Lower the Low-density Lipoprotein Cholesterol to the Level When You Born

Abstract

Introduction An elevated level of low-density lipoprotein cholesterol (LDL-C) is associated with higher risk of atherosclerosis disease, and overwhelming evidence has demonstrated that lowering LDL-C reduces arteriosclerotic cardiovascular disease (ASCVD) events. However, many questions still remain regarding the use of LDL-C, such as “Are lower levels better?” and “How low is enough?” In this article, we discussed the optimal LDL-C level necessary to prevent atherosclerosis and cardiovascular events, reviewed the LDL-C level of newborns and adolescents, summarized the updated evidence of imaging and clinical benefits with lower LDL-C concentrations, and discussed the possible ways to reach lower levels of LDL-C and its safety. Atherosclerotic diseases were among the most important causes of death worldwide. Epidemiological, clinical, genetic, experimental, and pathological studies had clearly shown the role of lipoproteins in atherosclerosis. LD was the major atherogenic lipoprotein and many guidelines define it as the primary target of lipid-lowering treatment. Although the level of LDL, the primary target in the treatment of dyslipidemia, had been set to below 100 mg/dl in coronary heart diseases (CHDs) and CHD risk equivalents, it had been pulled down to below 70 mg/dl for the group defined as very high risk by guidelines following the new clinical studies. Was this target level low enough? Under intensive lipid-lowering therapy, even to the level as low as 55 mg/dL, the rate of cardiovascular events still remained at 0.77 and 1.36/100 person-years.[1] Hence, the optimal level of LDL-C may be lower than we had anticipated. As we already know, atherosclerosis begins in childhood as deposits of cholesterol and its esters, referred to as fatty streaks, in the intima of large muscular arteries. In adolescence, some fatty streaks accumulated more lipids and begin to develop a fibromuscular cap, forming the lesion termed a fibrous plaque. Further changes in fibrous plaques render them vulnerable to rupture, an event that precipitates occlusive thrombosis and clinically manifest diseases (sudden cardiac death, myocardial infarction, stroke, or peripheral arterial disease). In the neonatal stage, the progression of atherosclerosis was not yet initiated, so this suggests that the LDL levels should potentially be lowered to the levels at birth. Physical Low-density Lipoprotein Cholesterol Level in Newborn A sample of umbilical cord venous blood was obtained from 156 normal newborns (76 male) immediately after delivery: mean values of LDL-C in males, females, and in the total sample were 28.3, 32.4, and 30 mg/dl, respectively.[2] Cord blood mean (standard deviation [SD]) LDL-C values in 378 full-term Iranian newborns was 35.9 ± 22.4 in girls and 32.1 ± 16.3 in boys.[3] Another trial taken in Brazil showed that total cholesterol concentrations were 70.42 ± 1.63 mg/dl, and LDL-C level was 34.38 ± 1.29 mg/dl in the term group.[4] A study taken in china also determined the lipid profile in 242 healthy full-term newborn infants. The mean values of LDL-C in cord blood were 31.15 ± 8.08 mg/dL (mean ± SD).[5] A study was carried out in 137 healthy newborns (63 boys and 74 girls) coming from normal, physiological pregnancies, spontaneously born, and generally in good condition. The mean cholesterol LDL value was 34.12 ± 14.08 mg/dl. Recently, a cross-sectional study from Brazil tested the lipid profile of 435 parturient and their newborn babies. The mean LDL-C level in parturient and neonates were 112.7 mg/dL and 29.9 mg/dL, respectively. In addition, The LDL-C level in newborn is not influenced by change in the maternal lipid profile.[6] So according to the epidemiological studies, the natural cord blood and neonatal LDL level is about 30 mg/dL. Since atherosclerosis has not yet developed at birth, this may be the optimal physical cholesterol level for preventing atherosclerosis. Low-density Lipoprotein and Atherosclerosis in Children and Adolescent The LDL-C level and atherosclerosis both increase with aging. Many studies have investigated the LDL level in children ranging from 3 to 18 years old. The LDL level was 80-125 mg/dL.[7-14] It was normal according to the adult criteria in the practice guidelines, but much higher than in newborns. Meanwhile, studies showed that atherosclerosis also initiated at this period and progressed with age. A multicenter cooperative study,[15] Pathobiological Determinants of Atherosclerosis in Youth (PDAY) showed the extent of both fatty streaks and raised lesions (fibrous plaques and other advanced lesions) in the right coronary artery and in the abdominal aorta was associated positively with nonhigh-density lipoprotein -cholesterol (HDL-C) concentration. By 15-19 years of age, fatty streaks occupied ≈25% of the aortic intima in both the thoracic and abdominal aortas. By the age of 30-34 years, raised lesions occupied <0.5% of the thoracic aorta, but occupied ≈5% of the abdominal aortic surface. In the right coronary artery, fatty streaks increased in extent from ≈2% of the intimal surface at the age of 15-19 years to ≈8% at the age of 30-34 years and were equal in men and women. Raised lesions increased from ≈0.5% at the age of 15-19 years to >2% at the age of 30-34 years. The same phenomenon was observed in the Bogalusa Heart Study. Another study[10] related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9-11 years. A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. The mean LDL in the population was 110 [SD 25.4] mg/dL. There was a significant, inverse relation between LDL-C and distension of the artery across this range (linear regression P < 0.005). Hence LDL-C levels had an impact on arterial distensibility in the first decade of life. Although the LDL-C seems to be normal at in children and during the adolescent period, it still initiates damage to the vessel and progression of atherosclerosis. The fatty steak and small plaque develop with age. Low-density Lipoprotein Cholesterol Lowering and Atherosclerosis Progression and Regression Abundant data from many prospective trials revealed a strong and direct relationship between LDL levels and rates of atherosclerotic progression. Recently, trials showed that intensive lipid-lowering with statins or other drugs can halt or even reverse atherosclerosis. These randomized controlled trials showed that the atherosclerosis progression or regression was closely related to the on-treat LDL level. Intima-Media Thickness Evaluation Clinical sequelae, however, are preceded by silent changes. It has been now widely endorsed and standardized for measurement of intima-media thickness (IMT). Nowadays, carotid IMT changes over time have become an important surrogate endpoint in clinical intervention trials. Some studies demonstrated the relationship between LDL-C value and IMT. The effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia was studied using a randomized, double-blind clinical trial in 325 patients.[16] After 2-year therapy, IMT decreased by 0.031 mm in the atorvastatin 80 mg group, whereas in the simvastatin 40 mg group, it increased by 0.036 mm. The LDL-C level was reduced from 307.69 mg/dl to 149.23 mg/dl and 320.38 mg/dl to 185 mg/dl, respectively. At the end of the ENHANCE[17] study, the mean (± SD) LDL-C level was 192.7 ± 60.3 mg/dl in the simvastatin group and 141.3 ± 52.6 mg/dl in the combined therapy group. The primary outcome, the mean (± SE) change in IMT, was 0.0058 ± 0.0037 mm in the simvastatin-only group and 0.0111 ± 0.0038 mm in the simvastatin plus ezetimibe group (P = 0.29). The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trial[18] used 80 mg/d atorvastatin or 40 mg/d pravastatin in 161 patients with a mean baseline LDL of 150 mg/d. Atorvastatin reduced LDL to mean levels as well as to 76 mg/dl and 110 mg/dl in pravastatin. The IMT regressed 0.038 mm in atorvastatin compared with a mean progression of 0.026 mm in the pravastatin group. Another 984 patients were enrolled in Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR).[19] Among the patients who took rosuvastatin 40 mg, the LDL-C level of 155 mg/dl was reduced to 78 mg/dl. The change was −0.0014 mm/y and 0.0131 mm/y in rosuvastatin and in the placebo. Thus, rosuvastatin resulted in LDL-C levels as low to 78 mg/dl and induced statistically significant reductions in the rate of progression of maximum CIMT over 2 years versus placebo. Mean IMT measures (0.83 ± 0.13 mm vs. 0.87 ± 0.16 mm) were also significantly lower among those with Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene variant when compared with the noncarriers with lower LDL-C level (95.5 ± 32.1 mg/dL vs. 109.6 ± 32.0 mg/dL) in a recent study.[20] These trials have further supported that decreasing LDL-C levels can delay thickening of IMT and intensive medication therapy can even stop or regress the progression of atherosclerosis, with LDL-C level around the 70-80 mg/dl. However, since the regression was very small, it seems that we should induce a greater reduction of LDL levels. Intravascular Ultrasound Evaluation Intravascular ultrasound (IVUS) imaging had emerged as the predominant approach for evaluating coronary atherosclerosis. IVUS provided a precise and reproducible method for determining the change in atheroma burden. The early trial used minimal lumen diameter change as endpoints. Recent trials measured atheroma volume, especially percent atheroma volume (PAV), the most rigorous IVUS parameter of disease progression and regression. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study[21] was an 18-month trial comparing the effects of intensive versus moderate lipid-lowering therapy on plaque progression in patients. A total of 253 patients were randomized to atorvastatin 80 mg/d and 249 patients were randomized to pravastatin 40 mg/d. LDL-C levels decreased from a baseline mean of 150 mg/dL in both groups to 79 mg/dL in the atorvastatin group and 110 mg/dL in the pravastatin group. For the primary end-point of percent change in total atheroma volume, a significantly lower rate of progression from baseline was observed with atorvastatin (−0.4%) than with pravastatin (2.7%) (P = 0.02). More recently, prospective, open-label blinded trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) enrolled 507 patients,[22] and 40 mg/d rosuvastatin were administered for 24 months. The LDL-C was reduced by 53.2%, from 130.4 mg/dL to 60.8 mg/dL (P < 0.01). The mean (SD) change in PAV was −0.98% (3.15%), with a median of −0.79% (97.5% confidence interval [CI] -1.21% to −0.53%) (both P < 0.01 vs. baseline). The investigator suggested that very high-intensive statin therapy with lower LDL-C level can regress atherosclerosis in CHD patients. The results of Multicenter Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound In Japanese Subjects (COSMOS) was published last year.[23] This 76-week open-label trial was performed in Japan. A total of 126 patients were given 2.5-20 mg/d rosuvastatin and had baseline and follow-up IVUS measurement. The mean (SD) LDL-C was reduced from 140.2 (31.5) mg/dl to 82.9 (18.7) mg/dl. The mean (SD) plaque volume was decreased from 72.1 (38.1) mm3 to 66.8 (34.0) mm3. Rosuvastatin also exerted significant regression of coronary plaque volume in Japanese patients with stable CAD. PRECISE-IVUS Trial[24] in Japanese patients who underwent percutaneous coronary intervention showed that the combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 vs. 73.3 mg/dl; P < 0.001). For the absolute change in PAV, the mean difference in ezetimibe combination group was noninferior compared with atorvastatin group. However, the absolute change in PAV did show superiority for the dual lipid-lowering strategy (−1.4%; 95% [CI]: −3.4% to −0.1% vs. −0.3%; 95% CI: −1.9% to 0.9% with atorvastatin alone; P < 0.001). For PAV, a significantly greater percentage of patients who received atorvastatin/ezetimibe showed coronary plaque regression (78% vs. 58%; P < 0.004). If the LDL-C level reduced to about 80 mg/dl, progression of atherosclerosis was halted in REVERSAL. When LDL level further decreased to 60-80 mg/dl, as low as 60.8 mg/dl in ASTEROID trial with intensive statin therapy and 63.2 mg/dl in PRECISE-IVUS trial with combination therapy, atherosclerosis was regressed [Figure 1]. Although the extent of regression was just about 0.2%-1.4%, it still supported the hypothesis that we should reduce LDL to newborn levels.Figure 1:: Relationship between low-density lipoprotein and change of atheroma (both percent atheroma volume and minimal lumen diameter change). Use Pearson correlation test. (PRECISE-IVUS study is not included)Low-density Lipoprotein and Clinical Events Many trials and meta-analyses had demonstrated the relationship between LDL level and coronary heart disease, including WOSCOPS, AFCAPS, ASCOT, and JUPITER in primary prevention and 4S, LIPID, CARE, HPS, IDEAL, TNT, and PROVIT-IT in secondary prevention. In a previous aggregated analysis, results indicated[25] that the LDL level at which the CHD rate predicated to approach 0 is 57 mg/dl for primary prevention and 30 mg/dl for secondary prevention. All these data support the theory “the lower the better.” In recent famous trial - Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),[1] after rosuvastatin 20 mg/d treatment, LDL can be further reduced to 55 mg/dl, the lowest level in large clinical trial. The mean baseline LDL-C level was at 108 mg/dl. The combined primary end-point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes can also be reduced, 1.60% versus 2.82%. Recently, IMPROVE-IT study caught attention and discussion worldwide since its main results published not only because it is a mega trial in CV area but also because of its scientific significance. IMPROVE-IT study was an international, multicenter, randomized, double-blind active comparator trial of 18,144 patients with high-risk acute coronary syndromes (ACS).[26] At 7 years, 32.7% of patients taking ezetimibe plus simvastatin experienced a first primary end-point event (major cardiovascular event) compared to 34.7% of patients taking simvastatin alone, corresponding to a 6.4% relative risk reduction (absolute risk reduction 2%, hazard ratio of 0.936, 95% CI: 0.887-0.988, P = 0.016). The mean LDL-C in the study at 1 year was 53 mg/dL in the ezetimibe plus simvastatin arm and 70 mg/dL in the simvastatin arm. The conclusion from this study could be summarized as: Even lower is even better (achieved mean LDL-C 53 vs. 70 mg/dL at 1 year) to further reduce cardiovascular events in ACS patients. However, even with LDL levels at 53 mg/dL, cardiovascular risk still remained. Either in primary or secondary prevention, it seemed that we should reduce LDL even more. The results of IMPROVE-IT also supported that the extent of the benefit was consistent with that seen in previous trials, with a similar reduction in cardiovascular events according to the degree of LDL-C lowering in lower LDL-C levels. Thus, maybe we could have more clinical benefits by decreasing LDL-C to about 20-30 mg/dL as in newborns [Figures 2 and 3].Figure 2:: Relationship between low-density lipoprotein and coronary heart disease events (%) in primary prevention. Composite cardiovascular events for JUPITER trial. Use Pearson correlation testFigure 3:: Relationship between low-density lipoprotein and coronary heart disease events (%) in secondary prevention. Composite cardiovascular events for TNT trial. Use Pearson correlation testPCSK9 inhibitors are a new class of drugs that have shown to further decrease LDL-C by 50%-70% when administered as a monotherapy or in combination with statins.[27] The ongoing trials, such as ODYSSEY OUTCOMES, SPIRE-1, and SPIRE-2, will provide evidence for “the lower the better.” We will see whether the cardiovascular events can be further decreased with very-low LDL-C level by PCSK9 inhibitor. Too Low To Go? And How To Go There? The safety concerns stem from two different questions: A. Are very-low LDL-C levels safe? B. Are drugs leading to very-low LDL-C safe? First of all, cholesterol is an essential component of cell membranes and is a necessary precursor for bile acid, steroid hormone, and Vitamin D synthesis. The newborn LDL-C levels were enough for physical need. When human fibroblasts were grown in cell culture, they took up media LDL through the LDL receptor pathway until sufficient cholesterol was internalized to meet cellular needs, leading to the downregulation of LDL receptors. The amount of LDL-C that was needed in such cultures was only 2.5 mg/dl. Because there was a 10:1 gradient between plasma and interstitial fluid LDL levels, this implied that a plasma level of 25 mg/dl LDL-C would be sufficient to supply peripheral cholesterol needs.[28] People with heterozygous hypobetalipoproteinemia had LDL-C levels as low as 30 mg/dl. These patients were always free of atherosclerosis with longevity. There was also lack of other adverse effects that might have been caused by such a low LDL level.[29] In healthy persons with a nonsense mutation in each PCSK9 gene, LDL-C concentrations were reported as low as 14-16 mg/dl.[30,31] Thus, it seemed that a very-low level of LDL-C, as low as newborns, was safe. Second, clinical trials showed that the intensive statin therapy could decrease LDL-C value safely. The cumulative data with statin therapy showed impressive cardiovascular benefits without a corresponding increase in adverse events such as malignancy or noncardiovascular mortality. In the JUPITER trial[1] in which LDL-C levels were as low as 55 mg/dl, there was no difference between rosuvastatin (40 mg) and placebo in any serious adverse events, including muscular weakness/stiffness/pain, myopathy, rhabdomyolysis, newly diagnosis cancer, death from cancer, gastrointestinal disorder, renal disorder, and hepatic disorder. Hence, high-intensive statin therapy is recommended as first-line (Class I, A) for patients <75 years old with clinical ASCVD.[32] However, many meta-analysis also showed that the side effects of statins such as liver dysfunction, myopathy,[33] or newly diagnosed diabetes[34] were dose-dependent and more common in high intensive statins, where high dose of statins are usually needed for reaching lower LDL-C targets. Furthermore, it should be noticed that the safety of high doses of statins in the Chinese population is not yet confirmed. In 2013 American Heart Association and American Stroke Association guidelines,[32] evidence among Asian populations was not included, therefore, it is recommended that moderate intensive statins could be used in Asian ancestry, to avoid statin-associated side effects. The most common side effects of statin, liver, and muscle toxicity, was seen with high dose of statins, but not in relationship to the on-treatment LDL level. Therefore, combination therapy or a new potent drug might be an alternative to reach the much lower LDL-C level. IMPROVE-IT study[26] had confirmed the safety of intensive LDL-C lowering by combining ezetimibe with simvastatin. The mean LDL-C was 53 mg/dL in the combination group. There were no significant differences between the two study groups in any of the prespecified safety end-points or in the rate of discontinuation of study medication owing to adverse events including the incidence of rhabdomyolysis or myopathy, alanine aminotransferase and aspartate aminotransferase ≥3×, ULN, and cancer, etc. Add-on ezetimibe to statins did not show significant increase of adverse event. PCSK9 could reduce LDL-C dramatically as monotherapy and combination with statin, and the reduction is not affected by the dose of background statins. In published phase 3 trial, the rate of serious adverse events was 2%-6%. Adverse events causing discontinuation of the drug occurred in 2%-10%. Elevation of liver aminotransferase >3 times of upper normal limit was observed in >2% of the patients. Elevation of creatinine was similarly rare.[27] Summary Atherosclerosis develops progressively with age and is closely related to the LDL-C levels. It was not initiated in healthy newborns with LDL levels around 30 mg/Dl but had begun in children and adolescents with normal LDL-C values. Clinical trials had shown that reducing LDL could retard or even reverse atherosclerosis in much lower LDL levels (53-80 mg/dL) with intensive medication therapy, evaluated by IMT, IVUS, or clinical end-points. However, the extent of the regression was small and the risk of cardiovascular events remained. So maybe we should lower LDL to the safe levels that you are born with, which are around 30 mg/dL, to prevent the development of atherosclerosis or provide the best treatment effects. More well-designed trials (combination therapy or with new drugs) are needed to support this hypothesis and confirm its safety. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.