Subcutaneous weekly semaglutide with automated insulin delivery in type 1 diabetes: a double-blind, randomized, crossover trial

Study design

The study was a randomized, double-blind, crossover trial carried out at the Research Institute of the McGill University Health Centre in Montreal, Quebec, Canada. Each arm was 15 weeks, with 2 weeks of washout, for a total study duration of 32 weeks. The protocol was approved by the research ethics board of the McGill University Health Centre and Health Canada, and is available in the supplementary materials. The study was registered on the ClinicalTrials.gov website, with registration no. NCT05205928, before study commencement.

Participants

We enrolled participants aged 18 years old and older with a diagnosis of T1D for 1 year or longer, use of an insulin pump for 3 months or longer, HbA1c of 11% or less, and if applicable, agreement to use a highly effective method of birth control in persons of child-bearing potential or active avoidance of pregnancy during the trial. Exclusion criteria included current or recent (<2 weeks) use of an antihyperglycemic agent other than insulin, planned or ongoing pregnancy or breastfeeding, severe hypoglycemic episode within 3 months, diabetic ketoacidosis requiring medical attention and intravenous insulin within 6 months, history of acute or chronic pancreatitis or gallbladder disease, BMI of 21 kg m⁻² or less, personal or family history of medullary thyroid cancer or type 2 multiple endocrine neoplasia, bariatric surgery within 6 months, any prior adverse reaction to GLP1-RAs, regular use of hydroxyurea, any serious medical or psychiatric illness that may interfere with trial participation, clinically significant diabetic retinopathy or gastroparesis, failure to comply with the study protocol or research group recommendations, inability or unwillingness to comply with safe diabetes management practices, inability to use AID system, or any other concern for safety for the participant as per clinical judgment of the investigator. The BMI cutoff was chosen to best assess the primary endpoint (time in range, that is, glycemic control) through several hypothetical mechanisms of semaglutide, while reducing the risk of participants becoming underweight. This is similar to past trials assessing GLP1-RAs in T1D²³. Recruitment was performed in the Division of Endocrinology at the McGill University Health Centre and from prior study participants interested in being contacted for future studies.

Procedures

At the initial visit, study procedures began after written informed consent was obtained and documented. Demographics such as age, duration of diabetes, medical history and medications were obtained; both participant-reported biological sex and gender were obtained. Laboratory testing and a physical examination were performed. This was combined with a training visit, where 30–60 min of diabetes management review (for example, hypoglycemia and exercise management) and a training on the drug (semaglutide or placebo) injection technique were performed.

After the initial visit, an 11-week drug dose titration period was initiated: 0.25 mg weekly for 4 weeks, then 0.5 mg weekly for 4 weeks, then 1 mg onward. The study team de-escalated the doses in case of participants’ intolerance of side effect. Participants remained on their usual pump therapy throughout the titration period. Remote review of side effects and CGM reports was performed at days 7, 21, 32, 56, 63 and 77 (±2 days) of the dose titration periods, and additionally as prespecified in the study protocol, as needed per the research team’s judgment. Insulin adjustments were made to reduce hypoglycemia and overt hyperglycemia.

After the dose titration period, participants used our research-based AID system for 28 days. A research-based AID system was chosen to minimize the selection bias of pump users who had the latest pump hardware, and because commercial AID use was not as widespread in Canada at the time of protocol creation. The system included an Ypsomed pump (Ypsomed), Dexcom G6 CGM (Dexcom) and a Pixel 2 smartphone with an application running the McGill insulin dosing algorithm⁴⁴. The system was initialized with participants’ total daily insulin doses, carbohydrate ratios and insulin basal rates. The system target glucose was set at 6 mmol l⁻¹ initially but was reduced to 5.5 mmol l⁻¹ if time spent below 3.9 mmol l⁻¹ was low. Remote follow-ups were performed on days 4, 7 and 21 (±2 days) of AID use to review CGM reports and make adjustments to carbohydrate ratios and basal rates, if needed. Additional follow-ups were made as needed as per the research team’s judgment for safety reasons; these additional follow-ups were prespecified in the protocol.

At the end of AID use, laboratory testing and anthropometric measurements were performed. Participants returned to their usual insulin for a washout period of 2 weeks. After the washout period, the second study drug was initiated, with identical procedures to the first intervention. The 2-week period was a ‘mock washout’; because of the long (11 weeks) dose titration period and the primary outcome being measured during the following 4 weeks, participants had 13 weeks of functional washout period.

Data handling

Glucose, insulin and meal data from the AID system were automatically synched to a secure cloud server whenever the participant’s device was connected to the internet. A research team member manually retrieved the data in JSON format from the cloud server onto a research-dedicated device for further analysis. A custom script preprocessed the JSON data to compute relevant graphs and metrics for follow-ups and study outcomes. For the titration period data, CGM outcomes, insulin requirements and carbohydrate intake were manually input from the pumps and CGM commercial software into a secure database. Manual entries were confirmed independently by two team members.

Randomization and masking

Participants were randomized to their intervention sequence, either semaglutide then placebo, or placebo then semaglutide. Block randomization was performed with randomly selected block sizes of 4, 6 or 8 by a researcher uninvolved with participants using the Sealed Envelope Ltd online tool⁴⁵. After eligibility and enrollment were confirmed, participants were officially entered into the randomization sequence. An envelope with the participant’s study ID and randomization sequence was placed in storage to be opened in case of an emergency in the trial; a second envelope with the participant’s study ID and randomization sequence was opened and placed in the participant’s study case report form. This second envelope was opened, signed and dated by one of the trial’s investigators. Randomization sequences were revealed only after the last participant’s last visit was completed. Semaglutide or placebo were dispensed by the research pharmacy, who were unblinded to drug allocations.

To mask study drug, semaglutide or placebo (saline) in sterile amber glass vials were given to participants, along with insulin syringes, dispensed by the research pharmacy, who were unblinded to drug allocation. Participants would administer 0.19, 0.37 or 0.74 ml to correspond to 0.25, 0.5 and 1 mg, respectively. Participants, investigators and other research personnel were blinded to allocation.

Outcomes

The primary endpoint was time in the target glucose range of 3.9–10.0 mmol l⁻¹ (time in range) between semaglutide (at maximum tolerated dose) and placebo, over the 28 days of AID use. Secondary endpoints included mean glucose level, s.d. and coefficient of variation of glucose levels, and times spent in hyperglycemia (above 10.0 and 13.9 mmol l⁻¹) and hypoglycemia (less than 3.0 and 3.9 mmol l⁻¹). Daytime (6:00–24:00 h) and nighttime (24:00–6:00 h) outcomes were also assessed. Other secondary endpoints included anthropometrics, insulin requirements, carbohydrate intake and laboratory analyses (for example, HbA1c).

Statistical analysis

A difference of 6.25 percentage points (that is, 90 min per day) in time in range was deemed significant^44,46. Assuming an s.d. of 10% in the difference^46,47,48, 23 participants would provide 80% power to detect this difference at a 5% significance level. To account for a 20% dropout rate, 28 participants were recruited.

A linear mixed effects model was used to assess the effects of treatment while adjusting for the order of interventions. To examine for carry-over effect in the primary and secondary outcomes, the models were fitted with the treatment by period interaction terms. Residual values were examined for normality and, if skewed, a Wilcoxon signed-rank test was used. P < 0.05 was deemed significant. Results are reported as the median (IQR) or mean (s.d.). No correction for multiplicity was made for the secondary comparisons. AE outcomes included all participants in the study to provide comprehensive safety reporting, while all other outcomes were reported for those who completed the study and had analyzable paired measures (that is, for both semaglutide and placebo). Pearson correlation and subanalyses were also performed for the associations of outcomes with baseline characteristics, such as age, sex and duration of diabetes. Sex and gender were to be analyzed separately if there were discrepancies in participants.

Data processing was performed using MATLAB (v.R2024a); statistical analysis were performed with SPSS (v.29.0.1.1).

Safety monitoring

A Data Safety and Monitoring Board consisting of two endocrinologists specialized in T1D adult care, independent of the study, intermittently reviewed data for safety. The Data Safety and Monitoring Board reviewed blinded data and had two meetings. The first meeting reviewed data for participants 1–6 and the second meeting reviewed data for participants 7–14. Meetings could also be scheduled if there was a serious AE suspected to be caused by the study, but this did not occur. The purpose of the data review was to confirm the absence of extreme, potentially unsafe reductions in insulin doses, carbohydrate intake or weight, and the absence of unsafe glucose levels (for example, time spent below 3.9 mmol l⁻¹ more than 4%) in either intervention.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.