Diabetes Metab J.  2022 Sep;46(5):722-732. 10.4093/dmj.2021.0225.

Myocardial Infarction, Stroke, and All-Cause Mortality according to Low-Density Lipoprotein Cholesterol Level in the Elderly, a Nationwide Study

• Lee YB
• Koo M
• Noh E
• Hwang SY
• Kim JA
• Roh E
• Hong Sh
• Choi KM
• Baik SH
• Cho GJ
• Yoo HJ

• KMID: 2533641
• DOI: http://doi.org/10.4093/dmj.2021.0225

Abstract

Background
We assessed the myocardial infarction (MI), stroke, and all-cause death risks during follow-up according to the low-density lipoprotein cholesterol (LDL-C) levels among older adults.
Methods
The Korean National Health Insurance Service datasets (2002 to 2020) were used for this population-based cohort study. The hazards of MI, stroke, and all-cause mortality during follow-up were analyzed according to LDL-C level in individuals aged ≥65 years without baseline cardiovascular diseases (n=1,391,616).
Results
During a mean 7.55 years, 52,753 MIs developed; 84,224 strokes occurred over a mean 7.47 years. After a mean 8.50 years, 233,963 died. A decrease in LDL-C was associated with lower hazards of MI and stroke. The decreased hazard of stroke in lower LDL-C was more pronounced in statin users, and individuals with diabetes or obesity. The hazard of all-cause death during follow-up showed an inverted J-shaped pattern according to the LDL-C levels. However, the paradoxically increased hazard of mortality during follow-up in lower LDL-C was attenuated in statin users and individuals with diabetes, hypertension, or obesity. In statin users, lower LDL-C was associated with a decreased hazard of mortality during follow-up.
Conclusion
Among the elderly, lower LDL-C was associated with decreased risks of MI and stroke. Lower LDL-C achieved by statins in the elderly was associated with a decreased risk of all-cause death during follow-up, suggesting that LDL-C paradox for the premature death risk in the elderly should not be applied to statin users. Intensive statin therapy should not be hesitated for older adults with cardiovascular risk factors including diabetes.

Keyword

Aged; Cardiovascular diseases; Hydroxymethylglutaryl-CoA reductase inhibitors; Lipoproteins; LDL; Mortality

Figure

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  Fig. 1 Kaplan–Meier estimates of cumulative incidence of (A) myocardial infarction, (B) stroke, and (C) all-cause death during follow-up according to the ranges of low-density lipoprotein cholesterol (LDL-C) levels.

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  Fig. 2 Hazard ratios for incident (A) myocardial infarction, (B) stroke, and (C) all-cause death during follow-up according to the low-density lipoprotein cholesterol (LDL-C) levels. Curves represent hazard ratios adjusted for age, sex, body mass index, current smoking, heavy alcohol consumption, regular exercise, low-income status, diabetes, hypertension, and statin use. Solid lines indicate hazard ratios and dashed line indicate 95% confidence intervals using restricted cubic spline regression.

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  Fig. 3 Adjusted hazard ratios and 95% confidence intervals (CIs) for the incidence of (A) myocardial infarction, (B) stroke, and (C) all-cause death during follow-up according to the ranges of low-density lipoprotein cholesterol (LDL-C) levels in subgroups stratified by statin use. Adjusted for age, sex, body mass index, current smoking, heavy alcohol consumption, regular exercise, low-income status, diabetes, hypertension, and statin use.

Reference

1. Felix-Redondo FJ, Grau M, Fernandez-Berges D. Cholesterol and cardiovascular disease in the elderly: facts and gaps. Aging Dis. 2013; 4:154–69.

2. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016; 316:1289–97.

3. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002; 360:1623–30.

4. Han BH, Sutin D, Williamson JD, Davis BR, Piller LB, Pervin H, et al. Effect of statin treatment vs usual care on primary cardiovascular prevention among older adults: the ALLHAT-LLT randomized clinical trial. JAMA Intern Med. 2017; 177:955–65.

5. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010; 152:488–96.

6. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001; 358:351–5.

7. Corti MC, Guralnik JM, Salive ME, Harris T, Ferrucci L, Glynn RJ, et al. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Ann Intern Med. 1997; 126:753–60.

8. Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE, Westendorp RG. Total cholesterol and risk of mortality in the oldest old. Lancet. 1997; 350:1119–23.

9. Brescianini S, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, et al. Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly?: results from the Italian Longitudinal Study on Aging. J Am Geriatr Soc. 2003; 51:991–6.

10. Tilvis RS, Valvanne JN, Strandberg TE, Miettinen TA. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17-year population study. Ann Med. 2011; 43:292–301.

11. Liang Y, Vetrano DL, Qiu C. Serum total cholesterol and risk of cardiovascular and non-cardiovascular mortality in old age: a population-based study. BMC Geriatr. 2017; 17:294.

12. Strandberg TE, Tilvis RS, Pitkala KH, Miettinen TA. Cholesterol and glucose metabolism and recurrent cardiovascular events among the elderly: a prospective study. J Am Coll Cardiol. 2006; 48:708–14.

13. Lee YB, Han K, Kim B, Lee SE, Jun JE, Ahn J, et al. Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study. Cardiovasc Diabetol. 2019; 18:157.

14. Seong SC, Kim YY, Khang YH, Park JH, Kang HJ, Lee H, et al. Data resource profile: the National Health Information Database of the National Health Insurance Service in South Korea. Int J Epidemiol. 2017; 46:799–800.

15. Lee YH, Han K, Ko SH, Ko KS, Lee KU; Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Data analytic process of a nationwide population-based study using National Health Information Database established by National Health Insurance Service. Diabetes Metab J. 2016; 40:79–82.

16. Lee YB, Kim DH, Kim SM, Kim NH, Choi KM, Baik SH, et al. Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study. Cardiovasc Diabetol. 2020; 19:77.

17. Lee YB, Han K, Kim B, Jun JE, Lee SE, Ahn J, et al. Risk of end-stage renal disease from chronic kidney disease defined by decreased glomerular filtration rate in type 1 diabetes: a comparison with type 2 diabetes and the effect of metabolic syndrome. Diabetes Metab Res Rev. 2019; 35:e3197.

18. Lee YB, Lee JS, Hong SH, Kim JA, Roh E, Yoo HJ, et al. Optimal blood pressure for patients with chronic kidney disease: a nationwide population-based cohort study. Sci Rep. 2021; 11:1538.

19. Kim MK, Han K, Koh ES, Kim ES, Lee MK, Nam GE, et al. Blood pressure and development of cardiovascular disease in Koreans with type 2 diabetes mellitus. Hypertension. 2019; 73:319–26.

20. Kim MK, Han K, Kim HS, Park YM, Kwon HS, Yoon KH, et al. Cholesterol variability and the risk of mortality, myocardial infarction, and stroke: a nationwide population-based study. Eur Heart J. 2017; 38:3560–6.

21. Lee YB, Han K, Park S, Kim SM, Kim NH, Choi KM, et al. Gamma-glutamyl transferase variability and risk of dementia: a nationwide study. Int J Geriatr Psychiatry. 2020; 35:1105–14.

22. Stampfer MJ, Kang JH, Chen J, Cherry R, Grodstein F. Effects of moderate alcohol consumption on cognitive function in women. N Engl J Med. 2005; 352:245–53.

23. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40:373–83.

24. Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol. 2004; 57:1288–94.

25. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499–502.

26. Rhee EJ, Kim HC, Kim JH, Lee EY, Kim BJ, Kim EM, et al. 2018 Guidelines for the management of dyslipidemia in Korea. J Lipid Atheroscler. 2019; 8:78–131.

27. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41:111–88.

28. Park JH, Lee MH, Shim JS, Choi DP, Song BM, Lee SW, et al. Effects of age, sex, and menopausal status on blood cholesterol profile in the Korean population. Korean Circ J. 2015; 45:141–8.

29. Kim MK, Lee WY, Kang JH, Kang JH, Kim BT, Kim SM, et al. 2014 Clinical practice guidelines for overweight and obesity in Korea. Endocrinol Metab (Seoul). 2014; 29:405–9.

30. Bezin J, Moore N, Mansiaux Y, Steg PG, Pariente A. Real-life benefits of statins for cardiovascular prevention in elderly subjects: a population-based cohort study. Am J Med. 2019; 132:740–8.

31. Valdes-Marquez E, Parish S, Clarke R, Stari T, Worrall BB, METASTROKE Consortium of the ISGC, et al. Relative effects of LDL-C on ischemic stroke and coronary disease: a Mendelian randomization study. Neurology. 2019; 92:e1176–87.

32. Khovidhunkit W, Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res. 2004; 45:1169–96.

33. Myasoedova E, Crowson CS, Kremers HM, Roger VL, Fitz-Gibbon PD, Therneau TM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011; 70:482–7.

34. Sittiwet C, Simonen P, Gylling H, Strandberg TE. Mortality and cholesterol metabolism in subjects aged 75 years and older: the Helsinki Businessmen Study. J Am Geriatr Soc. 2020; 68:281–7.

35. Jun JE, Cho IJ, Han K, Jeong IK, Ahn KJ, Chung HY, et al. Statins for primary prevention in adults aged 75 years and older: a nationwide population-based case-control study. Atherosclerosis. 2019; 283:28–34.

36. Lee JK, Grace KA, Foster TG, Crawley MJ, Erowele GI, Sun HJ, et al. How should we measure medication adherence in clinical trials and practice? Ther Clin Risk Manag. 2007; 3:685–90.

37. Choo PW, Rand CS, Inui TS, Lee ML, Cain E, Cordeiro-Breault M, et al. Validation of patient reports, automated pharmacy records, and pill counts with electronic monitoring of adherence to antihypertensive therapy. Med Care. 1999; 37:846–57.

38. Kim J, Lee HS, Lee KY. Effect of statins on fasting glucose in non-diabetic individuals: nationwide population-based health examination in Korea. Cardiovasc Diabetol. 2018; 17:155.

39. Kim NH, Han KH, Choi J, Lee J, Kim SG. Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study. BMJ. 2019; 366:l5125.

40. Lee M, Sun J, Han M, Cho Y, Lee JY, Nam CM, et al. Nationwide trends in pancreatitis and pancreatic cancer risk among patients with newly diagnosed type 2 diabetes receiving dipeptidyl peptidase 4 inhibitors. Diabetes Care. 2019; 42:2057–64.

41. Lee J, Jang S, Jeong H, Ryu OH. Validation of the Friedewald formula for estimating low density lipoprotein cholesterol: the Korea National Health and Nutrition Examination Survey, 2009 to 2011. Korean J Intern Med. 2020; 35:150–9.