Pioglitazone + Weight Loss for Kidney Stones

Overseen by Khashayar Sakhaee, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: University of Texas Southwestern Medical Center

Must not be taking: SGLT2-i, GLP-1, others

Disqualifiers: Bariatric surgery, CHF, bladder cancer, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests the effects of Pioglitazone, weight loss, or both in overweight and obese patients with uric acid kidney stones. Pioglitazone helps the body use insulin better and reduces urine acid, while weight loss improves health and reduces the risk of stones.

Will I have to stop taking my current medications?

The trial requires that you do not use certain medications like insulin, thiazolidinediones, SGLT2 inhibitors, GLP-1 analogs, gemfibrozil, topiramate, and rifampin. If you are taking any of these, you may need to stop before participating.

What evidence supports the effectiveness of the drug pioglitazone for kidney stones?

Research shows that pioglitazone can reduce kidney stone formation in rats by decreasing inflammation and oxidative stress, which are common factors in both kidney stones and metabolic syndrome. ^{1 2 3 4 5}

Is pioglitazone safe for humans?

Pioglitazone, used for type 2 diabetes, has been linked to a potential risk of bladder cancer, as noted by health agencies. Some studies also suggest it may cause liver and heart issues, but it has shown no toxic effects on normal kidney cells in certain cancer treatments. ^{1 2 3 4 6}

How does the drug pioglitazone help with kidney stones?

Pioglitazone is unique in treating kidney stones because it not only helps control blood sugar in diabetes but also reduces inflammation and oxidative stress, which are linked to kidney stone formation. Additionally, it can increase urine pH, making the urine less acidic and potentially reducing the risk of uric acid stone formation. ^{1 3 4 7 8}

Research Team

Khashayar Sakhaee, MD

Principal Investigator

UTSW

Eligibility Criteria

This trial is for adults over 21 with a specific type of kidney stone (over 90% uric acid) who are overweight but weigh less than 165 kg. They should have normal kidney function and not be on certain medications or have conditions like chronic diarrhea, heart failure, or uncontrolled diabetes.

Inclusion Criteria

My kidney stones are mostly made of uric acid.

I am older than 21 years.

Your kidney function is normal.

Exclusion Criteria

I have chronic diarrhea.

Your HbA1c level is higher than 8.5%.

I frequently get urinary tract infections.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive Pioglitazone, Weight Loss intervention, or a combination of both for 24 weeks

24 weeks

Baseline and end of 24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pioglitazone (Thiazolidinedione)
• Pioglitazone + Weight Loss (Other)
• Weight Loss (Behavioral Intervention)

Trial Overview The study tests the effects of Pioglitazone (a diabetes drug), weight loss, or both combined on patients with uric acid kidney stones. Participants will follow a fixed diet and be monitored through various medical assessments over a period of 24 weeks.

Participant Groups

Group I: Weight Loss, Behavioral Experimental Treatment 1 Intervention

Weight loss following the Group Lifestyle Balance Program based on the Diabetes Prevention Program that utilizes cognitive behavioral strategies (goal setting, problem solving, self-monitoring, stimulus control),and provides written education materials to support health and nutrition behavior changes for weight management and disease prevention.

Group II: Pioglitazone Drug (including Placebo) Experimental Treatment 1 Intervention

45 mg/day- one pioglitazone tablet once daily throughout the 24 weeks of the study

Group III: Pioglitazone + Weight Loss Experimental Treatment 1 Intervention

Pioglitazone 45 mg/day + Weight Loss following the Group Lifestyle Balance Program based on the Diabetes Prevention Program that utilizes cognitive behavioral strategies (goal setting, problem solving, self-monitoring, stimulus control),and provides written education materials to support health and nutrition behavior changes for weight management and disease prevention.

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Daniel K. Podolsky

University of Texas Southwestern Medical Center

Chief Executive Officer since 2008

MD from Harvard Medical School

Robert L. Bass

University of Texas Southwestern Medical Center

Chief Medical Officer since 2019

MD from University of Texas Southwestern Medical School

Findings from Research

Pioglitazone (PIO) effectively inhibits the growth and viability of renal adenocarcinoma cells, demonstrating cytotoxic activity by inducing cell cycle arrest and apoptosis at low doses.

When combined with methotrexate (MTX), PIO enhances the sensitivity of renal cancer cells to MTX without harming normal kidney cells, suggesting a potential for safer combination therapies in treating kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone as a modulator of the chemoresistance of renal cell adenocarcinoma to methotrexate. Piątkowska-Chmiel, I., Gawrońska-Grzywacz, M., Natorska-Chomicka, D., et al.[2021]

In a rat model of chronic kidney disease, pioglitazone significantly improved kidney structure and function, as shown by reduced levels of harmful substances like blood urea nitrogen and creatinine.

Pioglitazone enhanced the kidney's antioxidative capacity and inhibited harmful angiogenesis by down-regulating key angiogenic factors, suggesting it could be a promising treatment for chronic kidney diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone, a Peroxisome Proliferator-Activated Receptor x03B3; Agonist, Ameliorates Chronic Kidney Disease by Enhancing Antioxidative Capacity and Attenuating Angiogenesis in the Kidney of a 5/6 Nephrectomized Rat Model. Sun, L., Yuan, Q., Xu, T., et al.[2019]

In a study using hyperoxaluric rats, pioglitazone significantly reduced kidney crystal formation compared to a control group, indicating its potential as a preventive treatment for kidney stones.

Pioglitazone also decreased cell injury, apoptosis, and oxidative stress, while lowering the expression of pro-inflammatory markers, suggesting that its protective effects are linked to its anti-inflammatory and antioxidative properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone, a peroxisome proliferator activated receptor γ agonist, decreases renal crystal deposition, oxidative stress and inflammation in hyperoxaluric rats. Taguchi, K., Okada, A., Yasui, T., et al.[2018]

Recent large cohort studies suggest a potential association between the use of pioglitazone (Actos) and an increased incidence of bladder cancer, prompting warnings from the U.S. FDA and the European Medicines Agency.

There is currently a lack of urology literature specifically addressing the relationship between pioglitazone and bladder cancer, highlighting a gap in research that needs to be explored further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between pioglitazone and urothelial bladder cancer. Barbalat, Y., Dombrovskiy, VY., Weiss, RE.[2018]

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]

A study on 120 mice showed that prolonged use of pioglitazone, an oral antidiabetic drug, resulted in significant toxicity affecting liver, kidney, heart, and bladder functions, with effects worsening at higher doses.

The research highlights the potential risks associated with sub-chronic use of pioglitazone, indicating that it can lead to serious health issues, including abnormalities in liver and kidney function and changes in cardiac and hematological indices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicological evaluation of subchronic use of pioglitazone in mice. Elshama, SS., El-Kenawy, Ael-M., Osman, HE.[2020]

In a study of 204 patients undergoing radical cystectomy for bladder cancer, diabetic patients showed similar cancer stage distributions regardless of whether they used pioglitazone, suggesting that pioglitazone use may not significantly impact cancer progression.

The rates of lymph node involvement and cancer-specific death were comparable among non-diabetic patients, diabetic non-users, and diabetic users of pioglitazone, indicating that pioglitazone may not increase the severity of bladder cancer in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathology of bladder cancer among diabetic patients undergoing radical cystectomy with a history of pioglitazone (Actos) use. Romero, V., Peyton, C., Gray, I., et al.[2021]

In a study of 36 adults with idiopathic uric acid nephrolithiasis, treatment with pioglitazone for 24 weeks significantly increased urine pH and improved metabolic syndrome features, indicating its potential to reduce acidity in urine.

Pioglitazone also enhanced ammonium excretion and reduced net acid excretion, suggesting it may help lower the risk of uric acid stone formation by improving the urinary biochemical environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased production and reduced urinary buffering of acid in uric acid stone formers is ameliorated by pioglitazone. Maalouf, NM., Poindexter, JR., Adams-Huet, B., et al.[2021]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Pioglitazone as a modulator of the chemoresistance of renal cell adenocarcinoma to methotrexate. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Pioglitazone, a Peroxisome Proliferator-Activated Receptor x03B3; Agonist, Ameliorates Chronic Kidney Disease by Enhancing Antioxidative Capacity and Attenuating Angiogenesis in the Kidney of a 5/6 Nephrectomized Rat Model. [2019]

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

Pioglitazone, a peroxisome proliferator activated receptor γ agonist, decreases renal crystal deposition, oxidative stress and inflammation in hyperoxaluric rats. [2018]

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

Association between pioglitazone and urothelial bladder cancer. [2018]

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

Spotlight on pioglitazone in type 2 diabetes mellitus. [2019]

6. Iran pubmed.ncbi.nlm.nih.gov

Toxicological evaluation of subchronic use of pioglitazone in mice. [2020]

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

Pathology of bladder cancer among diabetic patients undergoing radical cystectomy with a history of pioglitazone (Actos) use. [2021]

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

Increased production and reduced urinary buffering of acid in uric acid stone formers is ameliorated by pioglitazone. [2021]