Metformin for Prostate Cancer Patients with Glucose Intolerance or Overweight

(PragMet Trial)

Recruiting at 3 trial locations

Overseen By Ryan M Lanning, MD

Age: 18+

Sex: Male

Trial Phase: Phase < 1

Sponsor: University of Colorado, Denver

Must not be taking: Antidiabetics, Carbonic anhydrase inhibitors

Disqualifiers: Diabetes therapy, Liver disease, others

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how metformin could aid men with prostate cancer who also face glucose intolerance or are overweight. Researchers aim to determine if combining metformin with lifestyle changes proves more effective than lifestyle changes alone. Ideal participants are men diagnosed with prostate cancer who either struggle with blood sugar management or have a BMI of 25 or higher, indicating overweight status. As an Early Phase 1 trial, this research seeks to understand metformin's effects in people, offering participants an opportunity to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

If you are currently taking medications for diabetes or any drugs that interact with metformin, you will need to stop those before joining the trial. This includes medications like insulin, glipizide, and others listed in the exclusion criteria.

Is there any evidence suggesting that metformin is likely to be safe for humans?

Research shows that metformin is generally safe for use. It is a common drug for treating type 2 diabetes and may offer benefits in other areas. Studies have found that men with prostate cancer who took metformin experienced better health outcomes, such as a lower risk of cancer-related issues.

While side effects can occur, they are usually mild. The most common ones include stomach upset, diarrhea, and nausea, which often subside as the body adjusts to the medication. Serious side effects are rare.

Metformin's widespread use in diabetes treatment has established its safety, making it a relatively safe choice for those considering participation in a clinical trial involving this medication. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using metformin for prostate cancer patients with glucose intolerance or who are overweight because it offers a dual benefit. Unlike standard treatments for prostate cancer that primarily target cancer cells, metformin also addresses metabolic issues like insulin resistance, which is often a concern in these patients. This treatment is unique because it leverages metformin's ability to lower blood sugar levels, potentially improving the patient's overall metabolic health while simultaneously supporting cancer treatment. Additionally, combining metformin with lifestyle modifications could enhance the effectiveness of both approaches, offering a more holistic strategy to managing prostate cancer in these patients.

What evidence suggests that metformin might be an effective treatment for prostate cancer patients with glucose intolerance or overweight?

Research has shown that metformin might help people with prostate cancer live longer and slow disease progression, particularly in those with diabetes. Studies have found that prostate cancer patients who took metformin incidentally experienced better outcomes. Some research suggests that metformin could improve measures such as cancer-free survival and overall survival. While it doesn't significantly reduce the risk of developing prostate cancer, evidence indicates potential benefits. In this trial, participants in the Metformin and Lifestyle Modification Arm will receive metformin, which might benefit prostate cancer patients, especially those with blood sugar issues or who are overweight. Meanwhile, participants in the Lifestyle Modification Only Arm will receive standard lifestyle modification recommendations. ^{1 2 4 6 7}

Who Is on the Research Team?

Thomas W. Flaig

Principal Investigator

Colorado Research Center

Are You a Good Fit for This Trial?

Men over 18 with prostate cancer and either glucose intolerance (HbA1c of 5.7-6.4%) or a BMI≥25 kg/m2 can join this study if they have an MHC Account, consent to participate, and are under the care of a participating UCHealth provider. They must not be on certain drugs that interact badly with metformin, have severe kidney issues, liver diseases like cirrhosis or fibrosis, alcohol disorders, or allergies to metformin.

Inclusion Criteria

You have high blood sugar or are overweight, and can take metformin.

Provision to sign and date the consent form in MHC or otherwise via Epic

Subjects must have an MHC Account to participate in the study

Exclusion Criteria

I am not on medications that badly interact with metformin.

I have not taken any medication that increases the risk of lactic acidosis.

Contraindication for metformin use which include any of the following which are exclusionary (in Epic will use most recent lab values): Estimated glomerular filtration rate (eGFR) of < 50 ml/minute (calculated according to the formula utilized within Epic), Known Total Bilirubin ≥3 mg/dL, Diagnosis of fibrosis or cirrhosis of the liver (ICD10: K74), Diagnosis of alcohol related disorders (ICD10: F10), Metformin allergy in Epic (ICD10: T50.995A), Non-English-speaking patient until Spanish language consent form and relevant materials can be made available. Due to the novel aspect of this trial, we plan to get some experience in treating approximately the first 50 patients, make any changes needed in the study operations and then implement a Spanish consent, as feasible

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 either metformin plus lifestyle modification or lifestyle modification alone

2 years

Quarterly visits (virtual or in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 years

Long-term follow-up

Participants are monitored for prostate cancer progression and overall survival

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Metformin

Trial Overview This trial is checking if adding metformin to lifestyle changes helps control blood sugar better than just lifestyle advice in men with prostate cancer who also have high blood sugar levels or are overweight. Participants will randomly receive either both treatments or only lifestyle modification information.

How Is the Trial Designed?

Group I: Metformin and Lifestyle Modification Arm Active Control 2 Interventions

For the metformin arm: metformin will be obtained as a standard of care medication from the patient's general pharmacy. This will be given for a clinical indication (e.g. prediabetes or overweight/obese). It will not be supplied by the study, but billed to Medicare, self pay or 3rd party payer. Lifestyle modification and prediabetes information will be provided via MHC or other electronic means on a quarterly basis.

Group II: Lifestyle Modification Only Arm Placebo Group 1 Intervention

Patients randomized to this arm will receive standard lifestyle modification recommendations. This will include the general recommendation to increase exercise level mildly, after discussing with the medical provider. There is a potential low-level risk in increasing one's exercise levels.

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Published Research Related to This Trial

The novel biguanide derivative IM176 significantly reduced the viability of prostate cancer cell lines and patient-derived castration-resistant prostate cancer (CRPC) cells, showing lower IC50 values than metformin and phenformin, indicating it may be more effective in treating these cancers.

IM176 activates AMP-activated protein kinase, inhibits the mammalian target of rapamycin (mTOR), and induces apoptosis in prostate cancer cells, suggesting a strong mechanism of action that could make it a promising candidate for prostate cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways. Kim, Y., Yoo, S., Lim, B., et al.[2023]

In a study of 2,298 men undergoing prostate brachytherapy, metformin use did not show a significant association with improved biochemical survival or cancer-specific survival compared to those not taking metformin.

Diabetic men not using metformin had a higher overall mortality rate (72.7%) compared to non-diabetic men (47.0%), suggesting that while metformin did not improve cancer outcomes, it may play a role in overall health for diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin is not associated with improved biochemical free survival or cause-specific survival in men with prostate cancer treated with permanent interstitial brachytherapy. Taira, AV., Merrick, GS., Galbreath, RW., et al.[2022]

Metformin use in prostate cancer patients showed a marginal association with reduced risk of biochemical recurrence, with a pooled hazard ratio of 0.82, suggesting it may help prevent the return of cancer after treatment.

However, metformin did not significantly impact the risk of metastases, all-cause mortality, or prostate cancer-specific mortality, indicating that more rigorous randomized trials are needed to confirm its efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Raval, AD., Thakker, D., Vyas, A., et al.[2018]

In a study of 1449 patients with localized prostate cancer, those using metformin showed a significant reduction in the risk of biochemical failure (BF) at 5 years after treatment, indicating potential benefits of metformin in managing prostate cancer outcomes.

While univariate analysis did not show differences in BF rates at 1, 3, and 5 years, multivariate analysis revealed that metformin use was associated with a 40% relative risk reduction in BF, suggesting its role warrants further investigation in improving disease-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective Effects of Metformin Against Biochemical Failure Following Radical Prostatectomy or Radiation Therapy in Localized Prostate Cancer. Huynh, LM., Keit, E., Huang, E., et al.[2022]

In a study of 326 prostate cancer-free men with type 2 diabetes, higher doses of metformin were associated with a significant decrease in serum prostate-specific antigen (PSA) levels, suggesting a potential protective effect against prostate cancer.

The decrease in PSA levels was more pronounced in men who had diabetes for 6 years or longer, indicating that metformin's impact on prostate biology may be more significant in those with a longer duration of diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Relationship Between Metformin and Serum Prostate-Specific Antigen Levels. Jayalath, VH., Ireland, C., Fleshner, NE., et al.[2018]

In a study of 6689 prostate cancer patients, those with preexisting type 2 diabetes mellitus (T2DM) had a higher overall mortality risk, but there was no significant difference in prostate cancer-specific survival between diabetic and non-diabetic patients.

Patients with T2DM who were not treated with metformin had a notably lower overall survival rate, while those on metformin showed a trend towards lower prostate cancer-specific mortality, suggesting potential benefits of metformin in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preexisting diabetes, metformin use and long-term survival in patients with prostate cancer. Linkeviciute-Ulinskiene, D., Patasius, A., Kincius, M., et al.[2022]

Metformin is a safe and well-tolerated medication that can be used alongside standard treatments for prostate cancer, potentially reducing side effects from castration.

The STAMPEDE trial, starting in summer 2016, will evaluate the effectiveness of metformin as a repurposed treatment for men with high-risk prostate cancer, aiming to confirm its additional anticancer benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repurposing Metformin as Therapy for Prostate Cancer within the STAMPEDE Trial Platform. Gillessen, S., Gilson, C., James, N., et al.[2021]

In a study of 25,695 male patients with type 2 diabetes, metformin users had a 20% lower risk of developing new-onset prostate cancer compared to those using sulfonylureas, indicating a potential protective effect of metformin.

Metformin was also associated with a 11% reduction in all-cause mortality compared to sulfonylurea users, suggesting that it may offer additional health benefits beyond blood sugar control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of New-Onset Prostate Cancer for Metformin Versus Sulfonylurea Use in Type 2 Diabetes Mellitus: A Propensity Score-Matched Study. Lee, YHA., Zhou, J., Hui, JMH., et al.[2022]

In a study of 2901 prostate cancer patients, those using metformin showed significantly better clinical outcomes, including improved prostate cancer-specific mortality (PCSM) and reduced risk of developing castration-resistant prostate cancer (CRPC) compared to diabetic patients not using metformin.

Metformin use was associated with a nearly doubled rate of prostate-specific antigen-recurrence-free survival (PSA-RFS) and a more than threefold increase in distant metastases-free survival (DMFS), suggesting its potential as a beneficial treatment in localized prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Spratt, DE., Zhang, C., Zumsteg, ZS., et al.[2022]

In a study of 552 patients (276 with diabetes mellitus and 276 without), diabetes did not negatively affect short-term overall survival rates in prostate cancer patients, with 5-year survival rates of 88% for those with diabetes compared to 93% for those without.

Prostate cancer and its treatment did not significantly impact glycemic control in patients with diabetes, indicating that having both conditions does not worsen health outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CO-EXISTING PROSTATE CANCER AND DIABETES MELLITUS: IMPLICATIONS FOR PATIENT OUTCOMES AND CARE. Karlin, NJ., Amin, SB., Verona, PM., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05515978

Pragmatic Trial of Metformin for Glucose Intolerance or ... Population-based, retrospective studies have reported improved outcomes, including prostate cancer specific mortality, with the incidental use of metformin in ...

2. withpower.com withpower.com/trial/early-phase-1-prostatic-neoplasms-2023-df1b9?condition=&query=Metformin&overallStatus=Recruiting&hasNoPlacebo=false

Metformin for Prostate Cancer Patients with Glucose ... Research suggests that Metformin may help improve survival rates and reduce the risk of prostate cancer progression, especially in patients with diabetes. It ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4612916/

Metformin therapy and prostate cancer risk At last, we found that metformin use was not significantly associated with a reduced risk of prostate cancer, although a trend was noted. Meta-regression ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1470204525002311

Metformin for patients with metastatic prostate cancer ... We hypothesised that metformin might improve survival in patients with metastatic hormone-sensitive prostate cancer and reduce metabolic complications ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4034673/

Metformin and Prostate Cancer: Benefit for Development of ... To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC ...

6. auajournals.org auajournals.org/doi/10.1097/JU.0000000000004695

A Randomized Phase 3 Trial of Metformin in Patients ... We investigated whether metformin decreases metabolic syndrome (MS) risk in patients with prostate cancer (PCa) receiving androgen deprivation therapy (ADT) ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6709307/

Metformin use and prostate cancer risk: A meta-analysis of ... In a random-effect pooled analysis, metformin use was not significantly associated with the risk of prostate cancer (RR 0.97, 95% CI 0.80–1.16, P = .711).