Metformin side effects, use for diabetes treatment, dosage
November 19 2018 by
Ray Sahelian, M.D.

Metformin is a drug used to treat type 2 diabetes mellitus. With this type of diabetes, insulin produced by the pancreas is not able to get sugar into the cells of the body where it can work properly. Using metformin alone, with a type of oral antidiabetic medicine called a sulfonylurea, or with insulin will help to lower blood sugar when it is too high and help restore the way you use food to make energy. Many people can control type 2 diabetes with diet alone or diet and exercise. Following a specially planned diet and exercising will always be important when you have diabetes, even when you are taking medicines. To work properly, the amount of metformin you take must be balanced against the amount and type of food you eat and the amount of exercise you do. If you change your diet, your exercise, or both, you will want to test your blood sugar to find out if it is too low. Your health care professional will teach you what to do if this happens. At some point, metformin may stop working as well and your blood glucose will increase. You will need to know if this happens and what to do. Instead of taking more metformin, your doctor may want you to change to another antidiabetic medicine. If that does not lower your blood sugar, your doctor may have you stop taking the medicine and begin receiving insulin injections instead.
   Metformin does not help patients who have insulin-dependent or type 1 diabetes because they cannot produce insulin from their pancreas gland. Their blood glucose is best controlled by insulin injections. Metformin is available only with your doctor's prescription.

Adverse reactions, negative outcomes, toxicity
Bad smell and nausea as side effect
The commonly used diabetes drug metformin stinks, literally, and this may explain why many patients stop taking it. The drug smells like fish or dirty socks to some people and this could account for the well-known side effects of the drug, which can make people nauseated. But the problem could be solved by coating the pills so they do not smell or release the odor into the stomach, where it can be burped up. Annals of Internal Medicine, 2010.

A recommendation from the American Diabetes Association suggests that metformin not be used in patients with heart failure.

Medications can play a part in the makeup of your gut bacteria. Antibiotics, the diabetes drug metformin and antacids can cut down on gut bacterial diversity.

Vitamin B12 deficiency
Although treatment with the anti-diabetes drug metformin has improved the prognosis of some adults with type 2 diabetes, it appears to be associated with an increased risk of vitamin B12 deficiency. Lack of vitamin B12, if unrecognized, causes nervous system damage. Dr. Kai Ming Chow of the Chinese University of Hong Kong and colleagues conducted a case-control study involving 155 patients with diabetes and metformin -related vitamin B12 deficiency. Another 310 similar patients who did not have low vitamin B12 while taking metformin acted as controls. After adjustment for many potential confounders, the risk of vitamin B12 deficiency increased with current dose and duration of metformin. Each 1-gram daily increment in the dose of metformin added a twofold risk for developing vitamin B12 deficiency. Archives of Internal Medicine October 9, 2006.

Patients treated over long periods with metformin, a common drug for diabetes, are at risk of developing vitamin B12 deficiency which is also likely to get worse over time. BMJ, 2010.

Rev Med Chir Soc Med Nat Iasi. 2013. Metformin induced lactic acidosis--particularities and course. A rare but serious side effect of biguanides is lactic acidosis. This paper presents a number of 13 cases of metformin-associated lactic acidosis, which outline the circumstances triggering the adverse event and the clinical therapeutic measures applied in the poisoned patients. The main situations that favor metformin-associated lactic acidosis are renal impairment and tissue hypoxia, and the intervention is adapted to the particular patient condition and symptoms, such as marked hypotension and cardiac arrest. Although there are commonalities in describing the consulted patients, the final prognosis is not dependent on the dose or metformin plasma levels, but rather on the associated pathologies and medication.

Long-term metformin therapy increases the probability of vitamin B12 and folate deficiency, and might contribute to the progression of diabetic peripheral neuropathy. Med Hypotheses. 2013. Adverse effect of metformin therapy on serum vitamin B12 and folate: Short-term treatment causes disadvantages?

Rev Med Chir Soc Med Nat Iasi. 2016. LOW LEVELS OF SERUM CYANOCOBALAMIN IN A METFORMIN-TREATED PATIENT. CASE REPORT AND COMPARISON with literature data. Metformin is a widely used oral antidiabetic biguanide compound. According to the literature, metformin may lower the serum cyanocobalamin levels. We present the case of a 71-old-male treated with metformin for 15 years. When presenting to a periodic checkup, low serum cyanocobalamin levels where found. Laboratory tests showed levels below normal range for hemoglobin (12.7 g/dL) and hematocrit (37.8%). After patient reevaluation, a change in antidiabetic treatment will be considered if metformin will be found the cause of low serum cyanocobalamin levels. Other cases reported in the literature support this hypothesis, justifying the study of the influence of metformin therapy on serum vitamin B12 levels in patients diagnosed with diabetes.

Advances in Nutrition, 2018. Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications. There is clear evidence that proton-pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), and metformin can reduce serum vitamin B-12 concentrations by inhibiting the absorption of the vitamin.

Thyroid problems
Metformin, a drug commonly used to treat diabetes, may raise the risk of low levels of thyroid-stimulating hormone (TSH) among patients with an underactive thyroid, CMAJ (Canadian Medical Association Journal), news release, 2014.

Use in young adults
Metformin can induce long-term weight loss in obese, non-diabetic adolescents, and could possibly be useful in a regimen to help achieve weight loss in adolescents, who may have developed type 2 diabetes type due to overweight, according to a study presented at the Endocrine Society's 88th Annual Meeting (ENDO 2006). Previous studies have shown that short-term metformin therapy is associated with weight loss, however, whether such weight loss persists over time was undetermined. Metformin is also known to improve glucose, lipid abnormalities, and hyperandrogenism in obese adolescents with insulin resistance. Researchers from the Endocrine Clinic at St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, United States, conducted a chart review of 26 adolescents who were obese but did not have diabetes, and who were followed at the Endocrine Clinic. Obesity was defined as body mass index over 95th percentile. Fourteen of the 26 had received metformin (1000 mg/day) for 12 months due to abnormal high-density lipoprotein (HDL) cholesterol level, triglycerides (TG) level, fasting insulin level or oligo/amenorrhea. In the treated group, metformin significantly reduced the BMI baseline score at 6 and 12 months. There was no significant change in the BMI scores of the untreated group. When comparing the treated and untreated groups, changes in BMI baseline score were different both at 6 and 12 months. After 12 months of metformin, the mean values of homeostasis model assessment and TG were lower than at baseline, while HDL cholesterol was higher; however, none of these changes reached statistical significance, possibly due to the small sample size. According to lead investigator, Dorit Koren, MD, a general pediatrician, the effect of metformin on weight further supports the indication for its use in obese adolescents with insulin resistance. A prospective study conducted in a larger population sample is warranted.
     Dr. Sahelian says: I am uncomfortable starting a drug in teenagers who may need to take it for prolonged periods. There are many instances where we find out later that the regular use of a 'safe' drug leads to potential long term side effects. I think diet and exercise are not pushed enough first before resorting to drug use.

Precocious Puberty
Treatment with metformin can help delay the onset of puberty in girls with precocious pubarche, defined as pubic hair first appearing at younger than 8 years of age.

Meformin and arterial stiffness
Increase in adiponectin level after treatment with the insulin sensitizers pioglitazone and metformin may improve arterial stiffness in patients with type 2 diabetes mellitus.

Acta Physiol (Oxford). 2015. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium.

Effect on cancer rates
Women who have used the diabetes drug metformin for more than five years may have a lower risk of breast cancer than diabetic women on other treatments. The possible beneficial effect of the drug was, however, based on a small number of women. Only 17 women had used metformin for more than five years and had a diagnosis of breast cancer. Moreover, the design of the study precludes any conclusions about cause-and-effect, note the researchers, led by Dr. Christoph R. Meier of the University Hospital Basel in Switzerland. Dr. Christoph R. Meier had the study published in Diabetes Care, online March 18, 2010.

Metformin for Diabetes Prevention
In a large study, individuals who adhered to a metformin -based diabetes preventive strategy had a reduced risk of developing diabetes. The Diabetes Prevention Program (DPP) investigated the value of intensive lifestyle intervention (diet and exercise) or metformin in delaying or preventing type 2 diabetes in high-risk individuals with impaired glucose tolerance, a precursor to full-blown diabetes. Dr. Elizabeth A. Walker, of George Washington University, Rockville, Maryland, and colleagues examined medication adherence and health outcomes in the metformin and placebo arms of the DPP. A total of 2155 subjects who were randomly assigned to either the metformin or placebo treatment arms were included in the analysis. The overall adherence rates -- that is, the proportion of patients taking at least 80 percent of the prescribed dose -- were 71 percent in the metformin group and 77 percent in the placebo group. Compared to patients who were adherent to placebo, those adherent to metformin had a 38 percent reduced risk of developing diabetes, the investigators report. Walker's team finds that the most commonly reported barriers to taking the medication as prescribed were forgetting to take doses (22 percent), adverse effects (8 percent), and disruption of routines (8 percent). Overall, 15 percent of women and 10 percent of men reported adverse effects in the metformin group. Diabetes Care, 2006.
     Dr. Sahelian comments: I wonder if natural options for diabetes care would provide just as good or better benefits than metformin with fewer side effects.

Interactions with medications

Interactions with dietary supplements
I read with great interest your section on Inositol. I have been treated for PCOS for around 10 years and have been taking 2000mg a day metformin and would like to begin taking inositol now that I've read on your website that it has been used in treatment of PCOS. Have there been any contraindications of using both metformin and inositol. If inositrol affectively lowers blood sugar I'm wondering if it would necessitate lowering the medication dosage as a result. Many thanks in advance for your information.
    I have not seen any research regarding the combination of the nutritional supplement and the medication. However, as a general rule, when introducing a new product or supplement to one's already existing regimen, it is a good idea to begin with low dosages.

I had been on metformin for about 3 months. Prior to that, I was in Italy doing a great deal of walking. Due to severe arthritis in my feet, I was taking some medrol packs to reduce the pain. Upon return, I had my A1C checked. (An earlier A1C test had resulted in a reading of 6.1, and a fasting blood glucose level of slightly over 120. I was considered pre-diabetic. I have a significant family history of type 2 diabetes and am 60 years old.) My returning A1C was about 8.5 with a high blood glucose level. I started metformin, and with some exercise, had my A1c at 6.2 and fasting blood glucose level at <100 in three months. After a short time on Januvia, probably just enough to build up the proper level in my blood, I began having severe flu-like symptoms, disorientation and lightheadedness. It did not seem to affect my glucose level as monitored by me any better than metformin alone. Within a week, I was forced to stop Januvia due to the debilitating effects. I had become very cautious about driving due to a “spacey” feeling I experienced and one glass of red wine made the symptoms intolerable. This is just an FYI that you may wish to use with your patients. I’m going back to my standard of waiting until a drug has been on the market for several years before trying it. It seems that for me, metformin and exercise is all that I need at this point. By the way, I was 220 lbs when diagnosed and I am now 195 and still dropping through diet and exercise and metformin.

Q. You wrote: At some point, metformin may stop working as well and your blood glucose will increase. Well, it seems that's what's happening to me and 4 other friends and acquaintances. I have been on 2000 mg, taken at night, in order to reduce my fasting glucose in the morning, which used to be between 150 to 350 before taking the before-bedtime metformin. Been on it since 2005. Now, in 2018, however, it is having NO effect on my blood glucose, plus the hellish itching it causes. The additional problem I am facing is that if I DO take metformin, then my whole body from scalp to bottom of my feet itches horribly. So, I have stopped taking it and am relying on powders of: bitter melon berberine amla (an indian thing) which do help, albeit, they are not able to take my glucose level to near 70 or 80. Best I can accomplish with these powders is 108 mg/dl.