Dyslipidemia Drugs PDF

PHARMACOLOGY II LECTURE TITLE: Drugs for the Treatment of Dyslipidemia LECTURER: Amy M. Franks, Pharm.D. RECOMMENDED VIEWING: Cholesterol Metabolism RECOMMENDED READING: Goodman & Gilman’s: The Pharmacologic...

PHARMACOLOGY II LECTURE TITLE: Drugs for the Treatment of Dyslipidemia LECTURER: Amy M. Franks, Pharm.D. RECOMMENDED VIEWING: Cholesterol Metabolism RECOMMENDED READING: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed, Chapter 33: Drug Therapy for Dyslipidemia LEARNING OBJECTIVES: After completing this 2-hour lecture, the student will be able to: 1. Describe the two major complications of dyslipidemia. 2. Identify atherogenic and anti-atherogenic lipoproteins. 3. List benefits of lipid-lowering therapy. 4. Explain the mechanisms of action for drugs used to treat dyslipidemia, including the impact on lipoprotein metabolism. 5. Describe the effects of specific drugs on lipoproteins levels (LDL, triglycerides, etc). 6. Describe the major adverse effects of the drugs used to treat dyslipidemia. 7. Discuss the mechanisms by which specific drug interactions may increase risk for adverse effects in patients taking drug therapy for dyslipidemia. 8. Discuss specific drug properties and patient care considerations that impact the selection and use of drugs for the treatment of dyslipidemia. 9. Discuss the role of statin intolerance in anti-dyslipidemic drug therapy and potential ways to mitigate it. 10. Recommend necessary monitoring parameters for drugs used to treat dyslipidemia. Franks – Dyslipidemia 1 DEFINITIONS AND TERMINOLOGY I. Cholesterol: Most common steroid in body. Essential for formation of cell membranes, bile acids, vitamin D, estrogens, androgens, progesterone, and other hormones. II. Triglyceride (TG): particle made of glycerol and 3 fatty acids. Important source of stored energy because TG are sent to adipose tissue for storage. III. Lipoprotein: spherical macromolecule containing __________ and __________. Lipoproteins transport hydrophobic TGs and cholesterol esters in the bloodstream. A. Hydrophobic core (cholesterol esters, TGs) surrounded by water-soluble components (apoproteins, phospholipids, unesterified cholesterol) to provide structural stability. B. Lipoproteins are classified according to their density. IV. Dyslipidemia: disorder of lipoprotein metabolism, including lipoprotein excess (e.g., LDL cholesterol, TG) or Ahnström, J. (2009). Apolipoprotein M: Studies of Structure and Function. deficiency (e.g., HDL cholesterol). V. Hyperlipidemia: increased plasma lipid concentrations of cholesterol and/or TG. VI. Hypertriglyceridemia (hyperlipemia): increased levels of TG VII. Atherosclerotic Cardiovascular Disease (ASCVD): includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin. CLINICAL RELEVANCE OF DYSLIPIDEMIA I. 2 major clinical complications A. Atherosclerosis and ASCVD 1. Atherosclerotic plaques (atheromas) contain foam cells (transformed macrophages) and smooth muscle cells filled with cholesterol esters. a. Interactions with “scavenger receptors” result in lipoproteins being taken up into the vascular cell wall by endocytosis B. Acute pancreatitis – in patients with severe hypertriglyceridemia (>1000 mg/dl) II. Familial hypercholesterolemia (FH) results from mutations in lipoproteins or their receptors and can accelerate atherosclerosis. Franks – Dyslipidemia 2  A. Most commonly involves mutations of LDL receptor gene, resulting in defective or absent LDL receptors. This causes high plasma LDL. B. Homozygous familial hypercholesterolemia (HoFH) is associated with accelerated ASCVD and early death if untreated. C. Overall FH prevalence ~1:200-300 people; HoFH prevalence ~1:300,000 MAJOR LIPOPROTEIN CLASSES To effectively use anti-dyslipidemic drug therapy effectively, it is important to understand the characteristics of the major lipoprotein classes and their roles in cholesterol metabolism. Please review material from previous courses and/or view this detailed review video: https://www.youtube.com/watch?v=wQY0xpwqPfQ I. Low-Density Lipoproteins (LDL) A. Atherogenic B. Derived from VLDL & IDL C. Major cholesterol carrier in body (cholesterol-rich). D. Function: transport cholesterol to tissues other than the liver 1. Upon oxidation, LDL is taken up by macrophages, leading to foam cell formation in atheromas. 2. LDL receptors in the liver take up ~75% of LDL from plasma. a. **Key point: manipulation of _____________________________________ is the major way diet and drugs lower plasma LDL cholesterol** Franks – Dyslipidemia 3 II. High-Density Lipoprotein (HDL) A. Antiatherogenic (protective) 1. ____________________________________: removes excess cholesterol from cells (arterial wall) and transports back to liver to be removed or used for normal processes (synthesizing cell membranes, hormones, etc). 2. Also likely to have properties that decrease inflammation, oxidation, & thrombosis B. Association with ASCVD risk 1. Low HDL (hypoalphalipoproteinemia) independently increases risk for ASCVD 2. Cigarette smoking and diabetes are associated with low levels of HDL LIPOPROTEIN METABOLISM I. Endogenous and Exogenous Pathways of Lipid Transport Reverse Cholesterol Transport Endogenous and exogenous lipid transport (Figure taken from Harrison’s Principles of Internal Medicine, 12th Edition, p. 1816). A. Enterohepatic Circulation: Approximately 50% of the cholesterol entering the intestine is reabsorbed and recirculates back to the liver. The remaining cholesterol is excreted through the feces. The majority (97%) of bile acids are reabsorbed from Franks – Dyslipidemia 4  the intestine and transported back to the liver. This circulation of cholesterol regulates new synthesis of _______________ and ________________ in the liver. DRUG THERAPY FOR DYSLIPIDEMIA I. In general, lipid-lowering therapy results in: A. Reduced/improved lipoprotein levels B. Reduced atheroma size (slowly reduced after starting therapy) C. Reduced macrophage inflammatory activity (quickly) D. *Reduced risk for ASCVD events within months of starting therapy (likely mostly attributable to reduction in inflammatory activity) E. **Reduced mortality risk (statins) HMG-COA REDUCTASE INHIBITORS (STATINS) I. Available agents: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin II. MOA: competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate. This inhibits an early, rate-limiting step in cholesterol synthesis. Therefore, statins reduce LDL by ___________________________ and increasing expression of ________________ on liver cell membranes. III. Effects A. **Overwhelming evidence of mortality reduction and ASCVD event reduction** B. Lipid effects 3. Averages for class (considerable variation between agents) a. LDL:  ~30%, with greater % reduction in patients with higher baseline values b. HDL:  5-10% c. TG:  10-30%, with greater % reduction for higher baseline values 4. Dose-dependent LDL reduction: ___________________ 5. Maximal effects on plasma lipids in about __________________ 6. Effective for almost all patients with high LDL. HoFH is exception; little response due to both alleles on LDL receptor gene coding for dysfunctional LDL receptors. C. Non-lipid (pleiotropic) effects of statins are likely important and may vary with the agent. Examples include improved endothelial function and decreased inflammation, oxidation, and platelet aggregation. Franks – Dyslipidemia 5 IV. Specific Drug Properties A. Intensity classification High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin Therapy Therapy Therapy Daily dose lowers LDL Daily dose lowers LDL by Daily dose lowers LDL by by ~ 50% on average ~30% to 40 ULN. Byproducts of muscle breakdown overload filtration by the kidneys and can result in myoglobinuria, acute kidney injury, electrolyte disturbances, and can progress to multi-organ failure and death. 4. Risk factors include: a. _______________________________ effect i. Higher doses ii. Drug interactions iii. Advanced age, especially >80 years iv. Hepatic dysfunction v. Renal dysfunction b. Untreated hypothyroidism c. Strenuous exercise B. Hepatotoxicity – very rare (1 case per million person-years of use). Check ALT at baseline. No need to monitor during therapy unless patient has clinical signs/symptoms suspicious of liver injury. Discontinue if ALT is ______ upper limit of normal. Usually contraindicated in patients with active or chronic liver disease. C. Hyperglycemia & diabetes – Fasting plasma glucose increases 5-7 mg/dL with statin use. Small increases in incidence of ___________________ have been seen in clinical trials. Mortality benefit outweighs risk for new-onset diabetes. D. Renal – At least one study has demonstrated a higher risk for hematuria, proteinuria, and progression to kidney failure with rosuvastatin compared to atorvastatin. 1. eGFR < 30 ml/min/1.73 m2: reduce to rosuvastatin 5-10 mg/day VI. Patient Care Considerations A. Timing of Dose: Take in evening (why?) 1. Not necessary for atorvastatin, pitavastatin, & rosuvastatin B. Pregnancy: Cholesterol synthesis is important to fetal development. Statins should be discontinued during pregnancy. Franks – Dyslipidemia 7  1. FYI: The FDA is asking manufacturers to remove the blanket contraindication of statins in all pregnant patients but acknowledges that most pregnant patients should d/c statin therapy. See information here: https://www.fda.gov/media/150774/download. C. Statin intolerance: incidence reports vary from 5-30% 1. Patient’s inability to tolerate sufficient dose of statin to achieve therapeutic objectives. 2. What to do if a patient is unable to tolerate a statin: a. Remove risk factors (eliminate drug interactions, treat hypothyroidism, etc) b. Washout c. Try different/multiple strategies: lower dose, different statin, non-daily dosing i. Generally recommend trying at least 2 different statins with the lowest approved daily dose. VII. Monitoring: A. Fasting lipid profile at baseline and 4-6 weeks after initiation or dose change. B. AST, ALT at baseline. C. Do not routinely monitor CK; only when muscle symptoms develop. NIACIN I. Available agents – niacin (aka nicotinic acid, vitamin B3) Supplied as crystalline/immediate-release (IR), sustained release (SR), and extended release (ER) dosage forms. IR and SR formulations are available OTC; ER is Rx only. II. MOA – several mechanisms have effects on lipids: A. Adipose tissue: inhibits lipolysis of TGs, reducing transport of FFA to liver, thus reducing hepatic TG synthesis B. Liver: inhibits TG production by inhibiting both synthesis and esterification of fatty acids. This results in decreased VLDL production, which ultimately reduces LDL. C. Increases LPL to increase clearance of chylomicrons and VLDL TGs. D. Increases HDL by decreasing clearance of apo A-I (apolipoprotein contained in HDL) III. Effects Reduces TG by ________ Reduces LDL by 15-25% Increases HDL by 30-40%, but lesser effect in those with HDL 3x ULN. C. Do not routinely monitor CK; only when muscle symptoms develop. INHIBITOR OF CHOLESTEROL ABSORPTION I. Available agent: ezetimibe Also available as fixed-dose combination products: Vytorin (with simvastatin); Roszet (rosuvastatin); Nexlizet (with bempedoic acid) II. MOA: Inhibits ______________________ of cholesterol by inhibiting the transport protein NPC1L1. Reduced delivery of cholesterol to liver results in upregulation of LDL receptors. Reduced hepatic delivery of cholesterol also triggers compensatory increase in hepatic cholesterol synthesis. III. Effects: Reduces LDL cholesterol by ______when used alone. Adding ezetimibe to a statin results in additional ______ over statin alone (compare to rule of 6 with statin dose increase) IV. Specific Drug Properties A. Bile acid sequestrants inhibit absorption of ezetimibe. B. Eliminated in the feces primarily as unchanged drug. V. Adverse effects – well tolerated VI. Patient Care Considerations – can use with other lipid-lowering agents except bile acid sequestrants. VII. Monitoring A. Lipid panel B. Other monitoring as needed if used in combination with other agents Franks – Dyslipidemia 10 BILE ACID SEQUESTRANTS I. Available agents: cholestyramine, colestipol, colesevelam II. MOA – Positively charged; bind with negatively charged bile acids to prevent reabsorption of bile acids and excretion in feces. Increase excretion of bile acids 10-fold. Hepatic cholesterol content is diminished with increased production of bile acids, leading to upregulation of LDL receptors in liver. A. Effect is partially offset by increased endogenous production of cholesterol by upregulation of HMG-CoA reductase (attenuated by coadministration of statin). III. Effects – Primary effect is LDL reduction (15-20% alone). No substantial effect on HDL. TG levels may ____________ through up-regulation of VLDL production in the liver. IV. Adverse effects – very safe (not absorbed) but not well tolerated A. GI – bloating, dyspepsia, constipation common and often dose-limiting. GI effects of colesevelam may be better tolerated. Constipation and bloating may be relieved by increasing dietary fiber. GI s/s affect adherence. B. Increased TGs V. Patient Care Considerations A. Patient counseling about how to take dosage forms (powder, etc) B. Drug interactions – general rule to take other meds at least ___ hour before or ____ hours after BAS. C. Contraindicated in patients with severe hypertriglyceridemia. VI. Monitoring – lipids, especially frequent monitoring of TGs in patients with hypertriglyceridemia OMEGA-3 FATTY ACIDS I. EPA (eicosapentaenoic acid) + DHA (docosahexaenoic acid) ethyl esters II. Available agents: multiple fish oil/krill oil supplements (OTC), Lovaza (Rx, EPA + DHA ethyl esters ), Vascepa (Rx, EPA ethyl ester) III. MOA: likely reduces hepatic VLDL production and enhances TG clearance from VLDL; exact mechanism unknown Franks – Dyslipidemia 11 IV. Effects: Reduce TGs ______ in patients with hypertriglyceridemia. LDL may __________ as much as 45%. Small increase in HDL (5-10%). V. Specific Drug Properties A. Doses of _____ g/d are required for TG reduction B. Some evidence that products with EPA + DHA have increased LDL cholesterol in patients with severe hypertriglyceridemia, whereas EPA-only products may not increase LDL (e.g., no change in LDL in Vascepa clinical trial) VI. Adverse effects A. Common: belching (“fishy burps”), dyspepsia, taste perversion B. Increased LDL C. Some concern about increased incidence of atrial fibrillation VII. Patient Care Considerations A. Drug interaction: Increased risk for ________ in patients taking antithrombotic agents. B. Reduce adverse effects: refrigerate supplements, take with meals. C. Caution in patients with fish and/or shellfish allergies. VIII. Monitoring A. Lipid panel at baseline and every 4-12 weeks. B. ALT periodically ADENOSINE TRIPHOSPHATE-CITRATE LYASE (ACL) INHIBITOR I. Available agent: bempedoic acid (Nexletol). Combination with ezetimibe (Nexlizet) II. MOA: ACL is an enzyme upstream from HMG-CoA reductase in the cholesterol biosynthesis pathway. Inhibits ACL to inhibit cholesterol synthesis in liver and reduce plasma LDL via upregulation of LDL receptors. III. Effects: Reduces LDL by ________ on top of other therapies Reduces HDL by 5-10% No change in TGs IV. Specific Drug Properties A. Both parent drug and active metabolite undergo glucuronidation and are primarily eliminated in the urine Franks – Dyslipidemia 12  B. Drug interactions: increase risk for myopathy when used with concomitant simvastatin or pravastatin. Limit doses of these statins. C. Cost ~$10-15/day V. Adverse effects A. Hyperuricemia (26%), gout (2%) B. Rare (60 years, concomitant use of corticosteroids or fluroquinolones, renal insufficiency, prior tendon disorders VI. Patient Care Considerations A. No adjustment for renal or hepatic impairment. B. Weak inhibitor of OATP transporters a. Increases serum concentrations of estradiol and norethindrone by inhibiting OATP transporter responsible for hepatic uptake. Avoid combination. b. Limit simvastatin to 20 mg daily when co-administered because of likely inhibition of OATP 1B1. i. PK studies with other high-dose statins did not result in clinically significant increases in serum concentrations of other statins. VII. Monitoring A. Lipid panel at baseline and 8-12 weeks after initiation. B. Uric acid as indicated by s/s. C. s/s of tendinopathy DRUGS FOR FAMILIAL HYPERCHOLESTEROLEMIA I. PCSK9 inhibitors – monoclonal antibodies Available agents: alirocumab (Praluent), evolocumab (Repatha) A. MOA: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that binds to the hepatic LDL receptor and enhances its degradation, resulting in a higher plasma LDL concentration. PCSK9 inhibitors are monoclonal antibodies that bind free PCSK9 to prevent its binding to the LDL receptor. This increases availability of LDL receptors to clear LDL from plasma. Inhibit PCSK9 activity for 2-3 weeks after administration, then LDL levels begin to rise. Complementary effect to statins, since statins stimulate production of LDL receptors. Franks – Dyslipidemia 13  B. Effects: 1. Reduce LDL up to ______ during monotherapy; up to _____ in patients already on statin 2. Reduce TGs by 12-30% 3. Reduces Lp(a) by 25%. C. Specific Drug Properties 1. Administered as SQ infusions every 2 or 4 weeks. Alirocumab: auto-injector (20-second injection) Evolocumab: Sureclick® autoinjector (15-second injection); Pushtronex® (5- minute infusion); prefilled syringe 2. High cost ($5,000-6,000/year) 3. No expected drug interactions D. Adverse effects 1. Injection site reactions 2. Flu-like symptoms 3. Do not appear to increase risk for myopathy 4. Neurocognitive effect ($2,000/capsule) D. Adverse effects 1. GI: diarrhea (79%), nausea (65%), vomiting (34%) 2. Hepatoxicity: increased AST/ALT (34%) 3. Hepatic steatosis (78% mild, 13% significant fat increase), may lead to fatty liver disease. Results from accumulation of TGs in the liver. E. Patient Care Considerations 1. REMS: use restricted to patients with HoFH 2. Administer ________________ to minimize GI adverse effects. Adhering to a strict low-fat diet may also improve GI effects. Franks – Dyslipidemia 15  F. Monitoring 1. Lipid profile 2. Liver profile (AST/ALT and alkaline phosphatase, bilirubin) before initiation and periodically thereafter. Franks – Dyslipidemia 16