Objective
The primary objective of this study is to evaluate improvement in a composite outcome (glucose time in range 70% with time below range of 70% with TBR of <5% and reduction in body weight by 5%) after 26 weeks of treatment with Semaglutide or placebo. Hypothesis: Semaglutide will increase the odds of achieving the composite outcome compared to placebo.
Specific Aim 2: Examine changes in surrogate cardiovascular markers (aortic and cardiac structure and function, carotid atherosclerosis, arterial stiffness) with semaglutide treatment. Hypothesis: Semaglutide treatment will reduce central and peripheral arterial stiffness and carotid atherosclerosis compared to placebo over 26 weeks.
Specific Aim 3: Examine changes in ectopic fat depots (pericardial and intrabdominal) and serum markers of oxidative stress and inflammation with semaglutide treatment and associations with changes in surrogate CVD markers. Hypothesis: Semaglutide treatment will reduce ectopic fat depots, markers of oxidative stress and inflammation; these changes will correlate with weight and CVD marker changes.
Background Rationale
Due to the complexity of managing type 1 diabetes (T1D) and hypoglycemia associated with intensive insulin therapy, only 30% of patients with T1D are able to achieve desirable glycemic control (HbA1c <7%), as recommended by the American Diabetes Association, leading to complications that include kidney, eye and cardiovascular disease (CVD). CVD is the leading cause of death in T1D, and despite improvements in care, deaths from CVD remain elevated 2-8 fold and contribute to a loss of 11-13 years in life expectancy. Even those people who do achieve an HbA1c < 7% remain at a 3-fold increased risk for CVD mortality. Moreover, the prevalence of overweight and obesity is increasing among patients with T1D. Insulin resistance and inflammation, both increased by obesity, are linked with higher CVD risk in T1D.
Hybrid closed-loop (HCL) systems, also known as the artificial pancreas, include an insulin pump that delivers an insulin dose based on continuous glucose monitor (CGM)-based glucose values by means of controller (mathematical) algorithm. Studies with HCL have been shown to improve glycemic control and reduce hypoglycemia in children, adolescents, and adults with T1D, but are also associated with weight gain. In our clinic, among adults with suboptimal glycemic control, the Tandem Control IQ HCL reduced HbA1c by 1.6% on average, but resulted in a weight gain of 3 kg over the first 6 months of use. This weight gain could offset the CVD risk reduction due to improvements in glycemic control, and could increase insulin resistance.
HCL systems are the most advanced diabetes management tools in the armamentarium of diabetes management. With increasing use of diabetes technologies such as CGM and HCL, diabetes care is now moving from HbA1c centric to CGM-based metrics such as time-in-range (TIR; sensor glucose between 70-180 mg/dL), time-below range (TBR; sensor glucose 180 mg/dL). International consensus recommends TIR>70% with TBR of 7% a 4-fold risk of CVD events in adults with T1D. Therefore, obese adults with T1D who are at suboptimal glycemic control despite HCL use may be an ideal population to target for weight loss and CVD reduction through adjunct therapy with semaglutide.
Description of Project
Hybrid closed loop (HCL) automated insulin delivery systems are considered the gold standard in type 1 diabetes management. Use of HCL has been shown to improve glycemic control and therefore is the best method to decrease diabetes related complications. However, increase of blood glucose after meals is still a challenge in patients using HCL systems. In addition, HCL system use is associated with modest weight gain. Obesity is increasing among patients with type 1 diabetes, which leads to suboptimal glycemic control and increased risk for cardiovascular diseases. Therefore, there is a need for adjunctive medications to treat obesity to reduce cardiovascular disease risk and improve metabolic outcomes in adults with type 1 diabetes.
There are two class of drugs, SGLT-2 inhibitor and GLP-1RA, that showed improved glycemic and cardiovascular outcomes in patients with type 2 diabetes. Both classes of drugs are associated with weight loss and improvement in insulin sensitivity. However, SGLT-2 inhibitors are associated with increased risk for diabetic ketoacidosis (DKA) and hence, was not approved by the US FDA for management of type 1 diabetes. Long-acting GLP-1RA are very effective weight loss agents, reduce cardiovascular events and do not increase the risk for DKA. Therefore, long-acting GLP-1RA such as once-weekly semaglutide may have a role in glycemic and metabolic management of type 1 diabetes.
This study aims to investigate the long-term safety and effectiveness of semaglutide in obese patients with type 1 diabetes who are already on HCL therapy but still are not able to achieve recommended glycemic goals (HbA1c <7%). This study will examine effect of semaglutide compared to placebo on glycemic control and cardio-renal outcomes over 26 weeks.
Anticipated Outcome
In SUSTAIN 1, 4 and 5 clinical trials, Semaglutide 0.5 mg and 1 mg per week for 30 weeks in patients with type 2 diabetes resulted in 2.5-4.5 kg, and 3.5-6 kg weight loss compared to baseline. 30-40% of patients with type 2 diabetes with baseline BMI between 30-35 kg/m2 achieved weight loss of >5% using Semaglutide 0.5 mg weekly compared to comparator and 45-60% had weight loss >5% using Semaglutide 1 mg weekly compared to comparator. Based on these data, we conservatively estimated that 40% of patients with T1D using HCL and randomized to semaglutide with BMI >30 kg/m2 will achieve >5% weight loss after 26 weeks of treatment with semaglutide. None of the clinical trials in T1D demonstrated weight loss with the use of HCL therapy and in fact, our preliminary data show weight gain with HCL. Therefore, we don’t expect adults with T1D using HCL and randomized to placebo to lose >5% of body weight.
Our previous real-life study of adults with T1D using Medtronic 670 G had mean ± SEM percent TIR of 67%±1.2% after 3 months of using HCL. In our clinical experience of using semaglutide in adults with T1D with mean HbA1c of 7.7±1.4 at baseline, there was a drop in HbA1c to 7.2±1.1 after 3 months (unpublished data). Each 5% improvement in TIR approximates reduction in HbA1c by 0.3-0.4% and therefore, based on our preliminary data, we expect that a greater percentage of adults with T1D randomized to semaglutide will have improvement in TIR by at least 5% than adults with T1D randomized to placebo. We estimate that >75% of adults with T1D using HCL and randomized to semaglutide will achieve TIR >70%. Moreover, most adults with T1D using HCL system have TBR 75% of adults with T1D on HCL and randomized to either semaglutide or placebo would have TIR >70% and TBR < 5%. Considering the data from the above studies, we expect that 30-40% adults with T1D using HCL and randomized to semaglutide will achieve the composite outcome compared to 0-5% of adults randomized to placebo. If this study is successful, it will be the first clinical trial to demonstrate safety and efficacy of semaglutide adjunct therapy in adults with type 1 diabetes. Further, we plan to examine the effect of semaglutide treatment on surrogate cardiovascular and kidney markers to inform future clinical trials of semaglutide and cardiovacular events in type 1 diabetes.
Relevance to T1D
There are a number of anti-diabetic treatments for type 2 diabetes that have been demonstrated to improve glycemic control and to also reduce cardiovascular risk, including sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonist (GLP-1RA) drugs. However, neither class of drugs has been approved in people with type 1 diabetes, due to increased risk of diabetic ketoacidosis with SGLT2 inhibitors, and lack of evidence from clinical trials in the case of GLP-1RA. This proposed study will examine semaglutide, a GLP-1RA, as adjunct therapy in adults with type 1 diabetes who are obese and inadequately controlled on optimal insulin therapy using a hybrid closed loop system. This randomized clinical trial is powered to examine efficacy in a multi-center, blinded and placebo-controlled trial, with a composite outcome of meeting glycemic targets (>70% glucose time in range and <5% glucose below target range) and weight loss. Both weight loss and improved glycemic control have the potential to also improve cardiovascular risk, and so we are planning a pilot investigation of surrogate cardiovascular markers at two of the four clinical trial sites.
This proposed trial will therefore move forward the science of adjunct therapies in people with type 1 diabetes, and will also provide valuable pilot data to plan larger scale clinical trials of cardiovascular outcomes, should the data indicate that treatment with semaglutide reduces cardiovascular surrogate markers.