Finan et al studied the co-administration of equimolar [] of a GLP-1R and a GIPR agonist, revealing greater reduction in food intake, body weight, and fat mass in mice with HFD-fed diet-induced obesity relative to administration of the single agents alone. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans Sci Transl Med. 2013 Oct 30;5(209):209ra151 findings replicated in additional preclinical studies examining combined activation of both the GLP-1R and GIPR as reviewed here Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease Mol Metab. 2021 Apr;46:101090. doi: 10.1016/j.molmet.2020.101090.

Unimolecular GLP-1:GIP co-agonists

A 40 amino acid single peptide chimera on a glucagon backbone exhibited balanced activity at the GLP-1 and GIP receptors, minimal GCGR activity with prolonged action in vivoUnimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans Sci Transl Med. 2013 Oct 30;5(209):209ra151. This co-agonist dose-dependently reduced body weight, and adipose tissue mass, with greater efficacy vs. equimolar doses of exendin-4 and liraglutide.

Single dose administration of the PEGylatedGLP-1:GIP co-agonist in healthy humans increased insulin secretion and lowered blood glucose levels in the context of an associated glucose infusion. Analysis of 53 subjects with T2D treated with once-weekly co-agonist revealed dose-dependent reductions in HbA1c ( -0.53% to -1.-11%). 

RG7697/NNC0090-2746

The acylated version of the GLP-1:GIP co-agonist originally described by Finan and colleagues (described above) is represented by the designations RG7697 and NNC0090-2746 Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 after single subcutaneous administration in healthy subjects Diabetes Obes Metab. 2017 Oct;19(10):1446-1453. Single dose RG7697/NNC0090-2746 was evaluated in 51 healthy volunteers

Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 after single subcutaneous administration in healthy subjects Diabetes Obes Metab. 2017 Oct;19(10):1446-1453   Doses of G7697/NNC0090-2746≥ 1.8 mg, reduced glucose and insulin levels during a meal tolerance test. RG7697/NNC0090-2746 and once daily administration for 2 weeks reduced HbA1c by -0.67% and body weight (-3.0 kg). RG7697/NNC0090-2746 1.8mg daily was evaluated in 108 people with T2D inadequately with a comparator of daily injections of liraglutide. RG7697/NNC0090-2746 reduced HbA1c levels and body weight with reductions similar to those achieved with liraglutide The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes Cell Met 2017 Aug 1;26(2):343-352.e2.

Tirzepatide (LY3298176)

Although several GIP-GLP-1 co-agonists initially failed to impress in clinical testing, more recent data for trizepatide (originally known as LY3298176) demonstrated compelling reduction of blood glucose and body weight in both preclinical 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 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009 and clinical studies. Tirzepatide (LY3298176) is a 39 amino acid peptide based on a GIP sequence modified to include substitution of the second amino acid with aminoisobutyric acid (DPP-4 resistance) and containing a C20 unsaturated di-acid acyl chain, to enable non-covalent albumin binding and once-weekly subcutaneous dosing 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 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009 Tirzepatide exhibits comparable binding affinity and potency at the human GIPR relative to native GIP yet binds with 5-fold less affinity and is 13-fold less potent at the human GLP-1R, compared to native GLP-1 thus exhibiting bias for the GIPR. Several of the key dose ranging studies and clinical trials are highlighted here Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial Lancet. 2018 Nov 17;392(10160):2180-2193. An overview of the Phase 3 Tirzepatide SURPASS program for Type 2 diabetes was presented by Eli Lilly on Nov 20 2020 and the SURPASS trials have been published highlighting the efficacy of Tirzepatide in people with T2D. The SURPASS phase 3 clinical trial program assessed the efficacy of Tirzepatide in people with type 2 diabetes. The results are summarized below, for HbA1c and weight loss.‍ ‍