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Cited by 420Heart Rate Variability and Autonomic ControlCardiovascular Function and Risk FactorsDiabetes Management and Research

Heart rate variability in type 2 diabetes mellitus: A systematic review and meta–analysis

Open access
Benichou, Thomas, Pereira, Bruno, Mermillod, Martial, Tauveron, Igor, Pfabigan, Daniela, Maqdasy, Salwan, Dutheil, Frédéric·2018·PLOS ONE
DOI 10.1371/journal.pone.0195166PMC PMC5880391
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Abstract

BACKGROUND: Cardiac autonomic neuropathy in type 2 dibetes mellitus (T2DM) patients is frequent and associated with high cardiovascular mortality. Heart rate variability (HRV) is the gold standard to measure cardiac autonomic neuropathy. We aimed to conduct a systematic review and meta-analysis to evaluate the impact of T2DM on HRV parameters. METHODS: The PubMed, Cochrane Library, Embase and Science Direct databases were searched on 1st October 2017 using the keywords "diabetes" AND ("heart rate variability" OR "HRV"). Included articles had to report HRV parameters in T2DM patients and healthy controls measured during 24 hours with a Holter-electrocardiogram. Measurements of HRV retieved were: RR-intervals (or Normal to Normal intervals-NN), standard deviation of RR intervals (SDNN), percetange of adjacent NN intervals differing by more than 50 milliseconds (pNN50), square root of the mean squared difference of successive RR intervals (RMSSD), total power, Low Frequency (LF), High Frequency (HF) and LF/HF ratio, as per Task Force recommendations. RESULTS: We included twenty-five case-control studies with 2,932 patients: 1,356 with T2DM and 1,576 healthy controls. T2DM patients had significantly (P<0.01) lower RR-intervals (effect size = -0.61; 95%CI -1.21 to -0.01), lower SDNN (-0.65; -0.83 to -0.47), lower RMSSD (-0.92; -1.37 to -0.47), lower pNN50 (-0.46; -0.84 to -0.09), lower total power (-1.52; -2.13 to -0.91), lower LF (-1.08; -1.46 to -0.69]), and lower HF (-0.79; -1.09 to -0.50). LF/HF did not differ between groups. Levels of blood glucose and HbA1c were associated with several HRV parameters, as well as Time from diagnosis of T2DM. CONCLUSIONS: T2DM was associated with an overall decrease in the HRV of T2DM patients. Both sympathetic and parasympathetic activity were decreased, which can be explained by the deleterious effects of altered glucose metabolism on HRV, leading to cardiac autonomic neuropathy.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis found that type 2 diabetes mellitus (T2DM) is associated with an overall decrease in heart rate variability (HRV), with both sympathetic and parasympathetic activity reduced. The authors attribute this to deleterious effects of altered glucose metabolism leading to cardiac autonomic neuropathy.

Key findings

Twenty-five case-control studies with 2,932 patients (1,356 T2DM, 1,576 healthy controls) showed significantly lower HRV in T2DM for RR intervals (effect size = –0.61; 95%CI –1.21 to –0.01), SDNN (–0.65; –0.83 to –0.47), RMSSD (–0.92; –1.37 to –0.47), pNN50 (–0.46; –0.84 to –0.09), total power (–1.52; –2.13 to –0.91), LF (–1.08; –1.46 to –0.69), and HF (–0.79; –1.09 to –0.50). LF/HF did not differ between groups (effect size = 0.02; 95%CI –0.38 to 0.43; P = 0.914). Meta-regressions found age and male gender associated with decreased LF and HF; blood glucose and total cholesterol associated with increased LF and HF; higher HbA1c associated with shorter RR intervals; and time from T2DM diagnosis linked with higher SDNN and lower total power.

Methods

Systematic review and meta-analysis of case-control studies reporting 24-hour Holter-electrocardiogram HRV parameters in T2DM patients and healthy controls, following Task Force recommendations. Databases searched were PubMed, Cochrane Library, Embase, and Science Direct (search date reported as 1 October 2017; text also states between 30 October 2015 and 1 October 2017). Random-effects meta-analyses (DerSimonian and Laird) calculated standardised mean differences, with heterogeneity assessed by I² and meta-regressions for clinically relevant variables; study quality was assessed with STROBE and CONSORT.

Limitations

The paper states that meta-analyses inherit limitations of included studies and are subject to selection bias; included studies varied in quality, most were cross-sectional, measurement conditions differed, and inclusion criteria were not identical. The paper also states that control health status was not detailed in all studies, some studies were monocentric, the final number of patients was not very high, and missing or declarative data were potential biases. Evident from the text: heterogeneity was significant for all meta-analyses (e.g., I² = 91.6% for RR intervals, 94.0% for RMSSD, 93.5% for total power), and many variables (HbA1c, BMI, blood pressure, insulin, HOMA-IR, neuropathy scores) were missing or unreported across studies, limiting meta-regression analyses.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0195166

Cites

101 of 101 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 13 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In T2DM patients compared with healthy controls, LF was significantly lower (effect size = -1.08; 95% CI -1.46 to -0.69; P < 0.001; I2 = 91.3%).

    “lower LF (–1.08; –1.46 to –0.69])”
    • Also stated in: § Meta–analyses of HRV values in T2DM · boosted
      “lower LF (effect size = –1.08; 95%CI –1.46 to –0.69; p < 0.001; I2 = 91.3%) (Fig 7) [42,45,47–54,57,63,65,66]”
    Quote in the paperSubstantial claim
  • Findingown data

    Blood glucose levels were significantly associated with an increase in RMSSD (coefficient = 4.2; 95% CI 1.7-6.6; P = 0.003).

    “Blood glucose levels were also significantly associated with an increase in RMSSD (coefficient = 4.2; 95%CI 1.7–6.6, P = 0.003) and with an increase in SDNN (coefficient = 24; 95%CI 17–30, P < 0.001).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Body mass index was associated with an increase in HF (coefficient = 0.7; 95% CI 0.3-1.1; P = 0.005).

    “Body mass index was associated with both an increase in LF (coefficient = 0.8; 95%CI 0.3–1.3, P = 0.003) and in HF (coefficient = 0.7; 95%CI 0.3–1.1, P = 0.005).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Blood glucose levels were associated with an increase in LF (coefficient = 112; 95% CI 31-193; P = 0.015).

    “Similarly, both blood glucose levels and total cholesterol were associated with both an increase in LF (coefficient = 112; 95%CI 31–193, P = 0.015; coefficient = 1133; 95%CI 408–1858, P = 0.01; respectively) and in HF (coefficient = 34; 95%CI 6–63, P = 0.024; coefficient = 490; 95%CI 100–879, P = 0.023).”
    Quote in the paperNot a substantial claim
  • Findingown data

    LF/HF did not differ between T2DM patients and healthy controls (effect size = 0.02; 95% CI -0.38 to 0.43; P = 0.914; I2 = 90.1%).

    “LF/HF did not differ between groups.”
    • Also stated in: § Meta–analyses of HRV values in T2DM · plain
      “LF/HF did not differ between groups (effect size = 0.02; 95%CI –0.38 to 0.43; P = 0.914; I2 = 90.1%) (Fig 9) [42,44,46–48,50–54,57,65,66]”
    Quote in the paperSubstantial claim
  • May combine two claims. 9
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingreasoning

    Both sympathetic and parasympathetic activity were decreased in T2DM patients.

    “Both sympathetic and parasympathetic activity were decreased, which can be explained by the deleterious effects of altered glucose metabolism on HRV.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingcitation

    LF decreases with male gender.

    “Finally, in line with the literature, we demonstrated a decrease in both LF and HF with age [95] and the male gender [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] P Pavithran, 2008, Sex differences in short-term heart rate variability in patients with newly diagnosed essential hypertension, J Clin Hypertens Greenwich Conn source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    RMSSD and pNN50 are associated with high-frequency power (HF) and hence parasympathetic activity, whereas SDNN is correlated with low-frequency power (LF).

    “The RMSSD and pNN50 are associated with high–frequency power (HF) and hence parasympathetic activity, whereas SDNN is correlated with low–frequency power (LF) [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] H Otzenberger, 1998, Dynamic heart rate variability: a tool for exploring sympathovagal balance continuously during sleep in men, Am J Physiol

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    T2DM has a negative influence on almost all HRV parameters, reflecting that diabetes leads to a cardiac autonomic dysfunction.

    “With the exception of the LF/HF ratio, which did not differ in our meta–analysis due to comparable changes in the LF and HF components, T2DM has a negative influence on almost all HRV parameters, reflecting the fact that diabetes leads to a cardiac autonomic dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In T2DM patients, both sympathetic and parasympathetic activity were decreased compared with non-T2DM patients.

    “Both sympathetic and parasympathetic activity were decreased, which can be explained by the deleterious effects of altered glucose metabolism on HRV, leading to cardiac autonomic neuropathy.”
    • Also stated in: § An alteration of both sympathetic and parasympathetic activity · boosted
      “However, we demonstrated that T2DM patients had a decrease in both parasympathetic and sympathetic activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The metaregression finding that time from diagnosis of T2DM was linked with higher SDNN is not contradictory to the decreased SDNN in T2DM but may simply highlight that cardiac parasympathetic activity in T2DM is affected before sympathetic activity.

    “Despite we demonstrated a decreased SDNN in T2DM patients, the metaregression is not contradictory but may simply highlights the fact that cardiac parasympathetic activity in T2DM is affected before sympathetic activity [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] RK Goit, 2012, Cardiovascular autonomic function and vibration perception threshold in type 2 diabetes mellitus, J Diabetes Complications source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Dyslipidaemia and high blood pressure are linked with a decreased HRV in T2DM.

    “Dyslipdaemia and high blood pressure are linked with a decreased HRV in T2DM.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Two authors reviewed the abstracts independently and checked whether articles could be included according to inclusion criteria; when consensus was not reached, a third author reviewed the debated articles.

    “Two authors (Thomas Benichou and Frédéric Dutheil) reviewed the abstracts independently and checked if article could be included in our metanalaysis according to inclusion critera. When consensus on suitability was not reached, a third author (Bruno Pereira) reviewed the debated articles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The final number of patients included in the meta-analysis was not very high.

    “Similarly, the final number of patients included in the metaanalysis was not very high and may precluded generalizability, however the mean age could be considered as quite representative.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    For the observational studies, STROBE scores varied from 50% to 71%, with a mean score of 59%.

    “Results varied from 50% [59] to 71% [56] for the observational studies (STROBE), with a mean score of 59%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The populations investigated in the meta-analysis appeared to be equally distributed around the world.

    “However, included studies were homogeneous according to funnel plots, and the populations investigated in the meta–analysis appeared to be equally distributed around the world.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The decrease in sympathetic and parasympathetic activity can be explained by the deleterious effects of altered glucose metabolism on HRV.

    “Both sympathetic and parasympathetic activity were decreased, which can be explained by the deleterious effects of altered glucose metabolism on HRV.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The mean age of included patients could be considered quite representative.

    “Similarly, the final number of patients included in the metaanalysis was not very high and may precluded generalizability, however the mean age could be considered as quite representative.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The use of broader keywords in the search strategy limits the number of missing studies.

    “However, the use of broader keywords in the search strategy limits the number of missing studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Inclusion criteria of participants were similar but not identical across studies.

    “Though there were similarities between the participants’ inclusion criteria, they were not identical.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    For the randomized trials, CONSORT scores varied from 52% to 67%, with a mean score of 59.5%.

    “Results varied from 52% [59] to 67% [57] for the randomized trials (CONSORT), with a mean score of 59.5%.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The quality of the twenty-five included studies was assessed using the STROBE and CONSORT criteria.

    “The assessment of the quality of the twenty–five studies that were included was performed using the STROBE and CONSORT criteria.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Potential publication bias was assessed using funnel plots of the meta-analyses.

    “We searched for potential publication bias using funnel plots of these meta–analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Variables retrieved from declarative data in each study are a putative bias.

    “Variables retrieved from declarative data in each study included are also a putative bias.”
    Quote in the paperNot a substantial claim
19 of 19

  • The paper relies on this without support.

    HRV is the gold standard to measure cardiac autonomic neuropathy.

    “Heart rate variability (HRV) is the gold standard to measure cardiac autonomic neuropathy.”

  • The paper relies on this without support.

    HRV parameters are associated with high inter- and intra-individual variability.

    “with different measurement conditions for HRV parameters associated with a high inter and intra–individual variability.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Both diabetes mellitus and prediabetes are independently associated with lower heart rate variability (HRV).

    “Both DM and prediabetes are independently associated with lower heart rate variability (HRV), which suggests that cardiac autonomic dysfunction may be characteristic of prediabetes2–5.”

    From Sleep and temperature data from wearable devices support noninvasive detection of diabetes mellitus in a large-scale, retrospective analysis (2026) · cites this paper as [3]

    The Discussion and Conclusion report substantially lower HRV in patients with type 2 diabetes than in those without it. Our copy does not report a corresponding finding for prediabetes or establish that both associations are independent (searched: “prediabetes” and “independent association”). (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Study designs described as both prospective cohorts and mostly cross-sectional

    Major

    The study-design section describes all but one study as prospective cohorts, while the limitations section says most included studies were cross-sectional.

  • LF/HF was not significantly decreased

    Minor

    The limitations section says all measured HRV parameters were significantly decreased, whereas the results explicitly say the LF/HF ratio did not differ between groups.

  • Randomized-trial quality range includes a study not identified as randomized

    Minor

    The quality assessment gives a randomized-trial score for study [59], but the study-design section identifies [57] as the sole randomized study.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. L Boer-Martins, 2012, Leptin and aldosterone in sympathetic activity in resistant hypertension with or without type 2 diabetes, Arq Bras Cardiol, 99, 642

Cited by

Sorted by citations

Related

Authors
Benichou, T., Pereira, B., Mermillod, M., Tauveron, I., Pfabigan, D., Maqdasy, S., & Dutheil, F.
Affiliations
  • Centre Hospitalier Universitaire de Clermont-Ferrand (FR)
  • Centre National de la Recherche Scientifique (FR)
  • Peking University (CN)
Corresponding author
Dutheil, Frédéric
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2018-04-02
Volume
13
Issue
4
Pages
e0195166
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0195166
PMC
PMC5880391
OpenAlex
W2888208815
Cited by
419
References
101
Citations by year
2026: 43 · 2025: 63 · 2024: 72 · 2023: 59 · 2022: 66 · 2021: 54 · 2020: 33 · 2019: 23 · 2018: 5
FWCI
5.36
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
type 2 diabetes, heart rate variability, cardiac autonomic neuropathy, autonomic dysfunction, sympathetic activity, parasympathetic activity, blood glucose, HbA1c, cardiovascular mortality, Holter electrocardiogram, RR interval, spectral analysis of HRV, autonomic reinnervation
MeSH terms
Adult, Aged, Diabetes Mellitus, Type 2, Female, Heart Rate, Humans, Male, Middle Aged, Regression Analysis, Risk Factors, Body Mass Index, Case-Control Studies

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