Beta-hydroxybutyrate for Type 2 Diabetes

(Protocol1 Trial)

No longer recruiting at 1 trial location

Overseen By Carolina Solis-Herrera, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: The University of Texas Health Science Center at San Antonio

Must not be taking: GLP-1 RA, DPP4i, Pioglitazone, Insulin

Disqualifiers: Pregnancy, Breastfeeding, MRI contraindications, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how beta-hydroxybutyrate (also known as Farxiga or dapagliflozin) affects heart function and sugar use in people with Type 2 diabetes. It tests three different doses to assess improvements in heart strength and blood sugar management. Individuals with long-standing Type 2 diabetes and moderate heart failure may be suitable candidates. Participants will undergo heart imaging and other tests to measure these effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical knowledge.

Will I have to stop taking my current medications?

If you are taking medications like GLP-1 RA, DPP4i, pioglitazone, SGLT2 inhibitors, or insulin, you will need to stop them to participate in this trial. The protocol does not specify about other medications, so it's best to discuss with the trial team.

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

Research has shown that beta-hydroxybutyrate is usually safe for people. It is a natural substance produced by the body during fasting or a low-carb diet. Although specific clinical trial data on beta-hydroxybutyrate is limited, this study is in an early stage, so the treatment's safety is still under evaluation.

As an early-phase trial, the primary goal is to assess the safety of beta-hydroxybutyrate. Researchers will monitor participants closely for any side effects. These early trials are crucial in determining whether a treatment can be tested on a larger scale.

In summary, while beta-hydroxybutyrate naturally occurs in the body, its use as a treatment remains under investigation. By participating in this trial, individuals can help researchers gather more information about its safety for people with Type 2 diabetes. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Beta-hydroxybutyrate is unique because it introduces a new approach to managing Type 2 Diabetes by leveraging the benefits of ketone bodies, which are typically produced during fasting or low-carbohydrate diets. Unlike standard treatments like metformin and insulin, which primarily focus on regulating blood sugar levels, beta-hydroxybutyrate may enhance energy metabolism and improve insulin sensitivity by mimicking a state of nutritional ketosis. Researchers are excited about this treatment as it offers a novel mechanism that could complement existing therapies, potentially leading to better control over blood glucose levels and improved overall metabolic health for patients with Type 2 Diabetes.

What evidence suggests that beta-hydroxy-butyrate might be an effective treatment for type 2 diabetes?

Research has shown that beta-hydroxybutyrate (B-OH-B) might benefit people with type 2 diabetes. In animal studies, B-OH-B improved heart function and energy utilization. It provides an alternative energy source for cells, potentially enhancing heart performance and managing blood sugar levels. Early results suggest B-OH-B can improve heart muscle function and reduce the heart's reliance on glucose, the main blood sugar. Although more research is needed, the science behind B-OH-B offers hope for better heart and blood sugar control in type 2 diabetes. Participants in this trial will receive different dosages of B-OH-B to evaluate its effects on these outcomes. ^{2 3 4 6 7}

Who Is on the Research Team?

Ralph A DeFronzo, MD

Principal Investigator

UT Health San Antonio

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with Type 2 diabetes and heart failure (Class II-III NYHA) who have an ejection fraction below 50%. Participants should have a BMI of 23-38, stable blood pressure, and specific levels of HbA1c and NT-proBNP. Those on certain diabetes medications or with conditions that could risk safety or affect results can't join.

Inclusion Criteria

Your body mass index (BMI) is between 23 and 38.

My heart's pumping ability is reduced, and I have some limitations on physical activity.

Your HbA1c level is between 6.0% and 9.0%.

Exclusion Criteria

I am not pregnant or breastfeeding.

Any other condition that in the opinion of the investigator create a hazard to the subject safety, endanger the study procedures or interfere with the interpretation of study results

I am currently taking medication for diabetes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline cardiac MRI and blood samples are taken to measure cardiac functional parameters and various biomarkers

1 day

1 visit (in-person)

Treatment

Participants receive a prime-continuous infusion of racemic B-OH-B to increase plasma B-OH-B concentration, followed by MRI and PET studies

1 day

1 visit (in-person)

Follow-up

Participants return for a repeat PET/18F-2-DOG study to examine the effect of hyperketonemia on myocardial glucose uptake and blood flow

14 days

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Beta-hydroxy-butyrate

Trial Overview The study tests how different levels of beta-hydroxy-butyrate (B-OH-B), a ketone body, affect heart muscle function and sugar uptake in the heart using advanced imaging techniques like cardiac MRI and PET scans in people with Type 2 diabetes suffering from heart failure.

How Is the Trial Designed?

Group I: Group I Beta-Hydroxy-Butyrate Active Control 1 Intervention

Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end

Group II: Group II Beta-Hydroxy-Butyrate Active Control 1 Intervention

Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end

Group III: Group III Beta-Hydroxy-Butyrate Active Control 1 Intervention

Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end

Beta-hydroxy-butyrate is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Farxiga for:

• Type 2 diabetes

Approved in United States as Farxiga for:

• Type 2 diabetes
• Heart failure

Approved in Japan as Forxiga for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

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]

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]

Dapagliflozin is an effective SGLT2 inhibitor for managing type 2 diabetes, showing consistent reductions in blood glucose levels and body weight over long-term follow-up periods of 1-4 years across various clinical trials.

It has a low risk of causing hypoglycemia and is generally well tolerated, although it can lead to genital infections, particularly in women, and is not recommended for patients with moderate to severe renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: a review of its use in patients with type 2 diabetes. Plosker, GL.[2022]

Dapagliflozin, an SGLT2 inhibitor, has been shown to effectively lower plasma glucose levels in patients with type 2 diabetes, with reductions in hemoglobin A1c ranging from 0.54-0.89% over 12-24 weeks, while also improving insulin sensitivity.

The drug has a favorable safety profile, with low rates of hypoglycemia similar to placebo, although it may increase the risk of genital and urinary tract infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. Shah, NK., Deeb, WE., Choksi, R., et al.[2021]

A new bioanalytical assay for dapagliflozin has been developed, achieving a lower limit of quantitation of 0.2 ng/mL, which is five times more sensitive than previous methods, allowing for better detection in human plasma.

This assay not only measures dapagliflozin but also its major metabolite, BMS-801576, and has been validated for use in pediatric and critical clinical studies, supporting future research on this diabetes medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective reaction monitoring of negative electrospray ionization acetate adduct ions for the bioanalysis of dapagliflozin in clinical studies. Ji, QC., Xu, X., Ma, E., et al.[2021]

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 (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

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8855933/

Effectiveness and safety of dapagliflozin in real-life patients This study aims to evaluate dapagliflozin in patients with type 2 diabetes (T2D) in clinical practice in Spain.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1812389

Dapagliflozin and Cardiovascular Outcomes in Type 2 ... With respect to efficacy, dapagliflozin resulted in a lower rate of cardiovascular death or hospitalization for heart failure than placebo (4.9% ...

3. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.058103

Efficacy and Safety of Dapagliflozin in Type 2 Diabetes ... Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9–2.9; P<0.0001) compared with placebo at 48 months. The beneficial effects of ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2772417424000396

A new hope for the therapeutic treatment of type 2 diabetes ... Data suggests that 10 mg of the drug can cause roughly 1.80 kg of weight loss in comparison to a placebo [38,39]. This is viewed as an advantage due to ...

5. jamanetwork.com jamanetwork.com/journals/jamacardiology/fullarticle/2794142

Efficacy and Safety of Dapagliflozin According to ... Dapagliflozin consistently reduced the risk of a composite of CV death or hospitalization for heart failure (HHF), HHF alone, and progression of kidney disease.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5836959/

Dapagliflozin in patients with type 2 diabetes mellitus Over 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively.

7. cardiab.biomedcentral.com cardiab.biomedcentral.com/articles/10.1186/s12933-025-02875-6

Efficacy and safety of dapagliflozin in patients hospitalized ... Among patients with T2D, the prevention outcome occurred in 10.9% receiving dapagliflozin versus 13.9% receiving placebo (hazard ratio [HR] 0. ...