Metformin in All its Glory – Part 1

Updated: Oct 7, 2022

Introduction

What you need to know:

WARNING: This medication has a BLACK BOX warning for lactic acidosis, a rare but potentially serious buildup of lactic acid in the blood. Symptoms include muscle pain, trouble breathing, dizziness, feeling weak or tired. This medication should not be used if you have serious kidney disease, metabolic acidosis or liver disease.

Side effects:

• See https://www.drugs.com/metformin.html#side-effects for a more complete list.

• Gastrointestinal side effects are the most common. About 20-30% of users can expect symptoms like stomach pain, abdominal cramping, nausea, vomiting, diarrhea, bloating, and gas. Take with food to minimize these affects. These symptoms can be intense and for some intolerable. If symptoms do not subside win two weeks, patients should report this to the prescriber for further assistance.

• metallic taste

• decreased appetite

• low blood sugar (more likely to occur when taken with other diabetes medications). Symptoms include excess sweating, extreme hunger, fainting, fatigue, shakiness, nausea or vomiting, anxiety, headache, dry mouth, confusion, blurred vision and lightheadedness. Immediately take some food or drink that contains sugar to alleviate these symptoms.

• Vitamin B12 depletion:

Loss of vitamin B12 is an often-overlooked consequence of taking metformin. At risk conditions (i.e. pregnancy, certain neurological disorders, and being over 75 years old) should be supplemented accordingly. In one study, the amount of B12 found in most multivitamin supplements was not effective in preventing Vitamin B 12 deficiency in people with T2DM that were taking metformin. If you’ve been on metformin for a while, have your provider check your B12 level. Low B12 can cause numbness/tingling in hands and feet, fatigue, palpitations, low energy, headache, muscle pain, red/swollen tongue, brain fog and cognitive decline.

Common signs of Vitamin B12 deficiency

Alcohol:

Alcohol use should be limited as it can increase the risk of developing lactic acidosis and hypoglycemia. Consult your provider before using alcohol.

Pregnancy:

• Metformin decreases the maternal weight gain that is seen with insulin use during pregnancy. One study showed that other outcomes improved (i.e., preeclampsia, hypoglycemia risk) but the results were not statistically significant.

• Metformin does cross the placenta and the levels found in the umbilical cord at delivery can be as high as that of the mother.

• There is a significant risk of lower birth weight in infants due to fetal growth restriction.

• Vitamin B12 and folate levels are lower in expecting mothers who take metformin

o Low levels of these vitamins have a significant impact on fetal growth and development as they are essential nutrients for these processes. Altered gene expression is one implication.

o Low folate can cause premature labor, stillbirth, and neural tube defects

o Supplementing with folate is already a requirement for prenatal care. When on metformin, a higher dosage may be necessary, however, levels should be checked to guard against overdosing.

• The effects of metformin vary depending on the tissue involved and tissue concentrations. For example, it can have a promising anti-tumor effect in one scenario and cause restricted fetal growth in another scenario.

Summary of Proposed Mechanism for metformin effects on placenta and fetus. Figure created using Biorender.com.

Ref 7, 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/).

Breastfeeding:

Metformin is absorbed in breast milk at less than 1% of the mother’s dose which is well within the established safe limit of 10%. No adverse effects have been found but use caution in newborns and pre-mature infants with poor kidney function.10.1007/s00125-002-0939-x

How does metformin work?

Common uses for metformin

Treatment:

• Diabetes

• Polycystic Ovarian Disease (PCOS)

• Gestational Diabetes (GDM)

• Prediabetes with high body mass index (BMI)

• Weight loss in obese patients

Prevention:

• Type 2 Diabetes

• Weight gain associated with atypical antipsychotics (a newer class of antipsychotics that causes less movement disorders as a side effect but tend to cause more weight gain)

Complications of type 2 diabetes:

People with T2DM, are 2 to 4 times as likely to have a heart attack or stroke that leads to death. T2DM is a disease of diet and lifestyle. In most instances the diet is too rich in simple carbohydrates, added sugars, and processed foods. This type of inflammatory diet damages the blood vessels leading to all organs producing very serious complications like:

• heart attack

• stroke

• blindness

• kidney disease

• nerve damage

• poor wound healing

• decreased sexual function

• cognitive decline

• Fatty liver disease

Metformin for Treatment of Diabetes

Metformin remains the first choice for the treatment of T2DM. The typical starting dose is 1000mg a day with food and then gradually increased until glucose is controlled. There is usually no benefit beyond 2000mg a day. It is recommended to be used in combination with diet and lifestyle to control symptoms and limit progression of the disease.

Benefits:

• On average, metformin, provides a 1-2% reduction in the HbA1c (average blood glucose over 3 months). According to Hirst et al, the lower dose range (1000-1500mg) will provide a 1.12% decrease in HbA1c. When increased to 2000mg an additional 0.26% reduction was achieved. When added to insulin therapy, the HbA1c was reduced 0.83%.

• It is taken by mouth, is inexpensive, does not cause weight gain and does not have the storage issues associated with insulin. It has less risk of causing low blood sugar compared to the older sulfonylurea drugs (i.e., glyburide, glipizide) and insulin.

• It can be used in combination with other diabetes medications. Preferentially, the added medication should be one that also targets any other co-existing diseases such as heart failure or kidney disease.

• Metformin does appear to offer some level of protection from cardiovascular events.

• It shows promise in improving cancer treatment modalities

• It decreases maternal weight gain during pregnancy as compared to insulin (however, there are risks to the fetus, see Pregnancy section)

Risks:

• The gastrointestinal effects can be severe enough to decrease appetite leading to weight loss.

• There are many other potential side effects, of which lactic acidosis is the most severe. Anyone with severely impaired kidney function should not use this medication. Any evidence of liver disease may warrant avoiding metformin as well due to a decreased ability to eliminate the lactic acid with liver impairment.

• Metformin has the potential for a large number of drug interactions. According to Drugs.com there are 355 drug interactions with metformin, 19 being major and 307 moderate, and 29 minor. Many are due to additive hypoglycemic effects.

• Development of vitamin B12 deficiency can lead to or aggravate nerve pain

• Low levels of B12 and folate could cause individuals with single nucleotide polymorphisms (SNPs) (gene variations) that involve folate or B12 to be at a greater risk for altered gene expressions.

• There is no data available which conclusively determined that metformin provides the level of cardiovascular protection that the newer anti-diabetic drugs offer.

Benefit vs Risk

Metformin is credited with preventing many of the complications associated with T2DM. It’s ease of use, cost-effectiveness and ability to lower blood sugar keep it at the top of the list of drugs to treat T2DM. Being able to provide cardio-protection is an important consideration in drug therapy for T2DM. As of 2008, manufacturers of new diabetes drugs (i.e., Trulicity*, Victoza*, Ozempic*) were required to show that these medications decreased the risk of Atherosclerotic Cardiovascular Disease (ASCVD) and not just blood sugar. Metformin was not a part of this process and that might put it at a disadvantage when it comes to choosing a drug therapy that meets these requirements.

However, consider the following by Ding Y, et al:

a) the atherosclerotic risk factors seen in patients with T2DM (hyperglycemia, high insulin, insulin resistance and elevated lipids) are what produce cardiovascular events

b) the ability to reduce hyperglycemia had the greatest impact on whether there was damage to the lining of the blood vessels.

c) hyperglycemia is linked to excessive inflammation and clot formation due to its direct effect on plaque destabilization and rupture.

Based on this information, one could infer that metformin provides cardio-protection.

Additional suggestions that metformin provides cardio-protection are:

• The Prospective Diabetes Study which reported that metformin not only treats hyperglycemia and lowers insulin but also reduces oxidative stress (cellular damage), inflammation, lipoprotein (LDL, HDL like substances) metabolism and clot production.

• A review that looked at over 11,000 patients on oral diabetes medications concluded that metformin offers moderate cardiovascular protection.

Taking care to intervene by drug therapy or lifestyle is critical to managing the potential risks for ASCVD. It is critical to get high risk patients into the safe zone as quickly as possible to minimize the risk of having a cardiovascular event.

Treatment or Cure?

Research and clinical data support the fact that diet and lifestyle are the most effective means to address the underlying causes of diabetes. It is the destructive inflammatory diets and lifestyles that produce these events.

In the current healthcare system, treatment means disease management. It does not mean cure. Herein lies the problem with the drug therapy approach to this disease. Patients are told that they will be on these drugs for the rest of their lives. Why is this the case? When drugs work to lower blood sugar, lower insulin resistance and decrease the risk for cardiovascular events, they only act like band-aids while the causative factors remain and continue to wreak havoc on the body.

Not all patients are willing to go the diet and lifestyle route to address the root cause of T2DM or would prefer to accept drug therapy alone. It should ultimately be their decision and that decision should be made with as much available information as possible on all available proven treatments.

*Registered trademarks

REFERENCES

1. Brand KMG, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diab Res Care 2022;10:e002363. doi:10.1136/ bmjdrc-2021-002363

2. Corcoran C, Jacobs TF. Metformin. [Updated 2022 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. A

3. Ding Y, Zhou Y, Ling P, Feng X, Luo S, Zheng X, Little PJ, Xu S, Weng J. Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function. Theranostics. 2021 Sep 9;11(19):9376-9396. doi: 10.7150/thno.64706. PMID: 34646376; PMCID: PMC8490502.

4. Hale TW, Kristensen JH, Hackett LP, Kohan R, Ilett KF. Transfer of metformin into human milk. Diabetologia. 2002 Nov;45(11):1509-14. doi: 10.1007/s00125-002-0939-x. Epub 2002 Sep 25. PMID: 12436333.

5. Hirst JA, Farmer AJ, Ali R, Roberts NW, Stevens RJ. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care. 2012 Feb;35(2):446-54. doi: 10.2337/dc11-1465. PMID: 22275444; PMCID: PMC3263873.

6. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. (2002) 346:393–403.

7. Owen MD, Baker BC, Scott EM, Forbes K. Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. Int J Mol Sci. 2021 May 28;22(11):5759. doi: 10.3390/ijms22115759. PMID: 34071182; PMCID: PMC8198407.

8. Tarry-Adkins, J.L., Ozanne, S.E. & Aiken, C.E. Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis. Sci Rep 11, 9240 (2021). https://doi.org/10.1038/s41598-021-88650-5

The Drugless Pharmacist

CEO, Nutritional Pathways Functional Wellness

DrET@druglesspharmacist.com