Predisposing Factors for Any and Major Hypoglycemia With Saxagliptin Versus Placebo and Overall: Analysis From the SAVOR-TIMI 53 Trial

Abstract

OBJECTIVETo analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODSPatients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied. RESULTSAt least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA 1c £7.0% and not in those with baseline HbA 1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA 1c , macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONSThe identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.

Risk Factors for Severe Hypoglycemia in Black and White Adults With Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study

“…Our finding that blacks are at higher risk of hypoglycemia is consistent with those of prior studies (6,8–10,27) demonstrating major racial disparities in hypoglycemia risk. In sensitivity analyses, we found that the observed racial disparities were not entirely explained by the available metrics of socioeconomic status.…”

“…It is likely that our study had limited power to detect a moderate association with reduced kidney function; indeed, there were few people with very poor kidney function (only 45 participants with eGFR <45 mL/min/1.73 m 2 ). Other studies (27,35) have found a strong dose-response relationship between lower eGFR and increased risk of severe hypoglycemia.…”

“…In our minimally adjusted analyses, obesity appeared to be associated with increased risk of hypoglycemia, but after adjustment this association was no longer statistically significant. Because several prior studies (2,6,27) have shown increased risk of hypoglycemia among normal-weight persons rather than obese persons, we conducted a post hoc analysis examining waist circumference and waist-to-hip ratio. Neither of these alternative measures was associated with hypoglycemia.…”

Effects of saxagliptin add-on therapy to insulin on blood glycemic fluctuations in patients with type 2 diabetes

“…[ 16–20 ] In agree with these studies, our data demonstrated that 5 mg saxagliptin add-on insulin therapy provided further improvement of glycemic fluctuations, decrease in time to achieve euglycemic control, insulin doses, and insignificant weight gain. The incidence of hypoglycemic episodes were relatively increased with saxagliptin in patients taking sulfonylureas (SURs), lowering the dose of SURs when initiating saxagliptin should be paid more attention as the SAVOR-TIMI 53 trial revealed [29] . A higher risk for hospitalized heart failure was not observed in users of saxagliptin or sitagliptin compared with other selected antihyperglycemic agents in a large cohort study [30] .…”

Hypoglycaemia manifestations and recurrent events: Lessons from the SAVOR‐TIMI 53 outcome study

“…Hypoglycaemia was one of the prespecified safety endpoints of the study and was actively collected by the investigators . We have previously described, in a heterogeneous population of people with diabetes, the risk factors of major and any hypoglycaemia in those randomized to saxagliptin vs placebo and in the overall SAVOR‐TIMI 53 trial population . In the present study, we describe the features of the hypoglycaemic events, as reported by the patients, analysing the precipitating factors and clinical manifestations associated with any and major hypoglycaemic events and the predictors of recurrent hypoglycaemia.…”