The Incretin That Came Back: A Physician’s Read on GIP, Tirzepatide and the SURMOUNT Trials

Andres Zuleta, MD · A physician's read

When I trained, GIP was the incretin we mentioned and then set aside. It is a good reminder of how a careful negative finding can be true and still not be the end of the story.

Brown's group in Vancouver isolated and sequenced GIP by 1971, and Dupre and colleagues showed in 1973 that it stimulates insulin secretion in people. In 1993, Nauck and colleagues infused GIP and GLP-1 in type 2 diabetes: GLP-1 retained about 71% of its insulinotropic effect, while the maximal GIP effect was 54% lower than in healthy controls. The field moved to GLP-1.

In 2013, Finan and colleagues (Tschöp and DiMarchi groups) reported a unimolecular dual GIP and GLP-1 receptor agonist with additive metabolic effects in rodents and monkeys. Lilly's LY3298176, tirzepatide, followed: a fatty acid modified peptide for once weekly dosing (Coskun 2018).

The trial record:

• SURPASS-2 (1,879 people with type 2 diabetes, 40 weeks): HbA1c fell 2.01 to 2.30 points vs 1.86 on semaglutide 1 mg, with 1.9 to 5.5 kg more weight loss.
• SURMOUNT-1 (2,539 adults without diabetes, 72 weeks): -15.0%, -19.5% and -20.9% at 5, 10 and 15 mg vs -3.1% on placebo; 57% on 15 mg lost 20% or more. GI events were mostly mild to moderate and clustered in dose escalation; adverse events led 4.3% to 7.1% to stop vs 2.6%.
• SURMOUNT-4: after 36 weeks of lead in, switching to placebo regained 14.0% over 52 weeks vs a further 5.5% loss on drug.
• SURMOUNT-5 (751 adults, open label, maker funded): -20.2% vs -13.7% on semaglutide at 72 weeks.

What I take from it: exactly how much the GIP half adds is still being studied, and the head to head data come from a single sponsor funded open label trial. But the clinical lesson holds: combined signals produced the largest effects so far, and the effect lasts only as long as treatment does.

The patient version, with the full story and every source, is on the ThriveMed blog: https://www.thrivemed.us/thrivecityblog/one-molecule-two-hormones-gip-tirzepatide-surmount

Sources

• Brown JC, Dryburgh JR. Can J Biochem 1971;49:867. PMID 5120249.
• Dupre J, et al. J Clin Endocrinol Metab 1973;37:826. PMID 4749457.
• Nauck MA, et al. J Clin Invest 1993;91:301. PMID 8423228.
• Finan B, et al. Sci Transl Med 2013;5:209ra151. PMID 24174327.
• Coskun T, et al. Mol Metab 2018;18:3. PMID 30473097.
• Frías JP, et al. SURPASS-2. N Engl J Med 2021;385:503. PMID 34170647.
• Jastreboff AM, et al. SURMOUNT-1. N Engl J Med 2022;387:205. PMID 35658024.
• Aronne LJ, et al. SURMOUNT-4. JAMA 2024;331:38. PMID 38078870.
• Aronne LJ, et al. SURMOUNT-5. N Engl J Med 2025;393:26. PMID 40353578.
• Drugs@FDA: NDA 215866 (May 13, 2022); NDA 217806 (November 8, 2023).

Educational only, not medical advice. Andres Zuleta, MD.