A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study

Simon R Heller, Milan S Geybels, Ahmed Iqbal, Lei Liu, Lily Wagner, Elaine Chow, Simon R Heller, Milan S Geybels, Ahmed Iqbal, Lei Liu, Lily Wagner, Elaine Chow

Abstract

Aims/hypothesis: Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated.

Methods: LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used.

Results: We demonstrate that there is an association between NSHEs (2-11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2-11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]).

Conclusions/interpretation: The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs.

Trial registration: ClinicalTrials.gov (NCT01179048).

Keywords: Cardiac complications; Hypoglycaemia; Macrovascular disease.

© 2021. Crown.

Figures

Fig. 1
Fig. 1
Time-dependent covariate analysis of a Cox proportional hazards model for severe hypoglycaemia, MACE, cardiovascular death and all-cause mortality by NSHE rate groups: (a) unadjusted; (b) adjusted for baseline characteristics (excluding renal function); (c) adjusted for baseline characteristics (including renal function). Reference group, Group A: <2 NSHEs per year; Group B: 2–11 NSHEs per year; Group C: ≥12 NSHEs per year
Fig. 2
Fig. 2
Sensitivity analyses for the association of NSHE and other events. (a) Time-dependent covariate sensitivity analysis of NSHEs and outcomes, where exposure time was split when a new outcome event occurred. (b) The first year of exposure was used to group participants in one of three risk categories, and the remainder of the exposure time was used to study the association between risk category and time to first event. (c) Same as main analysis but severe hypoglycaemia events were excluded from the dataset. Reference group, Group A: <2 NSHEs per year; Group B: 2–11 NSHEs per year; Group C: ≥12 NSHEs per year

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