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Metabolic Risk/Epidemiology
Temporal Changes in Resting Heart Rate and Risk of Diabetes Mellitus
Mi Kyoung Son, Kyoungho Lee, Hyun-Young Park
Received August 29, 2023  Accepted November 13, 2023  Published online February 2, 2024  
DOI:    [Epub ahead of print]
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
To investigate the association between the time-varying resting heart rate (RHR) and change in RHR (∆RHR) over time and the risk of diabetes mellitus (DM) by sex.
We assessed 8,392 participants without DM or atrial fibrillation/flutter from the Korean Genome and Epidemiology Study, a community-based prospective cohort study that was initiated in 2001 to 2002. The participants were followed up until December 31, 2018. Updating RHR with biennial in-study re-examinations, the time-varying ∆RHR was calculated by assessing the ∆RHR at the next follow-up visit.
Over a median follow-up of 12.3 years, 1,345 participants (16.2%) had DM. As compared with RHR of 60 to 69 bpm, for RHR of ≥80 bpm, the incidence of DM was significantly increased for both male and female. A drop of ≥5 bpm in ∆RHR when compared with the stable ∆RHR group (–5< ∆RHR <5 bpm) was associated significantly with lower risk of DM in both male and female. However, an increase of ≥5 bpm in ∆RHR was significantly associated with higher risk of DM only in female, not in male (hazard ratio for male, 1.057 [95% confidence interval, 0.869 to 1.285]; and for female, 1.218 [95% confidence interval, 1.008 to 1.471]).
In this community-based longitudinal cohort study, a reduction in ∆RHR was associated with a decreased risk of DM, while an increase in ∆RHR was associated with an increased risk of DM only in female.
Effect of the Glucagon-Like Peptide-1 Receptor Agonists on Autonomic Function in Subjects with Diabetes: A Systematic Review and Meta-Analysis
Carla Greco, Daniele Santi, Giulia Brigante, Chiara Pacchioni, Manuela Simoni
Diabetes Metab J. 2022;46(6):901-911.   Published online April 12, 2022
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  • 5 Web of Science
  • 6 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes.
According to the Cochrane Collaboration and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in diabetic subjects chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs).
In the studies enrolled, HR significantly increased after treatment (P<0.001), whereas low frequency/high frequency ratio did not differ (P=0.410); no changes in other measures of HRV were detected. Considering CARTs, only the 30:15 value derived from lying-to-standing test was significantly lower after treatment (P=0.002), but only two studies reported this measurement. No differences in other CARTs outcome were observed.
The meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function.


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    Jonathan Goldney, Jack A. Sargeant, Melanie J. Davies
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    Susumu Z. Sudo, Tadeu L. Montagnoli, Bruna de S. Rocha, Aimeé D. Santos, Mauro P. L. de Sá, Gisele Zapata-Sudo
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Cardiovascular Risk/Epidemiology
Association between Variability of Metabolic Risk Factors and Cardiometabolic Outcomes
Min Jeong Park, Kyung Mook Choi
Diabetes Metab J. 2022;46(1):49-62.   Published online January 27, 2022
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  • 221 Download
  • 5 Web of Science
  • 7 Crossref
Graphical AbstractGraphical Abstract AbstractAbstract PDFPubReader   ePub   
Despite strenuous efforts to reduce cardiovascular disease (CVD) risk by improving cardiometabolic risk factors, such as glucose and cholesterol levels, and blood pressure, there is still residual risk even in patients reaching treatment targets. Recently, researchers have begun to focus on the variability of metabolic variables to remove residual risks. Several clinical trials and cohort studies have reported a relationship between the variability of metabolic parameters and CVDs. Herein, we review the literature regarding the effect of metabolic factor variability and CVD risk, and describe possible mechanisms and potential treatment perspectives for reducing cardiometabolic risk factor variability.


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    Diabetes Research and Clinical Practice.2023; 199: 110666.     CrossRef
  • Association between lipid variability and the risk of mortality in cancer patients not receiving lipid-lowering agents
    Seohyun Kim, Gyuri Kim, So Hyun Cho, Rosa Oh, Ji Yoon Kim, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Jae Hyeon Kim
    Frontiers in Oncology.2023;[Epub]     CrossRef
  • Association between visit-to-visit lipid variability and risk of ischemic heart disease: a cohort study in China
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  • Variability of Metabolic Risk Factors: Causative Factor or Epiphenomenon?
    Hye Jin Yoo
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  • Long-Term Variability in Physiological Measures in Relation to Mortality and Epigenetic Aging: Prospective Studies in the US and China
    Hui Chen, Tianjing Zhou, Shaowei Wu, Yaying Cao, Geng Zong, Changzheng Yuan
    SSRN Electronic Journal .2022;[Epub]     CrossRef
Original Articles
Clinical Diabetes & Therapeutics
Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea
Sol Jae Lee, Su Jin Jeong, Yu Chang Lee, Yong Hoon Lee, Jung Eun Lee, Chong Hwa Kim, Kyung Wan Min, Bong Yun Cha
Diabetes Metab J. 2017;41(4):275-283.   Published online July 6, 2017
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  • 68 Download
  • 18 Web of Science
  • 16 Crossref
AbstractAbstract PDFPubReader   

Diabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV).


In this randomized, double-blind, placebo-controlled, multicenter trial, 75 patients were randomly assigned to one of two groups. One group (n=41) received α-lipoic acid (ALA) at an oral dose of 600 mg/day for the first 12 weeks and then 1,200 mg/day for the next 12 weeks. The other group (n=34) received placebo treatment for 24 weeks. CAN was assessed by measuring HRVs in people with diabetes.


Most of the baseline measures for HRVs were similar between the ALA and placebo groups. Although there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial, we found a positive tendency in some of the HRV parameters of the ALA group. The standard deviations of normal-to-normal RR intervals in the standing position increased by 1.87 ms in the ALA group but decreased by −3.97 ms in the placebo group (P=0.06). The power spectrum of the low frequency (LF) band in the standing position increased by 15.77 ms2 in the ALA group, whereas it declined by −15.04 ms2 in the placebo group (P=0.08). The high frequency/LF ratio in the upright position increased by 0.35 in the ALA group, whereas it declined by −0.42 in the placebo group (P=0.06). There were no differences between the two groups regarding rates of adverse events.


Although a slight improvement tendency was seen in HRV in the ALA group, there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial. However, the high oral dose of ALA was well-tolerated.


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  • Evaluating treatment options for cardiovascular autonomic neuropathy in patients with diabetes mellitus: a systematic review
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  • The effects of alpha lipoic acid (ALA) supplementation on blood pressure in adults: a GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials
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  • Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway
    George J. Dugbartey, Quinsker L. Wonje, Karl K. Alornyo, Louis Robertson, Ismaila Adams, Vincent Boima, Samuel D. Mensah
    Frontiers in Pharmacology.2022;[Epub]     CrossRef
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  • Efficacy and safety of oral alpha-lipoic acid supplementation for type 2 diabetes management: a systematic review and dose–response meta-analysis of randomized trials
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  • An updated systematic review and dose-response meta-analysis of the effects of α-lipoic acid supplementation on glycemic markers in adults
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  • Effect of alpha-lipoic acid on arterial stiffness parameters in type 2 diabetes mellitus patients with cardiac autonomic neuropathy
    Victoria A. Serhiyenko, Ludmila M. Serhiyenko, Volodymyr B. Sehin, Alexandr A. Serhiyenko
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  • The Role of Alpha-lipoic Acid Supplementation in the Prevention of Diabetes Complications: A Comprehensive Review of Clinical Trials
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  • Safety Evaluation of α-Lipoic Acid Supplementation: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Clinical Studies
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  • Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet
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  • Alpha-lipoic acid (ALA) supplementation effect on glycemic and inflammatory biomarkers: A Systematic Review and meta- analysis
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  • Response: Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea (Diabetes Metab J 2017;41:275-83)
    Chong Hwa Kim, Sol Jae Lee, Bong Yun Cha
    Diabetes & Metabolism Journal.2017; 41(5): 420.     CrossRef
  • Letter: Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea (Diabetes Metab J2017;41:275-83)
    Jeongmin Lee, Jae Hyoung Cho
    Diabetes & Metabolism Journal.2017; 41(5): 417.     CrossRef
The Status of Diabetes Mellitus and Effects of Related Factors on Heart Rate Variability in a Community.
Kyeong Soon Chang, Kwan Lee, Hyun Sul Lim
Korean Diabetes J. 2009;33(6):537-546.   Published online December 1, 2009
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  • 2 Crossref
AbstractAbstract PDF
This study was performed to examine the status of diabetes mellitus (DM) in the community and effects of related factors on heart rate variability (HRV). METHODS: The author conducted HRV testing, a questionnaire survey, and blood chemistry analysis for fasting blood sugar (FBS) and HbA1c levels in 855 patients in a community over a period of 10 days, from August 14 to 25, 2006. The subjects were divided into a DM group and normal group by our study criteria. RESULTS: The proportion of DM was 12.6% and increased with old age. The mean measures of HRV (SDNN, Tp, Vlf, Lf, Hf, Lf/Hf) in the DM group were 22.7 (1.6) msec, 364.9 (2.7) msec2, 174.1 (3.0) msec2, 88.1 (3.2) msec2, 55.3 (3.2) msec2, and 1.6 (2.6), respectively, while those in the normal group were 32.2 (1.6) msec, 676.6 (2.8) msec2, 295.7 (3.1) msec2, 169.2 (3.4) msec2, 117.2 (3.2) msec2, and 1.4 (2.6), respectively. All parameters except for Lf/Hf were significantly lower in the DM group than in the normal group (P < 0.01). The Spearman's correlation coefficients between HRV and FBS or HbA1c were SDNN -0.222/-0.244 (P < 0.01), Tp -0.211/-0.212 (P < 0.01), Vlf -0.149/-0.132 (P < 0.01), Lf -0.188/-0.235 (P < 0.01), Hf -0.207/-0.204 (P < 0.01), and Lf/Hf (P > 0.05), respectively. CONCLUSION: This study shows that the DM group had a reduced HRV and increased pulse rate in comparison with the normal group. According to our results, the HRV test may be used accessorily for the early detection of cardiovascular autonomic neuropathy (CAN) and its related factors, as well as to prevent CAN.


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Detection of Diabetic Autonomic Neuropathy by 24-Hour Heart Rate Variability Analysis in Type 2 Diabetes Mellitus Patients.
Young Hee Rho, Nan Hee Kim, Dong Lim Kim, Dong Hyun Shin, Sin Gon Kim, Kyung Mook Choi, Woo Hyuk Song, Sei Hyun Baik, Woo Keun Seo, Min Kyu Park, Dong Seop Choi
Korean Diabetes J. 2002;26(3):208-219.   Published online June 1, 2002
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  • 19 Download
AbstractAbstract PDF
Diabetic autonomic neuropathy is a relatively common diabetic complication, associated with high long-term mortality. Ewing's test is known as the 'gold standard' for evaluating and diagnosing this disease, yet is not widely used due to the inconvenient procedures of the test. 24-hour Holter EKG monitoring, and the analytical product, heart rate variability, is being introduced as a relatively simple and reliable procedure for the evaluation of diabetic autonomic neuropathy. We explored whether such heart rate variability products derived from Holter monitoring, correlated with the presence, absence, or severity of diabetes mellitus, and whether it correlated well with conventional autonomic tests. METHODS: We compared 59 type 2 diabetic patients with 71 normal subjects. All underwent 24-hr Holter EKG monitoring and basic autonomic evaluations, such as the head-up tilting, hand grip, and deep breathing-heart rate variability tests. Those who had diabetes also underwent evaluation for basic blood chemistry, and complication studies, for things such as: 24-hour urine albumin excretion, fundoscopy and nerve conduction. RESULTS: Variables for heart rate variability were expressed as SDDN, rMSSD, LF, HF, and LF/HF, where SDDN is the Standard Deviation of all RR intervals, rMSSD the square root of the mean of the sum of the squares of differences between adjacent RR intervals, LF the power in the Low Frequency range and HF the power in the High Frequency range, with LF/HF being the ratio between LF and HF. Heart rate variability was significantly lower in terms of rMSSD, LF, HF, but not in terms of the LF/HF ratio, for the diabetic patients compared to the normal subjects. These three variables also correlated with the conventional autonomic tests of systolic blood pressure changes during standing up (negatively), and heart rate variability during deep breathing (positively). SDDN, rMSSD, LF, and HF also correlated negatively with the duration of diabetes. SDDN, LF and HF were significantly lower among patients who had complications such as: retinopathy, nephropathy or peripheral neuropathy, than in those who did not. CONCLUSION: Heart rate variability was lower in type 2 diabetic patients than the control subjects, which correlated well with the duration of diabetes mellitus, diabetic chronic complications and the conventional autonomic nervous function tests, so could be an useful adjunct or even a replacement, for conventional autonomic nervous system testing procedures. More research is needed in this field.

Diabetes Metab J : Diabetes & Metabolism Journal