Pioglitazone or Tirzepatide for Type 2 Diabetes

Overseen By Tracey McLaughlin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Stanford University

Must not be taking: Insulin, Pioglitazone, Weight loss medications

Disqualifiers: Pregnancy, Liver disease, Kidney disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how two treatments, pioglitazone (a thiazolidinedione) and tirzepatide (a potential drug acting as a GIP/GLP-1 receptor agonist), might aid individuals with normal-weight type 2 diabetes. Researchers aim to determine if these treatments can enhance insulin handling and fat management. Participants will be divided into groups, with one group receiving tirzepatide first and the other pioglitazone, including a break between treatments. The trial seeks adults with type 2 diabetes who have a stable weight and do not use insulin. As a Phase 4 trial, this research involves treatments already FDA-approved and proven effective, aiming to understand how they benefit more patients.

Will I have to stop taking my current medications?

The trial allows all diabetes medications except insulin and pioglitazone. If you're taking a GLP-1 receptor agonist, your dose must be stable for at least 3 months.

What is the safety track record for these treatments?

A previous study found pioglitazone safe for treating type 2 diabetes and potentially beneficial for heart health. However, using pioglitazone for over a year could increase the risk of bladder cancer. Another study found a low chance of pioglitazone causing low blood sugar.

For tirzepatide, research suggests general safety, though real-world safety data remains limited. Some studies indicate it might reduce the risk of serious heart and kidney problems. Overall, past research has shown both treatments to be safe, but each carries its own risks and benefits. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard treatments for type 2 diabetes, like metformin and insulin, pioglitazone and tirzepatide stand out for their unique mechanisms. Pioglitazone works by increasing the body's sensitivity to insulin, which helps control blood sugar levels more effectively. Tirzepatide is even more exciting because it targets two receptors, GLP-1 and GIP, which not only help lower blood sugar but may also promote weight loss. Researchers are particularly excited about tirzepatide's dual action, offering a promising new approach for managing type 2 diabetes by tackling both blood sugar and weight issues simultaneously.

What evidence suggests that this trial's treatments could be effective for type 2 diabetes?

In this trial, participants will receive either pioglitazone or tirzepatide to manage type 2 diabetes. Studies have shown that pioglitazone lowers blood sugar levels, reducing HbA1c, a measure of long-term blood sugar control, by up to 1.60%. Tirzepatide, another treatment option in this trial, has also proven effective, demonstrating even greater reductions in both HbA1c and body weight compared to some other treatments. It works by affecting hormones that control blood sugar and appetite. Both treatments have shown promising results in managing type 2 diabetes by improving blood sugar levels and potentially aiding in weight control. ^{3 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults aged 30-70 with normal-weight type 2 diabetes (BMI of 19-24.9) and stable body weight, not on insulin or pioglitazone but other diabetes meds are okay if stable for 3 months. It's also for similar healthy controls without diabetes.

Inclusion Criteria

My HbA1c is between 5.7% and 8%, and I've maintained my treatment or lifestyle for 3 months.

Normal-Weight Diabetes (NWD) Group:

BMI: Between 19 and 24.9 kg/m²

Exclusion Criteria

Active Psychiatric Disease or Eating Disorders: Individuals with these conditions are excluded due to potential impacts on study compliance and data integrity

Pregnancy or Lactation: Women who are pregnant, planning to become pregnant, or breastfeeding are excluded due to potential risks to the fetus or infant

Unstable Body Weight: Individuals with a body weight change of more than 2 kg in the last 3 months are excluded to ensure stable metabolic conditions

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Testing

Baseline testing to assess adipocyte function, insulin resistance, and fat distribution

1-2 weeks

Treatment with Tirzepatide

Participants receive tirzepatide for 16 weeks to assess its effect on insulin resistance and adipocyte function

16 weeks

Regular visits for monitoring and assessment

Washout Period

A 5-week washout period between treatment phases

5 weeks

Treatment with Pioglitazone

Participants receive pioglitazone for 16 weeks to assess its effect on insulin resistance and adipocyte function

16 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pioglitazone
• Tirzepatide

Trial Overview The study tests whether treatments targeting fat cells—pioglitazone and tirzepatide—can improve insulin resistance and fat distribution in those with normal-weight type 2 diabetes, compared to non-diabetic controls using various diagnostic tools.

How Is the Trial Designed?

Group I: Normal weight with diabetes tirzepatide first pioglitazone second Experimental Treatment 8 Interventions

Baseline testing Intervention with tirzepatide for 16 weeks Retesting Washout for 5 weeks Intervention with pioglitazone for 16 weeks Retesting

Group II: Normal weight with diabetes pioglitazone first, tirzepatide second Experimental Treatment 8 Interventions

Baseline testing Intervention with pioglitazone for 16 weeks Retesting Washout for 5 weeks Intervention with tirzepatide for 16 weeks Retesting

Group III: Normal weight controls Experimental Treatment 6 Interventions

Control

Pioglitazone is already approved in United States for the following indications:

Approved in United States as Actos for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

Tirzepatide (Mounjaro™) is a new treatment for type 2 diabetes that acts on both GIP and GLP-1 receptors, showing strong results in lowering blood glucose and promoting weight loss based on evidence from five SURPASS clinical trials.

The safety profile of tirzepatide is similar to that of existing GLP-1 receptor agonists, making it a promising option for early intervention in managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Drug: Tirzepatide (Mounjaro™). Gettman, L.[2023]

Tirzepatide demonstrated a dose-dependent ability to lower HbA1c levels in adults with type 2 diabetes, with reductions ranging from -17.71 to -22.35 mmol/mol compared to placebo, and was also more effective in reducing body weight than other treatments.

While tirzepatide did not increase the risk of hypoglycaemia compared to placebo and showed lower rates than basal insulin, it was associated with a higher incidence of gastrointestinal side effects, particularly nausea and vomiting, especially at the 15 mg dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Karagiannis, T., Avgerinos, I., Liakos, A., et al.[2023]

Tirzepatide significantly reduces body weight in patients with type 2 diabetes and obesity, with an average weight loss of -9.81 kg compared to placebo, based on a meta-analysis of 10 studies involving 9,873 patients.

While tirzepatide is effective for weight loss, it has a higher incidence of gastrointestinal side effects compared to placebo, although serious adverse events and hypoglycemia are less common, indicating a need for monitoring these reactions during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weight loss efficiency and safety of tirzepatide: A Systematic review. Lin, F., Yu, B., Ling, B., et al.[2023]

Tirzepatide, a new medication approved by the FDA, acts as an agonist for both GLP-1 and GIP receptors, which helps improve blood sugar control in patients with type II diabetes when combined with diet and exercise.

This drug represents a significant advancement in diabetes management, offering a new approach to treatment by targeting multiple pathways involved in glucose regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: A New Generation Therapeutic for Diabetes Type 2. Al-Horani, RA., Chedid, M.[2023]

Tirzepatide, a dual GIP and GLP-1 receptor agonist, has been shown to significantly improve glycemic control and reduce body weight in adults with type 2 diabetes, based on results from the phase 3 SURPASS clinical trials.

It is currently considered the most effective agent for managing type 2 diabetes, with ongoing studies evaluating its potential cardiovascular benefits, with results expected in 2024.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on tirzepatide for the management of type 2 diabetes: a focus on the phase 3 clinical development program. Frías, JP.[2023]

Pioglitazone effectively increases insulin sensitivity and improves glycemic control in patients with type 2 diabetes, whether used alone or in combination with other medications, based on clinical trials.

The medication is generally well tolerated, with weight gain and edema being the most common side effects, and it also shows potential benefits in reducing cardiovascular risk and arteriosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. Waugh, J., Keating, GM., Plosker, GL., et al.[2019]

Pioglitazone effectively lowers blood glucose levels in patients with type 2 diabetes, achieving reductions of up to 95 mg/dL and glycosylated hemoglobin by up to 2.6%, based on a review of 11 studies.

While pioglitazone can improve lipid profiles by reducing triglycerides and increasing HDL cholesterol, it is also associated with significant weight gain and mild edema, suggesting it may be best used in combination with other medications like metformin or sulfonylureas for better overall management of diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Chilcott, J., Tappenden, P., Jones, ML., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3920795/

Do We Still Need Pioglitazone for the Treatment of Type 2 ... In addition to providing sustained glycemic control in T2DM patients, pioglitazone resulted in a 70% reduction in the risk of developing T2DM in the Actos Now ...

2. nature.com nature.com/articles/s41598-019-41854-2

Efficacy and Safety of Pioglitazone Monotherapy in Type 2 ... In primary outcome analysis of 16 studies, pioglitazone monotherapy reduced HbA1c by 0.05% with no significant difference (95% CI: −0.21 to 0.11 ...

3. takeda.com takeda.com/en-us/newsroom/news-releases/2004/actos-pioglitazone-hcl-shows-sustained-efficacy-throughout-two-year-period-in-patients-with-type-2-diabetes/

ACTOS® (pioglitazone HCl) Shows Sustained Efficacy ... ACTOS added to metformin resulted in a 2% increase in LDL cholesterol, while gliclazide added to metformin resulted in a 6% decrease (p=0.001).

4. diabetesjournals.org diabetesjournals.org/care/article/23/11/1605/19458/Pioglitazone-hydrochloride-monotherapy-improves

Pioglitazone hydrochloride monotherapy improves glycemic ... RESULTS: Patients treated with 15, 30, or 45 mg pioglitazone had significant mean decreases in HbA1c (range -1.00 to -1.60% difference from ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S014929182400198X

Efficacy and Safety of Pioglitazone Add-on in Patients with ... The purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D)

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3411525/

Pioglitazone in the Treatment of Type 2 Diabetes In conclusion current evident suggests that pioglitazone has an acceptable safety profile, may have beneficial cardiovascular and pleotropic effects and is ...

7. fda.gov fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-update-ongoing-safety-review-actos-pioglitazone-and-increased-risk

Update to ongoing safety review of Actos (pioglitazone) ... Use of the diabetes medication Actos (pioglitazone) for more than one year may be associated with an increased risk of bladder cancer.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT00521820

Safety Comparison of Pioglitazone and Glyburide in Type 2 ... With regard to congestive heart failure, the risk of congestive heart failure is increased in subjects with diabetes in the absence of coronary artery disease; ...