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Toxicology Rounds

A Non-Diabetic with Lactic Acidosis? Ask about Metformin Anyway

Gussow, Leon MD

doi: 10.1097/01.EEM.0000578596.62981.b5
Toxicology Rounds

Figure

Figure

Metformin is not just for diabetes anymore. The drug is now the star of an uncontrolled spontaneous experiment on what happens when non-diabetics take it.

A psychiatrist in Los Angeles told me that “everyone” in Hollywood is taking metformin to lose weight, improve health, and increase longevity. Evidently, this practice is also prevalent in the Silicon Valley tech community and even among some clinical specialists in aging at major medical schools.

Metformin (Glucophage) is by far the most frequently used oral antihyperglycemic agent for type 2 diabetes mellitus, and is the eighth most commonly prescribed drug in the United States. (Diabetologia. 2017;60[9]:1561; http://bit.ly/2Rb7yA9.)

The drug is a biguanide derived from Galega officinalis, a legume also called goat's rue, French lilac, and Professor Weed. The plant has been employed to treat diabetes at least since 1772 when the English botanist and apothecary Sir John Hill used it in patients to reduce symptoms of increased thirst and frequent urination, common early manifestations of diabetes mellitus. (Diabetologia. 2017;60[9]:1566; http://bit.ly/2R7rWC8.)

Table

Table

Metformin is considered relatively safe. Its major side effects are nausea, diarrhea, abdominal pain, bloating, and anorexia. These often resolve over time or when the dose is reduced. Unlike many other antihyperglycemic agents, metformin does not generally cause hypoglycemia or weight gain, but everyone fears the dreaded adverse albeit rare effect of metformin-associated lactic acidosis.

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Good News for Mice

The use of metformin by non-diabetics stems from some evidence that metformin can decrease inflammation, protect against cardiovascular disease and cognitive impairment, minimize cancer risk and progression, and prolong life. Much of this evidence is good news if you're a mouse or a hamster but of uncertain import for humans.

A retrospective observational study of nearly 200,000 patients seemed to indicate that type 2 diabetics treated with metformin not only lived longer than those treated with sulfonylurea but also outlived non-diabetic matched controls. (Diabetes Obes Metab. 2014;16[11]:1165; http://bit.ly/2Rb8Ued.) Of course, association is not causation, and a zillion possible confounders could have skewed the results. Things may become clearer if the randomized prospective placebo-controlled study—the Targeting Aging with Metformin (TAME) trial—is completed. That project intends to enroll thousands of subjects to determine whether metformin delays or prevents the progression of chronic ailments of aging such as heart disease, cancer, and dementia. Results of this study will not be available for at least three years.

Emergency physicians should be aware that many people are experimenting with metformin off-label at who knows what doses. Any patient with unexplained lactic acidosis should be asked specifically about metformin even if non-diabetic.

Metformin has many beneficial metabolic effects in patients with type 2 diabetes. (See table.) It decreases insulin resistance, and interrupts its cycle of increased insulin release followed by still greater insulin resistance. That cycle is a key feature in the development and progression of type 2 diabetes. It is still not clear if these effects will also be seen in non-diabetics who take the drug or how they may affect general health.

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Pharmacologic Features

Metformin is not metabolized and is eliminated unchanged in the urine. Roughly 20 percent is filtered at the glomerulus, and the rest undergoes tubular secretion. Acute or chronic renal failure can produce increased metformin levels and lead to metformin-associated lactic acidosis.

Metformin is a small molecule that does not bind to plasma proteins, and it is susceptible to removal by hemodialysis even though it has a somewhat large volume of distribution. It is distributed peripherally to most tissues, especially the liver, kidney, and intestinal wall. Hemodialysis will help reduce the drug burden and correct acidosis in cases of known or suspected metformin-associated lactic acidosis.

A number of combination drugs include metformin with another anti-diabetic agent. Often these drugs will include “met” in the proprietary name, like Avandamet, Metaglip, ActoPlus Met, and Janumet.

The most feared adverse effect of metformin therapy is its associated lactic acidosis. This complication has a mortality rate of 30-50 percent, but is actually quite rare. The estimated incidence is approximately three cases per 100,000 patient-years. (N Engl J Med 1996;334[9]:574.)

The entire concept of metformin-associated lactic acidosis is complicated and murky. Some note that what's really important is actually metformin-induced lactic acidosis; others say it does not exist (they are wrong).

Next month: Metformin's clinical implications.

Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog atwww.thepoisonreview.com, follow him on Twitter @poisonreview, and read his past columns athttp://bit.ly/EMN-ToxRounds.

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