#37 Lipids, PCSK9, and ezetimibe: Lower is better.

May 1, 2017 | By Matthew Watto, MD

Learn the latest in lipid lowering therapy in this extensive discussion with Dr. Paul S. Jellinger, MD, MACE, Professor of Medicine at the University of Miami and Chair of the writing committee for the American Association of Clinical Endocrinologists (AACE) 2017 Guidelines for the Management of Dyslipidemia and Prevention of Cardiovascular Disease (CVD). Topics include ezetimibe, PCSK9, FOURIER trial, statin myopathy, CoQ10, fish oil, fibrates and more. For a more basic discussion of dyslipidemia check out episode #10.

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Clinical Pearls:

1. Dyslipidemia: umbrella term for lipid disorders e.g. familial hypercholesterolemia, hypertriglyceridemia, mixed hypercholesterolemia, diabetic dyslipidemia
2. ASCVD = astherosclerotic cardiovascular disease (usually defined as coronary death or nonfatal myocardial infarction, or fatal or nonfatal stroke)
3. Identify primary defect: Is it elevated LDL? Or insulin resistance with high triglycerides and low HDL? Or both (aka “mixed hypercholesterolemia”)?
4. “Diabetic dyslipidemia”: insulin resistance, elevated triglycerides (TG) and low HDL
5. Homozygous familial hypercholesterolemia: Total cholesterol of 700-800s, LDL in 300s and coronary disease at young age e.g. 20 years old
6. Heterozygous familial hypercholesterolemia (HeFH): Diagnosis via genetic analysis for $1500 (not covered), or use Simon Broome (recommended), Dutch Lipid Clinic Network, or MedPed criteria.
7. Lp (a): Strongly transmitted in families. Associated with early familial coronary disease. Lowered by niaspan and PCSK9 inhibitors. Aggressive lowering of LDL also lowers risk from Lp (a).
8. Apo B: Attached to every particle of LDL, thus gives a sense of LDL particle number and concentration. High Apo B means small, dense, and atherogenic LDL particles. Consider checking in high risk patients who appear to be at LDL goal. If Apo B remains elevated, then you need to lower LDL further.
9. Screening: Check total cholesterol, LDL, HDL, triglycerides and calculation of non-HDL cholesterol. Fasting preferred if patient has hypertriglyceridemia. No need for routine Lp(a), or Apo B.
10. Screening: Start age 20 years old then check every 5 years. If family history of CVD then check before 20 years old.
11. Risk calculators: use Framingham, Reynold’s (women above 45yo), UKPDS, or MESA.
12. Extreme risk category (AACE 2017): Goal LDL <55 mg/dl. “Progressive ASCVD, including unstable angina that persists after achieving an LDL-C <70 mg/dL, or estab- lished clinical ASCVD in individuals with diabetes, stage 3 or 4 CKD, and/or HeFH, or in individuals with a history of premature ASCVD (<55 years of age for males or <65 years of age for females)”
13. Statin myopathy: About 10-15% get muscle aches. If present, stop drug for 2-3 weeks, then trial same drug or at least 3 different drugs before giving up. Consider every other day dosing with atorvastatin and rosuvastatin (long acting statins).
14. PCSK9: A proprotein convertase involved in degradation of  LDL receptors in liver. Blocking activity of PCSK9 with monoclonal antibodies reduces the degradation of LDL receptors and increases clearance of LDL cholesterol.
15. Fibrates: Mainly lower TG, not LDL. Five studies have shown that if TG >200 and low HDL, then addition of fibrate to statin shows trend towards less CVD events.
16. Ezetimibe: Can further lower LDL by about 18% on top of statin therapy.
17. Niacin: Lowers TG and Lp (a). Poorly tolerated.
18. Fish oil: Need at least 4gm daily to lower TG. Over-the-counter preps have only 400-500 mg versus 1,000mg per capsule Rx strength. No proven benefit on CV outcomes.
19. IMPROVE-IT Trial: Ezetimibe plus statin versus statin plus placebo. Cardiovascular events lowered in ezetimibe plus statin group (average LDL of 53) versus high dose statin alone.
20. Cholesterol Treatment Trialists Collaboration: More intensive statin therapy produces further reductions in CVD; Statin therapy even benefits those at low risk of CVD
21. FOURIER Trial: Statins alone (median LDL in 92) versus statins plus PCSK9 inhibitor (median LDL 30). No decrease in CV death over 2.2 years, but 1.5% absolute risk reduction in composite CV events (acute coronary syndrome, stroke, revascularization).
22. GLAGOV Trial: PCSK9 inhibitor added to statin achieved 0.95% coronary plaque regression by intravascular ultrasound.

Goal: Listeners will gain advanced knowledge and practice changing tips in the evaluation and management of dyslipidemia.

Learning objectives:
By the end of this podcast listeners will:

1. Define and classify the types of dyslipidemia
2. Diagnose heterozygous familial hypercholesterolemia
3. Utilize Lp(a), Apo B, and LDL particle concentration for advanced lipid management
4. Recall the appropriate lipid screening tests, and frequency
5. Evaluate the appropriate LDL response to lipid lowering therapy
6. Identify patients who may benefit from non-statin medications
7. Utilize appropriate therapy for hypertriglyceridemia
8. Counsel patients on statin myopathy and possible use of CoQ10
9. Become familiar with recent landmark trials of dyslipidemia and cardiovascular risk reduction
10. Identify patients in the extreme risk category who may need an LDL under 55 mg/dl
11. Utilize ezetimibe and PCSK9 inhibitors for patients at extreme risk

Disclosures:
Dr. Jellinger reports work for AMGEN as a speaker and scientific advisor. AMGEN is the maker of evolocumab (Repatha), which was featured in the FOURIER trial.

Time Stamps
00:00 Intro
03:10 Rapid fire questions
08:15 Dyslipidemia defined
10:26 Classifying dyslipidemia
13:21 Diagnosing Familial Hypercholesterolemia
17:48 A difficult lipid case discussed
22:40 Lp (a), Apo B and LDL particle concentration
28:40 What labs to order
31:31 ACC/AHA versus other risk scores
38:21 IMPROVE-IT
41:35 Non-statin medications discussed
45:05 Hypertriglyceridemia fibrates and fish oil
48:25 How often to check the lipid panel
49:58 Statin Myopathy and CoQ10
54:17 FOURIER, PCSK9 and very low LDLs
59:43 Extreme risk category discussed
62:34 Is plaque regression possible?
64:12 Take home points
67:08 Outro

Links from the show:

1. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease © 2017
2. Simon Broome Diagnostic Criteria for Familial Hypercholesterolemia on MDCalc.com https://www.mdcalc.com/simon-broome-diagnostic-criteria-familial-hypercholesterolemia-fhd
3. Risk calculators: use Framingham, Reynold’s (women above 45yo), UKPDS, or MESA.
4. Cannon, C et al. IMPROVE-IT: Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM June 2015
5. Cholesterol Treatment Trialists Collaboration: More intensive statin therapy produces further reductions in CVD; Statin therapy even benefits those at low risk of CVD
6. Nicholls SJ, et al. GLAGOV: Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated PatientsThe GLAGOV Randomized Clinical Trial. JAMA. 2016;316(22):2373-2384. doi:10.1001/jama.2016.16951