Glucagon Response Study for Non-alcoholic Fatty Liver Disease

Overseen By Jeanette Laugen

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Adrian Vella

Disqualifiers: Abdominal surgery, Systemic illness, Vascular disease, MRI contraindications, Alcohol, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how glucagon, a hormone that raises blood sugar, affects the liver, particularly in individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Researchers seek to determine if issues with glucagon relate to liver fat or obesity. Participants will receive two doses of glucagon to assess its effects. Suitable candidates for this trial include adults with type 2 diabetes, healthy adults, or obese adults who have not undergone major upper abdominal surgery and do not drink alcohol excessively. As a Phase 1 and Phase 2 trial, this research focuses on understanding glucagon's function in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

Is there any evidence suggesting that glucagon is likely to be safe for humans?

Research shows that glucagon, a hormone that helps control blood sugar and break down proteins, has been tested for safety in humans. Studies on similar drugs, called glucagon receptor agonists, have shown positive results. These treatments are usually well-tolerated by people with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.

In these studies, side effects were mostly mild. Some participants felt nauseous or had headaches, but serious side effects were rare. Since glucagon is also used in emergency medicine, researchers have a good understanding of its safety, especially in controlled environments. As this trial is in its early stages, the main goal is to confirm its safety and learn how glucagon works in different health conditions.

In summary, while typical side effects are mild, glucagon's use in other medical situations suggests it is generally safe when used carefully. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Most treatments for non-alcoholic fatty liver disease (NAFLD), like lifestyle changes and medications such as vitamin E or pioglitazone, focus on reducing liver fat or managing associated conditions like diabetes. But glucagon works differently, targeting the regulation of glucose and lipid metabolism directly. Researchers are excited about glucagon because it helps improve liver health by influencing how the liver processes fats and sugars, which could offer a more direct and efficient way to tackle liver issues in NAFLD. This unique approach holds the potential for more immediate and significant improvements in liver function compared to current options.

What evidence suggests that glucagon might be an effective treatment for non-alcoholic fatty liver disease?

Research has shown that glucagon, a hormone that helps control blood sugar, might also manage non-alcoholic fatty liver disease (NAFLD). Studies have found that treatments using glucagon or similar substances can improve liver health and blood sugar levels. For instance, treatments targeting both glucagon and other body systems have successfully reduced liver fat and improved liver function in people with NAFLD. This trial will examine the effects of glucagon in various groups, including adults with type 2 diabetes, healthy adults, and obese adults, to explore how glucagon can enhance liver health, particularly for those with diabetes and obesity. ^{2 4 6 7 8}

Who Is on the Research Team?

Adrian Vella

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults with obesity, Type 2 Diabetes, or Non-alcoholic Fatty Liver Disease who can consent to participate. It's not suitable for those with a history of certain abdominal surgeries, MRI contraindications like metal implants or claustrophobia, severe anemia (low hematocrit), abnormal thyroid levels (TSH), active illness/malignancy, significant vascular disease symptoms, or high alcohol consumption.

Inclusion Criteria

Willing to participate

Able to give consent

Exclusion Criteria

TSH less than 0.4 or greater than 5.5

I have another active illness or cancer.

I have had surgery in my upper stomach area before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a hyperglycemic clamp with 2 doses of glucagon to study hepatic metabolism

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Glucagon

Trial Overview The study investigates how glucagon—a hormone that affects blood sugar—interacts with liver metabolism in people who are lean and obese and may have Type 2 Diabetes. The focus is on understanding glucagon's role in breaking down amino acids and its relationship with liver fat content.

How Is the Trial Designed?

Group I: Obese Adults Experimental Treatment 1 Intervention

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Group II: Healthy Adults Experimental Treatment 1 Intervention

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Group III: Adults with Type 2 Diabetes Experimental Treatment 1 Intervention

We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon.

Who Is Running the Clinical Trial?

Adrian Vella

Lead Sponsor

Trials

9

Recruited

210+

Published Research Related to This Trial

A systematic review of 11 randomized controlled trials involving 936 middle-aged individuals found that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduced liver fat content and serum liver enzyme levels in patients with nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) over a median treatment duration of 26 weeks.

GLP-1 RAs, particularly liraglutide and semaglutide, also showed greater histological resolution of NASH without worsening liver fibrosis, indicating their potential as effective treatments for these liver conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials. Mantovani, A., Petracca, G., Beatrice, G., et al.[2021]

In a study using non-obese mice with nonalcoholic steatohepatitis (NASH), the GLP-1 analogue exendin-4 significantly reduced liver fat accumulation and inflammation after four weeks of treatment, indicating its potential efficacy in managing NASH.

Exendin-4 works by inhibiting the influx of free fatty acids into the liver and reducing oxidative stress, which helps to alleviate the symptoms of hepatic steatosis and inflammation associated with NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice. Yamamoto, T., Nakade, Y., Yamauchi, T., et al.[2022]

In a study of 4442 patients with type 2 diabetes, liraglutide 1.8 mg significantly reduced liver enzyme levels (ALT) compared to placebo, indicating potential benefits for liver health.

The improvement in liver enzymes was primarily linked to weight loss and better blood sugar control rather than a direct effect of liraglutide on liver injury, suggesting that its efficacy may be mediated through these mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Armstrong, MJ., Houlihan, DD., Rowe, IA., et al.[2022]

In a study involving 10 non-diabetic patients with non-alcoholic fatty liver disease (NAFLD) and 10 matched controls, GLP-1 infusion effectively suppressed glucagon levels in both groups, indicating that the glucagon-suppressive effect of GLP-1 is preserved in NAFLD patients.

Despite the presence of fasting hyperglucagonaemia in NAFLD patients, GLP-1 did not affect endogenous glucose production, suggesting that while GLP-1 enhances insulin secretion in these patients, it does not alter glucose output from the liver.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease. Junker, AE., Gluud, LL., van Hall, G., et al.[2018]

In a 52-week weight management trial, semaglutide significantly reduced alanine aminotransferase (ALT) levels by 6%-21% in subjects with elevated ALT, indicating its potential effectiveness in treating non-alcoholic fatty liver disease (NAFLD).

Semaglutide also led to significant reductions in high-sensitivity C-reactive protein (hsCRP) levels by 25%-43% compared to placebo, suggesting an anti-inflammatory effect that may benefit individuals at risk for NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Newsome, P., Francque, S., Harrison, S., et al.[2021]

Citations

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Glucagon-Like Peptide-1 Receptor Agonists for Non-Alcoholic ... Glucagon-like peptide-1 receptor agonist treatment shows promise in improving both diabetes and non-alcoholic fatty liver disease phenotype.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0168827823003422

A phase IIa active-comparator-controlled study to evaluate ... This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10 mg ...

3. nature.com nature.com/articles/s41392-024-01931-z

Glucagon-like peptide-1 receptor: mechanisms and ... This innovative compound demonstrates dose-dependent efficacy in regulating glycemic control, suppressing appetite, delaying gastric emptying, ...

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Pharmacological Approaches to Nonalcoholic Fatty Liver ... Both pioglitazone and GLP-1 receptor agonists decrease hepatic glucose production and improve plasma lipid metabolism.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7522518/

Efficacy of Glucagon-Like Peptide-1 Analogs in Nonalcoholic ... Overall, treatment of NAFLD patients with these GLP-1 analogs brought a reduction of the levels of ALT, AST, and GGT by 59.5%, 52.8%, and 44.8%, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11712088/

Current Status of Glucagon-like Peptide-1 Receptor Agonists ... GLP-1RAs contribute to metabolic adjustments in MASLD by controlling fat deposition, inflammation, and potentially fibrosis.

7. frontiersin.org frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.609110/full

Glucagon-Like Peptide-1 Receptor Agonists for Non- ... Glucagon-like peptide-1 receptor agonist treatment shows promise in improving both diabetes and non-alcoholic fatty liver disease phenotype.

8. mdpi.com mdpi.com/2077-0383/9/10/3213

One Year's Treatment with the Glucagon-Like Peptide 1 ... Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue ...