Statin Muscle-related Adverse Events Sharmisa Martin, APRN, MSN, - - PowerPoint PPT Presentation

Statin Muscle-related Adverse Events

Sharmisa Martin, APRN, MSN, ANCC RIHVH Cardiology

Introduction

• Statins: cholesterol lowering for both primary

and secondary prevention.

• Effective and generally safe.
• Approximately 10% pts experience myalgias
• Clinical Rhabdomyolysis: rare, perhaps 0.1% of

Pts.

• Ann intern med 2002;137:617, JAMA 2004; 292:2585

Outline

• Pathogenesis
• Definition
• Epidemiology
• Risk factors
• Clinical features
• Diagnosis
• Management

Pathogenesis

• Mechanism for muscle toxicity not well

understood.

• Reduction in ubiquinone (Coenzyme Q10)
• Increased fatty acid oxidation in statin

intolerant pts.

• Gene polymorphisms
• J Am Coll Cardio 2013; 61:44

Outline

• Pathogenesis
• Definition
• Risk factors
• Clinical features
• Diagnosis
• Management

Definitions:

• Myalgia: a symptom of muscle discomfort,

including muscle aches, soreness, stiffness, tenderness or cramps with or soon after exercise with a normal creatine kinase (CK). Myalgia symptoms can be described as similar to what would be experienced with a viral syndrome such as influenza.

Definitions: cont

• Myopathy: muscle weakness (not due to pain)

with or without elevation in CK level.

• Myositis: muscle inflammation.

Definitions: cont

• Myonecrosis: elevation in muscle enzymes

compared to either baseline CK levels (While not on statin therapy) or the upper limit of normal that has been adjusted for age, race and sex:

• Mild: 3 fold to 10 fold elevation in CK
• Moderate: 20 fold to 50 fold elevation in CK.
• Severe: 50 fold or greater elevation in CK

Definitions: cont

• Clinical rhabdomyolysis: defined by the task

force as myonecrosis with myoglobinuria or acute renal failure (an increase in serum creatinine of at least 0.5 mg/dl [44 micromol/L] )

• Defined by 2014 National lipid association statin muscle task force. J Clin Lipidol 2014; 8:S58

Outline

• Pathogenesis
• Definition
• Epidemiology
• Risk factors
• Clinical features
• Diagnosis
• Management

Epidemiology

• Meta analysis of 42 randomized trials of

statins found little or no excessive risk of myalgias, CK elevations, Rhabdo or discontinuation vs placebo. Am Heart J 2014;168:6

• Perceived side effects are common- esp

muscle (60%) J Clin Lipidol 2012; 6:208

• Myonecrosis- CK 10x normal with muscle sx in

less than 0.5% in trials. Arch Int Med 1996; 156:2085

Outline

• Pathogenesis
• Definition
• Epidemiology
• Risk factors
• Clinical features
• Diagnosis
• Management

Risk factors : Pt Characteristics

• Genetics: esp. with Simvastatin. Chinese, esp with

Simvastatin and Niacin.

• Age >80, frail, female, small body frame, Liver

disease and severe renal disease.

• Pre-existing neuromuscular disorders. Esp. ALS,

need cholesterol, increased survival Natl Acad Sci USA 2004;

101:11159

• Hypothyroidism, Low Vitamin D
• N Engl J Med 2008; 359:789, Can J Cardio 2013; 29:1553

Risk factors : Drug Therapy

• Statin Characteristics: higher doses, increased

incidence.

• Hydrophilic vs hydrophobic : muscle penetration
• f statin.
• CYP3A4 metabolism: Increased interactions with

Simvastatin, Lovastatin .

• Pravastatin, rosuvastatin: Hydrophilic, not

extensively metabolized by CYP3A4

• Many drug interactions : HIV, antifungals, others
• J Am Coll Cardio 2017;70:1290

Risk factors : cont.

• Exercise: unaccustomed vigorous exercise,

increase in muscle injury.

• Disease becomes clinically apparent with

statins: Myasthenia gravis, myopathies, motor neuropathies.

• Grapefruit juice: inhibits CYP3A4.

Consumption of 8 oz or less, or ½ half grapefruit unlikely adverse interaction.

• Br J Clin Pharm 2011; 72:34

Outline

• Pathogenesis
• Definition
• Epidemiology
• Risk factors
• Clinical features
• Diagnosis
• Management

Clinical features

• Proximal, symmetrical muscle weakness and/or

soreness, tenderness.

• Possible functional impairment such as difficulty

raising arms above head, arising from a seated position or stair climbing.

• May include cramping, possibly nocturnal.
• Elevations in serum CK in some but not all.
• Onset: weeks to months.
• BMJ 2008; 337:a2286

Outline

• Pathogenesis
• Definition
• Epidemiology
• Risk factors
• Clinical features
• Diagnosis
• Management

Diagnosis

• Serum Creatine kinase (CK) elevation, 3 to 10

fold elevation. May be due to exercise, impact

• Statin assoc muscle sx clinical index (SAMS-CI)
• May have muscle sx with out CK elevation
• Take history for other causes of myalgias
• Muscle biopsy not typically used, unless sx

don’t resolve with statin discontinuation.

• Ann intern med 2002;137:6581

What it is not

• Joint pain esp if pre-existing.
• Usually not unilateral.
• Pts report pain after being warned of muscle

side effects. Concerns may heighten perception of pain from other causes.

• Single pt trials for statin myalgia
• Ann intern med 2014; 160:301

Outline

• Pathogenesis
• Definition
• Epidemiology
• Risk factors
• Clinical features
• Diagnosis
• Management

Management

• Discontinue therapy
• If CK elevated, large amount of fluids to facilitate

excretion on myoglobin

• Assess drug interactions: HIV drugs, amiodarone,

cyclosporine, fibrates, colchicine, niacin.

• Assess for Vitamin D deficiency and

hypothyroidism and correct. Then resume statin with careful monitoring.

• J Pharm2017; 30:521

Management

• If Rhabdomyolysis: should not be treated with

statin again due to risk of reoccurrence.

• Switch statin :pravastatin, fluvastatin, pitavastatin

– have fewer interactions

• Alternate day dosing
• May need lipid control for Coronary disease,

consider lipid clinic referral for PCSK9 inhibitor

• J Pharm2017; 30:521

Management- other therapy

• CoQ10: may play a role in myalgias but little

evidence showing benefit. Anecdotal evidence for 30-250 mg QD. J Am Coll Cardio 2012;110:526

• Red yeast Rice: compound similar to
• lovastatin. May be tolerated but lack of
• utcome studies. Supplements not regulated

Eur J Intern Med 2014; 25:592

• Niacin: Not recommended due to lack of

evidence.

Summary

• Myalgias and myopathy frequency 2-11%.
• Severe myonecrosis, Rhabdo are rare, 0.5-

1.0%.

• Can have myalgias without CK elevations.
• Muscle injury risk higher with lovastatin,

simvastatin and atrovastatin when taken with a drug that interferes with CYP3A4.

Summary- cont.

• Increased susceptibility to myopathy in renal ,

liver disease and hypothyroidism.

• Muscle symptoms may begin within weeks of

starting and usually return to normal over days to weeks after discontinuation of statin.

• CK: no routine monitoring, may check prior to
• initiation. Elevated with exercise.
• Check interactions, Vit D, Thyroid .

Closing thought

• Many pts complain of myalgias that they feel

are due to the statin. Upon careful evaluation and discussion this may not be the case.

Questions