Tirzepatide

Tirzepatide is a synthetic 39-residue peptide derived from the GIP sequence and modified so that it also activates the GLP-1 receptor. This is an important distinction: it is not a GLP-1 analogue with added activity, but a GIP analogue engineered toward GLP-1.

It carries a C20 fatty diacid at Lys20 for albumin binding, and non-standard Aib residues at positions 2 and 13 to resist DPP-4 — the same two engineering problems every peptide in this class must solve, solved in a comparable way.

Its agonism is not balanced. Tirzepatide is substantially more potent at the GIP receptor than at the GLP-1 receptor, and that imbalance is itself an active research question rather than an incidental property.

Glucose-dependent insulinotropic polypeptide is the other major incretin, and its inclusion was not obvious. Earlier work suggested GIP receptor signalling was impaired in type 2 diabetes and that GIP promoted fat storage — reasoning that pointed toward antagonism rather than agonism.

That GIP receptor agonism combined with GLP-1 agonism produced greater effects than GLP-1 alone is one of the more genuinely surprising results in recent metabolic pharmacology, and reconciling it with the earlier data remains an open problem. Proposed explanations include central GIP receptor populations, effects on adipose tissue insulin sensitivity, and receptor desensitisation dynamics.

• SURPASS 1-5 — type 2 diabetes, including head-to-head comparison against semaglutide in SURPASS-2.

• SURMOUNT-1 and -2 — obesity, with and without type 2 diabetes.

• SURMOUNT-OSA — obstructive sleep apnoea, an endpoint outside metabolic measures.

• SUMMIT — heart failure with preserved ejection fraction.

• SYNERGY-NASH — hepatic endpoints in MASH.

SURPASS-2 is the study most often cited in a research context, because a direct comparison between a dual and a single agonist is the cleanest available test of whether adding GIP does anything.

Supplied as a lyophilised powder. As with other acylated incretin analogues, reconstitute gently — aggregation at the air-liquid interface is the relevant stability risk — and store reconstituted material refrigerated and protected from light.

Semaglutide is the single-receptor comparator this compound is most often tested against. Retatrutide extends the same logic to a third receptor, and Mazdutide and Survodutide pair GLP-1 with glucagon instead of GIP.