THE LATEST IN CARDIOVASCULAR RISK LIPID MANAGEMENT

Transcription

1 THE LATEST IN CARDIOVASCULAR RISK LIPID MANAGEMENT Thomas F. Whayne, Jr, MD, PhD, FACC Professor of Medicine (Cardiology) Gill Heart Institute University of Kentucky April (0 is the number zero) No conflicts whatsoever to declare.

2 Characteristics of Plaques Prone to Rupture From Inflammation and LDL Fibrous cap Media Lumen Lipid Core Vulnerable plaque Lumen Stable plaque Lipid Core T lymphocyte Macrophage foam cell (tissue factor) Activated Intimal SMC (HLA-DR+) Normal medial SMC Libby P. Circulation. 1999; 91:

3 Log-Linear Relationship Between LDL Relative Risk for CHD, Log Scale Levels and Relative Risk for CHD LDL-C, mg/dl LDL-C = low-density lipoprotein cholesterol; CHD = coronary heart disease. This relationship is consistent with a large body of epidemiologic data and data available from clinical trials of LDL-C lowering therapy. Goal for high CV risk is LDL < 70 mg/dl. These data suggest that for every 30 mg/dl change in LDL, the relative risk for CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL = 40 mg/dl. Reprinted with permission from Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110: ;

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6 ASTEROID STUDY, 2006 Atheroma Area mm 2 Baseline IVUS Exam Lumen Area 6.16 mm 2 Atheroma Area 5.81 mm 2 Follow-up IVUS 24 months rosuvastatin Lumen Area 5.96 mm 2

7 Residual Cardiovascular Risk Despite LDL-C Lowering Therapies based on LDL-C lowering reduce the risks of CAD 0 4S CARE WOSCOPS LIPID AFCAPS HPS PROSPER CARDS ASCOT 10 Relative risk reduction (%) % 24% 29% 24% 37% 24% 15% 37% 36% Despite the benefits of LDL lowering, 60-70% residual risk remains 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; WOSCOPS=West of Scotland Coronary Prevention Study; LIPID=Long-term Intervention with Pravastatin in Ischemic Disease; AFCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS=Heart-Protection Study; PROSPER=Prospective Study of Pravastatin in Elderly at RISK; CARDS=Collaborative Atorvastatin Diabetes Study; ASCOT-LLA=Anglo-Scand. Cardiac Outcomes Trial.

8 The Majority of Statin Monotherapy LDL Reduction Is Seen With the Initial Dose Pravastatin Simvastatin Atorvastatin Rosuvastatin 5 Mean change in LDL-C from untreated baseline, % % 4% 6% 28% 7% 4% 7% 37% 6% 5% 3% 46%*, 6% 3% 10 mg 20 mg 40 mg 80 mg *P<0.001 vs atorvastatin 10 mg; simvastatin 20 mg and 40 mg; and pravastatin 10 mg, 20 mg, and 40 mg. P=0.026 vs atorvastatin 20 mg Jones PH et al. Am J Cardiol. 2003;92:152.

9 Zetia: Recent Supporting Data. IMPROVE-IT: Modest Benefit When AddingEzetimibe to Statins in Post-ACS Patients, as reported at American Heart Association, Fall, 2014 and just published in New Engl J Med, June 2015.* Greater coronary plaque regression with atorvastatin/ezetimibe vs. atorvastatin alone in 2015 PRECISE-IVUS trial. # *Cannon CP, et al. N Engl J Med 2015;372: #Tsujita K, et al. J Am Coll Cardiol 2015;66:

10 IMPROVE-IT: 2016 ADDITIONAL ASSESSMENT IMPROVE-IT: TOTAL PRIMARY (FIRST) ENDPOINTs (PEP): CV death, MI, Stroke, Unstable angina with hospitalization, and Coronary revascularization.* Assessing total PEP more than doubled the number of events prevented compared to 1 st PEP with p< Further support for intensive lipid lowering in association with high CV risk. Challenges the premise of the 2013 ACC/AHA guidelines that LDL goal is not important compared to dose of statin. + *Murphy SA, et al. J Am Coll Cardiol 2016;67: Wright RS and Murphy J. J Am Coll Cardiol 2016;67:

11 SOME RECENT ISSUES, NEW APPROACHES, AND CONTROVERSIES IN CARDIOVASCULAR DISEASE PREVENTION

12 Summary of 2013 ACC/AHA Rx of Blood Cholesterol Guidelines* CV risk focused on 4 groups that appear to benefit from a statin. 1. Established clinical CV disease. 2. Documented LDL-C 190 mg/dl. 3. Presence of DM in patient aged yrs without clinical CV disease and LDL-C mg/dl. 4. Absence of Clinical CV disease or DM, LDL-C mg/dl, and estimated 10-yr CV risk 7.5%. Goal is to use high-dose statin to attain a significant LDL-C reduction of 50% from the untreated baseline without specifying a specific LDL-C target. Estimation of 10-yr CV risk by internet cohort equations. Future updates implied. *Stone NJ et al. J Am Coll Cardiol 2014;63:

13 Conflicts of Interest involving the 2013 ACC/AHA Guidelines British Med J* reported in 2013 that: One of 2 cochairs on panel had ongoing pharma ties. Other chair severed ties in 2008 and promised no pharma ties for 2 yrs after guideline release. Six other panelists had ongoing pharma ties. Therefore, on panel of 15, 8 had the appearance of possible conflicts. Unfortunately, in 2010, ACC specified that only 51% of writing committees have no pharma ties. # *Lenzer J. BMJ. 2013;347:f6989. # Quality-Standards/Relationships-With-Industry-Policy.aspx.

14 Other Blood Cholesterol Guidelines Other interested specialty organizations have not universally accepted the ACC/AHA 2013 Guideline: International Atherosclerosis Society in 2014 recommended optimal LDL-C < 100 mg/dl for primary prevention and LDL-C < 70 mg/dl for secondary prevention.* Amer. Assoc. of Clin. Endocrinologists # and Natl. Lipid Assoc.^ are opposed to removing LDL-C goals as per ACC/AHA, In 2011, Eur. Soc. Cardiol. and Eur. Atheroscler. Soc. published treatment targets, either/or, as follows: + LDL-C < 70 mg/dl for very high CV risk patient. A 50% decrease in baseline LDL-C of high CV risk patient. *Expert Dyslipidemia Panel. J Clin Lipidol 2014;8: ^Jacobsen TA. J Clin Lipidol 2014;8: # Miller N. Internal Medicine News, Jan 2014, page ESC/EAS Guidelines. Eur Heart J 2011;32:

15 HDL: GOOD, BUT CAN BE BAD HDL reverse transport appears beneficial. ApoA-1 Milano beneficial and can result in CHD plaque reduction.* Inflammation et al. (eg myeloperoxidase mediated oxidation) can change HDL structure and impair HDL function. # Increasing HDL is not a guarantee of CV benefit. No routine diagnostic assays of HDL function. Statins not HDL well; after 1 year, HDL may fall below starting baseline with atorvastatin. *Nissen SE, et al. JAMA 2003;290: # Fisher EA, et al. Arterioscler Thromb Vasc Biol 2012;32:

16 Niaspan Efficacy Combined Data from Pivotal Studies Change from Baseline % -5% -3% 16% -8% -12% -14% 21% -13% -17% -21% 24% -16% -25% -32% 30% 29% -22% -30% -39% 500 mg % -26% -44% HDL LDL Lp(a) TG Kashyap ML, et al. J Am Coll Cardiol 2000;35(SupplA):326A. Gotto AM. Am J Cardiol 1998;81:492.

17 Anacetrapib: A Cholesteryl Ester Transfer Protein (CETP) Inhibitor* Torcetrapib and Dalcetrapib out. Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE-phase 3). Anactrapib 100 mg daily vs. placebo: 76 weeks. HDL-C increased 138.1%. Anti-inflammatory properties of HDL not impaired. # LDL-C decreased 39.8%.* Non-HDL-C levels decreased 31.7%. Lipoprotein (a) reduced 36.4%. Good initial safety profile reported. A recent concern is detection of anacetrapib in the blood as much as 4 years later (likely due to uptake by fat). *Cannon CP, et al. N Engl J Med 2010;363: # Han S, et al. Biochim Biophys Acta 2013;183:

18 2013 FDA-Approved Orphan Drug Rx for Homozygous Familial Hypercholesterolemia Mipomersen (Kynamro /Genzyme): An antisense therapeutic. Targets messenger RNA for apo B. Administered by injection. No personal experience with this Rx.

19 2013 FDA-Approved Orphan Drug Rx for Homozygous Familial Hypercholesterolemia Lomitapide (Juxtapid /Aegerion). A microsomal triglyceride transfer protein (MTP or MTTP) inhibitor of VLDL assembly/secretion in liver. Daily oral dose of 10 to 60 mg. Special care with liver function. Bad personal experience including investigation of Aegerion Inc. by FBI.

20 PROPROTEIN CONVERTASE SUBTILISIN- LIKE/KEXIN TYPE 9 (PCSK9) ANTIBODY Normal function of PCSK9 is to decrease LDL receptor levels by binding to the receptor; i.e. negative feedback. With LDL receptors bound by PCSK9, there is an increase in LDL. A monoclonal antibody to PCSK9 can be highly specific and result in up to a 72% decrease in LDL.* Idea for possible monoclonal antibody for PCSK9: PCSK9 loss-of-function mutations that resulted in LDL. PCSK9 gain-of-function mutations that resulted in LDL. Administration is subcutaneous every 2 or 4 weeks. *McKenney J et al. J Am Coll Cardiol 2012;59:

21 Atherosclerosis Risk in Communities (ARIC) Findings* In blacks with nonsense mutations of PCSK9. a 40 mg/dl reduction of LDL = 88% CHD reduction. In whites with a different nonsense mutation of PCSK9. a 20 mg/dl reduction of LDL = 50% CHD reduction. *Cohen JC. N Engl J Med. 2006;354:

22 Patients With Double Loss-of-Function PCSK9 Mutations Two cases of homozygous loss-of-function mutations in PCSK9 have been described. 32-year-old woman with compound mutations, no measurable PCSK9, LDL-C of 14 mg/dl, was healthy and normotensive, and had normal liver and renal function year-old Zimbabwean black woman with homozygous C679X mutation of PCSK9 and LDL-C of 15 mg/dl. 2 One case with heterozygous mutations for 2 PCSK9 missense mutations, R104C and V114A, has been reported year-old French male hospitalized for new-onset diabetes, with no detectable PCSK9 levels, LDL-C of 16 mg/dl, apo B of 25 mg/dl, was healthy and had normal liver function. 1. Zhao Z et al. Am J Hum Genet. 2006;79: Hooper AJ et al. Atherosclerosis. 2007;193: Cariou B et al. Arterioscler Thromb Vasc Biol. 2009;29:

23 Key Points of PCSK9 Function* PCSK9 increases plaque vulnerability.* PCSK9 promotes proinflammatory LDL oxidation and plaque formation. PCSK9 inhibition is anti-inflammatory and may stabilize plaques. PCSK9 expressed in hepatocyte and to a lesser extent in the intestine and kidney.+ Expression modulated by same transcription factor that upregulates HMG-CoA reductase and LDL receptors, i.e. a response to cholesterol. *Navarese EP, et al. Ann Intern Med 2016;doi: /M McKenney JM. J Clin Lipidol 2015;9:

24 Key Points of PCSK9 PCSK9 expressed from single genetic locus.* Inactive PCSK9 translocated to endoplasmic reticulum for autocleavage by its convertase moiety to active PCSK9, which is then just a binding protein. Fenofibrate especially increases PCSK9 which may explain its decrease benefit for LDL.+ Statins cause a lesser and mainly transient increase in PCSK9 which may just be a response to the LDL receptors. *McKenney JM. J Clin Lipidol 2015;9: Costet P, et al. Atherosclerosis 1010;212:

25 How Low is Too Low? Epidemiologic studies show that people with naturally low LDL-C levels have improved longevity 1 Newborn human infant has LDL-C of approximately 30 mg/dl 2 Some findings suggests that LDL-C level of 25 mg/dl would be sufficient to nourish body with cholesterol 2 How Low is Too Low --- UNKNOWN 1. O Keefe JH et al. J Am Coll Cardiol. 2004;43: Brown MS, Goldstein JL. Science. 1986; 232: 34 47

26 Mechanism of PCSK9 Inhibitors. PCSK9 PCSK9 reduces LDL-C receptors and this reduction is decreased by PCSK9 Inhibitors LDL-C Receptor LDL-C Receptor LDL-C Receptor CELL

27 ODYSSEY LONG TERM: CONCLUSIONS* This large-scale trial of 2,341 high-risk patients provided data on the long-term efficacy and safety of alirocumab treatment over a 78 week period when added to a maximally tolerated dose of a statin with or without other lipid-lowering therapy. Overall, alirocumab reduced LDL-C levels by 62% vs. placebo at 24 weeks. LDL-C reduction in the alirocumab group was consistent over the 78-week treatment period. *Robinson JG, et al. N Engl J Med. 2015;372: ALI

28 ODYSSEY LONG TERM: OUTCOMES DATA* 2,341 HIGH CV RISK PATIENTS ON MAX. STATIN RECEIVED ALIROCUMAB 150 mg vs PLACEBO EVERY 2 WEEKS FOR 78 WEEKS. LDL DECREASED 62% BY ALIROCUMAB. MACE: CAD DEATH, NONFATAL MI, FATAL/NONFATAL STROKE, UNSTABLE ANGINA. MACE (ALIROCUMAB): 1.7%. MACE (PLACEBO): 3.3% (p=0.02). *Robinson JG, et al. N Engl J Med. 2015;372:

29 OSLER: OUTCOMES DATA WITH EVOLOCUMAB* OSLER REPORTED DURING 1 YEAR THAT EVOLOCUMAB WITH STANDARD Rx vs. ONLY STANDARD Rx, SIGNIFICANTLY REDUCED LDL AND ALSO SIGNIFICANTLY DECREASED CV EVENTS DESCRIBED BY THE AUTHORS AS A PRESPECIFIED BUT EXPLORATORY ANALYSIS. *Sabatine MS, et al. N Engl J Med. 2015;372:

30 Summary of Adverse Events Number of patients (%)* Alirocumab (N=1550) Placebo (N=788) P-value Any adverse event 1255 (81.0) 650 (82.5) 0.40 Serious adverse event 290 (18.7) 154 (19.5) 0.66 Adverse event leading to studydrug discontinuation 111 (7.2) 46 (5.8) 0.26 Adverse event leading to death 8 (0.5) 10 (1.3) 0.08 Neurocognitive effects have been main concern but occurrence versus placebo has been very minimal.+ Any cerebral expression of PCSK9 is insignificant. *Robinson JG, et al. N Engl J Med 2015; 372: Swiger KJ and Martin SS. Drug Saf 2015;38: ALI

31 Specific FDA PCSK9 Inhibitor Approvals (Similar in Europe) FDA: alirocumab 1. HeFH patients on maximum tolerated statin therapy.* 2. Provable cardiovascular atherosclerotic disease with additional LDL-C lowering indicated.* mg every 2 weeks. FDA: evolocumab 1. HeFH and HoFH.# 2. Provable cardiovascular atherosclerotic disease with additional LDL-C lowering indicated.# mg every 2 weeks or 420 mg every month. * + guidetoprescriptiondrugs.com/article/repatha-evolucomabfirst-pcsk9-inhibitor-world-approved-europe. #

32 PATIENT OF MINE FROM TOLUCA, MÉXICO A 32 yo Mexican male with acute myocardial infarction (STEMI) involving LAD artery. Atorvastatin 80 mg per day prescribed in hospital before cath. and stent placement. Referred to me for consultation and follow up; on the atorvastatin, LDL-C 131 mg/dl. Ezetimibe decreased the LDL-C to 100 mg/dl. Alirocumab 75 mg sc q 2 weeks added and after approximately 3-4 weeks, LDL-C 75 mg/dl; significant further LDL-C decrease expected. Working full time in construction.

33 Patient RI. LAD lesion. Very aggressive LDL lowering and essentially no angina. (never forget atherosclerosis as a metabolic disease)

34 CONCLUSIONS LDL-C is still the gold standard of cardiovascular (CV) risk and it is essential to make it the target of treatment. Statins still initial standard of care. Ezetimibe has been subjected to ENHANCEd hype. Newest medications place focus on marked LDL-C reduction, especially PCSK9 inhibitors. The treatment of HDL may be next major focus in the reduction of CV risk but still no major Rx ready. Failure to treat and decrease LDL-C in a patient with high primary or secondary CV risk, without a specific reason, is malpractice.