Semaglutide for Heart Failure

(SEMAHEART Trial)

Recruiting at 2 trial locations

Overseen By Bojan Vrtovec, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University Medical Centre Ljubljana

Disqualifiers: Diabetes, Cancer, Liver dysfunction, 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: 4

Duration: 16 weeks

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, primarily used for treatment of type-2 diabetes mellitus. GLP-1 receptors are present on pancreatic islet β-cells, δ-cells and α-cells. Their stimulation increases insulin and somatostatin secretion, and decreases glucagon secretion. In addition, GLP-1 receptor agonists appear to have multiple extrapancreatic actions, which remain poorly defined. In large clinical trials, semaglutide improved the outcomes in obese patients, patients with heart failure with preserved ejection fraction, and decreased the heart failure hospitalizations in patients with type 2 diabetes. The aim of the present study is to investigate the underlying mechanisms of the beneficial clinical effects of semaglutide in the setting of chronic heart failure.

Will I have to stop taking my current medications?

The trial requires that you have been on stable doses of your heart failure medications for at least 3 months, so you should not stop taking them. However, the protocol does not specify about other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Semaglutide for heart failure?

Research shows that Semaglutide, a drug used for type 2 diabetes, also helps reduce cardiovascular events and body weight, which can be beneficial for heart health. Although its impact on heart failure specifically isn't fully described, these benefits suggest potential effectiveness in heart-related conditions. ^{1 2 3 4 5}

Is semaglutide safe for humans?

Semaglutide has been tested in people with type 2 diabetes and is generally considered safe, with its cardiovascular safety being similar to a placebo in high-risk patients. It is available in both oral and injectable forms and has been shown to help with blood sugar control and weight loss. ^{4 5 6 7 8}

How is the drug Semaglutide unique for treating heart failure?

Semaglutide is unique for heart failure treatment because it is primarily known as a medication for diabetes and weight management, working by mimicking a hormone that regulates appetite and insulin levels, which is different from traditional heart failure drugs that typically focus on improving heart function directly. ^{9 10 11 12 13}

Eligibility Criteria

This trial is for heart failure patients who are also obese. It's exploring how a diabetes medication, Semaglutide, can help them. To join, participants must meet certain health conditions but the specific inclusion and exclusion criteria aren't provided here.

Inclusion Criteria

N-terminal pro B-type natriuretic peptide levels >350 pg/mL

I have heart failure.

My BMI is 27 or higher.

Exclusion Criteria

My kidney function is very low.

Pregnancy or potential to become pregnant

I have cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive subcutaneous semaglutide with a dose escalation over 16 weeks

16 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Semaglutide

Trial Overview The study tests Semaglutide, a drug used for type-2 diabetes that affects insulin and other hormones. Researchers want to understand why it helps with heart failure and reduces hospital visits for these patients.

Participant Groups

Group I: Semaglutide Therapy Experimental Treatment 1 Intervention

Timepoints: * Baseline (Week 0) * Week 2 (Visit 1) * Week 4 (Visit 2) * Week 12 (Visit 3) * Week 16 (Visit 4) Medication Schedule: Subcutaneous semaglutide (Ozempyc, Novo Nordisk A/S Bagsvaerd, Denmark) First 2 weeks: Semaglutide; 0.25 mg weekly Second 2 weeks: Semaglutide; 0.5 mg weekly Remaining 12 weeks: Semaglutide; 1 mg weekly

Semaglutide is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Canada as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Japan as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Wegovy for:

• Obesity

Approved in United States as Rybelsus for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University Medical Centre Ljubljana

Lead Sponsor

Trials

290

Recruited

87,200+

Greenstone Biosciences

Collaborator

Trials

3

Recruited

70+

Stanford University

Collaborator

Trials

2,527

Recruited

17,430,000+

Findings from Research

In a study of 136 obese patients with type 2 diabetes and heart failure, once-weekly semaglutide significantly improved heart failure symptoms and functional status, as evidenced by a notable increase in Kansas City Cardiomyopathy Questionnaire scores and a reduction in patients classified as New York Heart Association functional class III.

Semaglutide was found to be safe and well-tolerated, leading to significant reductions in glycated hemoglobin and body weight, while also decreasing hospitalizations related to heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Semaglutide for the Management of Obese Patients With Type 2 Diabetes and Chronic Heart Failure in Real-World Clinical Practice. Pérez-Belmonte, LM., Sanz-Cánovas, J., García de Lucas, MD., et al.[2022]

In a study of 112 patients with Type 2 diabetes in Pakistan, Semaglutide significantly reduced HbA1c levels by an average of 1.2% and weight by 4.0 kg after at least 3 months of treatment, demonstrating its efficacy in this population.

Despite some gastrointestinal side effects like dyspepsia and nausea, 72.3% of patients reported satisfaction with Semaglutide, indicating a favorable tolerability profile for this anti-diabetic medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Tolerability of Semaglutide in Patients With Type-2 Diabetes Mellitus: Experience of a Tertiary Care Hospital, Pakistan. Wajid, M., Sattar, S., Khalid, F., et al.[2023]

Semaglutide, a GLP-1 receptor agonist with a long half-life, effectively promotes insulin secretion in a glucose-dependent manner, making it a valuable treatment for type 2 diabetes, approved for use worldwide and in Japan since 2018.

Oral semaglutide (Rybelsus®) is the first GLP-1 receptor agonist available in pill form, showing continuous benefits in glycemic control for patients with type 2 diabetes across various stages, as demonstrated in multiple global clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New drug for type 2 diabetes: introduction of oral Semaglutide (Rybelsus® tablets), an oral GLP-1 receptor agonist]. Miyasaka, K.[2022]

The PIONEER 6 trial is assessing the cardiovascular safety of oral semaglutide in 3183 patients with type 2 diabetes at high risk for cardiovascular events, aiming to determine if it poses any additional cardiovascular risk compared to a placebo.

The study will evaluate the time to first occurrence of serious cardiovascular events, such as CV death or non-fatal heart attacks and strokes, providing important data on the safety of this new oral medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. Bain, SC., Mosenzon, O., Arechavaleta, R., et al.[2021]

Oral semaglutide (Rybelsus®) has been shown to provide better glycaemic control and promote weight loss in patients with type 2 diabetes (T2DM) compared to standard oral glucose-lowering medications, based on data from the PIONEER clinical trial program involving 9543 patients.

The safety profile of oral semaglutide is similar to other GLP-1 receptor agonists, and it demonstrated cardiovascular safety comparable to placebo in high-risk patients, making it a viable option for T2DM management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oral semaglutide, first oral GLP-1 receptor agonist (Rybelsus®)]. Paquot, N.[2022]

In the combined analysis of the SUSTAIN and PIONEER trials, semaglutide significantly reduced the risk of major adverse cardiovascular events (MACE) by 24% compared to placebo, primarily due to a reduction in nonfatal strokes.

However, semaglutide did not show a beneficial effect on hospitalization for heart failure, particularly in patients with a history of heart failure, indicating that its cardiovascular benefits may not extend to all high-risk groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Husain, M., Bain, SC., Jeppesen, OK., et al.[2021]

Oral semaglutide, particularly at doses of 14 mg or flexibly dosed, significantly reduced HbA1c levels and body weight in patients with type 2 diabetes compared to other treatments, especially in those with higher baseline HbA1c levels.

The safety profile of oral semaglutide was comparable to that of other treatments, although it was associated with a higher incidence of gastrointestinal adverse events, which were consistent across different patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Aroda, VR., Bauer, R., Christiansen, E., et al.[2022]

Semaglutide (Ozempic®) is an effective once-weekly treatment for type 2 diabetes, showing superior glucose-lowering effects and greater weight loss compared to other GLP-1 receptor agonists in Phase III clinical trials.

It is approved for use in Belgium for patients with type 2 diabetes who have not achieved adequate control with other antidiabetic therapies, particularly in those with a body mass index of 30 kg/m² or higher.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Semaglutide, once weekly GLP-1 receptor agonist (Ozempic®)]. Scheen, AJ.[2019]

The study synthesized three analogues of Cilengitide, a peptide that targets integrin receptors, with increasing lengths of N-oligoethylene glycol (N-OEG) chains, which enhanced their hydrophobicity compared to the original peptide.

The N-OEG2 analogue maintained the same effectiveness as Cilengitide in inhibiting cell adhesion, while the larger N-OEG11 and N-OEG23 analogues showed even greater potency, although their synthesis was more challenging and yields decreased with longer chains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl group of cilengitide by N-oligoethylene glycol (N-OEG) chains. Fernández-Llamazares, AI., Adan, J., Mitjans, F., et al.[2014]

In a study of 31 patients shortly after acute myocardial infarction (AMI), the PET tracer [68Ga]Ga-NODAGA-RGD showed increased uptake in the ischemic area, indicating higher αvβ3 integrin expression associated with heart tissue injury.

Higher uptake of [68Ga]Ga-NODAGA-RGD was linked to better recovery of left ventricular function over 6 months, suggesting it could be a useful predictor of heart recovery after AMI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging of Myocardial αvβ3 Integrin Expression for Evaluation of Myocardial Injury After Acute Myocardial Infarction. Nammas, W., Paunonen, C., Teuho, J., et al.[2023]

The PET tracer [68Ga]Ga-NODAGA-RGD effectively detects myocardial inflammation in a rat model of autoimmune myocarditis, showing significantly higher accumulation in inflamed myocardium compared to controls (SUVmean 0.4 vs. 0.1).

Histological analysis confirmed that the tracer's uptake co-localized with inflammatory lesions, indicating that targeting the αvβ3 integrin could be a promising method for identifying active inflammation in heart tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of [68Ga]Ga-NODAGA-RGD for PET Imaging of Rat Autoimmune Myocarditis. Jahandideh, A., Ståhle, M., Virta, J., et al.[2022]

The novel cyclic RGD peptide, cyclo(-RGDf==V-), effectively binds to the integrin alpha(V)beta3 and shows strong anti-angiogenic properties, significantly reducing microvessel density in tumors in vivo, particularly in a mouse model of colon cancer.

In vitro studies demonstrated that all three cyclic RGD peptides inhibited the growth and adhesion of human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner, with cyclo(-RGDf==V-) and cyclo(-RGDf-MeV-) showing the strongest effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel synthetic Arg-Gly-Asp-containing peptide cyclo(-RGDf==V-) is the potent inhibitor of angiogenesis. Kawaguchi, M., Hosotani, R., Ohishi, S., et al.[2016]

The new radiotracer 99mTc-4P-RGD3 was successfully prepared and demonstrated high tumor-targeting capability and metabolic stability in a study involving BALB/c nude mice with human glioma xenografts.

99mTc-4P-RGD3 showed similar tumor uptake and biodistribution properties compared to the existing radiotracer 99mTc-3P-RGD2, indicating that increasing the peptide multiplicity does not enhance tumor-targeting effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of biological properties of 99mTc-labeled cyclic RGD Peptide trimer and dimer useful as SPECT radiotracers for tumor imaging. Zhao, ZQ., Yang, Y., Fang, W., et al.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Semaglutide for the Management of Obese Patients With Type 2 Diabetes and Chronic Heart Failure in Real-World Clinical Practice. [2022]

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

Efficacy and Tolerability of Semaglutide in Patients With Type-2 Diabetes Mellitus: Experience of a Tertiary Care Hospital, Pakistan. [2023]

3. Japan pubmed.ncbi.nlm.nih.gov

[New drug for type 2 diabetes: introduction of oral Semaglutide (Rybelsus® tablets), an oral GLP-1 receptor agonist]. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. [2021]

5. Belgium pubmed.ncbi.nlm.nih.gov

[Oral semaglutide, first oral GLP-1 receptor agonist (Rybelsus®)]. [2022]

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

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. [2022]

8. Belgium pubmed.ncbi.nlm.nih.gov

[Semaglutide, once weekly GLP-1 receptor agonist (Ozempic®)]. [2019]

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

Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl group of cilengitide by N-oligoethylene glycol (N-OEG) chains. [2014]

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

Imaging of Myocardial αvβ3 Integrin Expression for Evaluation of Myocardial Injury After Acute Myocardial Infarction. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Evaluation of [68Ga]Ga-NODAGA-RGD for PET Imaging of Rat Autoimmune Myocarditis. [2022]

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

A novel synthetic Arg-Gly-Asp-containing peptide cyclo(-RGDf==V-) is the potent inhibitor of angiogenesis. [2016]

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

Comparison of biological properties of 99mTc-labeled cyclic RGD Peptide trimer and dimer useful as SPECT radiotracers for tumor imaging. [2018]