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

Abstract

Funding information SAVOR-TIMI 53 was sponsored by AstraZeneca and Bristol-Myers Squibb. Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycae-mic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose <3.0 mmol/l (<54 mg/dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in >60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event. K E Y W O R D S hypoglycaemia, type 2 diabetes 1 | INTRODUCTION Hypoglycaemia has been identified as a limiting factor in the treatment of diabetes, preventing patients from achieving optimum gly-caemic control. An episode of severe hypoglycaemia may result in significant clinical consequences including neurological symptoms, seizures, falls and potential deterioration to coma or death. 1-3 Patients reporting symptomatic hypoglycaemia in the previous 4 weeks or a major episode (requiring assistance) in the past year are at increased risk of having a major hypoglycaemic event. 4 The use of hypoglycaemic medications, caloric intake that does not match the medical regimen, exercise or intercurrent illness are the most common causes of hypoglycaemia in patients with type 2 diabetes. 5 Better understanding of the association of these variables with hypoglycaemia may assist in counselling patients to manage and prevent recurrent events. The SAVOR-TIMI 53 trial was a cardiovascular outcome trial designed to assess the cardiovascular safety of saxagliptin vs placebo added to standard care. 6 Hypoglycaemia was one of the pre-specified safety endpoints of the study and was actively collected by the investigators. 6 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. 7 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 hypo-glycaemic events and the predictors of recurrent hypoglycaemia.

Hypoglycemia Among Patients with Type 2 Diabetes: Epidemiology, Risk Factors, and Prevention Strategies

“…[72] In the SAVOR-TIMI 53 trial of saxagliptin therapy, there was an identifiable precipitant in 47.3% of hypoglycemic events in the saxagliptin arm and 48.4%in the placebo arm, including illness (2.5 % and 3.1%, respectively), overdose of hypoglycemic agent (9.8% and 7.8%, respectively), and missed meals (50.7% and 48.7%, respectively). [73]…”

Hypoglycaemia and its management in primary care setting

“…Additional risk factors include impaired kidney function with low glomerular filtration rate (eGFR) due to reduced renal gluconeogenesis and reduced insulin clearance, and long‐standing diabetes which is associated with more severe endogenous insulin deficiency 5,6 . A previous history of hypoglycaemia is recognized as risk factor for future episodes of severe hypoglycaemia and recurrent events 7 . Body mass index and baseline HbA 1c have not been consistently shown to be associated with either increased or decreased risk of hypoglycaemia 6 …”