Pioglitazone + Weight Loss for Kidney Stones

Overseen By Miranda King, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 4

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 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: 24

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if pioglitazone, a diabetes medication, combined with weight loss can prevent kidney stones in overweight or obese individuals. Participants will be divided into three groups to receive either pioglitazone, follow a weight loss program, or do both. Ideal participants have a history of uric acid kidney stones. The study will monitor changes in specific health markers, including urine acidity. As a Phase 4 trial, this research seeks to understand how the already FDA-approved and effective treatment benefits a broader range of patients.

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 is the safety track record for these treatments?

A previous study found that pioglitazone was well tolerated by patients with various levels of kidney function, with no increase in serious side effects. Another study showed that pioglitazone can lower the risk of death and other health problems in people with type 2 diabetes and advanced kidney disease.

For weight loss, research indicates it is a safe method for people who have had kidney stones. Lifestyle programs, like the one used in this study, have shown positive results without major safety issues.

Researchers have studied the combination of pioglitazone and weight loss for their effects on kidney stones. Since pioglitazone is already approved for other uses, this provides some reassurance about its safety. Overall, both treatments appear safe based on current evidence. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for kidney stones because they combine a drug called pioglitazone with weight loss strategies. Unlike standard treatments like hydration and pain management, pioglitazone may help by reducing inflammation and potentially altering the metabolic processes that contribute to stone formation. The addition of a structured weight loss program, based on cognitive behavioral strategies, aims to further reduce risk factors by promoting healthier lifestyle changes. This dual approach not only targets the root causes but also encourages sustainable long-term health benefits.

What evidence suggests that this trial's treatments could be effective for kidney stones?

Research has shown that pioglitazone, which participants in this trial may receive, can help lower acid levels in the kidneys, benefiting individuals with kidney stones. One study found that pioglitazone reduced acid stress on the kidneys and made urine less acidic, which can hinder kidney stone formation. Another treatment arm in this trial focuses on weight loss, which has also been shown to lower the risk of kidney stones, particularly in overweight individuals. Participants in a separate arm will receive both pioglitazone and weight loss interventions, potentially providing a dual benefit by addressing both acid levels and obesity, known risk factors for kidney stones. These treatments have shown promise in past studies, offering hope for kidney stone prevention. ^{2 3 4 6 7}

Who Is on the Research Team?

Khashayar Sakhaee, MD

Principal Investigator

UTSW

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Pioglitazone
• Pioglitazone + Weight Loss
• Weight Loss

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.

How Is the Trial Designed?

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.

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?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6478507/

Increased production and reduced urinary buffering of acid ... Treatment of patients with idiopathic uric acid nephrolithiasis with pioglitazone for 24 weeks led to a reduction in the acid load presented to the kidney and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1884238/

The pharmacokinetics of pioglitazone in patients with ... The results of this study have confirmed that renal impairment has only minimal effects on pioglitazone pharmacokinetics. In summary, no accumulation of ...

3. researchgate.net researchgate.net/publication/331205949_Increased_production_and_reduced_urinary_buffering_of_acid_in_uric_acid_stone_formers_is_ameliorated_by_pioglitazone

Increased production and reduced urinary buffering of acid ... Treatment of patients with idiopathic uric acid nephrolithiasis with pioglitazone for 24 weeks led to a reduction in the acid load presented to the kidney and a ...

4. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2397834

Pioglitazone Use and Risk of Bladder and Other Cancers Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, ...

5. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0206722

Safety and efficacy of low dose pioglitazone compared with ... Available data among patients with CKD suggest that pioglitazone was effective and safe, with no increase in serious adverse effects. However, ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0085253818309050

Increased production and reduced urinary buffering of acid ... Treatment of patients with idiopathic uric acid nephrolithiasis with pioglitazone for 24 weeks led to a reduction in the acid load presented to the kidney and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7510024/

Pioglitazone Reduces Mortality and Adverse Events in ... Pioglitazone reduces mortality and adverse events in patients with type 2 diabetes and with advanced chronic kidney disease: national cohort study.