Diabetes & Metabolism Journal

Original Articles

Lifestyle and Behavioral Interventions
Association between the Life’s Essential 8 Health Behaviors Score and Mortality Risk in US Adults with Cardiovascular-Kidney-Metabolic Syndrome Stage 0–3: Junlin Zhang, Limei Yin, Yuping Liu, Xiang Xiao, Ping Shuai; Received April 26, 2025 Accepted June 16, 2025 Published online December 12, 2025; DOI: https://doi.org/10.4093/dmj.2025.0366 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
The American Heart Association’s novel cardiovascular-kidney-metabolic (CKM) syndrome framework underscores the interconnected pathophysiology of metabolic dysfunction, chronic kidney disease, and cardiovascular disease (CVD). While the Life’s Essential 8 (LE8) has demonstrated strong associations with CVD risk in general populations, its prognostic relevance remains unexplored in individuals stratified by CKM syndrome stages.
Methods
This study analyzed longitudinal data from the nationally representative National Health and Nutrition Examination Survey (2005–2018). The eight components of the LE8 metric—diet quality, physical activity, nicotine exposure, sleep health, body mass index, blood lipid profiles, glycemic status, and blood pressure—were systematically evaluated and scored on a 0–100 scale. A Cox proportional hazards regression model was implemented to assess associations between LE8 scores and all-cause mortality risk. Mortality outcomes were prospectively tracked through December 31, 2019, using linked mortality records from the National Center for Health Statistics.
Results
Among 9,152 participants (mean age 45.08±0.29 years; 48.24% male), baseline CKM staging distributed as follows: stage 0 (12.08%, n=916), stage 1 (25.76%, n=2,162), stage 2 (60.02%, n=5,721), and stage 3 (2.14%, n=353). Unexpectedly, during a median follow-up of 7.92 years, the total LE8 score was not related with all-cause mortality in individuals with CKM stage 2–3 (P>0.05). However, fully adjusted analyses revealed a 22% and 13% decreased all-cause mortality risk per 10-points LE8 health behaviors score increment in CKM 0-1 (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.68 to 0.88) and CKM 2-3 (HR, 0.87; 95% CI, 0.81 to 0.93), respectively. Restricted cubic spline models confirmed a negative linear dose-response relationship between health behaviors score and all-cause mortality across all CKM stages 0–3.
Conclusion
This national cohort study establishes LE8 health behaviors score as a robust, linearly associated predictor of all-cause mortality in CKM syndrome populations, independent of disease stage severity. These findings advocate for integrating LE8 health behaviors score into routine metabolic-cardiovascular risk stratification protocols, particularly for early intervention in CKM stage 0–3 individuals.

Metabolic Risk/Epidemiology
Association of Remnant Cholesterol Inflammation Index with Cardiovascular Risks and All-Cause Mortality in Individuals with Diabetes or Prediabetes: Qi-Lin Ma, Lei-Lei Du, Jia Peng; Received April 8, 2025 Accepted June 27, 2025 Published online October 2, 2025; DOI: https://doi.org/10.4093/dmj.2025.0305 [Epub ahead of print]

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Background
Remnant cholesterol (RC) and low-grade inflammation are established contributors to cardiovascular disease (CVD) risks in diabetes. However, their combined prognostic impact remains unclear in dysglycemia. We evaluated the remnant cholesterol inflammation index (RCII), integrating RC and high-sensitivity C-reactive protein (hsCRP), for predicting mortality and CVD risks in diabetes/prediabetes.
Methods
This study included 2206 United States adults with diabetes/prediabetes from National Health and Nutrition Examination Survey 2015–2018. RCII was calculated as [RC (mg/dL)×hsCRP (mg/L)]/10. All-cause mortality was tracked via National Death Index until 2019; CVD risk was assessed cross-sectionally. Cox proportional hazard regression determined the hazard ratio (HR) and 95% confidence intervals (CIs) of RCII for all-cause mortality. Logistic regression models estimated the odds ratio (OR) and 95% CIs of RCII for CVD risks.
Results
For CVD risks, Q4 vs. Q1 demonstrated increased odds (OR, 2.32; 95% CI, 1.23 to 4.37), though per-standard deviation (SD) increments were non-significant (OR, 1.15; 95% CI, 0.98 to 1.35; P=0.083). During a median of 38 months follow-up, higher RCII quartiles showed graded associations with all-cause mortality (Q4 vs. Q1: HR, 2.45; 95% CI, 1.08 to 5.58; per 1-SD increase: HR, 1.21; 95% CI, 1.08 to 1.35). Restricted cubic splines confirmed dose-dependent relationships for CVD risks and all-cause mortality (all P=0.005 for overall). Subgroup analyses revealed consistent mortality associations but sex-specific CVD interactions (P=0.047 for interaction).
Conclusion
Our study found the RCII as a biomarker for predicting all-cause mortality and CVD risks in individuals with prediabetes or diabetes, highlighting the synergistic effects of RC and low-grade inflammation on adverse outcomes in this population and may facilitate early identification of individuals at heightened risk for CVD.

Citations

Citations to this article as recorded by

Association of remnant cholesterol inflammation index with future cardiovascular disease risk in patients with cardiovascular-kidney-metabolic syndrome stages 0–3
Nanshan Xie, Lihuan Zeng, Xiangming Hu, Zejia Wu, Weiling Lu, Songyuan Luo, Jianfang Luo
Diabetes Research and Clinical Practice.2026; 233: 113146. CrossRef
Association Between the Remnant Cholesterol Inflammation Index and Cardiac Syndrome X
İbrahim Aktaş, Erdoğan Yaşar, Kadir Uçkaç
Diagnostics.2026; 16(8): 1113. CrossRef

Cardiovascular Risk/Epidemiology
Comparison of on-Statin Lipid and Lipoprotein Levels for the Prediction of First Cardiovascular Event in Type 2 Diabetes Mellitus: Ji Yoon Kim, Jimi Choi, Sin Gon Kim, Nam Hoon Kim; Diabetes Metab J. 2023;47(6):837-845. Published online August 23, 2023; DOI: https://doi.org/10.4093/dmj.2022.0217

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Background
A substantial cardiovascular disease risk remains even after optimal statin therapy. Comparative predictiveness of major lipid and lipoprotein parameters for cardiovascular events in patients with type 2 diabetes mellitus (T2DM) who are treated with statins is not well documented.
Methods
From the Korean Nationwide Cohort, 11,900 patients with T2DM (≥40 years of age) without a history of cardiovascular disease and receiving moderate- or high-intensity statins were included. The primary outcome was the first occurrence of major adverse cardiovascular events (MACE) including ischemic heart disease, ischemic stroke, and cardiovascular death. The risk of MACE was estimated according to on-statin levels of low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), highdensity lipoprotein cholesterol (HDL-C), and non-HDL-C.
Results
MACE occurred in 712 patients during a median follow-up period of 37.9 months (interquartile range, 21.7 to 54.9). Among patients achieving LDL-C levels less than 100 mg/dL, the hazard ratios for MACE per 1-standard deviation change in ontreatment values were 1.25 (95% confidence interval [CI], 1.07 to 1.47) for LDL-C, 1.31 (95% CI, 1.09 to 1.57) for non-HDL-C, 1.05 (95% CI, 0.91 to 1.21) for TG, and 1.16 (95% CI, 0.98 to 1.37) for HDL-C, after adjusting for potential confounders and lipid parameters mutually. The predictive ability of on-statin LDL-C and non-HDL-C for MACE was prominent in patients at high cardiovascular risk or those with LDL-C ≥70 mg/dL.
Conclusion
On-statin LDL-C and non-HDL-C levels are better predictors of the first cardiovascular event than TG or HDL-C in patients with T2DM.

Citations

Citations to this article as recorded by

Current Status of Continuous Glucose Monitoring Use in South Korean Type 1 Diabetes Mellitus Population–Pronounced Age-Related Disparities: Nationwide Cohort Study
Ji Yoon Kim, Seohyun Kim, Jae Hyeon Kim
Diabetes & Metabolism Journal.2025; 49(5): 1040. CrossRef
Managing dyslipidemia in chronic kidney disease: a comprehensive overview of evidence and recommendations
Ji Yoon Kim, Suk Min Chung, Nam Hoon Kim
The Korean Journal of Internal Medicine.2025; 40(6): 876. CrossRef

Drug/Regimen
Comparison of Serum Ketone Levels and Cardiometabolic Efficacy of Dapagliflozin versus Sitagliptin among Insulin-Treated Chinese Patients with Type 2 Diabetes Mellitus: Chi-Ho Lee, Mei-Zhen Wu, David Tak-Wai Lui, Darren Shing-Hei Chan, Carol Ho-Yi Fong, Sammy Wing-Ming Shiu, Ying Wong, Alan Chun-Hong Lee, Joanne King-Yan Lam, Yu-Cho Woo, Karen Siu-Ling Lam, Kelvin Kai-Hang Yiu, Kathryn Choon-Beng Tan; Diabetes Metab J. 2022;46(6):843-854. Published online April 28, 2022; DOI: https://doi.org/10.4093/dmj.2021.0319

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Background
Insulin-treated patients with long duration of type 2 diabetes mellitus (T2DM) are at increased risk of ketoacidosis related to sodium-glucose co-transporter 2 inhibitor (SGLT2i). The extent of circulating ketone elevation in these patients remains unknown. We conducted this study to compare the serum ketone response between dapagliflozin, an SGLT2i, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, among insulin-treated T2DM patients.
Methods
This was a randomized, open-label, active comparator-controlled study involving 60 insulin-treated T2DM patients. Participants were randomized 1:1 for 24-week of dapagliflozin 10 mg daily or sitagliptin 100 mg daily. Serum β-hydroxybutyrate (BHB) levels were measured at baseline, 12 and 24 weeks after intervention. Comprehensive cardiometabolic assessments were performed with measurements of high-density lipoprotein cholesterol (HDL-C) cholesterol efflux capacity (CEC), vibration-controlled transient elastography and echocardiography.
Results
Among these 60 insulin-treated participants (mean age 58.8 years, diabetes duration 18.2 years, glycosylated hemoglobin 8.87%), as compared with sitagliptin, serum BHB levels increased significantly after 24 weeks of dapagliflozin (P=0.045), with a median of 27% increase from baseline. Change in serum BHB levels correlated significantly with change in free fatty acid levels. Despite similar glucose lowering, dapagliflozin led to significant improvements in body weight (P=0.006), waist circumference (P=0.028), HDL-C (P=0.041), CEC (P=0.045), controlled attenuation parameter (P=0.007), and liver stiffness (P=0.022). Average E/e’, an echocardiographic index of left ventricular diastolic dysfunction, was also significantly lower at 24 weeks in participants treated with dapagliflozin (P=0.037).
Conclusion
Among insulin-treated T2DM patients with long diabetes duration, compared to sitagliptin, dapagliflozin modestly increased ketone levels and was associated with cardiometabolic benefits.

Citations

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Comparative Efficacy of SGLT2 Inhibitors in MASLD: Bayesian Network Meta‐Analysis of CAP–LSM Outcomes and Time Effects
Demver P. Gomez, Wilmyr F. Hababag, Celeste C. Ong‐Ramos
JGH Open.2026;[Epub] CrossRef
Beyond insulin therapy: Comparing relative benefits of adding SGLT2 versus DPP4 inhibitors in poorly controlled type 2 diabetic patients: A systematic review and meta-analysis
Navami K.S., Christy Thomas, Roopa Satyanarayan Basutkar
Primary Care Diabetes.2026;[Epub] CrossRef
Dapagliflozin improves diabetic kidney disease by inhibiting ferroptosis through β-hydroxybutyrate production
Yan Tian, Chenxia Zhou, Qun Yan, Ziyi Li, Da Chen, Bo Feng, Jun Song
Renal Failure.2025;[Epub] CrossRef
Ketosis and ketoacidosis in hospitalized patients receiving SGLT2 inhibitor therapy
Frank M. Gao, Kartik Kishore, Dinesh Pandey, Hossein Jahanabadi, Meg Stevens, Ashani Lecamwasam, Rinaldo Bellomo, Leonid Churilov, Elif I. Ekinci
Diabetes, Obesity and Metabolism.2025; 27(11): 6367. CrossRef
Monitoring Ketonemia in People with Diabetes: Preliminary Findings from Real-World Studies
Richard M. Bergenstal, Naunihal Virdi, Farhan Quadri, Shridhara Alva
Diabetes Technology & Therapeutics.2025; 27(S4): S25. CrossRef
Dipeptidyl Peptidase-4 Inhibitors Improved Lipid Levels in Patients With Type 2 Diabetes: A Meta-analysis of Randomized Clinical Trials
Lijia Zhao, Jie Meng, Jingjing Li, Hengri Cong, Changbin Liu, Yu Yang, Yangfeng Wu, Xin Liu
Nutrition Reviews.2025;[Epub] CrossRef
Serum thrombospondin‐2 level changes with liver stiffness improvement in patients with type 2 diabetes
Jimmy Ho Cheung Mak, David Tak‐Wai Lui, Carol Ho‐Yi Fong, Chloe Yu‐Yan Cheung, Ying Wong, Alan Chun‐Hong Lee, Ruby Lai‐Chong Hoo, Aimin Xu, Kathryn Choon‐Beng Tan, Karen Siu‐Ling Lam, Chi‐Ho Lee
Clinical Endocrinology.2024; 100(3): 230. CrossRef
SGLT-2 inhibitors as novel treatments of multiple organ fibrosis
Junpei Hu, Jianhui Teng, Shan Hui, Lihui Liang
Heliyon.2024; 10(8): e29486. CrossRef
Innovations and applications of ketone body monitoring in diabetes care
Naoki Sakane
Diabetology International.2024; 15(3): 370. CrossRef
Effect of dapagliflozin on readmission and loop diuretics use in patients with acute heart failure: a retrospective propensity score-matched cohort study
Dong Wu, Zhen Ma, Xiaoying Wang, Xiaowu Wang, Xiaojuan Wang
BMC Cardiovascular Disorders.2024;[Epub] CrossRef
Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside
Urna Kansakar, Crystal Nieves Garcia, Gaetano Santulli, Jessica Gambardella, Pasquale Mone, Stanislovas S. Jankauskas, Angela Lombardi
Journal of Clinical Medicine.2024; 13(23): 7391. CrossRef
Effect of sodium-glucose cotransporter protein-2 inhibitors on left ventricular hypertrophy in patients with type 2 diabetes: A systematic review and meta-analysis
Yao Wang, Yujie Zhong, Zhehao Zhang, Shuhao Yang, Qianying Zhang, Bingyang Chu, Xulin Hu
Frontiers in Endocrinology.2023;[Epub] CrossRef
Effects of SGLT2 inhibitors on hepatic fibrosis and steatosis: A systematic review and meta-analysis
Peipei Zhou, Ying Tan, Zhenning Hao, Weilong Xu, Xiqiao Zhou, Jiangyi Yu
Frontiers in Endocrinology.2023;[Epub] CrossRef
The impact of sodium-glucose Cotransporter-2 inhibitors on lipid profile: A meta-analysis of 28 randomized controlled trials
Gang Fan, Dian long Guo, Hong Zuo
European Journal of Pharmacology.2023; 959: 176087. CrossRef

Review

Cardiovascular Risk/Epidemiology
Management of Cardiovascular Risk in Perimenopausal Women with Diabetes: Catherine Kim; Diabetes Metab J. 2021;45(4):492-501. Published online July 30, 2021; DOI: https://doi.org/10.4093/dmj.2020.0262

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Cardiovascular disease is the primary cause of mortality in women and men with diabetes. Due to age and worsening of risk factors over the menopausal transition, risk of coronary heart disease events increases in postmenopausal women with diabetes. Randomized studies have conflicted regarding the beneficial impact of estrogen therapy upon intermediate cardiovascular disease markers and events. Therefore, estrogen therapy is not currently recommended for indications other than symptom management. However, for women at low risk of adverse events, estrogen therapy can be used to minimize menopausal symptoms. The risk of adverse events can be estimated using risk engines for the calculation of cardiovascular risk and breast cancer risk in conjunction with screening tools such as mammography. Use of estrogen therapy, statins, and anti-platelet agents can be guided by such calculators particularly for younger women with diabetes. Risk management remains focused upon lifestyle behaviors and achieving optimal levels of cardiovascular risk factors, including lipids, glucose, and blood pressure. Use of pharmacologic therapies to address these risk factors, particularly specific hypoglycemic agents, may provide some additional benefit for risk prevention. The minimal benefit for women with limited life expectancy and risk of complications with intensive therapy should also be considered.

Citations

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Yu Yang, Yu Chen, Changju Liu, Su Wang, Yijing Zhao, Wen Cao, Kun Wang, Syed Anees Ahmed
Journal of Diabetes Research.2025;[Epub] CrossRef
Sex hormones correlate with heart rate variability in healthy women and this correlation is conserved in women with well-controlled type 2 diabetes mellitus
Adriana Robles-Cabrera, Claudia Lerma, Silvia Ruiz-Velasco Acosta, Iván Pérez-Díaz, Ruben Fossion, Nejka Potocnik
PLOS ONE.2025; 20(4): e0320982. CrossRef
Impact of sex and menopausal hormonal therapy on cardiovascular diseases in people with diabetes or prediabetes
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Scientific Reports.2025;[Epub] CrossRef
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