Patrick McHargue
Sorry for a long answer; this is what I sent to my doctor:
Thanks for a great appointment and for being willing to look at some data on Metformin. These first few papers address the question of whether or not Metformin can be blamed for causing Lactic Acidosis.
The first study is a comprehensive search identifying all the comparative trials or observational cohort studies published between January 1, 1959, and March 31, 2002, that evaluated metformin therapy, alone or in combination with other treatments, for at least 1 month. Results: Pooled data from 194 studies revealed no cases of fatal or nonfatal lactic acidosis in 36,893 patient-years in the metformin group or in 30,109 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals, the probable upper limit for the true incidence of lactic acidosis in the metformin and non-metformin groups was 8.1 and 9.9 cases per 100,000 patient-years, respectively. There was no difference in lactate levels for metformin compared with placebo or other nonbiguanide therapies.
Conclusion: There is no evidence to date that metformin therapy is associated with an increased risk of lactic acidosis or with increased levels of lactate compared with other anti-hyperglycemic treatments if the drugs are prescribed under study conditions.
There are cases of people on Metformin getting lactose acidosis, but they are associated- not causal. “The investigators conclude that it is the underlying systemic dysfunction and not the particular treatment that is the main determinant for the appearance of lactic acidosis. In support of that conclusion, the results of this review reveal that there is no evidence of an increased risk of lactic acidosis associated with metformin use if it is prescribed under the study conditions, taking into account contraindications.”
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/216377
This second paper begins by introducing how the idea that metformin caused lactic acidosis developed because of its association with the older drug phenformin, which did increase rates of lactic acidosis. The paper includes some specific studies and concludes that: “In none of the studies submitted to the U.S. Food and Drug Administration (FDA) in support of these indications were there any episodes of lactic acidosis.”
The article continues: “In contrast to the findings from controlled trials, cases of lactic acidosis continue to be reported in patients taking metformin. Among the first million patients (approximately) to have received metformin in the U.S., there were 47 reports (20 fatal) to the FDA of lactic acidosis. Of these patients, 43 had renal failure (labeled contraindication for metformin) or risk factors for lactic acidosis besides metformin (primarily congestive heart failure). There were only four patients who did not have other risk factors for lactic acidosis when metformin was initially given. In one of these four case subjects, lactic acidosis appears to have been precipitated by an episode of urosepsis. None of these four patients died.”
After citing several other studies, the conclusion includes: “Metformin rarely, if ever, causes lactic acidosis when it is used as labeled. Metformin is associated with lactic acidosis in patients with conditions that can themselves cause lactic acidosis (heart failure, hypoxia, sepsis, etc.). … When metformin is used as labeled, the increased risk of lactic acidosis is either zero or so close to zero that it cannot be factored into ordinary clinical decision making.
http://care.diabetesjournals.org/content/27/7/1791.long
In “Consequences of Metformin Intoxication” we do see some lactic acidosis in diabetic patients caused by extreme accumulations caused by preexisting renal failure or overdosage (in this case, in people taking massive doses from 7.65 to 76.5 grams.) Most of these patients had also ingested other drugs as well.
https://www.ncbi.nlm.nih.gov/pubmed/9802770
Some investigators have attributed the association between metformin and lactic acidosis to the fact that type 2 diabetes is itself a risk factor for lactic acidosis. Additionally, studies indicate that many people remain on metformin even when contraindications arise. One such study found that 24.5% of patients receiving metformin had preexisting contraindications to its use, and 87% already taking metformin continued to take it despite developing a new contraindication.
https://www.ncbi.nlm.nih.gov/pubmed/11472468
Metformin is so safe, even among people with certain levels of kidney impairment, that the FDA recently revised its warnings so that patients with mild to moderate kidney function can now take it:
https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certain
Taken together, I can find no evidence that Metformin would cause lactic acidosis in an individual like me. I have no kidney problems in my family, nor that I’m aware in my extended family, and I have none of the other contraindications. Metformin does cause a reduction in B12, and so I would want to take a B12 supplement. I have found no evidence that it could cause me harm, but what are the benefits?
https://www.ncbi.nlm.nih.gov/pubmed/25041462
In the above large-scale study, involving over 180,000 people, patients treated with type 2 diabetes that were treated with metformin lived longer than people without the condition.
It is again worth pointing out that most, if not all, of the wealth of available research on metformin uses samples who have diabetes, which represent a population with additional health concerns. In the Western world, 44% of patients with type 2 diabetes die within 10 years of diagnosis. Diabetics classically succumb to the effects of accelerated aging, manifested as premature development of cancer, atherosclerotic heart disease, Alzheimer’s dementia, and any number of other age-related diseases. How can people with diabetes have a 15% reduction in death compared to the rest of us?
One reason is that it increases our insulin sensitivity, and therefore lowers circulating levels of the inflammatory hormone insulin. Heart disease requires LDL particles, but the other requirement is the inflammatory immune response. Less inflammation results in longer life.
A second reason is that metformin reduces the mTOR pathway, similar to the anti-rejection drug rapamycin (unfortunately to a much smaller degree). This reduces circulating levels of human growth hormone and insulin-like growth factor (IGF), which drive not only atherosclerotic plaque, but also cancer-forming processes.
The following study concludes: “Epidemiological and basic studies have demonstrated that it may also inhibit the growth of a variety of tumor cells, and an increasing number of ongoing clinical trials on the antitumor activity of metformin are being processed for the treatment of cancer.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772929/
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.9013
In addition to its ability to inhibit glucose being released from the liver, metformin activates AMP kinase, which acts as a master switch in cellular energy regulation, hormone expression, and protein synthesis. As it up regulates AMP kinase, it drives fat-burning similar to what is experienced during the fasted state. The best proven life-extending strategy is caloric restriction, and metformin mimics this effect by expressing AMPK.
All of this makes metformin a very exciting area of research. A quick google of “metformin life extension” yields a wealth of citations. You can read a better summery of its benefits here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/
https://clinicaltrials.gov/ct2/show/NCT02432287
As if all that wasn’t enough…. It has the additional benefit of reducing Total Cholesterol, Triglycerides, and LDL cholesterol… which has now become a concern for me. I am hopeful that I can reduce my LDL via some changes to my diet and lifestyle, but there is a lot of evidence to suggest that metformin would help too.