Metformin use and prostate cancer risk

Feng, Zishuai; Zhou, Xiaofeng; Liu, Naibo; Wang, Jianfeng; Chen, Xing; Xu, Xin

doi:10.1097/md.0000000000014955

Cited by 35 publications

(15 citation statements)

References 49 publications

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“…Such differences could be driven by differences in biases stemming from study design, such as differing levels of selection bias induced by inevitably only selected survivors of the exposure and competing risk. As such, it remains inconclusive whether the observed inverse relation between metformin and various cancers is a reflection of immortal time bias, notwithstanding the observations concerning metformin and prostate cancer are unclear 13. Results from randomized controlled trials and Mendelian randomization studies using genetic risk scores for AMPK in large well-designed biobanks would provide a more definitive answer to this important clinical question.…”

Section: Discussionmentioning

confidence: 99%

“…Others argued the approach to correct for immortal time bias remains controversial and requires additional validations 10. Potentially stronger study designs, such as the marginal structural models applied to electronic health records with inverse probability weighting,11 and Mendelian randomization using biomarkers of metformin12 did not provide strong evidence for a causal role of metformin in breast cancer, with similar findings for prostate cancer in a recent meta-analysis 13. Given the relation between antidiabetes medications and breast cancer risk appears to vary across classes of medication with different modes of actions (eg, metformin vs sulfonylurea),14 this may imply glycemic traits per se are not the main factors accounting for any reduction in cancer risk among metformin users.…”

Section: Introductionmentioning

confidence: 99%

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Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study

Yeung

Schooling

2019

BMJ Open Diab Res Care

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ObjectivesObservational studies suggest glycemic traits and type 2 diabetes are positively associated, and metformin inversely associated with breast and prostate cancer risk. However, observational studies are susceptible to unmeasured confounding while studies of metformin use are also vulnerable to immortal time bias. The use of Mendelian randomization may reduce confounding due to random allocation of relevant genetic markers at birth, and may reduce immortal time bias (for metformin-related variants analysis) since the start of exposure is at birth.Research design and methodsWe identified strong genetic predictors of fasting glucose, glycated hemoglobin, and type 2 diabetes from the Meta-Analyses of Glucose and Insulin-related traits Consortium and Diabetes Genetics Replication And Meta-analysis Consortium (n=140 595 for glucose; n=123 665 for HbA1c; n=898 130 for type 2 diabetes) and of AMPK-instrumented HbA1c reduction as a proxy of metformin and applied them to large genome-wide association studies of breast cancer (Breast Cancer Association Consortium; BCAC) and prostate cancer (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome; PRACTICAL). We used inverse variance weighting to obtain estimates. Sensitivity analyses included use of MR-Egger, weighted median, exclusion of pleiotropic instruments, and validation using UK Biobank (breast cancer only).ResultsThere was no association of fasting glucose (OR 1.03 per mmol/L, 95% CI 0.85 to 1.25), HbA1c (OR 1.02 per %, 95% CI 0.73 to 1.45), or type 2 diabetes (OR 0.98 per log odds, 95% CI 0.95 to 1.01) with breast cancer in BCAC, with similar findings from UK Biobank. There was no association of fasting glucose (OR 0.93 per mmol/L, 95% CI 0.73 to 1.17), HbA1c (OR 0.90 per %, 95% CI 0.58 to 1.40) or type 2 diabetes (OR 1.02 per log odds, 95% CI 0.97 to 1.07) with prostate cancer in PRACTICAL. No strong evidence was observed for AMPK-instrumented HbA1c reduction on cancer risk.ConclusionGlycemic traits and type 2 diabetes unlikely cause breast and prostate cancer. Whether metformin can be repurposed for cancer prevention remains unclear.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study

Yeung

Schooling

2019

BMJ Open Diab Res Care

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“…Eighteen cohort or nested case-control studies were included with a total of 52,328 cases. 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 = 0.711) [81].…”

Section: Metformin and Cancermentioning

confidence: 90%

“…After multivariable adjustment, the risk for the development of cancer among metformin users was not significantly different from that among controls (HR = 0.96; 95% confidence interval, 0.89-1.03; p = 0.250), suggesting a lack of association between metformin therapy and the risk of cancer among patients with diabetes [80]. Feng et al, conducted a meta-analysis of cohort studies to evaluate a potential association of metformin use with prostate cancer risk [81]. Eighteen cohort or nested case-control studies were included with a total of 52,328 cases.…”

Section: Metformin and Cancermentioning

confidence: 99%

Cancer Biology and Prevention in Diabetes

Srivastava

Goodwin

2020

Cells

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The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.

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“…A recent meta-analysis found no association between metformin use and prostate cancer risk (Relative risk was 0.97, 95% CI 0.80 to 1.16) but had significant heterogeneity between studies. 29 Similarly, another systematic review included a comprehensive bias evaluation and concluded that the studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk. 30 A recent Taiwanese study found that treatment…”

Section: Comparison With the Exsting Literaturementioning

confidence: 99%

Metformin use and long-term risk of benign prostatic hyperplasia: a population-based cohort study

2020

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ObjectiveTo assess whether metformin use affects risk of benign prostatic hyperplasia (BPH) by comparing the risk of BPH in men with type 2 diabetes who initiated first-line treatment with either metformin or sulfonylurea monotherapy between 2000 or 2006 in Northern Denmark. In this period, sulfonylurea and metformin were both frequently used as first-line glucose-lowering drug (GLD) treatment.DesignA population-based cohort study.SettingNorthern Denmark.ParticipantsAll men who filled at least two prescriptions for metformin or for sulfonylurea, respectively, during their first 6 months of GLD treatment. Follow-up started 6 months after treatment start.Primary outcome measuresRates of subsequent BPH, identified based on community prescriptions for BPH-related treatment or hospital BPH diagnoses, and rates of transurethral resection of the prostate (TURP). Rates in metformin and sulfonylurea users were compared overall and stratified by 6-month haemoglobin A1c (HbA1c) using Cox regression and an intention-to-treat (ITT) approach and an as-treated analysis.ResultsDuring follow-up, less than five persons were lost to follow-up due to emigration. In 3953 metformin initiators with a median follow-up of 10 years, the 10-year cumulative BPH incidence was 25.7% (95% CI 24.2 to 27.1). Compared with 5958 sulfonylurea users (median follow-up 8 years, 10-year cumulative incidence 27.4% (95% CI 26.2 to 28.6)), the crude HR for BPH was 0.83 (95% CI 0.77 to 0.89) and adjusted HR in the ITT analyses was 0.97 (95% CI 0.88 to 1.06). For TURP, the adjusted HR was 0.96 (95% CI 0.63 to 1.46). In the as-treated analysis, adjusted HR for BPH was 0.91 (95% CI 0.81 to 1.02).ConclusionsCompared with sulfonylurea, metformin did not substantially reduce the incidence of BPH in men with diabetes.

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Metformin use and prostate cancer risk

Cited by 35 publications

References 49 publications

Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study

Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study

Cancer Biology and Prevention in Diabetes

Metformin use and long-term risk of benign prostatic hyperplasia: a population-based cohort study

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