Treatments for Prediabetes and Obesity

(Pre-DM Trial)

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: Selected therapies

Disqualifiers: Type 2 diabetes, Major oncologic, others

Compensation: Varies

Number of Visits: 19

Duration: 6 months

64 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore new treatments for individuals with prediabetes and obesity to help normalize blood sugar levels, promote weight loss, and reduce the risk of heart issues. Participants will receive one of several treatments: Actos (pioglitazone), Jardiance (empagliflozin), Metformin, Rybelsus (semaglutide), or a placebo. The trial will also examine the effects of these treatments on metabolism and overall body function. It is suitable for those diagnosed with prediabetes, experiencing obesity, and belonging to the Hispanic ethnic group. As a Phase 1 trial, the research focuses on understanding how the treatment works in 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 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.

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

Research shows that the treatments tested in the trial are generally well-tolerated. For empagliflozin, studies have found a low risk of low blood sugar and no weight gain. It is considered safe for people with type 2 diabetes, even those with advanced kidney disease, with no new safety concerns reported.

Rybelsus, another treatment in the trial, can cause some stomach issues like nausea and diarrhea. However, these effects are common and usually mild. The treatment has been shown to help with weight loss safely.

Metformin, often used with empagliflozin, has a strong safety record. It is known to protect the heart in people with type 2 diabetes or prediabetes. When used with empagliflozin, side effects were mostly mild.

Overall, these treatments have been tested in other conditions and have a good safety profile. However, since this is an early-phase trial, the focus is mainly on how well people tolerate these treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for prediabetes and obesity because they target the condition in innovative ways. Actos, a thiazolidinedione, works by improving insulin sensitivity, which can help regulate blood sugar levels more effectively. Jardiance, an SGLT2 inhibitor, not only helps lower blood sugar levels by preventing glucose reabsorption in the kidneys but may also support weight loss. Rybelsus, a GLP-1 receptor agonist, enhances insulin secretion and slows gastric emptying, which can lead to reduced appetite and better weight management. Metformin, when combined with an SGLT2 inhibitor like Jardiance, offers a dual approach to managing blood sugar and weight, potentially offering enhanced benefits compared to using metformin alone. These treatments offer new mechanisms that could complement or even surpass the effects of current standard therapies.

What evidence suggests that this trial's treatments could be effective for prediabetes and obesity?

Research has shown that the treatments studied in this trial could help with prediabetes and obesity. Participants in the SGLT2 inhibitor group will receive Empagliflozin, which aids in weight loss and improves heart health, particularly in individuals with obesity and diabetes. It also slows the transition from prediabetes to diabetes. Those in the GLP-1 receptor agonist group will receive Rybelsus, which has led to significant weight loss, with many patients losing over 10% of their body weight. The Metformin with SGLT2 inhibitor group will receive a combination of Metformin and Empagliflozin, which controls blood sugar and promotes weight loss more effectively than Metformin alone. These treatments have demonstrated various benefits, making them promising options for managing prediabetes and obesity. ^{6 7 8 9 10}

Who Is on the Research Team?

Carolina Solis-Herrera, 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 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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Actos
• Jardiance
• Metformin
• Rybelsus

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Actos for:

• Type 2 diabetes

Approved in European Union as Actos for:

• Type 2 diabetes

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+

Published Research Related to This Trial

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 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]

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 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]

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]

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]

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]

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]

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]

Thiazolidinedione derivatives, such as pioglitazone and rosiglitazone, are effective for lowering blood glucose in type 2 diabetes, showing comparable efficacy to sulphonylureas and metformin, but are not the first choice for monotherapy.

These medications are particularly suitable for obese patients, although long-term data on their efficacy and side effects remain limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiazolidinedione derivatives in type 2 diabetes mellitus. Tack, CJ., Smits, P.[2018]

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]

The review highlights that while there are many innovative drugs being developed for type 2 diabetes, several have faced serious safety issues, leading to their withdrawal or halting of development.

It discusses the current state of treatments, including glitazones, incretin mimetics, SGLT-2 inhibitors, and new experimental drugs, emphasizing the need for better methods to predict and differentiate drug-related adverse events from natural disease occurrences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Benefits and risks of current pharmacotherapy in the treatment of type 2 diabetes]. Schindler, C., Barthel, A., Fischer, S., et al.[2021]

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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2307563

Semaglutide and Cardiovascular Outcomes in Obesity ... Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9758543/

Efficacy and Safety of Semaglutide for Weight Loss in ... Combining the results of the trials showed that semaglutide is indeed associated with weight loss with a mean difference of 11.85% compared with placebo.

3. nature.com nature.com/articles/s41591-024-02996-7

Long-term weight loss effects of semaglutide in obesity ... At week 104, 52.4% of patients treated with semaglutide achieved improvement in BMI category compared with 15.7% of those receiving placebo.

4. diabetesjournals.org diabetesjournals.org/diabetes/article/74/Supplement_1/1733-P/159240/1733-P-Two-Year-Real-World-Effectiveness-of

Two-Year Real-World Effectiveness of Semaglutide in Patients ... Body weight reductions of ≥5%, ≥10%, ≥15%, and ≥20% from baseline at 2 years were observed in 90.5%, 69.8%, 46.9%, and 29.6% of patients, ...

5. thecardiologyadvisor.com thecardiologyadvisor.com/news/higher-semaglutide-dose-demonstrates-superior-efficacy-in-obesity-t2d/

Higher Semaglutide Dose Demonstrates Superior Efficacy ... Participants receiving semaglutide 7.2 mg vs 2.4 mg and placebo had higher rates of gastrointestinal events (70.8% vs 61.2% and 42.8%) and ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa1504720

Empagliflozin, Cardiovascular Outcomes, and Mortality in ... Safety data were reviewed by an independent academic data monitoring committee every 90 days or at the discretion of the committee.

7. diabetesjournals.org diabetesjournals.org/care/article/45/6/1445/145036/Safety-of-Empagliflozin-in-Patients-With-Type-2

Safety of Empagliflozin in Patients With Type 2 Diabetes and ... Use of empagliflozin in patients with type 2 diabetes and advanced CKD raised no new safety concerns and may have beneficial effects on the development of ...

8. nature.com nature.com/articles/s41598-024-83820-7

Effect of empagliflozin on weight in patients with ... In this study, empagliflozin led to reductions in weight, body mass index (BMI), waist circumference, Fasting plasma glucose (FPG), and HbA1c ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4890479/

A Safety Evaluation of Empagliflozin for the Treatment of Type ... The evidence for empagliflozin is robust with regard to glycemic efficacy and safety. Low risk of hypoglycemia, absence of weight gain, and demonstrated ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9506669/

Empagliflozin Ameliorates Progression From Prediabetes ... The purpose of this paper is to demonstrate how EMPA ameliorates progression from prediabetes to diabetes and improves hepatic lipid metabolism.