Interpretation of NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patients_Chinese Journal of Evidence-Based Medicine

Authors：

WU Yang ¹ , LI Tianli ² , LI Bochen ¹ , WANG Jing ¹ , HAN Wenbo ³ ,  WANG Xian ¹

1. Department of Cardiology, the Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing 100700, P. R. China;
2. National Integrated Traditional and Western Medicine Center for Cardiovascular Disease, China-Japan Friendship Hospital, Beijing 100029, P. R. China;
3. Department of Cardiology, the Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing 100029, P. R. China;

Corresponding author：

WANG Xian, Email: wx0515@hotmail.com

Keywords：

Statin therapy; Statin intolerance; Non-statin therapy; Atherosclerotic cardiovascular disease

DOI：

10.7507/1672-2531.202302038

Video：

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In June 2022, the American Lipid Society released "NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient", which provides the latest definition, modifiable factors, and treatment strategies of statin intolerance. According to the guidelines, for statin intolerance, the statin medication regimen should be adjusted first (reducing the dose, switching to another statin, reducing the frequency of medication), and if the patient is still intolerant, non-statin drugs should be considered to reduce the risk of ASCVD in the patient. The interpretation of this guideline will help clinicians and researchers identify, manage and intervene in the statin intolerance syndrome.

Citation： WU Yang, LI Tianli, LI Bochen, WANG Jing, HAN Wenbo, WANG Xian. Interpretation of NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patients. Chinese Journal of Evidence-Based Medicine, 2023, 23(9): 999-1004. doi: 10.7507/1672-2531.202302038 Copy

1.	Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation, 2019, 139(25): e1082-e1143.
2.	Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J, 2017, 38(32): 2459-2472.
3.	Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J, 2020, 41(1): 111-188.
4.	Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J, 2015, 36(17): 1012-1022.
5.	Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol, 2019, 39(2): e38-e81.
6.	Gomez Sandoval YH, Braganza MV, Daskalopoulou SS. Statin discontinuation in high-risk patients: a systematic review of the evidence. Curr Pharm Des, 2011, 17(33): 3669-3689.
7.	De Vera MA, Bhole V, Burns LC, et al. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol, 2014, 78(4): 684-698.
8.	Guyton JR, Bays HE, Grundy SM, et al. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol, 2014, 8(3 Suppl): S72-S81.
9.	Cheeley MK, Saseen JJ, Agarwala A, et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol, 2022, 16(4): 361-375.
10.	周奇, 邢丹, 李沁原, 等. 指南解读类文献报告规范的制订指南(RIGHT for INT). 中国循证医学杂志, 2022, 22(5): 497-507.
11.	Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol, 2006, 98(10): 1363-1368.
12.	Cohen JD, Brinton EA, Ito MK, et al. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10, 138 current and former statin users. J Clin Lipidol, 2012, 6(3): 208-215.
13.	Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation, 2013, 127(1): 96-103.
14.	Bytyçi I, Penson PE, Mikhailidis DP, et al. Prevalence of statin intolerance: a meta-analysis. Eur Heart J, 2022, 43(34): 3213-3223.
15.	Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med, 2017, 376(18): 1713-1722.
16.	Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med, 2018, 379(22): 2097-2107.
17.	Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA, 2016, 315(15): 1580-1590.
18.	Howard JP, Wood FA, Finegold JA, et al. Side effect patterns in a crossover trial of statin, placebo, and no treatment. J Am Coll Cardiol, 2021, 78(12): 1210-1222.
19.	Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet, 2011, 377(9784): 2181-2192.
20.	Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med, 2015, 372(25): 2387-2397.
21.	Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med, 2008, 359(13): 1343-1356.
22.	Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe Lipid-lowering trial on prevention of atherosclerotic cardiovascular disease in 75 or older (EWTOPIA 75): a randomized, controlled trial. Circulation, 2019, 140(12): 992-1003.
23.	Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, 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(9753): 1670-1681.
24.	Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated ldl cholesterol. N Engl J Med, 2020, 382(16): 1507-1519.
25.	Ruscica M, Greco MF, Ferri N, et al. Lipoprotein(a) and PCSK9 inhibition: clinical evidence. Eur Heart J Suppl, 2020, 22(Suppl L): L53-L56.
26.	Henney NC, Banach M, Penson PE. RNA silencing in the management of dyslipidemias. Curr Atheroscler Rep, 2021, 23(11): 69.
27.	Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol, 2020, 27(6): 593-603.
28.	Frick MH, Elo O, Haapa K, et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med, 1987, 317(20): 1237-1245.
29.	Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med, 1999, 341(6): 410-418.
30.	Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation, 2000, 102(1): 21-27.
31.	Meade T, Zuhrie R, Cook C, et al. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ, 2002, 325(7373): 1139.
32.	Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005, 366(9500): 1849-1861.
33.	ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010, 362(17): 1563-1574.
34.	Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am Heart J, 2018, 206: 80-93.
35.	王增武, 刘静, 李建军, 等. 中国血脂管理指南(2023年). 中国循环杂志, 2023, 38(3): 237-271.
36.	Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on coronary plaque composition. J Am Coll Cardiol, 2018, 72(17): 2012-2021.
37.	Nicholls SJ, Kataoka Y, Nissen SE, et al. Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction. JACC Cardiovasc Imaging, 2022, 15(7): 1308-1321.
38.	Räber L, Ueki Y, Otsuka T, et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. JAMA, 2022, 327(18): 1771-1781.
39.	陈荣, 陈凯聪, 曾智桓, 等. 依洛尤单抗的不良反应. 医药导报, 2021, 40(9): 1281-1284.
40.	汪静, 郑淑芬, 钟诗龙. PCSK9抑制剂不良反应信号的挖掘与评价. 实用药物与临床, 2022, 25(3): 199-204.

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation, 2019, 139(25): e1082-e1143.
2. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J, 2017, 38(32): 2459-2472.
3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J, 2020, 41(1): 111-188.
4. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J, 2015, 36(17): 1012-1022.
5. Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol, 2019, 39(2): e38-e81.
6. Gomez Sandoval YH, Braganza MV, Daskalopoulou SS. Statin discontinuation in high-risk patients: a systematic review of the evidence. Curr Pharm Des, 2011, 17(33): 3669-3689.
7. De Vera MA, Bhole V, Burns LC, et al. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol, 2014, 78(4): 684-698.
8. Guyton JR, Bays HE, Grundy SM, et al. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol, 2014, 8(3 Suppl): S72-S81.
9. Cheeley MK, Saseen JJ, Agarwala A, et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol, 2022, 16(4): 361-375.
10. 周奇, 邢丹, 李沁原, 等. 指南解读类文献报告规范的制订指南(RIGHT for INT). 中国循证医学杂志, 2022, 22(5): 497-507.
11. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol, 2006, 98(10): 1363-1368.
12. Cohen JD, Brinton EA, Ito MK, et al. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10, 138 current and former statin users. J Clin Lipidol, 2012, 6(3): 208-215.
13. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation, 2013, 127(1): 96-103.
14. Bytyçi I, Penson PE, Mikhailidis DP, et al. Prevalence of statin intolerance: a meta-analysis. Eur Heart J, 2022, 43(34): 3213-3223.
15. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med, 2017, 376(18): 1713-1722.
16. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med, 2018, 379(22): 2097-2107.
17. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA, 2016, 315(15): 1580-1590.
18. Howard JP, Wood FA, Finegold JA, et al. Side effect patterns in a crossover trial of statin, placebo, and no treatment. J Am Coll Cardiol, 2021, 78(12): 1210-1222.
19. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet, 2011, 377(9784): 2181-2192.
20. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med, 2015, 372(25): 2387-2397.
21. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med, 2008, 359(13): 1343-1356.
22. Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe Lipid-lowering trial on prevention of atherosclerotic cardiovascular disease in 75 or older (EWTOPIA 75): a randomized, controlled trial. Circulation, 2019, 140(12): 992-1003.
23. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, 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(9753): 1670-1681.
24. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated ldl cholesterol. N Engl J Med, 2020, 382(16): 1507-1519.
25. Ruscica M, Greco MF, Ferri N, et al. Lipoprotein(a) and PCSK9 inhibition: clinical evidence. Eur Heart J Suppl, 2020, 22(Suppl L): L53-L56.
26. Henney NC, Banach M, Penson PE. RNA silencing in the management of dyslipidemias. Curr Atheroscler Rep, 2021, 23(11): 69.
27. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol, 2020, 27(6): 593-603.
28. Frick MH, Elo O, Haapa K, et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med, 1987, 317(20): 1237-1245.
29. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med, 1999, 341(6): 410-418.
30. Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation, 2000, 102(1): 21-27.
31. Meade T, Zuhrie R, Cook C, et al. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ, 2002, 325(7373): 1139.
32. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet, 2005, 366(9500): 1849-1861.
33. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med, 2010, 362(17): 1563-1574.
34. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am Heart J, 2018, 206: 80-93.
35. 王增武, 刘静, 李建军, 等. 中国血脂管理指南(2023年). 中国循环杂志, 2023, 38(3): 237-271.
36. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on coronary plaque composition. J Am Coll Cardiol, 2018, 72(17): 2012-2021.
37. Nicholls SJ, Kataoka Y, Nissen SE, et al. Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction. JACC Cardiovasc Imaging, 2022, 15(7): 1308-1321.
38. Räber L, Ueki Y, Otsuka T, et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. JAMA, 2022, 327(18): 1771-1781.
39. 陈荣, 陈凯聪, 曾智桓, 等. 依洛尤单抗的不良反应. 医药导报, 2021, 40(9): 1281-1284.
40. 汪静, 郑淑芬, 钟诗龙. PCSK9抑制剂不良反应信号的挖掘与评价. 实用药物与临床, 2022, 25(3): 199-204.

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Interpretation of NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patients

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