Incretin Hormones for Cystic Fibrosis

Overseen By Paola Alvarado

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Pennsylvania

Must not be taking: Corticosteroids

Disqualifiers: Non-CF diabetes, Pancreatitis, Transplant, others

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

Compensation: Varies

Number of Visits: 1

Duration: 5 hours

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how certain hormones, called incretins, might help with diabetes that develops in some individuals due to cystic fibrosis (CF). Researchers seek to determine if these hormones can boost insulin production, crucial for managing blood sugar levels. The trial involves two main treatments using incretin hormones: GIP (Glucose-dependent insulinotropic polypeptide) and GLP-1 (Glucagon-like peptide-1). Individuals with cystic fibrosis who have normal blood sugar levels but experience digestive issues might be suitable participants. As an unphased study, this trial offers a unique opportunity to contribute to groundbreaking research that could improve diabetes management for those with CF.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you should not have had any changes in therapy, including antibiotics, within 6 weeks prior to the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies with GLP-1, a hormone that helps control blood sugar, have shown improved lung function and better blood sugar levels in people with cystic fibrosis (CF) who used it. Most participants tolerated it well, though some discontinued use due to side effects. This treatment already has approval for type 2 diabetes, which suggests a level of safety.

For GIP, another hormone that aids insulin function, research has shown that short-term use is generally safe. While it may not increase insulin as effectively as GLP-1, it plays a crucial role in managing blood sugar levels. Overall, both treatments appear well-tolerated based on available evidence. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using incretin hormones like GLP-1 and GIP for cystic fibrosis because they offer a novel approach to managing glucose levels. Unlike traditional treatments that primarily focus on managing respiratory and digestive symptoms, these hormones target the body's insulin response, potentially improving glucose metabolism. GLP-1 and GIP are infused directly into the bloodstream, which is different from standard oral medications, allowing for a more immediate effect on glucose regulation. By exploring these new pathways, researchers hope to expand the therapeutic options available for cystic fibrosis, addressing a broader spectrum of the disease's complications.

What evidence suggests that this trial's treatments could be effective for cystic fibrosis related diabetes?

Research has shown that certain hormones, like GLP-1 and GIP, could help manage diabetes-related issues. In this trial, participants will receive either GLP-1 or GIP in separate treatment arms. GLP-1 helps the body produce more insulin, which benefits people with type 2 diabetes. Some studies have found that treatments using GLP-1 lead to significant weight loss and improved lung function. GIP works differently; it might not increase insulin as much as GLP-1, but it helps reduce bone loss, which is important for overall health. These findings suggest that these hormones might help manage diabetes related to cystic fibrosis by improving insulin function and other health markers. ^{4 6 7 8 9}

Who Is on the Research Team?

Michael Rickels, MD, MS

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for adults over 18 with cystic fibrosis and pancreatic insufficiency, who may have glucose tolerance issues but not severe diabetes. Women must test negative for pregnancy. Excluded are those with prior transplants, severe liver disease, abnormal kidney function, certain blood disorders or any condition that could interfere with the study.

Inclusion Criteria

I have been diagnosed with cystic fibrosis based on a sweat test or genetic testing.

My pancreas does not work properly.

My glucose tolerance test shows I have a form of diabetes related to cystic fibrosis without high blood sugar when fasting.

Exclusion Criteria

Medical co-morbidities that are not CF-related or are unstable per investigator opinion (i.e. history of bleeding disorders, immunodeficiency)

Hemoglobin less than10g/dL, within 90 days of Visit 1 or at Screening

Subjects, who in study team opinion, may be non-compliant with study procedures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive GLP-1 or GIP incretin hormone infusions and undergo GPA tests to measure insulin response

5 hours

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

• GIP
• GLP-1

Trial Overview

The study investigates how incretin hormones (GLP-1 and GIP) affect insulin production in cystic fibrosis patients to better understand and treat CFRD. It includes CF patients with normal glucose levels and non-CF controls to compare responses.

How Is the Trial Designed?

Group I: GLP-1 Incretin Hormone Experimental Treatment 1 Intervention

The incretin, Glucagon-Like-peptide-1 (GLP-1) will be infused into the veins starting 30 minutes prior to initiating the GPA test. This infusion will continue for a total of 90 mins. (during the GPA for 230 mg/dL glucose levels) and then this will be stopped. The GPA test will be performed for the 340 mg/dL glucose levels but no incretin will be infused during this part of the test. These data will be compared when the subject repeats the GPA test with a placebo (saline or salt containing solution) infusion.

Group II: GIP Incretin Hormone Experimental Treatment 1 Intervention

The incretin, Glucose-dependent Insulinotropic Polypeptide (GIP) will be infused into the veins starting 30 minutes prior to initiating the GPA test. This infusion will continue for a total of 90 mins (during the GPA for 230 mg/dL glucose levels) and then this will be stopped. The GPA test will be performed for the 340 mg/dL glucose levels but no incretin will be infused during this part of the test. These data will be compared when the subject repeats the GPA test with a placebo (saline or salt containing solution) infusion.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Published Research Related to This Trial

In a patient with cystic fibrosis-related diabetes (CFRD), adding semaglutide, a GLP-1 receptor agonist, to basal insulin significantly improved glycemic control, reducing HbA1c from 9.1% to 6.7% within 3 months.

The treatment did not lead to any increase in plasma pancreatic enzyme concentrations, indicating a safe profile for semaglutide when used in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide in Cystic Fibrosis-Related Diabetes. Gnanapragasam, H., Mustafa, N., Bierbrauer, M., et al.[2022]

Tirzepatide, the first dual GIP/GLP-1 receptor co-agonist approved for type 2 diabetes, significantly reduces HbA1c levels (by 1.24 to 2.58%) and body weight (by 5.4-11.7 kg) in clinical trials involving type 2 diabetic patients, outperforming the selective GLP-1 RA semaglutide.

The safety profile of tirzepatide is similar to that of other GLP-1 receptor agonists, with common side effects including nausea and diarrhea, and it shows potential cardiovascular safety, as no significant increase in major adverse cardiovascular events was observed during the trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Nauck, MA., D'Alessio, DA.[2022]

Tirzepatide is a first-in-class medication that acts as a dual agonist for GLP-1 and GIP, effectively improving glycemic control in adults with type 2 diabetes by increasing insulin secretion and reducing glucagon levels, as demonstrated in pivotal phase 3 SURPASS trials.

In addition to lowering HbA1c levels, tirzepatide also promotes weight loss and has a favorable safety profile, with gastrointestinal issues being the most common side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: A Dual Glucose-dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 Agonist for the Management of Type 2 Diabetes Mellitus. Wong, E., Cope, R., Dima, L., et al.[2023]

Tirzepatide, approved in 2022, is a novel treatment for type 2 diabetes that acts on both GLP-1 and GIP pathways, showing significant efficacy in lowering blood sugar levels and promoting weight loss in various patient groups.

Clinical trials, including the SURPASS and SURMOUNT studies, indicate that tirzepatide has a safety profile similar to traditional GLP-1 receptor agonists, with common gastrointestinal side effects, making it a promising option for patients needing better glycemic and weight management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: Clinical review of the "twincretin" injectable. Krauss, Z., Hintz, A., Fisk, R.[2023]

Tirzepatide, a dual GIP/GLP-1 receptor agonist, has demonstrated significant glucose-lowering and weight loss effects in clinical trials, indicating its potential as an effective treatment for type 2 diabetes mellitus (T2DM).

The combination of GIP and GLP-1 in Tirzepatide enhances insulin response and reduces glucagon levels more effectively than administering each hormone separately, suggesting a synergistic mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment. Pelle, MC., Provenzano, M., Zaffina, I., et al.[2022]

Oral semaglutide at doses of 7 mg and 14 mg significantly reduced hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes, with reductions of 1.06% and 1.10% respectively compared to placebo, based on a meta-analysis of 11 randomized controlled trials involving 9821 patients.

Both doses of semaglutide also led to significant weight loss, but the 14 mg dose was associated with a higher incidence of gastrointestinal side effects, such as nausea and vomiting, leading to more medication discontinuations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide in type 2 diabetes mellitus: A systematic review and meta-analysis. Li, A., Su, X., Hu, S., et al.[2023]

Patients with cystic fibrosis (CF) and cystic fibrosis-related diabetes (CFRD) have significantly lower levels of active GLP-1 compared to healthy controls, which may impact their insulin regulation and diabetes progression.

The study suggests that the inactive form of GLP-1 is more prevalent in CF patients, indicating a potential area for further research into GLP-1 analogues as a treatment option for improving metabolic health in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus. Hillman, M., Eriksson, L., Mared, L., et al.[2012]

GLP-1 receptor agonists have evolved significantly over the years, improving from a short half-life of 2-3 minutes to medications that can be administered once a week, demonstrating their efficacy in treating obesity and type 2 diabetes.

Recent developments in dual-agonists that target both GLP-1 and GIP receptors have shown promising results, leading to significant improvements in body weight and glucose control for patients with obesity and type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes. Tan, Q., Akindehin, SE., Orsso, CE., et al.[2022]

In a study of 32 adults with pancreatic insufficient cystic fibrosis (PI-CF) and abnormal glucose tolerance (AGT), GLP-1 significantly improved second-phase insulin secretion, suggesting it could be a beneficial treatment for enhancing insulin response in this population.

In contrast, GIP did not enhance insulin secretion in PI-CF patients but did increase the proinsulin secretory ratio, indicating a potential loss of its insulin-stimulating effects in these patients, which may provide insights into diabetes development in cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis. Nyirjesy, SC., Peleckis, AJ., Eiel, JN., et al.[2023]

Tirzepatide, a dual GIP and GLP-1 receptor agonist, showed significant reductions in Hemoglobin A1c levels (up to 3.02%) and weight loss in adults with uncontrolled type 2 diabetes, outperforming both placebo and active comparators like semaglutide.

The safety profile of tirzepatide was comparable to semaglutide regarding gastrointestinal adverse effects, and it did not increase the incidence of major cardiovascular events compared to insulin glargine, indicating it may be a valuable addition to diabetes treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide, the Newest Medication for Type 2 Diabetes: A Review of the Literature and Implications for Clinical Practice. Bradley, CL., McMillin, SM., Hwang, AY., et al.[2023]

In a 6-month study involving 26 adults with pancreatic insufficient cystic fibrosis (PI-CF) and abnormal glucose tolerance (AGT), the DPP-4 inhibitor sitagliptin significantly increased levels of incretin hormones (GLP-1 and GIP), which are important for insulin secretion.

While sitagliptin improved early insulin secretion and glucagon suppression, it did not lead to significant changes in postprandial glycemia or overall glucose tolerance, indicating that while it enhances certain hormonal responses, it may not fully correct glucose metabolism issues in PI-CF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance. Kelly, A., Sheikh, S., Stefanovski, D., et al.[2022]

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