Side Effects of Metformin

Metformin ("Glucophage") has a broad array of possible side effects and implications for your health. Has your doctor discussed with you all of the possible problems associated with metformin?

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Did you know that 10%- 25% of women who take Glucophage just don't feel well?

They experience a general malaise, fatigue and occasional achiness that lasts for varying lengths of time. Malaise a warning signal for your doctor to closely monitor your body systems, including liver, kidneys, and GI tract.

GI Disturbance

About one third of women on metformin experience gastrointestinal disturbances, including nausea, occasional vomiting and loose, more frequent bowel movements, or diarrhea.

This problem occurs more often after meals rich in fats or sugars, so eating a healthier diet will help.

The symptoms lessen over time, so if you can tolerate the GI upset for a few weeks, it may go away. Some women have found it helps to start with a very low dose and gradually increase it.

Vitamin B12 Malabsorption

Most people think that aside from possible gastrointestinal upset, there are no side effects from taking metformin, and thus you can take it for a very long time. This is not true! The sneakiest side effect of all is a vitamin B12 insufficiency.

A substance formed in the stomach called "intrinsic factor" combines with B12 so that it can be transferred into the blood. Metformin interferes with the ability of your cells to absorb this intrinsic factor-vitamin B12 complex.(12)

Over the long term, vitamin B12 insufficiency is a significant health risk. B12 is essential to the proper growth and function of every cell in your body. It's required for synthesis of DNA and for many crucial biochemical functions. There is also a link between B12 insufficiency and cardiovascular disease.

According to some research, 10%-30% of patients show evidence of reduced vitamin B12 absorption. The Hospital de ClĂ­nicas de Porto Alegre in Brazil has shown that one of every three diabetics who takes metformin for at least a year have evidence of a vitamin B12 deficiency.

In other words, the longer you take metformin, the more likely it is that you will develop a vitamin B12 deficiency.

Long-term use of metformin also causes a decrease in folic acid (a B vitamin), and an increase in homocysteine, which in an undesirable metabolic substance if there is too much of it.

A deficiency in vitamin B12 and folic acid, and an excess of homocysteine, would be very detrimental to your developing baby if you are pregnant or trying to conceive.

At least one study raises the concern that even if metformin is withdrawn, the vitamin B12 malabsorption may continue in some people.

A simple solution to this problem is to take a high-quality multi-vitamin/mineral that contains substantial B12 and folic acid.

Women with PCOS who are vegans and who are taking metformin definitely need B12 supplementation because there is insufficient B12 in their diet.

At least one study raises the concern that even if metformin is withdrawn, the vitamin B12 malabsorption may continue in some people.(13) The apparent cause is continued problems with availability of intrinsic factor, which is required for B12 absorption.

Nervo M et al, Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil, Am J Clin Nutr. 2011 Mar;93(3):652-62
de Jager et al, Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial, BMJ. 2010 May 20;340:c2181
Ting RZ et al Risk factors of vitamin B(12) deficiency in patients receiving metformin, Arch Intern Med, 2006; 166(18): 1975-9

Elevated Homocysteine

People who take metformin tend to have higher homocysteine levels.(14) Women with PCOS also tend to have elevated homocysteine.(15)

Homocysteine is an amino acid in the blood. A normal amount is OK. But an elevated level means that your metabolic processes are not working properly.

Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia,(16) cognitive impairment.(17), and cervical cancer. (18)

Vitamin B12, along with vitamin B6 and folic acid (another B vitamin), is responsible for metabolizing homocysteine into less potentially harmful substances (19). Therefore, when metformin reduces absorption of vitamin B12, you lose one of the nutrients needed to reduce homocysteine and thus reduce your risk of cardiovascular disease.

Elevated Homocysteine and Pregnancy Complications

Pre-eclampsia is a complication of pregnancy characterized by increasing blood pressure and edema. If left untreated, pre-ecampsia can lead to eclampsia, a serious condition that puts you and your baby at risk. In a study conducted at the Center for Perinatal Studies at Swedish Medical Center in Seattle, a second trimester elevation of homocysteine was associated with a 3.2 fold increased risk of pre-eclampsia.(20)

The Dept. of Obstetrics and Gynecology, Nijmegen, The Netherlands, reviewed a series of studies on the linkage between elevated homocysteine and early pregnancy loss. They concluded that high homocysteine levels are a risk factor for recurrent early pregnancy loss.(21)

Ovarian follicular fluid contains detectable amounts of homocysteine along with B12, B6, and folic acid. The follicular fluid provides nourishment to the egg by facilitating transport of nutrients from blood plasma. High levels of homocysteine as well as an insufficiency of B vitamins may adversely influence the process of fertilization and early fetal development.(22)

NOTE: We are suggesting that elevated homocysteine, not metformin itself, could contribute to pregnancy complications in some women. However, metformin does contribute to increased homocysteine levels.

Pregnancy Warning

Many women use metformin in their pursuit of a successful pregnancy. However, Glucophage is a category B drug, meaning its safety for use while pregnant has not been established. It is found in breast milk so it's not advisable to breast feed while taking Glucophage.


By preventing optimal absorption of vitamins B12 and folic acid, metformin could induce or contribute to megaloblastic anemia.(23) Megaloblastic anemia occurs when your bone marrow doesn't have enough B vitamins to manufacture red blood cells. Your bone marrow then releases immature and dysfunctional red blood cells into circulation.

Although anemia is not common among people taking metformin, it remains a risk for those whose B12 and folic acid levels were already low when metformin therapy was started.

Liver or Kidney Problems

If you have liver or kidney problems of any kind, metformin could pose a problem, because it alters liver function and is excreted through the kidneys. A healthy liver and kidneys will improve your outcome with metformin. Liver and kidney function should be assessed before starting metformin and rechecked at least once a year while taking it. A blood chemistry screen and a complete blood count will tell your physician how well your system is doing with this drug.

Multiple Medications

You may be at risk for health problems or symptoms if you take metformin in addition to other medications. The more drugs you take, and the higher the dosage, the greater the probability there will be some kind of interaction between the drugs or some unexpected effect from the combined drugs. The effect of combined drugs also depends on the state of your health, your genetic uniqueness, and your diet and lifestyle. Always consult with your doctor if you add or change any medication, or if you develop any symptoms.

Hair Loss

Female hair loss is a big problem for women who have PCOS, or who have androgenetic alopecia.

Metformin may contribute to male pattern hair loss at the temples and top of head. Although there's nothing in the medical literature to support this linkage, some women have reported that hair loss was made worse by metformin.(24)

Lactic Acidosis

About 3 of every 100,000 people who take metformin will develop a medical emergency called "lactic acidosis". Lactic acid is a metabolic byproduct that can become toxic if it builds up faster than it is neutralized. Lactic acidosis is most likely to occur in people who with diabetes, kidney or liver disease, multiple medications, dehydration, or severe chronic stress.

Lactic acidosis can gradually build up. Symptoms to watch for include a need to breathe deeply and more rapidly, a slow, irregular pulse, a feeling of weakness, muscle pain, sleepiness, and a sense of feeling very sick. Treatment requires intravenous administration of sodium bicarbonate. Contact your doctor or go immediately to a hospital emergency room if you have these symptoms.

Bile Abnormalities

Bile is produced by the liver, stored in the gallbladder, and secreted into the intestines in order to absorb fats into the bloodstream. One possible reason for the GI problems is that metformin reduces normal reabsorption of bile from the intestines back into the bloodstream, which causes elevated bile salt concentrations in the colon.(25) Most studies suggest that colonic bile salts cause free radical damage to DNA and may contribute to colon cancer.(26,27)

In addition, bile acids may stimulate cells in the colon to produce leukotriene B4 (LTB4), a highly inflammatory substance. LTB4 would be a contributor to any intestinal inflammatory condition.(28) Byproducts of bacterial action on bile salts may lead to intestinal cell damage and absorption of "foreign" molecules such as food or bacteria particles into the bloodstream, possibly causing allergies and other immune responses.(29)

Moreover, many PCOS women have switched to a high-protein diet. If that protein consists of beef and other meats, bile acid concentration in the intestines is increased.(30)   A diet high in meats is also linked to a higher risk of colon cancer.

Consult with Your Physician to Minimize Risk

If you think you may have symptoms of PCOS, your physician should always do a thorough medical history and metabolic assessment before putting you on metformin. Not everyone who has PCOS will need this drug.

You should be re-checked at least once a year for as long as you take this drug. Long-term use runs the risk of developing a vitamin B12 deficiency.

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