Review of LDL-C Lowering with Focus on New and Emerging Agents Eliot A. Brinton, MD, FAHA, FNLA, FACE Disclosure Note: This CME activity includes discussion about medications not approved by the US Food and Drug Administration and uses of medications outside of their approved labeling. CONTINUING MEDICAL EDUCATION LEARNING OBJECTIVES Dr. Brinton serves on the advisory board METHOD OF PARTICIPATION • Identify the benefits and limitations of for Esperion, Amarin, 89bio, AstraZen- PHYSICIANS: To receive CME credit, statin therapy as a treatment option for eca, Kowa and Novartis, and on the please read the journal article and, on lowering LDL-C. speakers’ bureau for Amarin and Esper- completion, go to www.pceconsortium. • Intensify treatment in appropriate pa- ion. He is a grant recipient for Kowa. Dr. org/hyper to complete the online post-test tients or refer for intensification. Backes, editorial support, discloses that and receive your certificate of completion. • Describe the safety and efficacy of he serves on the speakers' bureau for PHYSICIAN ASSISTANTS AND NURSE ezetimibe, bempedoic acid, PCSK9 in- Kowa Pharmaceuticals. Dr. Scott, edito- PRACTITIONERS: AANP, ANCC, and hibitors, LDL apheresis. rial support, discloses that he has no real AAPA accept certificates of participation • Describe the safety and efficacy of or apparent conflicts of interest to report. of educational activities certified for AMA medications in late-stage development PRA Category 1 Credit™ from organiza- or under review by the FDA for LDL-C SPONSORSHIP tions accredited by ACCME. reduction. This activity is sponsored by Primary Care Education Consortium, in collabo- SUPPORT TARGET AUDIENCE ration with the Primary Care Metabolic This article is supported by an educa- Family physicians and clinicians who Group. tional grant from Novartis Pharmaceutical wish to gain increased knowledge and Corporation. greater competency regarding primary ACCREDITATION care management of hyperlipidemia. The Primary Care Education Consortium FACULTY is accredited by the ACCME to pro- DISCLOSURES vide continuing medical education for Eliot Brinton MD, FAHA, FNLA, FACE, Past President, American Board of Clini- As a continuing medical education pro- physicians. cal Lipidology, President, Utah Lipid Cen- vider accredited by the ACCME, PCEC ter, Salt Lake City, UT. requires any individual in a position to CREDIT DESIGNATION influence educational content to disclose AMA PRA Category 1 – Primary Care Ed- ACKNOWLEDGMENT any financial interest or other personal ucation Consortium designates this en- relationship with any commercial interest. during material for a maximum of 1.0 AMA Editorial support was provided by Jim Mechanisms are in place to identify and PRA Category 1 credit(s)™. Physicians Backes, PharmD, and Gregory Scott, resolve any potential conflict of interest should claim only the credit commensu- PharmD, RPh of PCEC. prior to the start of the activity. In addi- rate with the extent of their participation in tion, any discussion of off-label, experi- the activity. CME is available September mental, or investigational use of drugs or 1, 2020 to August 31, 2021. devices will be disclosed by the faculty. INTRODUCTION ASCVD risk.4-8 Further, extensive mechanistic data strongly There is growing consensus that the “LDL Hypothesis” has support a causal role for LDL in atherogenesis.9 Causation is been proven. First, essentially every well-conducted cardio- further supported by several Mendelian randomization stud- vascular outcomes trial (CVOT) with low-density lipopro- ies of a wide variety of genetic conditions, which have consis- tein cholesterol (LDL-C)-lowering has also shown reduction tently reported decreased or increased ASCVD risk related to in atherosclerotic cardiovascular disease (ASCVD). This is genetically decreased or increased LDL-C, respectively. true not only for the many CVOTs with statins, but also for This first section of this review will discuss familial hyper- at least 5 other classes of medications as well as 3 non-phar- cholesterolemia (FH), the most important disease of elevated macological treatments.1-3 Meta-analyses of these trials show LDL-C levels, in the context of other causes of LDL-C eleva- a log-linear relationship between on-treatment LDL-C and tions. Next, it will discuss risk assessment and stratification, Supplement to The Journal of Family Practice | Vol 69, No 7 | SEPTEMBER 2020 S69 REVIEW OF LDL-C LOWERING relevant to decision-making for LDL-C lowering treatment. major ASCVD events (acute coronary syndrome within the Next, LDL-C lowering medications will be covered, begin- past 12 months, heart attack, ischemic stroke, or symptomatic ning with statins, which are by far the best-established agents peripheral arterial disease) or one such event plus ≥2 high- and which are universally used as first-line treatment for risk conditions (age ≥65 years, HeFH, history of coronary LDL-C lowering and ASCVD prevention. Finally, existing and revascularization [outside of a major ASCVD event], diabetes emerging statin adjuncts will be discussed, regarding their mellitus [DM], chronic kidney disease, hypertension, smok- use in management of patients who cannot achieve appro- ing, congestive heart failure, or LDL-C ≥100 mg/dL despite priate LDL-C control with a statin alone. maximally-tolerated statin therapy). These patients warrant maximally-tolerated statin therapy followed by ezetimibe FAMILIAL HYPERCHOLESTEROLEMIA and then a PCSK9i mAb for LDL-C ≥70 mg/dL. FH may be the single most common monogenic disease,10 Patients with a prior event who do not meet these crite- with the prevalence of heterozygous FH (HeFH) estimated ria are termed “not very high-risk ASCVD” and are divided by to be ~1/200 patients in the general population,11 and homo- age ≤75 or >75 years. In the former group, treatment is similar zygous FH (HoFH) being rare, at roughly 1/300,000.12 HeFH to that for very high-risk but PCSK9i are not indicated. For the typically presents with untreated LDL-C levels ≥190 mg/ former group, high- or moderate-intensity statins are war- dL, Achilles tendon xanthomas (after ~40 years old), and a ranted, whereas for patients age >75 years, statin continuation positive family history of LDL-C >190 mg/dL and premature may be considered, but initiation of statin therapy is not said ASCVD. In contrast, patients with HoFH typically present to be warranted. That said, a CVOT with ezetimibe in patients with LDL-C levels >500 mg/dL and widespread xanthomas age >75 years (EWTOPIA, see below) was first reported at the or even a CV event in childhood.13 time of the presentation of the 2018 Multi-Society guidelines. The 2018 American College of Cardiology (ACC)/Ameri- The results of EWTOPIA showed convincing ASCVD benefit can Heart Association (AHA)/National Lipid Association with ezetimibe monotherapy, which should, therefore, be (NLA) Multi-Society Guideline on the Management of Blood considered in these patients. Cholesterol recommends that patients age 20 to 75 years The 2018 guidelines also state that, for patients without without ASCVD but with an LDL-C ≥190 mg/dL should be a prior ASCVD event, those with DM and age 40-75 years treated with maximally tolerated statin therapy to achieve should receive at least moderate-intensity statin therapy an LDL-C reduction >50%. Further, statin adjuncts are to be regardless of calculated ASCVD risk. High-intensity statins considered for secondary prevention if LDL-C remains above are warranted in patients with DM in the setting of multiple a treatment threshold of 70 mg/dL for very high-risk and 100 additional risk factors, independent of age. Treatment of mg/dL for high-risk patients.14 The addition of ezetimibe is patients age 40-75 years without prior ASCVD, DM, or FH the first of statin-adjunct. In patients failing to achieve an may be guided by the estimated 10-year ASCVD risk score. LDL-C decrease of 50%, or with LDL-C remaining above For risk <5%, lifestyle is sufficient. For risk 5% to 20%, mod- 100 mg/dL, with both a statin and ezetimibe, use of a pro- erate-intensity statins are usually recommended, depend- protein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) ing on the presence and number of ASCVD “risk enhancers” may then be considered.15 For HoFH, early identification [eg, family history of premature ASCVD, South Asian ances- and referral to a lipid specialist is needed. Treatment is more try, metabolic syndrome, Lp(a) or triglycerides, renal insuf- aggressive than for HeFH in that more than 1 statin adjunct is ficiency and/or inflammatory conditions/markers]. For a always required, and usually also LDL-apheresis (also used 10-year ASCVD risk ≥20%, statins are always warranted, with for more severe HeFH) and sometimes lomitapide (indicated a goal to reduce LDL-C by ≥50%.14 only for HoFH) as well. BEYOND STATINS RISK STRATIFICATION AND PATIENT SELECTION A key question for clinicians is: What is the overarching strat- FOR STATINS AND STATIN ADJUNCTS egy for LDL-C lowering? In contrast to treatment of hyperten- Risk stratification is crucial, first, to identify which patients sion or type 2 DM, where overtreatment is always a practical warrant consideration of statin therapy, then to determine concern, there is good evidence for additional benefit and no the appropriate level of statin intensity, and finally, to direct harm from treatment to very low LDL-C levels. Patient cost any needed use of statin adjuncts. and inconvenience, and side effects of LDL-lowering medi- For patients with