GIP Infusion Does Not Improve Glycemic Control in Type 2 Diabetes

Navigating Incretin Therapies: The Evolving Role of GIP in Type 2 Diabetes Management

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, have significantly advanced the management of type 2 diabetes by improving glycemic control and often leading to substantial weight loss [1, 2, 3]. These agents, like tirzepatide, leverage the synergistic effects of activating both GIP and GLP-1 pathways, resulting in greater reductions in hemoglobin A1c and body weight compared to GLP-1 RAs alone [4, 5]. Beyond glycemic benefits, these therapies also show promise in improving lipid profiles and liver health in patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease [6, 7, 8]. However, the precise contribution of GIP when administered in isolation or as a simple add-on to existing GLP-1 RA therapy has remained an area of active investigation, distinct from the established efficacy of dual agonists [9]. A new study now offers fresh insights into the direct effects of GIP in this therapeutic landscape.

Investigating GIP's Direct Glycemic Impact

Despite the established role of dual GIP/GLP-1 receptor agonists in type 2 diabetes management, the long-term glycaemic effects of glucose-dependent insulinotropic polypeptide (GIP) when administered alone or as an add-on to GLP-1 receptor agonists have remained unclear. To address this knowledge gap, the study aimed to assess whether a 6-week subcutaneous infusion of GIP, either alone or in combination with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, would enhance glycaemic control in individuals with type 2 diabetes. This investigation was structured as a single-centre, double-blind, parallel-group, randomised, placebo-controlled trial, conducted at the Center for Clinical Metabolic Research in Hellerup, Denmark. Participants were selected based on specific inclusion criteria: age 18-74 years, a diagnosis of type 2 diabetes for at least 6 months, stable treatment regimens, an HbA1c of 6·5-10·5% (48-91 mmol/mol), and a body mass index (BMI) of 25-50 kg/m2.

Participants were randomly assigned in a 1:1:1:1 ratio using a block randomisation list to one of four treatment arms: placebo plus placebo, placebo plus GIP, semaglutide plus placebo, or semaglutide plus GIP. All treatments were self-administered subcutaneously. The regimen commenced with an 8-week semaglutide or placebo run-in period, involving 4 weeks at 0·25 mg once weekly, followed by 4 weeks at 0·50 mg once weekly. After this run-in, participants continued on 0·50 mg semaglutide or placebo for an additional 6 weeks, concurrently receiving continuous subcutaneous infusions of GIP or placebo at a rate of 16 pmol/kg per min. To maintain study integrity, both participants and investigators were masked to treatment assignment. The primary outcome measure was the change in 14-day mean glucose concentration, assessed by continuous glucose monitoring, from baseline to the end of treatment at 14 weeks. This outcome was evaluated within the efficacy population. The study is registered on ClinicalTrials.gov under the identifier NCT05078255.

Participant Demographics and Study Flow

The study meticulously documented its recruitment and enrollment process. Between January 31, 2022, and September 4, 2024, a total of 134 individuals with type 2 diabetes were assessed for eligibility at the Center for Clinical Metabolic Research. Of these, 73 individuals were deemed ineligible based on the predefined inclusion and exclusion criteria. Consequently, 61 participants were enrolled and randomly assigned to one of the four treatment arms. Specifically, 15 participants were assigned to the placebo plus placebo group, 16 participants to the placebo plus GIP group, 15 participants to the semaglutide plus placebo group, and 15 participants to the semaglutide plus GIP group. During the course of the study, ten (16%) participants discontinued their involvement.

The baseline characteristics of the enrolled cohort provided a clear demographic profile. Participants had a median age of 64·0 years (interquartile range [IQR] 60·0-68·0). Their median HbA1c was 54·0 mmol/mol (IQR 49·0-60·0), and the median duration of their diabetes was 6·3 years (IQR 4·2-9·8). The mean body mass index (BMI) for the group was 31·6 kg/m2 (standard deviation [SD] 4·8). Demographically, 22 (36%) participants were female and 39 (64%) were male. All participants self-reported their ethnicity as White.

GIP Levels and Glycemic Outcomes

The study meticulously measured GIP concentrations to confirm the biological effect of the administered GIP infusion. At the end of treatment on week 14, fasting concentrations of intact, or bioactive, GIP were mean 7 pmol/L (standard deviation [SD] 4) in the placebo plus placebo group. In contrast, the placebo plus GIP group showed significantly elevated intact GIP levels at 45 pmol/L (SD 43). For participants receiving semaglutide, intact GIP concentrations were 10 pmol/L (SD 6) in the semaglutide plus placebo group and 85 pmol/L (SD 92) in the semaglutide plus GIP group. Similarly, fasting concentrations of total GIP at week 14 were 14 pmol/L (SD 7) in the placebo plus placebo group, rising to 375 pmol/L (SD 377) in the placebo plus GIP group. In the semaglutide arms, total GIP was 18 pmol/L (SD 19) in the semaglutide plus placebo group and 527 pmol/L (SD 338) in the semaglutide plus GIP group. These data confirm that the GIP infusion successfully increased both intact and total GIP levels in the treatment groups.

Despite the confirmed increase in GIP levels, the primary outcome, which was the change in 14-day mean sensor-detected glucose from baseline to the end of treatment, did not demonstrate a statistically significant improvement in glycemic control. The estimated effect of GIP on this change was 0·80 mmol/L (97·5% confidence interval [CI] -0·18 to 1·80; p=0·13) when comparing the placebo plus GIP group to the placebo plus placebo group. When GIP was added to semaglutide, the estimated effect on mean glucose change was 0·05 mmol/L (97·5% CI -0·85 to 0·95; p=1·00) for the semaglutide plus GIP group versus the semaglutide plus placebo group. Consequently, the researchers concluded that 6 weeks of subcutaneous GIP infusion as an add-on to placebo or semaglutide did not improve glycemic control in individuals with type 2 diabetes at the prespecified target of 1·50 mmol/L. The authors also noted that due to dropouts, firm conclusions on the effects of GIP as an add-on to placebo cannot be drawn, indicating a limitation in interpreting the results for the GIP monotherapy arm.

Adverse Event Profile

Regarding safety, the most frequently reported adverse event across all treatment arms was injection site reactions, occurring in 22 (36%) of the study participants. This finding is consistent with subcutaneous administration of medications.

Beyond local reactions, gastrointestinal adverse events were observed to be more frequent with semaglutide treatment. Specifically, these events affected nine (60%) of participants in the placebo plus placebo group, 11 (69%) in the placebo plus GIP group, 11 (73%) in the semaglutide plus placebo group, and 12 (80%) in the semaglutide plus GIP group. The higher incidence in groups receiving semaglutide aligns with the known side effect profile of GLP-1 receptor agonists.

Clinical Implications and Funding

The findings from this study provide important clinical context regarding the direct utility of GIP infusion in type 2 diabetes management. The research demonstrated that 6 weeks of subcutaneous GIP infusion, whether administered alone or as an add-on to semaglutide, did not improve glycemic control in individuals with type 2 diabetes at the prespecified target of 1·50 mmol/L. This outcome suggests that, under the conditions and duration tested, GIP monotherapy or simple GIP supplementation to a GLP-1 receptor agonist may not offer the direct glycemic benefits observed with dual GIP/GLP-1 receptor agonists, which are engineered to activate both receptor pathways simultaneously. Clinicians should note that while GIP is a component of highly effective dual agonists, its isolated administration in this manner did not meet the primary glycemic endpoint, indicating a potential difference in mechanism or efficacy when delivered as a continuous infusion versus a co-agonist molecule.

Understanding the limitations of GIP as a standalone or simple add-on therapy is crucial for guiding future research and clinical strategies in diabetes care. The study's results contribute to the evolving understanding of incretin biology and the specific roles of GIP and GLP-1 in glycemic regulation. For transparency, the study was funded by Novo Nordisk.

References

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