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    Low Hdl Hyper Tg Low Hdl Hyper Tg Presentation Transcript

    • Hypertriglyceridemia and Low HDL: Is it Linked with Increased Cardiovascular Risk? Iris Thiele C. Isip Tan MD, FPCP, FPSEM Ma. Luz Vicenta Guanzon MD, FPCP, FPSEM Herbert Ho MD, FPCP, FPSEM
    • The Case 45/F comes in for a physical Premenopausal Nonsmoker Sedentary Cholecystitis at age 36 No medication http://www.lipidsonline.org/clinical-cases
    • Family History Both parents, ages 70 and 72: type 2 diabetes Father: coronary heart disease at age 60 Mother: stroke at age 66 Mother currently on dialysis http://www.lipidsonline.org/clinical-cases
    • Family History 2 of 3 brothers have T2DM All of her 3 children obese Daughter, age 16, has “pre-diabetes” http://www.lipidsonline.org/clinical-cases
    • Initial PE BP 134/80 mm Hg HR 76 bpm Wt 200 lb Ht 5’4” BMI 34.4 kg/m2 Waist 41” Heart exam: normal Abdomen: obese with RUQ scar http://www.lipidsonline.org/clinical-cases
    • Initial Labs FBS 118 mg/dL TC 236 mg/dL TG 200 mg/dL LDL-C 140 mg/dL HDL-C 46 mg/dL http://www.lipidsonline.org/clinical-cases
    • Is this a high- risk patient? TC 236 mg/dL TG 200 mg/dL LDL-C 140 mg/dL HDL-C 46 mg/dL
    • She has none of the ATP-III risk factors Cigarette smoking Hypertension (BP >140/90 mm Hg or on medication) Low HDL cholesterol (<40 mg/dL) Family history of premature CHD (CHD in male first degree relative <55 y; CHD in female first degree relative <65 y) Age (men >45 y; women >55 y) NCEP-ATP III 2001
    • Life-habit risk factors Obesity Physical inactivity Atherogenic diet NCEP-ATP III 2001
    • “The life-habit risk factors are direct targets for clinical intervention, but are not used to set a lower LDL cholesterol goal of therapy.” NCEP-ATP III 2001
    • NCEP-ATP III 2001 Emerging risk factors Lp(a) Homocysteine Impaired fasting glucose Prothrombotic and Evidence of subclinical proinflammatory factors atherosclerotic disease
    • “The emerging risk factors do not categorically modify LDL-C goals ... utility in selected persons to guide intensity of risk-reduction therapy.” NCEP-ATP III 2001
    • NCEP-ATP III Patient is low-risk How will you address the patient’s dyslipidemia?
    • Table 5: LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories. Risk Category LDL Goal LDL Level LDL Level at Which to Initiate at Which to Therapeutic Lifestyle Consider Drug Changes (TLC) Therapy CHD or CHD Risk <100 mg/dL !100 mg/dL !130 mg/dL Equivalents (100-129 mg/dL: (10-year risk >20%) drug optional)* 10-year risk 10-20 %: 2+ Risk Factors <130 mg/dL !130 mg/dL !130 mg/dL (10-year risk quot;20%) 10-year risk <10 %: !160 mg/dL 0-1 Risk Factor† <160 mg/dL !160 mg/dL !190 mg/dL (160-189 mg/dL: LDL-lowering drug optional) * Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify tri- glycerides and HDL, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory. † Almost all people with 0-1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in people with 0-1 risk factor is not necessary. NCEP-ATP III 2001
    • Table 5: LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories. Risk Category LDL Goal LDL Level LDL Level at Which to Initiate at Which to Therapeutic Lifestyle Consider Drug Changes (TLC) Therapy CHD or CHD Risk <100 mg/dL !100 mg/dL !130 mg/dL Equivalents (100-129 mg/dL: (10-year risk >20%) drug optional)* 10-year risk 10-20 %: 2+ Risk Factors <130 mg/dL !130 mg/dL !130 mg/dL (10-year risk quot;20%) 10-year risk <10 %: !160 mg/dL 0-1 Risk Factor† <160 mg/dL !160 mg/dL !190 mg/dL (160-189 mg/dL: LDL 140 mg/dL: She is not a LDL-lowering drug candidate for drug therapy! optional) * Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify tri- glycerides and HDL, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory. † Almost all people with 0-1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in people with 0-1 risk factor is not necessary. NCEP-ATP III 2001
    • Figure IV.2–4. Therapeutic approaches to persons with 0–1 risk factor The LDL cholesterol goal is <160 mg/dL. Drug therapy can be considered if the LDL cholesterol level is !190 mg/dL after a trial of TLC. If LDL cholesterol is 160–189 mg/dL, drug therapy is optional depending on clinical judgment. LDL Public Health M essages <130 on Healthy Lif e Habits Reevaluation: 5 Years Public Health M essages LDL on Healthy Lif e Habits 130–159 Reevaluation: 1 Year 0–1 Risk Factor (10-year risk usually <10 %) LDL Continue <160 TLC LDL 3 mos !160 TLC Continue TLC & LDL LDL-Lo w ering Drugs 160–189 O ptional* Reinforce healthy life habits. LDL Continue TLC & Re-evaluate after 1 year. !190 Consider A dding LDL-Lo w ering Drugs * Factors favoring drug use are a severe single risk factor, a family history of premature CHD, and/or underlying or emerging risk factors in addition to a single major risk factor. NCEP-ATP III 2002
    • Philippine Dyslipidemia Guideline (2005) • Hypertension • Familial hypercholesterolemia For low-risk patients • LVH without evidence of • Smoking atherosclerosis, drug • Family history of therapy is not premature CAD recommended, • Male sex regardless of lipid levels • Age >55 years • Proteinuria/ Low risk: <3 risk factors albuminuria • BMI >25
    • For purposes of ATP III, the diagnosis of the metabolic syndrome i when three or more of the risk determinants shown in Table 8 are These determinants include a combination of categorical and bord She has the Metabolic Syndrome factors that can be readily measured in clinical practice. Table 8. Clinical Identification of the Metabolic Syndrome Risk Factor Defining Level Abdominal Obesity* Waist Circumference † Men >102 cm (>40 in) Women 41 cm >88 cm (>35 in) Triglycerides 200 mg/dL !150 mg/dL HDL cholesterol Men <40 mg/dL Women 46 mg/dL <50 mg/dL Blood pressure 134/80 mm Hg !130/!85 mmHg Fasting glucose 118 mg/dL !110 mg/dL NCEP-ATP III 2001 * Overweight and obesity are associated with insulin resistance and the metabolic syndrome. How
    • Metabolic syndrome confers intermediate risk Same as NCEP-ATP III definition except cut-off for abdominal obesity should geographic region-specific LDL-C target for intermediate-risk: <130 mg/dL High-risk <100 mg/dL and lower-to moderate-risk patients <160 mg/dL
    • At all stages of dietary therapy, physicians are encouraged to refer patients to registered dietitians or other qualified nutritionists for medical nutrition therapy, which is the term for the nutritional intervention and guidance Start TLC provided by a nutrition professional. Figure 1. A Model of Steps in Therapeutic Lifestyle Changes (TLC) Visit 1 Visit 2 Visit 3 Visit N 6 wks 6 wks Q 4-6 mos Begin Lifestyle Evaluate LDL Evaluate LDL Monitor Therapies response response Adherence to TLC LDL If LDL goal not achieved, intensify If LDL goal not achieved, consider 140 mg/dL LDL-lowering Tx adding drug Tx ! Emphasize ! Reinforce reduction in reduction in saturated fat and saturated fat and ! Initiate Tx for cholesterol cholesterol Metabolic ! Encourage ! Consider adding Syndrome moderate physical plant stanols/sterols ! Intensify weight activity ! Increase fiber intake management and ! Consider referral ! Consider referral physical activity to dietitian to dietitian ! Consider refer- Goal LDL ral to dietitian <130 mg/dL NCEP-ATP III 2001
    • ! Therapeutic options for enhancing LDL lowering such as plant stanols/sterols (2 g/day) and increased viscous (soluble) fiber (10-25 g/day) Weight reduction Enforce TLC diet ! ! Increased physical activity Table 6. Nutrient Composition of the TLC Diet Nutrient Recommended Intake Saturated fat* Less than 7 % of total calories Polyunsaturated fat Up to 10 % of total calories Monounsaturated fat Up to 20 % of total calories Total fat 25-35 % of total calories Carbohydrate † 50-60 % of total calories Fiber 20-30 g/day Protein Approximately 15 % of total calories Cholesterol Less than 200 mg/day Total calories (energy)‡ Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain NCEP-ATP III 2001 * Trans fatty acids are another LDL-raising fat that should be kept at a low intake. † Carbohydrate should be derived predominantly from foods rich in complex carbohydrates including grains, especially whole grains, fruits, and vegetables. ‡ Daily energy expenditure should include at least moderate physical activity (contributing approximately 200 Kcal per day).
    • based on the literature. Although cumulative responses Because of th have not been documented by clinical trial, a sizable long-term w summed response from the multiple components of tion should b LDL-Clikely. can be achieved with diet TLC is goal individuals t medical nutr Table V.5–2. Approximate and Cumulative LDL Cholesterol Reduction Achievable By Dietary Modification A second ele Dietary Dietary Approximate LDL drome is to Component Change Reduction should provi Major activity depe Saturated fat <7 % of calories 8–10 % and social ci Dietary cholesterol <200 mg/day 3–5 % given to refe Weight reduction Lose 10 lbs 5–8 % if this resour Other LDL-lowering options cise can caus Viscous fiber 5–10 g/day 3–5 % for CHD. Ex Plant sterol/ 2g/day 6–15 % that may be stanol esters V.2–6 and V Cumulative estimate 20–30 % should be pr amounts of v NCEP-ATP III 2002 Adapted From Jenkins et al. 768
    • American Heart Jour ari et al July 20 Proportion and projected number of US adults in 2007 with high LDL-C, TG and low HDL-C nd projected number of US adults in 2007 (N = 212 million) with combinations of high LDL-C, triglycerides, and low HDL-C. Ghandehari et al Am Heart J 2008
    • NNHES 2003: Mean Lipid Levels of Filipinos Male Female Total cholesterol 178.9 (0.98) 190.3 (1.13) LDL-C 112.4 (0.89) 126.8 (1.03) HDL-C 40.3 (0.24) 42.6 (0.24) Triglyceride 130.5 (2.3) 104.6 (1.4) Dans et al PJIM 2005
    • NNHES 2003: Prevalence of Abnormal Lipid Levels Male (%) Female (%) TC >240 mg/dL 5.8 (1.0) 11.5 (1.0) LDL-C >190 mg/dL 2.0 (0.0) 5.4 (1.0) HDL-C <40 mg/dL 60.2 (2.2) 47.7 (1.0) TG 200-399 mg/dL 11.8 (1.0) 5.3 (1.0) Dans et al PJIM 2005
    • HDL-C 46 mg/dL: Is that low? NCEP-ATP III defines low HDL as <40 mg/dL NCEP-ATP III 2001
    • HDL-C 46 mg/dL: Is that low? NCEP-ATP III definition of Metabolic Syndrome: HDL <50 mg/dL in women NCEP-ATP III 2001
    • High TG TG Classification: Normal <150 mg/dL Borderline-high 150-199 mg/dL High 200-499 mg/dL TC 236 mg/dL Very high >500 mg/dL TG 200 mg/dL LDL-C 140 mg/dL HDL-C 46 mg/dL NCEP-ATP III 2001
    • Is this a high- risk patient? Does the patient’s low HDL-C and high TG confer additional risk over and above that TC 236 mg/dL conferred by LDL-C TG 200 mg/dL level? LDL-C 140 mg/dL HDL-C 46 mg/dL
    • when LDL-cholesterol is normal, or near-normal.22,23 onary heart disease, compared with those who do not.28 Other epidemiological evaluations have confirmed these Data from the Health Survey for England show that HDL- findings. The Atherosclerosis Risk in Communities study cholesterol ,0.9 mmol/L (35 mg/dL) is more common (ARIC) followed 12 339 middle-aged subjects without cor- (P , 0.001) in men with cardiovascular disease (23%) onary heart disease at baseline for 10 years.24 The risk of compared with men without cardiovascular disease ARIC study: Cardiovascular risk increase developing coronary heart disease was strongly related to HDL-cholesterol in women and in men (Figure 1 ). (16%).29 A similar association was found for women (8 vs. 5%, respectively, P , 0.001). In men or women as serum HDL-C decreases N = 12 ,339 middle-aged subjects without coronary heart disease at Figure 1 Relationship between HDL-cholesterol at baseline and cardiovascular risk in the Atherosclerosis Risk in Communities Study (ARIC). Adapted with permission from Sharrett, Ballantyne, and Coady et al. 24 baseline; 10-y follow-up Chapman J. Eur Heart J 2005
    • population. cholesterol at baseline (Figure 2 ). These findings are consistent with the status of low HDL-cholesterol as an independent risk factor for cardiovascular disease, as atins eliminate the elevated coronary defined in epidemiological studies and described earlier. Incidence of CV events in statin trials y disease risk associated with low cholesterol at baseline Treatment with a statin provided similar absolute reduction in cardiovascular risk at all levels of HDL- inversely proportional to baseline HDL-C ervention trials? cholesterol, as the curves for active treatment and placebo in Figure 2 were, in general, roughly parallel. rom some of the major intervention trials with Thus, a similar relationship between the levels of HDL- have been stratified for HDL-cholesterol at cholesterol and cardiovascular risk holds in patients Chapman J. Eur Heart J 2005
    • Treatment with statin provided similar absolute reduction in CV risk at all levels of HDL-C Chapman J. Eur Heart J 2005
    • greater predictive potential in women compared 36,37 with men (Figure 2). More recently, the Lipid Research Clinics’ Follow-Up Study also demon- Risk of Coronary Heart Disease Increases as strated that both HDL-C and triglycerides were Triglyceride Increases (Framingham Data) TG and HDL-C levels may have greater predictive potential in women than in men. Adapted from Castelli WP. Am J Cardiol 1992
    • PROCAM scoring scheme includes triglycerides as major independent risk factor.
    • Metabolic Syndrome increases CV risk Multifactorial Causes of CHD in Metabolic Syndrome Hyperglycemia Hypertension Impaired fibrinolysis Atherogenic dyslipidemia Insulin resistance Inflammatory Hyperinsulinemia profile Abdominal obesity Ceska R. Diabetes Vasc Dis Res 2007
    • Anti-atherogenic action of HDL Chapman MJ et al. Curr Med Res Opin 2004 Reverse Anti- cholesterol inflammatory transport activity Anti- Anti- infectious oxidative activity HDL activity Anti- Anti- thrombotic apoptotic activity activity
    • CETP Inhibition (D): diminished heteroexchange of CE and TG between HDL and TG-rich proteins with normalization of HDL-particle turnover
    • Torcetrapib: CETP Inhibitor CETP inhibitors: most potent HDL-raising agents available Enhance reverse cholesterol transport from peripheral tissues to liver Correct HDL functional defects High CETP activity in T2DM and MetSyn: enriches TG content of HDL particles Kontush et al. Nat Clin Pract Cardiovasc Med 2007
    • Are all types of HDL-C-raising dangerous? Is the specific HDL-C-raising mechanism of Torcetrapib dangerous? Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) prematurely terminated Dec 2006: excess mortality 15,000 high CV-risk patients on atorvastatin randomized to 60 mg torcetrapib or placebo (median 550 d) HDL-C ↑72%, LDL-C ↓25% CV mortality ↑40%, CV events ↑25%, non-CV death ↑100% Kontush et al. Nat Clin Pract Cardiovasc Med 2007
    • TC 236 mg/dL TG 200 mg/dL LDL140 mg/dL Will raising her HDL-C reduce HDL 46 mg/dL cardiovascular risk?
    • Helsinki Heart Study: Primary Prevention Every 1% increase in HDL-C 34% reduction in coronary events Raise HDL-C by 11% 3% decrease in Reduce triglycerides by 35% coronary events Reduce LDL-C by 11% Greatest benefit for independent of changes in HDL-C <42 mg/dL (1.09 mmol/L) triglycerides and TG >200 mg/dL (2.20 mmol/L) LDL-C Manninen V et al. JAMA 1988
    • Effect of various drug classes on coronary stenosis progression or regression, as related to in-treatment changes in LDL-C and HDL-C Brown et al Should HDL-C and LDL-C be lipid therapy targets? 91 Brown et al J Clin Lipidology 2007 Change from baseline in mean ∆%S = 3.0 - 0.076 (%∆HDL-C) +0.06 (%∆LDL-C) R2=0.96; P<0.004 4 Placebo (6) proximal % stenosis Fibrates (1) 3 Statins (6) Statin+Resin (1) 2 (∆%S) Niacin Combos (4) 1 ↑Progression 0 ↓Regression -1 -2 0 25 50 75 %∆ HDL-C minus %∆ LDL-C, in Rx Placebo-adjusted (%) Figure 1 Effect of various drug classes on coronary stenosis progression, or regression, as related to in-treatment changes in low-density
    • Effect of various drug classes on trial primary clinical event rate, plotted against in-treatment changes in LDL-C and HDL-C 92 Journal of Clinical Lipidology, Vol 1, No 1, March 2007 Brown et al J Clin Lipidology 2007 %Event Red’n = - 1.28(%∆HDL-C) + 0.97 (%∆LDL-C) R2=0.93; P<0.0001 0 Placebo(23) Fibrates (3) %∆ 1ry Event Rate Statins (11) -20 Statin+Resin (1) Niacin (1) Niacin Combos(5) -40 (%) Ileal Bypass (1) -60 -80 0 25 50 75 %∆ HDL-C minus %∆ LDL-C, in Rx Placebo-adjusted (%)
    • NCEP-ATP III recommendations for the management of Metabolic Syndrome Reduce underlying causes (i.e. obesity and physical inactivity) Treat associated nonlipid and lipid risk factors Treatment of hypertension Aspirin in patients with CHD to reduce prothrombotic state Treatment of elevated TG and low HDL-C NCEP-ATP III 2001
    • NCEP-ATP III: Non-HDL cholesterol as secondary target of therapy in those with high triglycerides Table 9. Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals for Three Risk Categories Risk Category LDL Goal (mg/dL) Non-HDL-C Goal (mg/dL) CHD and CHD Risk Equivalent <100 <130 (10-year risk for CHD >20 %) Multiple (2+) Risk Factors and <130 <160 10-year risk quot;20 % 0-1 Risk Factor <160 236 - 46 = 190 <190 target of therapy. Aside from weight reduction and increased physical activi- ty, drug therapy can be considered in high-risk persons to achieve the non- HDL cholesterol goal. There are two approaches to drug therapy. First, the NCEP-ATP III 2001
    • Approaches to reaching the non-HDL-C goal Intensify therapy with an LDL-lowering drug Add nicotinic acid or fibrate NCEP-ATP III 2001
    • TC 236 mg/dL HDL 46 mg/dL LDL140 mg/dL Will lowering TG her TG improve 200 cardiovascular mg/dL outcomes?
    • Crucial Findings from Major Trials of Fibrate Therapy Study Drug and Lipid Levels Trial Duration (y) Population Daily Dose (% change) Outcomes CHD: ↓9% (NS) Men, secondary Clofibrate CDP ~5 TC ~8; TG ~ -25 Total mortality: no change prevention 1.6 g ↑cholelithiasis with clofibrate Nonfatal MI: ↓25% Men, primary Clofibrate Total mortality: ↑ with clofibrate WHO 5.3 TC -9 prevention 1.6 g ↑ cholelithiasis and cholecystectomy with clofibrate Men, primary Gemfibrozil TC -11; LDL -10 CHD: ↓34%; Nonfatal MI: ↓37%; HHS 5 prevention 200 mg TG -43; HDL +10 Total mortality: No change Men, secondary Gemfibrozil TC -4; LDL 0; CHD death and nonfatal MI: ↓22%; VA-HIT 5.1 TG -31; HDL +6 prevention 200 mg Total mortality: no change Fatal and nonfatal MI and sudden Men and women, Bezafibrate TC -4.5; LDL -6.5 BIP 6.2 death: ↓9% (NS); secondary prev 400 mg TG -21; HDL +18 Total mortality: no change CHD death and nonfatal MI: ↓11% Men and women Fenofibrate TC -11; LDL -12; (NS); Total CV events ↓11%; FIELD 5 with diabetes 200 mg TG -29; HDL +5 total mortality: ↑19% with mellitus fenofibrate (NS) CDP=Coronary Drug Project; WHO=World Health Organization; HHS=Helsinki Heart Study; VA-HIT=Veterans Affairs HDL Intervention Trial; BIP=Bezafibrate Infarction Prevention; FIELD=Fenofibrate Intervention and Event Lowering in Diabetes Backes et al Pharmacotherapy 2006
    • Mixed Results of Fibrate Trials? Fibrate was not always the best choice of drug therapy for patients enrolled in the trials Primary lipid abnormalities were ↑LDL and TC Study TC (mg/dL) HDL (mg/dL) LDL (mg/dL) TG (mg/dL) CDP 251 NR NR NR WHO 249 NR NR NR HHS 270 47 189 175 VA-HIT 175 32 111 161 BIP 212 35 148 145 FIELD 195 43 119 154 Backes et al Pharmacotherapy 2006
    • Should we start a fibrate despite mixed results? Trial data show 2 major subpopulations that appear to receive the greatest clinical benefit from fibrates Mixed dyslipidemia: low HDL-C and elevated triglycerides and/or Impaired glucose homeostasis (T2DM, prediabetes, metabolic syndrome) Backes et al Pharmacotherapy 2006
    • Should we start a fibrate despite mixed results? Fibrates have demonstrated reductions in some of the emerging CV risk factors associated with mixed dyslipidemia and metabolic syndrome CRP level, fibrinogen concentration, small dense LDL particles Backes et al Pharmacotherapy 2006
    • Would the management change if the TC 236 mg/dL patient was TG 200 mg/dL diabetic? LDL-C 140 mg/dL HDL-C 46 mg/dL
    • Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study 9, 795 T2DM patients in Australia and Finland Low-risk population; lipid profile more usually treated with a statin Randomized to fenofibrate 200 mg or placebo and co-prescription of other lipid-lowering agents (94% statins) was allowed Little information on combination: unequal statin drop-in 11% reduction in fatal and non-fatal coronary events (p=0.16) Wierzbicki W. Diab Vasc Res 2006
    • Start statin ADA 2008 Guideline Statin + lifestyle LDL-C goal in individuals therapy regardless of without overt CVD: <100 mg/dL baseline lipid levels (2.6 mmol/L) for diabetic patients with Alternative therapeutic goal in overt CVD those on maximal tolerated statin therapy: ~40% reduction without CVD, >40 from baseline years and have one or more other risk TG level <150 mg/dL (1.7 mmol/ factors L) and HDL-C >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women
    • Philippine Dyslipidemia Guideline 2005 Statement 6: For diabetic patients without evidence of atherosclerosis and with TC >190 mg/dL or LDL >100 mg/ dL, statins are recommended. Statement 7: Fibrates may be recommended as an alternative to statin in diabetic patients with HDL <35 mg/dL and LDL <90 mg/dL.
    • Statins: limited ability to raise HDL HDL level by atorvastatin dose (STELLAR trial) HDL Increase Atorvastatin Dose (mg/dL + SEM) 10 mg 2.9 + 0.05 20 mg 2.4 + 0.05 30 mg 2.2 + 0.04 40 mg 1.1 + 0.02 As dose of atorvastatin doubles, the effect upon HDL elevation declines, and the change across all doses is modest Choi et al Mt. Sinai J Med 2006
    • Safety concern with statin-fibrate combination Potential increased risk for myopathy and rhabdomyolysis Originally observed with gemfibrozil + lovastatin Gemfibrozil + cerivastatin; cerivastatin pulled out of the market Gemfibrozil ↑ blood concentrations of most statins: partial inhibition of statin acid byproducts Fenofibrate is safe: does not use this metabolic pathway Miller M. Medscape Family Medicine 2007
    • Recognize predisposing factors for myopathy Advanced age (>65 years) Impaired renal function (GFR <30 ml/min) Hepatic disease Hypothyroidism Small muscle mass Female gender Use low/starting dose of statin with fenofibrate and titrate upward.
    • TC 236 mg/dL HDL 46 mg/dL LDL140 mg/dL What are the TG benefits of 200 combined statin mg/dL and fibrates?
    • HHS: Fibrate Most Beneficial for High TG and Low HDL-C Slide from Ballantyne C. Medscape CME
    • High “Residual Risk” of CVD in High TG Patient on Statin HPS Collaborative Group. Lancet 2002;360:7-22 Sacks FM et al. Circulation 2000;102:1893-900 Slide from Ballantyne C. Medscape CME
    • Low HDL-C is a Risk Factor in Statin-treated Patients: A Meta-analysis of 14 Trials Slide from Ballantyne C. Medscape CME
    • Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (SAFARI ) Trial Grundy et al. Am J Cardiol 2005;95:462-8 Patients 21-68 y with combined hyperlipidemia (fasting TG levels >150 and <500 mg/dL, and LDL-C >130 mg/dL Slide from Dayspring T. Medscape CME
    • Therapies for Dyslipidemia Evidence of reduction Therapy ∆ LDL-C ∆ HDL-C ∆ TG of CV events Statin ↓18-55% ↑5-15% ↓7-30% ↑↑↑ Niacin ↓5-25% ↑15-35% ↓20-50% ↑↑ Fibrate ↓5-20% ↑10-35% ↓20-50% ↑↑ Bile-acid No effect or ↓15-30% ↑3-5% ↑↑ sequestrant increase Rx omega-3 ↑45% ↑9% ↓45% ↑↑↑ fatty acid Ezetimibe ↓18% ↑1% ↓8% None Slide from Ballantyne C. Medscape CME
    • Therapeutic strategies for HDL-raising across a wide range of low HDL-C phenotypes Monotherapy (%) Combination therapy (%) Up to 10 Statins Nicotinic acid + statin +30 (HATS) (CARE, HPS, ASCOT-LLA) Up to 10 +37 (CLAS-I) Fibrates Nicotinic acid + BAS (VA-HIT, DAIS, HHS) +43 (FATS) Nicotinic acid Up to 35 Statin + fibrate Up to 25 Statin + BAS Up to 15 ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial (lipid-lowering arm); BAS, blie acid sequestrant; DAIS, Diabetes Atherosclerosis Intervention Study; HHS, Helsinki Heart Study; HPS, Heart Protection Study;VA-HIT,Veterans Affairs HDL Intervention Trial Chapman J. Eur Heart J 2005
    • TC 236 mg/dL TG 200 mg/dL LDL140 mg/dL What are the benefits of HDL combined statin 46 mg/dL and nicotinic acid?
    • ol, with ifies low HDL-cholesterol as an important and indepen- atin and dent risk factor for adverse cardiovascular outcomes in HDL- (aforementioned), these guidelines tend to regard low Combination treatment simultaneouslyas a olesterol HDL-cholesterol more as a marker of risk, and outcome reducing LDL-C data package required for global component of the and increasing HDL-C nt Study cardiovascular risk calculators. For example, those eatment more effective in CV risk reduction Athero- Chapman J. Eur Heart J 2005 on regi- a statin reducing bination d reduce greater eatment ces LDL- ast, the as been flushing. h the use ing with earance formu-
    • The Safety and EfficAcy of a COmbination of NiAcin ER with SimvasTatin in Patients with Dyslipidemia: A Dose-Ranging Study Slide from Dayspring T. Medscape CME
    • highly atherogenic lipid profile. A wo Long-term efficacy of USA reached similar conclusions reg ance of low HDL-cholesterol as a t Discussion Niaspan combined and recommended ‘more frequent an intervention to correct low HDL-chole Substantial, and growing, epidemiological evidence has associated lowa statin with HDL-cholesterol with an increased risk of The improvements in the measurem Eligible patients of low HDL-cholesterol implicit in thes will support the future recognition of l TG <9.0 mmol/L (<800 alongside raised LDL-cholesterol as a mg/dL) target for intervention. Indeed, corr One of the following cholesterol should appear in mana in its own right. Given the likely CAD or DM with LDL-C >3.4 mmol/L (>130 mg/ dL) Table 2 CAD or DM to the position pap No Contributors but European Consensus Panel on HDL-choles other coronary risk factors with LDL-C >4.1 Thomas F Gerd Assmann (Germany) (>160 mg/dL) mmol/L (Switze D John Betteridge DM, No CAD or (UK) Luis Masa Eric Bruckert (France) Rodolfo P maximum of 1 coronary M John Chapman (France) Bernhard risk factor with LDL-C Terje R P Eduardo de Teresa (Spain) Figure 4 Long-term efficacy of Niaspanw combined with a statin.55 Figures in parentheses are numbers of patients. Eligible patients had >4.9 mmol/L (>190 mg/ James Sh Jean-Charles Fruchart serum triglycerides 9.0 mmol/L (800 mg/dL) and satisfied one of dL) (France) three further enrolment criteria: (a) positive history of coronary artery Andreas Hamann (Germany) Cesare Si disease or diabetes together with serum LDL-cholesterol 3.4 mmol/L Markolf Hanefeld (Germany) Luc Van G (130 mg/dL); (b) no history of coronary artery disease or diabetes, Francis Heller (Belgium) Eur Heart J 2005 W Chapman J. Anthony but with other coronary risk factors together with serum LDL-
    • COMBination of Prescription Omega-3s with Simvastatin: COMBOS Slide from Dayspring T. Medscape CME Adapted from Davidson MH et al Clin Ther 2007;29:1354-1367
    • Summary 45/F with Met Syn Low-risk if individual risk factors assessed: TLC Intermediate risk if Met Syn: TLC, may consider fibrates If patient were T2DM: statin Limited studies for combination therapy http://www.lipidsonline.org/clinical-cases
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