Cardiovasc Prev Pharmacother.  2023 Oct;5(4):126-133. 10.36011/cpp.2023.5.e18.

Lipid variability in patients with diabetes mellitus

• Lee J
• Lee SH

• KMID: 2547303
• DOI: http://doi.org/10.36011/cpp.2023.5.e18

Abstract

Diabetic dyslipidemia is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), elevated low-density lipoprotein cholesterol (LDL-C), and the predominance of small dense LDL particles caused by insulin resistance in patients with type 2 diabetes mellitus (DM) or insulin deficiency in patients with type 1 DM. Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease in individuals with DM, and lowering lipid levels can reduce the associated morbidity and mortality. The current guidelines for dyslipidemia management recommend an LDL-C goal lower than 55 to 100 mg/dL, depending on the underlying risk factors. However, greater visit-to-visit variability in cholesterol levels might be an independent predictor of major adverse cardiovascular events, high incidence of atrial fibrillation, poor renal outcomes, and cognitive dysfunction in patients with DM. This review focuses on the clinical implications of lipid variability in patients with DM.

Keyword

LDL cholesterol; Diabetes complications; Dyslipidemias; Triglycerides

Reference

1. Oh HJ, Yang DM, Kim CH, Jeon JG, Jung NH, Kim CY, et al. Exploring mortality rates for major causes of death in Korea. Open Public Health J. 2019; 12:16–25.

2. American Diabetes Association. 9. Cardiovascular disease and risk management. Diabetes Care. 2017; 40(Suppl 1):S75–87.

3. Hirano T. Pathophysiology of diabetic dyslipidemia. J Atheroscler Thromb. 2018; 25:771–82.

4. Bekele S, Yohannes T, Mohammed AE. Dyslipidemia and associated factors among diabetic patients attending Durame General Hospital in Southern Nations, Nationalities, and People’s Region. Diabetes Metab Syndr Obes. 2017; 10:265–71.

5. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 376:1670–81.

6. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019; 393:407–15.

7. Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. Endocrinol Metab Clin North Am. 2005; 34:49–62.

8. Wu L, Parhofer KG. Diabetic dyslipidemia. Metabolism. 2014; 63:1469–79.

9. Bonilha I, Hajduch E, Luchiari B, Nadruz W, Le Goff W, Sposito AC. The reciprocal relationship between LDL metabolism and type 2 diabetes mellitus. Metabolites. 2021; 11:807.

10. Srivastava RA. Dysfunctional HDL in diabetes mellitus and its role in the pathogenesis of cardiovascular disease. Mol Cell Biochem. 2018; 440:167–87.

11. Monaldi B, Bologna G, Costa GG, D’Agostino C, Ferrante F, Filice M, et al. Adherence to statin treatment following a myocardial infarction: an Italian population-based survey. Clinicoecon Outcomes Res. 2015; 7:273–80.

12. Heeschen C, Hamm CW, Laufs U, Snapinn S, Bohm M, White HD, et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002; 105:1446–52.

13. Zhang L, Wang W, Man F, Pan Q, Guo L. The effect of statin adherence on patients with type 2 diabetes after percutaneous coronary intervention for acute coronary syndrome. Cardiovasc Drugs Ther. 2023; 37:539–47.

14. Sposito AC, Carvalho LS, Cintra RM, Araujo AL, Ono AH, Andrade JM, et al. Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal. Atherosclerosis. 2009; 207:191–4.

15. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2019; 4:206–13.

16. Stephenson MC, Leverton E, Khoo EY, Poucher SM, Johansson L, Lockton JA, et al. Variability in fasting lipid and glycogen contents in hepatic and skeletal muscle tissue in subjects with and without type 2 diabetes: a 1H and 13C MRS study. NMR Biomed. 2013; 26:1518–26.

17. Tsalamandris C, Panagiotopoulos S, Allen TJ, Waldrip L, Van Gaal B, Goodall I, et al. Long-term intraindividual variability of serum lipids in patients with type I and type II diabetes. J Diabetes Complications. 1998; 12:208–14.

18. Bardini G, Dicembrini I, Rotella CM, Giannini S. Lipids seasonal variability in type 2 diabetes. Metabolism. 2012; 61:1674–7.

19. Rhee EJ, Han K, Ko SH, Ko KS, Lee WY. Increased risk for diabetes development in subjects with large variation in total cholesterol levels in 2,827,950 Koreans: a nationwide population-based study. PLoS One. 2017; 12:e0176615.

20. Lee SH, Kim HS, Park YM, Kwon HS, Yoon KH, Han K, et al. HDL-cholesterol, its variability, and the risk of diabetes: a nationwide population-based study. J Clin Endocrinol Metab. 2019; 104:5633–41.

21. Zhang Y, Qin P, Lou Y, Zhao P, Li X, Qie R, et al. Association of TG/HDLC ratio trajectory and risk of type 2 diabetes: a retrospective cohort study in China. J Diabetes. 2021; 13:402–12.

22. Lehti M, Donelan E, Abplanalp W, Al-Massadi O, Habegger KM, Weber J, et al. High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice. Circulation. 2013; 128:2364–71.

23. Kwon YH, Kim SK, Cho JH, Kwon H, Park SE, Oh HG, et al. The association between persistent hypertriglyceridemia and the risk of diabetes development: the Kangbuk Samsung Health Study. Endocrinol Metab (Seoul). 2018; 33:55–61.

24. Galli A, Arunagiri A, Dule N, Castagna M, Marciani P, Perego C. Cholesterol redistribution in pancreatic β-cells: a flexible path to regulate insulin secretion. Biomolecules. 2023; 13:224.

25. Kreger BE, Odell PM, D'Agostinol RB, Wilson PF. Long-term intraindividual cholesterol variability: natural course and adverse impact on morbidity and mortality: the Framingham Study. Am Heart J. 1994; 127:1607–14.

26. Hsu WH, Lai CW, Chen SC, Chiou HC, Hsiao PJ, Shin SJ, et al. Greater low-density lipoprotein cholesterol variability increases the risk of cardiovascular events in patients with type 2 diabetes mellitus. Endocr Pract. 2019; 25:918–25.

27. Wan EY, Yu EY, Chin WY, Barrett JK, Mok AH, Lau CS, et al. Greater variability in lipid measurements associated with cardiovascular disease and mortality: a 10-year diabetes cohort study. Diabetes Obes Metab. 2020; 22:1777–88.

28. Wang MC, Li CI, Liu CS, Lin CH, Yang SY, Li TC, et al. Effect of blood lipid variability on mortality in patients with type 2 diabetes: a large single-center cohort study. Cardiovasc Diabetol. 2021; 20:228.

29. Sheng CS, Miao Y, Ding L, Cheng Y, Wang D, Yang Y, et al. Prognostic significance of visit-to-visit variability, and maximum and minimum LDL cholesterol in diabetes mellitus. Lipids Health Dis. 2022; 21:19.

30. He P, Gan X, Wu Q, Ye Z, Yang S, Zhang Y, et al. Joint effect of visit-to-visit variability in LDL-cholesterol, HDL-cholesterol and HbA1c on cardiovascular and total mortality in patients with diabetes. Diabetol Metab Syndr. 2022; 14:132.

31. Clark D 3rd, Nicholls SJ, St John J, Elshazly MB, Kapadia SR, Tuzcu EM, et al. Visit-to-visit cholesterol variability correlates with coronary atheroma progression and clinical outcomes. Eur Heart J. 2018; 39:2551–8.

32. Lee EY, Yang Y, Kim HS, Cho JH, Yoon KH, Chung WS, et al. Effect of visit-to-visit LDL-, HDL-, and non-HDL-cholesterol variability on mortality and cardiovascular outcomes after percutaneous coronary intervention. Atherosclerosis. 2018; 279:1–9.

33. Suzuki S. “Cholesterol paradox” in atrial fibrillation. Circ J. 2011; 75:2749–50.

34. Lee HJ, Lee SR, Choi EK, Han KD, Oh S. Low lipid levels and high variability are associated with the risk of new-onset atrial fibrillation. J Am Heart Assoc. 2019; 8:e012771.

35. Lee S, Jeevaratnam K, Liu T, Chang D, Chang C, Wong WT, et al. Risk stratification of cardiac arrhythmias and sudden cardiac death in type 2 diabetes mellitus patients receiving insulin therapy: a population-based cohort study. Clin Cardiol. 2021; 44:1602–12.

36. Zakany F, Kovacs T, Panyi G, Varga Z. Direct and indirect cholesterol effects on membrane proteins with special focus on potassium channels. Biochim Biophys Acta Mol Cell Biol Lipids. 2020; 1865:158706.

37. Haas MJ, Mooradian AD. Regulation of high-density lipoprotein by inflammatory cytokines: establishing links between immune dysfunction and cardiovascular disease. Diabetes Metab Res Rev. 2010; 26:90–9.

38. Bangalore S, Breazna A, DeMicco DA, Wun CC, Messerli FH; TNT Steering Committee and Investigators. Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial. J Am Coll Cardiol. 2015; 65:1539–48.

39. Gosmanova EO, Mikkelsen MK, Molnar MZ, Lu JL, Yessayan LT, Kalantar-Zadeh K, et al. Association of systolic blood pressure variability with mortality, coronary heart disease, stroke, and renal disease. J Am Coll Cardiol. 2016; 68:1375–86.

40. Kim MK, Han K, Kim HS, Park YM, Kwon HS, Yoon KH, et al. Effects of variability in blood pressure, glucose, and cholesterol concentrations, and body mass index on end-stage renal disease in the general population of Korea. J Clin Med. 2019; 8:755.

41. Li L, Wang F, Xu M, Lu JL, Zhao ZY, Li M, et al. Association of visit-to-visit variabilities in metabolic factors with chronic kidney disease in Chinese adults living in Shanghai. Biomed Environ Sci. 2021; 34:761–72.

42. Chang YH, Chang DM, Lin KC, Hsieh CH, Lee YJ. High-density lipoprotein cholesterol and the risk of nephropathy in type 2 diabetic patients. Nutr Metab Cardiovasc Dis. 2013; 23:751–7.

43. Ceriello A, De Cosmo S, Rossi MC, Lucisano G, Genovese S, Pontremoli R, et al. Variability in HbA1c, blood pressure, lipid parameters and serum uric acid, and risk of development of chronic kidney disease in type 2 diabetes. Diabetes Obes Metab. 2017; 19:1570–8.

44. Matsuoka-Uchiyama N, Uchida HA, Okamoto S, Onishi Y, Katayama K, Tsuchida-Nishiwaki M, et al. The association of postprandial triglyceride variability with renal dysfunction and microalbuminuria in patients with type 2 diabetic mellitus: a retrospective and observational study. J Diabetes Res. 2022; 2022:3157841.

45. Wan EY, Yu EY, Chin WY, Lau CS, Mok AH, Wang Y, et al. Greater variability in lipid measurements associated with kidney diseases in patients with type 2 diabetes mellitus in a 10-year diabetes cohort study. Sci Rep. 2021; 11:8047.

46. Epstein M, Vaziri ND. Statins in the management of dyslipidemia associated with chronic kidney disease. Nat Rev Nephrol. 2012; 8:214–23.

47. Liu Q, Zhang J. Lipid metabolism in Alzheimer’s disease. Neurosci Bull. 2014; 30:331–45.

48. Smit RA, Trompet S, Sabayan B, le Cessie S, van der Grond J, van Buchem MA, et al. Higher visit-to-visit low-density lipoprotein cholesterol variability is associated with lower cognitive performance, lower cerebral blood flow, and greater white matter hyperintensity load in older subjects. Circulation. 2016; 134:212–21.

49. Lee SH, Han K, Cho H, Park YM, Kwon HS, Kang G, et al. Variability in metabolic parameters and risk of dementia: a nationwide population-based study. Alzheimers Res Ther. 2018; 10:110.

50. Chung HS, Lee JS, Kim JA, Roh E, Lee YB, Hong SH, et al. Variability in total cholesterol concentration is associated with the risk of dementia: a nationwide population-based cohort study. Front Neurol. 2019; 10:441.

51. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006; 368:387–403.

52. Chau YL, Yoo JW, Zhou J, LiutaoGuo C, Wong WT, Chang C, et al. Risk factors of dementia in type 2 diabetes mellitus: the Hong Kong diabetes study. Aging Health Res. 2023; 3:100155.

53. Mann DM, Glazer NL, Winter M, Paasche-Orlow MK, Muntner P, Shimbo D, et al. A pilot study identifying statin nonadherence with visit-to-visit variability of low-density lipoprotein cholesterol. Am J Cardiol. 2013; 111:1437–42.

54. Kim MK, Han K, Park YM, Kwon HS, Kang G, Yoon KH, et al. Associations of variability in blood pressure, glucose and cholesterol concentrations, and body mass index with mortality and cardiovascular outcomes in the general population. Circulation. 2018; 138:2627–37.

55. Smit RA, Jukema JW, Postmus I, Ford I, Slagboom PE, Heijmans BT, et al. Visit-to-visit lipid variability: clinical significance, effects of lipid-lowering treatment, and (pharmaco) genetics. J Clin Lipidol. 2018; 12:266–76.

56. Keating AJ, Campbell KB, Guyton JR. Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy. Ann Pharmacother. 2013; 47:398–404.

57. Qamar A, Giugliano RP, Keech AC, Kuder JF, Murphy SA, Kurtz CE, et al. Interindividual variation in low-density lipoprotein cholesterol level reduction with evolocumab: an analysis of FOURIER Trial Data. JAMA Cardiol. 2019; 4:59–63.