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Encouragement of Super-Aggressive LDL-Lowering Therapies

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Encouragement of Super-Aggressive LDL-Lowering Therapies J-STAGE advance published date: December 6, 2019 Review Article Encouragement of Super-aggressive LDL-lowering Therapies Hayato Tada, Kenji Sakata, Masayuki Takamura, and Masa-aki Kawashiri Clinical usefulness of aggressive LDL-lowering therapies using statin, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have been shown in primary as well as in secondary prevention settings. In addition, the idea that the lower, the better story in LDL appears to be true as low as ~30 mg/dl based on recent randomized controlled trials (RCT). Moreover, aggressive LDL-lowering therapies, for either of primary prevention setting, or secondary prevention setting has been shown to be quite effective in Japanese population as well. According to those facts, recent guidelines in Europe, and in Japan suggest to lower LDL cholesterol (LDL-C) level < 70 mg/dl for high-risk patients. However, the attainment rates of such “strict” goals seem to be quite low, probably because most cardiologists still have a feeling of anxiety of extremely low LDL-C level. In this review article, we provide the idea that LDL-C is one of the well-established causal factors for atherosclerotic cardiovascular disease (ASCVD) based on the findings from Mendelian randomization studies in addition to RCT. The beautiful consistency between RCT and Mendel randomization studies have reassured us that the lower, the better, as well as the earlier, the better appear to be true. KEY WORDS: cholesterol, genetics, LDL, lipoproteins, PCSK9 I. Introduction II. Lessons from extreme cases It has been definitively established that low-density lipopro- It is almost always useful to see the extreme cases to under- tein (LDL) cholesterol (LDL-C) is a causal risk factor for athero- stand the relationship between particular biomarkers and out- sclerotic cardiovascular disease (ASCVD). Over the decades, comes. In the case of LDL-C and ASCVD, the most important as LDL-lowering therapies, including statins, ezetimibe, and pro- well as understandable situation could be familial hypercholes- protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors terolemia (FH) and ASCVD. For example, the patients with ho- have been introduced in clinical settings, and they have contrib- mozygous FH whose LDL-C levels typically elevated to as high uted to better prognosis 1-4). It is of note that the beneficial effects as ~ 500 mg/dl exhibited premature ASCVD 11). Interestingly, of reducing ASCVD risk appear to be proportional to the abso- several phenocopies of this situation with extremely high lute degree of reducing LDL-C (Fig. 1). In addition, Mendelian LDL-C, including autosomal recessive hypercholesterolemia randomization studies, which could be considered as a substitute (ARH) 12) and sitosterolemia 13) caused by different genetic muta- of randomized controlled trials (RCT), consistently revealed that tions exhibit similar phenotypes, including, tendon/cutaneous genetic variations associated with LDL-C was robustly associat- xanthomas, and premature ASCVD, similar to those observed in ed with ASCVD in proportion to the degree of LDL-C changes homozygous FH (Fig. 2). Those cases simply indicate that (Fig. 1) 5-10). Those facts could make us confident that LDL-C is LDL-C is the causal factor of this situation regardless of genetic the true causal factor for ASCVD, in contract to other merely etiology. On the other hand, findings from the patients exhibiting biomarkers. In this article, we provide lessons obtained from re- extremely low LDL-C with any genetic backgrounds could also cent RCT targeting to lower LDL-C aggressively, as well as tell us a lot about the relationship between LDL-C and ASCVD. those obtained from Mendelian randomization studies including Our patient with abetalipoproteinemia (ABL) caused by micro- rare variations, and common single nucleotide polymorphism somal triglyceride transfer protein (MTTP) mutations (LDL-C = (SNP). 0 mg/dl) did not exhibit any coronary plaque nor aortic calcifica- tions at the age of 51 (Fig. 3), although he suffers from spinocer- Department of Cardiology, Kanazawa University Graduate School of ebellar ataxia, and retinal pigmentary degeneration due to lack of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8641, Japan fat-soluble vitamin 14). On the contrary, we have shown an inter- Email: [email protected] esting case of homozygous familial hypobetalipoproteinemia Received: April 23, 2019; Accepted: August 16, 2019 (FHBL) whose LDL-C was as low as 1 mg/dl 15). He does not ex- Doi: 10.7793/jcad.25.19-00005 hibit any complications relating fat-soluble vitamin deficiency ─ 1 ─ Tada-H.indd 1 2019/11/28 17:10 J-STAGE advance published date: December 6, 2019 J-STAGE advance published date: December 6, 2019 Fig. 1 Association between LDL-C lowering and ASCVD risk reduction. X-axis represents effects of LDL-C lowering either by genetic variants or by pharmacological interventions. Y-axis represents proportional risk ASCVD risk reduction either by genetic variants or by pharmacological interventions. Blue color indicates genetic variants. Pink color indicates pharmacological interventions. Fig. 2 Physical signs identifi ed among extreme cases caused by different etiologies. A: Orange colored xanthomas were identifi ed at elbows, back of the thighs, and back of the knees in a pa- tient with compound heterozygous FH. B: Achilles tendon thickness was observed in a patient with ARH. C: Orange colored xanthomas were identifi ed at both ankles in a patient with sitosterolemia. FH: familial hypercholesterolemia, LDLR: LDL receptor, PCSK9: proprotein convertase subtilisin-kexin type 9, ARH: autosomal recessive hypercholesterolemia, LDLRAP1: LDL receptor adaptor protein 1, ABCG5: ATP-binding cassette sub-family G member 5. described above, probably due to his preserved HDL cholesterol III. Lessons from Mendelian randomization studies (HDL-C) level containing fat-soluble vitamin. It would be im- portant to see none of the family members whose LDL-C was In any diseases, it should be critical, but diffi cult to think of quite low had atherosclerotic diseases. Also, it would be quite “causal” factors. For example, Koch’s postulates are four criteria interesting to understand that novel pharmacological interven- designed to establish a causative relationship between a microbe tions for LDL-lowering have been developed based on the fi nd- and a disease 16). It includes 1) The microorganism must be found ings obtained from those extreme cases (Table 1). in abundance in all organisms suffering from the disease, but ─ 2 ─ Tada-H.indd 2 2019/11/28 17:10 J-STAGE advance published date: December 6, 2019 J-STAGE advance published date: December 6, 2019 Fig. 3 Images of coronary computed tomography and carotid ultrasound in a patient with ABL. A: Coronary computed tomography obtained in a patient with ABL. There is no stenotic lesions nor any calcifi cations identifi ed in coronary arteries. ABL: abetalipoproteinemia, RCA: right coronary artery, LAD: Left anterior descending coronary artery, LCX: Left circumfl ex coronary artery. B: Carotid ultrasound image obtained in a patient with ABL. There is no stenotic lesions nor inti- ma-media thickness in right common carotid artery. C: Carotid ultrasound image obtained in a patient with ABL. There is no stenotic lesions nor inti- ma-media thickness in left common carotid artery. Table 1 Novel pharmacological interventions for LDL-lowering Deficiency Mendelian Target Compounds Randomized controlled trials or carriers of PTV randomization Heterozygous carriers NPC1L1 Ezetimibe IMPROVE-IT (Ref 2) Ref 7, 8 (1 in 650 individuals) Familial Evolocumab FOURIER (Ref 3) PCSK9 Ref 5, 6 hypobetalipoproteinemia Alirocumab ODYSSEY OUTCOMES (Ref 4) MTTP Abetalipoproteinemia Lomitapide NA Ref 6 Familial APOB Mipomersen NA Ref 27 hypobetalipoproteinemia Familial combined ANGPTL3 Evinacumab NA Ref 28 hypolipoproteinemia ACLY NA Bempedoic Acid NA Ref 31 NPC1L1: Niemann-Pick C1-Like 1, PCSK9: proprotein convertase subtilisin-kexin type 9, MTTP: microsomal triglyceride transfer protein, APOB: apolipoprotein B, ANGPTL3: Angiopoietin-like 3, Ref: reference, NA: not available, ACLY: ATP citrate lyase. should not be found in healthy organisms. 2) The microorganism should be the gold standard to establish a causal relationship be- must be isolated from a diseased organism and grown in pure tween a particular biomarker and a disease. On the other hand, culture. 3) The cultured microorganism should cause disease Mendelian randomization study is a technique that uses geno- when introduced into a healthy organism. 4) The microorganism types as instruments to assess a causal relationship between bio- must be re-isolated from the inoculated, diseased experimental markers and outcomes even in a cross- sectional manner 17). Us- host and identified as being identical to the original specific ing this scheme, genetic variants associated with LDL-C have causative agent. How about in cardiovascular diseases? RCT been robustly associated with ASCVD, regardless of genes as ─ 3 ─ Tada-H.indd 3 2019/11/28 17:10 J-STAGE advance published date: December 6, 2019 J-STAGE advance published date: December 6, 2019 Table 2 Effects of randomized controlled trials and Mendelian randomization study in PTV on LDL-C and on ASCVD Gene RCT Mendelian randomization study in PTV LDL-C ASCVD LDL-C ASCVD Trial name reduction (mg/dl) reduction (%) reduction (mg/dl) reduction (%) APOB NA NA NA 43 72 CETP REVEAL 26 9 12 30 NPC1L1 IMPROVE-IT 17 6 12 53 PCSK9 FOURIER/ODYSSEY 62/48 15/15 21 88 RCT: randomized controlled trial, PTV: protein truncating variant, ASCVD: atherosclerotic cardiovascular disease, APOB: apolipoprotein B, CETP: cholesteryl ester transfer protein, NPC1L1: Niemann-Pick C1-Like 1, PCSK9: proprotein convertase subtilisin-kexin type 9, NA: not available. stated above. It is interesting to note that genetic variants associ- consistently revealed that additional beneficial effects could be ated with HDL-C were not associated with ASCVD 18, 19), consis- obtained through such super-aggressive LDL-C lowering thera- tent with negative results of RCT targeting lower HDL-C 20-22).
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