There are controversies about the anti-cancer activity of metformin. Please read the next article for a deeper analysis

https://www.researchgate.net/publication/301594167_METFORMIN_AND_CANCER_UNDERSTANDING_FACTS_AND_CONTROVERSIES

Best regards

Conference Paper METFORMIN AND CANCER: UNDERSTANDING FACTS AND CONTROVERSIES

Dear Thomas:

I am trying to understand the pattern behind the several evidences you gathered in your study.

My approach is based on the effects of changes of of calcium ion concentrations in the growth of cancer tumors: if the ionic concentrations are too low they can lead to errors in cell division and to apoptosis failure. As far as metformin stimulates the calcium release system (from the endoplasmatic/sarcoplasmatic reticulum to mitichondria), it may produce a beneficial effect in the beginning, but after chronic ministration it can lead to a stress of the system causing the reduction of calcium ion concentratinons, and then the division errors and failure of apoptosis may occur.

Dear Alfredo

I have a personal view on metformin in cancer. I think it might explain the controversies. But I did not mention it in the article because I lack experimental support.

According to my view metformin generstes an acidic stress due to lactic acid accumulation. Those malignant cells that did not develop and increased MCT expression are affected by metformin. On the other hand if MCTs are overexpressed, metformin does not affect cancer cells.

Best regards

Tomas

Dear Tomas,

You should publish it in a review paper to be submitted to a journal that accepts theoretical discussions, as Medical Hypotheses or the Frontiers collection (they accept Hypothesis Papers)

Dear Alfredo

I sort of published something about this theory, but in a different context. You may read it in https://www.ncbi.nlm.nih.gov/pubmed/28122261

and in

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074768/

What I did not publish is the experience with 11 patients receiving the treatment based on metformin and other drugs. The results were extremely encouraging, but the treatments were not performed in an academic environment, so that I cannot show valid evidence. Thus I did not publish it.

Best regards

Tomas

Alfredo:

Thanks for an excellent and important issue, and a stimulating discussion.

I will here take an evidence-based contrarian perspective on the claimed anti-cancer and cancer-preventive claims of metformin, based on an internal review I was commissioned to undertake for a European regulatory authority, and the findings (reported in heavily condensed and compressed summary) support Tomas Koltai's caution (see above) on this score, and welcome further exchange on these complex but critical issues.

**********

METFORMIN MANIA

Metformin as a cancer preventive / risk- reductive or therapeutic modality is currently going through something of a oncology research craze of late, with over 110 active or pending clinical trials, and over 800 PUBMED-indexed papers published in just the last 10 years (close to 700 of which have been published in just the last 5 years), and over 1400 peer-reviewed references in Google Scholar under narrow search (metformin and cancer as search terms in the title, close to 90, 000 if we accept non-title abstract inclusion and allow preclinical studies).

Headlines blare:

"Metformin for cancer prevention: a reason for optimism" (Lancet);  "Metformin May Have Broad Utility in Cancer" (MD Anderson Cancer); "An Old Idea, Revived: Starve Cancer to Death" (New York Times); "Forget the Blood of Teens. This Pill Promises to Extend Life for a Nickel a Pop" (Wired); "Common Drug Has The Potential To Slow Aging, Boost Cancer Recovery" (Forbes); and so on.

The impression is, even from sober medical reporting media, that we are well on our way to defeating cancer just "for a nickel a pop"!

But only if we suspend Reason. So as I will demonstrate here there is in fact little evidentiary support for such over-optimistic claims, once these are subjected to the hard light of critical appraisal and review with methodological quality assessment and grading, and the overwhelming balance of such the appraised evidence base finds warrant only for a narrow scope of hypothesis-generating research. Here's why, in brief:

**********

METFORMIN: SEPARATING MYTH FROM REALITY

Dozens and dozens of studies and clinical trials have reported putative findings of statistically significant benefit for preventive, risk-reductive and therapeutic effects of metformin, as monotherapy or in various combination regimens as adjuncts to conventional anticancer agents. The magnitude of these claimed beneficial effects of metformin on cancer was in most studies quite spectacular, if not simply incredible. The Taiwanese National Health Insurance (TNHI) study [Lee 2011] reported that the use of metformin was associated with remarkably lower incidence of many cancers, such as rate ratios (RR) of 0.12 for any cancer, 0.36 for colorectal cancer, 0.06 for liver cancer, and 0.15 for pancreatic cancer, while another study using the same database reported a rate ratio of 0.55 (range: a 39% - 45% reduction in risk!) for lung cancer incidence with metformin use in just 9 months!, where even with the most effective chemotherapies and targeted therapies, nor smoking cessation programs, have been able to accomplished a fraction of such benefit [Lai 2012], so completely beyond  all credibility.

Methodology, as I have said often, is the devil in clinical research, as I show below:

1.  IMMORTAL TIME BIAS

We now know that all these over-optimistic, outcome-record-breaking studies were fatally methodologically compromised by immortal time bias (a species of survivorship treatment selection bias which occurs when there exists a period of time during which the outcome of interest for one of the cohorts cannot possibly occur) [Suissa 2012] [Suissa 2013] [Renehan 2012] [Suissa 2017], this bias systematically generating artificially exaggerated risk reductions in favor of the exposure.  In addition, a large body of studies deployed a flawed simplistic model, that of a binary contrast approach (exposure vs no exposure), and furthermore, the methods for the determination of the duration and cumulative dose of drug exposure show very wide variability between studies [Walker 2013].

But several of the more recent observational studies, that used corrected study designs and statistical methods of data analysis to avoid immortal time bias, did not find any association between metformin and the incidence of several cancers [Azoulay 2011] [Bodmer 2012] [Smiechowski 2013a] [Smiechowski 2013b] [Margel 2013] [Becker 2013] [Tsilidis 2014] [Mamtani 2014] [Becker 2015] [Zanders 2015] [Kowall 2015] [Frouws 2017]. And a very recent study controlling for time-related biases finds no evidence for a reduced risk of breast cancer with metformin use [Hong 2017], as also found in a study that evaluated the effect of treatment duration on the cancer risk among naive users of anti-diabetic medication as compared to non-users, where significant difference was observed in cancer risk between users and non-users after bias adjustment [But 2014].

The same is true for treatment - as opposed to prevention - studies, where observational studies of metformin as a treatment for or adjunct to prostate, colorectal, ovarian, and breast cancer, all reported major risk reductions on all-cause mortality, cancer-specific mortality, and cancer progression, under use of metformin. Here again, the spectacular magnitude in the reduction in cancer outcomes with metformin use, with hazard ratios ranging from 0.38 to 0.66! were all shown to be the result of immortal time bias introduced in these studies [Suissa 2012]. Thus we now know that these exaggerated mortality reductions were the direct result of immortal time bias caused by misclassifying the immortal time between cancer diagnosis (cohort entry) and first prescription of metformin in follow-up, when in fact it is still unexposed [Suissa 2012]. And this misclassification provides an artificial survival advantage to the users of metformin by incorrectly adding the immortal time to their survival.

Tellingly, recent observational studies that used correct statistical methods to avoid this bias did not find a benefit of metformin in women with breast cancer on all-cause and cancer-specific mortality, as well as in lung, colorectal and prostate cancers [Menamin 2016] [Bensimon 2014] [Oppong 2014]. [Spillane 2014] [Peeters 2013] [Cossor 2013] [Lega 2013] [Bayraktar 2012] [Menamin 2016b].

Beside immortal time bias, other domains raided serious methodological limitations:

2.  DIVERGENT OUTCOME, EXPOSURE, AND COMPARATOR DEFINITIONS AND CHOICES

Divergent outcome definitions as well as exposure definitions and choice of comparators are evident in may studies. Bias can be introduced because many studies have different time windows for the measurement of exposure so that likelihood of encountering subjects exposed to metformin is systematically different between cases versus controls, while in cohort studies future information is used to determine exposure definition. Tellingly, in one comprehensive systematic review of bias evaluation [Farmer 2017], near half of all studies actually defined exposure to metformin as ANY exposure, thus failing to weigh overall duration of treatment, not just the presence or absence of exposure [Framer 2017]. 

3.  BASELINE/STUDY ENTRY CONFOUNDERS

This is divergence in and failure to adjust for critical baseline / study entry confounders of smoking, gender, age, and grade or severity of diabetes, among others). Consider grade (severity) where treatment deployed is clearly going to be influenced by disease severity, and it would be illicit if patients were compared at differing disease stages without a countervailing adjustment for baseline disease severity.

4.  TIME-DEPENDENT CONFOUNDERS

This is failure to control/adjust for time-dependent confounders affected by previous treatment, such as other antidiabetic agent, or HbA1c, or BMI status, important in that, for example, use of metformin is likely to influence future HbA1c and BMI status and levels, and furthermore we have evidence that both HbA1c and BMI may themselves affect cancer risk, with current conventional models unable to reliably estimate the causal impact of time-variant treatment (metformin treatment changes through time).

5.  COMPROMISED CENSORING

Divergent / inconsistent censoring methods in cohort studies; so for example, for censoring, it was rare for cohort studies to report the numbers lost to follow-up, or the reason for such loss.

6.  MISSING DATA

Divergent / inconsistent missing data (sometimes with > 20% missing data, making the likely effect of residual confounding predictably large).

7.  CONFOUNDING BY INDICATION

We must acknowledge and control for the fact that patients using and not using metformin might differ in their previous susceptibility to dying as a result of cancer.

So in one study [Margel 2013] of metformin in prostate cancer, an HR of 0.76 for all-cause mortality was observed within the first six months after a prostate cancer diagnosis. This defies common sense and is against the evidence: it is simply not remotely plausible that a mere six months of using metformin would reduce mortality by 24%. In any robust RCT an HR of 1 would be  expected within that short time frame, and furthermore, the study reports an INCREASE in mortality for every six month follow-up AFTER the baseline HR, which is against reason since if there were in fact a true dose-response relationship between metformin and survival, the known expectation is for a DECLINE in HR values over time, not an increase, so this is almost assuredly the methodological flaw know as CONFOUNDING BY INDICATION, which was not controlled for.

Confounding by indication arises from the well-established fact that subjects who are prescribed, or take, a drug are inherently different from those who do not take the drug, because they are taking the drug FOR A REASON, and hence are said to have an INDICATION for the medication, and their bio-pathological profiles will therefore necessarily diverge from any comparator, and this can therefore introduce confounding variation in cancer risk between the medication group and the control groups.

**********

LESSONS LEARNED

It is likely that the largest protective effects that have been observed are a result of immortal time bias and other issues that I have detailed above, relating to how metformin use is defined. Studies without such biases tend to have estimates closer to the null, and although SOME (although not necessarily at clinically relevant levels of benefit) effect of metformin use on risk of subsequent cancer in patients with type 2 diabetes cannot be logically excluded, the previously reported questionably large protective associations are extremely unlikely, near impossible, to be truly causal.

**********

REFERENCES

[Azoulay 2011] Azoulay L, Dell’Aniello S, Gagnon B, Pollak M, Suissa S. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev 2011; 20:337–344.

[Bayraktar 2012]  Bayraktar S, Hernadez-Aya LF, Lei X, et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer 2012; 118:1202–1211.

[Becker 2013] Becker C, Meier CR, Jick SS, Bodmer M. Case-control analysis on metformin and cancer of the esophagus. Cancer Causes Control 2013; 24:1763–1770.

[Becker 2015] Becker C, Jick SS, Meier CR, Bodmer M. No evidence for a decreased risk of thyroid cancer in association with use of metformin or other antidiabetic drugs: a case-control study. BMC Cancer 2015; 15:719.

[Bensimon 2014] Bensimon L, Yin H, Suissa S, Pollak MN, Azoulay L. The use of metformin in patients with prostate cancer and the risk of death. Cancer Epidemiol Biomarkers Prev 2014; 23:2111–2118.

[Bodmer 2012] Bodmer M, Becker C, Jick SS, Meier CR. Metformin does not alter the risk of lung cancer: a case-control analysis. Lung Cancer 2012; 78:133–137.

[But 2014] But A, Wang H, Männistö S, Pukkala E, Haukka J. Assessing the effect of treatment duration on the association between anti-diabetic medication and cancer risk. PLoS One. 2014;  9(11):e113162.

[Cossor 2013] Cossor FI, Adams-Campbell LL, Chlebowski RT, et al. Diabetes, metformin use, and colorectal cancer survival in postmenopausal women. Cancer Epidemiol 2013; 37:742–749.

[Farmer 2017] Farmer RE, Ford D, Forbes HJ, et al. Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. Int J Epidemiol 2017 Apr 01; 46(2):728-744.

[Frouws 2017] Frouws MA, Sibinga Mulder BG, Bastiaannet E, et al. No association between metformin use and survival in patients with pancreatic cancer: An observational cohort study. Medicine (Baltimore) 2017; 96(10):e6229.

[Hong 2017] Hong JL, Funk MJ, Buse J, et al. Comparative effect of initiating metformin versus sulfonylureas on breast cancer risk in older women. Epidemiology 2017; 28:446–454.

[Kowall 2015] Kowall B, Stang A, Rathmann W, Kostev K. No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK. Pharmacoepidemiol Drug Saf 2015; 24:865–874.

[Lai 2012] Lai SW, Liao KF, Chen PC, Tsai PY, Hsieh DP, Chen CC. Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan. Clin Lung Cancer 2012; 13:143–148.

[Lee 2011] Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011; 11:20.

[Lega 2013] Lega IC, Austin PC, Gruneir A, Goodwin PJ, Rochon PA, Lipscombe LL. Association between metformin therapy and mortality after breast cancer: a population-based study. Diabetes Care 2013; 36:3018–3026.

[Margel 2013] Margel D, Urbach D, Lipscombe LL, et al. Association between metformin use and risk of prostate cancer and its grade. J Natl Cancer Inst 2013; 105:1123–1131.

[Mamtani 2014] Mamtani R, Pfanzelter N, Haynes K, et al. Incidence of bladder cancer in patients with type 2 diabetes treated with metformin or sulfonylureas. Diabetes Care 2014; 37:1910–1917.

[Margel 2013] Margel D, Urbach DR, Lipscombe LL, et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes J Clin Oncol 2013; 31: 3069–3075]

[Menamin 2016a] Menamin ÚC, Cardwell CR, Hughes CM, Murray LM. Metformin use and survival from lung cancer: a population-based cohort study. Lung Cancer 2016; 94:35–39.

[Menamin 2016b] Menamin ÚC, Murray LJ, Hughes CM, Cardwell CR. Metformin use and survival after colorectal cancer: a population-based cohort study. Int J Cancer 2016; 138:369–379.

[Oppong 2014] Oppong BA, Pharmer LA, Oskar S, et al. The effect of metformin on breast cancer outcomes in patients with type 2 diabetes. Cancer Med 2014; 3:1025–1034.

[Peeters 2014] Peeters PJ, Bazelier MT, Vestergaard P, et al. Use of metformin and survival of diabetic women with breast cancer. Curr Drug Saf 2013; 8:357–363.

[Renehan 2012] Renehan AG, Yeh HC, Johnson JA, Wild SH, Gale EA, Moller H. Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer. Diabetologia 2012; 55(6):1619–1632.

[Smiechowski 2013a] Smiechowski BB, Azoulay L, Yin H, Pollak MN, Suissa S. The use of metformin and the incidence of lung cancer in patients with type 2 diabetes. Diabetes Care 2013; 36:124–129.

[Smiechowski 2013b] Smiechowski B, Azoulay L, Yin H, Pollak MN, Suissa S. The use of metformin and colorectal cancer incidence in patients with type II diabetes mellitus. Cancer Epidemiol Biomarkers Prev 2013; 22:1877–1883.

[Spillane 2014] Spillane S, Bennett K, Sharp L, Barron TI. Metformin exposure and disseminated disease in patients with colorectal cancer. Cancer Epidemiol 2014; 38:79–84.

[Suissa 2012] Suissa S, Azoulay L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 2012; 35:2665–2673.]

[Suissa 2013] Suissa S, Azoulay L. Response to Yang and Chan. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes care 2012;35:2665-2673. Diabetes Care 2013; 36(6):e88.

[Suissa 2017] Suissa S. Metformin to Treat Cancer: Misstep in Translational Research from Observational Studies. Epidemiology 2017 May; 28(3):455-458.

[Tsilidis 2014] Tsilidis KK, Capothanassi D, Allen NE, et al. Metformin does not affect cancer risk: a cohort study in the U.K. Clinical Practice Research Datalink analyzed like an intention-to-treat trial. Diabetes Care 2014; 37:2522–2532.

[Walker 2013] Walker JJ, Johnson JA, Wild SH. Diabetes treatments and cancer risk: the importance of considering aspects of drug exposure. Lancet Diabetes Endocrinol 2013 Oct; 1(2):132-9.

[Zanders 2015] Zanders MM, van Herk-Sukel MP, Vissers PA, Herings RM, Haak HR, van de Poll-Franse LV. Are metformin, statin and aspirin use still associated with overall mortality among colorectal cancer patients with diabetes if adjusted for one another? Br J Cancer 2015 Jul 28; 113(3):403-10.

Constantine Kaniklidis

Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)

Oncology Reviewer, Current Oncology [journal]

Society for Integrative Oncology (SIO)

European Association for Cancer Research (EACR)

Dear Constantine:

Many thanks for sharing this important research with us.

Statistics is possibly the trickiest of all sciences! Assumptions impose strong biases on the calculations.

The take home message seems to be that the use of Metformin against Diabetes Type 2 is recommended with parsimony, in order to control glucose levels (together with physical exercise and an adequate diet), but it should not be abused and should be avoided in the long run, because instead of protecting against cancer tumors it may act to impair the cells' apoptosis mechanisms that fight the abnormal cell division process.

Dear ALFREDO

I think that metformin may be controversial in cancer. But I do not believe it may do any harm or decrease the effect of chemoradiotherapy.

Metformin increases autophagy. This is a defense against apoptosis. But autophgy sustained for prolonged time leads to apoptosis.

On the other hand if you associate metformin to an inhibitor of autophagia like chloroquine apoptosis is increased.

I think Constantins report is very interesting.

Best regards

Dear Alfredo:

Your point is well-taken as to exercising some caution re metformin in an oncology setting, but let me try to clarify this more carefully, as there is some important nuance here. At this time given the balance of critically-appraised, methodological-assessed data, claims of the beneficial anticancer effects of metformin stand as premature given the pervasive and sometimes fatal methodological flaws in the studies to date.

As to, however, the potential for negative effects on the anticancer activity of certain therapeutic modalities, the situation is more complex, as Tomas Koltai shrewdly points out in his last observation.

Here's what the evidence tells us:

There has been some early preclinical data suggesting that metformin may compromise certain anticancer activities of cisplatin chemotherapy, as for instance cisplatin-mediated apoptosis via metformin-induced activation of the Akt molecular pathway - a critical mediator of drug resistance - independently of AMPK [Janjetovic 2011]. Additional negative interactions have been claimed for gastric cancer cells [Lesan 2014]. But even in the widely-cited Janjetovic 2011 study, the negative interaction appears malignancy type-dependent: human and rat glioma cells, human neuroblastoma cells, mouse fibrosarcoma cells, and human leukemia cell lines, but in mouse melanoma cells metformin actually positively augmented cisplatin cytotoxicity. This malignancy-dependency is entailed from the pluripotent oncological activity of metformin over a wide spectrum of molecular mechanisms in interaction with different chemotherapeutic drugs, so that for example with hormone-active agents, AMPK/mTOR signaling pathway activation is the dominant mechansims, while with anti-metabolites it appears that suppression of protein expression of HIF-1, P-gp, and MRP1 is dominant, and with taxanes down-regulation of lipoprotein or cholesterol synthesis id dominant [Peng 2017] [Zhang 2016].

Based on these observations, and on the fact that a large number of studies have concluded for synergy and augmentation and sensitization, NOT compromise, of metformin interactions with oncological agents, as in osteosarcoma (in vitro) [Quattrini 2014] [Shang 2017], (in vivo) [Wang 2017a], esophageal squamous cancer (ESC) [Yu 2016], (in vitro and vivo) [Wang 2017b], gastric cancer (in vivo) [Yu 2015], cervical cancer [Tyszka-Czochara 2017] [Yudhani 2016], cholangiocarcinoma (in vitro) [Wandee 2017], in vitro and in vivo [Zhu 2016], oral squamous cell carcinoma [Qi 2016], among numerous others, I cannot find the original injunctions against concurrent administration of metformin and cisplatin sufficiently compelling to influence clinical practice, and indeed the original in vitro study [Lesan 2014] of a negative interaction in gastric cancer cells has been trumped by the evidentiary more powerful in vivo study [Yu 2015], leaving only some weak in cell-based concerns in the glioma , neuroblastoma, fibrosarcoma, and human leukemia context, which may or may not withstand further in vivo and human clinical data that may emerge BUT cannot as yet be wholly ignored in in the specialized context of CNS tumors, fibrosarcomas and hematologic cancers like leukemia, where until further data weighs in, we should exercise some caution in concurrent application.

In addition, several human clinical trials are in progress examining metformin with chemoradiation in locally advanced head and neck squamous cell carcinoma (SCC) [NCT02325401] [NCT02949700], with chemoradiation in locally advanced cervical cancer [NCT02394652], and with chemoradiation in advanced lung cancer [NCT02115464] which will bring human clinical data to bear more decisively or the question, but in the interim the balance of the evidence does not support an absolute contraindication of metformin deployed with cisplatin, nor with chemoradiation, although again the specialized contexts in note need more mature data to inform us of the safety of concurrent administration.

*****

REFERENCES

[Janjetovic 2011] Janjetovic K, Vucicevic L, Misirkic M, et al. Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. Eur J Pharmacol. 2011 Jan 25; 651(1-3):41-50.

[Lesan 2014] Lesan V, Ghaffari SH, Salaramoli J, et al. Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells. Int J Hematol Oncol Stem Cell Res. 2014 Jul 01; 8(3):12-9.

[Peng 2017] Peng M, Darko KO, Tao T, et al. Combination of metformin with chemotherapeutic drugs via different molecular mechanisms. Cancer Treat Rev. 2017 Mar; 54:24-33.

[Quattrini 2014] Quattrini I, Conti A, Pazzaglia L, et al. Metformin inhibits growth and sensitizes osteosarcoma cell lines to cisplatin through cell cycle modulation. Oncol Rep. 2014 Jan; 31(1):370-5.

[Qi 2016] Qi X, Xu W, Xie J, et al. Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis. Sci Rep. 2016 Oct 20; 6:35788.

[Shang 2017] Shang D, Wu J, Guo L, Xu Y, Liu L, Lu J. Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2. Int J Oncol. 2017 May; 50(5):1848-1856.

[Tyszka-Czochara 2017] Tyszka-Czochara M, Bukowska-Strakova K, Majka M. Metformin and caffeic acid regulate metabolic reprogramming in human cervical carcinoma SiHa/HTB-35 cells and augment anticancer activity of Cisplatin via cell cycle regulation. Food Chem Toxicol. 2017 Aug; 106(Pt A):260-272.

[Wandee 2017] Wandee J, Prawan A, Senggunprai L, Tusskorn O, Kukongviriyapan V. Metformin Enhances Cisplatin-Induced Cell Cytotoxicity and Antiproliferation in Cholangiocarcinoma Cells. ศรีนครินทร์เวชสาร (Srinagarind Medical Journal), [S.l.] 2017 July; 32(4):51.

[Wang 2017a] Wang Y, Wang Z, Shi D, et al. Metformin induces apoptosis of osteosarcoma U2OS and 143B cells through the mitochondria-dependent pathway and potentiates the anti-neoplastic activity of cisplatin in vivo. Int J Clin Exp Med 2017;10(4):6604-6612.

[Wang 2017b] Wang F, Ding X, Wang T, et al. Metformin inhibited esophageal squamous cell carcinoma proliferation in vitro and in vivo and enhanced the anti-cancer effect of cisplatin. PLoS One. 2017 Apr 13; 12(4):e0174276.

[Yu 2015] Yu Y, Fang W, Xia T, et al. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget. 2015;6(14):12748-12762.

[Yu 2016] Yu H, Bian X, Gu D, He X. Metformin Synergistically Enhances Cisplatin-Induced Cytotoxicity in Esophageal Squamous Cancer Cells under Glucose-Deprivation Conditions. BioMed Research International. 2016; 2016:8678634.

[Yudhani 2016] Yudhani RD, Pesik RN, Indarto D. Metformin Enhances Anti-proliferative Effect of Cisplatin in Cervical Cancer Cell Line. Indonesian J Clin Pharmacy 2016; 5(2).

[Zhang 2016] Zhang HH, Guo XL. Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemother Pharmacol 2016 Jul; 78(1):13-26.

[Zhu 2016] Zhu H, Ma J, Song X, et al. Metformin potentiates the anticancer activities of gemcitabine and cisplatin against cholangiocarcinoma cells in vitro and in vivo. Oncology Reports 2016; 36(6):3488-3496.

*****

Constantine Kaniklidis

Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)

Oncology Reviewer, Current Oncology [journal]

Society for Integrative Oncology (SIO)

European Association for Cancer Research (EACR)

Dear Constantine and Tomas:

Your answers to this question are excellent and valuable.

My concern when making the question was half practical, because I have diabetes type 2 and have taken metformin for some years. It is one of those drugs that physicians recomment to take during the whole life. If I live many years more, and take it for 30 years, what would be the long-term consequences for mitochondria? If I take the 850 mg tablet only once a day (instead of three times a day, as suggested by many physicians), may I have higher levels of glucose today, but a bonus in the long run?

To get a bonus on the long run you have to survive the short run. So my dear Alfredo I would recommend you to follow what your physicians prescribe. Insulin by the other hand is undoubtedly pro tumoral. If you can keep on metformine, no matter the dose and skip insulin you are making a good bargain for the long run.

Best regards

Tomaz

Dear Alfredo:

Excellent questions! I will take these up systematically below, and as you will see the evidence is reassuring for the safety - and persistent - efficacy of metformin in long-term use.

The evidence as we know overwhelmingly supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas) [Maruthur 2016] [Wang 2017], and numerous clinical trials are in favor of a protective effect of metformin on both coronary events and progression to heart failure [Nesti 2017].

Furthermore, we have strong evidence supporting diabetics on metformin: (1) have lower morality than non-diabetics and other diabetics; (2) less cardiovascular disease than other diabetics, with to this day, metformin being the only antidiabetic drug to be recommended by the 2013 AACE guidelines for cardiovascular benefit; (3) exhibit extend health and life spans independent of its effect on diabetes [Campbell 2017], and collectively this suggests that metformin could be extending life and healthspans by acting as a GEROPROTECTIVE and NEUROPROTECTIVE agent through the effective reduction of diseases of ageing, which may be consequent to its ability to cross the blood-brain barrier and activate AMPK in CNS tissue, along with its effects on inflammation and ROS, and thus modulate the ageing process independently of blood glucose regulation [Valencia 2017]. And emerging data suggests metformin may critically influences gut microbiota and the immune system in complex ways not yet sufficiently unraveled but which may also central to many of its benefits [Pollak 2017].

*******

EFFECTS ON DISEASES OF AGEING: GEROPROTECTIVE ACTIVITY

There also appears to be a reduction in risk of Dementia [Cheng 2014] [Hsu 2011] [Campbell 2017]. One meta-analysis investigated the class of insulin sensitizers compared to other forms of diabetes treatment, with a subgroup analysis for metformin, finding a statistical trend suggesting that metformin reduced the incidence of dementia [Ye 2016]., although we must still await robust controlled clinical trials now in progress to be decisive to this issue.

*******

EFFECTS ON MITOCHONDRIA

Metformin accumulates within mitochondria to concentrations up to 1000-fold higher than in the extracellular medium, which induces the inhibition of Complex I of the respiratory chain [Rena 2017] [Marshall 2017], leading to the suppression of ATP production and influencing oxidative phosphorylation via stimulation of ROS [Bridges 2014] [Bridges 2016]. And these effects, I hasten to note, are exerted all without triggering mitochondrial deterioration, and this contrasts metformin critically from all the other more hydrophobic guanide-containing drugs in that metformin inhibits energy transduction BUT does NOT produce the mitochondrial damage associated with those agents, but rather inhibits the mitochondria by a unique mechanism (inducing oxidation of the NADH/NAD+ couple, and selective suppression of the efficient coupling of the redox and proton transfer domains of complex I) [Cameron 2017].

*******

OPTIMAL DOSING

It's been found [Garber 1997] that metformin given at 500, 1000, 1500, 2000, or 2500 mg daily, lowers fasting plasma glucose and HbA1c in a dose-related manner, with benefits observed even with as little as 500 mg of metformin, although maximal benefits were observed at the upper limits of the recommended daily dosage. However attention has now shifted to the advantages of new extended-release (XR) formulations of metformin over the conventional "intermediate-release" (IR) schedules used until recently. The overwhelming evidence from controlled studies, systematic reviews and meta-analytic data finds that metformin XR formulation (commercially Glucophage XR, or Fortamet, or Glumetza), typically at once-daily metformin XR 2000 mg dosing, may be more effective than metformin IR (twice-daily metformin IR 1000 mg) - and therefore that once daily XR metformin dosing at 1000 mg ONCE daily as more effective than once daily IR metformin at 1000 mg ONCE daily (or 500 mg twice daily) - in inducing improvements in glyco-metabolic / glycemic control, lipid profile, and in the levels of certain adipocytokines (especially high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), as well as visfatin and vaspin) [Derosa 2017], but with metformin XR providing comparable clinical and metabolic benefits as standard /IR metformin at reduced dosage, and with dramatically fewer gastrointestinal side effects and higher tolerability, better QoL and increased compliance [Aggarwal 2017].

*******

ALFREDO: CAUTION

You are currently it appears taking 2550 mg of metformin in divided (3X) dosing, so if the 850 mg is a conventional (intermittent-release) formulation, than 850 mg conventional metformin once daily would provide proportionately, and significantly, less diabetic control - and associated benefits - than 2250 mg of conventionally-dosed metformin.

Therefore, to sustain the roughly comparable benefits profile of the 2250 mg current dosing, I would suggest you consider a once-daily extended-release formulation of 2000 mg daily total.

Since Glucophage XR comes in units of 500 mg and 750 mg tablets, then three 750 my tablets dosed daily, OR four tablets daily would be roughly equivalent. But both Fortamet and Glumetza come in both 500 mg and 1000 mg tablets, so to achieve a target of ~2000 mg total daily would just entail two 1000 mg tablets per day. Dosing in this way with an XR formulation will provide maximal benefits with significantly reduced side effect (especially GI upset) and superior tolerability as well as optimal steady-state concentrations (minimal variability throughout the day, something to consider.

HOWEVER, that said, I see no problem with a trial run of a lower maintenance dose - at 1500 mg XR metformin - to test if it is adequate for a long-term schedule, and if the parameters on monitoring are not substantially compromised (within say no more than 15% of their current values) on, say, two readings 3 - 6 months apart, the lower dose may prove to be all you need for effective control.

*******

QUESTIONS OF BALANCE

One study found that metformin's overall impact on serum homocysteine (Hcy) concentration could increase this concentration when exogenous B-group vitamins or folic acid supplementation was NOT given [Zhang 2016]. And Vitamin B12 is particularly critical, given that there is an association between metformin usage and lower levels of vitamin B12 by 57 pmol/L, which leads to frank deficiency or borderline status in some patients with type 2 diabetes. This suggests that it is prudent to monitor B12 levels in all patients who at potential increased risk of deficiency [Chapman 2016]. In addition, the widely presumed - but rare - association between metformin and MALA (metformin-associated lactic acidosis) has been effectively challenged [Lalau 2017], suggesting minimal real-world concern, so the safety of long-term diabetes control from metformin is once again reaffirmed when B12 and folic acid levels are assured not to be deficient or insufficient.

*******

REFERENCES

[Aggarwal 2017] Aggarwal N, Singla A, Mathieu C, et al. Metformin extended-release versus immediate-release: An international, randomized, double-blind, head-to-head trial in pharmacotherapy-naïve patients with type 2 diabetes. Diabetes Obes Metab 2017 Aug 31.

[Bridges 2014] Bridges HR, Jones AJ, Pollak MN2 Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014 Sep 15;462(3):475-87.

[Bridges 2016] Bridges HR, Sirviö VA, Agip AN, Hirst J. Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase. BMC Biol. 2016 Aug 9;14:65.

[Campbell 2017] Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev. 2017 Aug 10; 40:31-44.

[Cameron 2017] Cameron AR, Logie L, Patel K, et al. Metformin selectively targets redox control of complex I energy transduction. Redox Biol. 2017 Aug 26; 14:187-197.

[Chapman 2016] Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016 Nov; 42(5):316-327.

[Cheng 2014] Cheng C, Lin CH, Tsai YW, Tsai CJ, Chou PH, Lan TH. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol A Biol Sci Med Sci 2014; 69 10:1299–1305.

[Derosa 2017] Derosa G, D’Angelo A, Romano D, Maffioli P. Effects of metformin extended release compared to immediate release formula on glycemic control and glycemic variability in patients with type 2 diabetes. Drug Design, Development and Therapy. 2017; 11:1481-1488

[Graber 1997] Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997 Dec;103(6):491-7.

[Hsu 2011] Hsu CC, Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011; 24 3:485–493.

[Lalau 2017] Lalau J-D, Kajbaf F, Protti A, Christensen MM, De Broe ME, Wiernsperger N. Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm. Diabetes Obes Metab 2017;19:1502–1512.

[ Marshall 2017] Marshall SM. 60 years of metformin use: a glance at the past and a look to the future. Diabetologia September 2017; 60(9):1561–1565.]

[Maruthur 2016] Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med 2016;164:740–751.

[Nesti 2017] Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis. 2017 Aug; 27(8):657-669.

[Pollak 2017] Pollak M. The effects of metformin on gut microbiota and the immune system as research frontiers. Diabetologia September 2017; 60(9):1662–1667.

[Rena 2017] Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia September 2017; 60(9):1577–1585.

[Valencia 2017] Valencia WM, Palacio A, Tamariz L, Florez H.. Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia 2017.

[Wang] Wang Y-W, He S-J, Feng X, et al. Metformin: a review of its potential indications. Drug Design, Development and Therapy 2017;11:2421-2429.]

[Ye 2016] Ye F, Luo YJ, Xiao J, Yu NW, Yi G. Impact of Insulin Sensitizers on the Incidence of Dementia: A Meta-Analysis. Dement Geriatr Cogn Disord 2016; 41 (5–6):251–260.

[Zhang 2016] Zhang Q, Li S, Li L, et al. Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients 2016 Dec 09; 8(12).

*******

Constantine Kaniklidis

Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)

Oncology Reviewer, Current Oncology [journal]

Society for Integrative Oncology (SIO)

European Association for Cancer Research (EACR)

Dear Constantine, Many Thanks!

I am actually taking two IR 850 or two XR 750 mg twice a day, and from your suggestion I am inclined to take the 1500 XR once a day! I did not know about the need to supplement the treatment with B12 vitamin, and will ask my doctor.

Dear Alfredo:

Good, glad to help in any way, and best fortune to you!

Kind regards

Constantine

FDA Approves Metformin for New Cancer Trials

Some research has found that the drug metformin, commonly prescribed for diabetes and polycystic ovary syndrome (PCOS), has the potential to reduce multiple cancers by roughly 30% – an effect unique for any drug currently on the market. The study, published in Aging Cell, found that metformin reduces the body’s production of inflammatory cytokines, which accelerate aging.

Metformin is the generic name for an oral drug that was approved by the FDA in 1994 to lower blood sugar. Metformin was later found to stimulate ovulation, regulate periods, and increase fertility in women with PCOS and is now commonly prescribed for women whose PCOS hasn’t responded to hormonal treatment alone

Dear Sergey, Many thanks for the news.

It seems that it refers to the 2013 dated approval based on a research that was published in 2012 (see link to paper below), but the usage should be subject to the findings that our RG colleagues have kindly brought to our attention.

Article Metformin and cancer therapy

Very interesting opinion researchers.

What Dose of Metformin Prevents Cancer?

To date, the human data on metformin’s cancer preventing abilities have come from only from epidemiologic studies. Observational studies are a weaker form of evidence than randomized controlled trials.  However, don’t disregard the evidence. Remember the maxim “correlation does not imply causation – but it sure is a hint.”

Read in full: http://longevityfacts.com/metformin-prevents-cancer-says-researchers/

In the ISCAM conference that closed yesterday in Bertinoro Italy one of the papers presented at the conference showed that inhibition of mitochondrial complex I induces HIF-1alfa upregulation.

Metformin as an inhibitor of complex I may have protumor activities according to this new finding.

Dear Thomas, This result seems to converge with my conjecture that short-term use of metformin may help to prevent tumors, while long-term usage may cause mitochondrial stress and then protumor activity.

I have to admit that as time goes by I am more confused about metformin. I think there is room for more controversies.

Best regards

Dear Alfredo

I don't have much knowledge of this field, but one of my friend worked on metformin. He observed metformin inhibits cancer cell proliferation in vitro but in vivo results were just opposite. Mice treated with metformin showed increased tumor volume compared to control group. He explained in cell culture metformin increases lactate production which makes the media acidic limiting cell proliferation. But the same is not true for In vivo results. He published his research in Oncotarget. Article Targeting metabolic flexibility by simultaneously inhibiting...

Dear Aftab,

Thank you! The paper you cited is very interesting. Here is the Abstract:

"Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma."

Dear All:

I have diabetes type 2 and have taken metformin for more than 5 years. My body is a kind of Lab for discussion of metformin effects! It is surely good for the reduction of glucose levels, but severe fasting and exercise can do the same. Two weeks of fasting using diet shakes are sufficient to bring my levels back to 100 or less.

The interesting point in regard to the above paper is that I have recurrent skin problems: sporadic local eruptions in several parts of the body. The dermatologist told me it is probably caused by bacteria in the blood. Local application of antibiotic ointments help to heal the lesions, but some of them take more than one month to cure.

Dear Alfredo

I think that some interesting things have been put together in this lengthy chat.

May be it would be interesting to make a summary of all the concepts. As soon as I have some free time I will start to do it and put into consideration to the other participants of the chat.

Best regards

Tomas

Metformin Side Effects

In Summary

Commonly reported side effects of metformin include: lactic acidosis, diarrhea, nausea, nausea and vomiting, vomiting, and flatulence. Other side effects include: asthenia, and decreased vitamin b12 serum concentrate. See below for a comprehensive list of adverse effects.

No any data about cancer.

https://www.drugs.com/sfx/metformin-side-effects.html

Some side effects of metformin may not be reported.

Therefore you may report side effects to the FDA or EMA.

Dear Sergey: I am not a health professional, my interest in this issue is theoretical and personal.

Dear Alfredo,

In this case, it must be said that to date there is no clear evidence based on evidence-based medicine that metformin clearly increases the frequency of oncology.

It is only my opinion.

Sergey, The problem may happen in the long run because of mitochondrial stress. I hope it is a false alarm, but many drugs recommended for a person to take during her whole life may have this undesired kind of corollary effect.

Dear All:

I am really surprised by this experimental result (appearing this week in PubMed):

Brain Behav Immun. 2017 Dec 15. pii: S0889-1591(17)30549-4. doi:

10.1016/j.bbi.2017.12.009. [Epub ahead of print]

Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice.

Ou Z(1), Kong X(1), Sun X(1), He X(1), Zhang L(1), Gong Z(1), Huang J(1), Xu B(1), Long D(1), Li J(2), Li Q(1), Xu L(1), Xuan A(3).

Author information:

(1)Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Neurology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.

(2)Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.

(3)Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Neurology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: [email protected].

Alzheimer's disease(AD) is characterized by deposition of amyloid-β (Aβ)plaques, neurofibrillary tangles, andneuronal loss, accompanied by neuroinflammation. Neuroinflammatory processes are thought to contribute to AD pathophysiology. Metformin has been reported to have anti-inflammatory efficacy. However, whether metformin is responsible for the anti-neuroinflammation and neuroprotection on APPswe/PS1ΔE9 (APP/PS1) mice remains unclear. Here we showed that metformin attenuated spatial memory deficit, neuron loss in the hippocampus and enhanced neurogenesis in APP/PS1 mice. In addition, metformin administration decreased amyloid-β (Aβ)plaque load and chronic inflammation (activated microglia and astrocytes as well as pro-inflammatory mediators) in the hippocampus and cortex.

Further study demonstrated that treatment with metformin enhanced cerebral AMPK activation. Meanwhile, metformin notably suppressed the activation of P65 NF-κB, mTOR and S6K, reduced Bace1 protein expression. Our data suggest that metformin

can exert functional recovery of memory deficits and neuroprotective effect on APP/PS1 mice via triggering neurogenesis and anti-inflammation mediated by regulating AMPK/mTOR/S6K/Bace1 and AMPK/P65 NF-κB signaling pathways in the

hippocampus, which may contribute to improvement in neurological deficits.

Copyright © 2017. Published by Elsevier Inc.

DOI: 10.1016/j.bbi.2017.12.009

PMID: 29253574

Metformin and the prevention of cancer... Where is the position in 2017?

Obesity and its metabolic complications, including diabetes, have been associated with an increased risk of several cancers. Thus, the potential use of Metformin as a novel cancer prevention strategy has generated much excitement in view of its low cost, favorable safety profile, and its potential for biological specificity in disrupting the association between obesity and cancer. Metformin seems to affect multiple key processes related to cell growth, proliferation, and survival which stem from both metabolic and intracellular-signaling activity. Metformin decreases hepatic glucose production and reduces the bloodstream level and cellular uptake of insulin which results in reduced activation of insulin receptors on cell membranes, triggering a cascade of intracellular molecular effects, which are often activated in many types of cancer cells, in addition to up regulation of AMP-activated protein kinase, a key molecule in glucose and insulin regulation and also an inhibitor of mTOR. Treatment with Metformin has been associated in meta-analysis of case–control and cohorts with reduced breast, colon and pancreas cancer risk, although RCTs confirmed the inverse association or showed no impact of Metformin. It should be remembered that RCTs that find no association between Metformin and cancer were designed to analyze other outcomes, did not include adequate confounding factors and follow-up was too short (maximum 4 years). Despite this evidence the latest meta-analysis shows that Metformin decreased risk only for cancers of the liver, pancreas, colorectal and stomach. A meta-analysis of 8 cohorts, involving 2805 pancreatic patients with diabetes, demonstrated a favorable result for pancreatic cancer with improved overall survival (HR=0.78, 95% CI=0.66- 0.92). Metformin treatment is associated with a significant reduction in overall mortality irrespective of diabetes status in patients with endometrial cancer. Using Metformin as a cancer prevention strategy has been controversial and results have been inconsistent, but many analysis reveals that use of the drug is time-dependent, which may explain the disparity. Currently, doubt still remains whether the anti-cancer effects of Metformin observed in in vitro and in vivo studies will ultimately translate into clinical benefits in the ongoing clinical trials. While whether Metformin has a clinically-relevant chemo preventive or anti-cancer effect is not clear at present, the evidence from the ongoing human clinical trial studies will help to answer this critical issue.

Please see this review - as current state...!

Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis

Dear Sergey: The benefits reported in the review seem to be limited to prostate and colon cancers.

Dear Alfredo,

Yes, I agree with ypu.

We have limit data and future RCT will be answer on this question.

Have a nice Holidays!

Sergey.

For you too, Sergey! Thank you!

Dear Alfredo.. There are some suggestions that metformin might have some role in decreasing the incidence of certain cancers. It has probably have some role in better response to chemotherapy also. Some studies are available in relation to breast, pancreas, prostate and endometrial cancer. Several potential mechanism are probably responsible like..

Activation of LKB1/AMPK pathway

Induction of cell cycle arrest /apoptosis

Inhibition of protein synthesis

Reduction of circulating insulin leve

Inhibition of unfolded protein response

Activation of immune response

Eradication of cancer stem cells

Following link might help you

According article "The Clinical Effect of Metformin on the Survival of Lung Cancer Patients with Diabetes: A Comprehensive Systematic Review and Meta-analysis of Retrospective Studies" I have question. If we have differences of clinical effect Metformin of cancer patients with and without DM?

http://www.jcancer.org/v08p2532.pdf

Sergey, I think there may exist a difference between those DM patients who use metformin for a long time, and those who have used it for a short time. This difference is because long term use of metformin may cause endoplasmatic stress and mitochondrial swelling, preventing the apoptosis of tumoral cells. However, as the use of the drug is relatively recent, researchers will need to wait some years to make clinical studies about this difference.

Hi Sergey and Alfredo,,, I totally agreed with both of your opinion. Various studies have shown reduction of incidence of pancreatic, colonic and hepatocellular carcinoma in patient of diabetes with metformin. Some well designed study is needed to evaluate it's role in primary prevention of cancer in both diabetic and nondiabetic patient and look for any difference in efficacy in this respect in diabetic and nondiabetic patient.. Thanks

THE SCIENTIST online seminar

Cell Signaling and Metabolism: Bridging a Gap in Cancer Therapies

Wednesday, October 24, 2018 2:30-4:00 PM Eastern Time

That cancer cells display an altered metabolism has been known for almost a century, but the cell-signaling mechanisms responsible for this phenomenon are just beginning to be understood, with some drugs targeting key regulators of both cell metabolism and tumor progression. The repurposing of old drugs for the activation and/or inhibition of proteins at the center of the cell-signaling and metabolism web has been a popular strategy for addressing these challenges. Drugs like metformin, chloroquine, and various statins are just a few examples of those in clinical trials. They offer a cost-effective advantage in addition to an already-established pharmacokinetic and pharmacodynamic profile. To further explore cell metabolism as a novel avenue of drug discovery based on already-established cell signaling mechanisms essential for tumor progression, The Scientist is bringing together a panel of experts to discuss their research into this exciting and recently acknowledged hallmark of cancer.

Topics to be covered:

• Metabolic symbioses in tumor microenvironments
• Uncovering metabolic bottlenecks in genetic subtypes of lung cancer

Wednesday, October 24, 2018 2:30-4:00 PM Eastern Time

Association with Curcumin (thanks to Vera Maura Fernandes de Lima )

Article Curcumin combined with metformin decreases glycemia and dysl...

New Views in Medscape: Alternatives to Metformin; Metformin and Parkinson

https://www.medscape.com/viewarticle/931363

https://www.medscape.com/viewarticle/898478