Update in Lipid Management Rameshkumar Raman M.D. Endocrine Associates of The Quad Cities
Low-Density Lipoprotein (LDL) Consists of Multiple Distinct Subclasses Differing in Size and Lipid Content* Association with Cardiovascular Disease Risk Large 1 2 Weaker Small 3 4 Stronger * Distribution of subclasses is independent of LDL-cholesterol. Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379. Reduced clearance Greater entry into artery Greater retention Faster oxidation ATP III Update LDL-cholesterol Recommendations Risk Category 10 yr Risk % Very high >>20 High 20 Features ACS CHD + 1RF CHD + poor control RFs CHD + Metabolic syn CHD CHD Equivalents 2 RFs Goal mg/dl Option mg/dl <70 -- <100 <70 Moderately high 10-19 2 RFs <130 <100 Moderate 5-9 2 RFs <130 -- Low <5 1 RF <160 -- Circulation 2004: 110:227-239
Modified ATP III LDL-C Guidelines Low (<5%) CHD Risk Intermediate (5-9%) Moderately High (10-19%) High (>20%) Very High (ACS) <160 <130 LDL-Cholesterol Goals <130* * Treat other lifestyle risk factors, metabolic syndrome # Use non-hdl-c for additional drug treatment <100* # <70* # Circulation, July 13, 2004; 110:227-239 ATP III. NIH publication 01-3095.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. ATP III: Additional CHD Risk Factors
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. Δ mmol/l kg of Weight Loss Plasma Lipids Improve with Weight Loss Meta-analysis of 70 Clinical Trials 0.02 0.00-0.02-0.04-0.06 *P<0.05. Total Cholesterol * LDL-C TG HDL-C (weight stable) * HDL-C (actively losing) LDL-C=low density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; TG=triglycerides Dattilo et al. Am J Clin Nutr 1992;56:320. * * * 0.5 0.0-0.5-1.0-1.5-2.0-2.5 Δ mg/dl per kg of Weight Loss
Impact of Weight Loss on Risk ~5% Factors HbA1c Blood Pressure Weight Loss 1 2 5%-10% Weight Loss 1 2 Total Cholesterol HDL Cholesterol Triglycerides 3 3 3 3 4 1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753. 2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278. 3. Blackburn G. Obes Res. 1995;3 (Suppl 2):211S-216S. 4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270. Statins: Mechanism of Action Cholesterol synthesis Intracellular Cholesterol LDL receptor (B E E receptor) synthesis VLDL R LDL Apo B Apo E Apo B VLDL LDL receptor mediated hepatic uptake of LDL and VLDL remnants Serum LDL-C Serum VLDL remnants Serum IDL Hepatocyte Systemic Circulation Reduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-hdl particles from the systemic circulation.
Potential Time Course of Statin Effects LDL-C Inflammation lowered* reduced Vulnerable plaques stabilized Endothelial function restored Ischemic episodes reduced Cardiac events reduced* Days * Time course established Years Relation Between CHD Events and LDL-C Outcomes in Statin Trials 30 % with CHD event 10 CARE-Rx LIPID-PI WOSCOPS-PI PI=placebo Rx=treatment 150
No. of Events RRR, % ARR/1000 NNT P PI Statin (95% CI) (95% CI) (95% CI) Value CHD Risk Reduction with Statin Therapy Relative Risk Reduction (%) Endpoints +20 0 5 10 15 20 25 30 35 40 45 50 Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events Total mortality Strokes Intermittent claudication Angina La Rosa JC et al. JAMA 1999;282:2340-2346. Crouse JR III et al. Arch Intern Med 1997;157:1305-1310. Pedersen TR et al. Am J Cardiol 1998;81:333-335.
ATP III Treatment Priorities Reduce LDL-C to goal (new goals) Correct residual lipid/lipoprotein abnormalities( non-hdl-cholesterol) Address the metabolic syndrome Options for reducing LDL-cholesterol Statins Cholesterol absorption inhibitors Bile acid binding resins Niacin Stanol/sterol products
What factors should influence selection of a statin? Potency Safety Cost: level pricing Efficacy in reducing CV events Not, pleiotropic properties The LDL-C Lowering Efficacy of the Currently Available Statins Daily Dose Atorva/ Rosuv Fluva Lova Prava Simva 10 mg 20 mg 40 mg 80 mg 39%/ 43% 43%/ 48% 50%/ 53% 60%/ 58% 22% 30% 22% 27% 32% 38% 25% 32% 34% 41% 36% 42% 47%.
How low a LDL-C is safe? Newborn LDL-C is 35-50 mg/dl LDL Rc is high affinity Patients with hypobetalipoproteinemia are healthy and have enhanced survival * * * *P<0.001 compared to No/No patients. Adapted from Fonarow GC et al. Am J Cardiol. 2005;96:611-616.
1.5 1.3 1.1 0.9 0.7 0.5 0 0 1 1 2 2 3 3 4 4 5 5+
What are the options when statin therapy does not get the LDL-C to goal? Treatment intensity related to risk Increase dose, if therapeutic range permits Add Zetia or resin Add plant stanol/sterol products If other lipid abnormalities present add: Fibrates or niacin Ezetimibe (Zetia TM ) Inhibits cholesterol absorption Mono or combination therapy MonoRx/added to statin: ~ 20 % LDL-C VYTORIN (Z+Z); 10mg Z+10mg Z= 80mg Z Lower statin doses: 10mg L+10mg Z = 80mg L Minimal effect on TG and HDL-C
Bile Acid Resins: Mechanism of Action Gall Bladder Cholesterol 7-α7 hydroxylase Conversion of cholesterol to BA BA Secretion Terminal Ileum BA Excretion Bile Acid Enterohepatic Recirculation Reabsorption of bile acids LDL Receptors Liver VLDL and LDL removal Net Effect: LDL-C Clinical Features of BARs Products available: Cholestyramine (Questran), 4 164 g/d Colestipol (Colestid), 5 205 g/d Colesevelam (WelChol) 625 mg tablets, 6 76 7 tablets/d Reduce coronary events (LRC-CPPT) CPPT) Adverse effects GI intolerance: constipation, bloating, abdominal pain, flatulence Lack systemic toxicity Drug interactions (colestipol and cholestyramine) Bind other negatively charged drugs Impede the absorption of drugs and/or fat-soluble vitamins Must give other drugs 1 hour before or 4 64 6 hours after
Change in LDL-C Effect of Colesevelam on LDL-C (N=494 patients with baseline LDL-C C of 130 220 mg/dl and TG <300 mg/dl; after 24 weeks of therapy) 0% -5% -10% -15% -20% Placebo 0% 3.8 g/d 4.5 g/d 15% Davidson MH et al. Expert Opin Investig Drugs 2000;9:2663-2671. Reprinted with permission from Ashley Publications. 18% Mean Percent Change 0% -10% -20% -30% -40% -50% Simvastatin Alone and with Colesevelam: Percent Change in LDL-C (n=258 patients with baseline LDL-C C 160 220 mg/dl; treated for 6 weeks) 4% * 26% * 34% * * 42% 42% * p<0.05 vs placebo Knapp HH et al. Am J Med 2001;110:352-360. Reprinted with permission from Excerpta Medica Inc. Placebo Simvastatin 10 mg Simvastatin 20 mg Colesevelam 2.3 g + Simvastatin 20 mg Colesevelam 3.8 g + Simvastatin 10 mg
Nicotinic Acid: Mechanism of Action Mobilization of FFA TG synthesis Liver Apo B VLDL Hepatocyte VLDL secretion VLDL LD L Serum VLDL results in reduced lipolysis to LDL Serum LDL HDL Circulation Systemic Circulation Decreases hepatic production of VLDL and of apo B Clinical Features of Nicotinic Acid Products available (daily dose) Immediate-release, 2 42 4 g/d Extended-release (Niaspan ), 1 21 2 g/d OTC products, sustained-release, 2 2 g/d Best agent to raise HDL-C Reduces coronary events (Coronary Drug Project) Adverse effects Flushing, itching, headache (immediate-release, Niaspan ) Hepatotoxicity, GI (sustained-release) Activation of peptic ulcer Hyperglycemia and reduced insulin sensitivity Contraindications Active liver disease or unexplained LFT elevations Peptic ulcer disease
Percent Change The Effect of Adding Niaspan to a Stable Dose of a Statin 30% 20% 10% 0% -10% -20% -30% -8% 1 gram daily 2 grams daily 24% 24% LDL-C HDL-C TG 30% 20% 10% 0% -10% -20% -30% -40% Wolfe ML et al. Am J Cardiol 2001;87:476-479. 23% 27% 30% LDL-C HDL-C TG
Effects of Fenofibrate on Plasma Lipids Double-Blind, Multicenter, 24-Week Study in Patients with Primary Hypercholesterolemia or Mixed Hyperlipidemia (HPL) Hypercholesterolemia (%) Feno n=92 Plb n=88 Mixed HPL (%) Feno n=24 Plb n=22 Total Cholesterol 17.5 0.4 15.8 +4.6 LDL-C 20.3 +0.4 6.1 0.5 HDL-C +11.1 1.2 +15.3 3.5 Total Triglycerides 37.9 4.2 44.6 +22.3 LDL-C/HDL-C 27.1 1.9 13.3 0.0 VLDL-C 38.4 2.5 52.7 +8.4 p<0.01 except for LDL-C in Type IIb, where p>0.10 Brown WV et al. Arteriosclerosis 1986;6:670-678. 1999 Lippincott Williams & Wilkins. www.lww.com
% CHD Death/Nonfatal MI 30 25 20 15 10 5 0 Trials of Fibrates: Effects on Cardiac Events 34% Rx Placebo 2.7 4.1*** 2.7 Deaths 2.2 2.1 66% 8.0 PRIMARY PREVENTION 9% 42% 15.0 13.6 13.0 * Post hoc analysis of subgroup with TG >200 mg/dl and HDL-C <42 mg/dl. ** Post hoc analysis of subgroup with TG 200 mg/dl and HDL-C <35 mg/dl. *** Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05). Frick MH et al. N Engl J Med 1987;317:1237-1245. Manninen V et al. Circulation 1992;85:37-45. BIP Study Group. Circulation 2000;102:21-27. Rubins HB et al. N Engl J Med 1999;341:410-418. 22.3 22% 17.3 SECONDARY PREVENTION 21.7*** HHS HHS (Post Hoc)* BIP BIP (Post Hoc)** VA-HIT 2.1 10.4 9.9 15.7 17.4 Percent Change 30 20 10 0-10 -20-30 -40-50 -60 Statin + Fibrate 39% Simva + Gemfibrozil 230 332 LDL-C TG 50% 16% HDL-C 38 Prava/Simva + Fenofibrate 166 LDL-C 28% 191 41% Da Col PG et al. Curr Ther Res Clin Exp 1973;53:473-482. Ellen RL et al. Am J Cardiol 1998;81:60B-65B. TG 22% HDL-C 34
Triple-Drug Regimen Lovastatin 40 mg/d Niaspan + + 2 g/d Colestipol 20 g/d Baseline (mg/dl) 8 months (mg/dl) Change (%) LDL-C 215 85 60% HDL-C 46 52 13% LDL-C/HDL-C ratio 4.8 1.7 65% Brown BG et al. Am J Cardiol 1997;80:111-115. Progression of Drug Therapy for LDL-C Lowering Visit 1 Visit 2 Visit 3 Initiate LDL- lowering drug therapy 6 wks If LDL goal not achieved, intensify LDL- lowering therapy 6 wks If LDL goal not achieved, drug therapy or refer to a lipid specialist q 4 6 mo F/U Visits Monitor response and adherence to therapy Start statin or bile acid resin or nicotinic acid Consider higher dose of the statin or add a bile acid resin or nicotinic acid If LDL goal has been achieved, treat other lipid risk factors Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Treatment of Mixed Hyperlipidemia High LDL-C C and TGs Therapeutic Lifestyle Change Drug Therapy STEP STEP 1 2 Achieve the LDL-C C goal Achieve the non-hdl HDL-C C goal Increase LDL-C C lowering or Add a fibrate, niacin or fish oils Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Muscle Adverse Effects Myalgia Weakness Fatigue Myopathy without CK Predisposing factors: Combined hyperlipidemia Subclinical hypothyroidism Suboptimum thyroxine replacement 2005. American College of Physicians. All Rights Reserved.
Steps to Minimize the Risk of Muscle Toxicity with Fibrate Statin Combination Therapy Use statin alone for non-hdl-c goals Use fish oils or niacin rather than fibrates Keep the doses of the statin and fibrate low Dose the fibrate in the AM and the statin in the PM Avoid (or cautiously use) combo in renal impairment Assure no interactions Teach the patient to recognize muscle symptoms Discontinue therapy if muscle symptoms are present and CK is >10 times the upper limit of normal
Indication s: Fish Oils Adjunctive therapy to diet Hypertriglyceridemia (Type IV and V) With statins or other LDL-C lowering drugs in mixed hyperlipidemia Efficacy: Decrease TG 30 40% LDL-C remains the same or increases No change in HDL-C Side GI upset and a fish burp Effects: Interventi on Trials: Lyon Heart Study (dietary), GISSI Prevenzione Trial, others
Emerging Risk Factors Lp(a) LDL size hscrp Homocysteine Procoagulant
ATP III: Special Populations Older Adults, Younger Adults Utility of the non-hdl-cholesterol Total minus HDL-C Includes all atherogenic lipoproteins LDL-C, Lp(a), IDL, VLDL Surrogate for apoprotein B Optimum; add 30 mg/dl to LDL-C goals
Are statins anti-atherosclerosis drugs and should they be used in high risk patients regardless of the LDL-C? The purpose of therapy is to reduce risk and prevent CV events In patients with dyslipidemia or isolated low HDL-C getting the LDL-C to goal takes priority The intensity of LDL-C treatment is determined by risk; when the LDL-C is at or below new goals then fibrates or niacin should be used to treat the non-hdl-c.
Use of statins in patients with hypertriglyceridemia TG range in statin trials: 200-450 mg/dl Statin, fibrate or niacin? Statin effects best in patients with low HDL-C Reduced efficacy of statins in MetS? Use of information about emerging risk factors influences patient management. Can be used to increase or decrease the intensity of therapy of proven CHD risk factors No proven benefit of specifically treating the emerging risk factor
Lipid Management Strategy LDL-C At goal Intensify Rx Not @ goal LDL-C @ goal Other lipid/lipoprotein abnormalities None nhdl-c Fibrates or Niacin HDL-C Niacin