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1.
LDL-C was the primary lipid treatment target for most ASCVD outcomes trials, and LDL-C is the primary lipid treatment target according to most lipid guidelines [31], [139]. However, compared to LDL-C, apolipoprotein B, non-HDL-C and LDL particle number may be better predictors of ASCVD risk in select populations, such as patients with diabetes mellitus, obesity, hypertriglyceridemia, non-fasting blood samples, and those with very-low LDL-C levels [144], [145], [146].
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A general principle is that patients at the highest ASCVD risk require the most aggressive lipid-management. Ten year ASCVD risk for those 40 – 75 years of age can be assessed by inputting 10 CVD risk factors into the ACC/AHA ASCVD Risk Calculator found at http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/ (as well as lifetime risk for those 20 – 59 years of age) [31].
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3.
Once ASCVD risk is determined, it is generally recommended that patients with ASCVD initially receive high intensity statin therapy (i.e., atorvastatin 40 – 80 mg per day, or rosuvastatin 20 – 40 mg per day). The objective of lipid-altering therapy with statins is to achieve a ≥ 50% reduction in LDL-C and achieve an LDL-C ≤ 70 mg/dL [31]. In patients at very-high risk, achieving an LDL-C of < 55 mg/dL may also be appropriate, [139], [147] with no apparent threshold below which further incremental risk reduction is not observed. Achieving lower levels of LDL-C often requires addition of other lipid-lowering drugs to statin therapy, such as ezetimibe, proprotein convertase subtilisin kexin (PCSK) 9 inhibitors, bempedoic acid, or bile acid binding resins.
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4.
Imaging studies are another way to assess clinical ASCVD [93], [148]. For example, computerized tomography coronary artery calcium (CAC) assessment can help stratify ASCVD risk and may be useful for patients at intermediate ASCVD risk, [149] when the decision to administer statin therapy is unclear [93]. Patients with CAC scores ≥ 400 AU are at high ASCVD risk [4], [148], [150], 150, 148, 150] Perhaps as importantly, a CAC score of zero suggests a low risk of CVD risk. [4] Patients with a CAC score of ≥ 1000 AU represent a phenotype of extreme coronary atherosclerosis with mortality like high CVD risk patients. [4, 151]
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Lipoprotein (a) is an LDL-like particle conjugated to apolipoprotein (a). Lp(a) is both atherogenic and thrombogenic and is an established CVD risk factor which can help stratify ASCVD risk. Statins, nutritional intervention, and increased physical activity do not lower Lp(a); PCSK9 inhibitors do lower Lp(a). [152, 153] No CVD outcomes trials have yet shown that reducing Lp(a) levels reduces the risk of CVD events. However, Lp(a) levels can be reduced with lipoprotein apheresis and other pharmacotherapies in development (e.g., antisense oligonucleotides and small interfering ribonucleic acids). [154] The ongoing Lp(a) HORIZON cardiovascular outcome study is evaluating pelacarsen (i.e., antisense oligonucleotide targeting the LPA gene messenger RNA) regarding its effects upon major adverse cardiac events. [154, 155, 156] Until therapies that lower Lp(a) are proven to provide health benefits, a single accurate measure of Lp(a) may be sufficient to inform on CVD risk. [157]
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6.
Statins are the most recommended drug treatment for hypercholesterolemia due to their cholesterol-lowering efficacy, safety, and ASCVD benefits supported by numerous cardiovascular outcomes trials. [93] “High intensity statins” (atorvastatin 40 - 80 mg or rosuvastatin 20 – 40 mg) may lower LDL-C ≥ 50%, and are often recommended as first-line therapy in patients with ASCVD or at high risk for ASCVD. [31, 139] The most common clinical manifestation of statin intolerance is statin-associated muscle symptoms (SAMS), which may limit the dose or use of statins. [158, 159] SAMS can sometimes be mitigated by rechallenging with the same statin at a lower dose, using different statins, or recommending statins be administered a few days per week, rather than daily. [160, 159, 161] Occasionally, the maximally tolerated dose of a statin is no statin, requiring use of other lipid-altering drugs to achieve clinically desirable LDL-C levels. While some evidence exists regarding the objective presence of statin intolerance among some patients, [162] a small randomized crossover trial suggested that 90% of the side effects of a statin were also experience with a placebo. [163]
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Common non-statin oral lipid-altering drugs include ezetimibe (an intestinal cholesterol absorption inhibitor) [164]and bempedoic acid (an adenosine triphosphate citrate lyase inhibitor that reduces hepatic cholesterol synthesis). [165] Ezetimibe modestly lowers LDL-C levels ∼ 18% and provides incremental ASCVD risk reduction beyond statin therapy. [166] Bempedoic acid lowers LDL-C ∼ 18%, and when combined with ezetimibe in a fixed dose combination, lowers LDL-C ∼ 38%. A CVD outcome study of bempedoic acid in patients with statin intolerance is ongoing. [167, 168]
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PCSK9 inhibitors are injectable agents that lower LDL-C ≥ 50% and reduce ASCVD risk when added to high intensity or maximally tolerated statins. [31, 139] Evolocumab [169] and alirocumab [170] are injectable fully humanized monoclonal antibodies that bind and inhibit PCSK9 and that are administered every 2 – 4 weeks. Inclisiran is an injectable small interfering (or silencing) ribonucleic acid agent that impairs hepatic PCSK9 synthesis and is administered every 6 months (twice a year). [171]Oral PCSK9 formulations are in development.
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9.
Hypertriglyceridemia (≥ 150 mg/dL) generally increases the risk for ASCVD (i.e., high triglycerides are part of the diagnostic criteria for the metabolic syndrome) [31] and especially increases ASCVD risk if the elevated triglyceride (TG) levels represent an increase in atherogenic triglyceride-rich lipoproteins (e.g., very-low-density lipoproteins, intermediate density lipoproteins, remnant lipoproteins) [172] and their remnants. [136] In Europe, the risk for hypertriglyceride-induced pancreatitis is thought clinically significant at a severely elevated triglyceride level of 10 mmol/L (880 mg/dL).[139] In the US, very high triglyceride levels are typically defined as ≥ 500 mg/dL, [31] and represent levels that may not only increase ASCVD risk, but also increase the risk of hypertriglyceride-induced pancreatitis – sometimes resulting in recurrent bouts of hypertriglyceride-induced pancreatitis. [173, 174]
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Nutritional, physical activity, and pharmacotherapeutic interventions can reduce triglyceride levels. [175] Omega-3 fatty acids lower triglycerides and non-HDL-C. Prescription icosapent ethyl is an eicosapentaenoic acid, ethyl ester agent that reduces the risk of multiple CVD endpoints in patients at high ASCVD risk having triglyceride levels ≥ 150 mg/dL. [78] Fibrates are used to lower triglyceride levels. However, no CVD outcome study has yet shown that fibrates reduce CVD risk in patients with high triglycerides. Post hoc analyses support that fibrates may reduce ASCVD events in patients with high triglycerides (and low HDL-C levels). [176] A CVD outcome study of a selective peroxisome proliferator-activated receptor alpha modulator (pemafibrate) in patients with diabetes mellitus having hypertriglyceridemia and low HDL-C levels [177, 178] was discontinued in 2022 for futility.
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