Objective
We will examine weight loss of patients with the disease of obesity who also have type 1 diabetes after tirzepatide treatment in a randomized controlled trial. Benefits beyond weight loss including continuous glucose monitoring, HbAc1, cardiovascular risk factors, inflammation, markers of diabetic nephropathy and retinopathy, liver and heart imaging, body composition by DXA, liver, heart, kidney function tests, as well as psychosocial wellbeing will also be studied. Importantly, we will also be able to capture any safety signals to address this important knowledge gap. To reduce safety concerns, patients will be treated according to the SURMOUNT MMO trial dose escalation protocol, which will allow dose escalation to be slowed if patients have side effects such as nausea. This in turn will reduce vomiting and risk of hypoglycemia and diabetic ketoacidosis. Weight nadir will not be affected by this dose escalation protocol, but retention of participants will be enhanced.
Objectives:
Primary outcomes: safety and weight loss
Secondary outcomes: improvements in functionality, metabolic health, and mental health. Benefits beyond weight loss including continuous glucose monitoring, HbAc1, cardiovascular risk factors, inflammation, markers of diabetic nephropathy and retinopathy, liver and heart imaging, body composition by DXA, liver, heart, kidney function tests, as well as psychosocial wellbeing will also be studied.
Background Rationale
People in Kuwait have the highest rates in the world of the disease of obesity. The pathogenesis of the disease of obesity is poorly understood, but treatment of the disease has dramatically improved in the last 3 years. New medications such as tirzepatide is now licensed for the treatment of the disease of obesity, while patients with type 1 diabetes are not excluded in Europe, UK, and the Gulf countries. As an exception, the approved license for obesity in the USA excludes patients with obesity and type 1 diabetes. Thus, it will be within the Kuwaiti license of tirzepatide to treat people with the disease of obesity who also have type 1 diabetes.
Tirzepatide is a non-selective GLP-1 analogue which binds both the glucagon-like peptide 1 (GLP-1) and GIP receptors. The medication results in 22% weight loss in people without diabetes. Very little is known about safety and weight loss in patients with obesity and type 1 diabetes, but the existing real world data from Dasman Diabetes Institute (DDI) and randomized controlled trial data from DDI suggest that patients with obesity and type 1 diabetes do not have increased safety risks and lose similar amounts of weight than those without diabetes (1-3).
Side effects of tirzepatide are similar to other GLP-1 based medications which have been used for the last 19 years. These side effects can be significantly reduced by slowing dose titration and only increasing the dose when the patient is able to tolerate the medication.
• Nausea is common, especially when starting the medication or increasing the dose. Nausea subsides within weeks if the dose is not escalated. Vomiting is very rare if drug doses are only up titrated in patients without nausea.
• Diarrhea or constipation occur in 5-15% of individuals. Managing symptoms early and aggressively with lifestyle changes can control this side effect.
• Hypoglycemia: tirzepatide reduces insulin resistance and does not cause hypoglycaemia on its own. However hypoglyemia can occur when other glucose-lowering medications or insulin is used, albeit can can be prevented if insulin is carefully down titrated.
• Diabetic keto-acidosis rarely occur because of tirzepatide, but may be triggered by an incurrent illness or if insulin doses are reduced excessively.
• Injection site reactions can occur, but weekly injection makes this less common.
• Excessive weight loss can be prevented by slowing or adjusting dose titration to achieve maximum tolerable dose.
• Gallstones and pancreatitis are rare but associated with significant weight loss induced by diets, medications and bariatric surgery.
• Acute kidney injury can occur in patients who become volume depleted when they have uncontrolled vomiting. This should not occur in modern medical practice if patients are slowly titrated to reduce nausea.
The real-world evidence generated by the Dasman Diabetes Institute (DDI) on the combination of GLP-1 and SGLT2i in patients with obesity and type 1 diabetes is also reassuring as regards the relatively low rate of side effects, especially the low rate of diabetic keto-acidosis. Moreover, a recently completed randomized controlled trial at DDI in patients with obesity and type 1 diabetes show that GLP-1 therapy either alone or in combination with SGLT2i is safe and effective at reducing weight and insulin requirement albeit that glycaemia remains similar to the patients in the control arm. GLP-1 also appeared to reduce renal damage as measured by urine albumin creatinine ratios.
Description of Project
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 license 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 medications in type 1 diabetes can also be addressed thus addressing an important knowledge gap.
Anticipated Outcome
Based on the scant literature, we predict that the side effects of tirzepatide in patients with obesity and type 1 diabetes will be similar what have been seen with other GLP-1 based medications (18). We do not expect to see an increase in severe complications such as hypoglycaemia needing third party assistance or diabetic keto-acidosis. We expect weight loss in patients with type 1 diabetes would be similar as observed in people without diabetes (SURMOUNT 1 study) and more than people with type 2 diabetes (SURMOUNT 2 study). Alternatively, it may be that patients with type 1 diabetes lose less weight than people without diabetes and are more aligned with patients with type 2 diabetes. Either way this would be the first of its kind investigation and would provide novel and valuable information for clinicians and patients. The outcome of this study will benefit the people in Kuwait living with type 1 diabetes, because it will create an evidence base for the first time to allow clinicians in Kuwait to make decisions how to treat the more than quarter of people with type 1 diabetes who also have the disease of obesity. Given that Kuwait has some of the highest incidences of type 1 diabetes and the highest incidence of obesity in the world the number of patients who would benefit are substantial.
Relevance to T1D
Type 1 diabetes increases the risk of microvascular diseases, such as neuropathy, nephropathy, and retinopathy, and macrovascular diseases, such as coronary artery disease, peripheral arterial disease, and stroke (5-8). The macrovascular complications may further be exaggerated by obesity (9). Undeniably, type 1 diabetes is a global issue, but it is of particular concern in countries like Kuwait, where the age-adjusted comparative prevalence of type 1 diabetes in adults (age: 20–79 years) is estimated to be 0.6% (10). An added challenge in Kuwait is that more than 25% of patients with type 1 diabetes also have the disease of obesity. Tirzepatide is already available in Kuwait and being used clinically to treat people with obesity and type 1 diabetes according to tirzepatide's licence in the Gulf countries, Europe, and the UK.
Randomized controlled trial of patients with obesity and type 1 diabetes treated with liraglutide showed the cumulative incidence of nausea was 65% in the liraglutide groups vs. 17% in the placebo group. Self-reported moderate nausea was reported for the first 2–5 days after the initiation of liraglutide and then for another 2–4 days at the time of escalation of the dose. The dropout rate resulting from nausea was 9-10% in the liraglutide groups. Hypoglycaemia rates were 3% in both the placebo arm and the liraglutide 1.8mg arm of the study (11). 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 (12-13).
The concerns of semaglutide and tirzepatide worsening retinopathy appears only to relate to patients with type 2 diabetes with established retinopathy who then have dramatic improvements in glycaemic control. The blunted improvement in glycaemia in patients with obesity and type 1 diabetes makes such a risk very unlikely.