Six-Week Native GIP Infusion Does Not Improve Glycaemic Control in Type 2 Diabetes, Alone or With Semaglutide

Background

Glucose-dependent insulinotropic polypeptide, or GIP, is one of the two major incretin hormones released from the gut after eating. In healthy physiology, GIP helps stimulate insulin secretion in a glucose-dependent way, meaning it acts more strongly when blood sugar is elevated. In type 2 diabetes, however, the long-term glucose-lowering role of GIP has remained uncertain. This uncertainty is especially relevant now that incretin-based therapies are rapidly expanding, including GLP-1 receptor agonists such as semaglutide, which are already established treatments for improving glycaemic control and lowering body weight.

This study tested a simple but important question: if native GIP is infused under the skin for six weeks, does it improve glucose control in people with type 2 diabetes, either on its own or when added to semaglutide? The trial also examined whether combining the two hormones could produce an additive benefit, given that both act on related pathways involved in insulin secretion, appetite regulation, and post-meal metabolism.

Study design

This was a single-centre, double-blind, parallel-group, randomised, placebo-controlled trial conducted at the Center for Clinical Metabolic Research in Hellerup, Denmark. Adults aged 18 to 74 years were eligible if they had type 2 diabetes for at least six months, were on stable treatment, had HbA1c between 6.5% and 10.5% (48–91 mmol/mol), and a body-mass index between 25 and 50 kg/m2.

Participants were randomly assigned in a 1:1:1:1 ratio to one of four groups: placebo plus placebo, placebo plus GIP, semaglutide plus placebo, or semaglutide plus GIP. The treatment plan included an 8-week run-in phase with semaglutide or placebo: 0.25 mg once weekly for 4 weeks, then 0.50 mg once weekly for another 4 weeks. After that, participants continued semaglutide or placebo for 6 more weeks while receiving continuous subcutaneous infusion of native GIP or placebo at 16 pmol/kg per minute.

The study was masked, meaning neither participants nor investigators knew the treatment assignments. The main outcome was the change in mean glucose over 14 days, measured by continuous glucose monitoring, from the start of treatment to week 14. This glucose-based endpoint is clinically useful because it captures overall daily glycaemic exposure rather than relying only on isolated blood tests.

Who took part

Between January 31, 2022, and September 4, 2024, 134 people with type 2 diabetes were screened, and 61 were enrolled. They were assigned to placebo plus placebo (15 participants), placebo plus GIP (16), semaglutide plus placebo (15), or semaglutide plus GIP (15). Ten participants discontinued the study, which limited the precision of some comparisons.

The group had a median age of 64 years, median HbA1c of 54.0 mmol/mol, median diabetes duration of 6.3 years, and mean BMI of 31.6 kg/m2. Twenty-two participants were women and 39 were men. All participants self-reported as White. These characteristics suggest the findings are most directly applicable to a middle-aged and older, overweight population with established type 2 diabetes.

What the researchers found

The infusion clearly increased circulating GIP levels, showing that the hormone delivery worked as intended. At week 14, fasting concentrations of intact, biologically active GIP were much higher in the groups receiving GIP than in the groups receiving placebo. Total GIP levels were also markedly elevated in the active infusion groups.

Despite this pharmacological effect, GIP did not meaningfully improve glucose control over the study period. The estimated effect of adding GIP to placebo was an increase in mean sensor glucose of 0.80 mmol/L, with a 97.5% confidence interval from -0.18 to 1.80 and a p value of 0.13. In the semaglutide-treated participants, adding GIP produced essentially no change: 0.05 mmol/L, with a 97.5% confidence interval from -0.85 to 0.95 and a p value of 1.00.

The prespecified target for a clinically relevant improvement was 1.50 mmol/L, and GIP did not come close to meeting that threshold in either comparison. In practical terms, the trial did not show that six weeks of subcutaneous native GIP infusion improved overall glucose levels in people already receiving placebo or semaglutide.

Safety and tolerability

The treatment was generally tolerated, but side effects were common. Injection-site reactions were the most frequent adverse event, affecting 22 participants, or 36% of the study population. This is not unexpected in trials involving repeated subcutaneous administration and infusion devices.

Gastrointestinal adverse events were more common in the semaglutide-containing groups, consistent with the known side-effect profile of GLP-1 receptor agonists. These events were reported in 9 participants in the placebo plus placebo group, 11 in the placebo plus GIP group, 11 in the semaglutide plus placebo group, and 12 in the semaglutide plus GIP group. The study report did not identify a clear signal that GIP added major new safety concerns, but the high dropout rate means tolerability should still be interpreted cautiously.

What the results mean

This trial adds important evidence to the discussion about whether GIP has a useful glucose-lowering effect in type 2 diabetes when given as native hormone infusion. The results suggest that short-term continuous subcutaneous GIP infusion, even when combined with semaglutide, does not improve glycaemic control beyond the effects of placebo or semaglutide alone.

The findings are particularly relevant because GIP has been the subject of renewed interest in diabetes pharmacology. Some newer incretin-based therapies combine GLP-1 and GIP receptor activity, and there has been speculation that restoring or enhancing GIP signalling might help control glucose more effectively. This study, however, indicates that native GIP alone may not provide meaningful additional glucose lowering over six weeks in this patient population.

At the same time, the authors appropriately note a limitation: because several participants discontinued the study, the analysis of GIP added to placebo is less definitive than ideal. Therefore, while the data do not support a clear benefit, they do not completely rule out a smaller effect under different conditions, in different populations, or with longer exposure.

Clinical context

For patients and clinicians, the most important takeaway is that semaglutide remains a proven therapy for improving glycaemic control, and adding native GIP infusion did not enhance that benefit in this trial. This does not mean GIP-based strategies have no role in diabetes care. Rather, it highlights that hormone biology is complex, and the effect of a treatment depends on dose, duration, route of administration, and the metabolic state of the person receiving it.

It is also worth noting that this study evaluated native GIP infusion, not a dual-acting GIP/GLP-1 drug. Those are different interventions. Some approved or emerging therapies that target both pathways may still have clinically important benefits because they use engineered molecules and pharmacologic properties that differ from simply infusing native hormone.

Limitations

Several limitations should be kept in mind. First, the study was relatively small, with only 61 enrolled participants and 10 dropouts. Second, the follow-up period was short, lasting only six weeks during the intervention phase. Third, the population was homogeneous, with all participants self-reporting as White, which may limit generalisability to more diverse groups. Fourth, the trial tested a specific dose and delivery method of native GIP, so other regimens could yield different results.

Despite these limitations, the study was well designed, randomised, double-blind, and placebo-controlled, which strengthens confidence in the main conclusion: in this setting, native GIP infusion did not significantly improve glucose control.

Conclusion

In people with type 2 diabetes, six weeks of continuous subcutaneous infusion of native GIP did not improve glycaemic control when added to placebo or to semaglutide at the prespecified clinically meaningful target. The treatment increased circulating GIP levels as expected, but this did not translate into better glucose outcomes. More research is needed to determine whether different GIP strategies, longer treatment, or different patient groups might respond differently.

Study details

This trial was funded by Novo Nordisk and registered at ClinicalTrials.gov as NCT05078255. It was published in The Lancet Diabetes & Endocrinology. The study contributes to a growing body of evidence showing that while incretin biology is promising, not every incretin-based intervention will necessarily deliver the same metabolic benefit in type 2 diabetes.