The associations between stress hyperglycemia ratio and all-cause/cardiovascular/diabetes-related mortality in advanced cardiovascular-kidney-metabolic syndrome_Chinese Journal of Evidence-Based Medicine

Authors：

LIU Yiying ¹ , LIU Ruikang ^1,2 ,  LI Jun ¹ , LIU Yongmei ¹ , CHEN Cong ¹ , ZHANG Fuyuan ¹ , YUAN Yulian ³ , YE Guancheng ^2,4

1. Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P. R. China;
2. Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P. R. China;
3. Department of Nephrology and Endocrinology, Yuquan Hospital, Tsinghua University, Beijing 100040, P. R. China;
4. Department of Rheumatology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Dongcheng District, Beijing, 100700, P. R. China;

Corresponding author：

LI Jun, Email: gamyylj@163.com

Keywords：

Stress hyperglycemia ratio; Advanced cardiovascular-kidney-metabolic syndrome; NHANES; Diabetes-related mortality; All-cause mortality; Cardiovascular mortality; Risk prediction.

DOI：

10.7507/1672-2531.202508074

Video：

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Objective To investigate the association between the stress-induced hyperglycemia ratio (SHR) and all-cause, cardiovascular, and diabetes-related mortality in patients with advanced cardiovascular-kidney-metabolic (CKM) syndrome, and to evaluate the value of SHR as an independent prognostic marker. Methods This retrospective cohort study used data from the 1999–2018 U.S. National Health and Nutrition Examination Survey (NHANES). A total of 2 135 patients with advanced CKM (stages 3 and 4) were included. Kaplan-Meier analysis and multivariable Cox regression models were applied to assess the relationship between SHR and mortality outcomes. Restricted cubic spline (RCS) analysis was employed to explore potential non-linear associations. Subgroup analyses were conducted to identify possible effect modifiers. Results Over a mean follow-up of 248 months, 674 all-cause, 198 cardiovascular, and 31 diabetes-related deaths occurred. Elevated SHR was significantly associated with diabetes-related mortality (HR=3.48, P<0.001) in a dose-response manner. SHR exhibited a U-shaped relationship with both all-cause and cardiovascular mortality (non-linearity P<0.001), indicating increased risk at both low and high SHR levels. Subgroup analyses revealed that sex, BMI, and hyperlipidemia significantly modified the association between SHR and diabetes-related death. Conclusion SHR is an independent predictor of mortality risk in patients with advanced CKM syndrome, particularly for diabetes-related death. These findings support the integration of SHR into risk stratification of high-risk CKM populations and provide a basis for metabolic stress-targeted interventions.

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2.	Roth S, M'Pembele R, Matute P, et al. Cardiovascular-kidney-metabolic syndrome: association with adverse events after major noncardiac surgery. Anesth Analg, 2024, 139(3): 679-681.
3.	Chen Y, Wu S, Liu H, et al. Role of oxidative balance score in staging and mortality risk of cardiovascular-kidney-metabolic syndrome: insights from traditional and machine learning approaches. Redox Biol, 2025, 81: 103588.
4.	Huang YW, An YH, Yin XS, et al. Association of the stress hyperglycemia ratio and clinical outcomes in patients with cardiovascular diseases: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci, 2022, 26(24): 9258-9269.
5.	Li Y, Shen N, Xie E, et al. Predicting the impact of stress-induced hyperglycemia on in-hospital mortality in patients with chronic kidney disease and acute coronary syndrome: a retrospective study. J Diabetes Complications, 2024, 38(12): 108895.
6.	Shay CM, Ning H, Allen NB, et al. Status of cardiovascular health in US adults: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2003-2008. Circulation, 2012, 125(1): 45-56.
7.	Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation, 2023, 148(20): 1606-1635.
8.	Massy ZA, Drueke TB. Combination of cardiovascular, kidney, and metabolic diseases in a syndrome named cardiovascular-kidney-metabolic, with new risk prediction equations. Kidney Int Rep, 2024, 9(9): 2608-2618.
9.	Roberts GW, Quinn SJ, Valentine N, et al. Relative hyperglycemia, a marker of critical illness: introducing the stress hyperglycemia ratio. J Clin Endocrinol Metab, 2015, 100(12): 4490-4497.
10.	Hou W, Chen S, Zhu C, et al. Associations between smoke exposure and osteoporosis or osteopenia in a US NHANES population of elderly individuals. Front Endocrinol (Lausanne), 2023, 14: 1074574.
11.	Xiao Q, Cai B, Yin A, et al. L-shaped association of serum 25-hydroxyvitamin D concentrations with cardiovascular and all-cause mortality in individuals with osteoarthritis: results from the NHANES database prospective cohort study. BMC Med, 2022, 20(1): 308.
12.	MacGregor KA, Gallagher IJ, Moran CN. Relationship between insulin sensitivity and menstrual cycle is modified by BMI, fitness, and physical activity in NHANES. J Clin Endocrinol Metab, 2021, 106(10): 2979-2990.
13.	Dreimüller N, Lieb K, Tadić A, et al. Body mass index (BMI) in major depressive disorder and its effects on depressive symptomatology and antidepressant response. J Affect Disord, 2019, 256: 524-531.
14.	Chen TC, Clark J, Riddles MK, et al. National Health and Nutrition Examination Survey, 2015-2018: sample design and estimation procedures. Vital Health Stat 2, 2020, (184): 1-35.
15.	Tan MY, Zhang YJ, Zhu SX, et al. The prognostic significance of stress hyperglycemia ratio in evaluating all-cause and cardiovascular mortality risk among individuals across stages 0-3 of cardiovascular-kidney-metabolic syndrome: evidence from two cohort studies. Cardiovasc Diabetol, 2025, 24(1): 137.
16.	Alifu J, Xu B, Tuersun G, et al. The prognostic significance of stress hyperglycemia ratio for all-cause and cardiovascular mortality in metabolic syndrome patients: prospective cohort study. Acta Diabetol, 2025, 62(6): 903-913.
17.	Iacobini C, Vitale M, Haxhi J, et al. Mutual regulation between redox and hypoxia-inducible factors in cardiovascular and renal complications of diabetes. Antioxidants (Basel), 2022, 11(11): 2183.
18.	Gao S, Huang S, Lin X, et al. Prognostic implications of stress hyperglycemia ratio in patients with myocardial infarction with nonobstructive coronary arteries. Ann Med, 2023, 55(1): 990-999.
19.	Sasaki S, Inoguchi T. The role of oxidative stress in the pathogenesis of diabetic vascular complications. Diabetes Metab J, 2012, 36(4): 255-261.
20.	Bellis A, Mauro C, Barbato E, et al. Stress-induced hyperglycaemia in non-diabetic patients with acute coronary syndrome: from molecular mechanisms to new therapeutic perspectives. Int J Mol Sci, 2021, 22(2): 775.
21.	Zhang Y, Guo L, Zhu H, et al. Effects of the stress hyperglycemia ratio on long-term mortality in patients with triple-vessel disease and acute coronary syndrome. Cardiovasc Diabetol, 2024, 23(1): 143.
22.	Hong SB, Kim JE, Han SS, et al. Prevalence of cardiovascular-kidney-metabolic syndrome in Korea: Korea National Health and Nutrition Examination Survey 2011-2021. Epidemiol Health, 2025, 47: e2025005.
23.	Ji H, Sabanayagam C, Matsushita K, et al. Sex differences in cardiovascular-kidney-metabolic syndrome: 30-year US trends and mortality risks-brief report. Arterioscler Thromb Vasc Biol, 2025, 45(1): 157-161.
24.	Keane KN, Cruzat VF, Carlessi R, et al. Molecular events linking oxidative stress and inflammation to insulin resistance and β-cell dysfunction. Oxid Med Cell Longev, 2015, 2015: 181643.
25.	Aghadavod E, Khodadadi S, Baradaran A, et al. Role of oxidative stress and inflammatory factors in diabetic kidney disease. Iran J Kidney Dis, 2016, 10(6): 337-343.
26.	Nichols GA, Amitay EL, Chatterjee S, et al. The Bidirectional association of chronic kidney disease, type 2 diabetes, atherosclerotic cardiovascular disease, and heart failure: the cardio-renal-metabolic syndrome. Metab Syndr Relat Disord, 2023, 21(5): 261-266.
27.	Xu W, Song Q, Wang X, et al. Association of stress hyperglycemia ratio and in-hospital mortality in patients with coronary artery disease: insights from a large cohort study. Cardiovasc Diabetol, 2022, 21(1): 217.
28.	Gómez-Marcos MÁ, Recio-Rodríguez JI, Gómez-Sánchez L, et al. Gender differences in the progression of target organ damage in patients with increased insulin resistance: the LOD-DIABETES study. Cardiovasc Diabetol, 2015, 14: 132.
29.	Kranjcec D, Altabas V. Metabolic syndrome influencing infarct size and heart failure in patients with acute coronary syndrome: does gender matter. Endocr J, 2012, 59(12): 1065-1076.
30.	Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest, 2019, 129(10): 4001-4008.
31.	Suslova TE, Sitozhevskii AV, Ogurkova ON, et al. Platelet hemostasis in patients with metabolic syndrome and type 2 diabetes mellitus: cGMP- and NO-dependent mechanisms in the insulin-mediated platelet aggregation. Front Physiol, 2015, 5: 501.
32.	Cheng Y, Zhang H, Chen R, et al. Cardiometabolic risk profiles associated with chronic complications in overweight and obese type 2 diabetes patients in South China. PLoS One, 2014, 9(7): e101289.
33.	Rashvand S, Mobasseri M, Tarighat-Esfanjani A. Effects of choline and magnesium concurrent supplementation on coagulation and lipid profile in patients with type 2 diabetes mellitus: a pilot clinical trial. Biol Trace Elem Res, 2020, 194(2): 328-335.
34.	Hoseini A, Namazi G, Farrokhian A, et al. The effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease. Food Funct, 2019, 10(9): 6042-6051.
35.	Lee EY, Lee YH, Yi SW, et al. BMI and all-cause mortality in normoglycemia, impaired fasting glucose, newly diagnosed diabetes, and prevalent diabetes: a cohort study. Diabetes Care, 2017, 40(8): 1026-1033.
36.	Lin CC, Li CI, Liu CS, et al. Obesity paradox in associations between body mass index and diabetes-related hospitalization and mortality in patients with type 2 diabetes: retrospective cohort studies. Diabetes Metab, 2019, 45(6): 564-572.
37.	Amouzegar A, Honarvar M, Masoumi S, et al. Independent association of metabolic syndrome severity score and risk of diabetes: findings from 18 years of follow-up in the Tehran lipid and glucose study. BMJ Open, 2024, 14(9): e078701.

1. Cao Y, Wang W, Xie S, et al. Joint association of the inflammatory marker and cardiovascular-kidney-metabolic syndrome stages with all-cause and cardiovascular disease mortality: a national prospective study. BMC Public Health, 2025, 25(1): 10.
2. Roth S, M'Pembele R, Matute P, et al. Cardiovascular-kidney-metabolic syndrome: association with adverse events after major noncardiac surgery. Anesth Analg, 2024, 139(3): 679-681.
3. Chen Y, Wu S, Liu H, et al. Role of oxidative balance score in staging and mortality risk of cardiovascular-kidney-metabolic syndrome: insights from traditional and machine learning approaches. Redox Biol, 2025, 81: 103588.
4. Huang YW, An YH, Yin XS, et al. Association of the stress hyperglycemia ratio and clinical outcomes in patients with cardiovascular diseases: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci, 2022, 26(24): 9258-9269.
5. Li Y, Shen N, Xie E, et al. Predicting the impact of stress-induced hyperglycemia on in-hospital mortality in patients with chronic kidney disease and acute coronary syndrome: a retrospective study. J Diabetes Complications, 2024, 38(12): 108895.
6. Shay CM, Ning H, Allen NB, et al. Status of cardiovascular health in US adults: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2003-2008. Circulation, 2012, 125(1): 45-56.
7. Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation, 2023, 148(20): 1606-1635.
8. Massy ZA, Drueke TB. Combination of cardiovascular, kidney, and metabolic diseases in a syndrome named cardiovascular-kidney-metabolic, with new risk prediction equations. Kidney Int Rep, 2024, 9(9): 2608-2618.
9. Roberts GW, Quinn SJ, Valentine N, et al. Relative hyperglycemia, a marker of critical illness: introducing the stress hyperglycemia ratio. J Clin Endocrinol Metab, 2015, 100(12): 4490-4497.
10. Hou W, Chen S, Zhu C, et al. Associations between smoke exposure and osteoporosis or osteopenia in a US NHANES population of elderly individuals. Front Endocrinol (Lausanne), 2023, 14: 1074574.
11. Xiao Q, Cai B, Yin A, et al. L-shaped association of serum 25-hydroxyvitamin D concentrations with cardiovascular and all-cause mortality in individuals with osteoarthritis: results from the NHANES database prospective cohort study. BMC Med, 2022, 20(1): 308.
12. MacGregor KA, Gallagher IJ, Moran CN. Relationship between insulin sensitivity and menstrual cycle is modified by BMI, fitness, and physical activity in NHANES. J Clin Endocrinol Metab, 2021, 106(10): 2979-2990.
13. Dreimüller N, Lieb K, Tadić A, et al. Body mass index (BMI) in major depressive disorder and its effects on depressive symptomatology and antidepressant response. J Affect Disord, 2019, 256: 524-531.
14. Chen TC, Clark J, Riddles MK, et al. National Health and Nutrition Examination Survey, 2015-2018: sample design and estimation procedures. Vital Health Stat 2, 2020, (184): 1-35.
15. Tan MY, Zhang YJ, Zhu SX, et al. The prognostic significance of stress hyperglycemia ratio in evaluating all-cause and cardiovascular mortality risk among individuals across stages 0-3 of cardiovascular-kidney-metabolic syndrome: evidence from two cohort studies. Cardiovasc Diabetol, 2025, 24(1): 137.
16. Alifu J, Xu B, Tuersun G, et al. The prognostic significance of stress hyperglycemia ratio for all-cause and cardiovascular mortality in metabolic syndrome patients: prospective cohort study. Acta Diabetol, 2025, 62(6): 903-913.
17. Iacobini C, Vitale M, Haxhi J, et al. Mutual regulation between redox and hypoxia-inducible factors in cardiovascular and renal complications of diabetes. Antioxidants (Basel), 2022, 11(11): 2183.
18. Gao S, Huang S, Lin X, et al. Prognostic implications of stress hyperglycemia ratio in patients with myocardial infarction with nonobstructive coronary arteries. Ann Med, 2023, 55(1): 990-999.
19. Sasaki S, Inoguchi T. The role of oxidative stress in the pathogenesis of diabetic vascular complications. Diabetes Metab J, 2012, 36(4): 255-261.
20. Bellis A, Mauro C, Barbato E, et al. Stress-induced hyperglycaemia in non-diabetic patients with acute coronary syndrome: from molecular mechanisms to new therapeutic perspectives. Int J Mol Sci, 2021, 22(2): 775.
21. Zhang Y, Guo L, Zhu H, et al. Effects of the stress hyperglycemia ratio on long-term mortality in patients with triple-vessel disease and acute coronary syndrome. Cardiovasc Diabetol, 2024, 23(1): 143.
22. Hong SB, Kim JE, Han SS, et al. Prevalence of cardiovascular-kidney-metabolic syndrome in Korea: Korea National Health and Nutrition Examination Survey 2011-2021. Epidemiol Health, 2025, 47: e2025005.
23. Ji H, Sabanayagam C, Matsushita K, et al. Sex differences in cardiovascular-kidney-metabolic syndrome: 30-year US trends and mortality risks-brief report. Arterioscler Thromb Vasc Biol, 2025, 45(1): 157-161.
24. Keane KN, Cruzat VF, Carlessi R, et al. Molecular events linking oxidative stress and inflammation to insulin resistance and β-cell dysfunction. Oxid Med Cell Longev, 2015, 2015: 181643.
25. Aghadavod E, Khodadadi S, Baradaran A, et al. Role of oxidative stress and inflammatory factors in diabetic kidney disease. Iran J Kidney Dis, 2016, 10(6): 337-343.
26. Nichols GA, Amitay EL, Chatterjee S, et al. The Bidirectional association of chronic kidney disease, type 2 diabetes, atherosclerotic cardiovascular disease, and heart failure: the cardio-renal-metabolic syndrome. Metab Syndr Relat Disord, 2023, 21(5): 261-266.
27. Xu W, Song Q, Wang X, et al. Association of stress hyperglycemia ratio and in-hospital mortality in patients with coronary artery disease: insights from a large cohort study. Cardiovasc Diabetol, 2022, 21(1): 217.
28. Gómez-Marcos MÁ, Recio-Rodríguez JI, Gómez-Sánchez L, et al. Gender differences in the progression of target organ damage in patients with increased insulin resistance: the LOD-DIABETES study. Cardiovasc Diabetol, 2015, 14: 132.
29. Kranjcec D, Altabas V. Metabolic syndrome influencing infarct size and heart failure in patients with acute coronary syndrome: does gender matter. Endocr J, 2012, 59(12): 1065-1076.
30. Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest, 2019, 129(10): 4001-4008.
31. Suslova TE, Sitozhevskii AV, Ogurkova ON, et al. Platelet hemostasis in patients with metabolic syndrome and type 2 diabetes mellitus: cGMP- and NO-dependent mechanisms in the insulin-mediated platelet aggregation. Front Physiol, 2015, 5: 501.
32. Cheng Y, Zhang H, Chen R, et al. Cardiometabolic risk profiles associated with chronic complications in overweight and obese type 2 diabetes patients in South China. PLoS One, 2014, 9(7): e101289.
33. Rashvand S, Mobasseri M, Tarighat-Esfanjani A. Effects of choline and magnesium concurrent supplementation on coagulation and lipid profile in patients with type 2 diabetes mellitus: a pilot clinical trial. Biol Trace Elem Res, 2020, 194(2): 328-335.
34. Hoseini A, Namazi G, Farrokhian A, et al. The effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease. Food Funct, 2019, 10(9): 6042-6051.
35. Lee EY, Lee YH, Yi SW, et al. BMI and all-cause mortality in normoglycemia, impaired fasting glucose, newly diagnosed diabetes, and prevalent diabetes: a cohort study. Diabetes Care, 2017, 40(8): 1026-1033.
36. Lin CC, Li CI, Liu CS, et al. Obesity paradox in associations between body mass index and diabetes-related hospitalization and mortality in patients with type 2 diabetes: retrospective cohort studies. Diabetes Metab, 2019, 45(6): 564-572.
37. Amouzegar A, Honarvar M, Masoumi S, et al. Independent association of metabolic syndrome severity score and risk of diabetes: findings from 18 years of follow-up in the Tehran lipid and glucose study. BMJ Open, 2024, 14(9): e078701.

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Latest ArticlesThe associations between stress hyperglycemia ratio and all-cause/cardiovascular/diabetes-related mortality in advanced cardiovascular-kidney-metabolic syndrome

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