There are well over three thousand PubMed hits for <cancer metformin>, so I suppose there might be something to the rumor that Metformin has anti-cancer properties. LOL.
Bottom line: For someone with PCa, I feel that study [6a] trumps all others. Which is why I increased my daily Metformin dose to 2,000 mg. [6a] is the study that finally convinced Dr. Myers.
Metformin is the first line treatment for diabetes. It has been used in the U.S. only since 1995, but has a long track record - having been used in France for sixty years.
As a non-diabetic, my first thoughts are: do you have to be diabetic to get the benefit, or is there a separate anti-cancer effect? Muddying the issue is the fact that diabetics get more cancer of every type - except PCa, where diabetes seems to offer protection.
Some quotes from the American Diabetes Association [1]:
- "Prevalence: In 2012, 29.1 million Americans, or 9.3% of the population, had diabetes.
- "Prevalence in Seniors: The percentage of Americans age 65 and older remains high, at 25.9%, or 11.8 million seniors"
- "Prediabetes: In 2012, 86 million Americans age 20 and older had prediabetes; this is up from 79 million in 2010." (27.5%)
Presumably, prediabetes is also more prevalent in seniors.
Prediabetes is loosely defined as having elevated blood sugar, but not high enough to be classified as a diabetic.
PCa is different from other cancers in two significant ways:
i) prostate cells primarily use fatty acids as fuels, & this mostly does not change in cancer cells. A radiolabeled glucose PET scan is of little use in PCa. Normalizing glucose levels would not have any diect effect on PCa cells.
ii) men who have been diabetic for more than 12 months have a lower rate of PCa incidence.
This suggests to me that elevated insulin is an important PCa growth factor. Prediabetics, owing to insulin resistance, produce more insulin than normal. Diabetics, due to beta cell burnout, are no longer able to ustain high levels of insulin. Hence, diabetics are not really protected - rather, prediabetics have excess risk.
IMO, any treatment that increases insulin sensitivity (so that less is produced), is likely to lower the risk for PCa in prediabetics. For this reason alone, Metformin use should be beneficial even where insulin resistance is moderate. In addition, since insulin affects the PCa growth rate, rather than the incidence rate, any man diagnosed with PCa who has any degree of insulin resistance, should consider Metformin.
Here is a surrogate measure for insulin resistance: Triglycerides / HDL-Cholesterol. The target is ~1.0.
One of the problems with population studies that I have seen, is that Metformin use is examined out of context. When diabetes is diagnosed, the hope is that the diabetic may control glucose with diet plus Metformin. While insulin production is impaired in diabetes, there may nevertheless be enough insulin, provided that glucose spikes are avoided. Unfortunately, by the time a year has passed, a diabetic is often on an additional medication, with Metformin usually continued. Well, that is my understanding of the U.S. If insulin is part of treatment, that might have an impact on study results - assuming that insulin really is a mitogen in PCa.
A potential issue with population studies is that different countries may have different diabetes treatment protocols, different PCa screening approaches, & far fewer prediabetic seniors in the population compare to the U.S.
[2] Diabetes & PCa protection.
[2a] (2009 - U.S. - Health Professionals Follow-Up Study - Giovannucci) 4,511 PCa cases
"PCa risk was not reduced in the first year after diabetes diagnosis (HR: 1.30 ...)"
"was lower for men diagnosed for 1–6 years (HR: 0.82 ...)"
"and was even lower for men who had been diagnosed for 6–15 (HR: 0.75 ...)"
"While patients with DM phenotypically presents with hyperglycemia, they all present with a relative hypoinsulinemia. Insulin has been shown to be a growth factor for prostatic epithelium in vitro, to stimulate growth of a rat prostate cancer cell line in vitro, and is associated with both higher risk and recurrence of the prostate cancer. Therefore, decreased insulin may have a growth-inhibitory effect on these cells and if long-term diabetic patients experience reduced levels of circulating insulin, they may be at a reduced risk of developing prostate cancer. Additionally, there is evidence that higher serum insulin levels are associated with poor outcome in prostate cancer."
[3] Population Studies - for Metformin.
[3a] (2009 - U.S.) "Cases {1,001} were men aged 35–74 years diagnosed with PCa between 2002 and 2005 in King County, Washington."
"In Caucasian men, metformin use was more common in controls than in cases (4.7 vs. 2.8% ...), resulting in a 44% risk reduction for PCa"
[3b] (2014 - Australia - 9,486 diabetics)
"Type 2 diabetes mellitus, glycemic control, and cancer risk."
Here is an odd finding:
"prostate cancer risk was significantly higher with better glycemic control"
i.e. via "insulin, metformin, sulfonylurea" (nothing else is mentioned)
However:
"Metformin exposure was associated with reduced ... prostate cancer incidence".
The authors report:
"The data .. support hyperinsulinemia, rather than hyperglycemia, as a major diabetes-related factor associated with increased risk of breast and colon cancer."
i.e. no mention of PCa.
Makes no sense. If hyperinsulinemia is not a PCa risk factor and hyperglycemia reduces PCa risk, why does Metformin reduce PCa risk?
The problem might be that some of their conclusions are based on combined insulin, metformin & sulfonylurea use.
[3c] (2014 - Denmark - 12,226 PCa cases)
"Metformin use was associated with decreased risk of PCa diagnosis, whereas diabetics using other oral hypoglycemics had no decreased risk."
[3d] (2014 - Taiwan - "2,776 metformin ever-users and 9,642 never-users ")
"... hazard ratios for the first, second and third tertiles of cumulative duration of metformin therapy were 0.741 .., 0.474 ... and 0.231 .., respectively ..; and were 0.742 .., 0.436 ... and 0.228 ... for the respective cumulative dose"
[3e] (2016 - U.S.)
"There were significantly fewer deaths (23% versus 10%), fewer recurrences (15% versus 8%), fewer metastases (5% versus 0%) and fewer secondary cancers (17% versus 6%) in the metformin group"
[4] Population Studies - mixed.
These papers are from the same Canadian team, published a month apart. "Data were obtained from several Ontario health care administrative databases."
The first found no effect of Metformin on PCa incidence, but a 24% reduction in PCa mortality for "each additional 6 months of metformin use."
[4a] (Aug 2013)
"Within our cohort of 119,315 men with diabetes, there were 5,306 case subjects with prostate cancer and 26,530 matched control subjects. Within the cancer case subjects, 1,104 had high- grade cancer, 1,719 had low-grade cancer, and 3,524 had biopsy-diagnosed cancer. There was no association between metformin use and risk of any prostate cancer ..."
[4b] (Sep 2013)
"Within a cohort of men older than age 66 years with incident diabetes who subsequently developed PC, we examined the effect of duration of antidiabetic medication exposure after PC diagnosis on all-cause and PC-specific mortality."
"The cohort consisted of 3,837 patients. Median age at diagnosis of PC was 75 years ... During a median follow-up of 4.64 years .., 1,343 (35%) died, and 291 patients (7.6%) died as a result of PC. Cumulative duration of metformin treatment after PC diagnosis was associated with a significant decreased risk of PC-specific and all-cause mortality in a dose-dependent fashion."
"Adjusted HR for PC-specific mortality was 0.76 ... for each additional 6 months of metformin use."
"Increased cumulative duration of metformin exposure after PC diagnosis was associated with decreases in both all-cause and PC-specific mortality among diabetic men."
[5] Population Studies - neutral or against Metformin.
[5a] ((2014 - U.K. data - Canadian analysis)
"The cohort consisted of 935 men with prostate cancer and a history of type II diabetes. After a mean follow-up of 3.7 years, 258 deaths occurred, including 112 from prostate cancer. Overall, the post-diagnostic use of metformin was not associated with a decreased risk of cancer-specific mortality ..."
"In a secondary analysis, a cumulative duration ≥938 days was associated with" more than 3 times the risk.
"The post-diagnostic use of metformin was not associated with all-cause mortality (RR, 0.79 ...)" (!)
[5b] (2015 - U.S. - REDUCE trial)
"Among diabetic men with a negative prestudy biopsy who all underwent biopsies largely independent of PSA, metformin use was not associated with reduced risk of prostate cancer diagnosis."
[5c] (2016 - Sweden)
"The study consisted of 612,846 men, mean age 72 years .., out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years ... Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR = 0.85 ...) but among men with T2DM, those on metformin had no decrease (HR = 0.96 ...), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR = 0.73 ...), compared to men with T2DM not on anti-diabetic drugs."
[6] PCa - Metformin intervention studies.
[6a] (2013 - Switzerland)
This is the one that convinced Dr. Myers. & is also why he talks about a split daily dose of 2,000 mg.
"Forty-four men with progressive metastatic CRPC from 10 Swiss centers were included in this single-arm phase 2 trial between December 2010 and December 2011."
"The primary end point was the absence of disease progression at 12 wk."
"Thirty-six percent of patients were progression-free at 12 wk, 9.1% were progression-free at 24 wk, and in two patients a confirmed ≥ 50% prostate-specific antigen (PSA) decline was demonstrated. In 23 patients (52.3%) we observed a prolongation of PSA DT after starting metformin."
"The homeostatic model assessment index fell by 26% from baseline to 12 wk, indicating an improvement in insulin sensitivity."
"There was a significant change in insulin-like growth factor-1 and insulin-like growth factor binding protein 3 from baseline to 12 wk."
It is an impressive result. These were CRPC cases, yet over a third "were progression-free at 12 wk". (None had received chemo.)
It would be interesting to see how/if a response was related to insulin resistance sensitivity improvement.
It's good that they also looked at the effect on the IGF (insulin-like growth factor) axis. IGF-I is associated with a poor outcome. IGF has a number of binding proteins (IGFBPs) that reduce IGF-I availability. The most protective is IGFBP-3. PCa is usually able to downregulate IGFBP-3. The "significant change" mentioned above is presumably a drop in IGF-I & an increase of IGFBP-3. All good stuff.
[6b] (2014 - Germany-Canada)
This is one of those cute pre-prostatectomy interventions. They often last 3 weeks, but this one was 18-81 days (median = 41 days).
The significant finding, IMO, relates to the Ki-67 protein [6bx]:
"The Ki-67 protein ... is a cellular marker for proliferation. It is strictly associated with cell proliferation."
"In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 %" respectively.
& this was with the modest dose of 500 mg / day.
-Patrick
[1] diabetes.org/diabetes-basic...
[2a] ncbi.nlm.nih.gov/pmc/articl...
[3a] ncbi.nlm.nih.gov/pmc/articl...
[3b] ncbi.nlm.nih.gov/pubmed/239...
[3c] ncbi.nlm.nih.gov/pubmed/248...
[3d] ncbi.nlm.nih.gov/pubmed/252...
[3e] ncbi.nlm.nih.gov/pubmed/270...
[4a] jnci.oxfordjournals.org/con...
[4b] ncbi.nlm.nih.gov/pubmed/239...
[5a] ncbi.nlm.nih.gov/pubmed/250...
[5b] ncbi.nlm.nih.gov/pubmed/263...
[5c] ncbi.nlm.nih.gov/pubmed/277...
[6a] ncbi.nlm.nih.gov/pubmed/244...
