Treatment of the disease of obesity in patients with type 1 diabetes with tirzepatide: a protocol for a randomised controlled trial in a single-centre setting

Abstract

Introduction

Medication for the disease of obesity has improved, and clinical trials based on natural gut hormones such as tirzepatide, showed only mild side effects and ~22% weight loss maintenance. However, patients with type 2 diabetes only lose 15% bodyweight with tirzepatide while tolerating the medications very well, but little is known in patients with the disease of obesity who also have type 1 diabetes, especially regarding safety of the medications. Tirzepatide’s licence in the Gulf countries and Europe for obesity does not exclude patients with obesity and type 1 diabetes, unlike the USA. In Kuwait, more than a quarter of patients with type 1 diabetes also have the disease of obesity. Tirzepatide is not approved for glycaemic control in patients with type 1 diabetes, because it is unlikely to make a difference. Because tirzepatide is approved for the treatment of obesity in patients who also have type 1 diabetes we can now test how effective treatments for obesity such as tirzepatide are for patients with obesity and type 1 diabetes. Concerns regarding the safety of the medication in type 1 diabetes can also be addressed thus addressing an important knowledge gap.

Methods and analysis

This will be a randomised double blind controlled trial of 60 patients with obesity and type 1 diabetes to test usual care with or without maximum tolerable dose of tirzepatide to achieve weight loss. We will investigate the safety of the medications in patients with obesity and type 1 diabetes to address important knowledge gap which can change clinical practice.

Ethics and dissemination

The study has received ethical approval from the Dasman Diabetes Institute Ethical Review Committee (HR-RA-2025-03) and is registered at ClinicalTrials.gov (NCT07096908). Written informed consent will be obtained from all participants, with no financial compensation provided. Data will be reported in accordance with Consolidated Standards of Reporting Trials guidelines, ensuring participant anonymity. Findings will be disseminated through peer-reviewed publications and presentations at national and international conferences.

Trial registration number

NCT07096908.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• To our knowledge, this is the first randomised controlled trial to evaluate tirzepatide in adults with both obesity and type 1 diabetes.

• The study addresses an important evidence gap by assessing a population excluded from most incretin-based therapy trials, despite eligibility for obesity treatment under current regional guidelines.

• A double-blind, placebo-controlled design enhances internal validity and minimises bias, and strict inclusion criteria (eg, C-peptide <0.01 nmol/L) ensure a homogenous study population.

• Findings from this study may inform future clinical and regulatory decisions, including current restrictions on tirzepatide use in people with type 1 diabetes in some regions.

• Limitations include small sample size and single centre setting, mechanistic studies are needed to clarify the role of reduced insulin’s anabolic effects to weight loss.

Introduction

Obesity is a global health challenge, with Kuwait reporting the highest prevalence rates worldwide.¹ Despite ongoing research, the pathogenesis of obesity remains incompletely understood. However, therapeutic approaches have advanced significantly in recent years. Particularly with the development of novel pharmacological agents. Tirzepatide, a non-selective glucagon-like peptide 1 (GLP-1) analogue which binds both the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, has been recently approved for the treatment of obesity in the USA, Europe, the UK and the Gulf countries.²,⁴ Notably, regulatory approvals in the UK, Europe and Gulf countries do not exclude individuals with coexisting type 1 diabetes, thereby permitting the use of tirzepatide for obesity management in this population. However, data regarding the safety and efficacy of these agents in patients with both obesity and type 1 diabetes remain limited.^{5 6}

Type 1 diabetes is associated with an increased risk of microvascular complications, including neuropathy, nephropathy and retinopathy, as well as macrovascular diseases, such as coronary artery disease, peripheral arterial disease and stroke.⁷,¹⁰ The presence of obesity may further exacerbate the risk of macrovascular complications in this population.¹¹ While type 1 diabetes is a global health concern, it is particularly significant in Kuwait, where the age-adjusted comparative prevalence of type 1 diabetes among adults (aged 20–79 years) is estimated at 0.6%.¹ Notably, more than 25% of patients with type 1 diabetes in Kuwait are also affected by obesity, and tirzepatide is already available and used clinically to manage individuals with both conditions.

Recent evidence from the Dasman Diabetes Institute has provided important insights into the safety and efficacy of combining GLP-1 receptor agonists with sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 1 diabetes and obesity. Real-world data have shown that this combination is generally well tolerated, with a notably low incidence of diabetic ketoacidosis (DKA), a key concern in this population.¹² To further investigate these findings, Dasman Diabetes Institute conducted the Obesity Treatments in Type 1 Diabetes (OTID) study (NCT05390307), a single-centre pilot RCT involving 60 adults aged 21–60 years with type 1 diabetes, body mass index (BMI) >25 kg/m², and early chronic kidney disease. Participants were randomised to five arms: usual care, GLP-1 receptor agonist, SGLT2 inhibitor, their combination and combination with lifestyle modification. Over 6 months, the combination therapy with lifestyle intervention led to significantly greater weight loss and improved renal outcomes, without notable differences in glycaemic control or blood pressure.¹³ Adverse events were evenly distributed, supporting the intervention’s safety.¹²,¹⁴ These findings reinforce the potential of combination therapy with GLP-1 and SGLT2i as a safe and effective strategy for weight management in patients with type 1 diabetes and obesity. In all cases, weight loss induced by GLP-1 receptor agonists appears to be primarily mediated by reduced food intake,⁴ although the broader health benefits of such interventions in this population are not fully understood.

Tirzepatide shares a side effect profile similar to other GLP-1-based therapies that have been in use for nearly two decades.¹⁵ Common side effects such as nausea, gastrointestinal discomfort, and changes in bowel habits are typically mild and can be significantly reduced through gradual dose titration, allowing patients to adjust before increasing the dose. In clinical practice, this personalised approach results in fewer adverse effects compared with the fixed, forced titration schedules used in regulatory trials. An RCT in patients with obesity and type 1 diabetes treated with liraglutide demonstrated that nausea is a common side effect, with a cumulative incidence of 65% in the liraglutide groups compared with 17% in the placebo group. Most patients reported moderate nausea primarily during the first 2–5 days after starting liraglutide and again for 2–4 days following each dose escalation. Notably, the dropout rate due to nausea was 9–10% among those receiving liraglutide.¹⁶ These findings highlight the importance of gradual dose titration and patient support to improve tolerability and minimise discontinuation due to gastrointestinal side effects. Importantly, tirzepatide does not cause hypoglycaemia on its own, but the risk increases when used alongside insulin or other glucose-lowering agents.¹⁷ Programmes like Dose Adjustment for Normal Eating (DAFNE) play a critical role in educating patients on how to safely adjust insulin doses, particularly during inter-current illnesses or when initiating tirzepatide, thereby minimising the risk of hypoglycaemia and DKA. Patients with obesity and type 1 diabetes treated with 1.8 mg liraglutide demonstrated significant reduction in body weight and insulin doses without any additional effect on HbA1c compared with placebo.^{18 19} The concerns of semaglutide and tirzepatide worsening retinopathy appear only to relate to patients with type 2 diabetes with established pre-proliferative or proliferative retinopathy who then have dramatic improvements in glycaemic control.²⁰ The blunted improvement in glycaemia in patients with obesity and type 1 diabetes makes such a risk very unlikely.

A retrospective study at Mayo Clinic found that tirzepatide use in adults with type 1 diabetes and obesity resulted in a median weight loss of 8.5% (12.2% at 12 months), a 0.9% reduction in HbA1c, and a 31.6% decrease in daily insulin requirements, with no increase in hypoglycaemia or serious adverse events.²¹ Additionally, a recently published study by Snaith et al. (2025) (the 12-week TIRTLE1 study) on patients with type 1 diabetes has shown that tirzepatide can lead to significant fat mass loss (−10.3 kg, 95% CI −12.8 to −7.7 kg; p=0.0002) and reduced insulin requirements (35.1%, 95% CI −46.5 to −21.3%; p=0.0002) compared with placebo, without compromising safety.⁶

Tirzepatide results in a dynamic weight loss phase and a weight stable phase.²² In a subset of patients, the initial dynamic phase of weight loss is accompanied by gastrointestinal discomfort (nausea, burping, diarrhoea and constipation), common side effects of specific and non-specific binding of the GLP-1 receptor agonist.^{23 24} In clinical practice, the dose of tirzepatide can be titrated slowly and gradually over weeks to lessen the severity of side-effects and improve tolerance. The maximum tolerated dose does not have to be the maximum dose for all patients and the number of weeks needed to attain the maximum tolerable dose can vary between patients but should not be faster than 24 weeks. Body weight loss stabilises at ~15–22% 6 months after the tirzepatide maintenance doses are reached and 12 months after tirzepatide was started. Most side effects are mild or resolved by this time, but slowing the dose titration can further improve tolerability.²⁵ Tirzepatide may predominantly control functional/mechanical complications of the disease of obesity in patients with type 1 diabetes, with a smaller effect on glucose-related outcomes.

To our knowledge, the present study is among the first trials to address this research question. While a recent study by Snaith et al⁶ investigates a related question, there are important differences between the studies. In particular, our trial is designed to capture the nadir of weight loss over a longer follow-up duration (76 weeks), consistent with established obesity trial durations,²⁶ and includes a larger planned sample size (n=60). These design features allow for a more comprehensive assessment of sustained efficacy, safety and clinical applicability of tirzepatide in this population.

Objectives

This study aims to evaluate the long-term effectiveness and safety of tirzepatide in people with obesity and type 1 diabetes focusing on improvements in weight, metabolic health, mental well-being and functional outcomes over a 76-week period.

Methods and analyses

Trial design and setting

This protocol describes a 76-week, randomised, single-centre, double-blind, parallel-group, two-arm trial comparing the maximal tolerable dose of tirzepatide (up to 15 mg once weekly) with placebo in participants with type 1 diabetes and a BMI ≥27 kg/m². The study design is outlined in figure 1. All study assessments and procedures will be performed at the Dasman Diabetes Institute.

Figure 1. Study design for tirzepatide in participants with type 1 diabetes and obesity. AE, adverse event; CGM, continuous glucose monitoring; DR, disease-related; DXA, dual-energy X-ray absorptiometry; HbA1c, glycated haemoglobin.

Public and patient involvement

Prior to the study initiation, we engaged with a group of individuals with type 1 diabetes who met the study criteria to review and discuss the study plan. During these discussions, participants expressed concerns regarding the long study duration and the requirement to continue medication if they achieved their target weight, the need for flexibility in scheduling weekly visits, travel-related challenges, potential side effects, and the impact on blood glucose levels. All these concerns were carefully addressed in the study protocol and detailed explanations were provided to all participants to ensure clarity procedures and manage any issues raised.

Participants and recruitment

Adults diagnosed with both obesity and type 1 diabetes will be recruited. Eligibility requires self-reported history of at least one unsuccessful dietary attempt to lose weight. The definition of clinical obesity diagnostic aligns with the current tirzepatide prescribing indications: individuals with BMI ≥27 kg/m² and at least one obesity-related comorbidity (eg, hypertension, dyslipidaemia or obstructive sleep apnea) will be considered to have obesity. It is anticipated that over 90% of enrolled participants will have a BMI >30 kg/m² and one or more obesity-related complications.

Given that tirzepatide’s effects on glucose and other metabolic outcomes may vary by C-peptide status, only participants with C-peptide levels<0.01 nmol/L will be eligible. Additional inclusion criteria include an HbA1c between 6.5% and 10% and current treatment with either multiple daily insulin injections or continuous subcutaneous insulin infusion.

A screening period of up to 4 weeks will be implemented to assess eligibility. Participants may be re-screened once if prior ineligibility was due to a reversible factor, at the discretion of the investigator. Full eligibility criteria are provided in box 1.

Box 1. Eligibility criteria.

Inclusion criteria

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.

• Male or female, adults between the ages of 18 and 70 years.

• Documented diagnosis of type 1 diabetes mellitus (T1DM) (per American Diabetes Association (ADA), 2024 definition/criteria) for at least 1 year before screening visit with C-peptide level of less than 0.01 nm/L.

• Body mass index ≥ 27.0 kg/m².

• History of at least one self-reported unsuccessful dietary effort to lose body weight.

• Must be using a continuous glucose monitoring (CGM) device for at least 2 months before the screening visit and be willing to wear a CGM device for the duration of the study.

Exclusion criteria

Diabetes related:

• Glycated haemoglobin (HbA1c) ≥86 mmol/mol (10%) as measured by the central laboratory at screening.

• Treatment with a glucagon-like peptide-1 receptor agonist within 180 days before screening.

• Pre-proliferative or proliferative retinopathy.

• Experienced diabetic ketoacidosis within 6 months of screening visit.

• Experienced severe hypoglycaemia (level 3) within 6 months of screening visit.

Obesity-related:

• A self-reported change in body weight>5 kg (11 lbs) within 90 days before screening irrespective of medical records.

• Treatment with any medication for the indication of obesity within the past 90 days before screening.

• Previous or planned (during the trial period) obesity treatment with surgery or a weight-loss device. However, the following are allowed: (1) liposuction and/or abdominoplasty, if performed >1 year before screening; (2) lap banding, if the band has been removed >1 year before screening; (3) intragastric balloon, if the balloon has been removed >1 year before screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed >1 year before screening.

• Uncontrolled thyroid disease, defined as thyroid stimulating hormone >6.0 mIU/L or <0.4 mIU/L as measured by the central laboratory at screening.

Mental health:

• History of major depressive disorder within 2 years before screening.

• Diagnosis of other severe psychiatric disorders (eg, schizophrenia, bipolar disorder).

• A Patient Health Questionnaire-9 score of ≥15 at screening.

• A lifetime history of a suicidal attempt.

• Suicidal behaviour within 30 days before screening.

• Suicidal ideation corresponding to type 4 or 5 on the Columbia-Suicide Severity Rating Scale within the past 30 days before screening.

General safety:

• Use of non-herbal Chinese medicine or other non-herbal local medicine with unknown/unspecified content within 90 days before screening.

• Presence of acute pancreatitis within the past 180 days prior to the day of screening.

• History or presence of chronic pancreatitis.

• Calcitonin ≥100 ng/L as measured by the central laboratory at screening.

• Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.

• Renal impairment measured as estimated glomerular filtration rate value of <15 mL/min/1.73 m² as defined by Kidney Disease Improving Global Outcomes (KDIGO 2012) by the central laboratory at screening.

• History of malignant neoplasms within the past 5 years prior to screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.

• Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina or transient ischaemic attack within the past 60 days prior to screening.

• Subject presently classified as being in New York Heart Association Class IV.

• Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the opinion of the investigator.

• Known or suspected abuse of alcohol or recreational drugs.

• Known or suspected hypersensitivity to trial product(s) or related products.

• Previous participation in this trial. Participation is defined as signed informed consent.

• Participation in another clinical trial within 90 days before screening.

• Other subject(s) from the same household participating in any semaglutide trial.

• Female who is pregnant, breast-feeding, or intends to become pregnant, or is of childbearing potential and not using a highly effective contraceptive method.

• Any disorder, unwillingness, or inability, not covered by any of the other exclusion criteria, which in the investigator’s opinion, might jeopardise the subject’s safety or compliance with the protocol.

Procedures

Pre-intervention (baseline visit)

All eligible participants will undergo a discretionary insulin-adjustment period for up to 2 weeks, based on the stability and insulin regimen optimisation, aiming for fasting and pre-meal glucose levels between 3.9–7 mmol/L and postprandial peaks<10 mmol/L. CGM metrics and insulin dose data collected during this run-in phase (week −2 to day 1) will serve as baseline values.

Insulin dose adjustments during the pre-randomisation period will be guided by participants’ screening HbA1c levels. Those with HbA1c between 7.0% and <8.0% will receive an approximate 10% reduction in total daily insulin dose, while no initial adjustment will be made for participants with HbA1c>8.0%. A treat-to-target algorithm will be used to optimise basal insulin, aiming for fasting and pre-meal glucose levels of 4.4–7.2 mmol/L and postprandial peaks<10 mmol/L, based on CGM data. Adjustments will be made during in-clinic visits as needed by the investigator or qualified staff. All participants will have completed DAFNE training and be familiar with their insulin-to-carbohydrate ratios and insulin sensitivity factor. Insulin dose changes (basal, bolus and total daily doses) will be recorded throughout the study (week −4 to week 76). Participants may use either an FDA-approved insulin pump or multiple daily injections and must have used a CGM device for at least 2 months prior to screening. FreeStyle Libre 2 sensors will be provided and placed by clinic staff with accounts linked to the Dasman Diabetes Institute practice ID for weekly CGM data downloads, including the 2-week pre-randomisation phase and at each titrated dose level, as detailed in table 1. The number of hypoglycaemic events (levels 1, 2 and 3) will be recorded over the period of the trial.

Table 1. Continuous glucose monitoring metrics.

Description	Glycaemia criteria	Notes
Time in range	Glucose 3.9–10 mmol/L
Time spent in hypoglycaemia	Glucose <3.9 and ≥3.0 mmol/L	Level 1
	Glucose <3.0 mmol/L	Level 2
	A severe event characterised by altered mental and/or physical status requiring assistance for treatment of hypoglycaemia	Level 3
Time spent in hyperglycaemia	Glucose >10 and <13.9 mmol/L	Level 1
	Glucose >13.9 mmol/L	Level 2

Randomisation and blinding

Eligible participants will be randomised in a 1:1 ratio to receive either once-weekly tirzepatide or placebo, alongside a reduced-calorie diet and increased physical activity. The trial is conducted at Dasman Diabetes Institute, where all participants will be recruited. To maintain double-blind conditions, study injections will be administered weekly by a healthcare professional at Dasman Diabetes Institute unaffiliated with the scientific team. Dose adjustments will be made by the blinded clinical team based on reported side effects, ensuring safety and insulin optimisation to prevent hypoglycaemia and DKA.

To ensure blinding during medication administration, a contingency plan is in place should placebo pens be unavailable. Tirzepatide will be supplied in vials, allowing preparation via syringe. An unblinded pharmacist, independent from the study team and without involvement in data collection or analysis, will prepare a 0.6 mL of either tirzepatide or saline in identical syringe. A blinded study nurse will administer the injection, ensuring the participants in both treatment arms have identical experience, thereby maintaining blinding integrity.

Study interventions

Participants will receive a once-weekly subcutaneous injection of either tirzepatide or a volume-matched placebo administered in the upper arm. Treatment will begin at 2.5 mg weekly for the initial 4 weeks, followed by dose escalation phase every 4 weeks to reach a maximum maintenance dose of 15 mg/week by weeks 24–32. Escalation may extend up to 32 weeks if re-escalation is required due to gastrointestinal symptoms. This will be followed by a maintenance phase through week 76. Weekly site or remote visits will occur throughout both phases. A follow-up safety visit is scheduled 28 days after the final dose (ie, 21 days after week 76; see figure 1).

Participants are expected to maintain their usual lifestyle and standard of care for type 1 diabetes and any stable chronic conditions. Blood glucose metres and urine ketone strips will be provided for additional self-monitoring. Participants will be instructed to report hypoglycaemia symptoms, measure glucose levels, and document events, including ketone testing if symptoms of DKA occur.

Substantial weight loss is expected to improve insulin resistance in participants with obesity and type 1 diabetes. All participants will receive guidance on how insulin management, particularly basal and pre-prandial titration, and will have completed the DAFNE programme, which may reduce their risk of either hypoglycaemia or DKA. Weekly clinic visits will support early identification of glycaemic trends and safety concerns.

Anti-hyperglycaemia medications should follow American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) guidelines (P22-05567) and product labels. Use of anti-obesity medications such as GLP-1R agonists, GLP-1R agonist/insulin/GIP combinations, amylin analogues, and treatments for type 2 diabetes such as DPP-4i is not permitted during the study. All participants will receive dietary counselling targeting an ~500 kcal/day energy deficit and physical activity guidance (≥150 min/week) from qualified healthcare professionals at designated time points.

Baseline assessment

Prior to the first dose on day 1 (within a window of day −7 to day 1), participants will undergo a complete physical examination, including measurements of weight, waist, and hip circumference. Baseline procedures will include dual-energy X-ray absorptiometry (DEXA), patient-reported outcomes (PROs), safety and biomarker blood sampling for biobanking, cardiac and liver MRI, retinal scan, and ECGs as outlined in figure 1. Vital signs, including systolic and diastolic blood pressure and pulse rate, will be measured weekly and prior to each blood draw.

Following randomisation, dosing will occur only after completion of all baseline assessments and will be observed in-clinic. Participants will attend weekly study visits, with biweekly CGM device placement by qualified staff. Continuous subcutaneous insulin infusion and CGM data will be downloaded and uploaded into the study’s electronic data capture system (REDCap), while multiple daily injections users will manually enter insulin doses via the Libre 2 app.

Study outcome measures

Primary endpoint

The primary endpoint is the change in body weight after 76 weeks from baseline.

Secondary endpoints

Change in the following outcomes measured at 24 weeks and 76 weeks after tirzepatide treatment compared with placebo:

1. Adverse events incidence: nausea, vomiting, hypoglycaemia.

2. Severe adverse event incidence: DKA, gallbladder related diseases, pancreatitis, hospitalisation

3. Glycaemia: HbA1c (measured every 12 weeks), CGM metrics including time in range (3.9–10 mmol/L), time spent in hypoglycaemia Level 1 (<3.9 mmol/L) and Level 2 (<3.0 mmol/L), hyperglycaemia Level 1 (>10 mmol/L) and Level 2 (>13.9 mmol/L) over 18 weeks and at each titrated dose level (table 1).

4. Absolute and relative changes in basal, bolus and total daily insulin doses (units/day and units/kg/day) over 76 weeks and at each titrated dose level.

5. Metabolic control: blood pressure, lipid profile, inflammatory biomarkers, liver, heart, kidney function tests.

6. Quality of life assessments: The 36-Item Short Form Health Survey (SF-36) and the Impact of Weight on Quality of Life–Lite (IWQOL-Lite) questionnaires.

7. Microvascular disease: changes in retinopathy and urine albumin creatinine ratio.

8. Body composition: We will measure total fat, VAT fat mass, limb fat mass, lean mass and bone mineral density/content via DEXA. The radiation dose is very small (<10 micro Sievert) which is equivalent to 1-day background radiation received at sea level. The equipment used is the GE Lunar iDXA, performed on model encore version 18, GE 2022.

Exploratory endpoints

Liver and heart MRI scans will be performed on a 1.5 Tesla scanner (Signa Artist, GE Medical systems). The MRI-PDFF calculation for liver fat quantification is done with IDEAL-IQ sequence provided by the manufacturer. The study uses a 3-D fat fraction sequence called Iterative Decomposition of water and fat with Echo Asymmetry and Least square estimation (IDEAL-IQ). We will also measure stiffness through MR elastography. Cardiac MRI: Evaluation of left ventricular systolic and diastolic and LV mass with MRI to evaluate the following parameters will be measured at rest: LV ejection fraction, LV end systolic volume, LV end diastolic volume, LA maximal volume, LA minimal volume, LA mid diastolic volume, LV peak ejection rate, Ascending aorta distensibility, LV early peak filling rate, LV mass, early mitral inflow (E-waves) and LV strain (global, longitudinal and radial).

Safety assessment

This trial is designed in accordance with regulatory guidelines related to products in clinical development for chronic weight management (R22-1651, R22-1946). A 76-week treatment duration is considered sufficient to evaluate both safety and efficacy. Inclusion of a placebo comparator allows for clearer characterisation of treatment effects. Participants will receive standard care for type 1 diabetes and other stable chronic conditions, with investigators monitoring and adjusting concomitant therapies as needed. At each visit, participants will be assessed to ensure optimal management of weight-related complications.

Participants who discontinue the investigational medicinal product prematurely will be encouraged to continue the scheduled trial visits. Follow-up visits should be conducted in-clinic whenever possible; remote visits or phone calls (per local regulations) will be used to assess vital status. Body weight, adverse events and changes in concomitant therapy will be recorded. The end of trial is defined as the date the last participant completes their final visit, including follow-up.

Data management, efficacy and safety monitoring

Study data will be managed using REDCap, with pseudo-anonymised to ensure secure coding, monitoring and verification. Efficacy endpoints are defined in the methods section, with primary outcomes assessed at week 76 and secondary outcomes at weeks 24 and 76. Safety will be monitored throughout the study via weekly clinic visits, participant reported adverse events, physical exam, vital signs, ECG and laboratory tests (haematology, chemistry/metabolic panel, lipid profile, amylase, lipase, urinalysis), with all blood samples collected in a fasted state. PROs and self-reported events (such as DKA episode, gallbladder related disease, pancreatitis or hospitalisation) will be documented. Laboratory analyses will be conducted by Dasman Diabetes Institute, with reference ranges provided and clinically significant abnormalities reported as adverse events. Safety labs will include complete blood count with differential and reticulocyte count, clinical chemistry (liver, renal, pancreatic, electrolyte, protein, thyroid and metabolic parameters), glucose metabolism (fasting plasma glucose (FPG), HbA1c, C-peptide), lipid profile (cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), triglycerides, free fatty acids), urinalysis (semiquantitative and quantitative, including urine albumin-to-creatinine ratio (UACR)) and pregnancy testing for women of childbearing potential.

Sample size calculation

The target sample size is 60 participants, 30 receiving trizepatide and 30 receiving placebo. The power calculation was determined based on the effect size observed in the SURMOUNT-2 study,⁵ which reported a 15% weight loss from a baseline of 100 kg with a SD of 16 kg in patients with type 2 diabetes. Using a two-sided alpha of 0.05 and a beta of 0.1, the study is powered at 90% to detect a similar effect. To account for potential attrition, a conservative dropout rate of 15% has been incorporated into the sample size calculation.

Statistical analysis

All analyses will follow the intention-to-treat principle, with per-protocol analyses conducted as sensitivity analysis. The primary outcome, mean weight loss difference between treatment and placebo groups, will be assessed at week 76 post-treatment, with secondary outcomes evaluated at weeks 24 and 76. No interim analysis is planned. Exploratory outcomes, including liver and cardiac imaging, will provide preliminary effect size and variability estimates to inform future studies, as this is, to our knowledge, among the first randomised controlled trials of tirzepatide in patients with obesity and type 1 diabetes.

Statistical analyses will be performed using IBM SPSS software (V.29). An analysis of covariance model will be used to adjust for baseline imbalances and improve statistical power. Logistic regression will be applied for binary outcomes when covariates adjustment is needed; otherwise, Fisher’s exact test will be used to examine the treatment difference in categorical outcomes. All tests of treatment effects will be conducted at a two-sided alpha level of 0.05 and 95% CIs. Summary statistics for continuous measures will include sample size, mean, SD, median, minimum and maximum for continuous and count variables, and frequency and percentages for categorical variables. Data on treatment adherence, safety (including adverse events) and treatment satisfaction will be summarised and tabulated.

Ethics and dissemination

Ethics approval and trial registration

This study protocol was approved by the Ethical Review Committee of Dasman Diabetes Institute (HR-RA-2025-03). Written informed consent will be obtained from all participants (online supplemental material 1). Ethical considerations include the use of tirzepatide in individuals with type 1 diabetes, which is permitted under current regulatory approvals in Gulf countries, Europe and the UK. Participants randomised to the placebo arm will continue to receive best medical care, consistent with international standards. Post-trial access to tirzepatide is available in Kuwait and fully reimbursed for eligible patients.

Data sharing plan

Participant confidentiality will be strictly maintained. Identifiable information will be securely stored in accordance with International Conference on Harmonisation guidelines and local Dasman Diabetes Institute regulations. De-identified participant data and study materials will be made available upon reasonable request, in accordance with institutional and regulatory guidelines.

Dissemination policy

Study findings will be disseminated in accordance with the Consolidated Standards of Reporting Trials guidelines.²⁷ No identifying information will be disclosed. Results will be published in peer-reviewed journals and presented at national and international conferences, targeting audiences including clinicians and dietitians. All dissemination efforts will ensure participant anonymity.

The funder had no role in the design of this study and will have no role in data collection, data analysis, data interpretation or writing of the manuscript.