Risk of Severe Hypoglycemia With Newer Second-line Glucose-lowering Medications in Older Adults With Type 2 Diabetes Stratified by Known Indicators of Hypoglycemia Risk

Abstract

Abstract Background Severe hypoglycemia is associated with adverse clinical outcomes. We evaluated the risk of severe hypoglycemia in older adults initiating newer glucose-lowering medications overall and across strata of known indicators of high hypoglycemia risk. Methods We conducted a comparative-effectiveness cohort study of older adults aged >65 years with type 2 diabetes initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA) using Medicare claims (3/2013–12/2018) and Medicare-linked-electronic health records. We identified severe hypoglycemia requiring emergency or inpatient visits using validated algorithms. After 1:1 propensity score matching, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years. Analyses were stratified by baseline insulin, sulfonylurea, cardiovascular disease (CVD), chronic kidney disease (CKD), and frailty. Results Over a median follow-up of 7 (interquartile range: 4–16) months, SGLT2i was associated with a reduced risk of hypoglycemia versus DPP-4i (HR 0.75 [0.68, 0.83]; RD −3.21 [−4.29, −2.12]), and versus GLP-1RA (HR 0.90 [0.82, 0.98]; RD −1.33 [−2.44, −0.23]). RD for SGLT2i versus DPP-4i was larger in patients using baseline insulin than in those not, although HRs were similar. In patients using baseline sulfonylurea, the risk of hypoglycemia was lower in SGLT2i versus DPP-4i (HR 0.57 [0.49, 0.65], RD −6.80 [−8.43, −5.16]), while the association was near-null in those without baseline sulfonylurea. Results stratified by baseline CVD, CKD and frailty were similar to the overall cohort findings. Findings for the GLP-1RA comparison were similar. Conclusions SGLT2i was associated with a lower hypoglycemia risk versus incretin-based medications, with larger associations in patients using baseline insulin or sulfonylurea.