Warfarin, Sulfonylurea Combo Ups Severe Hypoglycemia Risk

Miriam E Tucker

December 21, 2015

Concurrent use of warfarin and the diabetes drugs glipizide and glimepiride appears to dramatically elevate the risk for severe hypoglycemia in older adults, a new analysis shows.

The findings, from a retrospective Medicare database analysis of adults aged 65 and older, were published December 7, 2015 in the BMJ by John A Romley, PhD, associate professor at the Leonard D Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, and colleagues.

The results suggest a "substantial positive association" between concurrent use of warfarin and glipizide or glimepiride and emergency-department visits and hospital admission for hypoglycemia and for fall-related fractures, particularly around the time that patients who are already on the sulfonylurea initiate warfarin.

Beyond just an association — which might be due to patient characteristics correlated with both warfarin use and hypoglycemia risk — the data actually point to the possibility of a significant drug interaction between the medications. "This potential interaction has not been widely appreciated, and healthcare professionals are not routinely alerted when patients on sulfonylureas start treatment with warfarin," Dr Romley and colleagues write.

Close monitoring and patient education are essential for patients who require both medications, principal investigator Anne L Peters, MD, University of Southern California (USC) professor of medicine and director of the USC Westside Center for Diabetes, told Medscape Medical News.

"It's a time to readdress the risk for [hypoglycemia] with sulfonylureas, tell patients how to prevent and prepare for lows, discuss the need to eat meals consistently, and reduce the dose of sulfonylurea if the patient is having lows. Preparation of the patient is key," Dr Peters said.

Asked to comment, Kasia J Lipska, MD, an endocrinologist at Yale University (New Haven, CT) who has studied hypoglycemia in the elderly, told Medscape Medical News, "I think this is an important study….These are commonly used drugs and they frequently lead to problems that require a hospital visit. This means that we have to pay attention to them and figure out how to make prescribing safer."

Evidence of Drug-Drug Interaction

The study population was derived from a random sample of over 12 million Medicare fee-for-service beneficiaries aged 65 or older from 2006 to 2011. Of those, 465,918 had type 2 diabetes and filled at least one prescription for either glipizide or glimepiride. And among those, 71,533 (15.4%) also filled a prescription for warfarin at some point during the study period.

The primary outcome was emergency-department treatment or hospital admission for hypoglycemia in a given calendar quarter ("person-quarter"). Concurrent use of warfarin and glipizide or glimepiride occurred in 9.6% of all person-quarters.

Overall, emergency-department visits and hospital admissions occurred in 0.018% of person-quarters when warfarin was used in addition to the sulfonylurea vs 0.009% of person-quarters without warfarin use.

After adjustment for age, sex, race, and 14 chronic comorbidities, emergency-department visit or hospital admission for hypoglycemia was significantly more likely during the person-quarters with concurrent use of both medications, with odds ratio (OR) 1.22. The individual rate of hospital admission for hypoglycemia was also significantly elevated (OR, 1.45), while the individual risk for emergency-department visit trended toward significance (OR, 1.17).

The association was stronger during person-quarters in which a patient first used warfarin compared with subsequent use, with odds ratios of 2.47 vs 0.88, respectively (P < .01 for the difference).

No such associations were seen for concurrent use of warfarin and other diabetes drugs, including thiazolidinediones and insulin, or for use of glipizide/glimepiride with statins. "These analyses suggest that the observed relation between use of warfarin with glipizide/glimepiride and risk of hypoglycemia may reflect a drug-drug interaction rather than unmeasured characteristics of patients that are correlated with both warfarin use and hypoglycemia risk," Dr Romley and colleagues write.

Concurrent use of warfarin and the two sulfonylureas was also associated with an increased risk for emergency-room visits and hospital admissions for fall-related fractures, with adjusted OR 1.47, and for altered consciousness/mental status (OR, 1.22).

Dr Peters commented, "I think the fall issue is very serious in our elderly patients. People lose lean body mass as they age and become more at risk for falls."

The mechanism for the interaction isn't clear. One theory is that warfarin displaces the sulfonylurea's binding ability and thereby increases the plasma drug concentration, although data have called the significance of this into question. Another theory has to do with competitive binding for the CYP2C9 hepatic metabolic pathway, through which both the sulfonylureas and warfarin are primarily metabolized. However, there is no empirical evidence for this, the authors note.

Dr Lipska pointed out that the absolute numbers of events here are probably underestimates, since most people with hypoglycemia don't end up in the emergency room and the investigators used only three ICD-9 diagnostic codes for hypoglycemia. "So what we see reported in the study is the tip of the iceberg," she told Medscape Medical News.

Dr Peters commented, "Many patients don't truly understand the risk of [hypoglycemia] on sulfonylureas. I think they should be warned that adding a new medication can increase that risk."

Dr Romley receives support from the National Institute on Aging, the Commonwealth Fund, and the Leonard D Schaeffer Center for Health Policy and Economics at the University of Southern California. Disclosures for the coauthors are listed in the article. Dr Peters has served as director, officer, partner, employee, advisor, consultant, or trustee for Amylin Pharmaceuticals, Eli Lilly, and Novo Nordisk; as a speaker or member of a speaker's bureau for Amylin Pharmaceuticals, Eli Lilly, Novo Nordisk, and Takeda Pharmaceuticals North America; and as a consultant or ad hoc speaker/consultant for AstraZeneca, Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Dexcom, Medtronic, Merck, Roche, and Sanofi. Dr Lipska has received grant support from the National Institutes of Health and some support from the Centers for Medicare and Medicaid Services

BMJ. Published online December 7, 2015. Article


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