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Side Effects — Good, Bad, and Neutral

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SUPPLEMENTARY CONTENT

Metformin’s job is to lower your blood glucose. But like all complex and imperfectly understood drugs, it has some side effects.

STOMACH IRRITATION, DIARRHEA
When starting metformin, around a third of people suffer some degree of stomach irritation, which usually resolves quickly. Only 3% to 10% of people in clinical trials experience symptoms severe enough that they stop taking the drug. Higher doses tend to cause more irritation, at least when comparing 500 milligrams (mg) to higher doses. Little difference is seen between doses of 1,000 mg and 2,500 mg.

Causes. Not fully established. The leading theory is that metformin slows the rate of bile salt reabsorption in the intestines, which in turn could disturb the activity of bacteria in the colon.

Solution. Start low and go slow. When starting metformin, most people do well with starting with 500 mg at night or with dinner, and staying at this dose for a full week. At that point, a second 500-mg pill can be added in the morning. After another week, a third pill can be added to the evening dose. After one more week, a fourth pill can be added to the morning dose, so that by the end of the month, the full daily dose of 2,000 mg is being taken.

People who experience chronic irritation on a full dose may still benefit from a partial dose of metformin, and people with chronic irritation who started on a full dose can sometimes eliminate this irritation by cutting back and slowly building back up to a full dose.

Alternate solution. Switch to the extended-release (XR) version of metformin, which is tolerated better by most people.

CARDIOVASCULAR PROTECTION
The UK Prospective Diabetes Study (UKPDS) revealed that taking metformin reduces the risk of heart attack by 39% compared with other blood-glucose-lowering drugs. For this reason, metformin is often continued even after it no longer adequately controls blood glucose by itself. Another drug or drugs are then “layered” on top of metformin to achieve blood glucose control.

Causes. Not entirely clear, but the leading theories are that metformin reduces oxidative stress, reduces hardening of the arteries, improves endothelial function (functioning of cells lining the blood vessels), or any combination of the above.

Solution. None needed, other than continuing to take metformin, even as other drugs are added to your diabetes control regimen.

CONTRAST DYE ISSUES
For imaging studies that require contrast dye, it’s highly recommended that metformin be temporarily discontinued.

Why. Metformin is cleared from the body by the kidneys, as are contrast dyes. When the two are combined, they carry a theoretical risk of kidney damage from overload. In addition, toxic levels of metformin can build up in the blood due to short-term reduced kidney function from the contrast dye, increasing the risk of lactic acidosis (an emergency situation in which the blood becomes acidic).

Solution. Stop taking metformin either before or at the time of the imaging study, and take no doses for at least 48 hours afterward, while the contrast dye is being cleared from the bloodstream.

VITAMIN B12 DEFICIENCY
Vitamin B12 deficiency is seen in about 5% of all people who take metformin, which is about double the rate seen in people who do not take the drug. However, the risk of B12 deficiency seems to increase the longer someone takes metformin, with as many as 30% of people who have taken the drug for at least 10–12 years showing some level of deficiency.

Causes. Unknown.

Solution. Studies to investigate how much B12 supplementation is needed are ongoing. For the time being, some doctors recommend an annual B12 shot, while others prefer monthly oral supplements.

APPEARANCE OF INTACT CAPSULE IN STOOL
This side effect only occurs when using the extended-release version. In this version, metformin diffuses through the capsule that contains the drug, and in many people the empty shell is not digested, passing apparently intact through the digestive tract. However, even though the pill appears intact, it’s just an empty husk; the medicine has been absorbed.

Causes. It’s unknown why the shell is digested in some people but not in others.

Solution. Ignore it.

INCREASED FERTILITY IN WOMEN
Fertility in women who take metformin can increase as much as fourfold.

Causes. Unknown.

Solution. Start or continue birth-control measures, or plan a visit to the maternity ward.

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