Sun and Statins What do vitamin D and statins have in common? - - PowerPoint PPT Presentation

Sun and Statins

What do vitamin D and statins have in common?

Tristan Melton Pharmacy Resident 2011-12

Objectives

1) Gain an appreciation and understanding for the pathophysiology behind statin induced myopathies 2) Review the evidence behind vitamin D supplementation for prevention and resolution of statin induced myopathies

Statins By The #s

All time best selling family of drugs

• 20 billion dollars annually (2009)

Most prescribed drugs in Canada

• 12 million prescriptions in 2009

“ASA of the 21st century”

Case: NM

• 85 y/o ♂ ht: 178 cm wt: 90 kg BMI = 28.4

Admitted March 19

• Chief complaint: Shortness of breath
• History of present illness: recently discharged

for upper GI bleed with progressive shortness

• f breath and weakness over previous 4-5

days.

Case: NM

PMH:

• Upper GI bleed  NSAID use

– VGH March 7-15

• Coronary artery disease

– Previous MI (1989)

• Atrial fibrillation
• Complete heart block pacemaker

– Hx infected pacemaker (reimplantation 2007)

• Aortic stenosis with aortic/mitral regurgitation
• Background CHF with preserved systolic fxn

Case: NM PMH:

• Hypertension
• Dyslipidemia
• Asthma (mild)
• Hx of ARF secondary to gentamicin
• Prostate cancer (radiation/hormone therapy)

Surgery: hernia repair x 3, left total knee replacement,

prostatectomy and multiple pacemaker procedures

Case: NM Social History:

• Lives with wife in senior’s condo
• Two daughters and one son
• Retired truck driver and crane operator
• Few glasses of wine/week
• Previous smoker ≈ 13 years (quit >50 years ago)

Allergies/Intolerances:

• Penicillin? – rash 50 years ago
• ACE inhibitors - dry cough

Case: NM

Medications prior to admission (BPMH)

• ASA 81 mg po daily
• Telmisartan 20mg po daily as directed
• Hydrochlorothiazide 25 mg po daily as directed
• KCl 8meq po daily
• Furosemide 40mg po daily
• Rosuvastatin 40mg po daily
• Ezetimibe 10mg po q2d
• Pantoprazole 40mg po bid

Case: NM

Medications prior to admission (BPMH)

• Ferrous fumarate 300mg po bid
• Advair inhaler – 500 mcg bid
• Salbutamol inhaler – 200mcg q4h prn
• Impatropium inhaler – 80mcg qid
• Omega 3 supplement – 1 capsule po daily

Vaccines up to date

• influenza
• pneumococcal

Case: NM

Systems: Vitals: HR=76 BP=130/80 RR: 20 Afebrile Gross: pale, unwell, overweight CNS: decreased sleep quality of late Resp: increasing SOB, scattered crackles in lung bases MSK: marked fatigue  unable to stand up

– “stiff muscles” unable to bend arm – “crampy” hands and legs – limited left shoulder ROM

Case: NM

LABS:

Marker (range) 19 20 22 23 26 29

CK Total (40-230 U/L) 3,973 2,897 1,029 371 Myoglobin (28-72 ug/L) 8,603 1,677 Serum Creatinine (60-100 umol/L) 155 148 172 171 120 86

Drug Therapy Problem

a) NM is at an increased risk for significant morbidity/mortaltiy secondary to experiencing myositis/rhabdomyolysis which is most likely attributable to his statin therapy and would benefit from discontinuation of his rosuvastatin. b) NM is at a high risk to experience a cardiovascular event given his complex past medical history and would benefit from an assessment of his dyslipidemia management.

Other DRPs

Anemia requiring Vitamin B12 and iron supplementation Inappropriate use of Advair inhaler Reassessment of ipratropium Requires warfarin teaching Requires adequate calcium supplementation Adherence concerns from recent medication changes Increased risk for ARF secondary to ARB Increased risk to experience a fall secondary to BP

Goals of Therapy

Health Care Team

• Identify and resolve cause of myositis/rhabdomyolysis

 Decrease associated morbidity and mortality

• Provide evidenced based medication to reduce future risk of

cardiovascular events

• Reduce/minimize any ADR with therapy
• Adherence assessment

Patient “I think your barking up the wrong tree”

• Resolve current muscle stiffness/cramping
• Increase strength
• Minimize/eliminate adverse drug reactions
• Have pharmacist prepare all meds for discharge!

Statin Induced Myopathy

• Most common reason for discontinuation

– Range very mild to severe signs/symptoms

• Incidence around 5-15%
• Two studies report repot a 1.5x increased risk of

muscle complaints compared to those on placebo

• Lower incidence in studies

– Exclude high risk patients (previous myopathy) – Exclude those with potential drug interactions THIN database: fluvastatin>pravastatin>atrovastatin=rosuvastatin

Statin Induced Myopathy

NM

CK SrCr

3,973 172 Myositis ± ?rhabdo

Statin MOA

a) HMG-CoA reductase inhibitors b) Atherosclerotic plaque stability

Statin Myopathy Mechanisms

1) Isoprenoid deficiency

• by-products of HMG-CoA reductase pathway
• deficiency disrupts cell apoptosis regulation & skeletal muscle cell structure

Statin Myopathy Mechanisms

2) CoQ10 inhibition

• required for oxidative phosphorylatoin and ATP production
• statins reduce CoQ10 by blocking mevalonate production

Statin Myopathy Mechanisms

3) Reduced sarcolemmal cholesterol

• reduced cholesterol levels lead to alterations in myocyte membrane
• Can cause modification in membrane integrity and fluidity  destabilization

Statin Myopathy Mechanisms

4) Altered calcium homeostasis

• secondary to increased expression of ryanodine receptors 3 (RR3) which are

responsible for causing a marked increase in intracelluar calcium

5) Autoimmune

• statin induced immune-mediated necrotizing myopathy
• single nucleotide polymorphism (rs4363657 SLC01B1 gene on chromosome 12)

Statin Myopathy Risk Factors

1) Demographic – female, elderly, low BMI, frail, heavy exercise 2) Genetics

• organic anion transporting polypeptides (OATP1B1)
• cytochrome P450 system
• glucuronidation
• CoQ10
• inherited muscle diseases

3) Co-morbidities – excessive alcohol consumption, major surgery, previous/family hx myopathy, AKD/CKD, hypothyroidism QUIZ: Which two statins are minimally excreted in the urine?

Statin Myopathy Risk Factors

4) Pharmacokinetics 5) Dose Silva et al. through a meta-analysis showed an increased risk of high dose statin causes CK>10xUNL (OR 9.97 95% (1.28-77.92) p=0.028 6) Drug interactions

So Why NM?

Demographic  elderly ✓ Genetics  unknown Co-morbidities  alcohol hx ✓ Pharmacokinetics  possibly Dose  high ✓ Interactions  ?pantoprazole, ?ezetimibe Research: Vitamin D insufficiency?

So Why NM?

Academic request for vitamin D level Granted by geriatrician

Marker (range) March 28

Vitamin D 25 (OH) (75-150 nmol/L) 78

PICO

Patient: experiencing myositis/rhabdomyolysis secondary to a statin Intervention: vitamin D supplementation Comparator: no therapy Outcome:

Primary: resolution of vitamin D deficiency prevent statin-induced myalgia Secondary: adequate vitamin D levels reduce statin-induced myalgia

Vitamin D and Myopathy

• First manifestation of deficiency  myalgias
• Serum levels are related to physical

performance in elderly MOA: (hypothetical)

• Interaction with statin on vitamin D deficient

skeletal muscle fibers

• “preferential shunting” for hydroxylation of

vitamin D through CYP3A4 reducing availability for statin metabolism

Literature Search

Search Terms:

• Statin
• Vitamin D
• Myositis
• Myalgia

Databases: PubMed, Cochrane, Embase, Medline, IPA, Limits: none

Literature Search

Results:

• 5 prospective cohorts
• 2 retrospective cohorts
• 2 case reports

CMRO 2011: 1683-90

P: 150/2,360 hypercholesterolemic pts (May 2007 – Jan 2011)

• Inclusion

– Serum vitamin D <32 ng/ml (80 nmol/L) – Previously taken or current use of statin – Myositis-myalgia causing cessation of statin therapy

• Exclusion

– Corticosteroids – Supplemental vitamin D at study entry – Co-morbidities  muscle or bone pain » Diabetic sensory neuropathy, fibromyalgia, polymalgia rheumatica, arthritis, peripheral vascular disease, sensory neuropathy, hypothrodisim – Patients who refused vitamin D supplementation – Previously reported statin intolerant patients treated with Vitamin D

Glueck 2011

I: Rx for Vitamin D 50,000 IU 2/week x3weeks  once

weekly Statin restarted after 3 weeks

C: prospective cohort O: Would vitamin D supplementation with resolution of

vitamin D deficiency result in statin tolerance

T: initial reassessment at 3 months, then q4 months

Glueck 2011

Results:

Glueck 2011

Duration (months)

Vitamin D (nmol/L)

VD Normalized (>80 nmol/L) Myositis- myalgia free Entry Follow-up

11.5 52.4 104.8* 78% 87%¶

*p<0.001 comparing study entry vs follow-up by paired Wilcoxon test

¶ Total cohort

Glueck 2011

Limitations:

• Size
• Non randomized, doubled blinded, placebo controlled trial
• Patient population (young, generally healthy)
• Duration of myositis-myalgia free
• Single centre
• Statin dose adjustments to reduce LDL
• Myalgia vs. non-myalgic groups based on subjective reports
• Definition of myositis-myalgia causing cessation of statin
• Initial myalgia to higher doses of statins
• 65% used rosuvastatin for statin reinstitution
• Other lipid lowering medications in some patients
• Increase in serum vitamin D secondary to statin (L, C)

Glueck 2011

Authors conclusion…

“Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent serum 25 (OH) vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle causing myalgia”

Translational Research 2009: 11-6

P: 128/621 statin treated pts with myositis-myalgia (May 2007 –

May 2008)

• Inclusion

– Started with 687 statin-treated patients – Normal TSH and thyroxine

• Exclusion

– Corticosteroids – Supplemental vitamin D at study entry – Co-morbidities  muscle or bone pain » Fibromyalgia, arthritis, peripheral vascular disease, sensory neuropathy

• All patients instructed not to take supplemental vitamins

Ahmed 2009

I: Rx for Vitamin D 50,000 IU qweekly x12 weeks for those

with serum 25 (OH) vitamin D <80 umol/L + myalgia

C: Patients with serum 25 (OH) vitamin D >80 umol/L with

• r without statin myalgia

O: a) if low serum 25 (OH) vitamin D was associated with

myalgia in statin-treated patients b) whether myalgia could be reversed by vitamin D supplementation while continuing statins

T: 12 weeks

Ahmed 2009

Ahmed 2009

Results:

Ahmed 2009

• Serum vitamin D level was lower in patients with myalgia than

asymptomatic patients (71.5 ± 33 vs 85.5 ± 34.5 umol/L, p<0.0001)

Results:

Ahmed 2009

• 64% of patients with myalgia vs

43% of asymptomatic patients had low serum vitamin D (x2 = 17.4; p<0.0001

• Of the 38 myalgic, vitamin D deficient, statin treated

patients mean serum Vitamin D increased from (51 ± 18.25 vs 120 ± 44.75 umol/L, p<0.0001) at 3 months follow-up

• 35/38 (92%) patients became free of myalgia

Ahmed 2009

Limitations:

• Size
• Non randomized, doubled blinded, placebo controlled trial
• Patient population (young, generally healthy)
• Duration of myositis-myalgia free
• Single centre
• More nonwhites (12 vs 5%) and women (59 vs 44%) present in

symptomatic group

• Myalgia vs. non-myalgic groups based on subjective reports
• Most statin myalgia patients studied with rosuvastatin
• Definition of myositis-myalgia
• Other lipid lowering medications?

Ahmed 2009

Authors conclusion…

“We speculate that symptomatic myalgia in statin-treated patients with concurrent vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle”

Summary of Evidence

• Patients who experience myalgia on

statins are more likely to have a vitamin D deficiency ~ 15-20%

• Low serum vitamin D may be

associated with myalgia in statin treated patients

• Adequate vitamin D supplementation

appears to largely reverse statin induced myalgia ~ 90%

NM: Course of Stay

• Statin therapy discontinued
• Started on Vitamin D 2000 units daily
• Lipid-lowering agent not restarted
• Medication teaching (inhalers, warfarin)
• Calcium, Vitamin B12, Iron started
• Med calendar
• Discharge prescription for blister packs
• Summary of admission sent to GP

NM: Therapeutic Alternatives

• Nonpharmacologic

– Exercise, reduce dietary cholesteral, trans-fat

• Pharmacologic

– Low does statin – Different statin – Fenofibrate – Outcomes? Ezetimibe, resins, nicotinic acid

PICO Monitoring

What Who When Efficacy Toxicity

Myopathies Dr, Rx, Patient Ongoing -permanently resolved -reoccurrence ADR Rx, Patient Daily

• medication is daily
• unlikely

Adherence Dr, Rx, Patient Ongoing -patient adherence

• pharmanet support
• follow-up
• no benefit

from therapy CV event Patient Ongoing -event free

• ex. Stroke, MI

Questions to Ponder

• Vitamin D doses of “normal”
• Prescreen high risk patients for serum Vitamin D
• Other myopathies from medications
• Duration of vitamin D therapy
• Synergistic or additive statin/vitamin D effect
• Resuming statin (time frame, dosage)

The Take Away Message!

Questions

References:

1) Abd, T. T., & Jacobson, T. A. (2011). Statin-induced myopathy: a review and

• update. Expert opinion on drug safety, 10(3), 373-87.

2) Mammen, A. L., & Amato, A. A. (2010). Statin myopathy: a review of recent

• progress. Current opinion in rheumatology, 22(6), 644-50.

3) Glueck, C. J., Budhani, S. B., Masineni, S. S., Abuchaibe, C., Khan, N., Wang, P., & Goldenberg, N. (2011). Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance. Current medical research and opinion, 27(9), 1683-90. 4) Ahmed, W., Khan, N., Glueck, C. J., Pandey, S., Wang, P., Goldenberg, N., Uppal, M., et al. (2009). Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Translational research: the journal of laboratory and clinical medicine, 153(1), 11-6

References:

5) Lee, J.H., O’Keefe, J.H., Hensrud, D.D., & Holick M.F. (2008). Vitamin D deficiency: an important, common, and easily treatable cardiovascular risk factor? Journal of the American College of Cardiology, 52(24), 1949-56. 6) Lee, P., Greenfield, J. R., & Campbell, L. V. (2009). Vitamin D insufficiency--a novel mechanism of statin-induced myalgia? Clinical endocrinology, 71(1), 154-5. 7) Katsiki, C., Athyros, V. G., Karagiannis, A., & Mikhailidis,. (2011). Editorial: vitamin D deficiency, statin-related myopathy and other links with vascular

• risk. Current medical research and opinion, 27(9), 1691-92

8) Silva, M., Matthews M.L., Jarvis, C., et al. (2007). Meta-analysis of drug- induced adverse events associated with intensive-dose statin therapy. Clinical Therapeutics, 29(2), 253-60

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Statin MOA

Efflux/Update Transporters