GLP-1 Analogue Therapy for Cardiometabolic Risk in Type 1 Diabetes

Overseen By Rehema Mtawali

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must not be taking: Adjunctive diabetes, Anti-obesity, Lipid lowering

Disqualifiers: Renal impairment, Liver disease, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

More than 40% of young adults with type 1 diabetes (T1D) also have overweight or obesity. Each of these diagnoses increase the risk of adverse cardiovascular events. Investigators aim to obtain reference data for individuals with T1D who do not have overweight obesity, to understand how close GLP-1 analogue obesity treatment in those with overweight/obesity brings physiologic markers of cardiometabolic risk to those with BMI in the normal range. Specifically, investigators will describe how drivers of gluconeogenesis and lipemia (specifically measured as visceral fat ratio, insulin resistance, and postprandial lipemia,) that contribute to cardiometabolic risk in T1D change over time.

Will I have to stop taking my current medications?

The trial requires that you do not use any adjunctive diabetes medication or anti-obesity medication, and you cannot use lipid-lowering medications other than statins or omega-3 products. If you are on these medications, you may need to stop them to participate.

Is GLP-1 Analogue Therapy safe for humans?

Liraglutide, a GLP-1 analogue marketed as Victoza and Saxenda, has been shown to be safe in clinical trials for treating type 2 diabetes and obesity. It is generally well-tolerated, with safety demonstrated in various studies, including those for obesity and weight management. ^{1 2 3 4 5}

How does the drug GLP-1 Analogue Therapy differ from other treatments for cardiometabolic risk in type 1 diabetes?

GLP-1 Analogue Therapy, using drugs like Victoza and Saxenda, is unique because it targets the GLP-1 receptor to improve insulin release and reduce glucagon (a hormone that raises blood sugar) secretion, which can help manage blood sugar levels and reduce cardiovascular risks. Unlike traditional insulin therapy, these drugs also help with weight loss and have a positive impact on heart health, making them a novel option for managing cardiometabolic risks in type 1 diabetes. ^{6 7 8 9 10}

What data supports the effectiveness of the drug GLP-1 Analogue Therapy for reducing cardiometabolic risk in Type 1 Diabetes?

Research shows that GLP-1 receptor agonists, like those used in the treatment, can help reduce cardiovascular risk factors such as body weight, blood pressure, and cholesterol levels in people with Type 2 diabetes. These benefits may also apply to people with Type 1 diabetes, potentially improving heart health. ^{6 7 11 12 13}

Who Is on the Research Team?

Michelle Van Name, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for young adults aged 18-30 with Type 1 Diabetes who are not overweight, use continuous glucose monitoring, have an HbA1c level ≤10%, and no severe kidney or liver issues. They must be willing to follow the study procedures for its duration and cannot be pregnant, lactating, or planning pregnancy.

Inclusion Criteria

I am willing and able to follow all study rules and attend all appointments.

I have had Type 1 Diabetes for over a year and my BMI is under 25.

Provision of signed and dated informed consent form

Exclusion Criteria

You cannot have an MRI scan due to safety reasons or if you feel very anxious in small spaces.

Pregnancy or lactation, or planning to become pregnant during the study period

I have kidney problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo baseline assessments including abdominal MRI, hyperinsulinemic-euglycemic clamp with stable isotope tracer, DEXA scan, and a High Fat Mixed Meal Tolerance Test

1-2 weeks

Monitoring

Participants are monitored for changes in visceral adipose tissue, hepatic insulin resistance, and triglycerides over 1 year

1 year

Follow-up

Participants are monitored for safety and effectiveness after the main study period

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• High Fat Mixed Meal Tolerance Test
• Hyperinsulinemic-euglycemic clamp

Trial Overview The study tests how a high-fat meal and insulin affect heart disease risk markers in people with Type 1 Diabetes by using two tests: a Hyperinsulinemic-euglycemic clamp to assess insulin resistance and a High Fat Mixed Meal Tolerance Test to measure fat levels after eating.

How Is the Trial Designed?

Group I: Young adults with T1D who have a body mass index <25 kg/m2 Experimental Treatment 2 Interventions

Young adults with T1D who have a body mass index \<25 kg/m2 will have: abdominal MRI, hyperinsulinemic-euglycemic clamp wtih stable isotope tracer, DEXA scan and a High Fat Mixed Meal Tolerance Test.

High Fat Mixed Meal Tolerance Test is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Victoza for:

• Type 2 diabetes
• Obesity

Approved in United States as Victoza for:

• Type 2 diabetes
• Obesity

Approved in Canada as Victoza for:

• Type 2 diabetes
• Obesity

Approved in Japan as Victoza for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

In a 26-week study involving 108 adults with type 1 diabetes, adding exenatide to insulin therapy led to a significant reduction in total fat mass by 2.6 kg, indicating its efficacy in promoting weight loss.

Despite the weight loss, exenatide did not affect key cardiovascular risk biomarkers, suggesting that while it may help with body composition, it does not improve cardiovascular risk factors in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of short-acting exenatide administered three times daily on markers of cardiovascular disease in type 1 diabetes: A randomized double-blind placebo-controlled trial. Johansen, NJ., Dejgaard, TF., Lund, A., et al.[2022]

Exenatide, a GLP-1 receptor agonist, showed promising improvements in metabolic risk factors, including fasting glucose and triglyceride levels, in two adolescents with morbid obesity and type 2 diabetes after 6 months of treatment.

This study suggests that exenatide could be a beneficial addition to treatment for adolescents who have not responded well to conventional therapies like insulin and Metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exenatide Effects on Cardiometabolic Risk and Weight in Adolescents with Morbid Obesity and Type 2 Diabetes Mellitus: Two Case Reports. Censani, M., Chin, VL., Fennoy, I.[2020]

In a study of 11 patients with type 1 diabetes using liraglutide, significant improvements were observed after 10 weeks, including a 4.2% reduction in body weight and a 19.2% decrease in total daily insulin dose, alongside a reduction in Hemoglobin A1c levels from 7.4% to 7.0%.

The addition of liraglutide to insulin therapy did not increase the risk of hypoglycemia, although nausea was a common side effect, leading to discontinuation in 4 out of 11 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Type 1 diabetes treatment beyond insulin: role of GLP-1 analogs. Harrison, LB., Mora, PF., Clark, GO., et al.[2016]

Incretin-based therapies (IBTs), particularly GLP-1 receptor agonists like liraglutide, not only lower blood sugar levels in type 2 diabetes patients but also significantly reduce cardiovascular risk factors such as body weight, blood pressure, and inflammation without increasing the risk of hypoglycemia.

Recent studies highlight liraglutide's potential to prevent the formation and progression of atherosclerotic plaques, showcasing its cardioprotective effects and marking a significant advancement in diabetes treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms. Rizzo, M., Nikolic, D., Patti, AM., et al.[2020]

GLP-1 is a crucial hormone that enhances insulin secretion and lowers glucagon levels, making it a key player in managing Type 2 diabetes by counteracting several diabetic symptoms such as insulin resistance and overeating.

Exogenous GLP-1 administration can normalize fasting hyperglycemia in Type 2 diabetic patients, but its short half-life necessitates the development of longer-lasting GLP-1 analogues or strategies to boost its natural release from the intestines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for type 2-diabetes. Nauck, MA., Holst, JJ., Willms, B., et al.[2018]

Liraglutide, approved for Type 2 diabetes and chronic weight management, works by increasing insulin secretion and decreasing appetite, which helps promote weight loss.

Recent findings suggest that liraglutide may also protect against prediabetes and prevent bone loss by enhancing bone formation after weight loss, highlighting its broader health benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liraglutide for Type 2 diabetes and obesity: a 2015 update. Iepsen, EW., Torekov, SS., Holst, JJ.[2015]

Liraglutide (Saxenda) has been shown to effectively promote weight loss in overweight and obese patients, with a higher percentage achieving 5% and 10% weight loss compared to placebo and orlistat, based on randomized controlled studies.

The medication is generally safe, with gastrointestinal side effects being the most common and typically dose-dependent, making it a viable adjunct to lifestyle changes for obesity management, especially in patients with prediabetes and women with PCOS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liraglutide: an injectable option for the management of obesity. Clements, JN., Shealy, KM.[2022]

In a study of 225 patients prescribed Saxenda and Victoza, 96% and 98.7% of prescriptions, respectively, were in line with approved indications, indicating high adherence to guidelines.

Only 5% of patients using Saxenda for 16 weeks or longer were non-adherent to the stopping rule, suggesting that these medications are being used safely and effectively in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the potential non-authorized use of two different formulations of liraglutide in Europe: A real-world drug utilization study. Sbraccia, P., Aberle, J., Olsen, AH., et al.[2023]

Liraglutide, now available at a higher dose of 3.0 mg for treating obesity, has been shown to effectively control appetite and promote weight loss when combined with diet and exercise, based on results from the SCALE studies.

The drug is already established for managing type 2 diabetes at lower doses, and its mechanism of action includes effects on the endocrine pancreas and appetite regulation in the hypothalamus, indicating a dual benefit for patients with obesity and diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[LIRAGUTIDE AT A DOSE OF 3.0 MG (SAXENDA): NEW INDICATION FOR THE TREATMENT OF OBESITY]. Scheen, AJ.[2016]

In a study of 11,245 patients prescribed low-dose liraglutide (LD-L), it was found that 17.5% of these patients did not have a type 2 diabetes (T2D) diagnosis, compared to only 2.7% of patients using other GLP-1 receptor agonists.

Patients without a T2D diagnosis were over six times more likely to be prescribed LD-L than other GLP-1 RAs, indicating a significant trend in the use of LD-L for non-diabetic patients, which raises concerns about the appropriateness of its prescription.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of low-dose liraglutide use versus other GLP-1 receptor agonists in patients without type 2 diabetes. Wittbrodt, ET., Eudicone, JM., Farahbakhshian, S., et al.[2019]

GLP-1 analogues significantly reduce epicardial adipose tissue (EAT) in patients with type 2 diabetes, as shown in a meta-analysis of 4 studies involving 160 patients, indicating a potential benefit in lowering cardio-metabolic risks.

In addition to reducing EAT, GLP-1 therapy also led to significant improvements in HbA1c levels, body mass index, and reductions in low-density lipoprotein and triglyceride levels, highlighting its efficacy in managing multiple aspects of type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of glucagon-like peptide-1 (GLP-1) analogues on epicardial adipose tissue: A meta-analysis. Berg, G., Barchuk, M., Lobo, M., et al.[2022]

GLP1 receptor agonists (GLP1RAs) are effective in treating type 2 diabetes mellitus (T2DM) by enhancing insulin release and suppressing glucagon, with variations in their structure leading to different effects on blood sugar control and weight loss.

Some GLP1RAs have shown positive cardiovascular outcomes in large-scale trials, indicating their potential benefits beyond just managing diabetes, and they are also being explored for treating obesity, prediabetes, and liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 in health and disease. Andersen, A., Lund, A., Knop, FK., et al.[2020]

A review of 16 head-to-head trials showed that different glucagon-like peptide-1 receptor agonists (GLP-1RAs) have varying effects on cardiovascular risk factors, with liraglutide notably increasing heart rate compared to its comparators.

While all GLP-1RAs effectively reduced blood sugar levels (HbA1c), exenatide and lixisenatide were less effective than other GLP-1RAs, indicating that the choice of GLP-1RA can be tailored based on individual patient needs and specific cardiovascular risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: A narrative review of head-to-head comparisons. Dalsgaard, NB., Vilsbøll, T., Knop, FK.[2022]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Effect of short-acting exenatide administered three times daily on markers of cardiovascular disease in type 1 diabetes: A randomized double-blind placebo-controlled trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Exenatide Effects on Cardiometabolic Risk and Weight in Adolescents with Morbid Obesity and Type 2 Diabetes Mellitus: Two Case Reports. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Type 1 diabetes treatment beyond insulin: role of GLP-1 analogs. [2016]

4. Netherlands pubmed.ncbi.nlm.nih.gov

GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for type 2-diabetes. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Liraglutide for Type 2 diabetes and obesity: a 2015 update. [2015]

7. United States pubmed.ncbi.nlm.nih.gov

Liraglutide: an injectable option for the management of obesity. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Investigating the potential non-authorized use of two different formulations of liraglutide in Europe: A real-world drug utilization study. [2023]

9. Belgium pubmed.ncbi.nlm.nih.gov

[LIRAGUTIDE AT A DOSE OF 3.0 MG (SAXENDA): NEW INDICATION FOR THE TREATMENT OF OBESITY]. [2016]

10. United States pubmed.ncbi.nlm.nih.gov

Comparison of low-dose liraglutide use versus other GLP-1 receptor agonists in patients without type 2 diabetes. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of glucagon-like peptide-1 (GLP-1) analogues on epicardial adipose tissue: A meta-analysis. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 in health and disease. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: A narrative review of head-to-head comparisons. [2022]