Metformin: What You Should Know About Side Effects and More

A registered pharmacist explains how this diabetes medication super hero works in the body.

metformin pill containerMetformin has been the standard of care for people with type 2 diabetes since its approval in 1994 thanks to its impressive safety profile, low cost and having weight loss as a side effect. (Photo: 123rf)

What Is Metformin?

Metformin is one of the oldest and most widely used-oral medications indicated for the treatment of  type 2 diabetes, to be taken in conjunction with diet and exercise.

To give you an idea of the widespread use of this drug in 2014, 14.4 million patients received a  prescription for it in the US. Metformin is in the class of drugs known as a biguanides and has been available in the US since receiving approval in 1994. This commonly-prescribed medication helps your body control the amount of glucose in the blood stream and use its own insulin more effectively.

It has been part of the standard of care for type 2 diabetes for more than two decades in part becaue of its impressive safety profile, low price point, and the fact that many patients actually experience weight loss while taking this medication. 

How It Works

Metformin works by decreasing the output of sugar from the liver (sugar is stored in the liver in the from of glycogen) as it simultaneously decreases the intestinal absorption of glucose. This unique action results in increased insulin sensitivity. 

Another advantage of metformin is that it works well in tandem with many other medications to manage diabetes. For example, when it's paired with a sulfonylurea such as gilipizide, it can enhance the glucose-lowering effect of the glipizde. Sulfonylureas work by increasing insulin output by the pancreas. The FDA has formally approved metformin for use with a wide category of other medications for diabetes such as insulin, DPP-4 inhibitors (Januvia, Onglyza,and others) and GLP-i analogs such as Byetta, Bydueon, and Victoza.

Metformin has also been combined with other medications that are taken together as one pill—Janumet is metformin combined with Januvia. Although these newer combination products can make it easier to take, the medications tend to be costly. Metformin alone is a generic product and inexpensive.

What Are The Side Effects?

All medications have potential side effects. Metformin most commonly impacts the gastrointestinal (GI) tract causing abdominal pain, bloating, nausea or diarrhea. Many patients do not experience any of these side effects, however. Using the sustained-release formulation of metformin generally results in fewer side effects. 

Metformin can be prescribed in a number of ways. A sustained-release formulation is taken one to two times a day; a regular-release formulation is taken 2 to 4 times a day. The drug is not recommended for patients under 10 years of age or pregnant women (although it is sometimes prescribed “off label” during pregnancy).

To help mitigate the potential for nausea and other GI side effects, healthcare providers generally start their type 2 patients with a dose of 500 mg once or twice daily always taken with food/meals. If you do experience GI symptoms, they will likely decrease over time.

Lactic acidosis is a rare but potentially dangerous side effect of metformin caused by a buildup of lactic acid in the body. This happens because the drug can potentially decrease the liver's uptake of lactate.

Risk factors for developing this rare side effect include kidney disease, liver disease, being over the age of 65, heart failure, excessive alcohol consumption, and the use of other medications.

Another potential risk of taking metformin is a vitamin B12 deficiency which can cause weakness and fatigue. (Vitamin B12 helps the body make red blood cells which assist in moving oxygen through the body—lack of oxygen results in fatigue.) The risk of this deficiency increases with age, the dose you take, the length of time you are on the medication, and how much B12 you consume as part of a healthy diet. Dietary sources of B12 include eggs, low-fat dairy, beef, chicken and liver.

But there's good news, too. One of the most welcome side effects of metformin is weight loss. Although weight loss will likely be modest—typically no more than 5% of person's weight before taking the drug— this can be enough to kick start the weight-loss process and encourage healthier eating.

Important Precautions

Impaired kidney function has remained one of the biggest precautions of taking metformin to avoid the lactic acid buildup that may result from inadequate elimination of this drug. Recently after reviewing several clinical studies, the FDA has changed the labeling on metformin, allowing expanded use in some patients with an eGFR (estimated glomerular filtration rate), a measure of kidney function. 

Drinking alcohol can cause low blood sugar or hypoglycemia while taking metformin so caution is advised when consuming alcoholic beverages. Alcohol also increases the risk of lactic acidosis.

Metformin should never be taken if there is evidence or concern about the presence of liver impairment or disease.

Promising Off-Label Uses of Metformin

As a pharmacist, I see medications being used “off label” quite often. This means that although the FDA has not yet given its blessing to use a drug in circumstances for which it was not originally intended.

Studies are often conducted to determine other possible applications for all kind of drugs. Latisse, for example, received FDA approval in 2011 for cosmetic use—eyelash lengthening and thickening—when  those effects were discovered during treatment for glaucoma with a drug called Lumigan. (Lumigan and Latisse share the same active ingredient.) 

As a consumer of medications, this practice may seem confusing, but as a pharmacist I see compelling evidence all the time for medications to be used effectively for conditions other than which they were originally intended.

The FDA does not condemn this practice as long as the provider finds a drug appropriate for a different patient population based on some evidence—including current studies—or having no better alternatives to treat a patient effectively.

Given the excellent safety profile of metformin, and it’s unique double-action mechanism (described above), it has also been used to treat polycystic ovarian syndrome (PCOS), diabetes in pregnancy (known as gestational diabetes), and most recently as an adjunct therapy to treat patients with type 1 diabetes.

The REMOVAL study, a large and well-respected clinical study that looked at the use of metformin in patients with type 1 diabetes suggested the drug may reduce the risk of cardiovascular disease in that population as well.

The Juvenile Diabetes Research Foundation (JDRF) recently invested 2.8 million dollars in a research grant to study metformin use in overweight adolescents with type 1 diabetes.

Finally,  metformin was also found to be beneficial in patients with prediabetes during the course of the ongoing DPP (Diabetes Prevention Program) funded through the National Institutes of Health (NIH) however this preventative usage is still considered “off label.”

Other ongoing research suggest that metformin may have anti-inflammatory effects that could impact everything from the aging process to the prevention of certain types of cancer.

I am certain we have not seen the last of the potential for this super hero among diabetes medications. To be continued …..

Updated on: June 3, 2019
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