New meta-analysis below [1].
"27 eligible studies were identified, including 123,212 participants.
"In prostate cancer, patients using metformin have significant benefits for:
... recurrence (HR = 0.74 ...),
...{cancer-specific survival} (HR = 0.74 ...), and
... {overall survival} (HR = 0.76 ...).
"Moreover, further subgroup analysis showed that the beneficial effects of metformin may be more significant for patients receiving radical radiotherapy."
***
Bear in mind that in almost all Metformin studies at this point, Metformin was prescribed for diabetes - not PCa.
However, insulin resistance - a pre-diabetes state - has been associated with more serious PCa, (and castration therapy is associated with increased insulin resistance.)
-Patrick
[1] pubmed.ncbi.nlm.nih.gov/346...
Review Biomed Res Int
. 2021 Oct 8;2021:5311828. doi: 10.1155/2021/5311828. eCollection 2021.
The Impact of Metformin Use with Survival Outcomes in Urologic Cancers: A Systematic Review and Meta-Analysis
Xiangyang Yao 1 , Haoran Liu 2 , Hua Xu 1
Affiliations collapse
Affiliations
1 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University, Hefei, China.
PMID: 34660791 PMCID: PMC8519697 DOI: 10.1155/2021/5311828
Abstract
Background: Conflicting results exist between the potential protective effects of metformin and the prognosis of urologic cancers. This meta-analysis summarized the effects of metformin exposure on the recurrence, progression, cancer-specific survival (CSS), and overall survival (OS) of the three main urologic cancers (kidney cancer, bladder cancer, and prostate cancer).
Methods: We systematically searched PubMed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure databases (January 2010 to December 2019), which identified studies regarding metformin users and nonusers with urologic cancers and extracted patient data. A random effect model or fixed effect model was used to analyze hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: Among the 1883 confirmed studies, 27 eligible studies were identified, including 123,212 participants. In prostate cancer, patients using metformin have significant benefits for recurrence (HR = 0.74; 95% CI: 0.61-0.90; P = 0.007; I 2 = 56%), CSS (HR = 0.74; 95% CI: 0.61-0.91; P = 0.002; I 2 = 79%), and OS (HR = 0.76; 95% CI: 0.65-0.90; P < 0.001; I 2 = 86%). Moreover, further subgroup analysis showed that the beneficial effects of metformin may be more significant for patients receiving radical radiotherapy. For kidney cancer, metformin was beneficial for progression (HR = 0.80; 95% CI: 0.65-0.98; P = 0.14; I 2 = 46%). Analysis revealed that the effect of metformin on the overall survival of kidney cancer patients may be related to nationality (American: HR = 0.76; 95% CI: 0.59-0.98; P = 0.88; I 2 = 0%). For bladder cancer, no obvious benefits of metformin use were identified. However, subgroup analysis indicated that metformin may improve the recurrence of bladder cancer, but this improvement was only found in patients with a median follow-up time of more than 4 years (HR = 0.43; 95% CI: 0.28-0.67; P = 0.61; I 2 = 0%).
Copyright © 2021 Xiangyang Yao et al.
Conflict of interest statement
The authors have declared that there is no competition of interests.
References
Wild S., Roglic G., Green A., Sicree R., King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care . 2004;27(5):1047–1053. doi: 10.2337/diacare.27.5.1047. - DOI - PubMed
Pollak M. N. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discovery . 2012;2(9):778–790. doi: 10.1158/2159-8290.CD-12-0263. - DOI - PubMed
Nicolucci A. Epidemiological aspects of neoplasms in diabetes. Acta diabetologica . 2010;47(2):87–95. doi: 10.1007/s00592-010-0187-3. - DOI - PubMed
Nilsen T. I., Vatten L. J. Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. British Journal of Cancer . 2001;84(3):417–422. doi: 10.1054/bjoc.2000.1582. - DOI - PMC - PubMed
Bernard L., Reix N., Benabu J. C., Gabriele V., Mathelin C. Breast cancer and diabetes mellitus: complex interactions. Gynecologie, obstetrique & fertilite . 2016;44(12):701–711. doi: 10.1016/j.gyobfe.2016.09.004. - DOI - PubMed
Coughlin S. S., Calle E. E., Teras L. R., Petrelli J., Thun M. J. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. American journal of epidemiology . 2004;159(12):1160–1167. doi: 10.1093/aje/kwh161. - DOI - PubMed
Verlato G., Zoppini G., Bonora E., Muggeo M. Mortality from site-specific malignancies in type 2 diabetic patients from Verona. Diabetes Care . 2003;26(4):1047–1051. doi: 10.2337/diacare.26.4.1047. - DOI - PubMed
Ha Y. S., Kim W. T., Yun S. J., et al. Multi-institutional analysis of localized renal cell carcinoma that demonstrates the impact of diabetic status on prognosis after nephrectomy. Annals of surgical oncology . 2013;20(11):3662–3668. doi: 10.1245/s10434-013-3147-7. - DOI - PubMed
Newton C. C., Gapstur S. M., Campbell P. T., Jacobs E. J. Type 2 diabetes mellitus, insulin-use and risk of bladder cancer in a large cohort study. International Journal of Cancer . 2013;132(9):2186–2191. doi: 10.1002/ijc.27878. - DOI - PubMed
Libby G., Donnelly L. A., Donnan P. T., Alessi D. R., Morris A. D., Evans J. M. M. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care . 2009;32(9):1620–1625. doi: 10.2337/dc08-2175. - DOI - PMC - PubMed
Kim Y. D., Park K. G., Lee Y. S., et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes . 2008;57(2):306–314. doi: 10.2337/db07-0381. - DOI - PubMed
Staels B. Metformin and pioglitazone: effectively treating insulin resistance. Current Medical Research and Opinion . 2006;22(supplement 2):S27–S37. doi: 10.1185/030079906X112732. - DOI - PubMed
Bulcao C., Ribeiro-Filho F. F., Sanudo A., Roberta Ferreira S. G. Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. American journal of cardiovascular drugs : drugs, devices, and other interventions . 2007;7(3):219–224. doi: 10.2165/00129784-200707030-00007. - DOI - PubMed
Dowling R. J., Zakikhani M., Fantus I. G., Pollak M., Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Research . 2007;67(22):10804–10812. doi: 10.1158/0008-5472.CAN-07-2310. - DOI - PubMed
Ruderman N. B., Carling D., Prentki M., Cacicedo J. M. AMPK, insulin resistance, and the metabolic syndrome. The Journal of clinical investigation . 2013;123(7):2764–2772. doi: 10.1172/JCI67227. - DOI - PMC - PubMed
Yin M., Zhou J., Gorak E. J., Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. The oncologist . 2013;18(12):1248–1255. doi: 10.1634/theoncologist.2013-0111. - DOI - PMC - PubMed
He X. K., Su T. T., Si J. M., Sun L. M. Metformin is associated with slightly reduced risk of colorectal cancer and moderate survival benefits in diabetes mellitus: a meta-analysis. Medicine . 2016;95(7, article e2749) doi: 10.1097/MD.0000000000002749. - DOI - PMC - PubMed
Stopsack K. H., Ziehr D. R., Rider J. R., Giovannucci E. L. Metformin and prostate cancer mortality: a meta-analysis. Cancer causes & control : CCC . 2016;27(1):105–113. doi: 10.1007/s10552-015-0687-0. - DOI - PubMed
Coyle C., Cafferty F. H., Vale C., Langley R. E. Metformin as an adjuvant treatment for cancer: a systematic review and meta- analysis. Annals of oncology : official journal of the European Society for Medical Oncology . 2016;27(12):2184–2195. doi: 10.1093/annonc/mdw410. - DOI - PMC - PubMed
Danzig M. R., Kotamarti S., Ghandour R. A., et al. Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes. Prostate cancer and prostatic diseases . 2015;18(1):63–68. doi: 10.1038/pcan.2014.47. - DOI - PubMed
Allott E. H., Abern M. R., Gerber L., et al. Metformin does not affect risk of biochemical recurrence following radical prostatectomy: results from the SEARCH database. Prostate cancer and prostatic diseases . 2013;16(4):391–397. doi: 10.1038/pcan.2013.48. - DOI - PMC - PubMed
Ahn J. H., Jung S. I., Yim S. U., Kim S. W., Hwang E. C., Kwon D. D. Impact of glycemic control and metformin use on the recurrence and progression of non-muscle invasive bladder cancer in patients with diabetes mellitus. Journal of Korean medical science . 2016;31(9):1464–1471. doi: 10.3346/jkms.2016.31.9.1464. - DOI - PMC - PubMed
Hakimi A. A., Chen L., Kim P. H., et al. The impact of metformin use on recurrence and cancer-specific survival in clinically localized high-risk renal cell carcinoma. Canadian Urological Association journal = Journal de l'Association des urologues du Canada . 2013;7(11-12):E687–E691. doi: 10.5489/cuaj.1447. - DOI - PMC - PubMed
Nayan M., Macdonald E. M., Juurlink D. N., et al. Medication use and survival in diabetic patients with kidney cancer: a population-based cohort study. Pharmacological research . 2016;113(Part A):468–474. doi: 10.1016/j.phrs.2016.09.027. - DOI - PubMed
Higgins J. P., Thompson S. G., Deeks J. J., Altman D. G. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed) . 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557. - DOI - PMC - PubMed
Mantel N., Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute . 1959;22(4):719–748. - PubMed
DerSimonian R., Laird N. Meta-analysis in clinical trials revisited. Contemporary clinical trials . 2015;45(Part A):139–145. doi: 10.1016/j.cct.2015.09.002. - DOI - PMC - PubMed
Psutka S. P., Boorjian S. A., Lohse C. M., et al. The association between metformin use and oncologic outcomes among surgically treated diabetic patients with localized renal cell carcinoma. Urologic Oncology: Seminars and Original Investigations . 2015;33(2):67.e15–67.e23. doi: 10.1016/j.urolonc.2014.07.008. - DOI - PubMed
Cheng J. J., Li H., Tan H. S., et al. Metformin use in relation with survival outcomes of patients with renal cell carcinoma. Clinical genitourinary cancer . 2016;14(2):168–175. doi: 10.1016/j.clgc.2015.12.012. - DOI - PubMed
Keizman D., Ish-Shalom M., Sella A., et al. Metformin use and outcome of sunitinib treatment in patients with diabetes and metastatic renal cell carcinoma. Clinical genitourinary cancer . 2016;14(5):420–425. doi: 10.1016/j.clgc.2016.04.012. - DOI - PubMed
Hamieh L., McKay R. R., Lin X., Moreira R. B., Simantov R., Choueiri T. K. Effect of metformin use on survival outcomes in patients with metastatic renal cell carcinoma. Clinical genitourinary cancer . 2017;15(2):221–229. doi: 10.1016/j.clgc.2016.06.017. - DOI - PubMed
Nayan M., Finelli A., Jewett M. A. S., et al. Metformin use and kidney cancer outcomes in patients with diabetes: a propensity score analysis. Clinical genitourinary cancer . 2017;15(2):300–305. doi: 10.1016/j.clgc.2016.06.008. - DOI - PubMed
Rieken M., Xylinas E., Kluth L., et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU international . 2013;112(8):1105–1112. doi: 10.1111/bju.12448. - DOI - PubMed
Rieken M., Xylinas E., Kluth L., et al. Effect of diabetes mellitus and metformin use on oncologic outcomes of patients treated with radical cystectomy for urothelial carcinoma. Urologic Oncology: Seminars and Original Investigations . 2014;32(1):49.e7–49.14. doi: 10.1016/j.urolonc.2013.07.006. - DOI - PubMed
Rieken M., Xylinas E., Kluth L., et al. Diabetes mellitus without metformin intake is associated with worse oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology . 2014;40(1):113–120. doi: 10.1016/j.ejso.2013.09.016. - DOI - PubMed
Nayan M., Bhindi B., Yu J. L., et al. The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder. Urologic Oncology: Seminars and Original Investigations . 2015;33(9):386.e7–386.e13. doi: 10.1016/j.urolonc.2015.05.024. - DOI - PubMed
Patel T., Hruby G., Badani K., Abate-Shen C., McKiernan J. M. Clinical outcomes after radical prostatectomy in diabetic patients treated with metformin. Urology . 2010;76(5):1240–1244. doi: 10.1016/j.urology.2010.03.059. - DOI - PubMed
He X. X., Tu S. M., Lee M. H., Yeung S. C. J. Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Annals of oncology : official journal of the European Society for Medical Oncology . 2011;22(12):2640–2645. doi: 10.1093/annonc/mdr020. - DOI - PMC - PubMed
Margel D., Urbach D. R., Lipscombe L. L., et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. Journal of Clinical Oncology . 2013;31(25):3069–3075. doi: 10.1200/JCO.2012.46.7043. - DOI - PubMed
Spratt D. E., Zhang C., Zumsteg Z. S., Pei X., Zhang Z., Zelefsky M. J. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. European urology . 2013;63(4):709–716. doi: 10.1016/j.eururo.2012.12.004. - DOI - PMC - PubMed
Zannella V. E., Dal Pra A., Muaddi H., et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clinical Cancer Research . 2013;19(24):6741–6750. doi: 10.1158/1078-0432.CCR-13-1787. - DOI - PubMed
Kaushik D., Karnes R. J., Eisenberg M. S., Rangel L. J., Carlson R. E., Bergstralh E. J. Effect of metformin on prostate cancer outcomes after radical prostatectomy. Urologic Oncology-Seminars and Original Investigations . 2014;32(1):43.e1–43.e7. doi: 10.1016/j.urolonc.2013.05.005. - DOI - PMC - PubMed
Rieken M., Kluth L. A., Xylinas E., et al. Association of diabetes mellitus and metformin use with biochemical recurrence in patients treated with radical prostatectomy for prostate cancer. World Journal of Urology . 2014;32(4):999–1005. doi: 10.1007/s00345-013-1171-7. - DOI - PubMed
Taira A. V., Merrick G. S., Galbreath R. W., Morris M., Butler W. M., Adamovich E. Metformin is not associated with improved biochemical free survival or cause-specific survival in men with prostate cancer treated with permanent interstitial brachytherapy. Journal of contemporary brachytherapy . 2014;6(3):254–261. doi: 10.5114/jcb.2014.45757. - DOI - PMC - PubMed
Lee H., Kuk H., Byun S.-S., Lee S. E., Hong S. K. Preoperative glycemic control status as a significant predictor of biochemical recurrence in prostate cancer patients after radical prostatectomy. PloS one . 2015;10(4, article e0124761) doi: 10.1371/journal.pone.0124761. - DOI - PMC - PubMed
Winters B., Plymate S., Zeliadt S. B., et al. Metformin effects on biochemical recurrence and metabolic signaling in the prostate. The Prostate . 2015;75(15):1694–1703. doi: 10.1002/pros.23049. - DOI - PMC - PubMed
Joentausta R. M., Kujala P. M., Visakorpi T., Tammela T. L. J., Murtola T. J. Tumor features and survival after radical prostatectomy among antidiabetic drug users. Prostate cancer and prostatic diseases . 2016;19(4):367–373. doi: 10.1038/pcan.2016.32. - DOI - PubMed
Richards K. A., Liou J.-i., Cryns V. L., Downs T. M., Abel E. J., Jarrard D. F. Metformin use is associated with improved survival for patients with advanced prostate cancer on androgen deprivation therapy. Journal of Urology . 2018;200(6):1256–1263. doi: 10.1016/j.juro.2018.06.031. - DOI - PubMed
Taussky D., Preisser F., Karakiewicz P. I., et al. Impact of diabetes and metformin use on prostate cancer outcome of patients treated with radiation therapy: results from a large institutional database. The Canadian journal of urology . 2018;25(5):9509–9515. - PubMed
Li Y., Hu L., Xia Q., Yuan Y., Mi Y. The impact of metformin use on survival in kidney cancer patients with diabetes: a meta-analysis. International urology and nephrology . 2017;49(6):975–981. doi: 10.1007/s11255-017-1548-4. - DOI - PMC - PubMed
Nayan M., Punjani N., Juurlink D. N., et al. Metformin use and kidney cancer survival outcomes a systematic review and meta-analysis. American Journal of Clinical Oncology-Cancer Clinical Trials . 2019;42(3):275–284. doi: 10.1097/COC.0000000000000512. - DOI - PubMed
Zannella V. E., Cojocari D., Hilgendorf S., et al. AMPK regulates metabolism and survival in response to ionizing radiation. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology . 2011;99(3):293–299. doi: 10.1016/j.radonc.2011.05.049. - DOI - PubMed