Association between use of warfarin with common sulfonylureas and serious hypoglycemic events: retrospective cohort analysis

Abstract

Study question: Is warfarin use associated with an increased risk of serious hypoglycemic events among older people treated with the sulfonylureas glipizide and glimepiride?

Methods: This was a retrospective cohort analysis of pharmacy and medical claims from a 20% random sample of Medicare fee for service beneficiaries aged 65 years or older. It included 465,918 beneficiaries with diabetes who filled a prescription for glipizide or glimepiride between 2006 and 2011 (4,355,418 person quarters); 71,895 (15.4%) patients also filled a prescription for warfarin (416,479 person quarters with warfarin use). The main outcome measure was emergency department visit or hospital admission with a primary diagnosis of hypoglycemia in person quarters with concurrent fills of warfarin and glipizide/glimepiride compared with the rates in quarters with glipizide/glimepiride fills only, Multivariable logistic regression was used to adjust for individual characteristics. Secondary outcomes included fall related fracture and altered consciousness/mental status.

Summary answer and limitations: In quarters with glipizide/glimepiride use, hospital admissions or emergency department visits for hypoglycemia were more common in person quarters with concurrent warfarin use compared with quarters without warfarin use (294/416,479 v 1903/3,938,939; adjusted odds ratio 1.22, 95% confidence interval 1.05 to 1.42). The risk of hypoglycemia associated with concurrent use was higher among people using warfarin for the first time, as well as in those aged 65-74 years. Concurrent use of warfarin and glipizide/glimepiride was also associated with hospital admission or emergency department visit for fall related fractures (3919/416,479 v 20,759/3,938,939; adjusted odds ratio 1.47, 1.41 to 1.54) and altered consciousness/mental status (2490/416,479 v 14,414/3,938,939; adjusted odds ratio 1.22, 1.16 to 1.29). Unmeasured factors could be correlated with both warfarin use and serious hypoglycemic events, leading to confounding. The findings may not generalize beyond the elderly Medicare population.

What this study adds: A substantial positive association was seen between use of warfarin with glipizide/glimepiride and hospital admission/emergency department visits for hypoglycemia and related diagnoses, particularly in patients starting warfarin. The findings suggest the possibility of a significant drug interaction between these medications.

Funding, competing interests, data sharing: JAR and DPG receive 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. ABJ receives support from the NIH Office of the Director. No additional data are available.

Fig 1 Odds ratios for hospital admission or emergency department visit for hypoglycemia in person quarters with concurrent use of warfarin and glipizide/glimepiride

Fig 2 Odds ratio for hospital admission or emergency department visit for hypoglycemia in person quarters with concurrent use of warfarin and glipizide/glimepiride, by subgroup. P values correspond to hypothesis tests of equal odds ratios. Low comorbidity is defined by having less than median total number of comorbidities per patient in sample

Fig 3 Odds ratio for hospital admission or emergency department visit for hypoglycemia associated with concurrent use of warfarin and glipizide/glimepiride, sensitivity analysis. Alternative risk adjustment uses hierarchical condition categories (HCC), as described in methods section. Adjusting for use of other diabetes drugs includes concurrent fills in analysis. Ever used warfarin analysis compares person quarters with concurrent warfarin/sulfonylurea use with person quarters without concurrent use within subsample of patients who ever used warfarin. Fixed effects analysis compares hypoglycemia rates during periods of concurrent warfarin/sulfonylurea use and non-use within same beneficiary over time. Statin analysis compares hypoglycemia rates according to concurrent sulfonylurea/statin use based on conditional fixed effects logistic specification

Fig 4 Odds ratio for hospital admission or emergency department visit for hypoglycemia associated with concurrent use of warfarin and various diabetes drugs. For each analysis, the sample includes person quarters with filled prescription of relevant diabetes drug

Fig 5 Odds ratio for hospital admission or emergency department visit for hypoglycemia related diagnoses associated with concurrent use of warfarin and glipizide/glimepiride