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Lipids & Hypertension Update Michael W. Cullen, MD, FACC Senior Associate Consultant, Assistant Professor of Medicine Mayo Clinic Department of Cardiovascular Diseases

34th Annual North Central Heart Cardiac Symposium November 4th, 2016

No financial disclosures

Learning objectives

1. Apply updated guidelines for lipid management to the primary and secondary prevention of heart disease.

2. Identify hypertension treatment targets for patients with and at high risk for heart disease.

Outline

• Lipid management

Indications for statins

Selecting and dosing statins

Statin intolerance

Non-statin medications

•Hypertension

Risks and benefits of intensive control

Treatment targets

Case #1

• 59 year old male

• No diabetes

• Never smoker

• No family history

Total cholesterol 187 mg/dL

Triglycerides 150 mg/dL

HDL-C 41 mg/dL

LDL-C 116 mg/dL

• Hypertension

Lisinopril 10 mg/day

BP 110/70 mmHg

• Attempted lifestyle modification

Stone NJ, et al. JACC 2014; 63(25): 2889-2934. Keaney JF, et al. NEJM 2014; 370(3): 275-78.

LDL-C ≥190 mg/dL

≥7.5%

5 – 7.5%

10-year risk

Strong family history

LDL-C 160 – 189 mg/dL

hs-CRP ≥2.0 mg/dL

Cor cal ≥300 Agatston units (≥75th percentile)

ABI ≤0.9

Other risk factors

Coronary disease (MI or angina)

Cerebrovascular disease

Peripheral arterial disease

Coronary or arterial revascularization

2° prevention

Age 40-75 years

AND

LDL-C ≥70 mg/dL

Diabetes mellitus

Who requires statin therapy?

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How should you select & dose statins?

2° prevention

Age ≤75 years

High intensity

Age >75 years

Moderate intensity

10-year risk

≥7.5% Moderate or high intensity

5-7.5% Moderate intensity

Diabetes mellitus, age 40-75, & LDL-C

≥70 mg/dL

10-year risk ≥7.5%

High intensity

10-year risk <7.5%

Moderate intensity

LDL-C ≥190 mg/dL High

intensity

Stone NJ, et al. JACC 2014; 63(25): 2889-2934. Stone NJ, et al. JACC 2014; 63(25): 2889-2934.

Intensity LDL lowering Examples

High ≥50% Atorvastatin 40-80 mg

Rosuvastatin 20-40 mg

Moderate* 30-50%

Atorvastatin 10-20 mg

Rosuvastatin 5-10 mg

Simvastatin 20-40 mg

Pravastatin 40-80 mg

Low* <30% Simvastatin 10 mg

Pravastatin 10-20 mg *Fluvastatin, lovastatin, & pitavastatin also have low- and moderate-intensity dose options.

How should you select & dose statins?

How should you assess cardiovascular risk?

http://tools.acc.org/ASCVD-Risk-Estimator/

Pooled Cohort Risk Assessment Calculator

Gender & race specific equations

Diabetes mellitus as predictor variable

Stroke as endpoint

Our patient’s risk

• 59 year old male

• No diabetes

• Never smoker

• No family history

Total cholesterol 187 mg/dL

Triglycerides 150 mg/dL

HDL-C 41 mg/dL

LDL-C 116 mg/dL

• Hypertension

Lisinopril 10 mg/day

BP 110/70 mmHg

• Attempted lifestyle modification

Patient returns 6 months later…

•59 year old male

• Treated hypertension

• Simvastatin 20 mg/day

Baseline 6 months later

Total cholesterol 187 mg/dL 150 mg/dL

Triglycerides 150 mg/dL 145 mg/dL

HDL-C 41 mg/dL 39 mg/dL

LCL-C 116 mg/dL 82 mg/dL

What happened to LDL-C goals?

“The Expert Panel did not find evidence to support titrating cholesterol-lowering drug therapy to achieve optimal LDL-C or

non–HDL-C levels…”

Stone NJ, et al. JACC 2014; 63(25): 2889-2934.

Catapano AL, et al. EHJ 2016; published online 26-Aug-2016.

10-year risk LDL-C goal

≥10% <70 m/gL

5-10% <100 mg/dL

<5% <115 mg/dL

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How low should we go? Pros and cons of an LDL-C goal

Pros

• Motivation

• Lower is better

• Concordant with other guidelines

• Encourages surveillance

• Reduction from baseline difficult to determine

Cons

• Simpler

• Emphasis on risk

• No data on titrating to goals

• Accuracy of goals

• Inappropriate use of medications

Cianzos-Achirica M, et al. MCP 2015; 90(9): 1262-71. Martin SS, et al. JACC 2013; 63(24): 2674-78.

• Focus initial decision on baseline risk

• Primary prevention Check decrease in lipid levels Assess adherence and lifestyle Consider additional therapy based on residual risk,

especially if LDL-C ≥100 mg/dL

• Secondary prevention Start high-intensity statin therapy Target LDL-C 50 – 80 mg/dL Consider adjunctive therapy based on residual risk

To goal or not to goal, that is the question…

The patient returns 6 months later…

•60 year old male with treated hypertension and hyperlipidemia

• “Doc, my legs are killin’ me…”

• “…and…I’ve seen the news reports about those statin medications…”

Statin-associated muscular effects Side effect Definition Frequency

Myalgias

Aches Soreness Stiffness

Tenderness Cramps with exercise

5 – 30%

Myopathy Weakness 1%

Myositis Inflammation --

Myonecrosis ≥3x elevation of CK ~1-2%

Rhabdomyolysis ≥3x elevation of CK

AND Acute renal failure OR myoglobinuria

<<0.1%

Rosenson RS, et al. J Clin Lipidol 2014; 8(3): S58-S71.

Myalgia scoring index

Symptom Score

Location

Bilateral hips and thighs 3

Bilateral calves 2

Bilateral proximal arms 2

Non-specific, asymmetric, intermittent 1

Onset since exposure to statin

<4 weeks 3

4-12 weeks 2

>12 weeks 1

Improvement after stopping statin

<2 weeks 2

2-4 weeks 1

>4 weeks 0

Recurrence upon re-challenge

Same symptoms <4 weeks 3

Same symptoms 4-12 weeks 1

Different symptoms, any time 0 Rosenson RS, et al. J Clin Lipidol 2014; 8(3): S58-S71.

Interpretation

Probable statin intolerance 9-11 points

Possible statin intolerance 7-8 points

Unlikely statin intolerance <7 points

Drugs potentially interacting with statins

Anti-microbials Calcium channel

blockers Others

HIV protease inhibitors Verapamil Amiodarone

Ketozonazole Diltiazem Cyclosporine

Itraconazole Amlodipine Danazol

Posaconazole Ranolazine

Erythromycin Nefazodone

Clarithromycin Gemfibrozil

Telithromycin Grapefruit juice (>1 quart daily)

Catapano AL, et al. EHJ 2016; published online 26-Aug-2016.

Egan A, Colman E. NEJM 2011; 365(4): 285-87.

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What about ezetimibe? • Decreases intestinal cholesterol absorption

• Lowers LDL-C when added to statin therapy

Davidson MH, et al. NEJM 2004; 350: 1495-1504.

Never been shown to improve outcomes

IMPROVE-IT Trial Ezetimibe + statin vs. statin alone

Cannon CP, et al. AHJ 2008; 156(5): 826-32.

Post-ACS patients

LDL-C ≤125 mg/dL

LDL-C ≤100 mg/dL if on statin

Standard medical therapy

Simvastatin 40-80 mg/day

Simvastatin 40-80 mg/day

+

Ezetimibe 10 mg/day

Primary outcome CV death, myocardial infarction, unstable

angina, revascularization, stroke

IMPROVE-IT Trial Results

Cannon CP, et al. NEJM 2015; 372: 2387-97.

Median LDL-C 70 mg/dL in simvastatin group 54 mg/dL in simvastatin + ezetimibe group

Event rate = 34.7%

Event rate = 32.7%

What is the role of ezetimibe? One cardiologist’s opinion...

• Generally well tolerated

• Add to patients who need additional LDL-C lowering…

Despite max dose statin therapy

Who can’t tolerate higher dose statin therapy

•May provide small benefit when added to a statin after acute coronary syndrome

• Supports hypothesis that “lower is better”

Evolocu… what?

• Evolocumab (Repatha)

•Alirocumab (Praluent)

• FDA approval July-August, 2015

•Monoclonal antibodies against PCSK-9 protein

•Block degradation of LDL receptor

•Reduce circulating LDL-C levels

PCSK-9 inhibitors LDL-C lowering with evolocumab

Mean LDL-C values

Atorvastatin + placebo

~105 mg/dL

Atorvastatin + ezetimibe

~80 mg/dL

Atorvastatin + evolocumab

~35 mg/dL

Robinson JG, et al. JAMA 2014; 311(18): 1870-83.

Atorvastatin 80 mg/day

Placebo

Ezetimibe

Evolocumab

440 patients

No statin

LDL-C ≥150 mg/dL

Non-intense statin

LDL-C ≥100 mg/dL

Intense statin

LDL-C ≥80 mg/dL

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Indications PCSK-9 inhibitors

• Homozygous familial hypercholesterolemia

• In addition to diet and max statin therapy, if further LDL-C lowering is necessary

Heterozygous familial hypercholesterolemia

Clinical atherosclerotic cardiovascular disease

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm Accessed October 12, 2016

So what’s the downside?

• Evolocumab (Repatha)

•Alirocumab (Praluent)

•Myalgias (~5%)

• Injection site reactions (~5%)

•Neurocognitive side effects (~1%)

•No prospective outcomes data http://www.reuters.com/article/2015/09/01/us-health-heart-amgen-europe-idUSKCN0R13VI20150901

Accessed October 12, 2016 Robinson JG, et al. NEJM 2015; 372: 1489-99.

PCSK-9 inhibitors

Bottom line

•Promising LDL-C lowering data

•Use limited by price and access

•Need outcomes data

What about the other non-statin meds?

•Niacin

•Bile acid sequestrants

• Fibrates

Frequent side effects Limited efficacy data

Isolated hypertriglyceridemia

Recap Lipid management

• Lipid management

Indications for statins

Selecting and dosing statins

Statin intolerance

Non-statin medications

•Hypertension

Risks and benefits of intensive control

Treatment targets

Case #2

•55 year old male

•Unstable angina 3 years ago

• Stent to right coronary artery

•Normal left ventricular function

•No diabetes or angina

•Creatinine = 0.9 mg/dL

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Vasan RS, et al. NEJM 2001; 345(18): 1291-97.

What is a good blood pressure?

2967 men without hypertension in Framingham Heart Study

<120 / 80 mmHg

120-129 / 80-84 mmHg

130-139 / 85-89 mmHg

Increased events with “high-normal” vs. “optimal” blood

pressure

How low is too low? J-shaped curve

Farnett L, et al. JAMA 1991; 265(4): 489-95.

Review of 13 hypertensive treatment studies

ACCORD Blood Pressure Study

ACCORD. NEJM 2010; 362(17): 1575-85.

4733 patients with diabetes mellitus + Cardiovascular disease or ≥2 risk factors

SBP <120 mmHg SBP <140 mmHg

SBP = 119 mmHg 2.1 meds

SBP = 134 mmHg 3.4 meds

Lower risk of stroke (HR = 0.59)

More adverse events

No difference in all-cause mortality

SPRINT Trial

SPRINT. NEJM 2015; 373(22): 2103-16.

SBP <120 mmHg SBP <140 mmHg

9361 patients ≥50 years old SBP 130 – 180 mmHg

Cardiovascular disease OR increased risk

Excluded diabetes mellitus and stroke

SBP = 121 mmHg 2.8 meds

SBP = 136 mmHg 1.8 meds

Decreased CV events (NNT = 61)

Decreased all-cause mortality (NNT = 90)

More adverse events

So what do the guidelines say? Blood pressure goals

JNC-8

James PA, et al. JAMA 2014; 311(5): 507-20.

Age ≥60 years SBP ≤150 mmHg DBP ≤90 mmHg

Age <60 years Diabetes mellitus

Chronic kidney disease

SBP ≤140 mmHg DBP ≤90 mmHg

ACC/AHA/ASH

Coronary disease Heart failure

SBP ≤140 mmHg DBP ≤90 mmHg

Coronary disease Stroke, TIA, PAD, AAA

Carotid disease

SBP ≤130 mmHg DBP ≤90 mmHg

Rosendorff C, et al. JACC 2015; 65(18): 1998-2038.

So what is a clinician to do?

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Recap Hypertension

• Lipid management

Indications for statins

Selecting and dosing statins

Statin intolerance

Non-statin medications

•Hypertension

Risks and benefits of intensive control

Treatment targets

Take home points 1. Consider an LDL-C goal of <100 mg/dL in

primary prevention and <70-80 mg/dL in secondary prevention.

2. In statin-intolerant patients, first try a low dose of an alternative statin.

3. PCSK-9 inhibitors offer promising LDL-C lowering potential but may see limited initial use.

4. A blood pressure goal of <130/80 mmHg is reasonable in patients with coronary disease.

Thank you!

cullen.michael@mayo.edu