Treatments for Prediabetes and Obesity

(Pre-DM Trial)

Overseen By Carolina Solis-Herrera, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Must not be taking: Selected therapies

Disqualifiers: Type 2 diabetes, Major oncologic, others

Trial Summary

What is the purpose of this trial?

The investigators are studying how to help people with prediabetes (Pre-DM) and obesity. The goal is to use new and affordable treatments to bring blood sugar levels back to normal and help participants to lose weight. The investigators also want to reduce participants risk of heart problems. The study team will look at how these treatments affect metabolism and other body functions to help find new ways to treat diabetes and obesity in the future.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that oral diuretics should be stable for at least 1 week before starting the trial. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drugs Actos, Pioglitazone, Jardiance, Empagliflozin, Metformin, Glucophage, Fortamet, Glumetza, Riomet, Rybelsus, and Semaglutide for prediabetes and obesity?

Research shows that pioglitazone, a component of Actos, can improve insulin sensitivity and may help prevent the progression of type 2 diabetes, which is related to prediabetes. Additionally, metformin, found in Glucophage, Fortamet, Glumetza, and Riomet, is effective in controlling blood sugar levels and is often used to manage weight in people with type 2 diabetes. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Metformin is generally safe but can cause stomach discomfort. Pioglitazone may increase the risk of bladder cancer, heart failure, and bone fractures in postmenopausal women. Thiazolidinediones, like pioglitazone, have been linked to heart issues, and their long-term safety is still being studied. ^{6 7 8 9 10}

What makes the drug combination of Actos, Jardiance, Metformin, and Rybelsus unique for treating prediabetes and obesity?

This drug combination is unique because it combines different mechanisms of action: Metformin improves insulin sensitivity, Pioglitazone (Actos) may help preserve pancreatic function, Empagliflozin (Jardiance) reduces blood sugar by increasing glucose excretion, and Semaglutide (Rybelsus) aids in weight loss and glucose control by enhancing insulin secretion and reducing appetite. ^{4 11 12 13 14}

Research Team

Carolina Solis-Herrera, MD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Eligibility Criteria

This trial is for individuals with prediabetes and obesity, aiming to prevent the progression of these conditions and reduce cardiovascular risk. The specific eligibility criteria are not provided, but typically participants would need to meet certain health standards.

Inclusion Criteria

Glycated Hemoglobin (HbA1c) = 5.7-6.4%

I was diagnosed with pre-diabetes in the last 6 months.

No contraindication for Magnetic Resonance Imaging (MRI) (metal plates, screws, shrapnel, pins, or cardiac pacemaker)

Exclusion Criteria

Cardiac resynchronization therapy

I am currently on a specific therapy.

I got a defibrillator implanted within the last 3 months.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive a 6-month treatment with Nutritional Consultation and either SGLT2 Inhibitor, Rybelsus, Metformin + Pioglitazone, or placebo

6 months

16 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Actos (Thiazolidinedione)
• Jardiance (SGLT2 Inhibitor)
• Metformin (Biguanide)
• Rybelsus (GLP-1 Receptor Agonist)

Trial Overview The study is testing the effectiveness of several treatments: a placebo (inactive pill), Jardiance (a diabetes medication), Metformin (commonly used for diabetes), Rybelsus Tablet, and Actos in improving blood sugar levels and aiding weight loss.

Participant Groups

Group I: SGLT2 inhibitor Group Experimental Treatment 1 Intervention

Randomization will occur 1:1:1:1 to this SGLT2 inhibitor group

Group II: Metformin with SGLT2 Inhibitor Group Experimental Treatment 2 Interventions

Randomization will occur 1:1:1:1 to this metformin plus SGLT2 inhibitor group

Group III: GLP-1 Receptor Agonist Group Experimental Treatment 1 Intervention

Randomization will occur 1:1:1:1 to this GLP-1 receptor agonist group

Group IV: Placebo Placebo Group 1 Intervention

Randomization will occur 1:1:1:1 to this placebo group

Actos is already approved in Canada, Japan for the following indications:

Approved in Canada as Actos for:

• Type 2 diabetes

Approved in Japan as Glustin 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+

Baptist Health Foundation of San Antonio

Collaborator

Trials

1

Recruited

60+

Findings from Research

In a study of 365 patients with type 2 diabetes, adding rosiglitazone to glyburide/metformin therapy significantly reduced HbA1C levels by 1.0% compared to placebo, with 42% of patients achieving HbA1C levels below 7%.

While the addition of rosiglitazone improved glycemic control, it was associated with mild-to-moderate side effects such as edema (8%), hypoglycemia (22%), and an average weight gain of 3 kg, but no severe hypoglycemia occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. Dailey, GE., Noor, MA., Park, JS., et al.[2022]

In a 24-week study involving 119 patients with type 2 diabetes, both pioglitazone and sitagliptin showed similar overall improvements in glycemic control, but pioglitazone resulted in a greater reduction in fasting plasma glucose (FPG) by 12.9 mg/dL.

Pioglitazone was associated with a significant decrease in inflammation markers (hs-CRP) and a higher mean weight gain compared to sitagliptin, which had more gastrointestinal side effects, indicating different safety profiles for the two medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of adding pioglitazone or sitagliptin to patients with type 2 diabetes insufficiently controlled with metformin and a sulfonylurea. Liu, SC., Chien, KL., Wang, CH., et al.[2022]

In a study of 101 insulin-naïve subjects with type 2 diabetes, the fixed-dose triple oral diabetes polypill (GMP) showed a trend towards a greater reduction in HbA1c levels compared to the insulin mix (IM), with a significant number of patients achieving a drop in HbA1c of over 1% (72.5% vs. 22%).

GMP was also rated as more effective and better tolerated by patients compared to IM, suggesting it may be a preferable treatment option for managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triple oral fixed-dose diabetes polypill versus insulin plus metformin efficacy demonstration study in the treatment of advanced type 2 diabetes (TrIED study-II). Bell, DS., Dharmalingam, M., Kumar, S., et al.[2022]

Pioglitazone, a thiazolidinedione, has shown promise in preventing the decline of beta-pancreatic cell function, which could help in preventing type 2 diabetes in at-risk individuals.

The QUARTET clinical study program suggests that pioglitazone may also contribute to cardiovascular prevention in type 2 diabetic patients, although further results from ongoing studies are needed to confirm these benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pioglitazone insulin sensitivity and type 2 diabetes mellitus: recent data]. Monnier, L., Sauvanet, JP.[2019]

Rosiglitazone and pioglitazone are effective treatments for type 2 diabetes that work differently from traditional therapies, potentially reducing cardiovascular risk while being well tolerated by most patients.

These medications can cause side effects like weight gain and fluid retention, and should be used with caution in patients with heart failure or liver disease, with liver enzyme monitoring recommended during the first year of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The "glitazones": rosiglitazone and pioglitazone. Papoushek, C.[2019]

In a study involving 303 patients with Type II diabetes, rosiglitazone significantly reduced fasting and postprandial glucose levels compared to placebo, demonstrating its efficacy in managing blood sugar levels.

The 4 mg twice-daily dose of rosiglitazone was found to be as effective as the higher 6 mg dose, suggesting that 4 mg may be the optimal maximum dose for treatment, with no significant increase in adverse events or hepatotoxicity observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes. Raskin, P., Rappaport, EB., Cole, ST., et al.[2022]

Insulin-dependent oral antidiabetic agents like metformin, sulfonylureas, and gliptins are generally safe but have limitations in maintaining long-term blood glucose control, with no single drug providing stable control for years.

Metformin can cause gastrointestinal discomfort, while sulfonylureas carry risks of hypoglycemia and weight gain; additionally, pioglitazone is linked to serious side effects such as bladder cancer and heart failure, highlighting the need for careful patient monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Limitations of insulin-dependent drugs in the treatment of type 2 diabetes mellitus]. Valerón, PF., de Pablos-Velasco, PL.[2018]

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]

Biguanides and sulfonylureas, introduced in the 1950s, remain widely used for diabetes management, with well-defined safety and tolerability profiles, while newer agents like thiazolidinediones have raised concerns about potential side effects such as heart failure and hepatotoxicity.

Rapid-acting non-sulfonylurea secretagogues may offer a safer alternative for certain patients, particularly those with renal impairment, and alpha-glucosidase inhibitors like acarbose have a strong safety record, although their use is limited by tolerability issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative safety of newer oral antidiabetic drugs. Krentz, AJ.[2022]

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]

Pioglitazone significantly reduced the incidence of type 2 diabetes mellitus (T2DM) in individuals at increased risk compared to placebo, with a moderate-certainty evidence based on 27 studies involving 4186 participants.

The evidence suggests that pioglitazone is equally effective as metformin in preventing T2DM, but the overall data on safety and long-term effects, including quality of life, remains limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Ipsen, EØ., Madsen, KS., Chi, Y., et al.[2023]

Incretin-based therapies, including DPP-4 inhibitors and GLP-1 receptor agonists, are effective treatments for type 2 diabetes (T2D) that enhance GLP-1 signaling, leading to better glucose regulation and significant weight loss with GLP-1 agonists.

These therapies show promise for patients with prediabetes as they can lower glycosylated hemoglobin and fasting plasma glucose levels, support weight management, and potentially preserve insulin-producing β-cell function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incretin therapy--present and future. Garber, AJ.[2021]

References

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

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. [2022]

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

Efficacy and safety of adding pioglitazone or sitagliptin to patients with type 2 diabetes insufficiently controlled with metformin and a sulfonylurea. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Triple oral fixed-dose diabetes polypill versus insulin plus metformin efficacy demonstration study in the treatment of advanced type 2 diabetes (TrIED study-II). [2022]

4. France pubmed.ncbi.nlm.nih.gov

[Pioglitazone insulin sensitivity and type 2 diabetes mellitus: recent data]. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The "glitazones": rosiglitazone and pioglitazone. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

[Benefits and risks of current pharmacotherapy in the treatment of type 2 diabetes]. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes. [2022]

8. Spain pubmed.ncbi.nlm.nih.gov

[Limitations of insulin-dependent drugs in the treatment of type 2 diabetes mellitus]. [2018]

9. 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]

10. England pubmed.ncbi.nlm.nih.gov

Comparative safety of newer oral antidiabetic drugs. [2022]

11. India pubmed.ncbi.nlm.nih.gov

Drug therapy in prediabetes. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. [2023]

13. Singapore pubmed.ncbi.nlm.nih.gov

Incretin therapy--present and future. [2021]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Thiazolidinedione derivatives in type 2 diabetes mellitus. [2018]