Targeting Lipids Strategies for Patients with Cardiometabolic Risk

Targeting Lipids Strategies for Patients with Cardiometabolic Risk

Faculty Disclosure David G. Carmouche, MD Director, Center for Cardiovascular Disease Prevention Baton Rouge Clinic ASH Specialist in Clinical Hypertension Diplomate, American Board of Clinical Lipidology COSEHC CME Committee Consultant: NovoNordisk, Abbott Labs, Bristol-Myers Squibb Speaker s Bureau: Takeda, Abbott, Kowa/Lilly

Objectives Describe the practical limitations of individual risk stratification using LDL-C Understand the basic pathophysiology of the common dyslipidemia seen in patients with cardiometabolic risk Explore the value of apob or non-hdl-c as important targets of lipid-modifying therapies Review important recent clinical trials which focus on the role of combination lipid therapy Propose a possible treatment algorithm Briefly review new statin label changes

Lipid Levels in 136,905 Patients Hospitalized with CAD Get With the Guidelines CAD Program LDL-C levels >130 mg/dl (23.1%) <100 mg/dl (49.6%) <70 mg/dl (17.6%) Mean LDL-C 104.9 + 39.8 mg/dl About half admits at NCEP ATP III goal Am Heart J 2009;157:111-7.e2.

LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000-2006 LDLC (mg/dl) < 100 100-129 130-159 > 160 Sachdeva et al, Am Heart J 2009;157:111-7.e2.

INTERHEART Study Population Attributable Risk, % Lancet. 2004 Sep 11-17;364(9438):937-52.

Focus on Lipoproteins

Dyslipidemia

A Common Phenotype Metabolic syndrome Type 2 DM PCOS NASH Familial combined hyperlipidemia Lipodystrophy (HIV)

Relationship Between LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides: The Framingham Offspring Study LDL Particles (nmol/l) 1800 1600 1400 1200 1000 LDL Particles LDL Cholesterol 180 160 140 120 100 1800 1600 1400 1200 1000 LDL Particles LDL Cholesterol 180 160 140 120 100 LDL Cholesterol (mg/dl) 20 40 60 80 100 HDL Cholesterol (mg/dl) 0 100 200 300 400 Triglycerides (mg/dl) HDL = high-density lipoprotein; LDL = low-density lipoprotein Reprinted from Otvos JD, et al. Am J Cardiol 2002;90:22i-29i, with permission from Elsevier Limited.

Understanding ApoB/ApoA1 and Non-HDL-C Non-HDL-C. Walldius G, Jungner I, Eur Heart J 2005;26:210-212

Non HDL-C Is Superior to LDL-C in Predicting CHD Risk Within non HDL-C levels, no association was found between LDL-C and the risk for CHD In contrast, a strong positive and graded association between non HDL-C and risk for CHD occurred within every level of LDL-C Non HDL-C is a stronger predictor of CHD risk than LDL-C Relative CHD Risk <130 130-159 160 <160 190 160-189 Non HDL-C, mg/dl Liu J, et al. Am J Cardiol. 2006;98:1363-1368.

ADA/ACC 2008 Consensus Statement Treatment Goals in Patients with Cardiometabolic Risk and Lipoprotein Abnormalities LDL-C Non-HDL-C ApoB Highest Risk Patients <70mg/dL <100 mg/dl <80mg/dL Known CVD DM + 1 additional major CV risk factor * High Risk Patients <100mg/dL <130mg/dL <90mg/dL No DM or known CVD but > 2 major CV risk factors DM but no other major CV risk factors * Major CV risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD. Brunzell JD, et al. Diabetes Care. 2008;31:811-822

2009 Canadian Cholesterol Guidelines Target lipid levels Primary targets Risk level Initiate treatment if: LDL-C Alternate High CAD, PVD, atherosclerosis Most patients with DM FRS>20% RRS>20% Consider treatment in all patients <2 mmol/l or >50% LDL-C Class 1, level A apob<0.80 g/l Class 1, level A Moderate FRS 10-19% LDL-C>3.5 mmol/l TC:HDL-C>5.0 Hs-CRP>2 mg/l Men>50 Women>60 Family Hx and hs-crp modulates risk (RRS) <2 mmol/l or >50% LDL-C Class 2a, level A apob<0.80 g/l Class 2a, level A Low FRS <10% LDL-C>5.0 mmol/l Can J Cardiol. Vol 25, No. 10, October 2009 >50% LDL-C Class 2a, level A

Relating LDL-C to non-hdl-c and apob Mayo Clinic Proceedings May 2010 vol. 85 no. 5 440-445

Effect of Statin Therapy Mayo Clinic Proceedings May 2010 vol. 85 no. 5 440-445

Barriers to Effective Non-HDL-C Treatment Knew that non-hdl could be calculated from a standard lipid panel Could calculate non-hdl from lipid panel Knew non-hdl treatment goals Aware that non-hdl is a secondary target Am J Med. 2011 Sep;124(9):876-80.e2 0% 10% 20% 30% 40% 50% 60% 70%

Proportion of CHD patients attaining goals for LDL-C, and in patients with high TG, combined goals for LDL-C and non- HDL-C ATP III goals * CHD patients (n=22,817) n (%) Overall cohort with LDL-C at goal 18,549 (81%) Subset of patients with TG >200 mg/dl 3,893 (17%) Both LDL-C and non-hdl-c at goal 1,997 (51%) LDL-C at goal 2.901 (75%) Non-HDL-C at goal 1,998 (51%) * LDL-C goal <100 mg/dl; in patients with TG >200 mg/dl, non-hdl-c goal <130 mg/dl Virani SS, et al. Am Heart J. 2011 Jun;161(6):1140-6. Epub 2011 May 11

Factors Associated with Dual Goal Attainment Significant Older age (65-74 yo) Diabetes Obesity Higher number of primary care visits Mild increase in illness severity of patients in provider s panel African American (less likely to achieve goals) Not significant Receipt of care from MD vs. non-physician Specialist vs. primary care Number of patients in provider s panel Percentage of patients with hyperlipidemia diagnosis Virani SS, et al. Am Heart J. 2011 Jun;161(6):1140-6. Epub 2011 May 11

Ezetimibe + Statin?

Is Ezetimibe a Reasonable Option? Arbiter 6 Trial J Am Coll Cardiol 2010; DOI: 10.1016/j.jacc.2010.03.017 Long acting niacin was superior in effects (positive lipid changes in HDL-C) compared to ezetimibe when combined with simvastatin on Carotid IMT. Sands Trial J Am Coll Cardiol 2008; 16; 52:2198-2205 Type 2 DM Native American trial with benefit of LDL < 70 whether ezetimibe given with or without simvastatin on Carotid IMT. Seas Trial N Engl J Med 2008; DOI: 10.1056/NEJMoa0804602 No improvement with ezetimibe, and raise question associated cancer risk which was later disproved. Enhance Trial N Engl J Med 2008; 358:1431-1443 No improvement (Carotid IMT) with ezetimibe, but disease burden too low

Study of Heart and Renal Protection (SHARP) 9270 patients with CKD either on dialysis or with a creatinine of >1.7 in men or >1.5 in women Assigned simvastatin/ezetimibe 20/10 mg or placebo Primary endpoint: first major atherosclerotic event (nonfatal MI, coronary death, nonhemorrhagic stroke, or any revascularization) Active treatment reduced primary endpoint by 17% 25% reduction in nonhemorrhagic stroke 21% reduction in revascularization 27% reduction in coronary revascularization Trend toward reduction in MI Lancet 2011; DOI 10.1016/S0140-6736(11)60739-3

Fibrate + Statin?

ACCORD Trial Lipid Arm Inclusion criteria T2DM with A1c >7.5 Age 40-79 if clinical CVD Age 55-78 if subclinical CVD or 2+ risk factors LDL-C 60-180 HDL <55 (women, blacks) HDL <50 (all others) TG <770 (if on no therapy) TG <400 (on therapy) Intervention Open label simvastatin + placebo or fenofibrate Baseline lipids TC 175 LDL 100 HDL 38 TG 162 (non-hdl 127) N Engl J Med 2010; 362:1563-1574

ACCORD Lipid: Primary Outcome Major Fatal or Non-fatal Major Cardiovascular Events HR (95% CI) 0.92 (0.79-1.08) P=0.32 HR (95% CI) 0.91 (0.75-1.10) P=0.33 N Engl J Med 2010; 362:1563-1574

Niacin + Statin?

AIM-HIGH Trial 3414 patients with CHD, low HDL, and raised TG All patients received simvastatin with or without ezetimibe to maintain LDL <80 mg/dl Randomized to placebo vs. 1500-2000 mg niacin ER Niacin increased HDL from 35 to 42 mg/dl Triglycerides lowered from 164 to 122 mg/dl LDL lowered from 74 to 62 mg/dl Trial stopped early due to futility and signal of excess ischemic CVA in niacin arm Final adjudication of stroke data showed non-statistical trend (P=0.11) N Engl J Med 2011; DOI: 10.1056/0a1107579

AIM-HIGH Results End points Niacin(%) Placebo(%) HR(95% CI) P Primary end point 16.4 16.2 1.02(0.87-1.21) 0.80 CHD death/nonfatal MI/ischemic CVA/ high-risk ACS 9.3 10.0 1.08(0.87-1.34) 0.49 CHD death/nonfatal MI/ischemic CVA 8.1 9.1 1.13(0.90-1.42) 0.30 N Engl J Med 2011; DOI: 10.1056/0a1107579

Understanding AIM-HIGH Baseline lipids TC 141 LDL 71 HDL 35 TG 161 Non-HDL 106 apob~80 Background therapy Previously on a statin (94%); statin > 1 year (76%) ACE/ARB (75%) Beta blocker (80%) ASA (98%)

JUPITER: HDL-C, apoa1 Ridker P, et al. Lancet 2010.(376)333-339.

Omega-3 + Statin?

Eicosapentaenoic acid (EPA) (1.8 g/d) reduced the incidence of major adverse coronary events in the Japan EPA Lipid Intervention Study (JELIS) RR 19% Prava 10 or simva 5 mg for all Randomized to PBO or EPA Average baseline LDL-C 183 mg/dl LDL-C reduced 25% in both arms Lancet. 2007;369(9567):1090-1098

STATIN <50 % LDL reduction needed to get to goal Simvastatin 40 Pravastatin 40-80 Lovastatin 40-80 Fluvastatin XL 80 Pitavastatin 2-4 >50 % LDL reduction neede to get to goal Atorvastatin 40-80 Rosuvastatin 20-40 Simvastatin/ezetimibe 10/20-10/40 Proposed Patient Treatment Algorithm - LIPIDS Primary Rx Intensification Rx Intensification Rx F/U 4-6 weeks Lab: lipids LDL-C not at goal Change to atorva, rosuva, simva/eze at max tolerated dose If on max tolerated dose of potent statin add ezetimibe 10, or Colesevelam 3.75 gram packet or three 625 mg tabs bid (especially if Hgb A1c > 6.5%) F/U 4-6 weeks Lab: lipids LDL-C at goal non-hdl-c not at goal apob not at goal LDL-P not at goal Fenofibrate (variety of dosages depending on product used) or fenobric acid 45-135 mg Niacin ER 500-2000 mg Omega-3 FA 1800-3400 mg EPA+DHA TIPS Statin-intolerant Patients Check TSH, 25-OH Vit D and correct deficiency Fluvastatin XL 80 least likely to cause myalgia Rosuva 2.5 mg 2-3 days/week CoQ10 200 mg/day Optimal dosing Bedtime: Prava, fluva Supper: Simva, lova Anytime: Atorva, rosuva, pitava TIPS Colesevelam Lowers glucose Raises TG when baseline TG > 500 Can bind other meds take 1 hour after or 4 hours before other meds Ezetimibe Avg LDL reduction 20-25% on top of statin Greater than expected response suggests low fat diet particularly helpful TIPS apob available through most national reference labs and through Atherotech (VAP test) LDL-P available through Liposcience as part of Lipoprofile Figure 2

Proposed Patient Treatment Algorithm - LIPIDS Agent Precautions Lab F/U LDL-C at goal But non-hdl-c not at goal apob not at goal LDL-P not at goal Fibrate: Event reduction in patients with TG > 200, HDL < 35; microvascular protection (retinopathy, proteinuria) Niacin ER: Decrease in recurrent non-fatal MI, plaque regression. lowers lipoprotein(a), potent effect on Lp- PLA2 Omega-3 FA: Event reduction in one study of CHD pts on statin; important to dose based on EPA+DHA content: 10% TG lowering per 850 mg EPA+DHA Cautions: creatinine can increase; myopathy risk; gallstones; potentiates warfarin; pancreatitis; thromboembolic events Cautions: cutaneous flushing; increase uric acid (gout); hyperglycemia; dyspepsia; can worsen atrial arrhythmias Cautions: dyspepsia; diarrhea; fishy odor or after-taste; mercury content Labs every 4-6 months: lipid panel, AST. ALT, CPK, creatinine If gemfibrozil has to be used for formulary issues only statin with which it can be used safely is fluvastatin Labs every 4-6 months: lipid panel, AST, ALT, glucose, Hgb A1c, uric acid Flushing management: ASA 325 mg 30 min. prior to dose; take at bedtime; lowfat snack; encourage compliance as flushing recurs when drug restarted; benadryl 25 mg + ibuprofen gel cap as bail -out therapy Labs every 4-6 months: lipid panel Lovaza is prescription O-3-FA; capsules can be frozen to decrease GI side effects; no effects on bleeding as previously thought

Proposed Patient Treatment Algorithm - LIPIDS To prevent acute pancreatitis Exclude common offending agents: Patient s Initial TG > 500 mg/dl Oral estrogens (patch, shot OK) Alcohol Corticosteroids Thiazide diuretics First and second generation betablockers (atenolol, propranolol, bisoprolol, pindolol,metoprolol) Carvedilol and nebivolol may be OK Exclude undiagnosed or under-treated diabetes: Check fasting glucose, Hgb A1c, 2 hr glucose after 75 g glucose (2 regular Cokes) diabetes if > 200 mg/dl Avoid all alcohol Weight loss Minimize saturated fat, simple sugars/carbs Treat diabetes aggressively Start fibrate or highdose Omega-3-FA (1700-3400 mg DHA+EPA) Re-evaluate labs q 2-4 weeks until at goal Once TG < 500, treat per LDL-C goal

QUESTIONS??