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Safety and Tolerability of Maximizing Oral Hypocholesterolemic Agents in Treating Severe FH

Zuhier Awan, MD, PhD, FAACC, FRCPC, FAHA, FACE Consultant and Associate Professor of Medicine, Clinical Biochemistry and Molecular Genetic. Conflict of Interest

Advisory Board, Speaker’s Bureau Pfizer Amgen Amryt (Aegerion)

Outline Presentation

1. Tolerability of Lipid Lowering Drugs

2. Safety and Tolerability of

3. Safety of Maximizing and Combining 18 Y student No medical illness Hx of premature CAD BMI 18 LDL 8 mmol/L Oral Lipid Lowering Drugs

Patient Therapy TC LDL-C HDL-C TG Tolerability

Statins* 19 – 37% 25 – 60% 4 – 12% 14 – 29% Good

Ezetimibe  13%  18%  1%  9% Good

Bile acid  7 – 10% 10 – 18%  3% Neutral or  Poor sequestrants

Nicotinic acid 10 – 20% 10 – 20% 14 – 35% 30 – 70% Reasonable to poor

Fibrates 19%  4 – 8% 11 – 13%  30% Good

*Daily dose of 40 mg of each drug, excluding rosuvastatin Yeshurun D et al. South Med J 1995;88:379–391. | NCEP. Circulation 1994;89:1333–1445. | Knopp RH. N Engl J Med 1999;341:498–511. | Gupta EK et al. Heart Dis 2002;4:399–409. Mechanism of Action

LDL apoB100 X Statin X

VLDL apoB100 X Bile acid sequestrants X

CM Remnant CM apoB48 apoB48 Oral Lipid Lowering Drugs

Drug Class Agents Side Effects Drug Interaction

HMG CoA Rosuvastatin (2C9) and Myopathy, and Protease Inhibitor reductase Atorvastatin (3A4) increased liver Rosuvastatin and inhibitors LDL (18-60) and () and LDL (30-50)

Inhibitor of Ezetimibe Headache, GI Bile acid sequestrants (4 hours NPC1L1  LDL( 14-18) distress spacing) and Fibric acids (Ezetimibe)

PPAR alpha Dyspepsia, Gemfibrozil and Atorvastatin agonist, gallstones, hydrolyzes TG TG (20-50) myopathy in lipoproteins () Doses of Currently Available Statins Required for a 30% to 50% LDL-C Reduction

Lipophilic (CYP 3A4) O HO O • 20–40 mg simvastatin (Zocor)  35–41% O HO O

OH • 40 mg (Mevacor) 31% OH • 10 mg atorvastatin (Lipitor) 39% CH F 3 CH3 Lipophilic (CYP 2C9) N F CH 3 CH3 • 40–80 mg (Lescol) 25–35% O N N

HN N H3C S CH3 Hydrophilic O O • 5–10 mg rosuvastatin (Crestor) 39–45% • 40 mg pravastatin (Pravachol) 34%

Grundy SM, et al. Circulation. 2004;110:227–239.

Intensity of Statin Therapy

High Moderate Low  LDL-C ≥50%  LDL-C 30 to <50%  LDL-C <30% Atorva 40-80 mg Atorva 10 mg Simva 10 mg Rosuva 20-40 mg Rosuva 10 mg Prava 10-20 mg Simva 20-40 mg Lova 20 mg Pravas 40 mg Fluva 20-40 mg Lova 40 mg Pitava 1 mg Fluva XL 80 mg Fluva 40 mg bid Pitava 2-4 mg

Statins in bold were evaluated in randomized controlled trials; those in italics were not 2013 ACC/AHA Guideline on the Treatment of Blood to Reduce Atherosclerotic Cardiovascular Risk in Adults, p 34 Atorvastatin vs. Rosuvastatin Rosuvastatin Dosing Considerations in Specific Populations

• Asians • May have higher blood concentrations and more risk of side effects than Caucasians • Start with 5 mg daily; maximum of 20 mg daily

• Patients with renal impairment • Start with 5 mg daily; maximum of 10 mg daily

• Patients who are predisposed to myopathy • Start with 5 mg daily Crestor® [package insert]; 2008. Statin Drug Interactions: Labeled Contraindications for Lovastatin and Simvastatin

Lovastatin and simvastatin are contraindicated with:

• Erythromycin • Cyclosporine • Clarithromycin • HIV protease • Fluconazole (2C9) inhibitors • Ketoconazole • • Amidiodarone • Grapefruit juice

HIV = human immunodeficiency virus Mevacor® [package insert]; 2008. | Zocor® [package insert]; 2008. FDA Warning (March 2010 + May 2011)

• No Simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone. • No simvastatin >10 mg with gemfibrozil, cyclosporine, or danazol • No simvastatin >20 mg with amiodarone or verapamil • No simvastatin >40 mg with diltiazem • Patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of -containing products. • caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products 18 Y student No medical illness Hx of premature CAD BMI 18 LDL 8 mmol/L Outline Presentation

1. Tolerability of Lipid Lowering Drugs

2. Safety and Tolerability of Statin

3. Safety of Maximizing and Combining Question: How safe are statins? Statin Associated Muscle Symptoms SAMS

MYALGIA  Pain

MYOPATHY  Weakness

MYOSITIS  CK >10X ULN

RHABDOMYOLYSIS  CK >40X ULN Statin Safety in Perspective

Number Needed to Treat: for 1 year to

Cause a GI Bleed1 Cause a Fatal GI Bleed1

Aspirin 248 2066

Cause Severe Myositis2 Cause Fatal Myositis2

Statins 100 , 000 1,000,000

1Derry S, Loke YK. 2000 2Thompson PD, et al. 2003

Fatal Rhabodmyolysis

Staffa JA, Chang J, Green L. and reports of fatal . N Engl J Med 2002; 346: 539-40 In Summary…The Risk is Small!

73 cases of fatal rhabdomyolysis in

484,273,000 Statin prescriptions

In 2014: 15 – 20 million statin users

only 3 deaths

Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002; 346: 539-40 US population: ± 300 million Peanut allergy 1.4% of population: 4.2 million affected  150 fatalities/year

Question: Will patients tolerate statins? Muscle Related Side Effects Statins Intolerance

No serial measurement of CK

Journal of Clinical Lipidology (2014) 8, STOMP Study

420 healthy statin naïve subjects Atorvastatin 80 mg vs. Placebo 6 months

Criculation 2013; 127: 96 - 103 The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study

Atorvastatin 80 mg vs. placebo 6 MONTHS n=420 • Exercise capacity  No significant changes • Muscle strength  No significant changes •  19 vs 10 (p=0.05) • CK ≥10 x ULN  none

Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69).

Circulation. 2013;127:96-103 The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study

Circulation. 2013;127:96-103 Ann Intern Med. 2013;158:526-534. Discontinuation of Statins in Routine Care

Statin use 2000 - 2008 Brigham's And Women's hospital Boston 120000 %120 107835 100000 %100

80000 %80

60000 57292 %60

40000 %40 18778 20000 %20

0 %0 patients discontinued documented events Ann Intern Med. 2013;158:526-534. Discontinuation of Statins in Routine Care

Statin use 2000 - 2008 Brigham's And Women's hospital Boston 3000 2721 %120 Re-challenge in 6 579 patients 2500 93% were on statin after 12 months %100 2000 %80 1500 1295 %60 996 1000 %40 500 %20 0 %0 same statin same dosage higher dosage

Ann Intern Med. 2013;158:526-534. Lesson Learned Statin Myalgia Clinical Index Score

 Region  Time  De-challenge Statin Myalgia Clinical Index Score Probable 9-11 Possible 7-8  Re-challenge Unlikely <7 Risk Factors for Statin-Associated Muscle Symptoms

• Anthropometric • Concurrent conditions/medications • Surgery • Related history • Genetics (muscular dystrophy) • Other risk factors Evaluate Drug Interactions symptoms Follow-Up

http://www.acc.org/StatinIntoleranceApp Hepatic Safety of Statins United Network for Organ Sharing (UNOS) Database • From 1990 – 2002 in the US: 51 741 liver transplants • 3 cases of acute liver failure related to statins* • 2  Cerivastatin • 1  Simvastatin

• These studies were retrospective analyses. • Formal causality assessment of DILI and confirmation that cases were bona-fide cases of DILI from statins were not performed!

* Russo MW, Galanko JA, Shrestha R, et al. Liver transplantation from drug induced liver injury in the United States. Liver Transpl 2004; 10:1018– 1023. Lancet 2010; 367: 1916-1922 Activity During 3-year Follow-up in Patients with Raised Liver Enzymes Patients on statin treatment (n=227)

Patients not statin treatment (n=210)

Athyros, V. et al., Lancet 2010;376:1916-22. Cardiovascular Events in Patients with

Normal and Abnormal LFT’s

12 63 (30%) of 210 117 (23%) of 510 patients patients 10 68% RRR 10% 23% RRR 8 P<0.0001 p<0001 patient patient years 7,6% 6 22 (10%) of 227 90 (14%) of 653 Statin patients patients

100 100 Control 4 4,6% 2 3,2%

0

Event rate rate Event / Abn LFT Norm LFT

Athyros, V. et al., Lancet 2010;376:1916-22. Cardiovascular Events in Patients with

Normal and Abnormal LFT’s

12 63 (30%) of 210 117 (23%) of 510 patients patients 10 68% RRR 10% 23% RRR 8 P<0.0001 p<0001 patient patient years 7,6% 6 22 (10%) of 227 90 (14%) of 653 Statin patients patients

100 100 Control 4 4,6% 2 3,2%

0

Event rate rate Event / Abn LFT Norm LFT

Athyros, V. et al., Lancet 2010;376:1916-22. NAFLD at Baseline and Follow up

Risk reduction of moderate to severe hepatic steatosis: 70% !

36 44 27 35 27 32 Am J Gastroenterol advance online publication, Summary of studies using statin therapy for NAFLD

F, fibrosis; CT, computed tomography; IN, inflammation; N / A, not applicable; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steato hepatitis; RCT, randomized control trial; S, steatosis; US, ultrasound.

Am J Gastroenterol advance online publication, Use of Atorvastatin or Pravastatin in Patients with NASH

5 patients with NASH 20 mg Prava for 6 months1  Normalization of liver enzymes in all patients  Some improvement in hepatic inflammation and steatosis (liver biopsies)

7 patients with NASH 20 mg Atorvastatin 21 months (± 2 months)2  Well tolerated  No increase in liver enzymes  Significant improvement of hepatic histology in some patients

1. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174: 193-196. 2. Horlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH. Gastroenterology 2001;120:A544. Statins and Liver Disease

Decrease the risk of developing hepato-cellular carcinoma (HCC) 1 Improve portal pressure and risk for bleeding liver cirrhosis2 Double survival in HCC patients3 Inhibit hepatitis C viral replication and improve treatment response rates4,5

1. El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with . Gastroenterology 2009; 136:1601– 1608. 2. Kawata S, Yamasaki E, Nagase T et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. British Journal of Cancer (2001) 84(7), 886–891 3. Abraldes JG, Albillos A, Banares R, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009; 136:1651–1658. 4. Harrison SA, Rossaro L, Hu K, et al. Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy. Hepatology 2010; 52:864–874. 5. Rao GA, Pandya PK. Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C. Gastroenterology 2011; 140:144–152. Statins and Liver Safety No serial measurement of liver enzymes

Journal of Clinical Lipidology (2014) 8, Statins and Liver Safety

1. Comprehensive List of Causes for Elevated Liver Enzymes

2. Comprehensive approach to patients with elevated liver blood testing (transaminases ,3 times the upper limits of normal)

Journal of Clinical Lipidology (2014) 8, Renal Safety of Statins GREACE Study Design

N= 1600 LDL >100 6W

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228 GREACE: Atorvastatin vs. Usual Care and No Statins on Renal Function 15

+ Atorvastatin (n=783)

10

* + Statins (n=97) 5 * *

0

* – Atorvastatin (n=17)

-5 * Estimated CrCl Change (%) Change CrCl Estimated – Statins (n=703)

-10 0 1.4 6 12 18 24 30 36 42 48

Time (months)

*Time at which difference became significant (p<0.05) compared with baseline. Athyros VG, et al. J Clin Pathol. 2004;57:728-734 Published Atorvastatin Post-hoc CKD Analyses of Clinical Outcome Trials

% CV Event Change in Renal Study Population CKD reduction in CKD function Comments CARDS Diabetes 34% ▼48% (HR .52 ) ▲0.18 mL/m /1.73/m/y No reduction A 10mg vs (3.9yrs) MCVD, p = 0.03 P = 0.01 vs. placebo. albuminuria, placebo ▼61% (HR.39) Stroke, Greater improvement in No increase p=0.04 patients with albuminuria in CV events in CKD GREACE Secondary 6% HR 1.10 - 5%▼ CrCl UCp ▼5.3% CrCl (703) Used A 24mg vs. UC CHD HR .73 -10%, ▲ CrCl SC A ▲ 12% CrCl (783) CG CrCl (3yrs) TNT Secondary 32% ▼32% MCVE ▲ A 10 3.5 mL/m/ 1.73 35%▲ of A 80mg vs. CHD HR 0.68, p <0.0003 m2 5.6% MCVE in CKD A 10mg (5yrs) ▲ A 80 5.2 mL/m/ 1.73 m2 8.3% ALLIANCE Secondary 24% ▼28% CVE (HR, 0.72), ▲A 40 0.8 mL/m/1.73m2 41% ▲of CVE A 40mg vs.UC CHD (4.3yrs) p< 0.02 ▼UC -1.36 mL/m/1.73m2 in CKD IDEAL Secondary 26% No difference in MCE, CKD eGFR ▲ A 5.21 Reduced A 80mg vs. S CHD ▼Any CVE HR 0.84 ml/min,▲ S 4.30 ml/min compliance 20mg-40mg (4.8yrs) p=0.021, and ▼33% p=0.026). non-CKD ▲A with A, reduction in stroke 0.35 ml/min, ▼S especially in HR 0.67, p=0.027 -1.44 ml/min, P < 0.001 older patients Statin and the Risk of Renal-Related Serious Adverse Events:Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and Other Placebo-Controlled Trials

Bangalore S et. Am J Cardiol 2014 PLANET I: Prospective EvaLuation of ProteinuriA and ReNal Function in DiabETic Patients With Progressive Renal Disease

Rosuvastatin 10 mg

353 Patients Rosuvastatin 20 mg Rosuvastatin 40 mg

•Type 1 or 2 diabetes Atorvastatin 40 mg Atorvastatin 80 mg •Mild •Fasting LDL-C ≥90 mg/dL •Moderate proteinuria Weeks 0 4 52 •Receiving ACE inhibitor and/or Period 1 Period 2 ARB treatment for >3 months

PRIMARY END POINT: KEY SECONDARY END POINTS: • Change in urinary/creatinine • Assessment of relationship ratio from baseline to between renal effects and lipid Week 52 parameters from baseline to Weeks 26 and 52 • Change in GFR from baseline to Weeks 26 and 52

de Zeeuw D. European Renal Association — European Dialysis and Transplant Association Congress, Munich, Germany, June 27, 2010. PLANET I: Change in eGFR

Week 26 Week 52

0

-1 Summary of renal adverse NS* -2 NS* events (%)

P=0.03 -3 Crestor Crestor Lipitor 10 mg 40 mg 80 mg -4 P=0.01 Serum 0 6 0 -5 Cr X 2 P=0.0001

-6 ARF 0 5 1 Change in eGFR (mL/min) eGFR in Change Rosuvastatin 10/10 -7 Rosuvastatin 20/40 Atorvastatin 40/80 P=0.0002 -8

*Exact eGFR data not given for atorvastatin but stated as 1-2 and NS versus baseline.

de Zeeuw D. European Renal Association — European Dialysis and Transplant Association Congress, Munich, Germany, June 27, 2010. Chemical Differences may Lead to Renal Toxicity with Rosuvastatin

The sulfonamide group for rosuvastatin is unique among statins and may contribute to a higher renal rate that leads to renal toxicity

O HO O O HO O

OH OH

CH F 3 CH3 N F CH 3 CH3 O N N

HN N H3C S CH Sulfonamide 3 Group O O

Atorvastatin Rosuvastatin (IC50 = 8nM) (IC50 = 5nM) 58 More than 10% patients taking high dose rosuvastatin experience proteinuria Prevalence of proteinuria is similar in atorvastatin and placebo

12%

(%)

+

2 ≥

4% 4% Proteinuria Proteinuria 3% 2% 2% 2% 2% 2% 1% 1% 0.5% 0.6% 0.4% 0%

5 mg 10 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 20 mg 40 mg rosuvastatin atorvastatin simvastatin pravastatin

Source: AstraZeneca FDA Advisory Committee Presentation. July 9, 2003. Available at: http//www.fda.gov/ohrms/dockets/ac/03/slides/3968s1.htm.

Statins and risk of incident diabetes: a collaborative meta-analysis of RCT

13 trials 91 140 participants DM in 4278 (2226 statins/2052 controls)

. 9% ↑ risk for incident diabetes (95% CI 1·02–1·17) . ↑risk in older participants . = baseline body-mass index and change in LDL-cholesterol concentrations

Treatment of 255 (95% CI 150–852) patients with statins for 4 years resulted in one extra case of diabetes.

Lancet 2010; 375: 735–42 Statins and risk of incident diabetes: a collaborative meta-analysis of RCT

Lancet 2010; 375: 735–42 Statin Effects 9:1 Benefit?

Of 255 Patients Treated +1 case of diabetes

Of 255 Patients Treated -9 cases of CAD/CVA

Lancet 2010; 375: 735–42 Major Cardiovascular Events

Event rate was almost the same in patients with new onset diabetes compared to patients without diabetes at baseline

HR: 1.02, 95% CI: 0.77 to 1.35

J Am Coll Cardiol 2011;57:1535–45 Statin Induced Impairment of Glucose Metabolism

 Inhibition of glucose-induced signaling-dependent insulin secretion

 Decrease Ubiquinone and Mitochondral transport/ATP production/Reduced Insulin secretion

 Inhibition of the Isoprenylation of GLUT4 transporter

 Beta cell oxidation, oxidative stress and nitric oxide production

 Apoptosis and beta cell destruction from LDL entry

Sampson UK, Linton MF and Fazio S, Curr Opin Cardiol. 2011 ; 26(4): 342–347 Risk of New-Onset DM2 According to Number of Risk Factors at Baseline

1. Baseline glucose >5.6 mmol/l (100 mg/dl) 2. Fasting >1.7 mmol/l (150 mg/dl) 3. BMI >30 kg/m2 4. History of hypertension

J Am Coll Cardiol 2011;57:1535–45 Diabetes Risk Assessment Form Age Body Mass/Waist Diet / Exercise Anti medication History of elevated glucose Family history Circle Answers and add up the points

N.A. Sattar et al. / Atherosclerosis Supplements 15 (2014) 1e15 Other Drugs That Affect Glucose

 Atypical antipsychotics

 β-blockers

 Thiazide diuretics

 Protease inhibitors

 Niacin Statins and Diabetes

Journal of Clinical Lipidology (2014) 8, Statins and Cognitive Function

Cognitive side effects of statins may occur in rare individuals. The medical evidence supporting a causal effect is weak or nonexistent.

Journal of Clinical Lipidology (2014) 8, Outline Presentation

1. Tolerability of Lipid Lowering Drugs

2. Safety and Tolerability of Statin

3. Safety of Maximizing and Combining Statin Dosing Strategies

 Start with dose needed to give appropriate LDL-C reduction.  Doubling the statin dose provides up to 6% to 7% additional LDL-C reduction.  May need combination therapy to achieve goals.  Monitor for efficacy and safety.

Grundy SM, et al. Circulation. 2004;110:227–239. | Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. | Jones P, et al. Am J Cardiol. 1998;81:582–587. No dose or statin type No titration Therefore, it is advisable to stat the patient on the right dose from the beginning

Musculoskeletal Adverse Events With the 80-mg Dose

2006 Safety Analysis PROVE IT* IDEAL* TNT*

Atv 10 Atv 80 Prav 40 Atv 80 Simva 20 Atv 80 Atv 10 Atv 80 Reported AE (n=7258) (n=4798) (n=2063) (n=2099) (n=4449) (n=4439) (n=5006) (n=4995)

Myalgia 2.9% 2.7% NR NR 1.1% 2.2% 4.7% 4.8%

Myopathy 0 0.02%† NR NR 0.25%† 0.14%† 0.06% 0.04%

Persistent CPK 0 0.06% NR NR NR NR 0 0 >10 x ULN Rhabdomyolysis 0 0 0 0 0.07% 0.05% 0.06% 0.04%

NR, not reported *Studies not included in 2006 safety meta-analysis †Investigator-reported cases: did not meet criteria for definition of myopathy (persistent CPK elevations >10 x ULN with muscle symptoms)

Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al. JAMA. 2005;294:2437-2445.

Combination Drug Strategies May Be an Option for Some Patients

• Consider combination therapy if: • Higher statin doses are not well tolerated • Lipid goals are not met • Statins + bile acid resins or ezetimibe: • ↓ LDL-C >50% • Fibrates, niacin, omega-3 fatty acids: • ↓ Triglycerides and nonHDL-C • ↑ HDL-C • Combination therapy may increase risk for drug interactions

Vasudevan AR, Jones PH. Curr Cardiol Rep. 2005;7:471–479. Summary

1. Lipid-lowering drugs vary in their tolerability

2. Statin are very tolerable and powerful drugs

3. Maximizing and combining drugs are needed in FH Questions?