Metformin in All its Glory – Part 2

Updated: Oct 27, 2022

Metformin, the most prescribed pill to treat type 2 diabetes (T2DM) is being explored for a long list of diseases including cancer and dementia. It is currently being used for diabetes prevention, pre-diabetes, gestational diabetes (GDM) , polycystic ovary syndrome (PCOS), and weight loss. Let’s see what we really know about these off-label uses and potential future indications. .

Metformin for Diabetes Prevention

In the largest and longest clinical trial for the prevention of T2DM in high-risk individuals, metformin was shown to be an effective agent. But, an aggressive lifestyle plan was shown to be even more effective than metformin, except in those who were obese with a body mass index (BMI) greater than 35 kg/m2). As a result of this study, the American Association of Diabetes recommended that an aggressive lifestyle be used in individuals with impaired glucose tolerance or a HgbA1c (average blood sugar over approx. 90 days) 5.7–6.4% to prevent T2DM. Metformin was also recommended for preventing T2DM in those with prediabetes (HgbA1c 5.7-6.4%) especially in persons with a BMI of >35 kg/m2 and women with a history of gestational diabetes in which metformin was even more effective.

Metformin for PCOS

PCOS is a hormonal disorder with a possible genetic link that occurs during the reproductive years in which there are fewer periods, difficulty getting pregnant due to irregular or no ovulation, overproduction of androgen (male hormones), hirsutism (excessive hair growth on places like the face, back and chest), oily skin or acne, excessive weight gain and male-pattern baldness. Weight loss and reducing insulin resistance are both important to minimizing the effects of PCOS.

• Insulin resistance: a condition in which persistently high insulin levels cause the cells to lose their response to insulin. In PCOS, the liver responds by producing hormones that trigger the ovaries to secrete androgens causing the potential for weight gain and the development of T2DM.

• High levels of androgens prevent the ovaries from releasing the egg which leads to irregular or missed periods

• Low-grade chronic inflammation tends to be present due to processes occurring in the body (i.e., insulin resistance, obesity, inflammatory food, etc.). Markers of inflammation (i.e., C-reactive protein (CRP) are often elevated and can be checked with laboratory testing. Reducing inflammation is an important aspect to improving the effects of PCOS.

Benefits vs Risks

Most experts conclude that metformin has little or no benefit on the characteristic androgenic hormonal effects (i.e. facial hair, acne, infertility). At least one study showed that metformin’s anti-inflammatory effects may be effective for PCOS but more evidence is needed.

A clinical trial is currently underway to evaluate the treatment of PCOS with an anti-inflammatory agent. It has an expected study completion date of July 31, 2023. If the anti-inflammatory agent proves to be effective, evaluation of the side effects must be considered as well. Meanwhile, instituting an anti-inflammatory diet to address the inflammation associated with PCOS without drugs deserves to be evaluated as well.

The use of a targeted anti-inflammatory diet to reduce inflammation is another example of how getting to the root cause of a condition before turning to potentially dangerous drugs should be a viable option.

Treatment of Gestational Diabetes

GDM is a form of diabetes developed in expecting mothers and is more likely to occur after 20 weeks of pregnancy. Exposure to high glucose levels in the uterus puts the fetus at risk to be born large for gestational age (LGA), birth trauma, preeclampsia, and stillbirth. Mothers are at a 7-fold risk of developing T2DM five to ten years later. Metformin is being used increasingly in place of insulin, the standard treatment for GDM, but because of weight gain and the risk for hypoglycemia, alternatives like metformin are used more and more.

There are no clinical guidelines and the decision to use metformin should be based on clinical experience and on a case-by-case basis. The outcomes for the mother seem to be beneficial however, the risk to the infant is not very favorable.

Figure 2. Summary of Proposed Mechanism for metformin effects on placenta and fetus. Figure created using Biorender.com. Ref 8, an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license(https://creativecommons.org/licenses/by/4.0/).

Metformin crosses the placenta, and the fetal concentrations are equal or higher than in the mother, but the resultant effects on the fetus are not completely understood. Regardless of the mechanism, metformin appears to cause both vitamin B12 and Folate deficiencies. These vitamins are critical to proper fetal development and more definitive work

needs to be done to focus more attention on these negative effects of metformin. Meanwhile, supplementation at higher doses is likely indicated in T2DM especially if they have been on or are currently taking metformin. Potential risks include increased risk of smaller birth weight and increased risk of childhood obesity which could increase the risk for metabolic disorders such as heart disease and diabetes in adulthood.

Treatment for Obesity

Metformin is not approved for weight loss in obese patients because the studies are inconsistent. It is not recommended for weight loss in obese patients unless there is another metabolic disorder present such as diabetes.

The Repurposing of Metformin

The current literature shows that there is resurgent interest in metformin. It appears to be a promising agent to treat diseases like cancer and dementia. Its promising research sprouts nearly as much excitement as the space industry’s newfound focus on going to the moon and Mars in search of answers to the most pressing issues of the 21st century. If metformin proves to provide answers to either of these diseases, the next step might be to formulate a drug or class of drugs that are similar to metformin and market them for these diseases and do so for a very large profit.

Evolving Mechanism(s) of Action of Metformin

Is metformin the wonder drug of the future? What is it about this drug that makes it a promising candidate for a variety of diseases? Here are some of the studies being done with metformin.

Cancer:

Very promising results have been demonstrated with metformin for its anti-tumor effects and its ability to provide immune system surveillance for cancer.

One example is a study of metformin as a co-therapy with chemotherapy in breast cancer treatment. Because of its effect on energy metabolism there was an improvement in the therapeutic rate of response.

As of August 2022, a clinical trial in Phase 3, is studying metformin vs placebo to determine whether metformin can prevent breast cancer. The trial includes 161 women who have a high risk for developing breast cancer. They either have “atypical hyperplasia” (tissue that is high risk for becoming cancerous) in the breast, or have a strong family history of breast cancer or be a known breast cancer (BRCA)1 or (BRCA)2 mutation carrier. The trial is due to be completed in August 2023. For further information visit the clinical trials website:

Anti-aging:

Metformin does not rise to the level of being called an anti-aging drug, but it is given credit for having the potential of being an anti-aging drug due to its cumulative life-extending effects. It is credited with an antioxidant effect, antihyperglycemic effect (lowers blood sugar), improved insulin sensitivity, improvement of vascular function, improved cellular energy and its ability to provide cancer surveillance.

Osteoarthritis:

Using metformin for osteoarthritis is probably a little easier to comprehend because of the similarities of risk factors between the two diseases. Common risk factors include age, obesity, oxidative stress, age related cellular dysfunction, and inflammation. For both osteoarthritis and type 2 diabetes, there is often poor nutrition and a lack of physical activity which contributes to obesity.

Obesity puts mechanical pressure on the weight bearing joints, causes misalignment of the joints and weakens the muscles. Obesity, or more specifically, fat tissue produces inflammatory substances, one being leptin which is associated with insulin resistance and T2DM. Leptin also causes inflammation that leads to degradation of cartilage. The inflammatory effect of osteoarthritis is exemplified by the fact that the disease also develops in the non-weight-bearing joints like the fingers and hands.

A study showed a decrease in cartilage loss over 4 years and a decreased risk for getting total knee replacement surgery after 6 years when metformin was taken with a cox-2-inhibitor (a select class of non-steroidal anti-inflammatory drugs that were introduced to decrease gastrointestinal effects) than with a cox-2 inhibitor alone. It is important to point out that other anti-diabetes medications were also able to exhibit similar benefits.

So there seems to be links between the causes of both diseases with the symptoms differing depending on where the causative factors occur in the body.

Metformin’s primary mechanism of action (stimulation of AMPK) is one of the keys to its ability to regulate glucose and fat metabolism, optimize cellular energy and decrease inflammation which is necessary in the management of both diseases.

Dementia:

One study actually compared metformin to other oral diabetes medications for their effects on memory. The difference seemed to be dependent on a) the drug used, b) the presence or absence of a diagnosis of Alzheimer’s Disease (AD) c) the existence of the APOE e4 carrier gene (high risk gene for AD). Metformin was associated with better immediate memory performance in people being treated for T2DM who had normal memory function which agrees with most other studies. But, metformin was less effective if AD was already present or if they had the carrier gene APOE e4 https://doi.org/10.1002/alz.12161 16 August 2020.

Another study aimed to determine if early intervention in T2DM patients made any significant difference as compared to those who were delayed treatment for 6 months. The conclusion was that lowering blood sugar was not the core reason that delayed the onset of dementia as there was no significant difference in the rate of onset under these set of circumstances. https://doi.org/10.1002/pds.5014.

Metformin has been added to the arsenal of drugs tried in the treatment of AD. There seems to be a range of actions that metformin can perpetrate that may have a role to play in impacting this disease–perhaps the reason for the sometimes-contradictory study results. It penetrates the brain and has an effect on blood sugar, insulin, energy, inflammation, and oxidative stress.

This long list of effects lines up more with one school of thought that thinks that AD may very well have many causes that require a broad spectrum approach to a cure.

Summary

The only FDA approved use for metformin is the treatment of Type 2 diabetes. There are several uses that have become commonplace over the years. Metformin is now being repurposed for other diseases such as cancer, Alzheimer’s disease, osteoarthritis, and aging. These areas are now being explored because of the evolution of our knowledge on how the drug seems to work on so many different levels.

Metformin’s primary mechanism of action involves activation of AMPK and inhibition of mTOR signaling in the mitochondria where it is transported by a carrier protein. However, there are additional mechanisms that work independent of AMPK that give metformin a broad set of potential applications.

It is important to know how metformin functions whether it be in treating T2DM, osteoarthritis, or any other disease. It is important to understand how the mechanism of action allows the drug to work.

Metformin takes a multitude of actions that :

• reduce gluconeogenesis (glucose production) in multiple ways

• reduce inflammation in multiple ways

• reduce fat production

• has an independent antioxidant effect

• may have a direct effect on ovarian tissue

• has multiple anti-tumor effects,

• reduce insulin resistance in skeletal muscles

• reduce insulin

• reduces hyperglycemia

• increase insulin sensitivity

• reduce AGEs

• increase autophagy (self eating) of cells

It is the wide range of both the direct and indirect effects of metformin that make it a potentially useful agent in a variety of illnesses. Knowing the facts about how metformin works can help in the development of successful treatment plans for various diseases whether they be for this drug, supplements or non-drug therapies. Taking steps to lower blood sugar, decrease inflammation and reduce oxidative stress, are ways to prevent and support both type 2 diabetes and osteoarthritis.

Understanding the processes that are involved in the drug actions of metformin or any drug can be useful in determining what actions can be undertaken to produce the same effects even if they are non-drug related. This is fundamental in developing and utilizing the concept of root cause treatment modalities in functional medicine.

REFERENCES

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