Diagnosis, Prevention and Management of Statin Adverse Effe - PowerPoint Presentation

Slide1

Diagnosis, Prevention and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016)

G.B. John Mancini, MD, Steven Baker, MD, Jean Bergeron, MD, David Fitchett, MD, Jiri Frohlich, MD, Jacques Genest, MD, Milan Gupta, MD, Robert A. Hegele, MD, Dominic Ng, MD, Glen J. Pearson, PharmD, Janet Pope, MD, A. Yashar Tashakkor, MD

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide2

BackgroundThe Canadian Consensus Working Group (CCWG) has published consensus statements in 2011 and 2013 regarding statin-associated adverse effects and intolerance.The Cardiovascular Imaging Research Core Laboratory (CIRCL), University of British Columbia maintained an updated library of relevant citations from the time of the 2013 publication to December 2015, this 2016 update is based on the latter reference base.Authors were assigned sections, created summaries and representative slides, presented to each other at a single

face-to-face meeting and then reviewed, critiqued and finalized a collated document for peer review and publication (CJC 2016).Logistical support for the meeting was provided by Bridge Medical Communications, Ontario Canada through a contract with AMGEN, Canada.Content, interpretations and recommendations were created solely and independently by the CCWG.

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide3

CCWG ParticipantsSteven Baker, MDMcMaster University,

Hamilton, ONRobert A. Hegele, MD

Schulich School of Medicine, London, ON

Jean Bergeron, MD

Laval University,

Quebec City, QC

G. B. John Mancini, MD

University of British Columbia,

Vancouver, BCDavid Fitchett, MDUniversity of Toronto, Toronto, ONDominic Ng, MD University of Toronto, Toronto, ONJiri Frohlich, MDUniversity of British Columbia, Vancouver, BCGlen J. Pearson, MD University of Alberta, Edmonton, ABJacques Genest, MDMcGill University, Montreal, QCJanet Pope, MDSchulich School of Medicine, London, ONMilan Gupta, MD McMaster University, Hamilton, ONA. Yashar Tashakkor, MD University of British Columbia, Vancouver, BC

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide4

There is continued, intense academic and social media interest in statins, particularly adverse effectsThere is also emergence of data supporting CV event reductions with statin + non-statin medicationEmergence of data supporting CV event reductions are largely determined by sustained maintenance of a physiologic state characterized by low LDL-C

Novel, non-statin agents, including biologics, are now availableTHESE FACTS ARE PARTICULARLY GERMANE IN THE STATIN INTOLERANT PATIENT WHOSE OSTENSIBLE SIDE EFFECTS REDUCE QUALITY OF LIFE, DETER ADHERENCE AND LIMIT THERAPEUTIC BENEFIT OF LDL-C LOWERINGPragmatic approaches to dealing with statin intolerance are needed.Introduction

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide5

Clinical Experience vs Randomized Clinical Trials:The Elephant in the Room regarding Goal-Inhibiting Statin Intolerance (GISI)Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide6

GOAL-INHIBITING CONCEPT: Intolerance vs ResistanceGoal-inhibiting Statin Intolerance (GISI)A clinical syndromeCharacterized by significant symptoms and/or biomarker abnormalities thatPrevent long term, indicated use of and adherence to statins asDocumented by challenge/de-challenge/re-challenge, when appropriate, using statins, including atorvastatin and rosuvastatin, that isNot due to drug-drug interactions or untreated risk factors for intolerance (e.g. hypothyroidism), and leading toFailure to maintain therapeutic goals as defined by national guidelines

Goal-inhibiting Statin Resistance (GISR) is present in patients who adhere to but do not achieve expected or adequate lipid lowering with tolerated and maximal doses of statins.Both groups may require combinations of lipid lowering drugs but side effects may be perceived differently.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide7

Principles of Management of GISIIs there an indication for statin therapy?Does the patient have features limiting or precluding use of statins?Is the patient fully aware of the indication for statin treatment, intended benefits and safety of statins, and properly counselled to avoid nocebo effects*?Have dietary, weight and exercise goals been included in the therapeutic plan? Have supplements used to avoid myalgia while taking statins been discouraged?Has systematic challenge/de-challenge/re-challenge occurred and failed to result in achievement of therapeutic goal?

If needed, which non-statin agent is likely to help achieve therapeutic goal with or without dual therapy to avoid polypharmacy?Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

*Nocebo effects;  perceived adverse reactions experienced by a patient who receives a placebo.Slide8

Statin ReluctanceAn attitudinal state characterized by a reluctance to use statins (“I hear that statins are bad, right?”)Often unwilling to accept other forms of prescription drug therapies (“I don’t like pills.”) but accepting of “natural” or “naturopathic” remedies and “health supplements”In spite of severity of dyslipidemia, level of CV risk and appropriate medical counselling, often feels that the problem can be addressed entirely through dieting, specific foods or exercise programsHighly susceptible to nocebo effects induced by media, internet sources, extensive “guidance” lists of side effects including those given at the time of prescription dispensation. May not be amenable to establishment of true Goal-inhibiting Statin Intolerance (GISI) or true Goal-inhibiting Statin Resistance (GISR)Slide9

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Guidelines undergo regular updating to insure that indications, targets and goals are current

Adherence to evidence-based guidelines ensures that practice effort is justifiable to patients, peers, regulators and

payers

Adherence to national guidelines will not affect the concept and intention of the pragmatic definitions of GISI (or GISR)

Importance of National Dyslipidemia Treatment Guidelines when Approaching GISISlide10

Predisposing Factors for Statin-Associated Adverse Effects: Endogenous Factors (1)Advanced age (older than 80 years)Female sexAsian ethnicityLow body mass index, small body frame, frailtyHistory of pre-existing/unexplained muscle/joint/tendon pain

History of creatine kinase elevationFamily history of myopathyFamily history of myopathy with statin therapySevere renal disease

Acute/decompensated hepatic diseaseHypertension/heart failure (renal side effects mainly)Hypothyroidism (untreated)

Diabetes mellitus

Neuromuscular Diseases

Genetic

polymorphisms

.

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003 Adapted from Mancini G.B. et al. Can J Cardiol. 2013;29:1553-1568Slide11

Predisposing Factors for Statin-Associated Adverse Effects: Endogenous Factors (2)Adapted from Mancini G.B. et al. Can J Cardiol. 2013;29:1553-1568.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

A

cid

maltase deficiency, amyotrophic lateral sclerosis, carnitine

palmitoyl

transferase II deficiency, cytoplasmic body myopathy, dermatomyositis, hyaline inclusion myopathy, inclusion body myositis,

McCardle

disease, malignant hyperthermia, mitochondrial myopathy [MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes], muscle phosphorylase B kinase deficiency, myasthenia gravis,

myoadenylate deaminase deficiency, myotonic dystrophy types I and II, necrotizing myopathy, peripheral neuropathy [length-dependent, mononeuritis multiplex], polymyositis [idiopathic, paraneoplastic], recurrent acute myoglobinuria [Lipin-1 mutation], rippling muscle disease (sporadic, autoimmune), spinobulbar muscular atrophySpecific cytochrome P isoenzymes, SLCO1B1 gene variants, “eyes shut” homolog [EYS] on chromosome 6, C34353T polymorphism in ABCB1, ABCG2 polymorphisms, ryanodine receptor (RYR1) gene, brain-derived neurotrophic factor [BDNF] Val66Met variant, Lipin-1 [LIPIN1] mutation, rs9806699 variant in glycine amidinotransferase

[GATM]

Neuromuscular diseases

Genetic polymorphisms Slide12

Predisposing Factors for Statin-Associated Adverse Effects: Exogenous FactorsHigh statin doseAlcohol abuseIllicit drug use (cocaine, amphetamines)AntipsychoticsFibrates

(primarily gemfibrozil)Nicotinic acidAmiodaroneVerapamil

WarfarinPolypharmacy therapy

Cyclosporine

Macrolide antibiotics

Azole antifungals

First generation

p

rotease inhibitorsNefazodoneLarge quantities of grapefruit (> 1 quart per day), pomegranate juice (?)Surgery with severe metabolic demandsHeavy and/or unaccustomed exerciseAdapted from Mancini G.B. et al. Can J Cardiol. 2013;29:1553-1568.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide13

Genetic Risk for Goal-inhibiting Statin IntoleranceBoth common and rare genetic variants have been studiedReported genes encode proteins that regulate:Statin pharmacokinetics (e.g. drug receptors, transporters and metabolizing enzymes)Statin pharmacodynamics (e.g. muscle metabolizing enzymes)

None consistently replicated or “ready for prime time” clinical useMancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide14

Patient Counselling: Avoid Nocebo EffectsImmediate impact of side effects negatively alters perceived long-term CV risk reduction benefit and may often outweigh themPrepare patients for repository of data on internet, social media, long list of side effects distributed by pharmacies etcEncourage patient to discuss any concerns with health care provider before jumping to any conclusions or making any treatment changes

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide15

Silver Bullets that Don’t Yet Hit the Target!Some patients attempt to try to “treat” myalgia with supplements while taking statins but patients should be counselled that none have definitely been proven to do so:Coenzyme Q10

Vitamin DRed yeast rice (N.B unregulated lovastatin-like drug in the rice fungus)Berberol (plant extract)Glucosamine

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

IDENTIFY

ALL

SUPPLEMENTS USED BY THE PATIENT AND READ THEIR LABELS

CAREFULLYSlide16

Challenge/De-challenge/Re-challenge: A Cornerstone for Documenting GISIEveryone has the potential to develop toxicity at a high enough dose of statins but currently available dosage maximums have been shown to be extremely safeThe terms “complete” and “partial” intolerance refer to approved dosages“Complete intolerance”: inability to tolerate any statin

“Partial intolerance”: ability to tolerate a statin at some doseMancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide17

Getting to Goal PragmaticallyAtorvastatin and rosuvastatin are the most potent statinsThey are both available in a broad dosage rangeThey are both more useful than other statins in alternate day or intermittent dosing strategies due to longer half lifeThey are most likely to achieve goal and so their failure to do so

IS A STRONG INDICATION FOR ADDING ANOTHER AGENT to either:the maximally tolerated dose and dosing frequency of either atorvastatin or rosuvastatinOR

the maximally tolerated dose of less potent statins (e.g. fluvastatin, lovastatin, pravastatin, simvastatin) as the main, “statin-based” component of LDL-C therapy

Mancini et al, DOI:

http://

dx.doi.org/10.1016/j.cjca.2016.01.003Slide18

When Statins Don’t Allow Goal

Attainment: What are the Options?

EzetimibeResins

Niacin

(Fibrates

)

PCSK9

inhibitors (ASCVD,

FH)Lomitapide (HoFH)Mipomersen* (HoFH)LDL-C apheresis (FH, high risk/recurrent CVE)ASCVD; Arteriosclerotic Cardiovascular Disease. FH; Familial Hypercholesterolemia. HoFH; Homozygous Familial Hypercholesterolemia. CVE; Cardiovascular Event. *Currently not available in CanadaMancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Readily AvailableLimited AccessSlide19

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003GISI in a NUTSHELL

START/STOP

LOWER

ADDSlide20

*Other statins (

Simva 40 mg, Lova 80 mg, Prava 40 mg, Fluva 80 mg) may be the only tolerated statins but due to lower potency and ineffectiveness of intermittent dosing schedules, failure to achieve goals solely through trials of these statins would not normally be considered adequate for establishing GISI.

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Trials of Atorvastatin

10-80 mg

d

aily/intermittently

Partial or complete

intoleranceTrials of Rosuvastatin5-40 mgdaily/intermittently Trials of Rosuvastatin5-40 mgdaily/intermittently Partial or completeintoleranceTrials of Atorvastatin 10-80 mgdaily/intermittently Partial or complete intolerance to Atorvastatin and/or Rosuvastatin*Slide21

*Other statins (

Simva 40 mg, Lova 80 mg, Prava 40 mg, Fluva 80 mg) may be the only tolerated statins but due to lower potency and ineffectiveness of intermittent dosing schedules, failure to achieve goals solely through trials of these statins would not normally be considered adequate for establishing GISI.

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Partial or complete intolerance to

Atorvastatin and/or Rosuvastatin*

LDL-C within ≤ 20% of Goal

LDL-C > 20% beyond goal

Add ezetimibe

(consider other agents based on patient preferences or patient characteristics)Options:Multiple standard agentsadded sequentially (ezetimibe, resin, niacin)PCSK9 InhibitorApheresis if availableLomitapide if HoFHComplex polypharmacySlide22

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Checklist Documenting Efforts to Identify Maximally Tolerated Statin-based Therapeutic RegimenSlide23

Mancini et al, DOI:

http://dx.doi.org/10.1016/j.cjca.2016.01.003

:

Management of Symptoms of Myalgia and/or

HyperCKemia

STOP STATIN

ASSESS if rhabdomyolysis

has impaired renal function (CONSIDER urine myoglobin)

REHYDRATE as warrantedRECONSIDER predisposing factors and treat or eliminate, if possibleFOLLOW until CK ≤ ULNand asymptomaticCONSIDER referral to specialist to weigh risk and benefits of restarting statinsCK > 10 times ULNModerate / SeverehyperCKemiaCONSIDER nonstatin drugs as adjuncts or replacement agents to achieve lipid targetsCONTINUE to emphasize dietary and health behavior measures to diminish need for pharmacotherapyNOSYMPTOMS OF MUSCLE PAIN OR WEAKNESS ON STATIN?

CK ≤ ULN

STOP STATIN

ASSESS if rhabdomyolysis

has impaired renal function (CONSIDER urine myoglobin)

REHYDRATE as warranted

RECONSIDER predisposing factors and

treat

or

eliminate

, if possible

FOLLOW until CK ≤ ULN

CONSIDER referral to

specialist to weigh risk and benefits of restarting

statins

CK > 10 times ULN

Moderate / Severe

hyperCKemia

STOP STATIN

RECONSIDER predisposing factors and

treat

or

eliminate

, if possible

FOLLOW until CK ≤ ULN

RESTART

statin

or

use lower dose or switch

MONITOR symptoms and enzymes in 3-6 weeks or sooner if symptoms recur

CK > 5 & ≤ 10 times ULN

Mild / Grade 2

hyperCKemia

CONTINUE therapy

and increase dose if needed

REASSESS enzymes in 6-12 weeks or sooner if symptoms occur

REASSESS as per algorithm above

CK ≤ 5 times ULN

Mild / Grade 1

hyperCKemia

CK > ULN

CK > ULN

Statin

Associated

Myositis

NO FURTHER TESTING unless symptoms occur or

statin

increased or switched

YES

STOP STATIN

RESTART

statin

or

use lower dose or switch

MONITOR symptoms and enzymes in 3-6 weeks or sooner if symptoms recur

CK ≤ 10 times ULN

Mild

hyperCKemia

RECONSIDER predisposing factors and

treat

or

eliminate

, if possible

FOLLOW until CK ≤ ULN

and symptomatic

STOP STATIN,

resume same

statin

at same dose when asymptomatic

REASSESS CK and symptoms in 6-12 weeks

or sooner if symptoms

recur

REASSESS as per

algorithm above

CK ≤ ULN

Statin

Associated

MyalgiaSlide24

After de novo initiation of a statin that is associated with a patient complaint of adverse effects, when is re-challenge/de-challenge with the same statin inappropriate or futile?Patient refuses to re-try the same drug, even at a lower daily dose or intermittently.Symptoms are significant, convincing, plausible and typical of statin side effects (mainly myalgia) and have resolved completely with cessation.Symptoms are severe, associated with eitherobjective muscle weakness, and/or associated with hyperCKemia (at least Mild, Grade 1b, > 5x ULN*)

significant ALT elevation (> 3x ULN)# Offending statin can be documented to be ineffective at achieving goal (note: this does not exclude trial of this particular statin in the future or use of this agent at lower doses as chronic therapy).Symptoms have not resolved or increase after a reasonable drug holiday raising the possibility of an underlying, non-statin related illness that needs investigation prior to addressing use of any statin or, rarely, immune mediated necrotizing myopathy possibly statin-related.

*Note that CK elevation should be considered in the context of baseline values if known, as well as ethnicity and athletic body habitus

#

Exclude

trauma- or exercise-induced

hyperCKemia

, drug-drug interactions or concomitant use of hepatotoxic drugs, etc

.)Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide25

Ezetimibe: Logical Next Choice in GISI within 20% of GoalAssociated with CV risk reduction in combination with statin (SHARP, IMPROVE-IT)Paucity of side effectsWell documented safetyMuscle-related side effect reports have been rare and not necessarily causal (no known mechanism):Myopathy (Simard C, Poirier P. Can J Cardiol.

2006;22:141-144; Brahmachari B, Chatterjee S. Indian J Pharmacol. 2015;47:563-564)Polymyositis (Garcia-Valladares I, Espinoza, L.R. J

Rheumatol. 2010;37:472)Mancini et al, DOI:

http://

dx.doi.org/10.1016/j.cjca.2016.01.003Slide26

PCSK9 Inhibitors: Logical Next Choice in GISI When LDL-C Goal is Beyond 20%SafeEffectiveFew intrinsic side effectsSpecifically studied in the GISI populationBut, access may be limited by price, indications, variability of coverage by insurers and provincial formulariesDefinitive RCT’s pending

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide27

Goal Achievement after Utilizing an Anti-PCSK9 Antibody in

Statin-Intolerant Subjects (

GAUSS): Results from a Randomized, Double-blind, Placebo and Ezetimibe Controlled Study

David Sullivan, MD, Anders G. Olsson, MD, Rob Scott, MD,

Jae B. Kim, MD, Allen Xue, MD, Thomas Liu, MD, Scott M. Wasserman, MD,

Evan A. Stein, MD

Sullivan D, et al.

JAMA

. 2012;308(23):2497-2506.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide28

Baseline Criteria: JAMA. 2012;308:2497-2506Adapted from Sullivan D, et al. JAMA. 2012;308(23):2497-2506.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

CharacteristicsAMG 145 Q4W

AMG 145

420 mg

Q4W

+ Ezetimibe 10 mg

N=30

Placebo Q4W + Ezetimibe

N=32280 mgN=32350 mgN=31420 mg N=32Sex, female, n(%)18 (56)21 (68)20 (63)23 (77)18 (56)Age, years, mean (SD)62 (10)62 (9)60 (9)62 (7)62 (7)LDL-C, mmol/L, mean (SD)5.04 (1.25)4.91 (1.25)5.28 (1.56)5.02 (1.56)4.73 (0.94)Free PCSK9, ng/mL, mean (SD)383 (98)396 (129)372 (87)

379 (111)390 (91)

NCEP high-risk, n (%)

14 (44)

12 (39)

11 (34)10 (33)15 (47)

Coronary artery disease, n (%)3 (9)

5 (16)3 (9)

6 (20)10 (31)

Statins failed (muscle-related events)

≥ 1, n (%)

32 (100)

31 (100)

32 (100)

30 (100)

32

(100)

≥ 2, n (%)

28 (53)

24 (77)

23 (72)

21 (70)

25 (78)

≥ 3, n (%)

11 (34)

12 (38)

12

(38)

6 (20)

11 (34)

Worst statin-related events,

any statin

Myalgia, n (%)

31 (97)

29 (91)

29 (91)

29 (97)

29 (91)

Myositis, n (%)

3 (9)

3 (10)

2 (6)

2 (7)

4 (13)Slide29

GAUSS: Safety and Tolerability: JAMA. 2012;308:2497-2506*Four serious adverse events were reported for AMG 145: acute pancreatitis, pancreatitis, coronary artery disease, hip fracture, and syncope. None were considered treatment related.AE: Adverse event, some patients experienced more than 1 AE.Adapted from Sullivan D, et al. JAMA. 2012;308(23):2497-2506.

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Adverse Events, Patient Incidence, N (%)

AMG 145 Q4W

AMG 145

420 mg

Q4W

+ Ezetimibe

10 mg N=30Placebo Q4W + EzetimibeN=32280 mg N=32350 mg N=31420 mg N=32Treatment-emergent AEs22 (68.8)15 (48.4)18 (56.3)20 (66.7)19 (59.4)Serious AEs*2 (6.3)1 (3.2)1 (3.1)0 (0.0)0 (0.0)Deaths0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Treatment-related AEs 8 (25.0)3 (9.7)

6 (18.8)5 (16.7)7 (21.9)

Muscle-related AEs

Myalgia

5 (15.6)1 (3.2)

1 (3.1)6 (20.0)1 (3.1)

Muscle Fatigue

2 (6.3)

0 (0.0)

0 (0.0)0 (0.0)

1 (3.1)Muscle Spasms

1 (3.1)

2 (6.5)

0 (0.0)

0 (0.0)

3 (9.4)

AEs

leading to discontinuation

0 (0.0)

1 (3.2)

1 (3.1)

1 (3.3)

2 (6.3)

Other most commonly reported AEs

Nasopharyngitis

2 (6.3)

2 (6.5)

1 (3.1)

3 (10.0)

5 (15.6)

Nausea

2 (6.3)

1 (3.2)

1 (3.1)

0 (0.0)

1 (3.1)

Fatigue

4 (12.5)

0 (0.0)

0 (0.0)

0 (0.0)

2 (6.3)Slide30

ODYSSEY ALTERNATIVE: Efficacy and safety of alirocumab versus ezetimibe, in patients with statin intolerance defined by placebo run-in and statin rechallenge arm

Patrick M Moriarty, MD, Paul D. Thompson, MD, Christopher P. Cannon, MD, John R. Guyton, MD, Jean Bergeron, MD, Franklin J. Zieve, MD, Eric Bruckert, MDTerry A. Jacobson, MD, Marie T. Baccara-Dinet

, MD, Jain Zhao, MD, Yunling Du, MD, Ronert Pordy

, MD, Daniel

Gipe

, MD

Moriarty

P,

et al. J Clin Lipidology. 2016;9(6):758-769. Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide31

ALTERNATIVE: Alirocumab Maintained LDL-C Reductions Week 4-23

Achieved calculated LDL-C over time – on-treatment analysis (modified ITT- Observed data only)Adapted from Moriarty P, et al.

J Clin Lipidology. 2016;9(6):758-769. Mancini et al, DOI:

http://

dx.doi.org/10.1016/j.cjca.2016.01.003

Week

LDL-C, mean (SE),

mmol

/L20161284001456

4.0

mmol

/L

2.5

mmol

/L

1.5

mmol

/L

49.5% received

150 mg Q2W at W12

2.4

mmol

/L

4.1

mmol

/L

1.7

mmol

/L

Alirocumab

Ezetimibe

24

2

3

2.58

mmol

/LSlide32

ALTERNATIVE: Safety Analysis Safety analysis from double-blind treatment period †TEAE (treatment emergent adverse event) period = time from first to last injection of study treatment + 70 days.SAE = serious adverse event.‡Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.

*Although not pre-planned analysis, the P-value is shown for descriptive purposes. Adapted from Moriarty P, et al. J Clin Lipidology. 2016;9(6):758-769. Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

% of patients

Alirocumab

(N-126)

Ezetimibe (N=124)

Atorvastatin

(N=63)

TEAEs†82.5%80.6%85.7%Treatment-emergent SAEs9.5%8.1%11.1%TEAES leading to death000TEAEs leading to discontinuation18.3%25.0%25.4%Any skeletal-muscle related TEAE‡32.5%41.1%46.0%HR (95% CI) alirocumab vs comparator-0.71 (95% CI: 0.47 to 1.06)0.61 (95% CI: 0.38 to 0.99)P-value vs alirocumab*-

0.0960.042

Skeletal-muscle related TEAE leading

to discontinuation15.9%

20.2%

22.2%

HR (95% CI) alirocumab vs comparator-

0.78 (95% CI: 0.43 to 1.41)

0.67 (95% CI: 0.34 to 1.32)

P-value vs alirocumab*

-0.409

0.240Slide33

Alirocumab

ALTERNATIVE: Fewer Skeletal Muscle AEs with Alirocumab than with AtorvastatinKaplan-Meier estimates for time to first skeletal muscle event†

†Pre-define category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.

ALI, alirocumab; ATV, atorvastatin; EZE, ezetimibe.

Adapted from Moriarty P, et al.

J

Clin

Lipidology. 2016;9(6):758-769. Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003WeekCumulative probability of event1640.00Cox model analysis:HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096AtorvastatinEzetimibe0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0

8

12

20

24

28

32

36Slide34

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Conclusions and Summary

Educate patients regarding the “elephant in the room” phenomenon: although many are considered to have GISI, few are verified i.e. the prognosis for symptomatic patients is very good

Adhere to the Principles of Management of Goal-inhibiting Statin IntoleranceSlide35

Summary: Principles of Management of GISIIs there an indication for statin therapy?Does the patient have features limiting or precluding use of statins?Is the patient fully aware of the indication for statin treatment, intended benefits and safety of statins, and properly counselled to avoid nocebo effects?Have dietary, weight and exercise goals been included in the therapeutic plan? Have supplements used to avoid myalgia while taking statins been discouraged?Has systematic challenge/de-challenge/re-challenge occurred and failed to result in achievement of therapeutic goal?If needed, which non-statin agent is likely to help achieve therapeutic goal with or without dual therapy to avoid polypharmacy?

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide36

Clinical Experience vs Randomized Clinical Trials:The Elephant in the Room regarding Goal-Inhibiting Statin Intolerance (GISI)Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide37

Supplementary SlidesSlide38

Challenging Scenarios and Issues

Starting off on the Wrong Foot

Drug-drug InteractionsAthletes and LaborersPatients with Liver DiseasePatients with Renal DiseasePatients with Rheumatic and Autoimmune DiseasesThe Elderly

Intracerebral Hemorrhage

Pregnancy and Breast Feeding

Children and Adolescents

Muscle Complaints and Myopathy

Immune-mediated necrotizing myopathy

Cognitive DysfunctionGlycemic Control and New Onset DiabetesGastrointestinal EffectsThyroid EffectsUrogenital HealthSexual HealthCataractsDermatologic IssuesInterstitial Lung DiseaseMancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003For the Generalist:For the Specialist:Slide39

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Ensure patient understands rationale for therapy and CV benefits

Judicious use of baseline and follow-up testing can ensure confidence in patient-physician relationship and avoid nocebo effects

Starting Off on the Wrong FootSlide40

Blood Testing at Time of Initial Statin Prescription:Lipid profile (may be non-fasting but a fasting value should be obtained if an initial, non-fasting profile shows abnormalities of triglycerides)Fasting glucose (may be reflective of pre-diabetic state or Metabolic Syndrome) or Hemoglobin A1c (may be non-fasting

)Estimated GFR*If cholestasis is suspected, consider alkaline phosphataseMancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Baseline

(to ensure proper risk assessment, identification of secondary causes of dyslipidemia and to provide comparative values in the event of muscle or liver related complaints during follow-up):

Urinary Albumin/Creatinine Ratio

CK

ALT*

AST

TSHElectrocardiogramLipid profileALTASTFirst Follow-up after Initiation of Statin, Switch to a Higher Dose, or Switch to a Different Statin:

CK

eGFR

HbA1c

If patient has symptoms ascribed to statin and feels the need to stop,

ensure that follow-up blood testing at the time of symptoms and cessation

is performed to assist in discussing side effects and to determine if cholesterol goals were met or not. Slide41

Adapted from Chauvin B, et al.

Clin

Phamacokinet

.

2013;52(10);815-831.

Mancini et al, DOI:

http://dx.doi.org/10.1016/j.cjca.2016.01.003

:Scheme of Drug Metabolizing Enzymes and Transporters involved in Statin DispositionBILECYP3A/2C9OATP1B1SLCO1B1OATP1B1

SLCO1B1

OATP1B1

SLCO1B1

NTCP

SEC104F

METABOLITE

LACTONE

STATIN

ACID

RSEP

ABCB11

HRP 2

ABCC1

MDR 1

(PGP)

A9CB1

BCRP

ABCG2

BILE

ENTEROCYTE

CYP3A4

BCRP

ABCG2

MDP 1

(P-CP)

ABCB1

MRP 2

ABCC2

METABOLITE

LACTONE

STATIN

ACID

HEPATOCYTE

LIVER

INTESTINE

LUMEN

PASSIVE DIFFUSION

STATIN ACID OR LACTONE FORM

STATIN ACID

LACTONE

PROXIMAL TUBULAR CELL

OAT3

SEC2248

STATIN

KIDNEY

Tubular

Secretion

LUMEN

BLOOD STREAM

URINE

Na+Slide42

Clinically Significant Drug Interactions with Statins and Dosing Recommendations (1)*Not available in CanadaFinks SW, Campbell JD. Nurse Pract. Vol 39. 2014:45-51. Kellick, K. A., Bottorff, M., & Toth, P. P. J Clin Lipidol. 2014:8(3

Suppl):S30-46.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Interacting MedicationPrecaution/Contraindication

Do Not Exceed

Amiodarone

Simvastatin

20 mg, Lovastatin

40 mg

Azole antifungals (itraconazole,ketoconazole, posaconazole,fluconazole, voriconazole)CI with simvastatin, lovastatinAtorvastatin 20 mg (with itraconazole); Fluvastatin 20 mg twice daily (with fluconazole)Macrolide antibiotics(erythromycin, clarithromycin,telithromycin)CI with simvastatin, lovastatinAtorvastatin 20 mg (with clarithromycin); Pravastatin 40 mg (with clarithromycin); Pitavastatin 1 mg* (with erythromycin)AmlodipineSimvastatin 20 mgBoceprevirCI with simvastatin, lovastatinAtorvastatin 40 mgColchicineCaution with lovastatin, simvastatin, fluvastatin, pitavastatin, pravastatinCyclosporineCI with simvastatin, pitavastatin; avoid with lovastatin, atorvastatinPravastatin 20 mgRosuvastatin 5 mgFluvastatin 20 mg twice dailyDanazolCI with simvastatinLovastatin 20 mgDigoxinMonitor for potential digoxin toxicity with simvastatin and atorvastatinSlide43

Clinically Significant Drug Interactions with Statins and Dosing Recommendations (2)Finks SW, Campbell JD. Nurse Pract. Vol 39. 2014:45-51. Kellick, K. A., Bottorff, M., & Toth, P. P. J Clin Lipidol. 2014:8(3 Suppl):S30-46.Mancini

et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Interacting Medication

Precaution/ContraindicationDo Not Exceed

Diltiazem

Simvastatin 10 mg; Lovastatin 20 mg

Dronedarone

Simvastatin 10 mg; Lovastatin 20 mg

Gemfibrozil

CI with simvastatin, avoid with lovastatin, pravastatin, pitavastatin, atorvastatin, fluvastatinRosuvastatin 10 mg (use only if needed, avoidance recommended)Other FibratesCaution with all statinsGrapefruit Juice (large quantities)Avoid with simvastatin, lovastatin and atorvastatin NiacinCaution ≥1 g/d with simvastatin, lovastatin, rosuvastatinNefazadoneCI with simvastatin and Lovastatin Protease inhibitorsCI with simvastatin and lovastatinReduce doses of rosuvastatinAvoid tipranavir and ritonavir with atorvastatinAtorvastatin 20 mg with saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir.Rosuvastatin 10 mg with lopinavir + ritonavir or atazanavir + ritonavirAtorvastatin 40 mg with nelfinavirSlide44

Clinically Significant Drug Interactions with Statins and Dosing Recommendations (3)*Not available in CanadaFinks SW, Campbell JD. Nurse Pract. Vol 39. 2014:45-51. Kellick, K. A., Bottorff, M., & Toth, P. P. J Clin Lipidol. 2014:8(3

Suppl):S30-46.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Interacting MedicationPrecaution/Contraindication

Do Not Exceed

Ranolazine

Consider dose adjustment with

lovastatin

Simvastatin 20 mg

RifampinCo-administer at same time with atorvastatinPitavastatin 2 mg*SimepravirCaution with simvastatin, lovastatin, atorvastatin, rosuvastatin, pravastatin, and pitavastatinTelaprevirCI with simvastatin, lovastatin, and atorvastatinTipranavirCI with atorvastatinVerapamilSimvastatin 10 mg; Lovastatin 20 mgSlide45

Effects of Statins in Chronic Liver Diseases AILD; Alcohol induced liver disease *Patients may present with high total cholesterol attributable mainly to LpX, not LDL-C or apo B containing particles; therefore apo B measurement is useful in this setting to identify atherogenic dyslipidemia possibly warranting therapyAdapted from Herrick C, et al. Card Clin. 2015;33(2):257-265.Mancini

et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Liver Disease Statin Effects

Routine LFTs (ALT)

No longer recommended (FDA/NLA)

No new unexpected safety concerns

Drug toxicity unlikely if Bilirubin < 2X ULN

Persistent > 3X ULN (2-3 % on 80 mg/d Rx)

NAFLD/NASHSafe. CV risk of not taking statins out-weigh risk of taking the drug. Reduced transaminases and improved steatosis/necroinflammation in some pilot studies. Not yet a treatment for NAFLD per se.PBC*To be considered in patients with additional CV risk factors. Effective in reducing TC/LDL and safe. No PBC progression and might have a beneficial effect on PBC itself (one study, 3 years).Drug-induced autoimmune hepatitisRare, variable in severity, likely idiosyncratic associations, but increasingly reported. Appears safe in systemic autoimmune disease with/without AILDSlide46

Effects of Statins in Chronic Liver Diseases and GI Tract Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Liver Disease

Statin Effects

Hepatitis C

Less severe liver enzyme elevations. Could improve antiviral response.

Reduced risk of cirrhosis/carcinoma.

Chronic liver disease

Compensated cirrhosis

(Child-Pugh A)

No contraindication for statins. Decrease carcinoma and may reduce CV risk.

Drug interactions to be considered in some specific diseases.

Liver transplantation

Safe with appropriate consideration for drug interactions.

Excessive ethanol intake

(> 1-2 Units/d)

May increase liver enzymes. No data for pharmacologic interactions in humans.

Nausea-Heartburn,

Constipation-Diarrhea

(bowel

dysmotility

)

Not seen in clinical trials and meta-analysis. Symptomatic benefit with discontinuation (some case reports).

Cholelithiasis

GI malignancies

Decrease in

cholelithiasis

, esophageal and colorectal cancers by potential pleiotropic effects in statin users. Slide47

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003:Statins and Suspected Liver Disease

Prior evaluation

≤ 5 times ULN

RESTART same

statin

at same or lower dose

or

SWITCH statinNO FURTHER Transaminase testing unless symptoms occur or statin increased or switched TRANSAMINASES≤ 3 TIMES ULNINVESTIGATE for intrinsic liver diseaseCONSIDER referralSTOP STATIN

CONTINUE to emphasize dietary and health behavior measures to diminish need for pharmacotherapy

CONSIDER

nonstatin

drugs as adjuncts or replacement agents to achieve lipid targets

REASSESS in 3-6 weeks or sooner if clinically warranted

TRANSAMINASES

≤ 3 TIMES ULN

Prior evaluation

> 5 and ≤ 8 times ULN

RESTART same

statin

at lower dose

or

SWITCH

statin

Prior evaluation

> 8 times ULN

SWITCH statin and use low initial dosing

CONSIDER referral

TRANSAMINASES

> 3 TIMES ULN

CONSIDER other causes (

eg

. Alcohol) and eliminate or

treat

if warranted

Symptomatic

Asymptomatic

TRANSAMINASES

> 3 TIMES ULN

REASSESS in 6-12 weeks

STOP STATIN

Absence or very low suspicion of acute or decompensated liver disease

Transaminases ≤ 3 times ULN

START statin

REASSESS in 6-12 weeks

or sooner if clinically warrantedSlide48

Statins and Rheumatic ConditionsThere is no absolute contraindication beyond usual contraindicationsThe higher CV burden in patients with chronic inflammatory conditions needs to be recognizedStatins decrease CV risk in these patientsUsually statins have other benefits (anti-inflammatory, anti-cytokine) but rarely perturbation of the immune system can be a problem:Statins

can give chronic inflammatory myositis associated with antibodies to HMGCoA reductase leading to pain and necrosis which is sustained after D/Cing the statin

Caution should be used in those with other hepatoxins and concomitant conditions that elevate CK or cause myalgias but this is due to uncertainty in attribution of side effects of statin vs. the

rheumatic disease being treated

Mancini et al, DOI:

http://

dx.doi.org/10.1016/j.cjca.2016.01.003Slide49

Statins and Intracerebral HemorrhageMeta-analyses show minimal to no association:32 studies involving >248,000 patients131 studies involving >193,000 patients2

11 studies involving >73,000 patients3 2o analysis of Women's Health Initiative (67,882 followed for 12 years): no relationship of statin and hemorrhagic stroke

4Meta-analysis of 11 observational studies of >6900 patients:

no

association of ongoing statin use before ICH

onset

5

Phase

3 RCT in 803 patients with aneurysmal SAH on simvastatin or placebo was neutral after 6 months61. Hackam DG, et al. Circulation. 2011;124:2233-42. 2. McKinney JS, et al. Stroke. 2012; 43:2149-56. 3. Wang W, et al. PLoS One. 2014; 9:e92388. 4. Salmoirago-Blotcher E, et al. BMJ Open. 2015;5:e007075. 5. Lei C, et al . Eur J Neurol. 2014;21:192-8. 6. Kirkpatrick PJ, et al. Lancet Neurol 2014;13:666-75.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide50

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Statin meta-analyses of RCT’s suggest positive event reductions and good tolerance except in frail elderly

Competing morbidity/mortality issues, frailty, patient/family preferences are important factors to weigh for use or non-use of statins

Advanced age is not a contraindication

Statins and

Elderly Slide51

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Cohort studies and meta-analysis do not identify a clear signal for harm

Early reports of congenital abnormalities or teratogenicity in children of women on statins have not been substantiated

Statistical power remains insufficient to challenge current recommendations of treatment discontinuation during pregnancy

Statins and PregnancySlide52

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Case report indicate that breast milk concentration of statins is low

There is a lack of data concerning levels of statins in the breast milk of mothers

In the absence of safety data, statins should not be used in

breast-feeding mothers

Statins and LactationSlide53

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Statin therapy in children > 10 years

is safe and

well tolerated

A healthy lifestyle is the therapeutic cornerstone for all children with

HeFH

Initiation of statins depends on additional variables, such as a high burden of cardiovascular disease risk factors, family history and the absolute LDL-C level

Statins and

Children Slide54

CCWG Terminology for Myopathic Syndromes and HyperCKemia Adapted from Mancini, et al. Can J Cardiol 2013;29:1553-1568. Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Characteristics

Term

Laboratory

Clinical

Myopathy

NA

General term referring to any disease of muscle

Symptomatic myopathy  MyalgiaCK ≤ ULNMuscle ache/weaknessMyositisCK > ULNMuscle ache/weaknessRhabdomyolysisCK > 10 times ULN(CK > 10,000 U/L)Muscle ache/weakness; renal dysfunction might result from myoglobulinuria; need for hydration therapyHyperCKemia  Mild, grade 1

CK > ULN, ≤ 5 times ULN

Might/might not have myositis

Mild, grade 2

CK > 5 times ULN, ≤ 10 times ULN

Might/might not have myositis

Moderate

CK > 10 times ULN; ≤ 50 times ULN

Might/might not have rhabdomyolysis with/without renal dysfunction

Severe

CK > 50 times ULN

Might/might not have rhabdomyolysis with/without renal dysfunctionSlide55

Continuous vs. DiscreteStatin-Associated Adverse Effects Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Myalgia

Myositis

VS.

Myalgia

MyositisSlide56

Definition of Muscle Side-effectsRhabdomyolysisSignificant CK elevation with weaknessMyoglobinuria is not a requirement Classification of CK elevations (arbitrary)Mild hyperCKemia: <10x ULN (?myositis)Moderate hyperCKemia: 10-50x ULN

Severe hyperCKemia: >50x ULN Myositis → Rhabdomyolysis is a continuum (CK < 10 ULN + weakness vs CK 10+ x ULN + weakness are not truly distinct so degree of hyperCKemia in the presence of neurological findings should not be overly weighed)

Mancini et al, DOI: http://

dx.doi.org/10.1016/j.cjca.2016.01.003Slide57

Distribution of Creatine Kinase in the General Population: Implications for Statin Therapy Adapted from Brewster, et al.

Am Heart J. 2007;154:655-661.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Log CK

Log CK

Number of Participants

250

120

0,5

200

150

100

50

0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

100

8

0

60

4

0

20

0

1,0

1,5

2,0

2,5

3,0

4,0

Number of Participants

Distribution of log CK within the population. Log CK shows a

polymodal

frequency distribution. The log of the ULN as provided by the assay manufacturer was 2.15 in women and 2.4 in men.

Distribution of log CK

in white and black people

Black

WhiteSlide58

Assessment of CK elevation in relation to ethnicity and sexAdapted from Brewster, et al. Am Heart J. 2007;154:655-661.

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Ethnicity

Sex

Ethnicity- and sex-specific 97.5

th

percentile

of CK

Relative Reference Value (97.5th percentile for white ethnicity and sex)Relative Upper Limit of Normal Compared to White EthnicityMild, Grade 1b “hyperCKemia” threshold relative to CK limits for white ethnicityWhiteFemale201201X 1.0> 5.0x ULNMale322322X 1.0> 5.0x ULNSouth East AsianFemale313201

X 1.6> 8.0x ULN

Male

641

322

X 2.0

> 10.0x ULN

Black

Female

414

201

X 2.0

> 10.0x ULN

Male

801

322

X 2.5

> 12.5x ULNSlide59

Causes of Asymptomatic orMinimally Symptomatic HyperCKemiaMancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Endocrine disorders

Hyperthyroidism

Hypothyroidism

Hypoparathyroidism

Connective tissue disorders

Cardiac disease

Acute kidney disease

Viral illnessesPregnancy Celiac diseaseMedicationsHMG-CoA reductase inhibitors (statins) FibratesAnti-retrovirals Beta-blockersClozapineAngiotensin receptor blocking agents Hydroxychloroquine Isotretinoin ToxinsEthanolCocaineHeroinMetabolic disturbancesHyponatremia Hypokalemia Hypophosphatemia Strenuous exerciseMuscle trauma Intramuscular injectionsNeedle electromyography Seizures Surgery Malignancy MacroCK

Idiopathic hyperCKemiaSlide60

CCWG Modification of Statin Associated Muscle Symptom (SAMS) Score#Intended to distinguish between patients reacting after only one dose compared to multiple, daily doses. *In rare cases of immune-mediated necrotizing myopathy symptoms may persist or worsen despite statin cessation. Ensure absence of hyperCKemia or markers of inflammation if significant symptoms persist off of statin.

Adapted from Rosenson, et al, Journal of Clinical Lipidology. 2014;8:S58-71.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

Regional distribution/pattern

Symmetric hip flexors/thigh

aches 3

Symmetric calf aches 2

Symmetric upper proximal aches 2

Non-specific, asymmetric, intermittent 1

Transient during continued statin use 0Temporal PatternSymptoms onset ≥ 2 days# and < 4 weeks 3Symptoms onset 4 – 12 weeks 2Symptoms onset > 12 weeks 1Symptom onset < 2# days 0De-challenge*Improves upon withdrawal (2 days to < 2 weeks) 2Improves upon withdrawal (2 – 4 weeks) 1Does not improve upon withdrawal (> 4 weeks) 0*Asymptomatic during day of first missed dose 0Clinical symptoms (new or increased unexplained muscle symptoms)

Re-Challenge

Same symptoms recur upon re-challenge ≥ 2 days and < 4 weeks 3

Same symptoms recur upon re-challenge 4 – 12 weeks 1Same symptoms occur with non-statin lipid lowering drugs 0

History of Response to Non-lipid Lowering MedicationsSame symptoms as reported with statins -5

Modified SAMS Score

Probable ≥ 9Possible 7 – 8

Unlikely < 7Slide61

Immune-mediated Necrotizing MyopathyAn autoimmune diseaseUsually assoc. w/ CK >5,000 U/LProximal distributionNo skin changes (i.e., malar rash, Gottron’s sign)Malar rash: butterfly rash over face and cheeks

Gottron’s sign: rash over extensor surfaces of digits (i.e. knuckles)Both Malar rash and Gottron’s sign are seen in dermatomyositis + Anti-HMGCR AbPersists or worsens despite statin withdrawal

Can develop without statin exposureBx: lack of inflammatory infiltrate, prominent necrosis

2 per million per year; 6% of acquired myopathy @ Johns Hopkins Myositis

Center

(Recent review:

Mammen

AL, NEJM 2016; 374;664-9.)

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide62

Toxic vs Autoimmune MyopathyCK, creatine kinase; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; MHC, major histocompatibility complex; SNP, single nucleotide polymorphism Adapted from Mohassel, et al. Curr Opin Rheumatol. 2013;25:747-52.

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003

A comparison

of toxic statin myopathy with statin-associated autoimmune myopathy

Toxic

statin myopathy

Statin-associated

autoimmune myopathy

Symptoms Myalgias common; Weakness infrequentMyalgias common; Weakness commonMaximum creatine kinase (IU/I)Normal (with mild disease) to > 100 000 (with rhabdomyolysis)1000-50 000 IU/IMuscle biopsyMild disease: cytochrome oxidase negative fibres, vacuolization; sever disease: myofiber necrosis and regeneration with minimal inflammation Myofiber necrosis and regeneration with minimal inflammation; MHC class I up-regulation; MAC deposition on non-necrotic fibers

Genetic r

isk factors

SNP in SLCO1B1

HLA-DRB1*11:01

Anti-HMGCR antibody

Absent

Present

Clinical course after statin discontinuation

Improvement

Persistent/progressive weakness and CK elevation

Appropriate therapy

Statin withdrawal (or dose reduction)

Statin withdrawal

and immunosuppressive therapySlide63

Inflammatory myopathy

Necrotizing

myopathy

Mancini et al, DOI:

http://

dx.doi.org/10.1016/j.cjca.2016.01.003

Statin

withdrawal

Statin withdrawalNon-immuneDysimmuneResolution ofToxicityPropagation of symptomsImmunosuppressionImmunophenotype-specific response

Statin Exposure

Myonecrosis

+

HyperCKemia

Metabotoxic

effectSlide64

HMGCR Ab seropositivity in necrotizing myopathies (NM), established by histopathologySummary of 5 studies examining the frequency of HMGCR Ab seropositivity in necrotizing myopathies (NM), established by histopathology, and the prevalence of statin exposure. *The total number of NM cases was not disclosed in this study. It was assumed, based on previous work, Christopher-StineA&R2010 that NM represents approximately 17% of all-cause acquired myopathies ( 750 x 0.17 = 128). Ab, antibody. Mancini et al, DOI: http://

dx.doi.org/10.1016/j.cjca.2016.01.003

Necrotizing

Myopathy

(n)

HMGCR

Ab+

(n)

HMGCRAb+/NM(%)StatinExposed(n)Ab+Exposed to Statins(%)Probability of Ab+ & Statin ExposureMammen 2011128*4535

30

67

0.23

Allenbach

2014

206

45

22

20

44

0.10

Kassardjian

2015

63

17

27

12

71

0.19

Watanabe 2015

26

8

31

3

38

0.12

Klein 2015

27

11

41

11

100

0.41

Totals

450

126

28

76

60

0.17Slide65

Myositis-specific AutoAbs

Top 3Amino-acyl tRNA synthetasesnti-Mi2 (nuclear helicase)

Anti-SRP (signal recognition particle)

Mancini et al, DOI:

http://

dx.doi.org/10.1016/j.cjca.2016.01.003

Novel

AutoAbs

Anti-MDA5 (CADM-140)Anti-MJ/NXP2 (nuclear matrix protein)Anti-TIF1-g (transcriptional intermediary factor 1-g)Anti-SAE (small ubiquitin-like modifier activating enzyme)Anti-HMGCRSlide66

Mancini et al, DOI:

http://dx.doi.org/10.1016/j.cjca.2016.01.003

:

Syndromes in the

Myositis

Spectrum

Anti-aminoacyl

tRNA

synthetasesAnti-MDASAnti-PmSclAnti-SAE Anti-MI2Anti-TIF1Anti-NXP2Anti-HMGCRAnti-SRP(Anti-Jo1, Anti-PL-7, Anti-EH, Anti-PL-12, Anti-KS, Anti-OJ)

Amyopathic

disease

Interstitial lung disease

Malignancy

Necrotising

myositis

These patients can present as a diagnostic challenge and/or have an ‘overlap’ feel. They may have minimal or no muscle involvement or similarly subtle/no cutaneous disease. They may initially present with

polyarthrititis

, ILD or rash in isolation and therefore may be assessed by a range of different specialties.

Skin disease

Polyarthritis

,

Raynaud’s

Phenomenon and Mechanic’s Hands

These patients are most likely to present with severe

myositis

with a very high CK and profound weakness.

These patients are most likely to present with both cutaneous and muscle disease. They may have an associated malignancy.Slide67

Consider a Muscle Biopsy When: Myoglobinuria*Second wind phenomenon*Weakness*Muscle hypertrophy/atrophy*

Persistent increase of CK (> 2-3 above baseline or ULN based on age, sex, ethnicity)*Myopathic EMG (fibrillations and/or +ve sharp waves)*Other considerations:

Abnormal neurologic examCK does not normalize after statin withdrawal

HyperCKemia

with re-exposure to statin

+ Family History

Mancini et al, DOI:

http://

dx.doi.org/10.1016/j.cjca.2016.01.003*European Federation of Neurological Sciences, Kyriakides, et al. Eur J Neurol. 2013;997 -1005.NB: 2nd wind (SOB and excessive perceived exertion at onset of exercise that then abates) and hypertrophy are NOT seen with statin myopathy; atrophy is not typical of statin myopathySlide68

Cognitive Adverse EffectsCognitive considerations should not play a routine role in medical decisions regarding prescription of statinsDecision to prescribe statins should not be altered on this basis for majority of patientsBaseline assessment of cognition prior to initiating statins not warrantedPatient-reported cognitive symptoms should be thoroughly investigated and not readily dismissed

Statins may have a dose and duration related protective effect on certain forms of dementiaLarger/better-designed studies needed to draw unequivocal conclusions about the protective effect of statins on cognitionMancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide69

Statins and New-Onset Diabetes: Mechanisms Mechanism remains to be elucidatedMurine studies → upregulation of PTEN, implicated in insulin resistanceDirect effect of HMG CoA reductase inhibition

Recent FH analysis reveals lower prevalence of DM compared to unaffected relatives, with variability in DM risk by LDL-receptor mutation type; suggesting a link between LDL-receptor mediated cholesterol transport and DMStatins may therefore cause NOD by upregulating cholesterol transport into hepatocytes and pancreatic beta cellsFH; Familial Hypercholesterolemia. NOD; New-onset of diabetes

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003Slide70

Statins and New-Onset Diabetes:Clinical ImplicationsFor every case of NOD caused by statin therapy, several more hard CV events are avoided, both in primary and secondary preventionGeneral consensus that clinical benefits of statins outweigh risk of NODVery long-term risk/benefit ratio remains unclear, though seems favorable from extension studies Risk of NOD should generally not be a factor in withholding statin therapy from deserving populations

Sattar N, et al. Lancet. 2010;375:735-42; Preiss D, et al. JAMA. 2011;305:2556-64; Ridker PM, et al. Lancet. 2012;380:565-71; Waters DD, et al. J Am Coll Cardiol. 2013;61:148-52; Kohli

P, et al. J Am Coll Cardiol. 2015;65:402-4; Fulcher J, et al. Lancet. 2015;385:1397-405;

Erqou

S, et al.

Diabetologia

. 2014;57:2444-52; Birnbaum Y, et al.

Cardiovasc

Drugs Ther. 2014;28:447-57; Besseling J, et al. JAMA. 2015;313:1029-36; Frayling TM. Lancet. 2015;385:310-2.Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003