HYPERLIPIDEMIA MED 341 2010 MED DEPARTMENT KING SAUD UNIVERSITY MOHAMED ALMAATOUQ, M.D.

OUTLINE: BACKGROUND WHY DO THINGS THE WAY WE DO? WHO , WHEN AND WHERE TO Rx? HOW TO Rx –THE EASY ONE? HOW TO Rx –THE DIFFICULT ONE? HOW TO Rx –THE CHALLANGING ONE? HDL TGs MISCELANEOUS

MEASUREMENTS: Atherogenic Particles Apolipoprotein B Non-HDL-C Not only is LDL-C a risk factor for cardiovascular disease, but triglyceride-rich lipoproteins—very low density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein (IDL)—may also increase the risk of heart disease. The NCEP ATP III uses non-HDL-C principally as a surrogate for these atherogenic particles. VLDL VLDLR IDL LDL Small, dense LDL TG-rich lipoproteins

Q & A WHY A FASTING SAMPLE? WHAT IS MEASURED IN A LIPID PROFILE? WHY DIET ALONE DOSE NOT WORK? WHAT DIETARY ADVICE TO GIVE? WHY STATINS AT BED TIME? WHICH STATIN TO USE?

BE SIMPLE CHOLESTEROL ABN TRIGLYCERIDES ABN COMBINATION ABN

Treatment of Hyperlipidemia DO IT YOUR SELF CALL A FREIND ASK THE DOC Treatment of hyperlipidemia Statins have been and remain the drugs of first choice for lowering LDL-C. They lower LDL-C more effectively than other currently available agents, and they reduce CHD risk. Because of their LDL-C–lowering efficacy, they are able to achieve LDL-C treatment goals in the majority of patients, regardless of their risk category. In fact, the more potent the LDL-C–lowering efficacy of the statin, the greater the percentage of patients who will achieve their LDL-C goal. Statins are also remarkably safe as will be described below. About 5–10% of patients will not be able to tolerate a statin and so the only alternative agents for lowering LDL-C are a bile acid resin and niacin. These drugs are not as effective in lowering LDL-C and cause bothersome side effects which make patient compliance a problem. However, they are effective in reducing CHD risk and in the majority of patients can be successfully taken. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. CALL IT A DAY

Treatment of Hyperlipidemia TG TSC BOTH R/O 2 ND CAUSES RISK PROFILE CAD / PANCREATITIS Treatment of hyperlipidemia Statins have been and remain the drugs of first choice for lowering LDL-C. They lower LDL-C more effectively than other currently available agents, and they reduce CHD risk. Because of their LDL-C–lowering efficacy, they are able to achieve LDL-C treatment goals in the majority of patients, regardless of their risk category. In fact, the more potent the LDL-C–lowering efficacy of the statin, the greater the percentage of patients who will achieve their LDL-C goal. Statins are also remarkably safe as will be described below. About 5–10% of patients will not be able to tolerate a statin and so the only alternative agents for lowering LDL-C are a bile acid resin and niacin. These drugs are not as effective in lowering LDL-C and cause bothersome side effects which make patient compliance a problem. However, they are effective in reducing CHD risk and in the majority of patients can be successfully taken. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. CHOOSE Rx & MONITER RESULTS

Causes of Secondary Dyslipidemia Diabetes Hypothyroidism Obstructive liver disease Chronic renal failure Drugs that raise LDL cholesterol and lower HDL cholesterol (progestins, anabolic steroids, and corticosteroids)

WHOM TO TREAT ?

WHOM TO TRx? THOSE WITH ATHEROSCLEROSIS THOSE V LIKELY TO DEVELOP IT

Categories of Risk Factors Major, independent risk factors Life-habit risk factors Emerging risk factors

Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goals Cigarette smoking Hypertension (BP 140/90 mmHg or on antihypertensive medication) Low HDL cholesterol (<40 mg/dL)† Family history of premature CHD CHD in male first degree relative <55 years CHD in female first degree relative <65 years Age (men 45 years; women 55 years) † HDL cholesterol 60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count.

CHD Risk Equivalents Risk for major coronary events equal to that in established CHD 10-year risk for hard CHD >20% Hard CHD = myocardial infarction + coronary death

CHD Risk Equivalents Diabetes Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) Diabetes Multiple risk factors that confer a 10-year risk for CHD >20%

Life-Habit Risk Factors Obesity (BMI  30) Physical inactivity Atherogenic diet

Emerging Risk Factors Lipoprotein (a) Homocysteine Prothrombotic factors Proinflammatory factors Impaired fasting glucose Subclinical atherosclerosis

Risk Assessment Count major risk factors For patients with multiple (2+) risk factors Perform 10-year risk assessment For patients with 0–1 risk factor 10 year risk assessment not required Most patients have 10-year risk <10%

Diabetes In ATP III, diabetes is regarded as a CHD risk equivalent.

Diabetes as a CHD Risk Equivalent 10-year risk for CHD  20% High mortality with established CHD High mortality with acute MI High mortality post acute MI

Serum cholesterol level Levels of Risk Associated with Smoking, Hypertension and Hypercholesterolaemia Hypertension (SBP 195mmHg) x3 x4.5 x9 x16 x1.6 x4 Multiple risk factors for CHD are usually present in an individual; rarely do they occur in isolation. When risk factors co-exist the sum of their combined effect is often much greater than the sum of their individual effects.1 Thus, the patient with severe hypercholesterolaemia may be at lower risk than the patient with moderate hypertension, moderately elevated lipid levels and who smokes. Reference 1. Poulter N. In Cardiovascular Disease: Risk Factors and Intervention. Eds: Poulter N, Sever P, Thom S. Radcliffe Medical Press, Oxford, 1993. x6 Smoking Serum cholesterol level (8.5mmol/l, 330mg/dl) (Adapted from Poulter et al., 1993)

WHEN TO TREAT ?

LDL C Goals and Cutpoints for (TLC) and Drug Tx in Diff Risk Categories Risk Category LDL Goal (mmol/L) LDL Level to Initiate (TLC) (mmol/L) LDL Level to Consider Drug Tx (mmol/L) CHD or CHD Risk Equivalents (10-year risk >20%) < 2.6  2.6  3.3 (2.6–3.3: drug optional) 2+ Risk Factors (10-year risk 20%) < 3.3  3.3 10-y risk 10–20%:  3.3 10-yr risk <10%:  4.1 0–1 Risk Factor < 4.1  4.1  4.9 (4.1–4.9: LDL-lowering drug optional)

Treatment Categories, LDL-C Goals and Cutpoints Risk Category LDL-C Goal Consider Drug Therapy CHD or CHD risk equivalent <100 mg/dL 130 mg/dL* 2 Risk Factors 10-yr risk 10–20% 10-yr risk <10% <130 mg/dL 130 mg/dL 160 mg/dL <2 Risk Factors <160 mg/dL 190 mg/dL Treatment categories, LDL-C goals and cutpoints The primary goal of clinical lipid management is reduction of low-density lipoprotein cholesterol (LDL-C) to lower coronary heart disease (CHD) risk. Individuals who do not or cannot achieve this goal with therapeutic lifestyle change (TLC) alone are candidates for drug therapy. TLC is an important component of any lipid-lowering program. It can obviate the need for drug therapy, augment the LDL-C lowering achieved with drug therapy, and provide benefits beyond LDL-C lowering which contribute substantially to CHD risk reduction. As with all considerations in the Adult Treatment Panel III (ATP III) recommendations, the decision to initiate drug therapy should be consistent with the patient’s CHD risk. Those with the highest risk should be offered the most aggressive treatment to reduce the risk optimally. Conversely, in patients with the lowest risk, drug therapy may not be cost-effective. Patients with CHD or a CHD risk equivalent have the highest risk, exceeding 20% in 10 years, and are candidates for lipid-modifying drug therapy. Those with levels above 130 mg/dL can be given drugs simultaneously with TLC as lifestyle change alone is unlikely to achieve the treatment goal. Those with levels between 100 and 129 mg/dL should first be treated with TLC, and after an appropriate trial (e.g., 3 months), lipid-lowering drug therapy (for example, a statin or fibrate) may be initiated. Some clinicians prefer to initiate drug therapy simultaneously with TLC in patients being discharged from the hospital following a CHD event or with a CHD risk equivalent. In this case, the therapy can be adjusted on a subsequent visit if the treatment goal is not achieved or if it is exceeded. For CHD or CHD risk equivalent patients who were given LDL-C–lowering drug therapy and have an on-treatment LDL-C of 100–129 mg/dL, clinical judgment should be applied to choose from a number of options. The majority of participants in the statin endpoint trials had on-treatment LDL-C values in this range. Choices include intensifying TLC, adjusting the dose of the LDL-C–lowering drug, initiating nondrug treatment of the metabolic syndrome if it is present, or intensifying treatment of nonlipid risk factors. Patients with 2 or more major risk factors and a 10-year risk between 10 and 20% have an LDL-C goal of <130 mg/dL and should be given TLC; if it is unlikely that this alone will achieve the treatment goal, drug therapy may be initiated simultaneously. In most cases, TLC is tried for about 3 months before making decisions to advance to drug therapy. After adequate LDL-C reduction has been achieved, other risk factors, including obesity and sedentary lifestyle, should be addressed. Patients with 2 or more risk factors and a 10-year risk of <10% as well as patients with <2 risk factors (who mostly have a 10-year risk of <10%) should be treated with TLC unless LDL-C levels are very high, because drug therapy in these patients is the least cost-effective. If treatment goal cannot be achieved with TLC alone, consideration can be given to using lipid-lowering drug therapy. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. * 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Clinical Judgment The NCEP ATP II guidelines recommend the use of clinical judgment in deciding whether to initiate drug therapy in Patients with CHD and LDL-C 100–129 mg/dl Patients without CHD who have 2 risk factors and LDL-C 130–159 mg/dl Middle-aged and older patients without CHD who have <2 risk factors and LDL-C 160–189 mg/dl Clinical judgment In patients whose LDL-C is above target yet below the cutpoints for initiation of drug therapy, the NCEP guidelines specify that clinical judgment should be used to determining whether to initiate drug therapy. Since the guidelines were written in 1993, abundant clinical trial evidence has become available on which to base clinical judgment. These data strongly support treatment in many of these patients.   Reference: National Cholesterol Education Program: Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:1329-1445. National Cholesterol Education Program Circulation 1994;89:1329–1445.

Selecting Successful Lipid-Lowering Treatments HOW TO TREAT?

Treatment of Hyperlipidemia DO IT YOUR SELF CALL A FREIND ASK THE DOC Treatment of hyperlipidemia Statins have been and remain the drugs of first choice for lowering LDL-C. They lower LDL-C more effectively than other currently available agents, and they reduce CHD risk. Because of their LDL-C–lowering efficacy, they are able to achieve LDL-C treatment goals in the majority of patients, regardless of their risk category. In fact, the more potent the LDL-C–lowering efficacy of the statin, the greater the percentage of patients who will achieve their LDL-C goal. Statins are also remarkably safe as will be described below. About 5–10% of patients will not be able to tolerate a statin and so the only alternative agents for lowering LDL-C are a bile acid resin and niacin. These drugs are not as effective in lowering LDL-C and cause bothersome side effects which make patient compliance a problem. However, they are effective in reducing CHD risk and in the majority of patients can be successfully taken. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. CALL IT A DAY

Treatment of Hyperlipidemia TG TSC BOTH R/O 2 ND CAUSES RISK PROFILE CAD / PANCREATITIS Treatment of hyperlipidemia Statins have been and remain the drugs of first choice for lowering LDL-C. They lower LDL-C more effectively than other currently available agents, and they reduce CHD risk. Because of their LDL-C–lowering efficacy, they are able to achieve LDL-C treatment goals in the majority of patients, regardless of their risk category. In fact, the more potent the LDL-C–lowering efficacy of the statin, the greater the percentage of patients who will achieve their LDL-C goal. Statins are also remarkably safe as will be described below. About 5–10% of patients will not be able to tolerate a statin and so the only alternative agents for lowering LDL-C are a bile acid resin and niacin. These drugs are not as effective in lowering LDL-C and cause bothersome side effects which make patient compliance a problem. However, they are effective in reducing CHD risk and in the majority of patients can be successfully taken. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. CHOOSE Rx & MONITER RESULTS

Treatment of Hyperlipidemia High LDL-C Therapeutic Lifestyle Change Drug Therapy Treatment of hyperlipidemia Statins have been and remain the drugs of first choice for lowering LDL-C. They lower LDL-C more effectively than other currently available agents, and they reduce CHD risk. Because of their LDL-C–lowering efficacy, they are able to achieve LDL-C treatment goals in the majority of patients, regardless of their risk category. In fact, the more potent the LDL-C–lowering efficacy of the statin, the greater the percentage of patients who will achieve their LDL-C goal. Statins are also remarkably safe as will be described below. About 5–10% of patients will not be able to tolerate a statin and so the only alternative agents for lowering LDL-C are a bile acid resin and niacin. These drugs are not as effective in lowering LDL-C and cause bothersome side effects which make patient compliance a problem. However, they are effective in reducing CHD risk and in the majority of patients can be successfully taken. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497. Therapy of Choice: Statin Alternatives: Resin / niacin, others Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

LDL-C–Lowering Efficacy of Statins Dose Atorva Fluva Lova Prava Simva 10 mg –39% –22% –30% 20 mg –43% –27% –32% –38% 40 mg –50% –25% –34% –41% 80 mg –60% –36% –42% –47% The LDL-C–lowering efficacy of the currently available statins The relative LDL-C–lowering efficacy of the various statins is presented in this slide. This information was taken from the prescribing information in the 2001 Physicians' Desk Reference. While the data do not represent a head-to-head comparison in the same patient population, they do allow us to see the relative LDL-C–lowering potency of the currently available statins. These reductions are superior to those achieved by any other lipid-modifying agents. The LDL-C reductions are dose-dependent and log-linear. With each doubling of the dose, an additional 6–7% reduction in LDL-C is usually achieved. Changes in high-density lipoprotein cholesterol (HDL-C) are usually modest, in the 5–10% range, and not consistently dose related; increases in HDL-C are greater in patients with low HDL-C and elevated triglycerides. Reference: Physicians' desk reference. 55th ed. Montvale, NJ: Medical Economics Company, Inc., 2001. Physician’s Desk Reference. 55th ed. Montvale, NJ: Medical Economics, 2001.

Effect of Lipid-lowering Therapies on Lipids Therapy Bile acid sequestrants Nicotinic acid Fibrates (gemfibrozil) Probucol Statins* TC Down 20% 25% 15% 15–30% LDL Down 15–30% 25% 5–15% 10–15% 24–50% HDL Up 3–5% 15–30% 20% Down 20–30% 6–12% TG Neutral or up Down 20–50% Neutral 10–29% Patient tolerability Poor Poor to reasonable Good Reasonable Lipid-lowering therapies include inhibitors of HMG CoA reductase (statins), fibrates, bile acid sequestrants (resins), nicotinic acid and its derivatives, and probucol. They have all shown varying degrees of efficacy in delaying the progression of atherosclerosis and some have also been shown to reduce MI and sudden death. A combination of two agents may be used to achieve greater efficacy in cases of severe hypercholesterolaemia. However, the most convincing evidence has been demonstrated with statins and, at present, they are first-line drugs in the treatment of dyslipidaemias. Bile acid sequestrants are potent cholesterol-lowering agents. However, compliance can be a problem as patients may object to the taste and texture, and common adverse events are gastrointestinal bloating, nausea and constipation.1,2 Nicotinic acid, a B-complex vitamin whose lipid-lowering properties were first described in the 1950s, is very effective at increasing HDL cholesterol levels and is indicated for all dyslipidaemias except congenital lipoprotein lipase deficiency. The value of nicotinic acid has been limited by the incidence of adverse events, which include flushing, skin problems, gastrointestinal distress, liver toxicity, hyperglycaemia and hyperuricaemia.1,2 Fibrates are effective triglyceride-lowering drugs and, as such, are effective for patients with type III hyperlipoproteinaemia. In some patients they modestly lower LDL cholesterol and raise HDL cholesterol. However, in the majority of patients they are only moderately successful in reducing LDL cholesterol.1,2 Probucol is prescribed for the treatment of high cholesterol levels. However, it has only a modest LDL cholesterol-lowering effect, and there is no evidence that it reduces CHD risk and there are limited long-term tolerability data.1,2 Statins are highly effective in lowering LDL cholesterol and have a good tolerability profile.1-3 References 1. Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–91. 2. National Cholesterol Education Program. Circulation 1994;98(3):1333–445. 3. Knopp RH. N Engl J Med 1999;341:498–511. TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug (cerivastatin 0.3mg) (Adapted from Yeshurun 1995, Knopp 1999)

Guidelines that aren’t implemented don’t work Guidelines won’t work unless they are implemented. Each of us needs to determine how we are going to successfully incorporate ATP III recommendations in our patient management. The guidelines challenge us with how best to treat patients to achieve their LDL-C goal. This challenge is especially pressing for patients with CHD or a CHD risk equivalent, as here the LDL-C goal is the lowest and treatment will have to be the most aggressive. Evidence from several surveys indicates that only about 18% of these patients achieve an LDL-C of <100 mg/dL even when given lipid-modifying drugs. ATP III has increased the number of patients who are candidates for LDL-C–lowering drug therapy from approximately 13 to 32 million; of these, about 20 million people would be assigned the lowest LDL-C goal of <100 mg/dL. This means that if we were doing a poor job with our LDL-C–lowering treatment prior to ATP III, we are at risk of doing an even worse job now. And if this happens, it will mean that many millions of patients will not receive the benefit of optimal therapy. Another challenge raised by the new guidelines is the new emphasis on high blood triglycerides and the secondary non-HDL-C treatment goals. Like anything that is new, clinicians have little or no prior experience or formal training from which to draw to manage these patients. Questions about the utility and safety of using high doses of statins or combining them with other lipid-modifying drugs to lower non-HDL-C immediately come to mind. Combining a statin and a fibrate raises questions about comparable efficacy and safety compared to other alternatives. These and related questions need to be considered so that the clinician will have ready and competent answers when these issues arise in the patient care setting.

THE DIFFICULT ONE

Combination Lipid-Altering Drug Therapy with Statins: Conclusion Need for combination lipid-altering drug therapy Ezetimibe and statins Bile acid sequestrants and statins PPAR agonists and statins Fish oils and statins Niacin and statins Slide 36. Combination lipid-altering drug therapy with statins: conclusion The use of statins in combination with other lipid-altering drugs may be appropriate for patients who are unable to achieve treatment goals with single lipid-altering drug treatment alone or who may be at risk for intolerance, toxicity, or adverse drug interactions with a higher dose of a single lipid-altering drug. In addition, the combined use of two or more lipid-altering drugs with complementary mechanisms of action may provide greater multidimensional improvements in other parameters that might better reduce atherosclerotic CHD risk than the use of either agent alone. Keywords: combination therapy Slide type: text

Combination Therapy: Pros and Cons LDL-C, TG, HDL-C May Lp(a) (niacin) LDL particle size Fibrinogen (fibrate) Angiographic data Increased adverse effects (rhabdomyolysis) Drug interactions Increased costs Lack of outcome studies Combination therapy: pros and cons In determining whether to initiate combination therapy in a patient with dyslipidemia, the advantages must be weighed against potential disadvantages. Although clinical trial evidence of the effects of combination therapy on morbidity and mortality is lacking, a composite analysis of angiographic trials demonstrated that combination therapy decreased per-patient diameter stenosis by 1–2% (net regression), whereas monotherapy slowed progression but did not induce regression. However, there are still no large prospective clinical event trials to show that the combination of a statin with either a fibrate or niacin provides greater event reduction than a statin alone. Combination therapy is more expensive and is associated with increased adverse events such as rhabdomyolysis. In addition, the package labeling of all statins carries a warning about using a statin in combination with a fibrate.   References: Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q. Brown BG, Zhao X-Q, Bardsley J, Albers JJ. Secondary prevention of heart disease amongst patients with lipid abnormalities: practice and trends in the United States. J Intern Med 1997;241:283-294.

STATIN A + STATIN B

TG

OUTLINE: BACKGROUND WHY DO THINGS THE WAY WE DO? WHO , WHEN AND WHERE TO Rx? HOW TO Rx –THE EASY ONE? HOW TO Rx –THE DIFFICULT ONE? HOW TO Rx –THE CHALLANGING ONE? HDL TGs MISCELANEOUS

HDL

Guidelines that are not followed are of no value Remember….. Guidelines that are not followed are of no value Remember: guidelines that are not followed are of no value Guidelines should be written in a way that they can be followed and successfully implemented. New evidence supports the use of statins in a wider range of patients than currently recommended in the NCEP ATP III guidelines. New evidence strongly supports the benefits of initiating statins in all patients with atherosclerosis or risk equivalents, regardless of baseline LDL-C. This new evidence provides scientific support for a more simplified and direct approach to patients with CHD and CHD risk equivalents. A revision of the guidelines to recommend a combination of cardiovascular protective medication including statins as initial therapy for all patients with CHD or CHD risk equivalents would serve to enhance treatment use and, as a result, save lives.