Effects of a 6-week subcutaneous infusion of native GIP alone or as add-on to semaglutide in people with type 2 diabetes: a single-centre, double-blind, parallel-group, randomised, placebo-controlled trial.

BACKGROUND: The long-term glycaemic effects of glucose-dependent insulinotropic polypeptide (GIP) remain unclear. We aimed to assess whether a 6-week subcutaneous infusion of GIP alone and in combination with the GLP-1 receptor agonist semaglutide would enhance glycaemic control in individuals with type 2 diabetes. METHODS: This single-centre, double-blind, parallel-group, randomised, placebo-controlled trial was conducted at the Center for Clinical Metabolic Research (Hellerup, Denmark). Inclusion criteria were age 18-74 years; a diagnosis of type 2 diabetes for at least 6 months; stable treatment; HbAof 6·5-10·5% (48-91 mmol/mol); and a BMI of 25-50 kg/m. Participants were randomly assigned (1:1:1:1), using a block randomisation list, to receive either placebo plus placebo, placebo plus GIP, semaglutide plus placebo, or semaglutide plus GIP (all self-administered subcutaneously). The regimen was 8-week semaglutide or placebo run-in period (4 weeks at 0·25 mg then 4 weeks at 0·50 mg once per week), after which participants continued 0·50 mg semaglutide or placebo for an additional 6 weeks while receiving continuous subcutaneous infusions of GIP or placebo (16 pmol/kg per min). Participants and investigators were masked to treatment assignment. The primary outcome was change in 14-day mean glucose concentration assessed by continuous glucose monitoring from baseline to the end of treatment at 14 weeks, assessed in the efficacy population. This study is registered at ClinicalTrials.gov, NCT05078255 (completed). FINDINGS: Between Jan 31, 2022, and Sept 4, 2024, we assessed 134 individuals with type 2 diabetes for eligibility, of whom 73 were ineligible. We enrolled and randomly assigned 61 participants (15 to placebo plus placebo, 16 to placebo plus GIP, 15 to semaglutide plus placebo, and 15 to semaglutide plus GIP). Ten (16%) participants discontinued the study. Participants had a median age of 64·0 years (IQR 60·0-68·0), HbAof 54·0 mmol/mol (49·0-60·0), diabetes duration of 6·3 years (4·2-9·8), and a mean BMI of 31·6 kg/m(SD 4·8). 22 (36%) participants were female and 39 (64%) were male and all self-reported as White. Fasting concentrations of intact (bioactive) GIP at the end of treatment on week 14 were mean 7 pmol/L (SD 4) in the placebo plus placebo group, 45 pmol/L (43) in the placebo plus GIP group, 10 pmol/L (6) in the semaglutide plus placebo group, and 85 pmol/L (92) in the semaglutide plus GIP group; whereas fasting concentrations of total GIP were 14 pmol/L (7), 375 pmol/L (377), 18 pmol/L (19), and 527 pmol/L (338), respectively. The estimated effect of GIP on change in 14-day mean sensor-detected glucose from baseline to end of treatment was 0·80 mmol/L (97·5% CI -0·18 to 1·80; p=0·13 in the placebo plus GIP vs placebo plus placebo groups) and 0·05 mmol/L (-0·85 to 0·95; p=1·00 in the semaglutide plus GIP vs semaglutide plus placebo groups). Injection site reactions were the most common adverse event (22 [36%]). Gastrointestinal adverse events were more frequent with semaglutide (nine [60%] with placebo plus placebo, 11 [69%] with placebo plus GIP, 11 [73%] with semaglutide plus placebo, and 12 [80%] with semaglutide plus GIP). INTERPRETATION: 6 weeks of subcutaneous GIP infusion as add-on to placebo or semaglutide did not improve glycaemic control in individuals with type 2 diabetes at the prespecified target of 1·50 mmol/L. Due to dropouts, we cannot draw firm conclusions on the effects of GIP as add-on to placebo. FUNDING: Novo Nordisk.