Drug Review: Metformin

metformin for type 2 diabetesMetformin is a major drug for treatment of type 2 diabetes.  In fact, it’s usually the first choice when a drug is needed. 

This review is quite limited—consult your physician or pharmacist for full details.  Remember that drug names vary by country and manufacturer.  Glucophage is a common brand name for metformin in the U.S. 

Class

Biquanide (it’s the only one in this class).

How does it work?

In short, metformin decreases glucose output by the liver.  The liver produces glucose (sugar) either by breaking down glycogen stored there or by manufacturing glucose from smaller molecules and atoms.  The liver then kicks the glucose into the bloodstream for use by other tissues.  Insulin inhibits this function of the liver, thereby keeping blood sugar levels from getting too high.  Metformin improves the effectiveness of insulin in suppressing sugar production.  In other words, it works  primarily by decreasing the liver’s production of glucose.

Physicians talk about metformin as an “insulin sensitizer,” primarily in the liver but also to a lesser extent in peripheral tissues such as fat tissue and muscle.  It doesn’t work without insulin in the body.

Metformin typically lowers fasting blood sugar by about 20% and hemoglobin A1c by 1.5% (absolute decrease, not relative).

When used as the sole diabetic medication, metformin is associated with decreased risk of death and heart attack, compared to therapy with sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, and meglitinides.

Not uncommonly, metformin leads to a bit of weight loss and improved cholesterol levels.  Insulin and sulfonylurea therapy, on the other hand, typically lead to weight gain of 8–10 pounds (4 kg) on average.

Usage

Metformin works by itself, but can also be used in combination with most of the other diabetic medications.  It’s usually taken 2–3 times daily.

Dose

Starting dose is typically 500 mg taken with the evening meal.  The dose can be increased every week or two.  If more than 500 mg/day is needed the second dose—500 mg—is usually given with breakfast.  Usual effective maximum dose is around 2,000 mg daily.

Side effects

Metallic taste, diarrhea, belly pain, loss of appetite.  Possible impaired absorption of vitamin B12, leading to anemia.  When used alone, it has very little risk of hypoglycemia.  Rare: lactic acidosis.

Don’t use metformin if you have . . .

Impaired kidney function (keep reading), congestive heart failure of a degree that requires drug therapy (this is debatable), active liver disease, chronic alcohol abuse.

Regarding impaired kidney function: don’t use metformin if your eGFR (estimated glomerular function rate) is under 30 ml/min/1.73 m squared), and use only with extreme caution if eGFR drops below 45 while using metformin. Don’t start metformin if eGFR is between 30 and 45. Your doctor can calculate your eGFR and should do so annually if you take metformin.

Steve Parker, M.D.

Updated April 10, 2016

5 Comments

Filed under Drugs for Diabetes

5 responses to “Drug Review: Metformin

  1. Good old metformin. Like a lot of drugs, it was originally tried for something else until someone noticed, hmmmm….the patient’s glucose seems to be going down. A lot of drug discovery relies on a prepared mind recognizing an opportunity, aka dumb luck.

  2. Isaac, you remind me of a favorite old aphorism:

    “Serendipity favors the prepared mind.”

  3. sujatha

    why the metformin is having only 50 to 60% bioavailability what is the reason fr that

  4. jim snell

    Attached is a latest Science news report on findings in Nature that talk about latest research on how metformin actually works:

    Most-Used Diabetes Drug Works in Different Way Than Previously Thought
    Jan. 6, 2013 — A team, led by senior author Morris J. Birnbaum, MD, PhD, the Willard and Rhoda Ware Professor of Medicine, with the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, found that the diabetes drug metformin works in a different way than previously understood. Their research in mice found that metformin suppresses the liver hormone glucagon’s ability to generate an important signaling molecule, pointing to new drug targets. The findings were published online this week in Nature.
    ________________________________________
    For fifty years, one of the few classes of therapeutics effective in reducing the overactive glucose production associated with diabetes has been the biguanides, which includes metformin, the most frequently prescribed drug for type 2 diabetes. The inability of insulin to keep liver glucose output in check is a major factor in the high blood sugar of type 2 diabetes and other diseases of insulin resistance.
    “Overall, metformin lowers blood glucose by decreasing liver production of glucose,” says Birnbaum. “But we didn’t really know how the drug accomplished that.”
    Imperfectly Understood
    Despite metformin’s success, its mechanism of action remained imperfectly understood. About a decade ago, researchers suggested that metformin reduces glucose synthesis by activating the enzyme AMPK. But this understanding was challenged by genetic experiments in 2010 by collaborators on the present Nature study. Coauthors Marc Foretz and Benoit Viollet from Inserm, CNRS, and Université Paris Descartes, Paris, found that the livers of mice without AMPK still responded to metformin, indicating that blood glucose levels were being controlled outside of the AMPK pathway.
    Taking another look at how glucose is regulated normally, the team knew that when there is no food intake and glucose decreases, glucagon is secreted from the pancreas to signal the liver to produce glucose. They then asked if metformin works by stopping the glucagon cascade.
    The Nature study describes a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. The team showed that metformin leads to the accumulation of AMP in mice, which inhibits an enzyme called adenylate cyclase, thereby reducing levels of cyclic AMP and protein kinase activity, eventually blocking glucagon-dependent glucose output from liver cells.
    From this new understanding of metformin’s action, Birnbaum and colleagues surmise that adenylate cyclase could be a new drug target by mimicking the way in which it is inhibited by metformin. This strategy would bypass metformin’s affect on a cell’s mitochondria to make energy, and possibility avoid the adverse side effects experienced by many people who take metformin, perhaps even working for those patients resistant to metformin.