Abstract
Aims/hypothesisHypoglycaemia 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.MethodsLEADER 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.ResultsWe 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/interpretationThe 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 registrationClinicalTrials.gov (NCT01179048).Graphical abstract
Highlights
There is considerable evidence that individuals with type 1 and type 2 diabetes benefit greatly from maintaining good glycaemic control [1, 2]; many do not reach their treatment targets [3]
The main analysis showed that participants in both Group B and Group C experienced higher rates of severe hypoglycaemia compared with Group A
The HRs for overall death for Groups B and C vs Group A were 1.04 [95% CI 0.90, 1.20] and 1.81 [95% CI 1.11, 2.94], respectively. This post hoc analysis of the LEADER data identified an association between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemic episodes
Summary
There is considerable evidence that individuals with type 1 and type 2 diabetes benefit greatly from maintaining good glycaemic control [1, 2]; many do not reach their treatment targets [3]. Analyses of major clinical trials have investigated the relationship between severe hypoglycaemia (defined as cognitive impairment requiring assistance from another person) and adverse cardiovascular outcomes These analyses demonstrated that severe hypoglycaemia was associated with an increased risk of all-cause mortality and/or adverse cardiovascular outcomes in individuals with type 2 diabetes [10,11,12,13,14,15]. In ACCORD (Action to Control Cardiovascular Risk in Diabetes), while an increased risk of death was seen in all participants experiencing symptomatic and severe hypoglycaemia, the risk of death was lower in those experiencing one or more hypoglycaemic episodes receiving intensive glucose control vs standard glucose control [11, 12]. The reduced risk of mortality observed in patients treated intensively and experiencing hypoglycaemia may be due to repeated episodes of hypoglycaemia leading to impaired sympathoadrenal responses, which are linked to adverse cardiovascular effects [16]
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