|Year : 2018 | Volume
| Issue : 4 | Page : 122-126
From intensive statins to intensive lipid lowering: Amplitude of low-density lipoprotein-cholesterol lowering is the core for atherosclerosis cardiovascular disease prevention
Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
|Date of Web Publication||19-Dec-2018|
Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011
Source of Support: None, Conflict of Interest: None
Cholesterol is a risk factor for atherosclerotic cardiovascular disease (ASCVD). The epidemiology, clinical intervention trials, and genetic studies that low-density lipoproteins (LDLs) cause ASCVD. Lowering LDL-C is a cornerstone and important strategy for the prevention and treatment of ASCVD. The benefit of reducing ASCVD by statins is completely dependent on the absolute reduction of LDL-C. Several recent large trials have also now shown that lowering LDL with non-statins reduces cardiovascular events. In ASCVD patients on statins, adding ezetimibe or a PCSK9 inhibitor led to reductions in CV events in the IMPROVE IT, FOURIER, and the ODYSSEY-OUTCOMES trials. Compared with high-dose statins, statins combined with nonstatins, such as ezetimibe, can more effectively lower LDL-C and can result in a more significant reduction in the risk of CVD. Therefore, this therapy is a lipid-lowering option with significant efficacy and sufficient evidence of benefit in clinical practice.
Keywords: Atherosclerosis cardiovascular disease, low-density lipoprotein-cholesterol lowering, lipid-lowering, statins
|How to cite this article:|
Peng D. From intensive statins to intensive lipid lowering: Amplitude of low-density lipoprotein-cholesterol lowering is the core for atherosclerosis cardiovascular disease prevention. Cardiol Plus 2018;3:122-6
|How to cite this URL:|
Peng D. From intensive statins to intensive lipid lowering: Amplitude of low-density lipoprotein-cholesterol lowering is the core for atherosclerosis cardiovascular disease prevention. Cardiol Plus [serial online] 2018 [cited 2021 Mar 5];3:122-6. Available from: https://www.cardiologyplus.org/text.asp?2018/3/4/122/247953
| Introduction|| |
Atherosclerosis (AS) is an ancient disease with many hypotheses about its pathogenesis, among which the cholesterol theory is the most profound. This hypothesis is supported by multilevel evidence from epidemiology, clinical intervention trials, and genetic studies and has been recognized as the “cholesterol principle.” In recent years, several large-scale clinical trials of nonstatins combined with statins have shown that further low-density lipoprotein-cholesterol (LDL-C) lowering could provide greater cardiovascular protection, confirming that the degree of LDL-C is at the core for cardiovascular benefits, and further verifying the “cholesterol principle.”
| Cholesterol is an Independent Risk Factor for Atherosclerosis|| |
The relationship between cholesterol and AS has been defined after more than a 100 years of exploration.
In 1889, Lehzen and Knauss reported that a 3-year-old girl with xanthomas experienced sudden death at the age of 11 years. The anatomy revealed that the aorta and other major vasculature, including the coronary arteries, had extensive xanthomas. Her 9-year-old sister also had cutaneous xanthomatosis.
In 1908, Pinkus and Pick for the first time described the specific elevation of cholesterol, rather than triglyceride, in blood and lesions of these patients. This suggested that cholesterol deposits in blood vessels and under the skin are responsible for the formation of xanthomas.
In 1910, the German chemist Adolf Windaus discovered that there were massive cholesterol deposits in AS plaque, and its content was 20–26 times greater than normal arterial walls.
In 1913, pathologist Anitschkow created the first AS animal model by feeding rabbits with 60 egg yolks within 70 days.
The study of 12,763 middle-aged male participants from 1958 to 1968 across seven countries had showed that the relative incidence of new coronary heart disease was linearly related to the cholesterol levels in different ethnic groups.
Subsequent observational epidemiologic studies had shown a linear correlation between total cholesterol level and the risk of coronary events in Framingham cohort.,
In the 1970s, the discovery of statin led to a revolutionary advance in treating atherosclerotic disease. Series of statin-specific clinical trials had consistently confirmed that these drugs could lower cholesterol and reduce the risk of cardiovascular disease (CVD), which has suggested that the causal role of cholesterol in AS. The cholesterol theory, however, has been challenged by the role of the pleiotropic effect of statin. This review will clarify the cholesterol principle by discussing the following key questions.
Q1. Is statin-mediated cardiovascular disease reduction dependent on the dose of statins or the degree of low-density lipoprotein-cholesterol lowering?
In the Scandinavian Simvastatin Survival Study (4S study), the first secondary prevention study of statin, simvastatin treatment resulted in a 42% reduction in the relative risk of death from coronary heart disease, which was the largest reduction among the subsequent studies comparing other statins with placeboes such as CARE, LIPID, HPS, and LIPS. What is the basis for this larger benefit? Baseline characteristics analysis found that the average LDL-C level of the 4S study participants was as high as 180 mg/dL. In the treatment group, the relative LDL-C reduction of 35% yielded an absolute LDL-C decrease of 63 mg/dL, which was the most significant [Figure 1]. These placebo-controlled studies have shown a linear correlation between absolute LDL-C reduction and CVD risk reduction. PROVE-IT, A-Z, TNT, IDEAL, and SEARCH studies which compared high-dose and low-dose statins also demonstrated the same trend seen in placebo-controlled studies. From these studies altogether, the greater absolute reduction in LDL-C resulted in greater decline in CVD risk suggesting the absolute degree of LDL-C lowering determines the decline of the CVD risk regardless of statin dose [Figure 2]. The meta-analysis also showed that in patients with satisfied LDL-C goals (<70 mg/dL) following statin therapy, and the risk of events in patients with LDL-C reduction by >50% was significantly lower than that in patients with LDL-C reduction by <50%.
|Figure 1: Comparison of statins and placebo showed that the more low-density lipoprotein-cholesterol lowering, the greater the reduction in cardiovascular disease|
Click here to view
|Figure 2: Comparison of high-dose and conventional-dose statin studies showed that the inverse relationship between low-density lipoprotein-cholesterol and cardiovascular disease|
Click here to view
The absolute degree of LDL-C lowering by statins depends not only on the intensity of the drug but also on the baseline LDL-C level and the patient's response. The lower the baseline LDL-C level, less benefit is achieved from the same relative degree of LDL-C lowering. Studies confirmed that there is an individual patient-to-patient difference in statin response. The same dose of statins can lead to a different degree of lowering LDL-C, while the degree of lowering LDL-C determines the progression of plaques and causing different degree of risk reduction of the events. It is suggested that the benefits of statin therapy are not determined by the dose but by the degree of LDL-C lowering; high-dose statins may not result in the expected decline in LDL-C, and the same cardioprotection was expected.
Q2. Can short-term high-dose statins therapy reduce the risk of long-term cardiovascular events?
Loading dose statins therapy in the postoperative period of percutaneous coronary intervention (PCI) has always been controversial. The early ARMYDA study, including 150–300 participants found that the preoperative loading dose statins use, could reduce cardiovascular events.,, However, subsequent ALPACAS study in the Chinese and Korean populations showed pre-PCI intensive statins therapy did not significantly reduce the risk of 30-day major adverse cardiac events (MACE) compared with conventional dosing statins therapy; the ISCAP study also confirmed that the peri-PCI loading dose statin therapy did not have any protective effect. Studies in patients with stable angina pectoris undergoing planned PCI also showed that loading dose statins treatment 2 days before the procedure did not reduce long-term MACE. The recently published SECURE-PCI study showed that post-PCI loading dose statin therapy did not reduce the risk of major cardiovascular endpoints in whole participants (30 days of all-cause mortality, nonfatal myocardial infarction [MI], stroke, and unplanned PCI) compared with the control group. The STICS study investigating statins treatment before and after cardiac surgery also showed that preoperative loading statin therapy in patients undergoing planned cardiac surgery did not reduce postoperative cardiac complications. These studies consistently suggest that short-term high-dose statins use has no effects and cannot reduce cardiovascular events.
Q3. Does the same degree of low-density lipoprotein-cholesterol lowering by nonstatins lead to proportionate reduction in cardiovascular disease events?
The IMPROVE-IT study confirmed for the first time that nonstatins had further cardiovascular benefit in combination with statins. Compared with statins alone, ezetimibe plus statins further lowered LDL-C levels (53.7 mg/dL vs. 69.5 mg/dL) and reduced the risk of primary endpoints (cardiovascular death, MI, hospitalization for unstable angina, revascularization, or stroke >30 days after randomization) by 6.4% (P = 0.016). The subsequent FOURIER study and the recently published ODYSSEY outcome study both confirmed that the addition of nonstatins PSCK9 inhibitors to statins therapy further reduced LDL-C and showed significant benefit in cardiovascular endpoint and even all-cause mortality.
It should be noted that meta-analysis of 25 statins studies showed a reduction by 1 mmol/L in LDL-C produced a reduction in CVD risk by 22%, while eight nonstatins studies also showed a reduction by 1 mmol/L in LDL-C caused a reduction in CVD risk by 22% suggesting that achieving the same reduction degree in LDL-C by nonstatins therapy can have the benefit of the similar reductions in CVD risk [Figure 3] and [Figure 4]. It is suggested that the benefit of lipid-lowering therapy is related to the degree of lowering LDL but not to the approaches to LDL-C lowering.
|Figure 3: Twenty-five statin studies showed a reduction by 1 mmol/L in LDL-C led to a reduction by 22% in CVD risk|
Click here to view
|Figure 4: Eight non-statins studies showed a reduction by 1 mmol/L in LDL-C led to a reduction by 22% in CVD risk|
Click here to view
Q4. High-dose statins versus combination therapy: Which is more effective in lowering low-density lipoprotein cholesterol?
Humans have a fine-tuned mechanism for maintaining cholesterol homeostasis. When statins suppress cholesterol synthesis in hepatocytes, this is detected by sterol regulatory element-binding protein (SREBP) which triggers a series of compensatory responses to elevate intracellular cholesterol. For example, promoting the uptake of circulating LDL-C by hepatocytes through upregulating the expression of the LDL receptor, which is also the main mechanism by which statins lower LDL-C. At the same time, cholesterol-sensing nuclear factor SREBP can increase the expression of HMG-CoA reductase to enhance cholesterol synthesis. More importantly, SREBP could upregulate hepatocyte PCSK9, which promotes the degradation of LDL receptors. In addition, SREBP can also upregulate NPC1L1 expression of intestinal cells to increase the intestinal cholesterol absorption. These compensatory mechanisms make it difficult to enhance the therapeutic effect by boosting statin. In the context of the “6” principle (doubling the dose of statins leads to LDL-C reduction by only 6%), three times of doubling the dose of statins (8-folds of the dose) can only increase the efficacy of LDL-C lowering by 18%. However, combining various cholesterol-lowering drugs with different mechanisms of action can significantly lower the lipids. For example, the combination of ezetimibe 10 mg with the statins can reduce the LDL-C by 25%. In MI, patients with the baseline LDL-C of 150 mg/dL, atorvastatin 20 mg + ezetimibe 10 mg resulted in an absolute reduction by 83.6 mg/dL in LDL-C, and a decrease by 41.3% (more effective than atorvastatin 80 mg alone) in CVD risk [Figure 5].
| Conclusion|| |
Lowering LDL-C is a cornerstone and important strategy for the prevention and treatment of ASCVD. The benefit of reducing ASCVD by statins is completely dependent on the absolute reduction of LDL-C. Several studies have confirmed that nonstatins can achieve the same cardiovascular endpoints benefit as statins by lowering LDL-C by the same extent. In addition, compared with high-dose statins, statins combined with nonstatins, such as ezetimibe, can more effectively lower LDL-C and can result in a more significant reduction in the risk of CVD. Therefore, this therapy is a lipid-lowering option with significant efficacy and sufficient evidence of benefit in clinical practice.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lehzen G, Knauss K. Ucber Xanthoma complex plane, tuberose, mollusciformis. Virchow. Arch Pathol Anat Histol 1889;116:85-104.
Windaus A. On the structure and genesis of symptomatic xanthomas. German Med Wchnschr 1908;34:1426-30.
Windaus A. On the content of normal and atheromatous aortae in cholesterol and cholesterol esters. Journal Physiol Chemistry 1910;67:174.
Anitschkow N. Experimental atherosclerosis in animals. In: Arteriosclerosis. New York, NY: Macmillan; 1933:271-322.
Keys A, Aravanis C, Blackburn H, Buzina R, Djordjevic BS, Dontas AS, et al
. Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. Cambridge, Massachusetts: Harvard University Press; 1980.
LaRosa JC, Hunninghake D, Bush D, Criqui MH, Getz GS, Gotto AM Jr, et al.
The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. The task force on cholesterol issues, American Heart Association. Circulation 1990;81:1721-33.
Castelli WP. Epidemiology of coronary heart disease: The Framingham study. Am J Med 1984;76:4-12.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al.
Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin survival study (4S) Lancet 1994;344:1383-9.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al.
The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med 1996;335:1001-9.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57.
Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7-22.
Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, et al.
Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: A randomized controlled trial. JAMA 2002;287:3215-22.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al.
Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.
de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, et al.
Early intensive vs. A delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z trial. JAMA 2004;292:1307-16.
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al.
Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al.
High-dose atorvastatin vs. Usual-dose simvastatin for secondary prevention after myocardial infarction: The IDEAL study: A randomized controlled trial. JAMA 2005;294:2437-45.
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, et al.
Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: A double-blind randomised trial. Lancet 2010;376:1658-69.
Bangalore S, Fayyad R, Kastelein JJ, Laskey R, Amarenco P, DeMicco DA, et al
. 2013 cholesterol guidelines revisited: Percent LDL cholesterol reduction or attained LDL cholesterol level or both for prognosis? Am J Med 2016;129:384-91.
Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR, et al.
Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: A meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485-94.
Kataoka Y, St John J, Wolski K, Uno K, Puri R, Tuzcu EM, et al.
Atheroma progression in hyporesponders to statin therapy. Arterioscler Thromb Vasc Biol 2015;35:990-5.
Ridker PM, Mora S, Rose L, JUPITER Trial Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: Potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J 2016;37:1373-9.
Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G, et al.
Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: Results from the ARMYDA (Atorvastatin for reduction of MYocardial damage during angioplasty) study. Circulation 2004;110:674-8.
Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, et al.
Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: Results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007;49:1272-8.
Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A, et al.
Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: Results of the ARMYDA-RECAPTURE (Atorvastatin for reduction of myocardial damage during angioplasty) randomized trial. J Am Coll Cardiol 2009;54:558-65.
Jang Y, Zhu J, Ge J, Kim YJ, Ji C, Lam W, et al.
Preloading with atorvastatin before percutaneous coronary intervention in statin-naïve Asian patients with non-ST elevation acute coronary syndromes: A randomized study. J Cardiol 2014;63:335-43.
Zheng B, Jiang J, Liu HL, Zhang J, Li H, Su X, et al
. Efficacy and safety of serial atorvastatin load in Chinese patients undergoing elective percutaneous coronary intervention: results of the ISCAP (Intensive Statin Therapy for Chinese Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention) randomized controlled trial. Eur Heart J Suppl 2015;17 Suppl B:B47-56.
Veselka J, Zemánek D, Hájek P, Malý M, Adlová R, Martinkovičová L, et al.
Effect of two-day atorvastatin pretreatment on long-term outcome of patients with stable angina pectoris undergoing elective percutaneous coronary intervention. Am J Cardiol 2011;107:1295-9.
Berwanger O, Santucci EV, de Barros E Silva PGM, Jesuíno IA, Damiani LP, Barbosa LM, et al.
Effect of loading dose of atorvastatin prior to planned percutaneous coronary intervention on major adverse cardiovascular events in acute coronary syndrome: The SECURE-PCI randomized clinical trial. JAMA 2018;319:1331-40.
Zheng Z, Jayaram R, Jiang L, Emberson J, Zhao Y, Li Q, et al.
Perioperative rosuvastatin in cardiac surgery. N Engl J Med 2016;374:1744-53.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al.
Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
Sabatine MS, Giugliano RP, Keech A, Honarpour N, Wang H, Liu T, et al.
Rationale and design of the further cardiovascular OUtcomes research with PCSK9 inhibition in subjects with elevated risk trial. Am Heart J 2016;173:94-101.
Steg P. Cardiovascular outcomes with alirocumab after acute coronary syndrome: results of the ODYSSEY outcomes trial, in: Presented at the 67th Annual Scientific Session of the American College of Cardiology (ACC), 10-12 March 2018 (Presentation Number 401-08). Orlando, FL, USA, 2018.
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.
Stein E. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J Suppl 2001;3 Suppl E:E11-6.
Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al
. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016;37:2999-3058.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]