SGLT2 Inhibitor + GLP-1 Agonist for Kidney Transplant Recipients

(HALLMARK Trial)

Overseen By Vesta Lai

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: SGLT2i, GLP-1RA

Disqualifiers: Type 1 diabetes, Multi-organ transplant, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, dapagliflozin (an SGLT2 inhibitor) and semaglutide (a GLP-1 agonist), to evaluate their effectiveness and safety for individuals who have had a kidney transplant. Researchers aim to understand how these treatments perform over a short period of 12 weeks, regardless of whether participants have type 2 diabetes. The trial seeks kidney transplant recipients who have been stable for at least three months, possess a certain level of kidney function, and manage their blood pressure. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have used SGLT2 inhibitors or GLP-1 receptor agonists within 30 days before the trial starts.

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

Research has shown that semaglutide is generally safe for people who have had a kidney transplant. One study found it helped lower blood sugar levels and weight in these patients. Another report suggested it might improve kidney health and patient survival. However, more studies are needed to confirm these benefits. Some research also highlights the lack of sufficient safety data, indicating a need for more evidence.

For dapagliflozin, studies indicate it is safe for patients with chronic kidney disease. It helps reduce protein in urine, which is a positive sign. It has also been shown to lower the risk of death and other negative outcomes in diabetic kidney transplant patients. Overall, both treatments appear promising, but ongoing research will provide more information about their safety for kidney transplant patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they bring a fresh approach to managing kidney health in transplant recipients. Unlike traditional treatments that mainly focus on immunosuppression, dapagliflozin and semaglutide target different pathways that can improve kidney function and overall metabolic health. Dapagliflozin, a type of SGLT2 inhibitor, works by helping the kidneys remove excess glucose from the bloodstream, which can be beneficial in managing complications like diabetes. Meanwhile, semaglutide, a GLP-1 agonist, helps control blood sugar levels and may offer cardiovascular benefits. Together, they offer a novel combination that could provide more comprehensive care for kidney transplant patients.

What evidence suggests that this trial's treatments could be effective for kidney transplant recipients?

In this trial, participants will receive either semaglutide or dapagliflozin. Research has shown that semaglutide can lower blood sugar and aid in weight loss for kidney transplant patients with diabetes, while also reducing the risk of serious kidney and heart problems. Studies on dapagliflozin indicate it can lower the risk of death and other complications in diabetic kidney transplant patients, as well as reduce blood pressure and body weight. Both treatments have demonstrated support for kidney health and improved overall survival. ^{1 2 3 5 6}

Who Is on the Research Team?

Sunita Singh, MD MSc FRCPC

Principal Investigator

University Health Network, Toronto General Hospital

Are You a Good Fit for This Trial?

This trial is for kidney transplant recipients aged 18 or older, with a BMI of 18.5-40 and stable blood pressure. They must be at least 3 months post-transplantation with decent kidney function (eGFR ≥20). Diabetics can join if their HbA1c is below 12%. Exclusions include recent use of similar drugs, risk of dehydration or electrolyte issues, severe infections, uncontrolled hypertension, hypersensitivity to the drugs tested, pregnancy, certain cancers or genetic conditions.

Inclusion Criteria

Estimated glomerular filtration rate (eGFR) equal to or greater than 20 ml/min/1.73m2

Body-mass index (BMI) between 18.5 and 40 kg/m2

I am over 18 and had a kidney transplant more than 3 months ago.

Exclusion Criteria

Any other clinical condition that, based on Investigator's judgment, would jeopardize patient safety during trial participation or would affect the study outcome (e.g. immunocompromised patients, active malignancy, patients who might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections, uncontrolled hypertension, cardiorenal and/or hepatorenal syndrome)

I am currently being treated for BK, CMV, or EBV infection.

I have had an amputation or experience pain at rest due to poor blood flow.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Treatment

Participants receive either semaglutide or dapagliflozin for 12 weeks

12 weeks

Weekly visits for semaglutide, daily monitoring for dapagliflozin

Combination Therapy Treatment

Participants receive a combination of semaglutide and dapagliflozin for 12 weeks

12 weeks

Weekly visits for combination therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dapagliflozin
• Semaglutide

Trial Overview

The study tests the combination therapy using Dapagliflozin and Semaglutide over a period of 12 weeks in kidney transplant recipients (KTR), both with and without type 2 diabetes (T2D). It aims to assess how effective this treatment is short-term and what safety concerns might arise.

How Is the Trial Designed?

Group I: Semaglutide Experimental Treatment 2 Interventions

Semaglutide Subcutaneous 0.25mg once weekly for 4 weeks, then 0.5mg once weekly for 4 weeks, then 1mg once weekly for 4 weeks.

Group II: Dapagliflozin Experimental Treatment 2 Interventions

Dapagliflozin Tablets Total Dose 10mg daily for 12 weeks

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

Approved in European Union as Forxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in United States as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in Canada as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

In a study of 92 patients with type 2 diabetes and preserved kidney function, both GLP1 receptor agonists (semaglutide) and SGLT2 inhibitors (empagliflozin) showed similar effects on kidney function over three years, indicating both treatments are effective for kidney protection.

Baseline urinary biomarkers did not predict how well patients would respond to either treatment, but those with an early decline in kidney function (eGFR) may benefit more from SGLT2 inhibitors, suggesting a tailored approach to treatment could be beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parameters influencing renal response to SGLT2 inhibitors and GLP1 receptor agonists in type 2 diabetes patients with preserved renal function: a comparative, prospective study. Biancalana, E., Petralli, G., Raggi, F., et al.[2023]

DPP-4 inhibitors and GLP-1 receptor agonists are considered safe and effective for managing diabetes in kidney transplant recipients, while SGLT2 inhibitors may pose risks such as urinary tract infections and a slight decrease in renal function.

SGLT2 inhibitors are less effective in kidney transplant recipients compared to non-transplant patients with type 2 diabetes, highlighting the need for careful selection of antidiabetic agents based on individual patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of Newer Antidiabetic Agents for Diabetes Management in Kidney Transplant Recipients. Anderson, S., Cotiguala, L., Tischer, S., et al.[2021]

GLP-1 receptor agonists significantly reduce the risk of composite renal outcomes by 17% and new-onset persistent macroalbuminuria by 25% in patients with type 2 diabetes, based on a meta-analysis of seven studies involving 48,101 patients.

However, these medications do not significantly affect the estimated glomerular filtration rate (eGFR) decrease, doubling of serum creatinine, or end-stage renal disease compared to placebo or insulin glargine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of glucagon-like peptide 1 receptor agonists on the renal protection in patients with type 2 diabetes: A systematic review and meta-analysis. Li, X., Song, Y., Guo, T., et al.[2022]

GLP-1 receptor agonists (GLP-1RA) like liraglutide and semaglutide have shown significant benefits in glycemic control and weight loss in patients with end-stage kidney disease (ESKD) and those undergoing kidney transplantation, with reductions in HbA1c by up to 2% and weight loss of around 8 kg over 12 months.

While GLP-1RA are effective, gastrointestinal side effects are common and may affect patient adherence, highlighting the need for larger, longer-term studies to better understand their safety and efficacy in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1 receptor agonists in end-staged kidney disease and kidney transplantation: A narrative review. Clemens, KK., Ernst, J., Khan, T., et al.[2023]

In a study of 120 individuals with type 2 diabetes, neither semaglutide nor empagliflozin improved kidney oxygenation after 32 weeks; in fact, empagliflozin was associated with reduced kidney oxygenation in the medulla.

Semaglutide significantly decreased kidney perfusion, while empagliflozin increased erythropoietin and haematocrit levels, indicating complex effects on kidney function that may not align with initial hypotheses about their protective roles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Separate and combined effects of semaglutide and empagliflozin on kidney oxygenation and perfusion in people with type 2 diabetes: a randomised trial. Gullaksen, S., Vernstrøm, L., Sørensen, SS., et al.[2023]

Dapagliflozin (DAPA) is an effective SGLT2 inhibitor for treating type 2 diabetes, showing favorable pharmacokinetics and pharmacodynamics that help lower blood sugar levels while having beneficial effects on other metabolic risk factors.

While DAPA is generally safe, it carries an increased risk of genital and urinary infections, and concerns about bladder cancer and cardiovascular safety remain, prompting the FDA to seek further data on these issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. Maranghi, M., Carnovale, A., Durante, C., et al.[2021]

Subcutaneous semaglutide (Ozempic®), a GLP-1 receptor agonist, has shown significant efficacy in improving glycemic control and reducing HbA1c, albuminuria, and blood pressure in patients with advanced diabetic kidney disease (DKD) during a 6-month follow-up study involving patients on maintenance hemodialysis.

The treatment not only aids in weight loss and appetite suppression but also helps preserve residual kidney function, potentially improving patient outcomes and facilitating their inclusion on kidney transplant waiting lists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Semaglutide, a Glucagon-Like Peptide-1 Receptor Agonist in Real-Life: A Case Series of Patients in Maintenance Incremental Hemodialysis. De la Flor, JC., Lorenzo, JD., Marschall, A., et al.[2022]

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors provide cardiovascular and renal protection for patients with diabetic kidney disease, but there is still a high residual risk and limited effectiveness in moderate to severe chronic kidney disease (CKD).

Oral semaglutide, a GLP-1 receptor agonist, offers a promising alternative with potent antihyperglycemic effects, low risk of hypoglycemia, and cardiovascular and renal benefits, potentially improving early treatment options for patients with type 2 diabetes and diabetic kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide 1(GLP-1) receptor agonists in the management of the patient with type 2diabetes mellitus and chronic kidney disease: an approach for the nephrologist. Cases, A.[2023]

In a 28-week study involving 695 patients with type 2 diabetes, the combination of exenatide and dapagliflozin significantly reduced HbA1c levels more than either drug alone, demonstrating enhanced efficacy in glycaemic control.

The dual treatment was well tolerated, with no major hypoglycaemia reported, and common side effects included gastrointestinal issues and urinary tract infections, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Frías, JP., Guja, C., Hardy, E., et al.[2022]

Dapagliflozin (Forxiga) is no longer authorized for the treatment of type 1 diabetes mellitus, indicating a significant change in its regulatory status.

This decision reflects safety concerns or efficacy issues that may have arisen from clinical evaluations or post-marketing surveillance, emphasizing the importance of ongoing drug safety assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin no longer licensed for type 1 diabetes. [2022]

Dapagliflozin is an effective treatment for type 2 diabetes, proven through multiple controlled clinical trials that assess its efficacy, safety, and tolerability.

It is approved by the FDA for use as a standalone therapy or in combination with other glucose-lowering medications, including insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. Davis, PN., Ndefo, UA., Oliver, A.[2021]

SGLT2 inhibitors (SGLT2i) significantly lower the risk of serious renal-related adverse events and all-cause death in type 2 diabetes patients with severe chronic kidney disease, based on a review of 19 studies involving 6,607 participants.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) effectively reduce HbA1c levels in these patients, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can be used as an additional treatment if blood sugar control is inadequate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of efficacy and safety of three novel hypoglycemic agents in patients with severe diabetic kidney disease: A systematic review and network meta-analysis of randomized controlled trials. Li, Y., Hu, Y., Huyan, X., et al.[2022]

Dapagliflozin (Farxiga) is approved for reducing the risk of declining kidney function and kidney failure in adults with chronic kidney disease, regardless of whether they have type 2 diabetes.

It also helps lower the risk of cardiovascular death and hospitalization for heart failure, highlighting its efficacy in managing both kidney and heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidiabetic Drug Approved to Reduce Risk of Kidney Disease. Aschenbrenner, DS.[2023]

Citations

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These findings indicate that SGLT-2i significantly reduces mortality and adverse events in diabetic KTR, underscoring its potential to improve post-transplant ...

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Efficacy and safety of dapagliflozin in patients with CKD

Dapagliflozin significantly reduced body weight (-1.3 kg), eGFR (-0.27 ml/min/month), and blood pressure (-3.6/-1.7 mmHg).

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clinicaltrials.gov

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Efficacy, Mechanisms and Safety of SGLT2 Inhibitors in ...

The primary outcome of the trial is to determine if dapagliflozin is superior to placebo in reduction of blood pressure in KTR. Detailed Description. Kidney ...

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nejm.org

nejm.org/doi/full/10.1056/NEJMoa2024816

Dapagliflozin in Patients with Chronic Kidney Disease

For the composite of long-term dialysis or kidney transplantation, there were 69 outcome events in the dapagliflozin group and 100 outcome events in the ...

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journals.lww.com

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Efficacy, Mechanisms, and Safety of SGLT2 Inhibitors in...

Dapagliflozin led to significant, placebo-adjusted reductions in iohexol-measured GFR from baseline to 1 week (4.2±1.5 ml/min/1.73m 2) & 12 weeks (3.48±1.41 ml/ ...

6.

sciencedirect.com

sciencedirect.com/science/article/pii/S0168822725003523

Mortality, kidney, and safety outcomes with SGLT2 ...

This trial is expected to provide insights into the safety and possible role of SGLT2 inhibitors in optimizing outcomes for kidney transplant recipients, ...