metformin: its many faces and potential benefits

A recent article evaluated metformin, finding it has a wide array of potential benefits independent of those for diabetes (see dm metformin drug for all diseases metab2022 in dropbox, or doi.org/10.1016/j.metabol.2022.155223); this article is replete with references (474 of them) to back all of the following findings 

 

Review: 

-- metformin is a synthetic biguanide, first used to treat type II diabetes in the late 1950s and has for years been the first choice drug for approximately 150 million diabetic patients 

    -- it was developed as an antidiabetic med based on information going back to the 17^th century when extracts of French Lilac (Galega officinalis, also called goat’s rue, Italian fitch, and, in the US, Professor Weed) were used to treat people with ‘sweet urine’ 

    -- French Lilac extracts have the toxic alkaloid galegine, which was synthesized in the late 19^th century to guanidine and biguanides (found to decrease blood sugar in rabbits) and subsequently to metformin synthesized in  1922 

    -- phenformin,  the more potent relative metformin, became the dominant biguanide used in the US, unfortunately leading to hepatotoxicity and nearly universally fatal lactic acidosis; phenformin was subsequently pulled from the market. However, metformin was used predominantly in Europe with great success, and large studies subsequently have shown to be remarkably safe (see http://gmodestmedblogs.blogspot.com/2018/06/metformin-and-lactic-acidosis-again.html and http://gmodestmedblogs.blogspot.com/2019/03/metformin-in-ckd-dec-cv-eventsmortality.html 

which also assesses its use and safety in those with CKD) 

-- and it is also pretty clear that metformin decreases cardiovascular mortality (eg see dm metformin dec CVD mortality CardDiab2019 in dropbox, or https://cardiab.biomedcentral.com/track/pdf/10.1186/s12933-019-0900-7.pdf )

-- the understanding of the mechanisms of action of metformin are still unfolding. For example, intravenous  administration of metformin does not reduce blood sugar, hepatic glucose production, or peripheral glucose disposal. Perhaps metformin needs to be given chronically? but there are a few lines of data suggesting that a major role of metformin may be its effect on the gut microbiome

     -- a part of metformin's mechanism of action may be related to creating a healthier gut microbiome. A study of diabetic mice found that those on metformin improved their glycemic profile (as expected), but there was a significant increase in the gut bacterium Akkermansia. In a parallel experiment, just increasing this bacterium in the gut (in the absence of metformin) also enhanced glucose tolerance and decreased adipose tissue inflammation, suggesting that an additional mechanism of action for metformin may be through its effect on the microbiome (see http://gmodestmedblogs.blogspot.com/2014/10/heart-failure-microbiome.html ).  

      -- the delayed release metformin has 50% reduced bioavailability but has a more profound effect on fasting plasma glucose, perhaps attributed to the fact that it is more available in the lower GI tract (since it is delayed release) than regular metformin??

          -- and, it may well be that the long-term effects of a healthier microbiome may be an added benefit above and beyond metformin's diabetic control: eg specifically for the array of bad outcomes related to chronic inflammation, such as heart disease, cancer, CKD, NAFLD, autoimmune disease, depression,... (see dm metformin microbiome GUT 2014 in dropbox, or doi.org/10.1136/gutjnl-2013-305370)  

-- One concern about metformin is that medication adherence may be less than some other drugs (e.g. DPP-4 inhibitors, STLT2 inhibitors), largely attributed to GI adverse effects (which also seem to be fewer with the delayed release version)

-- metformin can also lead to vitamin B 12 deficiency from malabsorption, and vit B12 levels should be checked periodically

-- the Diabetes Prevention Program (DPP) did find that metformin 2000 mg per day was inferior to lifestyle changes (low-fat diet, at least 150 minutes of exercise per week) in preventing the progression of glucose intolerance to diabetes, perhaps attributable to the fact that skeletal muscle insulin sensitivity improved 90% with exercise vs  55% with metformin [reinforcing that as with many illnesses, a healthy lifestyle is really important for diabetes treatment, and should be emphasized in those  needing meds or not]

    -- of note there is some concern that metformin may blunt the response that exercise provides

-- there are also suggestions that metformin may improve mitochondrial dysfunction, decrease oxidative stress associated with hyperglycemia and decrease insulin resistance. The article postulates many different mechanisms of action for metformin, all with either human or animal models, including general suppression of pro-inflammatory pathways and even direct anti-viral actions

 

Specific potential benefits (real and potential) for metformin: 

 

-- type II diabetes and cardiovascular disease: many studies support a role for metformin, as found in a meta-analysis of 40 studies with over 1 million patients: metformin use was associated with decreases in all-cause mortality, cardiovascular mortality, and cardiovascular events in patients with coronary artery disease and type II diabetes

   --  there is an argument that we should move to STLT2 inhibitors as primary therapy for diabetes, instead of metformin. But see http://gmodestmedblogs.blogspot.com/2022/07/diabetes-sglt-2-inhibitors-as-first.html for a review of an article promoting this, but suggesting that metformin still should be the first line therapy given its other benefits (esp a healthier microbiome) and has minimal severe adverse effects

 

-- endothelial effects of metformin: endothelial function is a surrogate for cardiovascular risk (perhaps the earliest indicator of the development of cardiovascular disease), defined as a reduction in endothelium-dependent vasodilation in response to an endothelium-dependent vasodilator. Several studies have found that endothelial dysfunction was corrected by administrative of metformin, likely from improved insulin sensitivity. Long-term studies have shown that several biomarkers of endothelial dysfunction were improved with metformin, including PAI-1, siCAM-1, t-PA and vWF. Flow-mediated vasodilation and aortic stiffness are  found in nondiabetics and some patients with type I diabetes

 

-- Type I diabetes: metformin added to insulin is associated with vascular protection, reduced endothelial impairment, improved glycemic control, as well as reducing insulin dosing requirements. This needs to be assessed further in studies, given that metformin does have adverse gastrointestinal effects

 

-- polycystic ovary syndrome (PCOS): metformin does help with insulin resistance associated with PCOS (as has some GLP-1 agonists). metformin may also have specific ovarian effects, including inhibition of in vitro androgen production, especially evident in the presence of insulin, and this benefit may be from decreasing circulating insulin levels. And, metformin does affect other ovarian enzymes directly

 

-- Cancer: several cancers are associated with diabetes (type I and type II). Some studies have suggested that phenformin enhanced the anticancer effects of some chemotherapeutic agents in mice; and some retrospective studies suggest that metformin reduced the risk of cancer in  type II diabetes in humans. The studies, of note, are not consistent in finding decreased cancer risk. More studies are clearly needed, though it should be pointed out that hyperinsulinemia (and insulin resistance) does have many effects in the body that may be unhealthy and potentially carcinogenic, including inflammation, an atherogenic lipid profile, development of type II diabetes, changes in fat storage, incident nonalcoholic fatty liver disease (which can be associated with hepatocellular carcinoma), endothelial dysfunction, (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735759/ ) , as well as arterial smooth muscle cell proliferation (which may have a role in atherosclerosis, see https://academic.oup.com/cardiovascres/article/103/2/324/300501 ); metformin decreases insulin levels, and seems to help with increasing vascular cell perfusion through its anti-platelet-derived growth factor actions

 

-- anti-aging effects: the anti-inflammatory effects of metformin could conceivably decrease senescence of cells as well as the body overall. Indeed, several studies (but not all) have found that metformin may well have anti-aging benefits: for example a systematic review of 53 studies found that metformin may extend both health span and lifespan independent of its actions as an anti-diabetic drug

 

-- neuro-degenerative diseases: these are increased in patients with diabetes (including stroke, Alzheimer’s and vascular dementias, and Parkinson’s). metformin does cross the blood brain barrier, though CSF levels are about 1/10 of basal plasma levels. Mitochondrial dysfunction is associated with Parkinson’s disease in particular, and metformin may improve mitochondrial function. The data are equivocal on any direct protective benefit of metformin (though perhaps if given early  enough, it could prevent these??? Prior to the horse being out of the barn….

 

-- infections: historically metformin has been used for treatment of malaria, influenza, Covid-19, and bacteria. However, it seems that the effects of metformin are not fundamentally different from that of other antidiabetic medications, and that improving glucose control by whatever means is helpful in controlling infections. Of note, metformin and other antidiabetic drugs have been shown to reduce morbidity and mortality associated with Covid 19, including potentially through phosphorylation of ACE-2 receptors, thereby reducing the ability of the SARS-CoV-2 virus from entering the host cells

 

 

Commentary: 

-- metformin has been around for about 70 years and is a basically safe, reasonably well-tolerated, and an effective medication for diabetes

-- this article suggests a wide array of actual and potential  mechanisms of action for metformin, beyond its effects on hyperglycemia: decreasing insulin resistance (associated with an array of medical problems, including PCOS and NAFLD) as well as inflammation (associated with a myriad of medical problems including cardiovascular disease, depression, etc); mitochondrial dysfunction; healthier microbiome changes; possibly various forms of neurocognitive problems; possibly aging; cancer; etc

-- but metformin is associated with some common GI effects. These can often be mitigated by using lower doses, prescribing extended-release formulations, or taking the medication with foods. And, lower doses of metformin, as with some other drugs such as statins, provide a large percent of the overall potential metformin benefit. Even 250 mg once a day does provide clinical benefit

 

so, a few points:

-- I am NOT advocating using metformin for nondiabetic patients; the above data is intriguing but not definitive. And some of the results are likely just from the hypoglycemic effects of metformin and are found with other anti-diabetic agents

-- it seems pretty clear that hyperinsulinism/insulin resistance in many studies is related to increased atherosclerotic risk, systemic inflammation, etc,  and treating diabetic patients with insulin and sulfonylureas can lead to high insulin states (short acting glipizide seems to be the best of the sulfonylureas)

-- but this paper reveals and reinforces that medications may well have a multiplicity of effects throughout the body:

    -- for example, DPP-4 inhibitors for diabetes do increased GLP-1 levels, but also inhibit many other pervasive important \ enzyme systems throughout the body, raising concern about potential short-term or long-term adverse effects from blocking these enzyme systems

    -- and, adverse reactions don’t fall from the sky, but are the nontarget effects of a medication on other cells leading to those “side-effects” (ie, side effects can reflect real effects of the medication on non-target cells)

-- all of this suggests that we continually challenge our understanding of how drugs work. The mechanisms of action proposed in studies may not be what is really happening in the body, and this all means that we should be hesitant to narrow our field of vision:

    -- metformin is a great example of this: it is good for diabetics, is easy to see that it lowers A1c, but so do other drugs. GLP-1 agonists and SGLT-2 inhibitors have cardiovascular and renal benefits. So why should we stick with metformin as the first line??

        --  for one thing, as mentioned above, metformin also seems to have pretty impressive effects on the microbiome, which could be lost if our vision were myopic and we did not look at the bigger picture

        -- and, focusing on A1c itself may not be the important clinical marker to measure, especially for macrovascular complications (most diabetics die from cardiovascular disease). The focus, I think, is A1c (especially for the microvascular complications in the kidneys, eyes, nerves) but in the context of a more global assessment of cardiovascular risk. And, to the extent possible, to use meds that decrease cardiovascular risk (eg GLP-1 agonists, SGLT-2 inhibitors, and pioglitazone); and trying to avoid those that increase hyperinsulinism/insulin resistance such as insulin and sulfonylureas.

 

geoff

 

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