Drugs for Dyslipidemias PDF

AQULOGO Drugs for Dyslipidemias HUSSEIN HALLAK, PH.D. AL-QUDS UNIVERSITY Triglycerides and Cholesterol Two primary forms of lipids in the blood Water-insoluble fats that must be bound to apoproteins, specialized lipid-carrying proteins Lipoprotein is the combination of triglyceride or...

AQULOGO Drugs for Dyslipidemias HUSSEIN HALLAK, PH.D. AL-QUDS UNIVERSITY Triglycerides and Cholesterol Two primary forms of lipids in the blood Water-insoluble fats that must be bound to apoproteins, specialized lipid-carrying proteins Lipoprotein is the combination of triglyceride or cholesterol with apoprotein  Types of Lipoproteins Lipid Content Protein content chylomicron Least very-low density lipoprotein (VLDL) Low Density Lipoprotein (LDL) intermediate-density lipoprotein (IDL) high-density lipoprotein (HDL) Most  Coronary Heart Disease Target total cholesterol in adults: Less than 200 mg/dL In subjects with no risk factors LDL levels between 100 and 130 mg/dL may be acceptable. Generally, aim for LDL levels below 100 High Risk Individuals: aim for LDL levels below 70 mg/dL a family history of premature heart disease (a father or brother who was diagnosed at 55 or younger, or a mother or sister diagnosed before age 65) smoking obesity Diabetes high blood pressure low levels of HDL (below 40 mg/dL). Triglycerides Target — Less than 150 mg/dL Coronary Heart Disease The risk of CHD in patients with cholesterol levels of 300 mg/dL is 3 to 4 times greater than that in patients with levels less than 300 mg/dL Per some studies, each 10% reduction of TC... ◦ Drops CHD mortality by 15%. ◦ Drops total mortality by about 10%. Dyslipidemia HMG-CoA reductase inhibitors (Statins) Cholesterol Absorption Inhibitors Fibric acid derivatives Niacin (nicotinic acid) Bile acid sequestrants  Drugs for Dyslipidemias: Drugs used to lower lipid levels These drugs are adjuncts to non-drug measures Their effects are fairly predictable Combined treatment may be indicated, may also pose additional risks unrelated to lipid lowering Lipid-lowering drugs aren’t permanent cures All these drugs pose potential dangers for pregnant women, breast-fed infants Treatment of Dyslipidemias is Generally Based On... Actual abnormalities in lipid profiles Age, gender, number and nature of other of coronary risk factors Presence of other co-morbidities that might contraindicate certain drug(s) Whether non-drug measures work adequately  The “Statins” Example: ® Atorvastatin (LIPITOR ) Inhibit HMG Co-A reductase, which is used by the liver to produce cholesterol Lower the rate of cholesterol production  VLDL production 1st choice for most pts. with hypercholesterolemia Usually more effective than any other drugs for lowering LDL, Total-C May also  HDL-C and  TGs  HMG-CoA: 3-hydroxyl-3- methylglutaryl-coenzyme A Rosuvastatin (Crestor®) Atorvastatin (Lipitor®) Simvastatin Pravastatin fluvastatin  Main Adverse Responses - I. Myositis and Myopathy (muscle pain) May be. ◦ Localized to certain muscle groups or diffuse. ◦ Mild to severe/life-threatening (from renal failure / rhabdomyolysis). Risk is: ◦ Dose-related. ◦  By drug interactions. ◦  By renal or hepatic disease (both are contraindications), advanced age, etc. Monitor and forewarn. Definitions Myositis (mi´´o-si´tis): inflammation of a voluntary muscle. Myopathy (mi-op´ah-the): any disease of a muscle. Adj., myopath´ic. Rhabdomyolysis (rab´´do-mi-ol´î-sis): disintegration of striated muscle fibers with excretion of myoglobin in the urine. Statin-Linked Rhabdomyolysis  Statin, Myopathy & Muscle Damage CMAJ 2009;181(1-2):E11-E18 Only 1 patient with structural injury had a circulating level of creatine phosphokinase (CPK) that was elevated more than 1950 U/L (10× the upper limit of normal) Interpretation: Persistent myopathy in patients taking statins reflects structural muscle damage A lack of elevated levels of circulating creatine phosphokinase does not rule out structural muscle injury Findings suggest that normal or moderately elevated levels of creatine phosphokinase do not exclude statin associated muscle injury. Thus, alternative treatment strategies for patients with muscle symptoms need to be evaluated Main Adverse Responses - II. Hepatotoxicity May be asymptomatic Requires monitoring as tx. starts Statins: Main Drug Interactions Hepatotoxicity/ myositis risk   by co-administration of Niacin Gemfibrozil, cyclosporin, erythromycin   risk of myopathy and renal consequences Risks vary among the various Statins Ezetimibe (Zetia®) Ezetimibe+Simvastatin (Vytorin®)  “Fibrates” Prototype: Gemfibrozil (LOPID®) Believed to work by activating lipase, which breaks down cholesterol Also suppress release of free fatty acid from the adipose tissue, inhibit synthesis of triglycerides in the liver, and increase the secretion of cholesterol in the bile Are mainly used to  TGs, can have variable “good or bad” effects on LDL Are alternatives to Niacin, often combined with statin for combined High Cholesterol & TGs Fibrates: Main Risks Cholelithiasis (possibly requiring cholecystectomy) from saturation of bile with cholesterol Myositis, hepatitis possible but less common than with statins (unless combined with them) ◦ Cholelithiasis (ko´´le-lî-thi´ah-sis): The presence or formation of "gallstones“ ◦ Cholecystectomy (ko´´le-sis-tek´to-me): excision of the gallbladder Fibrates: Main DDIs + Statins —>  risk, severity of myopathy Displaces highly-bound drugs from plasma-proteins, e.g., ◦ Warfarin ◦ Oral hypoglycemics ◦ Oral antithyroid drugs Other Fibrates Fenofibrate (TRICOR®) — basically a gemfibrozil “me-too” Clofibrate (ATROMID-S®) ◦ On market for many years ◦ High risk of GI malignancies in men ◦ Higher gall bladder complications in all pts. ◦ Not 1st line choice  Niacin (Nicotinic Acid; Vitamin B3) At “high doses”… Thought to increase activity of lipase, which breaks down lipids Reduces the metabolism or catabolism of Cholesterol and Triglycerides Niacin Uses Mainly used + statin for combined, severe, refractory hypercholesterolemia + hypertriglyceridemia Effective in lowering triglyceride, total serum cholesterol, and LDL levels Increases HDL levels  Niacin: Side Effects, Adverse Responses - I. Significant cutaneous flushing + pruritis (itching) shortly after dose Several strategies to handle ◦ Wait for tolerance to develop ◦ Small divided doses ◦ Aspirin premedication (if not contraindicated) ◦ Use sustained release prep instead (NIASPAN) Severe GI distress ( by antacids)  Niacin: Relative Contraindications Peptic ulcer disease Hyperuricemia, gout Diabetes mellitus Hepatic dysfunction Niacin: Key DDIs  Risk of statin-induced myopathy Antagonizes effects of all antidiabetic drugs: insulin, oral hypoglycemics, antihyperglycemics, e.g., ◦ Metformin (GLUCOPHAGE®) ◦ Glipizide, glyburide, other “sulfonylureas” Bile Acid Sequestrants: Cholestyramine and Colestipol Are nonabsorbable anion exchange resins (bile acid-binding resins)  Intestinal reabsorption,  fecal excretion of bile acids… —>  conversion of cholesterol to bile acids Up-regulation of LDL receptors —>  LDL uptake from blood Mainly reduce LDL-C May  TGs, esp. when TGs are high already Bile Acid Sequestrants Drug Interactions Adsorb,  absorption, of many other oral drugs Potentially clinically significant (symptomatic) deficiencies of fat-soluble vitamins ( absorption) Side Effects Constipation Heartburn, nausea, belching, bloating These adverse effects tend to disappear over time PCSK9 Inhibition  Evolocumab: % Change in UC LDL-C From Baseline - 140 mg every 2 weeks OR 420 mg once monthly SC injection 20 from Baseline, Mean (± SE) UC LDL-C Percent Change 6.0% 10 0 -10 -20 Treatment difference 57% -30 -40 -50 -60 -51.5% -70 Number of patients: -80 302 294 264 599 582 542 Baseline Week 12 Week 52 Study Week Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599) FAS = Full analysis set, UC = ultracentrifugation Lipid Lowering Implications Before beginning therapy, obtain a thorough health and medication history. Assess dietary patterns, exercise level, weight, height, VS, tobacco and alcohol use, family history. Assess for contraindications, conditions that require cautious use, and drug interactions. Lipid Lowering Implications Contraindications include biliary obstruction, liver dysfunction, active liver disease. Obtain baseline liver function studies. Patients on long-term therapy may need supplemental fat-soluble vitamins (A, D, K). Take with meals to decrease GI upset. Lipid Lowering Implications Patient must be counseled concerning diet and nutrition on an ongoing basis. Instruct on proper procedure for taking the medications. Powder forms must be taken with a liquid, mixed thoroughly but not stirred, and NEVER taken dry. Other medications should be taken 1 hour before or 4 to 6 hours after meals to avoid interference with absorption. Lipid Lowering Implications Clofibrate often causes constipation; instruct patients to increase fiber and fluid intake to offset this effect. To minimize side effects of niacin, start on low initial dose and gradually increase it, and take with meals. Small doses of aspirin or NSAIDs may be taken 30 minutes before Niacin to minimize cutaneous flushing.  Lipid Lowering Implications Inform patients that these agents may take several weeks to show effectiveness. Instruct patients to report persistent GI upset, constipation, abnormal or unusual bleeding, and yellow discoloration of the skin. Lipid Lowering Implications Monitor for side effects, including increased liver enzyme studies. Monitor for therapeutic effects: ◦ Reduced cholesterol and triglyceride levels