Statin intolerance. Pr Franck Boccara, MD, PhD Cardiologie, INSERM UMRS938 CHU St Antoine, UPMC, Paris, France

Transcription

1 Statin intolerance Pr Franck Boccara, MD, PhD Cardiologie, INSERM UMRS938 CHU St Antoine, UPMC, Paris, France

2 Disclosure Statement of Financial Interest I currently have, or have had over the last two years, an affiliation or financial interests or interests of any order with a company or I receive compensation or fees or research grants with a commercial company : Grant/Research Support: Amgen Consulting Fees/Honoraria: Abbott, ViiV Healthcare, MSD, Novartis, Gilead

3 Summary Definitions Epidemiology Consequences Guidelines

4 Definitions Epidemiology

5 Reported Adverse Effects of Statins Elevated hepato-cellular enzymes New diabetes Muscle-related symptoms Cancer Hemorrhagic stroke Fatigue Neuro-psychiatric effects and insomnia Proteinuria / hematuria Erectile dysfunction Alopecia

6 Liver Injury Associated with Statin Use Type of liver injury Frequency Comment Asymptomatic elevations in aminotransferases Clinically significant acute liver injury Fulminant hepatic failure Autoimmune hepatitis 0.1%-3.0% Very rare Extremely rare (isolated case reports) Case reports Dose-dependent; class effect; clinically not significant May be seen in combination with other medications It was estimated that risk of fulminant liver failure is 2 per million Statins may induce AIH in genetically susceptible individuals Bhardwaj SS et al. Clin Liver Dis 2007; 11:

7 ESC/EAS 2016 Recommendations for dyslipidemia ESC Guidelines dyslipidemia Eur Heart J 2016

8 Evidences for a relation between statin and diabetes Treatment of 255 patients with statins results in 1 additional case of diabetes over 4y Statin treatment prevented of 5.4 vascular events in these 255 patients Benefit of statin treatment exceeds risk Monitor fasting glucose and A 1 C Canadian Journal of Cardiology 2016

9 Muscle Adverse Effects of Statin (Muscle related side effects [MRSE]) Major symptom limiting the use of statins Clinical features include Muscle aches, myalgia, weakness Stiffness, and cramps CK not increased in most patients Compromises quality of life Reduces medication adherence Mancini GB et al. CJC 2011; 27:

10 Terminology for statin-associated muscle symptoms in literature Adapted from Stroes ES, Eur Heart J 2015 Stroes EK et al. EAS/ESC Eur Heart J. 2015;36:

11 Simplified terminology for statin-associated muscle symptoms by EAS/ESC 2015 Stroes EK et al. EAS/ESC Stroes Eur ES, Heart Eur J. Heart 2015;36: J

12 Rhabdomyolysis and Statins Very rare: 0.7 cases / 100,000 person-years Can also occur in absence of statin therapy Incidence for individual statins (AERS) (1 reported case per number of prescriptions) Lovastatin 5.2 million Atorvastatin 23.4 million Pravastatin 27.1 million Simvastatin 8.3 million Cerivastatin 320,000 FDA Adverse Reporting System Rosuvastatin incidence similar to other statins FDA Advisory 2005 Statin dose-related incidence of rhabdomyolysis Compared to Atorvastatin 10mg 40 mg HR 3.8 (95% CI ) 80mg HR 11.3 (95% CI ) Holbrook A et al. Can J Cardiol 2011; 27:146-51

13 SAMS in randomized placebo-controlled trials Newman CB, JAMA 2015

14 Incidence of Muscle-Related Symptoms during High-dose Statin Treatment 7924 subjects with hypercholesterolemia Received high dose statins for > 3 months Atorvastatin 40-80mg Fluvastatin ER 80mg Pravastatin 40mg Simvastatin 40-80mg Men : Women 2:1 832 (10.5%) reported muscle related symptoms Incidence related to statin type Fluvastatin 5.1% Pravastatin 10.9% Atorvastatin 14.9% Simvastatin 18.2% PRIMO Bruckert E et al. Cardiovascular Drugs and Therapy 2005; 19:403-14

15 PRIMO Bruckert E et al. Cardiovascular Drugs and Therapy 2005; 19: Predictors of myopathy in PRIMO History of: Muscle pain with prior LLD (OR 10.12; 95% CI, ; P ) Unexplained muscle cramps (OR 4.14; 95% CI, ; P ) Prior CK elevation (OR 2.4; 95% CI, ; P0.0001) Family history of muscle symptoms (OR 1.93; 95% CI, ; P 0.022), family history of muscle symptoms while using lipidlowering therapy (OR 1.89; 95% CI, ; P0.017) Hypothyroidism (OR 1.71; 95% CI, ; P 0.017) Interestingly, statin treatment for more than 3 months (OR 0.28; 95% CI, ; P ), and antidepressant use (OR 0.51; 95% CI, ; P0.0004) were associated with reduced myopathy risk.

16 Clinical Trials and Muscle Related Adverse Effects Why the low incidence in clinical trials? Patients highly selected Often have pre-randomisation run-in Definition of muscle adverse effects differ Motivated trial patients may minimize symptoms Muscle aches and pains are common in placebo group Mancini GB et al. CJC 2011; 27:

17 GAUSS 3, Initial phase Phase A 511 patients enrolled at 53 centers with a history of intolerance to multiple statins due to muscle-related adverse effects. 10 weeks Atorvastatin 20 mg Placebo 10 weeks Atorvastatin 20 mg Placebo Intolerable Muscle Symptoms N = 491 On atorvastatin, but not placebo 209 (42.6%)* On placebo, but not atorvastatin 130 (26.5%) On both placebo and atorvastatin 48 (9.8%) No symptoms on either treatment 85 (17.3%) Did not complete Phase A 20/511 Nissen S et al JAMA 2016

18 Nissen S et al JAMA 2016 Gauss 3, adverse events Muscle symptoms : 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P =.17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibetreated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%).

19 Mechanisms of Statin Myopathy Excess exposure to statins Increased plasma levels Increased transmembrane flux of statins Pre-existing neuromuscular disease May be previously undiagnosed Impaired calcium handling in skeletal muscle Statin induced myocellular metabolic dysfunction Immune mediated inflammatory myopathy Idiopathic inflammatory myopathy (polymyositis) Immune mediated necrotizing myopathy Mancini GB et al. CJC 2011; 27:

20 Effects potentially involved in statin-related muscle injury/symptoms Stroes EK et al. EAS/ESC Eur Heart J. 2015;36: Needham M, Mastaglia FL. Neuromuscul Disord 2014;24:4 15.

21 Risk factors for statin-associated muscle symptoms (SAMS) - Non-modifiable risk factors: >80 years, female, low BMI, Asian descent - Excess physical activity, alcohol or grapefruit juice - Acute infection, hypothyroidism, impaired renal or hepatic function, organ transplant recipient, trauma, HIV, diabetes - Vitamin D deficiency - History of CK elevation or unexplained muscle/joint/tendon pain, myopathy while receiving another lipid-lowering therapy - Inflammatory or inherited metabolic, neuromuscular/muscle defects - Polymorphisms in CYP450 isoenzymes or drug transporters Stroes EK et al. EAS/ESC Eur Heart J. 2015;36:

22 Risk Factors for Statin-Induced Myopathy Statin Dose and Pharmacodynamics Statin dose Muscle-related side effects not related to lipid lowering potency Dose threshold generally above approved doses High vs low statin dose 7 RCT meta analysis N= 29,395 No increase in myopathy Properties of statin Bioavailabity Lipophilicity Potential for drug interactions CYP450 inhibitors Inhibition of glucuronidation (eg. gemfibrozil) Josan K et al. CMAJ 2008; 178:576-84

23 Risk Factors for Statin-Induced Myopathy Drug Interactions related to CYP Metabolism CYP 3A4 Simvastatin Lovastatin Atorvastatin CYP 2C9 Fluvastatin Rosuvastatin No CYP Metabolism Pravastatin Inhibitors Protease inhibitors Cyclosporine Amiodarone Fibrates Macrolide antibiotics Diltiazem Inhibitors Cyclosporine

24 Recent review of statins benefit and safety The only adverse events that have been reliably shown to be caused by statin therapy are myopathy (defined as muscle pain or weakness combined with large increases in creatine kinase blood concentrations) and new-onset diabetes mellitus, along with a probable increase in strokes due to bleeding (ie, haemorrhagic strokes). Typically, treatment of patients for 5 years with a standard statin regimen (such as atorvastatin 40 mg daily) would be expected to cause about 5 cases of myopathy, new cases of diabetes, and 5 10 haemorrhagic strokes. Collins R, et al. Lancet. 2016;388:

25 Consequences

26 Impact of Postdischarge Statin Withdrawal on Long-Term Outcomes in Patients With Acute Myocardial Infarction 3,807 patients in the Korean multicenter registry who survived for 1 year after AMI 603 patients had a history of statin discontinuation and 3,204 patients continued statin Min Chul Kim et al. Am J Cardiol 2015;115:1-7

27 Guidelines

28 ESC Guidelines dyslipidemia Eur Heart J 2016

29 Prevention of Statin Intolerance Pre-treatment assessment Assess risk (e.g. elderly, prior muscle pains, FH of myopathy, renal disease, DM, hypothyroidism) Consider exogenous factors (e.g. statin dose, alcohol use, drug-drug interactions, excessive grapefruit juice use) Measure baseline CK, ALT, TSH, creatinine Counseling Inform that statins are very well tolerated in most people Inform about muscular symptoms and when to discontinue Monitoring Check CK / ALT when monitoring lipid lowering efficacy At 6-8 weeks after starting or with dose increase and then every 6-12 m Avoid severe exercise for several days prior to testing

30 CHECK-LIST for STATIN INTOLERANT PATIENT Canadian Journal of Cardiology 2016

31 Conclusions Adverse Effects of Statin Treatment More common than clinical trials suggest Probably more frequent at higher doses Important cause of poor adherence to treatment Prevent statin induced muscle adverse events Manage adverse events Use alternative statin Reduce frequency of statin Use non-statin agents as monotherapy or together with reduced dose or frequency statin

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