Assessment of the significance of factors associated with the development of long-term adverse cardiovascular events in type 2 diabetes mellitus

To study the factors associated with the development of long-term major adverse cardiovascular events (MACE), 94 patients with type 2 diabetes mellitus (T2D) aged 40-65 years (65% of women) with eGFR > 60 ml/min/1,73 m2 and without manifestations of moderate or severe chronic heart failure (CHF) were examined. In patients with T2D clinical and laboratory data were evaluated. A 6-minute walk test (6MWT) and echocardiography were performed. Concentration of N-terminal pro-brain natriuretic peptide (NTproBNP) was determined on an Immulait 2000 Siemens analyzer by immunochemiluminescence assay. Glycemic variability was assessed by calculating the standard deviation (SD) and coefficient of variation (CV) of glycemia during the day according to laboratory measurements of glucose levels at least 3 times a day for at least 3 days. The initial manifestations of CHF according to the clinical examination were detected in 40 out of 94 patients with T2D. According to the discriminant analysis results, they were interconnected with the presence and duration of stable coronary heart disease, an increase in the left ventricle posterior wall thickness and the left atrial (LA) size, an increase in triglyceride level, an increase in duration of diabetes, and a lower estimated glomerular filtration rate. A relationship was found between the initial manifestations of CHF and an increase in CV glycemia during the day and the presence of episodes of hypoglycemia in history. After 8.8 ± 0.72 years MACE were found in 38.6% of patients with T2D (n = 88). There were 12 deaths (10 of them from cardiovascular diseases), 5 cases of myocardial infarction, 9 cases of emergency myocardial revascularization, 4 cases of stroke, 4 cases of hospitalization due to decompensation of CHF. The relationship between MACE and the initial increase in the level of NT-proBNP, an increase in the LA size, and a decrease in 6MWT values was determined according to logistic regression analysis with a percentage of correct prediction of 81.9%. The development of long-term MACE in T2D patients was also influenced by the presence of episodes of hypoglycemia in history and increased glycemic variability. This was confirmed by the logistic regression analysis, which showed the relationship between the development of new cardiovascular complications and death with an initial increase in intraday glycemic CV, an increase in the LA size, and the presence of initial manifestations of CHF with a percentage of correct prediction of 87.8%. After 8.8 ± 0.72 years, 41 patients with type 2 diabetes underwent a repeated clinical and laboratory study and echocardiography with an assessment of left ventricular diastolic function (LV DD) according to the criteria of the RSC for CHF 2020. LV DD was detected in 51,2% of T2DM patients and was correlated with the initial increase in the level of NT-proBNP, especially in combination with the initial increase in the left ventricular myocardial mass index and body mass index according to the results of logistic regression analysis. The level of NT-proBNP more than 31.2 pg/ml can be considered as a prognostic marker of LV DD in T2D patients after 8.8 ± 0.72 years of followup with a sensitivity of 66.7% and a specificity of 100%.

1. Sun H., Saeedi P., Karuranga S. et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045 // Diabetes Res Clin Pract. 2022; 183: 109-119. DOI: 10.1016/j.diabres.2021.109119.

2. Dedov I. I., Shestakova M. V., Vikulova O. K. et al. Epidemiological characteristics of diabetes mellitus in the Russian Federation: clinical and statistical analysis according to the Federal diabetes register data of 01.01.2021 // Diabetes mellitus. 2021; 24 (3): 204-221. (In Russ.) DOI: 10.14341/DM12759.

3. Shabalin V. V., Grinshtein Yu. I., Ruf R. R. et al. Prevalence of carbohydrate metabolism disorders and association with cardiovascular diseases in a large Siberian region // Russian Journal of Cardiology. 2022; 27 (5): 4992. (In Russ.) DOI: 10.15829/1560-4071-2022-4992.

4. Viigimaa M., Sachinidis A., Toumpourleka M., et al. Macrovascular Complications of Type 2 Diabetes Mellitus // Curr Vasc Pharmacol. 2020; 18 (2): 110-116. DOI: 10.2174/1570161117666190405165151.

5. Bilak J. M., Gulsin G. S., McCann G. P. Cardiovascular and systemic determinants of exercise capacity in people with type 2 diabetes mellitus // Ther Adv Endocrinol Metab. 2021; 12: 2042018820980235. DOI: 10.1177/2042018820980235.

6. Zelniker T. A., Morrow D. A., Mosenzon O., et al. Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium-glucose co-transporter 2 inhibitor therapyin DECLARE-TIMI 58 // Eur J Heart Fail. 2021; 23 (6): 1026-1036. DOI: 10.1002/ejhf.2073.

7. Baldassarre S., Fragapani S., Panero A., et al. NTproBNP in insulin-resistance mediated conditions: overweight/obesity, metabolic syndrome and diabetes. The population-based Casale Monferrato Study // Cardiovasc Diabetol. 2017; 16 (1): 119. DOI: 10.1186/s12933-017-0601-z.

8. Lee D. Y., Han K., Park S., et al. Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes: retrospective cohort study // Cardiovasc Diabetol. 2020; 19 (1): 144. DOI: 10.1186/s12933-020-01134-0.

9. Bouthoorn S., Valstar G. B., Gohar A. et al. The prevalence of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction in men and women with type 2 diabetes: A systematic review and meta-analysis // Diab Vasc Dis Res. 2018; 15 (6): 477-493. DOI: 10.1177/1479164118787415.

10. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test // Am J Respir Crit Care Med. 2002; 166 (1): 111-117. DOI: 10.1164/ajrccm.166.1.at1102.

11. Jarolim P., White W. B., Cannon C. P. et al. Serial Measurement of Natriuretic Peptides and Cardiovascular Outcomes in Patients With Type 2 Diabetes in the EXAMINE Trial // Diabetes Care. 2018; 41 (7): 1510-1515. DOI: 10.2337/dc18-0109.

12. Nah E. H., Kim S. Y., Cho S. et al. Plasma NT-proBNP levels associated with cardiac structural abnormalities in asymptomatic health examinees with preserved ejection fraction: a retrospective cross-sectional study // BMJ Open. 2019; 9 (4): e026030. DOI: 10.1136/bmjopen-2018-026030.

13. Tromp J., Khan M. A., Klip I. T. et al. Biomarker Profiles in Heart Failure Patients With Preserved and Reduced Ejection Fraction // J Am Heart Assoc. 2017; 6 (4): e003989. DOI: 10.1161/JAHA.116.003989.

14. Palmer S. C., Tendal B., Mustafa R. A. et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials // BMJ. 2021; 372: m4573. DOI: 10.1136/bmj.m4573.

15. Gori M., Gupta D. K., Claggett B., et al. Natriuretic Peptide and High-Sensitivity Troponin for Cardiovascular Risk Prediction in Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study // Diabetes Care. 2016; 39 (5): 677-685. DOI: 10.2337/dc15-1760.

16. Froehlich L., Meyre P., Aeschbacher S. et al. Left atrial dimension and cardiovascular outcomes in patients with and without atrial fibrillation: a systematic review and meta-analysis // Heart. 2019; 105 (24): 1884-1891. DOI: 10.1136/heartjnl-2019-315174.

17. Wang Q., Wang J., Wang P. et al. Glycemic control is associated with atrial structural remodeling in patients with type 2 diabetes // BMC Cardiovasc Disord. 2019; 19 (1): 278. DOI: 10.1186/s12872-019-1249.

18. Seko Y., Kato T., Morita Y. et al. Association with left atrial volume index and long-term prognosis in patients without systolic dysfunction nor atrial fibrillation: an observational study // Heart Vessels. 2020; 35 (2): 223-231. DOI: 10.1007/s00380-019-01469-z.

19. Grundtvig M., Eriksen-Volnes T., Ørn S. et al. 6 min walk test is a strong independent predictor of death in outpatients with heart failure // ESC Heart Fail. 2020; 7 (5): 2904-2911. DOI: 10.1002/ehf2.12900.

20. Zhou J. J., Schwenke D. C., Bahn G., Reaven P.; VADT Investigators. Glycemic Variation and Cardiovascular Risk in the Veterans Affairs Diabetes Trial // Diabetes Care. 2018; 41 (10): 2187-2194. DOI: 10.2337/dc18-0548.

21. Echouffo-Tcheugui J. B., Zhao S., Brock G. et al. Visit-to-Visit Glycemic Variability and Risks of Cardiovascular Events and All-Cause Mortality: The ALLHAT Study // Diabetes Care. 2019; 42 (3): 486-493. DOI: 10.2337/dc18-1430.

22. Nagueh S. F. Left Ventricular Diastolic Function: Understanding Pathophysiology, Diagnosis, and Prognosis With Echocardiography // JACC Cardiovasc Imaging. 2020; 13 (1 Pt 2): 228-244. DOI: 10.1016/j.jcmg.2018.10.038.

23. Grigorescu E. D., Lacatusu C. M., Floria M., Mihai B. M., Cretu I., Sorodoc L. Left Ventricular Diastolic Dysfunction in Type 2 Diabetes-Progress and Perspectives // Diagnostics (Basel). 2019; 9 (3): 121. DOI: 10.3390/diagnostics9030121.

24. Playford D., Strange G., Celermajer D. S. et al.; NEDA Investigators. Diastolic dysfunction and mortality in 436 360 men and women: the National Echo Database Australia (NEDA) // Eur Heart J Cardiovasc Imaging. 2021; 22 (5): 505-515. DOI: 10.1093/ehjci/jeaa253.