Severe hypertriglyceridemia (i.e., triglyceride levels of >1000 mg/dl) requires therapy to prevent pancreatitis. Moderately elevated triglyceride levels (150 to 400 mg/dl) also are of concern because they often occur as part of the metabolic syndrome, which includes insulin resistance, obesity, hypertension, low HDL-C levels, and substantially increased CHD risk. The atherogenic dyslipidemia in patients with the metabolic syndrome is characterized by moderately elevated triglycerides, low HDL-C levels, and lipid-depleted LDL (sometimes referred to as "small, dense LDL") (Reaven, 2002; Reaven, 2003; Grundy et al., 2004a; Grundy et al., 2004c). The metabolic syndrome affects ~25% of adults and is common in CHD patients; hence, identification of moderate hypertriglyceridemia in a patient, even if the total cholesterol level is normal, should trigger an evaluation to identify this disorder
Table 35–1. National Cholesterol Education Program: Adult Treatment Guidelines (2001).Desirable Borderline to High1HighTotal cholesterol < 200 (5.2)2200–2392 (5.2–6.2)> 240 (6.2)2LDL cholesterol < 130 (3.4)3130–159 (3.4–4.1) > 160 (4.1)HDL cholesterol > 60 (1.55)Men > 40 (1.04)Women > 50 (1.30)Triglycerides < 150 (1.7) 150–199 (1.7–2.3) > 200 (2.3)1 Consider as high if coronary disease or more than 2 risk factors are present2 mg/dL (mmol/L)3 Optimal level is < 100 (2.6)
, When lowering of LDL-C is insufficient, the dosage may be increased to a (GFR 30 -60mL/min/1.73 m2)
, inadequately treated hypothyroidism
have shown that pitavastatin isOf the 2,800 patients randomized to LIVALO 1 mg to 4 mg in controlled clinical studies, 1,209 (43%) were 65 years and older.
Treatment Based on LDL-C Levels (2004 Revision of NCEP Adult Treatment Panel III Guidelines)RISK CATEGORY LDL-C GOAL THERAPEUTIC LIFESTYLE CHANGE DRUG THERAPY Very high risk <70 mg/dl* No threshold No threshold Atherosclerosis-induced CHD plus one of: (a) multiple risk factors,(b) diabetes mellitus, (c) a poorly controlled single factor,(d) acute coronary syndrome,(e) metabolic syndrome High risk <100 mg/dl* No threshold No threshold CHD or CHD equivalent Moderately high risk <130 mg/dl (Optional <100 mg/dl) ≥100 mg/dl ≥130 mg/dl (100-129 mg/dl)a 2+ risk factors 10-year risk: 10%-20% Moderate risk <130 mg/dl ≥130 mg/dl >160 mg/dl 2+ risk factors 10-year risk <10% 0-1 risk factor <160 mg/dl ≥160 mg/dl ≥190 mg/dl (Optional: 160-189 mg/dl)b
INTRODUCTION 11.5 years of life are lost- consequence of MI. Hyperlipidemia -atherosclerosis & associated condition like CAD CerebroVD PAD. Dyslipidemia -endothelial damage – HT. Fatal & nonfatel CHD events & strokes – reduced by 30-40%- statin. Higher cholesterol – higher CHD risk. NCEP-ATP3 – new target LDL-C <70mg/dl-high risk patient.
INTRODUCTIONNCMH- GOI- 62 million by 2015an inhibitor of HMG-CoA reductase.synthetic lipid-lowering agent for oraladministration.Hygroscopic and slightly unstable in light.comparative safety profile, fewer drug interactions.Effective in elderly, diabetic & those at high risk ofdeveloping CHD.
Classification of Plasma Lipid LevelsTotal cholesterol <200 mg/dl Desirable 200-239 mg/dl Borderline high ≥240 mg/dl High HDL-C <40 mg/dl Low (consider <50 mg/dl as low for women) >60 mg/dl HighLDL-C <70 mg/dl Optimal for very high risk (minimal goal for CHDequivalent patients) <100 mg/dl Optimal 100-129 mg/dl Near optimal 130-159 mg/dl Borderline high 160-189 mg/dl High ≥190 mg/dl Very highTriglycerides <150 mg/dl Normal 150-199 mg/dl Borderline high 200-499 mg/dl High ≥500 mg/dl Very high
PHARMACOKINETIC Bioavailability : 60% TMAX : 1 hour Volume of distribution : 148 L Half life : 11 hours Plasma protein binding : 96% Metabolism : hepatic (substrate of CYP2C9) Excretion : biliary
MECHANISM OF ACTIONCompetitive inhibitor of HMG-CoA reductase, whichis rate limiting enzyme in cholesterol synthesis inliver. INDICATION & USESPrimary hyperlipidemia and mixed dyslipidemia as an adjuvant therapy to diet to reduce elevated TC, LDL-C,TG and to increase HDL-C.
DOSAGE AND ADMINISTRATION Can be taken with or without food, at any time of day Dose Range: 1 mg to 4 mg OD. Primary hyperlipidemia and mixed dyslipidemia: Starting dose 2 mg, maximum of 4 mg/day Moderate renal impairment and ESRD on haemodialysis: Starting dose 1mg OD max. dose of 2mg/day Dosage Forms And Strengths: tab. 1 mg , 2 mg and 4 mg.
CONTRAINDICATIONS1) Known hypersensitivity2) Active liver disease3) Pregnancy and nursing mother4) Co-administration with cyclosporineADVERSE DRUG REACTIONS Most common: myalgia, back pain, diarrhea, constipation and pain in extrimity . Most serious: rhabdomyolysis , myopathy , myoglobinuria and ARF.
DRUG INTERACTIONSCyclosporine : C/ILopinavir/Ritonavir: combinationshould not be usedErythromycin : limit dose to 1 mgRifampin : limit dose to 2 mgFibrates : increased risk of skeletalmuscles effectsNiacin : increased risk of skeletalmuscles effects
WARNING PRECAUTIONS Skeletal muscle effects ( e.g., myopathy and rhabdomyolysis) : risk increases in dose dependent manner, with advance age, renal impairment and combination use with fibrates. Liver enzymes abnormalities and monitoring: persistent elevation in AST/ALT can occur. (>3 times upper limit of normal-decrease dose/ withdraws
USE IN SPECIFIC POPULATIONSPregnancy : Teratogenic effects: Pregnancy Category XNursing Mothers : Rat study-excreted into breast milk.Pediatric Use: Safety and have not been established.Geriatric Use: No significant differences in efficacy or safety were observed between elderly & younger patients.
CLINICAL STUDIES Active controlled study with atorvastatin (NK -104-301) For the percent change from baseline to endpoint in LDL-C, LIVALO was Superior to atorvastatin. for the two pair wise comparisons: LIVALO 2 mg vs. atorvastatin 10 mg and LIVALO 4 mg vs. atorvastatin 20 mg. Mean treatment differences (95% CI) were 1% (-1%, 3%) and 1% (- 2%,4%), respectively. Active-controlled study with simvastatin (NK-104-302): Active-controlled study with pravastatin in elderly (NK-104-306): Active-controlled study with simvastatin in patients with ≥ 2 risk factors for coronary heart disease (NK-104-304) Active-controlled study with atorvastatin in patients with type II diabetes mellitus (NK-104-305)
CLINICAL STUDY Dose-ranging study: to evaluate the efficacy of Livalo compared with placebo Dose-Response in Patients with Primary Hypercholesterolemia (Adjusted Mean % Change from Baseline at Week 12) Treatme- N LDL-C TC TG Apo -B HDL-C nt PLACEBO 53 -3 -2 1 -2 0 Livalo 1 52 -32 -23 -15 -25 8 mg Livalo 2 49 -36 -26 -19 -30 7 mg Livalo 4 51 -43 -31 -18 -35 5 mg