Statins. In Utero to Death and Everything In-Between. Bryce M Kayhart, PharmD, BCPS MFMER slide-1

Statins In Utero to Death and Everything In-Between Bryce M Kayhart, PharmD, BCPS 2017 MFMER slide-1

Disclosures I have no financial relationships related to the material of this presentation to disclose. 2017 MFMER slide-2

A Brief History 2017 MFMER slide-3

Objectives 1. Review the evidence supporting the use of statins in primary and secondary prevention of cardiovascular disease. 2. Identify strategies to manage statin intolerance. 3. Review the evidence surrounding statin use in pregnancy and end-of-life. 2017 MFMER slide-4

A Brief History Acetyl-CoA + Acetoacetyl-CoA Statins HMG-CoA Mevalonic acid Squalene Lanosterol Cholesterol 2017 MFMER slide-5

A Brief History Statins were almost simultaneously discovered by Japanese (Endo, et al) and British (Brown et al) researchers in the 1970s, though Endo was the first to note HMG-CoA reductase as their target. Mevastatin, the compound isolated by both teams, was studied in dogs and later abandoned due toxicity. Lovastatin, isolated from Aspergillus terreus by researchers at Merck, became the first statin available for public consumption in 1987. Tobert JA. Nature Reviews Drug Discovery. 2003 2017 MFMER slide-6

The First Trials Hyperlipidemia was linked with cardiovascular disease by the Framingham Cohort Study. In the 1980s, other lipid-lowering drugs (cholestyramine, gemfibrozil) had been shown to modestly improve cardiovascular outcomes in patients with hyperlipidemia. Statins were known to substantially reduce blood LDL levels, but their effect on cardiovascular disease outcomes was unproven. The 4S trial was the first large, randomized, prospective clinical trial evaluating the efficacy of a statin 2017 MFMER slide-7

4S - The Beginning of an Era 4,444 patients with established cardiovascular disease randomized to receive placebo or simvastatin (10-40 mg daily for target total cholesterol 116-201 mg/dl). Patients were followed for a median of 5.4 years for the primary outcome, overall mortality. Mortality % of patients 15 10 5 RR 0.58 95% CI 0.46-0.73 8.5 9.3 5 RR 0.65 95% CI 0.52-0.80 6.1 RR 0.70 95% CI 0.59-0.75 11.5 8.2 Placebo Simvastatin 0 Coronary Cardiovascular Overall Scandinavian Simvastatin Survival Study Group. Lancet. 1994 2017 MFMER slide-8

Statins vs. Placebo 4S marked the beginning of a long string of large phase three and four clinical trials 4S HPS ALLIANCE CARDS JUPITER ASCOT-LLA Post-CABG WOSCOPS PROSPER CARE LIPID ASPEN AURORA AFCAPS LIPS GISSI-HF 4D ALERT MEGA ALLHAT-LLT GISSI-P 0.5 0.75 1 1.25 1.5 Cholesterol Treatment Trialists Collaboration. Lancet. 2010 2017 MFMER slide-9

Secondary Prevention Statins clearly benefit patients with established cardiovascular disease compared with placebo Overall mortality OR 0.82 (95% CI 0.75 0.90) Major coronary events OR 0.69 (95% CI 0.62 0.77) The benefits of high intensity statin therapy are generally considered to outweigh risks. Naci H, et al. Eur J Prev Cardiol. 2013 Cholesterol Treatment Trialists Collaboration. Lancet. 2010 2017 MFMER slide-10

Statins in the water? Regulatory bodies in three nations commissioned studies examining concentrations of pharmaceutical substances in public water sources. Compound Mean PECdw (mcg/l) MTD (mg) MOS Tetrahydrocannabinol 1.377 1 726 Total NSAIDs 2.74 7.5 2,737 Total Statins 1.27 5 3,937 Methadone 0.082 1 12,173 MTD = minimum therapeutic dose MOS = margin of safety Pharmaceuticals in Drinking Water. World Health Organization. 2011 2017 MFMER slide-11

Primary Prevention Unlike statin use in secondary prevention, the utility of statins in primary prevention of cardiovascular disease is controversial. Inconsistent mortality benefit Drug cost Adverse effects De-emphasis on lifestyle changes The current AHA guidelines utilize age, presence/absence of diabetes, and ASCVD risk score to determine whether patients qualify for statin treatment How accurate is the ASCVD risk calculator? 2017 MFMER slide-12

Primary Prevention The Multi-Ethnic Study of Atherosclerosis (MESA) found that the ASCVD risk calculator overestimated 10 year event rate by 86% in men and 78% in women. The number needed to treat in primary prevention studies ranges from forty to several hundred. Major point of controversy surrounding the 2013 guidelines recommendations DeFilippis AP, et al. Ann Intern Med. 2015 2017 MFMER slide-13

Primary Prevention Two Cochrane reviews, from 2011 and 2013, both support statin use in primary prevention of cardiovascular disease. 2011 2013 Although reductions in all-cause mortality, composite endpoints, and revascularizations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events, and inclusion of people with cardiovascular disease Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Reductions in all-cause mortality, major vascular events, and revascularizations were found with no excess of adverse events among people without evidence of CVD treated with statins. Taylor F, et al. Cochrane Database Syst Rev. 2011 Taylor F, et al. Cochrane Database Syst Rev. 2013 2017 MFMER slide-14

Questions # 1 Which of the following statements is true? 1. Statins lower the incidence of non-fatal MI, but do not reduce mortality in patients with cardiovascular disease. 2. The 2013 AHA guidelines recommend statins as secondary prevention of cardiovascular disease and as primary prevention in high risk individuals. 3. The risks of high intensity statin therapy are generally believed to outweigh the benefits in patients with established cardiovascular disease. 2017 MFMER slide-15

Adverse Effects 2017 MFMER slide-16

Case (Diabetes) CJ is a 62 year old male recently discharged from the hospital after suffering an acute MI. He was discharged with several new prescriptions, one of which is atorvastatin. He says to you, I just heard on the news that this drug will make me diabetic. I m already at risk because my parents were diabetic. What should I do? 2017 MFMER slide-17

Diabetes Multiple post-hoc analyses of landmark statin trials have noted a possible correlation between statin use and new-onset diabetes JUPITER brought this issue to the forefront. 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Jupiter 2.8 3 2.4 1.6 Primary Endpoint Incident Diabetes Rosuvastatin Placebo Ridker, et al. N Engl J Med. 2008 2017 MFMER slide-18

Diabetes A meta-analysis of 13 trials determined that the relative risk increase of new diabetes diagnosis with statin therapy is 9% (OR 1.09, 95% CI 1.02 1.17). NNH = 255 for four years Sattar N, et al. Lancet. 2010 2017 MFMER slide-19

Diabetes Not all statins appear to affect glucose metabolism similarly Pitavastatin and pravastatin appear to have neutral effects on new diabetes diagnoses and Hgb-A1c. Notably, these are the two statins metabolized independent of the CYP450 system Rajpathak SN, et al. Diabetes Care. 2009 2017 MFMER slide-20

Do Statins Worsen Pre-existing Diabetes? Author Statin N (statin) N (control ) HbA1c (statin) HbA1c (control Colhoun, et al Atorva 10 1428 1410 8.3 8.1 Knopp, et al Atorva 10 1211 1199 7.8 7.7 Neil, et al Atorva 20 169 166 7.4 7.0 T2DM Neil, et al Atorva 20 163 160 7.3 7.1 Behounek, et al. Prava 20 165 156 7.54 7.7 Freed, et al Atorva 10 77 67 7.2 7.0 Freed, et al Atorva 20 71 67 7.1 7.0 DALI Atorva 10 73 72 8.0 8.1 DALI Atorva 80 72 72 8.6 8.1 Subtotal - - - - - Tajima, et al. Prava 20 853 893 7.0 6.9 T1DM Collins, et al. Simva 40 544 543 7.14 7.17 Konduracka, et al Atorva 40 154 50 7.0 7.1 Subtotal - - - - - Overall 0.12 (95% CI 0.04 0.20) Erqou, et al. Diabetolgia. 2014-0.5-0.25 0 0.25 0.5 0.75 1.0 2017 MFMER slide-21

Statins and Diabetes: Summary Most (but not all) statins have been implicated in impaired glucose metabolism. The effect size is small and the number of cardiovascular events prevented by statin use exceeds the number of incident diagnoses of diabetes. Patients who place considerable value on avoid diabetes may be offered pravastatin or pitavastatin. Note that neither are high intensity statins. 2017 MFMER slide-22

CJ is back CJ comes to see you again. Good news, doc, I don t have diabetes yet. The bad news is that my entire body hurts. 2017 MFMER slide-23

Statin Intolerance Statin intolerance is an umbrella term for a variety of symptoms and clinical syndromes associated with statin use. Approximately 30% of statin users will experience muscle symptoms while taking statins. Muscle symptoms typically appear within 6 weeks of starting a statin, but may also occur at any time during treatment. Stroes ES, et al. Eur Heart J. 2015 2017 MFMER slide-24

Statin Intolerance Myopathy - generic term for muscle disease Myalgia - muscle symptoms with normal creatine kinase Myositis - muscle symptoms with elevated creatine kinase Rhabdomyolysis - muscle symptoms with creatine kinase > 10x ULN and acute kidney injury 2017 MFMER slide-25

Statin Intolerance Who s at Risk? Patient Risk Factors Age > 75 Female Asian descent Low BMI Excess physical activity Alcohol abuse Renal and/or hepatic dysfunction Treatment Risk Factors Lipid-soluble statins Simvastatin Lovastatin Atorvastatin Fluvastatin Statin dose CYP3A4 Inhibitors Stroes ES, et al. Eur Heart J. 2015 Mancini GB, et al. Can J Cardiol. 2013 2017 MFMER slide-26

Statin Intolerance Management Hold the statin for 4 weeks for patients with: Intolerable symptoms CK elevations > 3x ULN Check renal and hepatic function Thorough medication review to rule out drug interactions Mancini GB, et al. Can J Cardiol. 2013 2017 MFMER slide-27

Managing Statin-Induced Myopathy 50% of patients will tolerate a re-challenge of the same statin. For patients experiencing muscle symptoms with a lipid soluble statin, it is reasonable to rechallenge with a water soluble statin. Pravastatin, rosuvastatin Extended dosing Twice weekly rosuvastatin 10 mg has been shown to reduce LDL by 26% Similar to simvastatin 20 mg daily Mancini GB, et al. Can J Cardiol. 2013 2017 MFMER slide-28

Managing Statin-Induced Myopathy There is no evidence supporting the use of coenzyme Q-10 to treat or prevent statinassociated myopathy. As a rule, patients who experience rhabdomyolysis during statin treatment should have the statin discontinued and not rechallenged. Taylor BA, et al. Atherosclerosis. 2015 Mancini GB, et al. Can J Cardiol. 2013 2017 MFMER slide-30

Questions # 2 Which of the following statements is true? 1. Patients who have experienced statinassociated myopathy should never be rechallenged with the same statin. 2. Routine CoQ-10 supplementation is recommended for patients experiencing muscle weakness while taking a statin. 3. Holding statin therapy for two weeks and introducing pravastatin is reasonable for a patient experiencing myalgia on simvastatin. 2017 MFMER slide-31

Case CT is a 32 year old female admitted with chest pain. She has new ST-segment depression but troponins are negative. She is diagnosed with unstable angina. 139 4.2 100 26 14 1.0 92 Medications fexofenadine 60 mg daily PRN 14.8 14.1 293 45.2 Total Cholesterol: 432 mg/dl LDL: 289 mg/dl TG: 407 mg/dl hcg: 288,000 miu/ml 2017 MFMER slide-32

Case: Pregnancy All statins have two things in common Reduce cholesterol Pregnancy category X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on data from investigational marketing experience, and the risks involved in the use of the drug in pregnancy women clearly outweigh the benefit. 2017 MFMER slide-33

Statins and Pregnancy FDA s X-rating is derived from two animal studies in rats and rabbits. Minsker, et al. Rats received mevinolin at daily doses of 800 mg/kg on days 6-17 of gestation. Fetal malformations occurred in 29% of litters and included: Vertebrae malformations Rib malformations Gastroschisis Teratogenicity was suppressed by supplementing mevalonic acid. Minster DH, et al. Teratology. 1983 2017 MFMER slide-34

Statins and Pregnancy Dostal, et al. Rats received daily doses of 0, 10 mg/kg, 100 mg/kg, or 300 mg/kg on days 6-15 of gestation. No maternal or developmental toxicity observed in rats receiving 10 mg/kg or 100 mg/kg. Treatment related deaths, decreases in maternal food consumption, post-implantation loss, and decreased fetal body weight occurred in rats receiving 300 mg/kg. Rabbits received daily doses of 0, 10 mg/kg, 50 mg/kg, or 100 mg/kg on days 6-18 of gestation. Marked maternal toxicity and spontaneous abortion was frequent at 50 and 100 mg/kg doses. Dostal LA, et al. Teratology. 1994 2017 MFMER slide-35

Statins and Pregnancy Inadvertent fetal exposure to statins is becoming more common. Study Design n Statin Exposure Manson, et al, 1996 Trimester Case series 136 Lovastatin or simvastatin 1 st trimester in 89% Outcomes 85% normal births, 4% congenital anomaly, 8% spontaneous abortion, 1% stillbirth, 2% other Edison, et al, 2004 Case series (reports submitted to FDA) 52 Lovastatin, simvastatin, atorvastatin, cerivastatin 1 st trimester 17% fetal malformation Taguchi, et al, 2008 Cohort 64 (with matched controls) Atorvastatin, simvastatin, pravastatin, rosuvastatin 1 st trimester No difference in rate of congenital abnormalities (2.2% vs 1.9%, p = 0.93). Birth weight lower in statin group. 2017 MFMER slide-36

Bateman, et al. Investigators screened Medicaid-enrolled women aged 12-55 who completed pregnancies. A total of 886,996 completed pregnancies were identified. Pregnancies associated with chromosomal abnormalities and those in which the mother used known teratogenic drugs were excluded. Lithium, antineoplastic agents, retinoids, thalidomide Using pharmacy records, 1152 pregnancies were linked to 1 st - trimester statin use. Primary outcome: presence of one or more congenital malformation(s) in the infant Bateman, et al. BMJ. 2015 2017 MFMER slide-37

Bateman, et al. Baseline Characteristics Characteristics Statins (n = 1152) No Statins (n = 885,844) Age 35 359 (31.2%) 45,018 (5.1%) Pre-existing diabetes 520 (45.1%) 27,090 (3.1%) Hypertension 468 (40.6%) 44,248 (5.0%) Obesity 269 (23.4%) 47,003 (5.3%) Tobacco Use 127 (11.0%) 68824 (7.8%) Alcohol use 46 (4.0%) 23153 (2.6%) Antihypertensive use 619 (53.7%) 58,882 (6.7%) Bateman, et al. BMJ. 2015 2017 MFMER slide-38

Bateman, et al. Baseline Characteristics Propensity score matched cohort Characteristics Statins (n = 1109) No Statins (n = 3,327) Age 35 324 (29.2%) 974 (29.2%) Pre-existing diabetes 477 (43.0%) 1313 (39.5%) Hypertension 436 (39.3%) 1268 (38.1%) Obesity 262 (23.6%) 766 (23.0%) Tobacco Use 125 (11.3%) 368 (11.1%) Alcohol use 44 (4.0%) 147 (4.4%) Antihypertensive use 576 (51.9%) 1684 (50.6%) Bateman, et al. BMJ. 2015 2017 MFMER slide-39

Bateman, et al. Results Statin Use Congenital Malformations HR Diabetes Adjustment Propensity Score Stratified No Statins 31,416/885,844 Reference Reference Reference Statins 73/1,152 1.79 (95% CI 1.43-2.23) 1.34 (1.07 1.68) 1.07 (0.85 1.37) CNS Malformations, HR 1.76 (95%CI 0.64 4.86) Cardiac Malformations, HR 1.25 (95%CI 0.93 1.70) Respiratory Malformations, HR 1.02 (95%CI 0.25 4.09) Facial and lip Malformations, HR 1.58 (95%CI 0.39 6.30) Gastrointestinal Malformations, HR 1.02 (95%CI 0.49 2.14) Genitourinary Malformations, HR 0.29 (95%CI 0.09 1.01) Musculoskeletal Malformations, HR 0.91 (95%CI 0.48 1.72) Other Malformations, HR 0.65 (95%CI 0.21 1.99) Bateman, et al. BMJ. 2015 0.1 0.2 0.5 1 2 3 4 5 2017 MFMER slide-41

Statins and Pregnancy - Summary Statins pregnancy X designation is based on animal data in which the subjects received doses many time higher than therapeutic doses used in humans. Observational data has been inconsistent at best, but the largest published to date suggests that statins are not teratogenic to the extent previously believed. Currently, there is not enough data to support statin use in pregnant women. Human studies evaluating pravastatin for prevention of preeclampsia in high-risk pregnant women are currently underway. Bateman, et al. BMJ. 2015 Constantine MM, et al. Obstet Gynecol. 2013 2017 MFMER slide-42

Case (End of Life) 15 years later, CJ is now 77 years old. Unfortunately, he just received a terminal diagnosis and the rest of his life will be measured in months. 2017 MFMER slide-43

Kutner et al. Kutner et al. randomized 381 patients on statins who had life expectancies of 1-12 months to either stop or continue statin therapy for 1 year. Characteristic Discontinue Continue Total P value Male, n (%) 98 (51.9) 112 (58.3) 210 (55.1) 0.20 Age, mean (SD) 74.4 (11.7) 73.5 (11.5) 74.1 (11.6) 0.29 History of CVD, n (%) 111 (58.7) 110 (57.3) 221 (58.0) 0.78 Malignancy, n (%) 84 (44.4) 102 (53.1) 186 (48.8) 0.09 2017 MFMER slide-44

Kutner et al. 2017 MFMER slide-45

Kutner et al. Kutner et al. randomized 381 patients on statins who had life expectancies of 1-12 months to either stop or continue statin therapy for 1 year. Outcome Discontinue Continue P value 60 day mortality, n (%) 45 (23.8) 39 (20.3) 0.36 Median time to death, days 190 229 0.60 Cardiovascular event, n (%) 13 (6.9) 11 (5.7) 0.64 McGill COL Score, mean AUC 7.11 6.85 0.04 2017 MFMER slide-46

End-Of-Life Average cost saving per patient in the statin discontinuation group was $3.37 per day and $716 over the study period. Discontinue statins in everyone with life expectancy less than one year? 2017 MFMER slide-47

End-Of-Life In addition to reducing adverse cardiovascular outcomes, statins have also been shown to: Improve ischemic pain in patients with angina Improve functional outcomes after ischemic stroke Delay the onset of Alzheimer s dementia in at-risk patients Cannon CP, et al. N Engl J Med. 2004 Marti-Fabregas J, et al. Stroke. 2004 Wanamaker BL, et al. Clin Cardiol. 2015 2017 MFMER slide-48

End-Of-Life - Recommendations Primary Prevention Consider withdrawing statins from patients with life expectancy less than one year Secondary Prevention In patients with life expectancy of less than one year, consider continuing statins in those with ongoing chest pain or recent ischemic stroke. Consider discontinuing statins in patients with life expectancy less than one month or if you suspect adverse effects. 2017 MFMER slide-49

Questions # 3 Which of the following statements is true? 1. Statins have been shown to prevent the onset of diabetes. 2. On average, statins can be expected to increase HbA1c by 2-3%. 3. Of the available statins, pravastatin is the most likely to cause or worsen diabetes. 4. None of the above are true. 2017 MFMER slide-50

Questions # 4 Which of the following statements is true? 1. It is reasonable to discontinue primary preventative statin therapy in a 77 year old with a life expectancy of < 1 year. 2. The highest quality available evidence has failed to show teratogenicity of statin use during the first trimester. 3. Statins should be offered to pregnant women at high risk for cardiovascular events. 4. 1 & 2 are true. 2017 MFMER slide-51

Questions and Discussion kayhart.bryce@mayo.edu 2017 MFMER slide-52