CARE SETTINGS AND OUTPATIENT CLINICS IN THE KINGDOM OF BAHRAIN

Transcription

1 GUIDELINE FOR MANAGEMENT OF DYSLIPIDEMIA IN PRIMARY Kingdom of Bahrain Ministry of Health Health Promotion Council CARE SETTINGS AND OUTPATIENT CLINICS IN THE KINGDOM OF BAHRAIN Together for Better Life 1

2 REVIEW GROUP Primary Care Group Secondary Care Group Dr. Fatima Bu Hassan, Consultant Family Physician, Head of Audit group at medical review office Dr. Hussain Taha, Consultant Endocrinologist, SMC Dr. Saniya AlSalehi, Consultant Family Physician, Primary Health Care Dr. Abeer AlGhawi, Consultant Family Physician, Nutrition Department, Public Health Dr. Taybaa Salman Al-Aradi Consultant Family Physician, Primary Health Care Dr. AbdulHusain Ali Dadi, Consultant Family Physician, Primary Health Care Reviewed Dr. Abdul Hussain AL Ajmi, Consultant Family Physician, Head of Non-Communicable Diseases Unit Dr. Mariam Al-Mulla Harmas Director of the public health Supervision Dr. Mariam Athbi Al-Jalahma Assistant Undersecretary, Primary Care and Public Health 2

3 Updated Dyslipidemia Guideline Index 1. Introduction 2. Screening 2.1 Recommendation for screening 2.2 Method of screening 3. Management of Hypercholesterolemia 3.1 Statin groups 3.2 ASCVD risk estimation 3.3 Drug Intensity Determination 3.4 Statin therapy follow up: 4. Specific Dyslipidemias a. Adherence to statin therapy and lifestyle b. Therapeutic response to statin therapy c. Statin Safety Recommendations 4.1 Management of Hypertriglyceridemia 4.2 Managing Metabolic syndrome 4.3 Management of Low HDL Cholesterol (Hypoalphalipoproteinemia) 5. Life Style Modification 6. Recommendations For referral to Other Services 7. References 3

4 1. Introduction Worldwide, non-communicable diseases (NCD) currently represent 43% of the burden of disease and are expected to be responsible for 60% of the disease burden and 73% of all deaths by (1) The link between cardiovascular risk and variation in blood lipid concentration was shown in a study of over 356,000 men aged years who were followed up for six years. The study demonstrated a continuous, graded, strong relationship between serum cholesterol and six year age adjusted CHD mortality. This relationship persisted in smokers and non-smokers, people with and without hypertension and was evident irrespective of the presence or absence of vascular disease. Low-density lipoprotein (LDL) cholesterol usually makes up 60-70% of total serum cholesterol and the strong relationship between total cholesterol level and CHD suggests that LDL cholesterol is a powerful risk factor. The role of LDL cholesterol in atherosclerosis is confirmed by studies carried out in individuals with genetic disorders that result in extreme elevations of cholesterol levels, such as familial hypercholesterolemia. These individuals tend to develop premature CHD with evidence of advanced atherosclerosis even in the absence of any other risk factor for coronary disease. The INTERHEART study assessed the importance of risk factors for coronary artery disease worldwide. Nine measured and potentially modifiable risk factors, accounted for more than 90% of the proportion of the risk for acute myocardial infarction. Smoking, history of hypertension or diabetes, waist hip ratio, dietary pattern, physical activity, alcohol consumption, blood Apo-lipoproteins and psychosocial factors were identified as the key risk factors (2). The effect of these risk factors was consistent in men and women across different geographic regions and by ethnic group. The British Regional Heart Study also found that smoking, blood pressure and cholesterol accounted for 90% of attributable risk of CHD. Worldwide, the two most important modifiable cardiovascular risk factors are smoking and abnormal lipids. Hypertension, diabetes, psychosocial factors and abdominal obesity are the next most important but their relative effects vary in different regions of the world (2). Chronic non-communicable diseases (NCDs) are major causes of morbidity and mortality in the Kingdom of Bahrain. Out of the 2388 total deaths reported in 2010, 379 (16%) were due to circulatory system diseases, 306 (13%) cancer-related deaths, 187 (8%) endocrine and metabolic disorders, including mainly Diabetes Mellitus and 148 (6%) diseases of respiratory system (1). According to the National Non-communicable Diseases Risk Factors Survey done in 2007 the overall prevalence of hypercholesterolemia ( 5.2 mmol/l) was 40.6% with no significant differences between male (41.2%) and female respondents (40.2%). There was an evident increase in the prevalence of hypercholesterolemia with increasing age reaching 61.2% in elderly of years. 4

5 Unless tackled and brought under control, such growing NCD burden would result in more losses of years of life due to death or disability, and could threaten to overwhelm already stretched health services and resources. In this respect, primary prevention is the most cost effective strategy to contain this emerging epidemic, as it is already known that most of this burden can be attributed to some key risk factors (namely; Diabetes Mellitus, Hypertension, Hyperlipidemia, Obesity, Physical inactivity, alcoholism and unhealthy dietary habits) that is amenable to intervention. The aim of dyslipidemia guideline in Primary Health Care (PHC) is to prevent atherosclerotic cardiovascular diseases (ASCVD) and improve the management of people who have these diseases through professional education and developing guidelines that promote optimal patient care and cardiovascular health. Toward these objectives, a team of family physicians, an endocrinologist, cardiologists, and nutritionist, have collaborated to update clinical practice guidelines management of dyslipidemia, which was initiated on This updated guideline was adopted from several international evidence based guidelines on the treatment of blood cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. The recommendation made by ACC/AHA guideline was derived from randomized trials, meta-analyses, and observational studies. The task force has indorsed the 2013 guideline that focused on the following objectives: Focus on treatment of blood cholesterol to reduce ASCVD risk in adults. Emphasize adherence to a heart healthy lifestyle as foundation of ASCVD risk reduction. Identify individuals most likely to benefit from cholesterol-lowering therapy through 4 statin benefit groups. Identify safety issues. There has been an increasing recognition that it is no longer sufficient to predict the risk of vascular disease only in terms of CHD as this underestimates the risk of stroke. All cardiovascular disease (CVD) should be considered as a spectrum of disorder including coronary artery disease, cerebrovascular disease and peripheral arterial disease and this new guideline has been extended to include the prevention of other forms of cardiovascular disease through including stroke as an outcome in the new ASCVD risk calculator. Recent meta-analysis of randomized controlled trials (RCTs) shows that statins are effective in the primary and secondary prevention not only of CHD events and coronary revascularization, but also of strokes and combined major vascular events. 5

6 2. Screening Dyslipidemias or lipid disorders are abnormalities of lipoprotein metabolism and include elevations of total cholesterol, LDL cholesterol, or triglycerides; or deficiencies of HDL cholesterol (3). 2.1 Recommendations for screening 1- Start screening adults of 20 years and above. 2- Young adults: - Men aged Years. - Women aged Years. Evaluate for dyslipidemia every 5 years. 3- Middle-Aged Adults: - Men Aged Years. - Women Aged Years. In the absence of atherosclerotic cardiovascular diseases (ASCVD) risk factors (see table 1), screen middle-aged persons for dyslipidemia at least every 1 to 2 years. 4- Adults Older Than 65 Years: Annually screen older adults with zero to one ASCVD risk factor (see table 1) for dyslipidemia. 5- Children and Adolescents (2-19 years of age): Screen every 3 to 5 years if they have CAD risk factors or a family history of premature CAD or dyslipidemia, are overweight or obese, have other elements of the insulin resistance syndrome, or have no available family history. Consider more frequent dyslipidemia assessments for all of the above age group patients with the following conditions: - Individuals with ASCVD risk factors (see table 1). - Family history of premature CAD (definite myocardial infarction [MI] or sudden death before age 55 years in father or other male first-degree relative, or before age 65 years in mother or other female first-degree relative). 6- Adults With Diabetes: Annually screen all adult patients with diabetes mellitus for dyslipidemia. 6

7 Major risk factors Advancing age High total serum cholesterol level High non HDL-C High LDL-C Low HDL-C < 40mg/dl (1mmol/L ) Diabetes mellitus Hypertension Cigarette smoking Family history of CAD Table 1: Major ASCVD Risk Factors Additional risk factors Obesity, abdominal obesity Family history of hyperlipidemia Small, dense LDL-C Apo B LDL particle number Fasting/postprandial hypertriglyceridemiad PCOS Dyslipidemic triad Nontraditional risk factors Elevated lipoprotein(a( Elevated clotting factors Inflammation markers (hscrp; Lp-PLA2( Hyperhomocysteinemia Apo E4 isoform Elevated uric acid Abbreviations: apo, apolipoprotein; CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; hscrp, highly sensitive C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Lp-PLA2, lipoproteinassociated phospholipase A2; PCOS, polycystic ovary syndrome. An HDL-C level > 60mg/dl (1.5mmol/L) is an independent negative risk factor in both sexes 2.2 Method of screening Complete lipoprotein profile (total cholesterol, LDL, HDL and triglycerides) after 9-12 h fasting. For greater accuracy a 12 hrs fasting blood sampling is performed as HDL and TG levels vary in fasting and non-fasting sample. HDL cholesterol is lower by 5-10% in non-fasting state than fasting state and TG is 20-30% higher 11. LDL cholesterol can be calculated directly by measuring total cholesterol, HDL cholesterol and triglyceride from non-fasting venous blood and applying Friedewald equation LDL=TC-HDL-(TG/5). This method is not applicable when TG is >4.5 mmol/l. Screen for secondary causes (see table 2) if TGD >4.5 mmol/l. 7

8 Table 2: Secondary causes of hyperlipidemia Secondary Cause Elevated LDL-C Elevated Triglycerides Diet Drugs Diseases Disorders and altered states of metabolism Saturated or trans fats, weight gain, anorexia Diuretics, cyclosporine, glucocorticoids, amiodarone Biliary obstruction, nephrotic syndrome Hypothyroidism, obesity, pregnancy* Weight gain, very lowfat diets, high intake of refined carbohydrates, excessive alcohol intake Oral estrogens, glucocorticoids, bile acid sequestrants, protease inhibitors, retinoic acid, anabolic steroids, sirolimus, raloxifene, tamoxifen, beta blockers (not carvedilol), thiazides Nephrotic syndrome, chronic renal failure, lipodystrophies Diabetes (poorly controlled), hypothyroidism, obesity; pregnancy* 8

9 3. Management of Hypercholesterolemia It must be emphasized that lifestyle modification remains a critical component of health promotion and ASCVD risk reduction, both prior to and in concert with the use of cholesterol-lowering drug therapies (see section 4). The new guideline identifies four major groups of patients for whom cholesterollowering drugs (statins) have the greatest chance of preventing stroke and heart attacks (4). 3.1 Groups that benefit from statin therapy (4) : Group1 Patients with clinical ASCVD: Includes acute coronary syndrome, history of MI, stable or unstable coronary or other arterial revascularization, Stroke, TIA, or peripheral arterial disease presumed to be atherosclerotic origin. Group 2 Patients with an LDL cholesterol level of 4.9mmol/l ( 190mg/dL). Group 3 Patients with Type 2 diabetes Who are years of age and with LDL cholesterol between mmol/l ( mg/dl). Group 4 Patients 10-year ASCVD risk 7.5% without diabetes and who are between 40 and 75 years of age and with LDLcholesterol between mmol/l ( mg/dl). 9

10 year ASCVD Risk estimation (4) Ten-year risk is defined as the risk of developing a first ASCVD event, defined as nonfatal myocardial infarction or coronary heart disease (CHD) death, or fatal or nonfatal stroke, over a 10-year period among people free from ASCVD at the beginning of the period (4). The 10-year risk estimation is used for patients without ASCVD and with a LDL less than 190mg/dl (4.9g/dl) (Group 3 & 4 in statin benefit groups). In order to estimate the risk for atherosclerotic cardiovascular disease, a pooled cohort equation is used, and the following information is required: Age, Gender, Race, Total cholesterol, HDL cholesterol, Systolic blood pressure, Blood pressure lowering medication use, Diabetes status, and Smoking status A downloadable spreadsheet enabling estimation of 10-year and lifetime risk for ASCVD and a web-based calculator are available at and 10

11 3.3 Drug Intensity Determination In all benefit groups consider evaluation and treatment of the following (4) : - Four statin benefit group: 1. Individuals with clinical ASCVD: High-intensity statin therapy should be initiated for adult s 75 years of age with clinical ASCVD who are not receiving statin therapy or the intensity should be increased in those receiving a low- or moderate-intensity statin (table 3). In individuals with clinical ASCVD in whom high-intensity statin is contraindicated or when characteristics predisposing to statin associated adverse effects are present (table 4), moderate-intensity statin should be used as the second option, if tolerated (figure1). Figure 1: Initiating Statin Therapy in Individuals with Clinical ASCVD (group 1). Clinical ASCVD - Secondary Prevention Not currently on statin therapy Initial evaluation prior to statin initiation Fasting lipid profile ALT CK (if indicated) see statin safety Consider evaluation for secondary causes and statin safety Evaluate and treat laboratory abnormalities 1.Triglycerides 5.6mmol/l ( 500mg/dL) 2. LDL-C 4.9 mmol/l ( 190mg/dL) - Secondary causes - If primary screen family for FH Age 75 Without contraindications, conditions or drug-drug interactions influencing statin safety, or a history of statin intolerance Age >75 Or With conditions or drug-drug interactions influencing statin safety, or a history of statin intolerance Initiate high-intensity statin therapy council on health lifestyle habits Initiate moderate-intensity statin therapy council on health lifestyle habits Monitor statin therapy 2. Individuals with primary elevations of LDL C 190 mg/dl(4.9mmol/l). 11

12 Adults 21 years of age with primary, severe elevations of LDLC 190mg/dL (4.9mmol/l)) have a high lifetime risk for ASCVD events. This is due to their lifetime exposure to markedly elevated LDL C levels arising from genetic causes. Thus, at age 21, these individuals should receive statin therapy if they have not already been diagnosed and treated before this age (figure 2). 3) Diabetes aged 40 to 75 years with LDL C 70 to189 mg/dl ( mmol/l) and without clinical ASCVD Moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age with diabetes mellitus. High-intensity statin therapy is reasonable for adults 40 to 75 years of age with diabetes mellitus with a 7.5% estimated 10-year ASCVD risk unless contraindicated. In adults with diabetes mellitus, who are <40 or >75 years of age, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects, for drugdrug interactions, and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy (figure2). 4) Individuals without clinical ASCVD or diabetes with LDL C 70 to189 mg/dl ( mmol/l) and estimated 10-year ASCVD risk >7.5%. In individuals 40 to 75 years of age with LDL C 70 to 189 mg/dl who are without clinical ASCVD or diabetes, initiation of statin therapy based on estimated 10-year ASCVD risk is recommended, regardless of sex, race or ethnicity (figure 2) 12

13 Figure 2: Initiating Statin Therapy in Individuals without Clinical ASCVD No Clinical ASCVD - primary prevention Not currently on statin therapy Initial evaluation prior to statin initiation Fasting lipid profile HbA1c ( if diabetes status unknown) ALT CK(if indicated) Consider evaluation for secondary causes and statin safety Assign statin benefit group Council on healthy lifestyle habits Group 2 & 3 LDL--C 190mg (4.9 mmol/l) or Diabetes Age y No diabetes Age y, and LDL-C mg/dl ( mmol/l) No yes Estimate 10y ASCVD risk using Pooled Cohort equations Group 4 >7.5% 10 y ASCVD risk 5% to <7.5% 10 y ASCVD risk <5% 10 y ASCVD risk Age <40y, and LDL--C < 190mg (4.9 mmol/l) Clinician and patient should engage in dicusionof the potential of: 1. ASCVD risk reduction benefits 2. Adverse effects 3. Drug-drug interactions 4. Patient preference In selected individual additional factors may be considered to inform treatment decision-making Initiate statin therapy Reemphasize healthy life habit Monitor statin therapy 13

14 Fig 3 statin benefit groups ASCVD Statin Benefit Groups Heart healthy lifestyle habits are the foundation of ASCVD prevention. In individuals not receiving cholesterol-lowering drug therapy, recalculate estimated 10- y ASCVD risk every 4-6 y in individuals aged 4075 without clinical ASCVD or diabetes and with LDL-C mg/dL ( mmol/L) Adult aged >21 y and a candidate for statin therapy Group 1 yes Clinical ASCVD No yes yes Age 75 y High-intensity statin (Moderate intensity statin if not candidate for High-intensity statin) Age >75 y or if not candidate for Highintensity statin No Moderate intensity statin Group 2 LDL-C 190 mg/dl (4.9mmo/L) yes High-intensity statin (Moderate intensity statin if not candidate for High-intensity statin) No Group 3 Diabetes type 1 or2 aged y No yes yes Moderate intensity statin Estimated 10y ASCVD risk 7.5 % High-intensity statin Estimate 10y ASCVD risk using Pooled Cohort equations Group % Estimated 10y ASCVD risk and age y yes Moderate intensity statin No In selected individuals, consider additional risk actors influencing ASCVD risk and potential ASCVD risk benefits and adverse effect, dug-drug interaction, and patient preference to statin treatment 14

15 Table3: Statin Therapy (High- Moderate- and Low-Intensity Statin Therapy) High-Intensity Statin Therapy Moderate-Intensity Therapy Statin Low-Intensity Statin Therapy Lowers LDL C on average, by approximately 50% Atorvastatin (Lipitor) (40) 80 mg Rosuvastatin(Crestor) 20 (40) mg Lowers LDL C on average, by approximately 30% to <50% Atorvastatin (Lipitor) 10 (20) mg Rosuvastatin (Crestor) (5) 10 mg Simvastatin (Zocor) mg Pravastatin (lipostat) 40 (80) mg Lovastatin 40 mg Fluvastatin (lescol) XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2 4 mg Lowers LDL C on average, by <30% Simvastatin ( Zocor) 10 mg Pravastatin (lipostat) mg Lovastatin 20 mg Fluvastatin (lescol) mg Pitavastatin 1 mg Table 4: Characteristics predisposing to statin associated adverse effects Multiple or serious comorbidities, including impaired renal or hepatic function. History of previous statin intolerance or muscle disorders. Unexplained ALT elevations >3 times ULN. Patient characteristics or concomitant use of drugs affecting statin metabolism (eg those who have undergone solid organ transplantation or are receiving treatment for HIV). >75 years of age. Additional characteristics that may modify the decision to use higher statin intensities may include, but are not limited to: History of hemorrhagic stroke. Asian ancestry. 15

16 3.4 Statin therapy follow up a. Monitoring Statin Therapy (4) The guideline recommends regular assessment for adherence to statin and lifestyle therapies and for evaluating the therapeutic response to statin (4). To determine patient s adherence, an initial fasting lipid profile should be performed, followed by a second lipid profile 4-12 weeks after initiating statin therapy. Thereafter assessment should be repeated every 3-12 months as clinically indicated see fig4. To monitor the response to therapy, the intensity of the statin therapy rather than specific LDL C or non-hdl C targets is recommended. The following indicators are used to monitor the therapeutic response to statin therapy: High-intensity statin therapy generally yields 50% average LDL-C reduction from untreated baseline Moderate-intensity therapy generally yields 30% to <50% average LDL-C reduction from untreated baseline LDL C levels and percent reductions are to be used only to assess response to therapy and adherence. They are not to be used as performance standards. In those already on a high-intensity statin, in whom the baseline LDL C is unknown, an LDL C <100 mg/dl was used as a fixed target. In individuals who have a less-than- anticipated therapeutic response or are intolerant of the recommended intensity of statin therapy, the following should be performed: Reinforce medication adherence. Reinforce adherence to intensive lifestyle changes. Exclude secondary causes of hyperlipidemia. Increase the statin intensity if tolerated In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated therapeutic response, addition of a nonstatin cholesterol-lowering drug s (Bile Acid Sequestrants, Fibrates, and Cholesterol Absorption Inhibitors) may be considered if the ASCVD riskreduction benefits outweigh the potential for adverse effects. (Table 5) Clinicians treating high-risk patients who have a less-than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant may consider the addition of a nonstatin cholesterol-lowering therapy. After statin therapy has been initiated, some individuals experience unacceptable adverse effects when taking the recommended intensity of statin therapy. Once the severity and association of adverse effects with statin therapy has been established, and once factors potentially contributing to statin intolerance are resolved, the patient should be given lower doses of the same statin or alternative appropriate statin, until a statin and dose that have no adverse effects have been identified. 16

17 Table 5 Nonstatin cholesterol-lowering drugs Non-Statin Drugs Effect Indications Examples Side Effects Fibrates Niacin Bile acid sequestrates Cholesterol absorption inhibitors Lowers triglycerides by 20% to 35% and increase HDL-C by 6% to 18%. Increases HDL-C by 29% and 19% to 24% Reduction in coronary events by 27%. Reduces LDL-C by 15% to 25% and increase HDL-C by 4% to 8% Reduces major coronary artery disease events by 19% Reduces LDL-C by 10% to 25%, with, favorable changes in triglycerides, apo B, and, in some trials, HDL-C Severe hypertriglyceridemia Patients at risk of CAD with elevated triglycerides and/or low HDL-C levels as primary lipid abnormality Potent LDL-C and triglyceride-lowering drug Substantially increases HDL-C. Effectively reduce LDL-C and moderately increase HDL-C Reduce LDL-C and may have beneficial effects on triglycerides, apo B, and HDL-C. Benefits are enhanced in combination therapy with statins. Bezafibrate Bezalip R 400mg od) gemfibrozil (600mg bd) fenofibrate tricor (45-120mg od) fenofibric acid trilipix (135mg od) Nicotinic Acid start with 100mg tds Maintenance 1-2g tds Max 6g/day cholestyramine, colestipol, and colesevelam. Ezetimibe zetia 10mg od) May increased serum creatinine levels (without affecting renal function, monitor renal function initially within 4 months then every 6 months). Rarely cause myositis, myalgia/myopathy, or rhabdomyolysis; (this risk increases with concomitant statin therapy) Flushing at the beginning of therapy often diminishes with continued use. Blood glucose elevations with higher doses and is transient and manageable. High discontinuation rates because of gastrointestinal tract symptoms (colesevelam, is better tolerated) Minimal adverse effects 17

18 Fig 4- Monitoring Statin Therapy 18

19 b. Statin Safety Recommendations (4) To maximize the safety of statins, selection of the appropriate statin and dose in men and non-pregnant/non-nursing women should be based on patient characteristics, level of ASCVD risk, and potential for adverse effects (4). Moderate-intensity statin therapy should be used in individuals in whom highintensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present. Characteristics predisposing individuals to statin adverse effects include, but are not limited to: Multiple or serious comorbidities, including impaired renal or hepatic function. History of previous statin intolerance or muscle disorders. Unexplained ALT elevations >3 times ULN. Patient characteristics or concomitant use of drugs affecting statin metabolism. >75 years of age. History of hemorrhagic stroke. Asian ancestry Recommendation for Muscle Symptoms: o CK should not be routinely measured in individuals receiving statin therapy. o Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events based on a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk for myopathy. o During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue. o Evaluate and treat muscle symptoms (pain, stiffness, tenderness, cramping, and weakness) in statin treated patients as follows: Obtain history of prior/current muscle symptoms to establish baseline before initiating statins If unexplained severe symptoms, fatigue during statin therapy: promptly discontinue statin, address possibility of rhabdomyolysis If mild-to-moderate symptoms develop during statin therapy: Discontinue statin until symptoms evaluated Evaluate for other conditions that might cause muscle symptoms If muscle symptoms resolve and no contraindication, give original or lower dose of same statin to establish causal relationship between muscle symptoms and statin therapy If causal relationship exists, discontinue original statin. When symptoms resolve, use different statin at low dose. Once a low dose of a statin is tolerated, gradually increase the dose as tolerated. 19

20 If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above. If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose. Recommendation for Hepatic dysfunction: Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiating statin therapy. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of the skin or sclera). Recommendation for other conditions: o Statins modestly increase the excess risk of type-2 diabetes in individuals with risk factors for diabetes. o Individuals receiving statin therapy should be evaluated for new-onset diabetes mellitus according to the current diabetes screening guidelines. o Those who develop diabetes mellitus during statin therapy should be encouraged to adhere to a heart healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events. o For individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for non-statin causes, such as exposure to other drugs and systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy. o A review of the manufacturer s prescribing information may be useful before initiating any cholesterol-lowering drug for individuals >75 years of age, as well as in individuals that are taking concomitant medications that alter drug metabolism or taking multiple drugs. o Decreasing the statin dose may be considered when 2 consecutive values of LDL C levels are <40 mg/dl. o It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of simvastatin to 80 mg daily 20

21 4. Specific Dyslipidemias 4.1 Management of Hypertriglyceridemia a. Hypertriglyceridemia is associated with an increased risk of cardiovascular events and acute pancreatitis. Along with lowering LDL-C levels and raising HDL-C levels, lowering triglyceride levels in high-risk patients (e.g., those with cardiovascular disease or diabetes) has been associated with decreased cardiovascular morbidity and mortality. Although the management of mixed dyslipidemia is controversial, treatment should focus primarily on lowering LDL-C levels. (5) Hypertriglyceridemia is defined as a fasting plasma triglyceride level that exceeds 2.26 mmol per L (200 mg/dl) and can be further classified as shown in (table 6). When triglyceride levels exceed5.65 mmol per L (500 mg/dl), patients may develop acute pancreatitis. Levels exceeding 1000 mg/dl define chylomicronemia which may result in lipemia retinalis, eruptive xanthomas, hepatomegaly, and potentially fatal acute pancreatitis. (6) Table-6 Serum triglyceride classifications Triglyceride classification ATP III levels ATP = Adult Treatment Panel. Normal Lower than 150 mg per dl (1.70 mmol per L) Borderline high 150 to 199 mg per dl (1.70 to 2.25 mmol per L) High 200 to 499 mg per dl (2.26 to 5.64 mmol per L) Very high 500 mg per dl (5.65 mmol per L) or highe 21

22 Causes of Hypertriglyceridemia Hypertriglyceridemia can be grouped into primary or secondary types (6), (Table 7). Table-7 Primary and Secondary Causes of Hypertriglyceridemia Primary causes: 1. Familial Hypertriglyceridemia (types IV and V) 2. Familial Combined Dyslipidemia (types IIa, IIb, and IV) 3. Polygenic Hypercholesterolemia (type IIa) 4. Broad Beta Disease (Type III) Secondary causes: 1. Overweight/obesity 2. Diet (high in saturated fats and carbohydrates) 3. Physical inactivity 4. Excessive ethanol consumption 5. Hypothyroidism 6. Lipodystrophies ( including metabolic syndrome) 7. HIV infection 8. Renal disease (including the nephrotic syndrome and renal dialysis) 9. Acute spinal cord injury 10. Anorexia nervosa 11. Cushing s syndrome 12. Organ transplant 13. Sarcoidosis 14. Systemic lupus erythematosus 15. Myeloma 16. Medications (antiretroviral therapy, glucocorticoids, estrogens, tamoxifen, 13- cis-retinoic acid, antihypertensives,(hydrochlorothiazide, nonselective β-blocker) and antipsychotics (clozapine, olanzapine) 22

23 Clinical Presentation Typically, patients with hypertriglyceridemia are asymptomatic. Patients with chylomicronemia may present with abdominal pain, a result of organomegaly caused by organ distention from fat infiltration that can trigger acute pancreatitis (6). Management a.initial management of hypertriglyceridemia should include counseling for therapeutic lifestyle changes and screening for metabolic syndrome. Patients also should be screened for other acquired or secondary causes (5). Routine laboratory tests, including measurement of serum glucose, serum creatinine, and blood urea nitrogen as well as thyroid and liver function testing, should be performed to rule out secondary causes of hypertriglyceridemia (6). If the patient has diabetes, optimizing glycemic control may help lower triglyceride levels without additional medications for hypertriglyceridemia. BORDERLINE-HIGH TRIGLYCERIDE LEVEL Drug therapy is not indicated for patients with borderline-high triglyceride levels (i.e., 150 to 199 mg per dl (1.70 to 2.25 mmol per L). Instead, the physician should consider screening for metabolic syndrome and other acquired or secondary causes of hypertriglyceridemia. Management of high cholesterol is the primary goal (5). HIGH TRIGLYCERIDE LEVELS Management of high cholesterol is the primary goal in patients with high triglyceride levels (i.e., 200 to 499 mg per dl (2.26 to 5.64 mmol per L). Statins with triglyceride-lowering properties like Rosuvastatin(Crestor), Atorvastatin (Lipitor) and to lower extent simvastatin(zocor) are the preferred first-line agents for patients with hypercholestrolemia. If goals not achieved, a fibrate, niacin, or fish oil can be considered. In patients with elevated triglyceride levels and normal LDL-C and HDL-C fibrate may be most appropriate. Whereas Niacin may be most appropriate in patients with low HDL-C and high LDL-C levels (5). 23

24 VERY HIGH TRIGLYCERIDE LEVELS Patients with very high triglyceride levels (i.e., 500 mg per dl (5.65 mmol per L) or higher usually require drug therapy in addition to therapeutic lifestyle changes. Fibrates or niacin is a practical first-line choice for these patients. The initial goal is to decrease the risk of acute pancreatitis, especially if triglyceride levels are above 1,000 mg per dl (11.30 mmol per L). In addition, patients with a triglyceride level of 1,000 mg per dl or higher should be placed on a very low-fat diet (i.e., 15 percent or less of caloric intake) (5). 4.2 Metabolic syndrome: Metabolic syndrome is defined as any three of the following: 1) Increased waist circumference ( 102 cm in men and 88 cm in women) ( 90 cm for Asian men and 80 cm in Asian women), indicating central obesity) 2) Elevated triglycerides ( 1.7 mmol/l) 3) Decreased HDL cholesterol (<1.03 mmol/l for men,<1.29 mmol/l for women) 4) Blood pressure above 130/85 mm Hg or active treatment for hypertension 5) Fasting plasma glucose level above 5.6 mmol/l or active treatment for hyperglycemia. Individuals with the metabolic syndrome have a cardiovascular risk approaching that of full diabetes and should be treated accordingly. The natural progression of untreated metabolic syndrome is to develop overt type 2 diabetes (7). Management of Metabolic Syndrome Action to prevent or reverse excess weight gain will prevent or sometimes even reverse the metabolic abnormalities and hypertension. Weight reduction often requires an exercise program as well as dietary intervention, since these individuals commonly have a low basal metabolic rate. Insulin sensitizing drugs (eg, metformin) are known to be effective in centrally obese patients with overt diabetes, and may also be useful in patients with metabolic syndrome and at high risk (7). 24

25 4.3 Management of Low HDL Cholesterol (Hypoalphalipoproteinemia) "Low HDL cholesterol is a strong independent predictor of CHD (coronary heart disease). Low HDL cholesterol is defined categorically as a level < 40 mg/dl (<1mmol/l). (8) The causes of low HDL cholesterol levels are listed in (table 8) (8). Table-8 Causes of low HDL cholesterol levels are Type II diabetes Overweight, obesity Elevated triglycerides (TGs) A lack of physical activity Cigarette smoking A very high carbohydrate intake (>60% of calories) Certain agents (such as progestational drugs, anabolic steroids, and beta blockers). Low HDL levels should be managed in the following manner (8) : Reducing low-density lipoprotein (LDL) levels is the primary goal. - Metabolic syndrome is the second target. - Treatment for isolated low HDL cholesterol is provided mainly to patients with CHD and CHD risk equivalents. - It is unclear whether pharmacologic agents should be used to raise the HDL cholesterol level in otherwise healthy persons, because no published clinical trials are available that demonstrate a benefit. - Niacin is the most effective agent currently available. However, many patients with isolated low HDL do not respond well to niacin. Gemfibrozil and fenofibrate modestly raise the HDL cholesterol level. They are most effective in the setting of concomitant hypertriglyceridemia. - Statins only mildly raise HDL cholesterol levels. They are not recommended for this purpose alone. - Identify and correct secondary factors:( smoke cessation, weight management, encourage regular exercise, eliminate medications associated with low HDL cholesterol levels and control diabetes optimally. 25

26 5. Lifestyle Management Lifestyle Management is an integral component of treating patient with dyslipidemia and is effective in improving the lipid profile and reducing LDL-C and risk factors associated with CVD. Nutrition therapy should be applied as the sole therapeutic approach for dyslipidemia management for at least 3 months for primary prevention. Depending on patient progress, nutritional therapy may be extended through 6 months before initiating lipid-lowering drug therapy. For high-risk patients, it is appropriate to institute nutrition therapy and pharmacotherapy simultaneously General lifestyle recommendations to reduce LDL-C (9) (10) : 1. Consume a heart healthy dietary pattern that emphasizes intake of: Fruits ( 2 servings/day) Vegetables ( 3 servings/day, 1 of these should be dark green or orange vegetables) Grains ( 6 servings/day, one-third of those as whole grains and high-fiber cereals) Low-fat dairy products Legumes, fish, lean meats, skinless poultry and nuts Vegetable oils excluding palm and coconut oils and limits intake of sweets, sugar-sweetened beverages, and red meats. Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions including diabetes. 2. Reduce saturated fat intake to 5% of total calories. There is strong evidence that reductions in LDL-C were achieved when saturated fat intake was reduced from 15% to 5% of calories. Reducing saturated fat intake lowers both LDL-C and HDL-C. But because the absolute effect tends to be greater for LDL-C than HDL-C, reducing saturated fat intake has a beneficial effect on the lipid profile. Favorable effects on lipid profiles are greater when saturated fat is replaced by polyunsaturated fatty acids, followed by monounsaturated fatty acids, and then carbohydrates. 3. Reduce percent of calories from trans fat. Reducing intake of trans fatty acids lowers LDL-C, with little or no effect on HDL-C or triglycerides levels. The main sources of trans fat are food prepared from partially hydrogenated vegetable oils such as cakes, donuts, French fries biscuits and other processed or fast food. Naturally occurring 26

27 trans fatty acids is present in the form of ruminant fat in meat and dairy products and reducing intake of saturated fat in meat and dairy fat will result in additional reductions in trans fat intake. 4. Regular aerobic physical activity Aerobic physical activity reduces LDL-C and non HDL-C and increases HDL-C. Regular Moderately intense physical activity also has beneficial effects on diabetes risk, hypertension, and hypertriglyceridemia. It is recommended to have at least 30 minutes of moderate-intensity physical activity (consuming 4-7 kcal/min) 4 to 6 times weekly, with an expenditure of at least 200 kcal/day. Or to have 3 4 sessions per week, lasting on average 40 min per session, and involving moderate- to vigorous-intensity physical activity. For weight loss or weight maintenance the duration of daily exercise should be extended to min. Suggested moderate activities include brisk walking, riding a stationary bike, water aerobics, cleaning/scrubbing, mowing the lawn, and sporting activities To improve adherence, daily physical activity goals can be met in a single session or in multiple sessions throughout the course of a day (10 minutes minimum). 5. Maintain a healthy body weight Losing 5 to 10 percent of body weight can help significantly reduce cholesterol levels in overweight and obese individuals. 6. Smoking cessation Smoking has an adverse effect on lipids and is probably the most important health behavior intervention for the prevention of CVD. 7. Limiting alcohol intake to 30 g or less per day (1-2 drinks) If a patient currently drinks alcohol, a maximum intake of one drink per day for women and up to two drinks per day for men should not be exceeded. This level of alcohol consumption has been associated with a reduced risk of CVD. Current evidence does not justify recommending that non-drinkers begin drinking alcohol. 27

28 5.2. Specific Dietary management and supplementations: The following section describes the macronutrient composition of the nutritional management of dyslipidemia and discusses the dietary supplementations (11). 1. The recommended macronutrient intake is: Total fat of 25-35%. Total protein of 15-20% Total carbohydrates (CHO) of 45-60% of kcals Fat Components <7% of calories from saturated fat. Trans-fatty acids consumption as low as possible. Cholesterol <200 mg per day. The majority of total fat intake should be derived from unsaturated fat sources, monounsaturated vegetable oil like olive or canola oils, or polyunsaturated vegetable oil like corn or sunflower oils. Carbohydrates and Protein Consider replacing saturated fat and trans-fatty acids with, high fiber/complex carbohydrates, and/or protein especially the legumes, fish and poultry. Avoid refined CHO Fibers Fiber-rich foods at least 25 g to 30 g of fiber per day Soluble fiber (7 g to 13 g). Foods rich in soluble fiber include fruits, vegetables, whole grains, high-fiber cereals, oatmeal, and legumes, especially beans. Diets high in total and soluble fiber can further reduce TC by 3% and LDL-C up to 7%. 2. Omega-3 Fatty Acids 2.2. Marine and Plant Food Sources Omega-3 Fatty Acids Omega-3 fatty acids are found in fish oil and in some vegetable oils, nuts, seeds and soy. Fish oil contains two important omega-3 fatty acids: eicosapentanoic acid (EPA) and docosahexanoic acid (DHA). Plant sources provide ALA (alpha-linolenic acid). Patient should be encouraged to eat food sources of both marine and plantderived omega-3 fatty acids to reduce risk of CVD. Studies report that in persons with CVD and higher plasma levels of (DHA) and (EPA) are associated with a reduction in arrhythmias and fatal heart disease and reduced progression of coronary atherosclerosis. Also it was found that higher intakes of plant-derived omega-3 fatty acids are associated with a decreased rate of cardiac death and non-fatal myocardial infarction (MI) and may be protective against recurrence of MI. In persons without CVD, consumption of fish and other marine-derived omega-3 fatty acids may or may not be associated with reduced incidence of arrhythmia. While higher intakes of plant-derived omega-3 are associated with a lower risk of fatal ischemic heart disease (IHD). 28

29 For patients without CVD: Recommend two fish servings per week (4 oz. servings each) For patients with CVD: Recommend two or more fish servings per week (4 oz. servings each) a. Omega-3 Supplements If persons choose to consume EPA plus DHA supplements or EPA alone to reduce the risk of CVD mortality, the healthcare provider should advise: Supplementation with 850 mg to 1 g per day of EPA and/or DHA can reduce sudden death by 45% in patients with CVD. Omega-3 supplementation up to 3 grams per day can be used for the management of hypertriglycemia. EPA and DHA supplements are contraindicated in patients with CVD with angina or implantable cardiovertor devices. Consumption of more than three grams of omega-3 fatty acids per day may cause gastrointestinal symptoms. 3. Nuts Daily consumption of unsalted peanuts and tree nuts, specifically walnuts, almonds, pecans, and pistachios can be incorporated into a cardioprotective dietary pattern. Consuming five ounces (average ~900 kcals) of nuts per week is associated with a reduced risk of CVD. Studies demonstrate that 1.75 to 4oz (½ to 1 cup or 315 to 720 kcals) nuts per day lower TC by 4% to 21% and LDL-C by 6% to 29%. The practicality of this recommendation is limited, because of the significant caloric contribution this amount of nuts provides. 4. Plant Stanols and Sterols Consider incorporating plant sterol and stanol ester-enriched foods into a cardio protective diet, for a total consumption of two to three grams per day. These doses further lower TC by 4% to 11% and LDL-C by 7% to 15%. Doses beyond three grams do not provide additional benefit. Plant stanols and plant sterols are also effective in people taking statin drugs. 5. Antioxidant Supplements (Vitamin E, Vitamin C, and Beta-Carotene) Antioxidant-rich foods such as fruits, vegetables, whole grains and nuts containing vitamin E, vitamin C, and β-carotene (and other carotenoids), have been shown to be associated with reduced CVD risk and should be encouraged. Supplemental vitamins E, C, and/or β-carotene should not be recommended for the prevention and treatment of CVD. Research indicates high doses of these antioxidants (above the Recommended Dietary Allowance RDA) do not provide cardiovascular benefit and may cause harm and even shorten life span. 6. Folate, Vitamin B6, Vitamin B12, 29

30 The food sources of folate, vitamin B6, and vitamin B12 should be included in the cardio protective dietary pattern to meet the DRI. Supplemental doses of these vitamins to lower CVD risk should not be recommended. Although supplemental B-vitamins (folic acid, vitamin B6, and vitamin B12) may lower homocysteine in people with high serum homocysteine levels (>13 µmol per L), this has not translated into reduced CVD events and in fact, may be harmful Patient Advice about Diet and Lifestyle The following are some practical tips on food choices and preparation that can be given to patient with dyslipidemia (12),(13) : 1. Use lean cuts of meat and remove skin from poultry before eating. Strictly limit organ meats, such as brain, liver, and kidneys they are high in cholesterol. Eat shrimp only occasionally it is moderately high in cholesterol. 2. Select milk and dairy products that are fat free (skim), 1%-fat, or low fat. 3. Use liquid vegetable oils like olive, canola, corn or sunflower oils in place of solid fats like butter, hard margarine, animal fat, coconut and palm tree oil. 4. Minimize the intake of trans fats which is found in vegetable shortening; partially hydrogenated vegetable oil; some margarines; deep fried chips; snack foods, many fast foods; most commercial processed foods and baked goods (e.g., muffins, doughnuts). To be on the safe side, assume that all such products contain trans fats unless they are labeled otherwise. 5. Limit processed meats like sausage and salami that are high in saturated fat and sodium. 6. Consume fish at least twice a week, especially oily fish, e.g. salmon and, Tuna. Several species of Arabian Gulf fish considered as good sources of the omega-3. Sardines (al-ooma in local language) had the highest content of omega-3 with more than 3 g/100 g followed by Grey Sweet Lip (Yanam) which contained nearly 0 7 g/100 g. Medium levels of around g/100 g were found Black Spot Snapper (Naisar), King Mackerel (Kanaad) and Mullet (Beyah) and Crevalle in Malabar (Zubaidy) Low levels of less than 0 2 g were found in Common Rabbit Fish (Saffi), Greasy Grouper (Hamour), and Orange Emperor (Sheari). Low levels were also found in crab and shrimp. 30

31 7. Grill, bake, or broil fish, meat, and poultry. 8. It is advisable to eat 2 or fewer yolks per week and to choose foods made with egg whites or egg substitute. Use egg white instead of whole eggs in recipes with more than one egg. (One egg yolk contains about 213 milligrams of cholesterol). 9. Nuts and seeds can be eaten in limited amount 4 to 5 servings per week. 10. Increase fiber intake by eating legumes, whole-grain products, fruits, and vegetables. Soluble fiber is known to reduce cholesterol level and found in barley, oats, apples, bananas, berries, citrus fruits, nectarines, peaches, pears, plums, prunes, broccoli, Brussels sprouts, carrots, dry beans, peas, soy products (such as tofu). 11. Consume a diet rich in different varieties of vegetables (3 5 servings a day) and fruits (2 4 servings a day). Encourage the consumption of whole vegetables and fruits in place of juices. 12. Choose foods made with whole grains. Common forms of whole grains are whole wheat, oats/oatmeal, rye, barley, corn, popcorn, brown rice, wild rice. 13. Minimize beverages and foods high in added sugars. Common forms of added sugars are sucrose, glucose, fructose, maltose, dextrose, corn syrups, concentrated fruit juice, and honey. 14. Prepare foods with little or no salt and reduce salt intake by: a. Consuming fresh food and limiting the processed and packaged food b. Comparing the sodium content of similar products and choosing products with less salt c. Choosing food products that are reduced in salt. d. Limiting condiments (e.g., soy sauce, ketchup). 15. Use the nutrition facts and ingredients list when choosing foods to buy and choose low saturated fat and trans fat free versions. 16. When you eat food that is prepared outside house, follow the healthy dining out strategies such as avoiding deep-fried foods, since many restaurants continue to use partially hydrogenated oils in their fryers. 17. Balance calorie intake and physical activity to achieve or maintain a healthy body weight. To achieve this you may need to track your weight, physical activity, and calorie intake, prepare and eat smaller portions and replace highcalorie foods with fruits and vegetables. 18. Increase physical activity to get at least 30 minutes of a moderate intensity physical activity, such as brisk walking, on most, and preferably all, days of the week. And Track and, when possible, decrease sedentary time (e.g. watching television, surfing the Web, playing computer games). Incorporate physical movement into habitual activities. 31