Beta-hydroxybutyrate for Type 2 Diabetes

(Protocol1 Trial)

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

78 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Beta-hydroxybutyrate, Farxiga, dapagliflozin for Type 2 Diabetes?

Dapagliflozin (Farxiga) is effective in treating type 2 diabetes by lowering blood sugar levels and is also approved to reduce the risk of kidney and heart problems in people with chronic kidney disease. It works by helping the kidneys remove sugar from the body through urine, and it has been shown to be effective and generally well-tolerated in numerous clinical trials. ^{1 2 3 4 5}

Is dapagliflozin (Farxiga) safe for humans?

Dapagliflozin (Farxiga) is generally considered safe for humans, with clinical trials showing it is well tolerated. Common side effects include genital and urinary tract infections, but it does not cause serious issues like liver or kidney damage. It is not recommended for people with moderate or severe kidney problems. ^{3 4 5 6 7}

How is the drug dapagliflozin unique in treating type 2 diabetes?

Dapagliflozin is unique because it works by blocking a protein in the kidneys called SGLT2, which helps remove excess sugar from the body through urine, and it does this without relying on insulin. This makes it a good option for people who need additional help managing their blood sugar levels alongside other diabetes medications. ^{1 2 3 4 5}

What is the purpose of this trial?

To examine the effect of an increase in plasma beta-hydroxy-butyrate (B-OH-B) levels, spanning the physiologic and pharmacologic range (+0.5, +2.0, and +5.0 mmol/L), on: (i) parameters of left ventricular (LV) systolic and diastolic function utilizing cardiac magnetic resonance imaging (MRI) and (ii) myocardial glucose uptake using positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose in type 2 diabetic patients with Class II-III New York Heart Association (NYHA).

Research Team

Ralph A DeFronzo, MD

Principal Investigator

UT Health San Antonio

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 (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]

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, 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. [2021]

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

Selective reaction monitoring of negative electrospray ionization acetate adduct ions for the bioanalysis of dapagliflozin in clinical studies. [2021]

3. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. [2021]

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

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

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

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

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

Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. [2021]