8  Cholesterol Management

TODO

• ASCVD Risk Categories for primary prevention
  • Low risk: < 5%
  • Borderline risk: 5-7.5%
  • Intermediate risk: 7.5-19.9%
  • High risk: ≥ 20%
• Recommendations generally refer to patients ages 40-75 years old. Evidence is now showing improved CV mortality and fewer ASCVD events in adults aged ≥ 75 yo w/o hx of baseline ASCVD taking statins (compared to non-statin users) in the VA population (Orkaby et al. 2020).
• What are the “high risk” ASCVD groups?
  • Acute coronary syndrome (ACS) in the last 12 months 
  • Multiple heart attacks
  • Ischemic stroke
  • Symptomatic peripheral artery disease (claudication with ABI < 0.85, or previous revascularization or amputation) 
  • Age > 65 years
  • Heterozygous familial hypercholesterolemia
  • Prior coronary bypass surgery or PCI outside of the above events
  • Diabetes mellitus
  • Hypertension
  • Chronic kidney disease
  • Current smoker
  • Persistently elevated LDL > 100 mg/dL despite max statin therapy and ezetimibe
  • Congestive heart failure
• Pts with established CAD, but do not meet any ‘high risk’ criteria are considered Stable ASCVD
  • Recommendations for Stable ASCVD:
    • < 75 yo → high-intensity statin (Goal LDL < 70 mg/dL)
    • 75+ yo → high/moderate-intensity statin
• Risk enhancing ASCVD factors should be considered to guide mgmt b/w borderline and intermediate risk groups (Grundy et al. 2019)
  • family history of premature CAD (♂ < 55 yo; ♀ < 65 yo)
  • primary hypercholesterolemia w/ LDL 160-189 mg/dL
  • metabolic syndrome
  • CKD
  • chronic inflammatory disorders (e.g. RA, HIV/AIDS)
  • premature menopause (menopause < 40 yo)
  • pregnancy-related adverse outcomes (e.g. pre-eclampsia)
  • non-fasting triglycerides > 175 mg/dL on at least 3 occasions
  • high-risk ethnicities (e.g. South Asians)
  • Other labs:
    • hs-CRP > 2 mg/dL
    • Lp(a) > 50 mg/dL
    • apoB > 130 mg/dL
  • Ankle-brachial index (ABI) < 0.9
• Coronary artery calcium (CAC) scoring may also be useful to guide management in unclear settings or when a pt is straddling b/w borderline/intermediate risk groups (especially if pt is reluctant to start a statin)
  • According to the MESA study, diabetics with a CAC score of zero had similar event rate as those without diabetes (Bertoni et al. 2016).
• Statin flavors:
  • High-intensity
    • Atorvastatin 40-80
    • Rosuvastatin 20-40
  • Moderate-intensity
    • Atorvastatin 10-20
    • Rosuvastatin 5-10
    • Simvastatin 20-40
    • Pravastatin 40-80
• LDL reduction goals on statin therapy
  • High-intensity: ↓ in LDL by > 50%
  • Moderate-intensity: ↓ in LDL by 30-49%
  • Low-intensity: ↓ in LDL by < 30%
• Follow-up
  • Repeat LDL 4-12 wks after initiation
  • Subsequent f/u: repeat LDL after 3-13 months (depending on the pt)
    • stable: check annually or even every 4-6 years in younger pts
• Who always is indicated to receive a statin?
  • DM + age > 40 yo
  • Primary hypercholesterolemia (LDL ≥ 190)
• Secondary prevention
  • High-intensity statin (unless > 75 yo, where recommended to start high/moderate-intensity statin)
  • If LDL goal is not met:
    • add ezetimibe (Zetia) (IMPROVE-IT trial)
    • if still not at goal → add PCSK9 inhibitor (ODYSSEY and FOURIER trials)
• Lifestyle modifications
  • Diet
    • 😋 Enjoy rich in fruits, veggies, polyunsaturated fats, lean meats, plant-based proteins, phytosterols and fiber
    • ⚠️ Avoid saturated fats, refined carbs/sweets and red meat
  • Exercise
    • Moderate/vigorous intensity aerobic exercise 3-4x/wk for 40 mins each session

Lipid Management (Curbsiders, Ep. 191)

Indication	Statin Intensity	Rx if not at LDL goal
Multiple major ASCVD events or Major ASCVD event + multiple high RFs	High	High-intensity: Aim for ≥ 50% ↓ in LDL If LDL ≥ 70 (or non-HDL ≥ 100): ezetimibe ± PCSK9i
LDL ≥ 190 mg/dL	High	High-intensity: Aim for ≥ 50% ↓ in LDL If LDL ≥ 100: ezetimibe ± PCSK9i
High-risk: ASCVD ≥ 20%	High	High-intensity: Aim for ≥ 50% ↓ in LDL If LDL ≥ 70: ezetimibe ± PCSK9i
Stable ASCVD: Clinical ASCVD w/o high RF	High/Moderate	High-intensity: Aim for ≥ 50% ↓ in LDL Mod-intensity: Aim for 30-49% ↓ in LDL If LDL ≥ 70: ezetimibe ± PCSK9i
DM	High/Moderate High if multiple RFs	High-intensity: Aim for ≥ 50% ↓ in LDL Mod-intensity: Aim for 30-49% ↓ in LDL
Intermediate risk: ASCVD 7.5-20%	Moderate	Mod-intensity: Aim for 30-49% ↓ in LDL
Low/Borderline-risk: ASCVD ≤ 7.5%	Shared decision making Consider risk enhancers

• Clinical features of severe hyperlipidemia
  • Xanthelasma
    • yellow plaques on eyelids
  • Xanthoma
    • hard, yellow masses typically found on tendons (finger extensors, Achilles, plantar tendons)
  • Pancreatitis - if severe hypertriglyceridemia

8.1 Hypertriglyceridemia

• First-line: lifestyle modification
• If TG persistently > 500 mg/dL → next step is to start a statin
• If TG > 1,000 mg/dL → start a fibrate (to avoid pancreatitis)
• Icosapent ethyl (REDUCE-IT trial) (Bhatt et al. 2019)
  • not the same thing as fish oil
  • can be added to pts with ↑ TG despite being on statins, i.e. add as an adjunct to statins
    • ↑ TG defined in REDUCE-IT trial: TG level of 135-499 mg/dL
  • Dose from REDUCE-IT trial: 2 g of icosapent ethyl BID

8.2 O’Keefe Lecture Notes

8.2.1 Statins

• Dr. O’Keefe is not a fan of Atorva 80 mg b/c side effects of statins are dose-dependent.
  • You can get rhabdo with high doses of statins. Dr. O’Keefe gave an example of post-transplant patient on Atorva 80 who got rhabdo and died a few months later.
  • Delta between 40 mg and 80 mg of atorva is 48% → 51% reduction (delta is only 3%)
• Atorva is the 🌟
• Rule of thumb: 6% reduction when doubling a statin dose. Better off adding ezetimibe: zetio on its own 16% reduction, zetia + statin (synergistic effect): 25% reduction.
• Newborn baby LDL is 25-30 mg/dL. Hunter/gatherers have also been studied and have like 40-50 mg/dL.
  • You don’t want a 0 LDL! Cholesterol is an important molecule, so you need some.
• Dr. O’Keefe gets nervous getting someones LDL < 30
• Side effects are not related to LDL level, rather related to statin dose.
• Mnemonic for statin side effects “LIPITOR”:
  • Liver effects
  • Increased blood sugar
  • Pain (muscles)
  • Impaired memory
  • Tiredness/Fatigue
  • Other (headaches)
  • Rhabdomyolysis
• SAMSON trial (BMJ, 2021)
  • 200 statin intolerant patients; “n-of-1” experiments
  • Compared atorva 20 mg vs placebo
  • Intolerable muscle sx: 9% in statin group discontinued, 7% discontinued placebo
• Dr. O’Keefe: “when I start someone on a statin, I also start them on CoQ10.”
  • If patient c/o myalgias, he’ll increase the dose of CoQ10
• Pitavastatin
  • a “cool” statin
  • Not as strong as atorva
  • 4 mg dose \(\approx\) 20 mg of atorva
  • Unlike atorva, rosuva, simva, Pitavastatin less likely to induce DM in patients. If anything pitava can lower A1c by 0.1%

8.2.2 Ezetimibe

• Dr O’Keefe loves ezetimibe
• EWTOPIA75 study out of Japan: zetia monotherapy vs control
• IMPROVE-IT trial
  • compared to folks on simva vs simva +zetia: combo further reduced cardiovascular events

8.2.3 PCSK9 inhibitors

• Evolocumab → reduction of MACE
• Injection once every 2 weeks
• Alirocumab and Lp(a)
• Statins, exercise, diet don’t do anything to effect Lp(a)
• Don’t do anything for TG or HDL, purely work on LDL

8.2.4 Omega-3

• REDUCE-IT trial → ↓ MACE 26%
  • icosapent ethyl (Vascepa) vs placebo
• You want to get TG < 150
• Dr O’Keefe: everybody should be on 1g of EPA+DHA
  • If strong indications (hyperTG, atherosclerosis) at least 2g
  • In certain patients, up to 4g/day
• May increase risk of AFib (dose-dependent)
  • Omega-3 is correlated with ↑ vagal effect (↓ HR, etc.), but there is a subset that increased risk of brady, APC → ↑ risk of AFib
• Bill Harris is aka “The Codfather” 😆

8.2.5 Fibrates

• Fenofibrates are really the only ones we use. We often use it with a statin.
• It’s 3rd line for hyperTG
  • First line is statin, second line is Omega-3
• Recall, goal is to get TG < 150
• Low glycemic diet, eliminating added sugars will lower TG dramatically

8.2.6 Niacin

• Dr. O’Keefe is not a fan. If someone shows up on it, he’ll take them off of it.

Bertoni, Alain G., Holly Kramer, Karol Watson, and Wendy S. Post. 2016. “Diabetes and Clinical and Subclinical CVD.” Global Heart 11 (3): 337. https://doi.org/10.1016/j.gheart.2016.07.005.

Bhatt, Deepak L., P. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Steven B. Ketchum, Ralph T. Doyle, et al. 2019. “Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.” New England Journal of Medicine 380 (1): 11–22. https://doi.org/10.1056/nejmoa1812792.

Grundy, Scott M., Neil J. Stone, Alison L. Bailey, Craig Beam, Kim K. Birtcher, Roger S. Blumenthal, Lynne T. Braun, et al. 2019. “2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” Circulation 139 (25). https://doi.org/10.1161/cir.0000000000000625.

Orkaby, Ariela R., Jane A. Driver, Yuk-Lam Ho, Bing Lu, Lauren Costa, Jacqueline Honerlaw, Ashley Galloway, et al. 2020. “Association of Statin Use with All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older.” JAMA 324 (1): 68. https://doi.org/10.1001/jama.2020.7848.