Combining Diabetes Drugs With Certain Antibiotics May Cause Dangerous Drops in Blood Sugar Levels

A study published in October revealed that older patients taking one of two commonly used oral diabetes drugs known as sulfonylureas — glipizide (GLUCOTROL, GLUCOTROL XL) or glyburide (DIABETA, GLUCOVANCE, GLYNASE) — in combination with one of five antibiotics have an increased risk of developing dangerously low blood sugar levels, a condition called hypoglycemia.[1]

Serious hypoglycemic episodes associated with diabetes treatment represent a significant and growing problem in the U.S., particularly in older patients. Avoiding drug combinations that can cause this potentially life-threatening adverse reaction must be a key component of diabetes management.

Diabetes drugs and hypoglycemia

Hypoglycemia is a well-recognized adverse effect of many drugs used to treat Type 2 diabetes. It is particularly common in patients treated with insulin or sulfonylurea medications.

Hypoglycemic episodes typically develop suddenly. Symptoms include nervousness, trembling, weakness, sweating, intense hunger, palpitations (a fluttering sensation in the chest due to a rapid or irregular heart rate) and disorientation. In the most severe cases, patients can lose consciousness.

Patients are more likely to develop hypoglycemia if they are older, have had diabetes for a long time, have kidney damage, use more than one diabetes drug, engage in intensive glucose control efforts, or have problems with memory or other cognitive functions.[2]

Severe hypoglycemia in older patients is associated with increased risk of major adverse cardiovascular events (such as heart attacks and strokes),[3] cognitive impairment,[4] dementia[5] and death.[6]

A study published in The New England Journal of Medicine in 2011 estimated that each year from 2007 through 2009, approximately 100,000 adults age 65 or older were urgently hospitalized in the U.S. for adverse drug reactions.[7] Insulin was implicated as the cause of the adverse event in 14 percent of these emergency hospitalizations, and an oral diabetes drug was implicated in 11 percent.[8] Of those hospitalizations related to diabetes drugs, nearly all (95 percent) involved hypoglycemia.[9]

A study in the July issue of JAMA Internal Medicine reported that from 1999 to 2011, approximately 400,000 Medicare beneficiaries with diabetes were hospitalized for hypoglycemia.[10] The annual rate of such hospitalizations increased 38 percent by 2007, and even with a subsequent decline, the 2011 rate was 12 percent higher than the 1999 rate.[11]

In contrast, during this same time period, the rate of hospitalizations for dangerously high levels of blood glucose decreased by almost 40 percent.[12] Notably, the rate of hospitalizations for low blood glucose levels has exceeded the rate of hospitalizations for high blood sugar levels since 2001.[13] These trends are likely due to more — perhaps overly — aggressive treatment of diabetes in older patients. The evidence suggests that efforts to maximize blood sugar control in older patients, in an attempt to prevent complications of diabetes such as vascular, kidney and eye disease, may come at the cost of significant drug-induced injury.

The antibiotic study[14]

For the most recent study on hypoglycemia in older patients taking sulfonylurea medications — published in October in JAMA Internal Medicine — researchers at the University of Texas Medical Branch at Galveston analyzed the prescription drug records and medical claims data from 2006 to 2009 for Texas Medicare beneficiaries ages 66 and older.

The researchers identified all patients who were prescribed either glipizide (approximately 31,000 patients) or glyburide (approximately 30,000 patients) and who were also prescribed one of the 16 most frequently prescribed antibiotics during the four-year study period.

For seven of these antibiotics, listed in the table below, there already was evidence suggesting that taking them with sulfonylureas either increased blood levels of or enhanced the action of the diabetes drugs, plausibly exposing patients to a greater risk of hypoglycemia. For the other nine antibiotics, there was no evidence of interactions with sulfonylureas and no plausible link to hypoglycemia.

Antibiotics Suspected of Interacting With Sulfonylureas

*Found to increase risk of serious hypoglycemic reactions in patients taking glipizide or glyburide in the September JAMA Internal Medicine study.
**Combination medication containing other active ingredients.

For each of the 16 antibiotics, the researchers calculated the rate of emergency room visits or hospital admissions for hypoglycemia within 14 days of the antibiotic prescriptions being filled. They compared the rates of such events in patients prescribed one of the seven antibiotics previously implicated in causing hypoglycemia in patients taking sulfonylureas with those in patients taking one of the other nine.

The researchers found that five antibiotics — ciprofloxacin, clarithromycin, levofloxacin, metronidazole, and the combination drug sulfamethoxazole and trimethoprim — were significantly associated with an increased risk of severe hypoglycemia. This increased risk was greatest for clarithromycin and least for ciprofloxacin. The researchers estimated that for every 71 patients taking glipizide or glyburide who are then prescribed clarithromycin, one will be treated in the emergency room or hospitalized for severe hypoglycemia (in this case, 71 is known as the number needed to harm). For the other four antibiotics, the estimated number needed to harm was: 131 for levofloxacin, 133 for sulfamethoxazole and trimethoprim, 187 for metronidazole and 334 for ciprofloxacin.

The researchers also found that among all patients prescribed glipizide or glyburide in 2009, 28 percent received a prescription for at least one of these five antibiotics, and more than 5,500 episodes of severe hypoglycemia requiring an emergency room visit or hospitalization occurred. Of these hypoglycemic events, 13 percent were preceded by a prescription for one of the five antibiotics implicated in causing hypoglycemia.

The investigators correctly concluded, “Interactions with certain antibiotics are a major cause of hypoglycemia in older patients with diabetes mellitus treated with sulfonylureas. … Greater efforts are required to limit the use of these antibiotics in this population.”

What You Can Do

You should take antibiotics only when you have or are likely to have a bacterial infection. Too often, patients request and doctors prescribe antibiotics for sore throats, cold symptoms and coughs caused by viruses. Antibiotics are not useful for treating such infections.

If you are taking glipizide or glyburide and have a bacterial infection that requires treatment with an antibiotic, you should follow these guidelines:

• Always try to avoid taking ciprofloxacin, clarithromycin, levofloxacin, metronidazole, and the combination of sulfamethoxazole and trimethoprim. For most infections, an alternative antibiotic is available.
• If for some reason you must take one of these five antibiotics, discuss with your doctor whether your dose of glipizide or glyburide should be temporarily reduced while taking the antibiotic. Regardless of whether your dose is reduced, increase the frequency of your blood-glucose monitoring and be alert for symptoms of hypoglycemia. Contact your health care provider promptly if your blood glucose level falls below 70 or if you experience any hypoglycemia symptoms.

If you develop symptoms of hypoglycemia, drink a sugar-containing beverage, such as regular soda or juice, or eat a piece of sugar-containing hard candy or a teaspoon of table sugar.

References

[1] Parekh TM, Raji M, Lin YL, et al. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylurea. JAMA Intern Med. Published online September 1, 2014. DOI:10.1001/jamainternmed.2014.3293.

[2] Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15):1410-1418.

[3] Ibid.

[4] Feinkohl I, Keller M, Morling, et al. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study. Diabetes Care. 2014:37(2):507-515.

[5] Yaffe K, Falvey CM, Hamilton N, et al. Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern Med. 2013;173(14):1300-1306.

[6] Ibid.

[7] Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):2002-2012.

[8] Ibid.

[9] Ibid.

[10] Lipska KJ, Ross JS, Wang Y, et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011. JAMA Intern Med. 2014;174(7):1116-1124.

[11] Ibid.

[12] Ibid.

[13] Ibid.

[14] Parekh TM, Raji M, Lin YL, et al. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylurea. JAMA Intern Med. Published online September 1, 2014. DOI:10.1001/jamainternmed.2014.3293.