The addition of glucose-dependent insulinotropic polypeptide (GIP) to semaglutide for 6 weeks did not improve glycemic control in people with type 2 diabetes (T2D), new research found.

The results, published online in The Lancet Diabetes & Endocrinology, call into question the role of the GIP component in dual GIP/GLP-1 receptor agonist medications such as tirzepatide, or other compounds in development that include a GIP agonist, study investigator Lærke S. Gasbjerg, MD, PhD, of the University of Copenhagen, Copenhagen, Denmark, told Medscape Medical News.

“Our main hypothesis is that the effects of tirzepatide might only be a GLP-1 effect. We cannot prove that any clinical outcome of tirzepatide is a GIP effect — it’s very difficult to prove because you cannot isolate or take out the GIP,” she said.

“Another reason could be that we evaluated the physiological level of GIP, so the GIP levels in these individuals were not in the range of tirzepatide,” Gasbjerg added.

Adding a GIP to Semaglutide

In the single-center trial, 61 adult participants with T2D were randomly assigned to one of four arms: placebo plus placebo (n = 15), placebo + GIP (n = 16), semaglutide + placebo (n = 15), or semaglutide + GIP (n = 15). The subcutaneous semaglutide dose was 0.25 mg/wk for the first 4 weeks, then 0.50 mg/wk for another 6 weeks. The GIP and placebo were given by infusions of 16 pmol/kg/min, starting at week 4.

Participants and investigators were blinded to treatment assignment. Ten participants discontinued the study, six of them due to difficulties with the infusion pump. Follow-up continued to 14 weeks.

The estimated effect of GIP on change in 14-day mean glucose from baseline to end of treatment, assessed by continuous glucose monitoring, was 0.80 mmol/L in the placebo + GIP group vs the placebo + placebo group (P = .13) and 0.05 mmol/L in the semaglutide + GIP group vs the semaglutide + placebo group (P = 1.00).

Because of the pump problem, the comparison of GIP vs placebo was underpowered; however, “we do have enough power to evaluate the semaglutide GLP-1 agonist with and without GIP. And here we did not see any effect when we added GIP to semaglutide,” Gasbjerg told Medscape Medical News.

There were also no statistically significant effects of GIP infusion on fasting plasma glucagon or plasma glucose concentrations between the comparison groups, nor were there differences in glycemic variability, time in glycemic ranges, A1c, bodyweight, waist circumference, systolic blood pressure, diastolic blood pressure, or heart rate. The trial wasn’t long enough to fully assess the impact on body weight, Gasbjerg noted.

Oral glucose tolerance testing conducted at baseline, 6-8 weeks, and 12-14 weeks showed no significant differences in change from baseline to end of treatment in fasting plasma glucose, maximum plasma glucose, time to maximum glucose, glucose area under the curve, insulin outcomes, C-peptide outcomes, beta-cell responsiveness, or paracetamol absorption rate.

Gastrointestinal events overall were the most common adverse event, occurring in 60%, 69%, 73%, and 80% of the placebo + placebo, placebo + GIP, semaglutide + placebo, and semaglutide + GIP groups, respectively. Injection site reactions to the pump were also common in the placebo + GIP (44%) and semaglutide + GIP (73%) groups. There were no deaths during the trial.

GIP Effect on Nausea?

Asked to comment, Simeon Taylor, MD, PhD, professor of medicine at the University of Maryland School of Medicine in Baltimore, offered two other possible explanations for the more potent effect of tirzepatide on both glycemia and weight than semaglutide.

“First, the [tirzepatide] dose may be limited by the need to avoid unacceptable nausea and vomiting. GIP has been shown to prevent nausea and vomiting, and this antiemetic effect is blocked by loss-of-function mutations in the GIP receptor,” said Taylor. “These data are consistent with the hypothesis that GIP receptor agonism enables patients to receive higher doses of tirzepatide without experiencing unacceptable nausea and vomiting.”

A second possible reason for the more potent effect of tirzepatide could be due to differences in desensitization, said Taylor. High doses of semaglutide can induce desensitization of the pathway, which can limit the incremental benefits of increasing the dose, he explained, while “tirzepatide has been demonstrated to be a biased agonist that does not induce desensitization, thereby making it possible to escalate the dose higher along the GLP-1 dose response curve.”

Gasbjerg said that he and his colleagues are looking further at the mechanisms related to nausea and activating the GIP receptor in the long term and doing more measurements, with higher doses, to see if they can answer more of these questions.

The study was funded by Novo Nordisk, which does not currently have a product containing a GIP agonist in its portfolio. Gasbjerg reported receiving a grant from the Novo Nordisk Foundation, being a shareholder and cofounder of Antag Therapeutics, and reported receiving a personal lecture fee from Novo Nordisk. Taylor reported receiving funding from the National Institutes of Health.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.