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.

Heller SR, Geybels MS, Iqbal A, Liu L, Wagner L, Chow E, Chow E

Diabetologia26 Oct 2021Cited by 25 (Europe PMC)

PMID34704120PMCIDPMC8660716DOI10.1007/s00125-021-05556-7PepBankPUB-34704120

Summary

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).

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study6

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone6

In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Liraglutide.

01HumanNot a test of Liraglutide aloneObservational studyOther
In people with type 2 diabetes in the LEADER trial, 2-11 non-severe hypoglycaemic episodes per year were associated with a higher risk of severe hypoglycaemia (unadjusted HR 1.98).
In plain wordsIn people with type 2 diabetes, having 2 to 11 mild low-blood-sugar episodes a year was linked to more severe low blood sugar.
Peptide
Liraglutide
Outcome
IncreaseSevere hypoglycaemia by non-severe hypoglycaemia rate, 2-11 per year
Study
n: not reported in source
Comparator
Participants with <2 NSHEs per year
Outcome group
Adverse events · Metabolic and weight
Measurements
HR
1.98 ratio
2-11 NSHEs per year, unadjusted
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
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 study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Show in the study text Report a problemFND-3470412001
02HumanNot a test of Liraglutide aloneObservational studyOther
In people with type 2 diabetes in the LEADER trial, 12 or more non-severe hypoglycaemic episodes per year were associated with a higher risk of severe hypoglycaemia (unadjusted HR 5.01).
In plain wordsIn people with type 2 diabetes, having 12 or more mild low-blood-sugar episodes a year was linked to much more severe low blood sugar.
Peptide
Liraglutide
Outcome
IncreaseSevere hypoglycaemia by non-severe hypoglycaemia rate, 12 or more per year
Study
n: not reported in source
Comparator
Participants with <2 NSHEs per year
Outcome group
Adverse events · Metabolic and weight
Measurements
HR
5.01 ratio
12 or more NSHEs per year, unadjusted
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
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 study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Show in the study text Report a problemFND-3470412002
03HumanNot a test of Liraglutide aloneObservational studyOther
In people with type 2 diabetes in the LEADER trial, 2-11 non-severe hypoglycaemic episodes per year were not associated with adverse cardiovascular outcomes.
In plain wordsIn people with type 2 diabetes, having 2 to 11 mild low-blood-sugar episodes a year was not linked to more heart events.
Peptide
Liraglutide
Outcome
No significant changeAdverse cardiovascular outcomes by non-severe hypoglycaemia rate, 2-11 per year
Study
n: not reported in source
Comparator
Participants with <2 NSHEs per year
Outcome group
Cardiovascular events · Cardiovascular
Source sentences
Summary
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]).
1 context sentence(design, population, supporting numbers)
Summary · context
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 study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Show in the study text Report a problemFND-3470412003
04HumanNot a test of Liraglutide aloneObservational studyOther
In people with type 2 diabetes in the LEADER trial, 12 or more non-severe hypoglycaemic episodes per year were associated with a higher risk of MACE (HR 1.50).
In plain wordsIn people with type 2 diabetes, having 12 or more mild low-blood-sugar episodes a year was linked to more major heart events.
Peptide
Liraglutide
Outcome
IncreaseMACE by non-severe hypoglycaemia rate, 12 or more per year
Study
n: not reported in source
Comparator
Participants with <2 NSHEs per year
Outcome group
Cardiovascular events · Cardiovascular
Measurements
HR
1.5 ratio
MACE, 12 or more NSHEs per year
95% CI
1.01 to 2.23 ratio
MACE
Source sentences
Summary
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]).
1 context sentence(design, population, supporting numbers)
Summary · context
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 study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Show in the study text Report a problemFND-3470412004
05HumanNot a test of Liraglutide aloneObservational studyOther
In people with type 2 diabetes in the LEADER trial, 12 or more non-severe hypoglycaemic episodes per year were associated with a higher risk of cardiovascular death (HR 2.08).
In plain wordsIn people with type 2 diabetes, having 12 or more mild low-blood-sugar episodes a year was linked to more deaths from heart causes.
Peptide
Liraglutide
Outcome
IncreaseCardiovascular death by non-severe hypoglycaemia rate, 12 or more per year
Study
n: not reported in source
Comparator
Participants with <2 NSHEs per year
Outcome group
Cardiovascular events · Cardiovascular
Measurements
HR
2.08 ratio
cardiovascular death, 12 or more NSHEs per year
95% CI
1.17 to 3.7 ratio
cardiovascular death
Source sentences
Summary
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]).
1 context sentence(design, population, supporting numbers)
Summary · context
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 study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Show in the study text Report a problemFND-3470412005
06HumanNot a test of Liraglutide aloneObservational studyOther
In people with type 2 diabetes in the LEADER trial, 12 or more non-severe hypoglycaemic episodes per year were associated with a higher risk of overall death (HR 1.80).
In plain wordsIn people with type 2 diabetes, having 12 or more mild low-blood-sugar episodes a year was linked to more deaths from any cause.
Peptide
Liraglutide
Outcome
IncreaseAll-cause death by non-severe hypoglycaemia rate, 12 or more per year
Study
n: not reported in source
Comparator
Participants with <2 NSHEs per year
Outcome group
Mortality · Whole body
Measurements
HR
1.8 ratio
overall death, 12 or more NSHEs per year
95% CI
1.11 to 2.92 ratio
overall death
Source sentences
Summary
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]).
1 context sentence(design, population, supporting numbers)
Summary · context
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 study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Show in the study text Report a problemFND-3470412006

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · 1 with posted results · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3Results postedNCT01179048

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

Novo Nordisk A/Sn = 9,34131 Aug 2010 to 17 Dec 2015

Diabetes · Diabetes Mellitus, Type 2

Trial page ClinicalTrials.govUpdated 17 Jul 2019

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Version 2Current
12 Oct 2026, 11:11 UTC
Study results updated
Version 1
9 Oct 2026, 03:05 UTC
First added · source update from Europe PMC

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