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.

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 SGLT2i vs. DPP-4i or SGLT2i vs. 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 vs. DPP-4i [HR 0.75 (0.68, 0.83); RD -3.21 (-4.29, -2.12)], and vs. GLP-1RA [HR 0.90 (0.82, 0.98); RD -1.33 (-2.44, -0.23)]. RD for SGLT2i vs. 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 vs. 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 vs. incretin-based medications, with larger associations in patients using baseline insulin or sulfonylurea.