 0.001), and waist change -18.4 cm versus -13.0 cm. The trial was open-label and funded by Lilly [9].
| Trial | Comparison | Result |
|---|---|---|
| SURPASS-2 [8] | Tirzepatide vs semaglutide 1 mg, type 2 diabetes, 40 weeks | HbA1c -2.01 to -2.30 vs -1.86 points |
| SURMOUNT-5 [9] | Tirzepatide vs semaglutide, obesity, 72 weeks | Weight -20.2% vs -13.7% |
| SURMOUNT-4 [10] | Continue tirzepatide vs switch to placebo, weeks 36 to 88 | Weight -5.5% vs +14.0% |
| SURPASS-CVOT [11] | Tirzepatide vs dulaglutide, type 2 diabetes with ASCVD | MACE HR 0.92, noninferior |
SURMOUNT-4 measured what happens on stopping. After a 36-week open-label tirzepatide lead-in (mean loss 20.9%), 670 participants were randomized to continue or switch to placebo. From week 36 to 88, weight changed -5.5% with tirzepatide and +14.0% with placebo. 89.5% of those who continued kept at least 80% of their loss, versus 16.6% on placebo [10]. Body composition and rebound are reviewed in GLP-1s: muscle, rebound, eyes and pancreas.
SURPASS-CVOT showed noninferiority to dulaglutide
SURPASS-CVOT randomized 13,299 patients with type 2 diabetes and atherosclerotic cardiovascular disease to tirzepatide (up to 15 mg) or dulaglutide 1.5 mg, a comparator with proven cardiovascular benefit. The composite of cardiovascular death, myocardial infarction or stroke occurred in 12.2% versus 13.1% (HR 0.92; 95.3% CI 0.83 to 1.01). That was noninferior (P = 0.003) and fell short of superiority (P = 0.09). There were more gastrointestinal events with tirzepatide [11].
A prespecified exploratory analysis estimated the effect versus an imputed placebo derived from REWIND: tirzepatide was associated with fewer major adverse cardiovascular events (HR 0.72) and lower all-cause mortality (HR 0.61) [12]. It is an indirect comparison, with several authors employed by the manufacturer, and it does not replace a placebo-controlled trial. The other hard-outcome areas (sleep apnea, heart failure, liver) are in GLP-1s beyond weight.
The limits, plainly
- Gastrointestinal tolerability. In SURPASS-2, nausea affected 17 to 22% with tirzepatide and 18% with semaglutide, and diarrhea 13 to 16% versus 12%. Serious adverse events were 5 to 7% versus 3% [8]. The antiemetic GIP hypothesis comes from animal models [6].
- Discontinuation. In a cohort of 125,474 US adults starting liraglutide, semaglutide or tirzepatide, 64.8% of those without diabetes stopped within the first year. Moderate or severe gastrointestinal events were associated with more discontinuation [13].
- Weight regain. Stopping was associated with substantial regain of lost weight [10].
- Cost-effectiveness. A US lifetime model placed tirzepatide’s cost per quality-adjusted life-year above usual thresholds. Reaching a commonly cited threshold would require an additional 30.5% discount on the net price [14].
- Funding. SURPASS-2, SURMOUNT-5 and SURPASS-CVOT were funded by the manufacturer, and SURMOUNT-4 had authors employed by the manufacturer [8][9][10][11].
What this means for you
Mouse genetics pointed to GIP as a cause of obesity [1]. Agonizing it, combined with GLP-1, produced the largest incretin effects in head-to-head trials against semaglutide [8][9]. That agonists and antagonists converge in the laboratory [3] is a reminder that the exact mechanism is still under study, even though the clinical benefit has been measured.
For your weight-management program, the practical points are the ones in the limits list: GI tolerability, a high first-year discontinuation rate and regain on stopping [8][10][13]. Plan for maintenance from the first visit. If a patient asks for a compounded version, the rules after the shortage are in compounded GLP-1s after the shortage.
References
- Miyawaki K, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002;8(7):738-42. PMID 12068290. Link
- Killion EA, et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci Transl Med. 2018;10(472):eaat3392. PMID 30567927. Link
- Killion EA, et al. Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism. Nat Commun. 2020;11(1):4981. PMID 33020469. Link
- Willard FS, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532. PMID 32730231. Link
- Coskun T, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3-14. PMID 30473097. Link
- Samms RJ, et al. GIPR agonism inhibits PYY-induced nausea-like behavior. Diabetes. 2022;71(7):1410-1423. PMID 35499381. Link
- Samms RJ, Sloop KW. A contemporary rationale for agonism of the GIP receptor in the treatment of obesity. Diabetes. 2025;74(8):1326-1333. PMID 40521890. Link
- Frías JP, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385(6):503-515. PMID 34170647. Link
- Aronne LJ, et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). N Engl J Med. 2025;393(1):26-36. PMID 40353578. Link
- Aronne LJ, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38-48. PMID 38078870. Link
- Nicholls SJ, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes (SURPASS-CVOT). N Engl J Med. 2025;393(24):2409-2420. PMID 41406444. Link
- Sattar N, et al. Estimating the true MACE benefits from tirzepatide in SURPASS-CVOT using an imputed placebo analysis of REWIND. Diabetes Care. 2026;49(10):1771-1778. PMID 41940793. Link
- Rodriguez PJ, et al. Discontinuation and reinitiation of dual-labeled GLP-1 receptor agonists among US adults with overweight or obesity. JAMA Netw Open. 2025;8(1):e2457349. PMID 39888616. Link
- Hwang JH, et al. Lifetime health effects and cost-effectiveness of tirzepatide and semaglutide in US adults. JAMA Health Forum. 2025;6(3):e245586. PMID 40085108. Link
- Jastreboff AM, et al. Once-monthly maridebart cafraglutide for the treatment of obesity, a phase 2 trial. N Engl J Med. 2025;393(9):843-857. PMID 40549887. Link
This is general information, not medical or legal advice. Rules vary by state and change. Confirm your own facts with counsel.