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Lipid Clinic

• In 2015 created the Lipid Clinic at CoxHealth.

• I have no financial disclosures.

• Review 2016 AHA/ACC update for utilization of Non-statin therapies

• Review new and emerging non-statin lipid lowering therapies

• Discuss the role of Lipid Clinics in managing Cardiovascular risks

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Patient population Treatment target•Stable ASCVD•No comorbidities*

•≥50% LDL-C reduction or•LDL-C <100 mg/dL**

•Clinical ASCVD•Comorbidities*

•≥50% LDL-C reduction or•LDL-C <70 mg/dL** or•non-HDL-C <100 mg/dL (with diabetes)**

•Clinical ASCVD•LDL-C ≥190 mg/dL

•≥50% LDL-C reduction or•LDL-C <70 mg/dL**

•No clinical ASCVD•LDL-C ≥190 mg/dL

•≥50% LDL-C reduction or•LDL-C <100 mg/dL**

•Age 40-75 years•No clinical ASCVD•With diabetes•LDL-C 70-189 mg/dL

•≥50% LDL-C reduction or•LDL-C <100 mg/dL** or•non-HDL-C <130 mg/dL (with diabetes)**

•Age 40-75 years•No clinical ASCVD or diabetes•LDL-C 70-189 mg/dL•10-year ASCVD risk ≥7.5%

•30-49% LDL-C reduction or•LDL-C <100 mg/dL**

Table 3. Populations and targets defined by the 2016 ACC consensus document*Comorbidities = diabetes, recent (<3 months) acute ASCVD event, ASCVD event while on a statin, baseline LDL-C >190 mg/dL not due to secondary causes, poorly controlled major ASCVD risk factors, elevated lipoprotein(a), and chronic kidney disease.

2016 ACC Expert Consensus Decision Pathway

Case Example – Mr. MTA 62 year-old-man presents for a checkup following hospitalization for NSTEMI 3 months ago. He reports no symptoms and has returned to normal activity.

Physical examination:BP 128/76 mmHgBMI 30.1 kg/m2

Medications:Atorvastatin 80 mg qdEzetimibe 10 mg qdClopidogrel 75 mg qdAspirin 81 mg qdMetoprolol 150 mg qdLisinopril 20 mg qd

Lipid panel:Total-C: 162 mg/dLLDL-C: 112 mg/dLHDL-C: 38 mg/dLTriglycerides: 140 mg/dL

According to 2013 guidelines, we are done…. Right??

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Statins remain the principle therapy for patients at risk for cardiovascular events

Utilization of NON-STATINS:1. Ezetimibe (Zetia)2. Bile acid sequestrants/resins (BAS = Welchol, etc)3. PCSK9 Inhibitors (Praluent/Repatha)4. Mipomersen(Kynamro)5. Lomitapide (Juxtapid)6. LDL apheresis (“Cholesterol dialysis”)

Group 1 CVD

(2 risk groups)

Group 2 LDL > 190

(Familial HC)

Group 3 DM

(2 risk groups)

Group 4 Everyone else with CVD risk

factors

Primary Prevention

Secondary Prevention

1. Address statin adherence

2. Intensify lifestyle intervention (including adding phytosterols and/or soluble dietary fiber)

3. Addressing other risk factors

4. Increasing statin intensity

5. Evaluating “statin intolerance”

6. Consider referral to lipid specialist and/or registered dietician.

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• Consider addition of non-statin therapy to maximum tolerated statin.

• “All treatment decisions should be based on clinician-patient discussion of potential benefits and risks of therapy”

1. Max tolerated mod/high intensity statin?

2. Less than 50% LDL reduction?

3. “Initiate discussion re: non-statins”/LDL>100

4. Try ezetimibe first; consider BAS if TG < 300

5. Try PCSK9 Inhibitors next

6. If “objective” achieved, perform serial lipid profiles

7. If “objective” not met, reassess med adherence and lifestyle

Group 1 CVD

(2 risk groups)Secondary Prevention

1. Max tolerated high intensity statin?

2. Less than 50% LDL reduction?

3. “Initiate discussion re: non-statins”/LDL>100

4. Try ezetimibe first; consider BAS if TG < 300

5. Try PCSK9 Inhibitors next

6. If “objective” achieved, perform serial lipid profiles

7. If “objective” not met, reassess med adherence and lifestyle.

8. Consider mipomersen, lomitapide, and/or LDL apheresis in appropriate patients.

Group 1 CVD

(2 risk groups)Secondary Prevention

*High risk = defined as diabetes, recent (<3 months) acute ASCVD event, ASCVD event while already taking a statin, baseline LDL-C >190 mg/dL not due to secondary causes, poorly controlled major ASCVD risk factors, elevated lipoprotein(a), and chronic kidney disease

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Case Example – Mr. MTA 62 year-old-man presents for a checkup following hospitalization for NSTEMI 3 months ago. He reports no symptoms and has returned to normal activity.

Physical examination:BP 128/76 mmHgBMI 30.1 kg/m2

Medications:Atorvastatin 80 mg qdEzetimibe 10 mg qdAspirin 81 mg qdMetoprolol 150 mg qdLisinopril 20 mg qd

Lipid panel:Total-C: 162 mg/dLLDL-C: 112 mg/dLHDL-C: 38 mg/dLTriglycerides: 140 mg/dL

According to 2016 guidelines –We could consider adding PCSK-9 Why?*Group 1 – High risk due to recent event 3 mos ago *Not at LDL goal <100 with high intensity statin + ezetimibe.

According to 2013 guidelines, we are done…. Right??

Lipid panel: + PCSK9Total-C: 122 mg/dLLDL-C: 46 mg/dL

1. Max tolerated high intensity statin?2. Strong recommendation for referral to lipid specialist3. Less than 50% LDL reduction?4. “Initiate discussion re: non-statins”/LDL>1005. Try ezetimibe first; consider BAS if TG < 3006. Try PCSK9 Inhibitors next7. If “objective” achieved, perform serial lipid profiles8. If “objective” not met, reassess med adherence and

lifestyle. 9. Consider mipomersen, lomitapide, and/or LDL

apheresis in appropriate patients.

Group 2 LDL > 190

(Familial HC)

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RISK Calculators & Framingham score NOT valid in FH ->>> DO NOT USE STANDARD RISK ASSESSMENT TOOLS TO ESTIMATE RISK

Why is this group separate?

Familial Hypercholesterolemia puts the patient at

20-fold increased risk of CVD

Group 2 LDL > 190

(Familial HC) Primary elevations of LDL‐C > 190

8/15 (prava 40)TC 505LDL 388HDL 40TG 299 (recently on steroids)

2/16 (prava 40 + ezet 10)TC 408LDL 325HDL 52TG 153

4/16 (statin/ezet + PCSK9)TC 146 HDL 53LDL 60 TG 147

Case Example – Mr. JCA 46 year-old-man referred to Lipid Clinic for high cholesterol. He reports no symptoms. Declined genetic testing and plasma apheresisPast MHx: NASH, CKD (idio segglomerular sclerosis), + fam hx ASCVD

Physical examination:BP 124/72 mmHgBMI 28 kg/m2

Medications:Pravastatin 40 mg qdEzetimibe 10 mg qdLisinopril 20 mg qd

Liver enzyme elevations and myalgiasprevent utilization of high intensity statin

Group 2 LDL > 190

(Familial HC)

1. Max tolerated mod/high intensity statin?

2. Expected LDL % reduction? Follow w/ serial FLPs

3. If % not achieved or LDL is >100 or NHDL>130, consider high intensity statin and monitor adherence

4. Additional therapy is not recommended.

Group 3 DM

(2 risk groups)

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1. Max tolerated mod/high intensity statin?

2. Increase to high intensity

3. If % not achieved or LDL is >100 or NHDL>130, consider ezetimibe or BAS if TG are <300 mg/dL;

use of PCSK9 inhibitors is NOT currently indicated

4. Monitor adherence.

Group 3 DM

(2 risk groups)

1. Consider high risk markers

2. Patient Clinician discussion, consider mod/high intensity statin and assess for % reduction

3. If % is inadequate, increase to high intensity statin

4. If % has been achieved but has high risk markers, consider non-statins for LDL > 100: ezetimibe or BAS (PCSK9 NOT indicated)

Group 4 CVD risk factors >7.5

Statin Benefit Groups‐ No PCSK9

3. Primary prevention: DM 40‐75 yr & LDL < 189

4. Primary prevention: Elevated risk (No clinical

CVD, No DM, LDL < 189 and estimated

10‐year ASCVD risk of > 7.5%)

PCSK9Group 4 CVD risk factors >7.5

Group 3 DM

(2 risk groups)

What is missing from the 2016 guidelines?? STATIN INTOLERANT THERAPY

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• Lipid Clinic – Multidisciplinary Approach– Advance Practice Provider (PA) – 45 min

• Patient-clinician discussion regarding risks vs benefits– Emphasize statin benefits vs non-statin benefits– Discuss genetic testing/counseling/family cascade screening

– Registered Dietician – 30 min• Personalized review of dietary habits and sets new goals.

– Health Coach – 30 min• Reviews “activity”/exercise levels and barriers. Provides

additional “free” community resources to enable positive lifestyle modifications (ie Feel Better Now classes).

• Sets new activity goals• Post visit phone calls to follow-up on goals

“Diet, weight control, and increased physical activity are the first steps in the prevention and treatment of coronary artery disease ~NCEP ATP, JNC, and Evidence Reports from the NHLBI.

• NLA – recommends less than 200 mg dietary cholesterol per day

• 2013 ACC/AHA lifestyle guidelines – #1 DASH diet,– #2 Mediterranean diet – PREDIMED trial (n=7447) randomized to

med diet + EVOO or med diet + nuts. Study ended early due to benefit at 4.8 yrs and primary endpoint of rates of CV events (MI, CVA, or death from CV).

• MCR and many health care plans cover Dietician consultation.

Eckel RH, et al. Circulation, 2013, published online November 12, 2013

• 2013 ACC/AHA Lifestyle Guidelines:

– Advise adults to engage in aerobic physical activity

• 3-4 sessions per week/40 minutes per session

• Moderate to vigorous intensity (IIaA)

– “Sitting is the new smoking”

• Encourage any activity

• Activity monitors

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Statins remain the principle therapy for patients at risk for cardiovascular events

Utilization of NON-STATINS:1. Ezetimibe (Zetia)2. Bile acid resins (BAS = Welchol, etc)3. PCSK9 Inhibitors (Praluent/Repatha)4. Mipomersen(Kynamro)5. Lomitapide (Juxtapid)6. LDL apheresis (“Cholesterol dialysis”)

Next few slides will answer the top 5 questions :

1. What are they?

2. Which patients get them?

3. What is the benefit? Risks?

4. Who prescribes them?

5. What is the cost?

Human Monoclonal Antibody that binds to an abnormal protein(PCSK9) that causes destruction of normal LDL receptors in the liver.

*PCSK9 = proprotein convertase subtilisin/kexin type 9

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#2 Which patients get them?

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Both agents are very effective -> additional 50-70% LDL reduction Evolocumab (Repatha), 2015Alirocumab (Praluent), 2015Bococizumab (pending 2017)

Preliminary Outcomes

High CV Risk Patients – Patients not at LDL-C goal with currently available therapies (including high doses of potent statins)

Familial Hypercholesterolemia – LDL-C levels often far from goal, even with potent statins and combination Tx – Life-long exposure to high LDL-C

Statin Intolerant Patients – LDL-C levels often far from goal, due to intolerance

Definition: unable to tolerate at least 2 statins, including one at the lowest dose

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Safety/Adverse Effects

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• The phase III GLAGOV trial (n=968) patients getting cardiac catheterization, who were on optimized background statin therapy and randomized to double-blind treatment with evolocumab (420 mg monthly) or placebo subcutaneous injections.

• Amgen said no new safety concerns emerged in the trial nor was there a difference in treatment-emergent adverse events between groups.

http://www.medpagetoday.com/Cardiology/Atherosclerosis/60354?xid=nl_mpt_cardiodaily_2016-09-26&eun=g1036849d0r

• Plaque regression is a marker not endpoint.

• Does regression = stable plaque or perhaps more unstable?

• Plaque stability – how to measure?

• Actual heart attacks are what we are trying to prevent.

• Critics: “Anything else measured is just fluff.”

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• Not specifically FDA-approved for treatment of statin intolerant patients.

• CV outcomes pending in this population.

• Current trial evidence suggests “strong efficacy” in this population:

– Odyssey Alternative (alirocumab vs ezetimibe: 45% vs 14.6% LDL reduction)

– GAUSS (evolocumab vs ezetimibe: 55% vs 18%)

• Cardiologists

• Endocrinologists

• Lipid specialists

• Family Practice can prescribe, but the insurance approval process is cumbersome and time consuming.

Question #4:

Question #5:

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Generic statins $150/yr

Brand statins $250/yr

Brand ezetimibe$3600/yr

Brand PCSK9-I$14,000/yr

Others & apheresis$40,000-$360K+/yr

MabPCSK9-I $14K

RA Mab$36-50K

MS Mab$60-120K

Onc Mab$480K

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• More PCSK9-I therapies in development– Bococucimab (Pfizer, 2017)– ALN-PCS (Alnylam, 2018) – q 3mo inject– Adnectins (sim to Mab)- annual inject/ ‘vaccine’ – q 12 mo– Fc fusion proteins, antisense oligonucleotides, and small

interfering RNA(siRNA)

• Omega fish oils + statins– Icosapent ethyl (Vascepa)– Omega-3 carboxylic acids (Epanova)

• Cholesterol ester transfer protein (CETP) inhibitor (anacetrapib, Merck)

• Diacylglycerol acyltransferase-1 (DGAT-1) inhibitor (Pradigastat)

You have the answers to the top 5 questions :

1. What are they?

2. Which patients get them?

3. What is the benefit? Risks?

4. Who prescribes them?

5. What is the cost?

• Statins are still foundation of lipid lowering therapy– 2013 “Statin Intensity”

• 2016 “Targets “ are back• Evidence is emerging for non-statin therapies

– Effective alternatives for “Statin intolerance”

• PCSK9 inhibitors– Efficacious in lowering LDL-C and Lp(a)– Well tolerated– Will test barriers of clinical practice– Cost effectiveness to be determined

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Importance The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain.

Results A total of 312 175 participants

Conclusions and Relevance In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events. The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events for primary prevention trials (1.5% lower event rate per each 1-mmol/L lower LDL-C) and secondary prevention trials (4.6% lower event rate per each 1-mmol/L lower LDL-C)

A Systematic Review and Meta-analysisMichael G. Silverman, MD1; Eugene Braunwald, MD1;Marc S. Sabatine, MD, MPH1,et al

JAMA. 2016;316(12):1289-1297. doi:10.1001/jama.2016.13985

Original Investigation September 27, 2016

• As part of a heart-healthy eating plan, consuming phytosterols in recommended quantities has been shown to lower total cholesterol up to 10 percent and LDL up to 14 percent.

• The effectiveness is so strong that the NCEP recommends 2 grams of phytosterols per day.

->Transfats??

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ODYSSEY: 48% RRR, but total # of events was “modest”OSLER: ~50% RRR, but total # events was “modest”FDA product package requires that the product label indicate that the effect of alirocumab and evolocumab on “cardiovascular morbidity & mortality have not been determined.”

Lipoprotein(a)

LDL particle

Apo(a)

ApoB-100

• Lp(a) consists of an LDL-like particle and the specific Apo(a), which is covalently bound to the ApoB

• Apo(a) is structurally homologous to plasminogen, Lp(a)

– Competitely inhibits plasmin generation –antifibrinolytic

– Can bind to plasmin and fibrinogen, promoting atherosclerosis

– Deposits oxidized phospholipids, increasing inflammation leading to atherosclerosis

– Promotes plaque inflammation and instability• Lp(a) has a causal relationship to increased CV

risk and is recognized to predict atherosclerosis, MI

• 2011 NLA Expert Panel cited Lp(a) as an independent driver of very high risk in FH

• In FH, Lp(a) levels increased 3-fold vs controls

Figure adapted from Brown WV, et al. J Clin Lipidol. 2010;4(4):240-247.

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Both PCSK9 I therapies lower Lp (a) ~ 30%

Lomitapide (Juxtapid) & Mipomersen (Kynamro)

Lomitapide (Juxtapid)

• FDA approved for Homozygous Familial HC• MOA: Inhibits microsomal triglyceride transfer

protein = decreases production of chylomicrons and VLDL

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Mipomersen (Kynamro)

• FDA approved for Homozygous Familial HC

• MOA: Selectively inhibits translation of apo B-100 mRNA, preventing formation of LDL and VLDL

LDL-C reductions withapheresis:• Acute: Up to 76%1

• Time averaged: 20-40%2

1 2 3 4 6 7 8 9 105

Treatments

LDL-

C (

mg/

dL)

Reproduced from Thompson GR. Curr Opin Lipidol. 2010.

1. Gordon BR, et al. Am J of Card. 1998;81(4):407-411. 2. Ito MK, et al. J Clin Lipidol. 2011;5(3 Suppl):S38-S45.

Cholesterol Rebound After Receiving LDL Apheresis