Diabetes Medications for Prediabetes

Overseen By Ralph A DeFronzo, MD

Age: 18+

Sex: Any

Trial Phase: Academic

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

Must be taking: Metformin, Pioglitazone

Must not be taking: Glucose metabolism, Neurosynaptic

Disqualifiers: Diabetes, Heart failure, Cancer, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

700 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

HYPOTHESIS: Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have distinct pathophysiologic etiologies. Therefore, therapeutic interventions designed to correct the specific underlying pathogenic abnormalities in IGT and IFG will be required to optimally prevent the progressive beta cell failure and development of overt type 2 diabetes.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications known to alter glucose metabolism, except for metformin and pioglitazone. If you're on other medications affecting glucose, you may need to stop them to participate.

Is the combination of saxagliptin, dapagliflozin, and metformin safe for humans?

The combination of saxagliptin, dapagliflozin, and metformin has been generally well tolerated in studies, with long-term safety evaluated over 4 years in patients with type 2 diabetes. It is associated with a low risk of hypoglycemia (low blood sugar) and no significant weight gain. ^{1 2 3 4 5}

How does this drug differ from other treatments for prediabetes?

This drug combination is unique because it includes Dapagliflozin, Metformin, Pioglitazone, and Saxagliptin, which work together to improve insulin sensitivity, reduce glucose production in the liver, and enhance incretin hormone action, potentially offering a more comprehensive approach to managing prediabetes compared to lifestyle changes alone. ^{1 6 7 8 9}

What data supports the effectiveness of the drug combination including Dapagliflozin, Saxagliptin, and Metformin for prediabetes?

Research shows that the combination of Saxagliptin and Dapagliflozin, along with Metformin, is effective in controlling blood sugar levels in people with type 2 diabetes, which suggests it might also help those with prediabetes. This combination has been shown to improve blood sugar control better than using Saxagliptin or Dapagliflozin with Metformin alone, and it also helps with weight loss and has a low risk of causing low blood sugar. ^{1 2 3 5 10}

Who Is on the Research Team?

Ralph A DeFronzo, MD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with pre-diabetes, specifically those with impaired fasting glucose and impaired glucose tolerance. They should have a BMI between 24-40 kg/m2 and stable weight. Participants must be in good health without major organ disease or history of heart failure, not pregnant, willing to use contraception, and not on certain medications.

Inclusion Criteria

My major organs are healthy based on recent exams and tests.

Your blood sugar levels are within a certain range when tested after fasting and after having a sugary drink.

Your body mass index (BMI) is between 24 and 40.

Exclusion Criteria

I haven't had any unstable illnesses in the last 3 months.

I have a close family member with diabetes.

I have never had heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pharmacologic interventions including dapagliflozin, saxagliptin, pioglitazone, or metformin based on their glucose tolerance status

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dapagliflozin
• Metformin
• Pioglitazone
• Saxagliptin

Trial Overview The study tests whether Dapagliflozin, Saxagliptin, Pioglitazone, or Metformin can prevent type 2 diabetes in people with early blood sugar issues. It's based on the idea that different treatments might be needed for different types of pre-diabetes.

How Is the Trial Designed?

Group I: Isolated IFG with Dapagliflozin Active Control 1 Intervention

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG \< 140) will receive dapagloflozin, 10mg/day

Group II: Isolated IGT with Metformin Active Control 1 Intervention

Healthy subjects with isolated IGT (FPG \< 100; 2-h PG = 140-199) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Group III: Isolated IGT with Pioglitazone Active Control 1 Intervention

Healthy subjects with isolated IGT (FPG \< 100; 2-h PG = 140-199) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two

Group IV: Isolated IFG with Saxagliptin Active Control 1 Intervention

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG \< 140) will receive saxagliptin, 10mg/day

Group V: IGT plus IFG with Saxagliptin Active Control 1 Intervention

Healthy subjects with IGT plus IFG will receive saxagliptin, 10mg/day

Group VI: IGT plus IFG with Pioglitazone Active Control 1 Intervention

Healthy subjects with IGT plus IFG will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two

Group VII: Isolated IFG with Pioglitazone Active Control 1 Intervention

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG \< 140) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two

Group VIII: Isolated IFG with Metformin Active Control 1 Intervention

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG \< 140) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Group IX: IGT plus IFG with Dapagliflozin Active Control 1 Intervention

Healthy subjects with IGT plus IFG will receive dapagliflozin, 10mg/day

Group X: IGT plus IFG with Metformin Active Control 1 Intervention

Healthy subjects with IGT plus IFG will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Group XI: Healthy normal glucose tolerance (NGT) subjects Active Control 1 Intervention

Subjects (Fasting Plasma Glucose or FPG \< 100 mg/dl and 2-h PG \< 140 mg/dl) without FH (family history) of diabetes in a first degree relative

Group XII: Isolated IGT with Dapagliflozin Active Control 1 Intervention

Healthy subjects with isolated IGT (FPG \< 100; 2-h PG = 140-199) will receive dapagliflozin, 10 mg/day

Group XIII: Isolated IGT with Saxagliptin Active Control 1 Intervention

Healthy subjects with isolated IGT (FPG \< 100; 2-h PG = 140-199) will receive saxagliptin, 5 mg/day

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?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

American Diabetes Association

Collaborator

Trials

148

Recruited

102,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

Saxagliptin, a recently FDA-approved DPP IV inhibitor for Type 2 Diabetes Mellitus (T2DM), effectively increases the action of incretin hormones, leading to improved glycemic control without causing weight gain over a 24-week period.

The drug is well absorbed, has a unique mechanism of covalently binding to the DPP IV enzyme, and is generally well tolerated, making it a suitable second-line treatment option alongside Metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Saxagliptin: a new drug for the treatment of type 2 diabetes. Thareja, S., Aggarwal, S., Malla, P., et al.[2019]

In a study of 78 patients with uncontrolled type 2 diabetes, dapagliflozin showed the most significant reduction in HbA1c levels after 24 months, with a mean change of -1.05%, compared to sitagliptin (-0.81%) and lobeglitazone (-1.08%).

Dapagliflozin also improved body composition by decreasing whole body fat percentage and increasing muscle percentage, while sitagliptin and lobeglitazone led to increases in body fat, suggesting dapagliflozin may be a better option for patients looking to improve their body composition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study. Hong, JH., Moon, JS., Seong, K., et al.[2023]

In four 24-week studies, saxagliptin significantly improved glycaemic control in patients with type 2 diabetes, achieving larger reductions in HbA(1c) compared to other treatments, especially when used in combination with metformin.

Saxagliptin was associated with a low incidence of hypoglycaemia, indicating it is a safe option for managing blood sugar levels without the common risk of low blood sugar episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinically relevant reductions in HbA1c without hypoglycaemia: results across four studies of saxagliptin. Karyekar, CS., Frederich, R., Ravichandran, S.[2022]

The study found that two fixed-combination drug products (FCDPs) containing dapagliflozin, saxagliptin, and metformin were bioequivalent to their individual components, indicating they can be used interchangeably without loss of efficacy.

Both FCDPs demonstrated a similar safety profile to their individual components, with no serious adverse events reported, supporting their use in treating type 2 diabetes mellitus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects. Tang, W., Engman, H., Zhu, Y., et al.[2021]

Saxagliptin/dapagliflozin fixed-dose combination tablets (Qtern®) are effective for improving glycaemic control in adults with type 2 diabetes, showing better results than either saxagliptin or dapagliflozin used alone with metformin in three phase III trials.

This combination not only helps control blood sugar levels but also leads to weight loss and has a low risk of causing hypoglycaemia, making it a safe and beneficial option for patients with inadequate glycaemic control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Saxagliptin/Dapagliflozin: A Review in Type 2 Diabetes Mellitus. Garnock-Jones, KP.[2021]

Saxagliptin, whether used alone or in combination with metformin, has been shown to be generally safe and well tolerated over a 4-year period, with no increased risk of hypoglycemia compared to placebo.

Patients taking saxagliptin plus metformin experienced a longer time to rescue or discontinuation due to inadequate glycemic control, and their HbA1c levels decreased, while those on placebo saw an increase in HbA1c.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes. Rosenstock, J., Gross, JL., Aguilar-Salinas, C., et al.[2022]

In a study of 686 subjects with prediabetes, prolonged-release metformin (metformin XR) effectively reduced fasting plasma glucose levels, normalizing them in 43% of participants after 12 weeks.

Metformin XR was well tolerated, with gastrointestinal side effects being the most common, supporting its use as a safe treatment option for managing prediabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observational study of the efficacy of prolonged-release metformin in people with prediabetes. Hostalek, U., Zilahi, Z.[2020]

Patients with impaired fasting glucose and impaired glucose tolerance are classified as having 'prediabetes', which significantly increases their risk of developing diabetes and cardiovascular diseases.

Various medications, including metformin and glitazones, have shown effectiveness in improving blood sugar levels in prediabetes, but none are currently recommended by professional organizations for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug therapy in prediabetes. Mukhopadhyay, P., Chowdhury, S.[2013]

A survey of 117 doctors in India revealed that while lifestyle modifications are commonly recommended for managing prediabetes, many practitioners prefer using metformin, with voglibose emerging as a popular second-line treatment option.

Voglibose, recently approved in Japan for prediabetes management, is considered relevant by most Indian doctors, although only about half have prescribed it, indicating a potential for increased adoption in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of voglibose in the treatment of prediabetes in Indian population: a cross-speciality survey. Dewda, PR., Agrawal, S.[2021]

Prediabetes affects a significant number of people, with nearly twice as many individuals diagnosed with prediabetes compared to diabetes, and it increases the risk of developing diabetes and cardiovascular issues by twofold.

Antihyperglycemic medications like metformin, acarbose, and thiazolidinediones can effectively improve insulin sensitivity and normalize carbohydrate metabolism in prediabetic patients, as shown in trials like DPP, STOP-NIDDM, and DREAM, without causing hypoglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Perspectives of the use of antihyperglycemic preparations in patients with metabolic syndrome and prediabetes]. Mamedov, MN., Shishkova, VN.[2017]

Citations

1. Netherlands pubmed.ncbi.nlm.nih.gov

Saxagliptin: a new drug for the treatment of type 2 diabetes. [2019]

2. Ireland pubmed.ncbi.nlm.nih.gov

Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study. [2023]

3. India pubmed.ncbi.nlm.nih.gov

Clinically relevant reductions in HbA1c without hypoglycaemia: results across four studies of saxagliptin. [2022]

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

Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects. [2021]

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

Saxagliptin/Dapagliflozin: A Review in Type 2 Diabetes Mellitus. [2021]

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

Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes. [2022]

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

Observational study of the efficacy of prolonged-release metformin in people with prediabetes. [2020]

8. India pubmed.ncbi.nlm.nih.gov

Drug therapy in prediabetes. [2013]

9. India pubmed.ncbi.nlm.nih.gov

Role of voglibose in the treatment of prediabetes in Indian population: a cross-speciality survey. [2021]

10. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Perspectives of the use of antihyperglycemic preparations in patients with metabolic syndrome and prediabetes]. [2017]