The Statin Intolerant Patient - Welcome to CCEHS · The Statin Intolerant Patient ... Grouped cognitive performance scores according to domains/processes ... ACC/AHA 2015 NLA Lipids

The Statin Intolerant Patient

44th Refresher Course in Family Medicine Pittsburgh, Pennsylvania

March 23, 2017 Presented by Amy Haver, PharmD, BCPS


• Review common side effects associated with statin medications

• Outline ways to manage patients with statin intolerances

• Discuss the role of non-statin therapies for management of ASCVD risk

Cardiovascular Disease (CVD) • 3 out of 10 deaths globally

• Leading cause of death in the United States

http://www.who.int/mediacentre/factsheets/fs310/en/index2.html http://www.cdc.gov/nchs/data/nvsr/nvsr65/nvsr65_02.pdf

Statins can modify CVD factors Primary prevention for patients at high risk

Secondary prevention for patients with coronary heart disease

“Statins? I can’t take statins.”

• Why?

– Side effect

– Friend or relative story

– Commercial

– Drug interaction

– Contraindication

– Cost

– Perception of benefit

Muscle aches/weakness Liver damage

Memory/cognition problems Diabetes

Cancer Headache

Difficulty sleeping Flushing of the skin

Drowsiness Dizziness

Nausea or vomiting Abdominal cramping or pain

Bloating or gas Diarrhea

Constipation Rash

Vaccine ineffectiveness

Are they intolerant to statins?

ACC. Expert Analysis. Statin Intolerance: Not a Myth. 12 Aug 2015. https://www.acc.org/latest-in-cardiology/articles/2015/08/11/09/16/statin-intolerance-not-a-myth “Atorvastatin.” Micromedex ® Solutions. Truven Health Analytics. Accessed 20 Feb 2017.

https://www.acc.org/latest-in-cardiology/articles/2015/08/11/09/16/statin-intolerance-not-a-myth













Statin Intolerance No universal definition

• American College of Cardiology (ACC) Task Force: – patients are documented to have unacceptable muscle-related

symptoms that resolve with discontinuation of therapy and occur with rechallenge on at least 2 to 3 statins, preferably ones that use different metabolic pathways and have different lipophilicity, and 1 of which is prescribed at the lowest approved dose

• NLA Statin Intolerance Task Force:

– Adverse symptoms, signs and/or laboratory abnormalities attributed by the patient and/or provider to a statin and perceived by the patient to interfere with daily life activities

• Estimated 10-20% patients are statin intolerant

Lloyd-Jones DM et al. J Am Coll Cardiol 2016;68:92-125.

National Lipid Association. 2 May 2014. www.lipid.org/util/comments/statin_release_final.pdf Banach M et al. Arch Med Sci 2015;11,1:1-23.

Adverse Effects

Let’s take a more in depth look on a few…

– Muscle related

– Memory

– New onset diabetes

http://www.philgalfond.com/lindgren-loans-and-a-little-advice/ethics-scale/

Muscle Related

• Myopathy…Myalgia…Myositis…Rhabdo…

Put together…1.5-5% rate of muscle complaints

• Not always higher than placebo

• Muscle complaints often exclusion criteria

Law M et al. Am J Cardiol. 2006 Apr 17;97(8A):52C-60C. Epub 2006 Feb 3. Katz DH et al. J of Cardiovascular Pharmacology and Therapeutics 2014; 19(6):533-542.

Muscle Related Rhabdomyolysis

• Less than 0.01% incidence in patients

Myopathy • 0.1-0.2% incidence in patients (or less)

NLA Task Force. Journal of Clinical Lipidology (2014) 8, S1–S4 Kashani. Circulation. 2006;114:2788-2797.

Banach M et al. Arch Med Sci 2015; 11,1:1-23. Law M. Am J Cardiol. 2006 Apr 17;97(8A):52C-60C. Epub 2006 Feb 3.

Katz. J of Cardiovascular Pharmacology and Therapeutics 2014; 19(6):533-542. Yusuf MB et al. N Engl J Med 2016; 374:2021-31

Taylor F. Cochrane Database Syst Rev. 2013;(1)CD004816

Statin Induced Mainly occurs in first 6 month of initiation/titration Affects large muscle groups Usually bilateral and symmetrical More likely with high intensity and concomitant fibrates

1 death per 23.4 million atorvastatin prescriptions

Some data shows no difference in rates of myalgia, CK, rhabdomyolysis, or discontinuation to adverse effects

Muscle Side Effects

• Occur in general population

• Dependent on definition

• Damage is rare

• If occur, check CK and stop statin

Adverse Effects

• Muscle-related

• Memory (Cognitive Impairment)

• Diabetes

Memory (Cognitive Impairment)

• Cognitive impairment reported in case reports

• February 2012 FDA Warning

“potential for generally non-serious and

reversible cognitive side effects (memory loss,

confusion, etc.)”

http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM293705.pdf

http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM293705.pdf

Grouped cognitive performance scores according to domains/processes

Dementia Alzheimer Disease Mild Cognitive Impairment

• No increased risk • Possible decrease



No worsening of cognitive performance scores:

• Global cognitive performance (among cognitively intact and impaired)

• Front-executive function and working memory

• Declarative memory

• Procedural memory • Attention • Processing speed • Visuoperception • Motor Speed

Queried FDA postmarketing surveillance:

Statins: 1.9 per million prescriptions Losartan: 1.6 per million prescriptions

Clopidogrel 1.9 per million prescriptions

Richardson et al. Ann Intern Med. 2013;159:688-697.

Other studies: No evidence

• No difference in tests of cognition

– Both cognitively normal or Alzheimer’s disease

• Statin use in the elderly (>70 years old)

– No increase risk

• Dementia (moderate*)

• Alzheimer Disease (low*)

• Mild cognitive impairment (moderate*)

• Worsening global cognitive performance (moderate*)

• Deterioration of memory function (moderate*)

Ott BR et al. J Gen Intern Med. 2015; 30(3):348-58

Samaras K. Trends in Cardiovascular Medicine. 2016;(26)550-565.

High Quality Evidence is Lacking

• Need larger, higher quality studies

• Selection bias

• Deficiencies of detailed testing

• Voluntary submission

Cognitive Impairment

• Evaluate for other non-statin causes

• Stop statin and watch for reversal

• FDA warning still present

• 2013 ACC/AHA Guidelines: – Evaluate for non-statin causes

Adverse Effects

• Muscle-related


• Diabetes

New Onset Diabetes (NODM)

• Highlighted in JUPITER (rosuvastatin) - 2008 – Prevented 134 vascular events for every 54 NODM

• Contradicted WOSCOPS (pravastatin) - 1995 – Reduced NODM

N Engl J Med 1995; 333:1301-1308. Ridker PM. Lancet. 2012 Aug 11; 380(9841): 565–571.

• Meta-analysis, 1994-2009 (13 trials, n=91,140)

– Placebo-controlled and standard-care-controlled statin trials

– Patients without diabetes

1 case NODM per 255 patients on statin for 4

years 9%

5.4 events avoided per 255 patients on statin for 4

years (CTT)

Sattar N et al. Lancet 2010; 375:735-42

2.0 additional NODM cases per 1000 patient years (18.9 with high vs 16.9 with moderate)

NNTH = 498

6.5 fewer first major cardiovascular events per 1000 patient years (44.5 with high vs. 51.0 with moderate)

NNT= 155

Preiss D et al. JAMA. 2011;305(24):2556-2564

8.4% developed diabetes

20.4% experienced major cardiovascular event

NODM

• Statins associated with NODM

• Dose related effects

• Most frequently with high risk individuals

• Cardiovascular benefit exists with statins

• Risk factors for DM2 • Elderly (>70 yo)

• Women • Asian ethnicity

• Metabolic syndrome (dose effect)

Betteridge and Carmena, Nature Reviews. 2016;(12)99-110. Cederberg H et al. Diabetologia (2015) 58:1109–1117

NLA Task Force. Journal of Clinical Lipidology (2014) 8, S1–S4

Proposed mechaniams insulin sensitivity insulin secretion

Adverse Effects

• Muscle-related


• Diabetes

Adverse Effects

• Medications are not without risk

• Patient-Clinician discussion for benefits vs. risks

When they do occur….how do we manage?





Consider Before Initiation: Baseline Monitoring

2013 ACC/AHA

2015 NLA

Lipids

• Fasting lipid panel • Measure for response • Monitor for adherence to lifestyle &

drug therapy every 3-12 months

• Baseline lipid panel • Check for response & adherence

every 4-12 months • If not at goal, intensify or send to lipid

specialist

Transaminase (ALT)

• Baseline ALT

--

Muscle Damage/Creatine Kinase (CK) Measurement

• Consider baseline CK • Check if muscle symptoms occur

--

2013 ACC/AHA Summary of Statin Initiation National Lipid Association 2015

Management of Statin Intolerance: Use Systematic Approach


Careful History (rule out other causes) Hypothyroid

Vitamin D Deficiency

Recent Exercise Interactions

Discontinue Statin

Observe Symptoms

Still there? Probably not statin

Rechallenge to verify recurrence of symptoms

Try 2-3 statins: Metabolic pathways

Lipophility Use a lower dose

Use alternative dosing

Statins Atorvastatin Fluvastatin XL Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin

Half-Life (Hours)

14 9 1.5 12 1.8 19 1.9

Meta-bolism

CYP3A4 CYP2C9 & CYP3A4 & CYP2C8*

CYP3A4 CYP2CP* CYP2C8*

CYP450* CYP2C9* CYP3A4

Solubility Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Hydrophilic Lipophilic

Admin Time

Any Any Bedtime Any Any Any Bedtime

Dose/Intensity

Low Intensity

-- -- 20mg 1mg 10-20mg -- 10mg

Moderate Intensity

10-20mg 80mg 40mg 2-4mg 40-80mg 5-10mg 20-40mg

High Intensity

40-80mg -- -- -- -- 20-40mg 80mg--AVOID

*Minimal Metabolism

2013 ACC/AHA Summary of Statin Initiation ACC App for iTunes. Statin Intolerance. Accessed 20 Feb 2017.





Discontinue Statin

Observe Symptoms







Alternative Dosing Data

• Decreased frequencymuscle recovery

• Decreased plasma concentration

• Use with longer half lives

– Rosuvastatin (t1/2=19 hours)

– Atorvastatin (t1/2=14 hours)

Keating et al. Ann Pharmacother 2013;47:398-404.

Alternate Dosing

• Decreases LDL-C

– Some studies showed no difference

~10-40% depending on frequency/dosing

• Increases tolerance

~70-90% previously intolerant patients tolerated

Every Other Day Weekly

Atorvastatin Fluvastatin

Rosuvastatin

Rosuvastatin

NLA Task Force. Journal of Clinical Lipidology (2014) 8, S1–S4 Keating et al. Ann Pharmacother 2013;47:398-404.

Strategies to Increase Tolerance

• Try another statin

• Lower dose

• Alternate Day/Weekly dosing

– start low, increase if tolerated

• What about…

– Vitamin D

– CoQ10

Vitamin D

• Not recommended in absence of low Vitamin D

– Maybe role when Vitamin D Levels are low

• Resolved myalgias when deficiencies treated suggested

• No prospective RCTs

• Statin related vs manifestation of low Vitamin D???

NLA Task Force. Journal of Clinical Lipidology (2014) 8, S1–S4 N Am J Med Sci 2015 Mar;7(3):86

Coenzyme Q10 (CoQ 10)

• Limited and conflicting evidence

• CoQ10 – mitochondrial energy production

• CoQ10 levels reduced – May parallel reduction in LDL

Statins block intermediate in

synthesis of CoQ 10

Marcoff L et al. J Am Coll Cardiol 2007;49:2231-7

CoQ 10: Meta-Analysis of RCTs

No significant

change in Plasma CK Activity

No significant effect on

muscle pain

Not recommended in guidelines

Marcoff L et al. J Am Coll Cardiol 2007;49:2231-7 ACC/AHA 2013 Guidelines





Discontinue Statin

Observe Symptoms






Use the App!


ACC Statin Intolerance App





2013 ACC/AHA Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults

Statins only therapy included

2016 ACC Expert Consensus

• Included literature not published in 2013

• Comments on non-statin therapies

– For statin intolerant

– For patients on statins not meeting goals


2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of ASCVD Risk

Not previously included in 2013

ACC/AHA


Non Statin Therapies

Fenofibric acids not mentioned Niacin NOT recommended

• Double blind, randomized trial (n=18,144) – ACS within 10 days and

– LDL-C 50-100mg/dL with lipid lowering therapy or 50-125mg/dL

Ezetimibe: -Reduces absorption of

cholesterol from intestine

-Lowers LDL-C 23-24% in addition to statins

Simvastatin 40mg +Placebo

LDL-C: 69.5mg/dL*

Simvastatin 40mg + Ezetimibe 10mg LDL-C: 53.7mg/dL

Primary end point at 7 years (composite endpoint) 32.7% (with ezetimibe) vs. 34.7% (with placebo)*

*Statistically significant Cannon CP et al. N Engl J Med 2015;372:2387-97.




Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) inhibitors

• Alirocumab (Praluent ®)

• Evolocumab (Repatha ®)

PCSK9 Protein: • Inactivates LDL receptors

PCSK9 Inhibitors • Monoclonal antibodies

• Bind to and inactivate PCSK9

• BLOCK receptor degradation

More LDL receptors to get rid of LDL-C

http://www.mayoclinic.org/-/media/kcms/gbs/patient-consumer/images/2015/11/12/16/37/kullo_fig1_ab_lg.jpgPathway pic

PCSK-9 Inhibitors • LDL-C reductions varying 26-67%

– Depending on monotherapy vs. combo with statins

– Some studies with minority patients on statins

– Familial Hypercholesteremia

• No outcome trials yet

– Cardiovascular outcomes reported have been secondary outcomes

McDonagh M et al. J Manag care Spec Pharm. 2016;22(6):641-53

Pooled data… Reduction in all-cause mortality &

Lower rates of myocardial infarction… MORE TO COME!

PCSK-9 Inhibitors: -As adjunct to diet and maximally tolerated statin therapy

-Who require additional LDL-C Lowering

Therapy Adults HeFH

HoFH Clinical CVD

Dosing (Subcutaneously)

Side Effects >5% and more common than placebo

Alirocumab x no x 75mg q 2 weeks If inadequate, 150mg q 2 weeks

• nasopharyngitis • injection site

reactions • Influenza

Evolocumab

x x* x Clinical CVD or HeFH: 140mg q2 weeks or 420mg once monthly HoFH: 420mg subQ once monthly

• nasopharyngitis, • upper respiratory

tract infection • influenza • back pain • injection site

reactions

*With other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) PRALUENT® (alirocumab) Prescribing Information. Sanofi/Regeneron Pharmaceuticals

Repatha® (evolocumab) Prescribing Information, Amgen

PCSK-9 Inhibitors

• Access (cardiologists/specialists/lipid clinics)

• Cost ($14,000 per year)

• Unknown outcomes (only lower LDL)

• Side effects…????

• Consensus report includes them as option

Specific algorithms for specific

patients

“Clinical ASCVD”

Not at goal… “Consider”


Future…

• Outcomes Trials

– FOURIER (Evolocumab-CVD endpoints)

– ODYSSEY Outcomes (Alirocumab-CVD endpoints)

– EBBINGHAUS (Evolocumab-Cognitive function)

• Third agent (Bococizumab®-Pfizer) discontinued

http://www.medpagetoday.com/cardiology/cardiobrief/62896

http://www.pfizer.com/news/press-release/press-release-detail/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_inhibitor

http://www.acc.org/latest-in-cardiology/articles/2016/05/18/14/34/current-indications-cost-and-clinical-use-of-anti-pcsk9-monoclonal-antibodies?w_nav=LC




Other non statin therapies

• Bile acid sequestrants

• Phytosterols and soluble dietary fibers

• Lipid specialists – Mipomersen

– Lomitapide

– LDL apheresis

-Cholestyramine, Colestipol, Colesevelam

-Drug Interactions -GI side effects

-No cardiovascular outcomes

-Vegetable oil, nuts, legumes, whole grains, fruits and vegetables

-Some foods fortified with sterols

-Must be consumed with/before food

-Supplements available

http://my.clevelandclinic.org/health/articles/phytosterols-sterols-stanols-heart-health/phytosterols-diet Lloyd-Jones DM et al. J Am Coll Cardiol 2016;68:92-125.

http://my.clevelandclinic.org/health/articles/phytosterols-sterols-stanols-heart-health/phytosterols-diet












Summary

• Many patients are intolerant to statins – Especially due to muscle complaints – Other adverse effects may occur

• Attempt to determine cause of intolerance – Use strategic approach to use statins

• Patients may benefit from non-statin therapies – Ezetimibe, PCSK-9 Inhibitors – More data is needed

http://www.philgalfond.com/lindgren-loans-and-a-little-advice/ethics-scale/





Documents

The Statin Intolerant Patient - Welcome to CCEHS · The Statin Intolerant Patient ... Grouped cognitive performance scores according to domains/processes ... ACC/AHA 2015 NLA Lipids