Rediscovering metformin

Hello everyone!

I am very excited to write my first blog. Thank God it doesn’t have to be in APA format!

If you are a nurse, a midlevel provider (nurse practitioner or physician assistant), or a physician, then I’m sure you’ve heard about metformin since almost all of your diabetic patients are on it. It has been the preferred first-line oral pharmacologic treatment for type 2 diabetes since the 1990s (Rojas & Gomes, 2013). Despite its known wonders in type 2 diabetes, metformin is not as popular as its other antidiabetic agent counterparts, like the newer type 2 diabetes medication, semaglutide, with injectable brand names, Ozempic, Wegovy, Zepbound, and oral brand name, Rybelsus. Wegovy and Zepbound are both FDA-approved treatment for weight loss management, but not Ozempic and Rybelsus, although Ozempic is a widely used effective drug for weight loss management, as well.

So what is it about the old cheap metformin that I find interesting to talk about? Well, metformin is getting a potential come back. In fact, Silicon Valley technology executives, and longevity and anti-aging industry investors and executives have been taking it daily over the past few years. They strongly believe in its potential efficacy in providing them a prolonged quality life span (Farr, 2019; Miller, 2020). Eric Verdin, who obtained his Doctorate of Medicine (MD) from the University of Liege, and also completed additional clinical and research training at Harvard Medical School, is one of the many longevity and anti-aging research leaders who take metformin. He is the President and Chief Executive Officer (CEO) of the Buck Institute, a globally renowned center for aging research outside San Francisco, (Miller, 2020).

Before I discuss with you where this metformin trend is coming from, I want to give you a little background about metformin. Metformin’s (dimethylbiguanide) history can be traced back to the discovery of Galega officinalis (goat’s rue) in 1918, a guanidine-rich herbal medicine in Europe, shown to lower blood glucose. Synthetic guanidine derivatives, including metformin and others, were used for diabetes in the 1920s and 1930s, but were eventually discontinued due to its toxicity, and increased availability of insulin. Metformin was rediscovered in the 1940s when researchers were exploring antimalarial agents. During clinical tests, metformin proved useful to treat influenza when it sometimes lowered blood glucose. The French physician, Jean Sterne, took interest in this property, and was the first to report the use of metformin to treat diabetes in 1957 (Bailey, 2017).

Unfortunately, metformin was overshadowed by other more potent glucose-lowering biguanides, such as phenformin and buformin, which were taken off the market in the late 1970s due to increased risk of lactic acidosis. Despite evident differences with other biguanides, metformin remained backstage for a while. However, because of its ability to decrease insulin resistance and lower blood glucose levels without weight gain or risk for hypoglycemia, metformin gained credibility in Europe. After intense scrutiny, the US Food and Drug Administration (FDA) approved metformin in 1994. It became available in the market in 1995. Today, metformin is still the most widely prescribed glucose-lowering agent worldwide in the setting of type 2 diabetes (Bailey, 2017).

Type 2 diabetes leads to peripheral vascular disease (PVD) with eventual skin ulcers, heart attack, and stroke secondary to macrovessel damage. It causes nephropathy (kidney disease, which eventually leads to end-stage renal disease, requiring dialysis), retinopathy (damage to the small blood vessels at the back of your eye causing vision problems, and may lead to blindness), peripheral neuropathy (nerve damage in your peripheries, causing weakness, numbness/tingling to your hands and feet), autonomic neuropathy (damage to the peripheral nervous system that regulates involuntary function, which can manifest as resting elevated heart rate, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, etc.) due to microvessel damage.

Metformin primarily acts at the liver by reducing the amount of glucose released from it, and by increasing glucose uptake in the cells, thereby lowering your blood glucose levels (Rojas & Gomes, 2013). In the Diabetes Prevention Program (DPP) trial, lifestyle changes and metformin has reduced diabetes incidence in prediabetics by 58%. In some randomized, controlled trials, metformin has showed a significant decrease in fasting blood glucose, glycosylated hemoglobin (HbA1c), weight, and total cholesterol in children and adolescents with type 2 diabetes. It is associated with short-term weight loss, decreased insulin resistance, and decreased visceral fat (Rojas & Gomes, 2013). Multiple studies have shown that metformin reduce cardiovascular risks in diabetic patients. Samaras et al. (2020) has found that metformin use over 6 years in older people with type 2 diabetes is associated with a slower cognitive decline and dementia risk. Metformin has also shown to prevent further neuronal damage in Parkinson’s disease in patients with type 2 diabetes, and plays a significant role in neuroprotection (Lu et al., 2020).

Studies on the important role of metformin in delaying the progression, and even the prevention, of other diseases in diabetic patients are endless, but how about its effect in non-diabetic patients. The United Kingdom Prospective Diabetes Study (UKPDS), conducted from 1977 to 1997, found early on that these improved cardiovascular risks in type 2 diabetes patients treated with metformin was attributed far beyond its glycemic control mechanism (Rojas & Gomes, 2013). The effects of metformin on the macrovascular complications of type 2 diabetes, such as heart attack and stroke, may be explained by its actions associated with the inflammatory and atherothrombotic processes. According to Rojas & Gomes (2013), “Metformin can act as an inhibitor of pro-inflammatory responses through direct inhibition of NF-kB by blocking the PI3K-Akt pathway” (para 35). It has antioxidant properties, which are not only dependent on its hypoglycemic control and insulin-dependent mechanisms, but also on other mechanisms. There are multiple studies that have shown a link between metformin use and decreased incidence of certain cancers. It has also shown direct positive effects on endothelial function (Rojas & Gomes, 2013), thereby decreasing the risks for thrombus formation, preventing atherosclerosis, and assisting blood pressure regulation.

Because metformin has shown to act on other mechanisms or pathways to reduce disease progression and even prevention, besides its hypoglycemic effect, it makes sense to hypothesize that it could potentially play a significant role in reducing cardiovascular and certain cancer risks, neuroprotection, and possibly even delay aging in diabetic and non-diabetic patients. Despite that, there are not enough direct studies that examine the important role of metformin in non-diabetic patients. Many believers of metformin, especially in the anti-aging industry feel that the effects of metformin in non-diabetic patients are under-studied, in part because there is not much of a financial incentive for the pharmaceutical industry to research the impact of an extremely cheap, generic drug (Farr, 2019). The results of the study by Bannister et al. (2014), showing longer survival in patients with type 2 diabetes initiated with metformin monotherapy, compared to non-diabetic controls who were not on metformin, were the motivating factor for the anti-aging industry executives, like Eric Verdin, to take metformin (Miller, 2020). There have been some studies that showed metformin’s ability to inhibit or eliminate senescent cells. Senescent cells are considered an aging hallmark because they accumulate in organismal tissues, which parallel age advancement, and they accelerate the age-related decrease in tissue regeneration (Cheng et al., 2022). Senescent cells increase in number as you age, and it is also widely seen in premalignant lesions from studied patients with cancer. Metformin is found to activate the AMP-activated protein kinase (AMPK) pathway, which coordinates cell growth, autophagy, and metabolism. Autophagy is your body’s catabolic recycling system that degrades and recycles dysfunctional or unnecessary cellular organelles and molecules to sustain cellular function (Cheng et al., 2022).

A renowned endocrinologist, Nir Barzilai, is now leading an international effort to approve drugs that can target aging. He is specifically launching a large clinical trial to examine the anti-aging properties of metformin in non-diabetic patients (Miller, 2020). According to the Albert Einstein College of Medicine, where Barzilai is a faculty member, “Targeting Aging with MEtformin (TAME) is a specific study designed to prove the concept that multi-morbidities of aging can be delayed by metformin, working with the FDA to approve this approach, which will serve as a template for further efforts to delay aging and its diseases in humans”.

When I married my husband, Patrick, in June 2018, I was at around 113 lbs, BMI of 22.1. Throughout the years after our marriage, I kept gaining weight due to unhealthy food choices and decreased physical activity. At one point, I reached 128 lbs, BMI of 25.0 (overweight for my height!). Finally, sometime in August or September of last year, I started myself on Metformin extended release (ER). ER is better tolerated than immediate release (IR), although Metformin is, generally, a well-tolerated medication. Its most common early side effect is diarrhea. I did not want to have diarrhea, and just stop taking it in the first few weeks. During the first two weeks, I could feel that my metabolism had increased. I was burning calories like I was in my late 30s. Working out was easy again. I certainly met my goal of losing 2 lbs per week. By the middle of October 2023, I was back to 111-113 lbs, BMI of 21.7 to 22.1.

Metformin is sometimes prescribed off-label for weight loss management, but it usually only works for overweight or obese patients with impaired glucose tolerance (Abdelgadir et al., 2017). I lost 2 lbs per week with metformin, but I was working out for about 1-2 hours, at least four times a week. I decided to take metformin to increase my metabolism, and for its positive effects on the endothelial function, its antioxidant and anti-inflammatory function, potential neuroprotection, and hopefully, its anti-aging effects.

Metformin, just like any other medication, has potential adverse effects. Note that adverse effects are different from side effects. Adverse effects are unintended reactions to a drug. They are more serious, but are also a lot less common than side effects. Lactic acidosis, a condition, in which the body produces lactic acid faster than it can metabolize, thus, causing it to accumulate in the bloodstream, can occur with metformin use. It can be a medical emergency, depending on the lactic acid level, and how quickly it occurs. According to Blough et al. (2015), “the estimated incidence of lactic acidosis is 6 cases per 100,000 patient-years” in metformin users. Blough et al. (2015) and Hsu et al. (2018) have shown in their studies that lactic acidosis in these patients were not due to metformin alone. It was also attributed by pre-existing chronic kidney disease (CKD) and hypoxic diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. These diseases alone, if not managed well, can cause lactic acidosis through hypoxia and ischemia. There are reported cases of acute kidney injury (AKI) with metformin, especially when used with nephrotoxic agents, such as contrast dye. Again, these AKIs occur in the presence of an existing CKD (Hsu et., 2018). Since I started working in healthcare in May 2005, I have not seen lactic acidosis in any of my patients taking metformin.

So will I prescribe you with metformin if you are non-diabetic? Well, it depends on a lot of things. What are your goals of wanting to take metformin, your latest lab results (HbA1c, TSH, lipid profile, Vitamin D level, etc.), age, medical history, family history, BMI, food choices, activity level, home/work circumstances, etc. Please fill out our secure new patient intake form online, and schedule an initial appointment with me. I would love to listen, and learn more about you. Let’s see which option is best for you. Reboot Health, PLLC has a lot of other options for you!

Below is a link on how to calculate your BMI, and its categories, for your reference.

https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm

References 

Abdelgadir, E., Ali, R., Rashid, F., & Bashier, A. (2017). Effect of Metformin on Different Non-  Diabetes Related Conditions, a Special Focus on Malignant Conditions: Review of   Literature. Journal of clinical medicine research, 9(5), 388–395. https://doi.org/10.14740/jocmr2922e

Bailey, C. J. (2017). Metformin: historical overview. Diabetologia, 60(9), 1566–1576. https://doi.org/10.1007/s00125-017-4318-z

Bannister, C. A., Holden, S. E., Jenkins-Jones, S., Morgan, C. L., Halcox, J. P., Schernthaner, G., Mukherjee, J., & Currie, C. J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, obesity & metabolism, 16(11), 1165–1173. https://doi.org/10.1111/dom.12354

Blough, B., Moreland, A., & Mora, A., Jr (2015). Metformin-induced lactic acidosis with emphasis on the anion gap. Proceedings (Baylor University. Medical Center), 28(1), 31–33. https://doi.org/10.1080/08998280.2015.11929178

Cheng, F. F., Liu, Y. L., Du, J., & Lin, J. T. (2022). Metformin's Mechanisms in Attenuating Hallmarks of Aging and Age-Related Disease. Aging and disease, 13(4), 970–986. https://doi.org/10.14336/AD.2021.1213

Farr, C. (2019). Silicon Valley techies are turning to a cheap diabetes drug to help them live longer. CNBC. https://www.cnbc.com/2019/03/23/metformin-for-cancer-prevention-longevity-popular-in-silicon-valley.html

Hsu, W., Hsiao, P., Lin, P., Chen S., Lee M., & Shin, S. (2018). Effect of metformin on kidney function in patients with type 2 diabetes mellitus and moderate chronic kidney disease. Oncotarget, 9, 5416-5423. https://www.oncotarget.com/article/23387/

Lu, M., Chen, H., Nie, F., Wei, X., Tao, Z., & Ma, J. (2020). The potential role of metformin in the treatment of Parkinson’s disease. The Journal of Bio-X Research, 3(1). https://journals.lww.com/jbioxresearch/fulltext/2020/03000/the_potential_role_of_metformin_in_the_treatment.6.aspx#:~:text=Metformin%20significantly%20improves%20insulin%20resistance,in%20neuroprotection%20and%20cognitive%20impairment.

Miller, M. (2020). Why Silicon Valley Execs are investing billions to stay young. Robb Report. https://robbreport.com/lifestyle/health-wellness/silicon-valleys-tech-elite-is-investing-billions-to-live-longer-2936782/

Rojas, L.B.A. & Gomes, M.B. (2013). Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr, 5(6). https://doi.org/10.1186/1758-5996-5-6

 Samaras, K., Makkar, S., Crawford, J. D., Kochan, N. A., Wen, W., Draper, B., Trollor, J. N., Brodaty, H., & Sachdev. P. S. (2020). Metformin use is associated with slowed cognitive decline and reduced incident dementia in older adults with type 2 diabetes: The Sydney memory and aging study. Diabetes Care, 43 (11). https://diabetesjournals.org/care/article/43/11/2691/35857/Metformin-Use-Is-Associated-With-Slowed-Cognitive