Drug Therapy for Dyslipidemia PDF

Drug therapy for dyslipidemias Drugs ❑ Drugs ❖ HMG-CoA Reductase inhibitors (Statins) ❖ Bile acid–binding resins ❖ Nicotinic acid ❖ Fibrates ❖ Omega-3 fatty acid ethyl esters ❖ PCSK9 Inhibitors (mAbs) ❖ Liver microsomal triglyceride transfer protein inhibitor ❖ ATP-citrate lyase inhi...

Drug therapy for dyslipidemias Drugs ❑ Drugs ❖ HMG-CoA Reductase inhibitors (Statins) ❖ Bile acid–binding resins ❖ Nicotinic acid ❖ Fibrates ❖ Omega-3 fatty acid ethyl esters ❖ PCSK9 Inhibitors (mAbs) ❖ Liver microsomal triglyceride transfer protein inhibitor ❖ ATP-citrate lyase inhibitor ❖ Angiopoietin-like protein 3 inhibitor (monoclonal antibody) Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ❑ HMG-CoA Reductase inhibitors (Statins) ❑ Drugs ❖ Atorvastatin ❖ Fluvastatin ❖ Lovastatin ❖ Pitavastatin ❖ Rosuvastatin ❖ Pravastatin ❖ Simvastatin ❖ Cerivastatin (rhabdomyolysis)* Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ❑ Lovastatin ❑ Fluvastatin* ❖ Oral: 10, 20, 40 mg tablets ❖ Oral: 20, 40 mg capsules ❖ ER: 20, 40, 60 mg ❖ ER: 80 mg caps ❑ Rosuvastatin* ❑ Pitavastatin: Tablet, Oral : ❖ Tablet, Oral: 5, 10, 20, 40 mg ❖ 1 mg, 2 mg, 4 mg ❖ Capsule, Sprinkle: 5, 10, 20, 40 mg*** ❑ Simvastatin** ❖ Oral: 5, 10, 20, 40, 80 mg tabs ❑ Pravastatin ❖ Oral: 10, 20, 40, 80 mg tablets ❑ Atorvastatin (Lipitor) ❖ Oral: 10, 20, 40, 80 mg tab Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ❑ MOA ❑ Inhibitor HMG-CoA reductase ❖ Hepatic cholesterol synthesis ▪ SREBP (SCAP, Insig) ▪ LDL receptor gene…. ▪ LDL catabolism ❑ Statins ❖ LDL-C levels (Significant, 20-50%) ❖ HDL-C (Modest, 6-12%) ▪ ApoA-I production* ▪ HDL neogenesis* ▪ CETP inhibition* ❖ TG levels: ▪ Higher doses ▪ 10-29% (VLDL) Figure 37–4 Lovastatin and the HMG-CoA reductase reaction. Figure 25.9 Commercially available HMG-CoA reductase inhibitors. inhibition of HMG CoA reductase reduces intracellular cholesterol levels; this activates a protease, which in turn cleaves SREBPs from the endoplasmic reticulum. The SREBPs translocate to the nucleus where they upregulate expression of the LDL receptor gene. Enhanced LDL receptor expression increases receptor- mediated endocytosis of LDL and thus lowers serum LDL. Inhibition of HMG CoA reductase also reduces intracellular levels of isoprenoids, which are intermediates in cholesterol biosynthesis. HMG: hydroxymethylglutaryl; LDL: low-density lipoprotein; LDLR: LDL receptor; SRE: sterol regulatory element; SREBP: SRE binding proteins. Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ❑ Order of decreasing LDL-C lowering potency, include…. ❖ Rosuvastatin ❖ Atorvastatin ❖ Pitavastatin ❖ Simvastatin ❖ Lovastatin ❖ Pravastatin, and ❖ Fluvastatin. Comparison of the percent reduction in serum LDL cholesterol with various statin drugs. Comparison of the efficacy of statin drugs Table 37–7 intensity of statins by approximate reductions in LDL-C with daily dosing High intensity statins Moderate-intensity statins Low-intensity statins Lower LDL-C by ≥50%* Lower LDL-C by 30% to 70% ❖ Renal (minor role)* Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ❑ Therapeutic uses ❖ Dyslipidemias ▪ Best-tolerated agents ▪ Most effective (esp elevated LDL-C) ▪ Exception → HoFH (both alleles) ❖ Drug therapy in children*…. ▪ 10 years or older ▪ Pravastatin, as young as 8 years old ▪ Younger than 10 years ― Genetic lipid disorder (such as FH) ― High-risk ASCVD condition (such as DM) ❖ Statins + resins** The combination of a statin and a bile acid binding resin is more effective than either alone The reduction in LDL cholesterol concentration and the increase in HDL concentration is greater with the combination of a statin and a bile acid binding resin, given as cholestyramine, when compared with therapy with either drug alone. The effects of both drugs decline exponentially with increasing doses. Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ADR ❑ ADR ❑ Myopathy ❖ Mild muscle soreness or weakness (myalgia) ❖ Life-threatening rhabdomyolysis. ❖ Rosuvastatin and pravastatin* → ▪ Better tolerated ▪ Hx of myalgias with other statins. Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ADR ❑ Myopathy ❖ Dose and plasma conc ▪ Factors that interfere with…. ― Hepatic uptake ― Statin catabolism ✓ Advanced age; ✓ Hepatic or renal dysfunction ✓ Small body size, and ✓ Untreated hypothyroidism. ▪ Drugs (catabolism or hepatic uptake) Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ADR ❑ The most common statin interactions occur with…. ❖ Fibrates, especially gemfibrozil (38%), and ❖ Cyclosporine (4%), ❖ Digoxin (5%), ❖ Warfarin (4%) ❖ Macrolide antibiotics (3%), and ❖ Azole antifungals (1%). ❑ Others that ↑ the risk of statin-induced myopathy include…. ❖ Niacin (rare), ❖ Protease inhibitors, ❖ Amiodarone, and ❖ Nefazodone. Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) ADR ❑ Hepatotoxicity ❖ Rare ▪ One case per million person-years of use; ❖ Liver enzymes ▪ At baseline ▪ Thereafter only when clinically indicated Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) Precautions ❑ Precautions ❑ Severe renal impairment* ❖ Atorvastatin ❖ Fluvastatin** ❖ No dose adjustment ❑ Statins ❖ Risk of DM (at high dose) ❖ Beneficial effects (ASCVD events) Vs increased risk Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) Contraindication ❑ Contraindication: ❖ Pregnancy (category X) ❖ Active liver disease. Drug therapy for dyslipidemias HMG-CoA Reductase Inhibitors (Statins) DDI ❑ DDI ❑ Interfere with statin oxidation (CYP3A4) ❖ Macrolide antibiotics (E.g., Erythromycin); ❖ Azole antifungals (E.g., Itraconazole); ❖ Cyclosporine; ❖ Nefazodone ❖ A phenylpiperazine antidepressant; ❖ HIV protease inhibitors; ❖ Amiodarone. ❑ Pravastatin, pitavastatin*, fluvastatin, rosuvastatin ❖ PLUS these predisposing drugs ▪ Less likely to cause myopathy ▪ CYP3A4 Drug therapy for dyslipidemias Statins ❑ Clinical pharmacology and tips D Properties promoting DI Clinically documented interaction ❖ Lovastatin, simvastatin, ❖ Amiodarone: [NP] Decreased atorvastatin, lovastatin, and simvastatin metabolism. and, to a lesser extent, Expect similar interactions with dronedarone atorvastatin are ❖ Antivirals: [P] Amprenavir, atazanavir, boceprevir, darunavir, delavirdine, fosamprenavir, susceptible to CYP3A4 indinavir, nelfinavir, ritonavir, saquinavir, simeprevir, and telaprevir inhibit the metabolism of atorvastatin, lovastatin, and simvastatin. inhibitors and inducers; ❖ Bosentan: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. additive risk with other ❖ Carbamazepine: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. drugs that can cause ❖ Clofibrate: [NP] Increased risk of myopathy. HMG-CoA reductase inhibitors myopathy ❖ Cobicistat: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin. ❖ Conivaptan: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin. ❖ Cyclosporine: [P] Decreased atorvastatin, lovastatin, rosuvastatin, pitavastatin, and simvastatin elimination. ❖ Gemfibrozil: [NP] Increased plasma lovastatin & simvastatin & increased risk of myopathy. (statins) ❖ Kinase inhibitors: [P] Decreased metabolism of atorvastatin, lovastatin, and simvastatin by ceritinib, dasatinib, imatinib, idelalisib, and lapatinib. ❖ Macrolide antibiotics: [P] Clarithromycin & erythromycin inhibit the elimination of statins. ❖ Nefazodone: [NP] Decreased atorvastatin, lovastatin, and simvastatin metabolism. ❖ Phenytoin: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. ❖ Rifampin: [P] Increased atorvastatin, lovastatin, and simvastatin metabolism. ❖ St. John’s wort: [NP] Increased atorvastatin, lovastatin, and simvastatin metabolism. ❖ CCBs: [P] Decreased atorvastatin, lovastatin, and simvastatin elimination with diltiazem, nicardipine, verapamil. ❖ Cyclosporin: [NP] Decreased metabolism of atorvastatin, lovastatin, and simvastatin. Myopathy and rhabdomyolysis noted in patients taking statins and cyclosporine. ❖ Azole antifungal: [HP] Decreased metabolism of lovastatin, simvastatin, and, to a lesser extent, atorvastatin. E, Expected; HP, Highly predictable. Interaction occurs in almost all pts receiving the interacting combination; P, Predictable. Interaction occurs in most pts receiving the combination; NP, Not predictable. Interaction occurs only in some pts receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. Drug therapy for dyslipidemias Cholesterol absorption inhibitor ❑ Cholesterol absorption inhibitor ❖ Ezetimibe Drug therapy for dyslipidemias Cholesterol absorption inhibitor ❑ Dosage forms ❖ Ezetimibe: Tablet, Oral: 10 mg ❖ Ezetimibe + rosuvastatin: tablet ▪ 10mg + 5mg ▪ 10mg +10mg ▪ 10mg + 20mg ▪ 10mg + 40mg ❖ Ezetimibe + simvastatin ▪ 10mg + 10mg ▪ 10mg + 20mg ▪ 10mg + 40mg ▪ 10mg + 80mg ❖ Ezetimibe+ Bempedoic acid + : 10mg + 180mg Drug therapy for dyslipidemias Cholesterol absorption inhibitor ❑ MOA ❑ Enterocytes ❖ Inhibiting niemann-Pick C1–like 1 (NPC1L1) transport protein. Figure 35–2 Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor. Drug therapy for dyslipidemias Cholesterol absorption inhibitor Ezetimibe ❑ Pharmacological effects ❑ ↓ Chylomicrons; ❑ ↓ Chylomicron remnants (liver) ❖ ↑ in cholesterol synthesis (Compensatory) ▪ Statin or ▪ ATP-citrate lyase [ACL] inhibitor). ❖ LDL receptor expression ▪ ↑ LDL-C clearance from the plasma Drug therapy for dyslipidemias Cholesterol absorption inhibitor Ezetimibe ❑ ADME ❖ Highly water insoluble ❖ Readily absorbed ❖ Metabolism: ▪ Intestine → Ezetimibe glucuronide ▪ Enterohepatic recirculation ▪ Not a substrate for P450 ❖ Half-life → 22 hours ❖ Excretion: ▪ Feces (70%) ▪ Urine (10%) Drug therapy for dyslipidemias Cholesterol absorption inhibitor Ezetimibe ❑ Therapeutic uses ❖ ASCVD, primary or secondary prevention ❖ HoFH, HeFH ❖ Homozygous sitosterolemia ❖ Monotherapy or Combination ▪ Monotherapy→ in pts with ↑ LDL-C who are statin intolerant ▪ Combination with statin or bempedoic acid → additive reductions in LDL-C Drug therapy for dyslipidemias Cholesterol absorption inhibitor Ezetimibe ❑ Preparations and use ❑ Ezetimibe ❖ 10-mg tablet ▪ Constant effect 5–20 mg/d. ▪ Daily dose of 10 mg. ❖ At any time during the day ❖ Administration. ▪ With food ▪ Without food → cholesterol excreted in the bile. ❖ In combination with other dyslipidemia medications ▪ Exception: bile acid sequestrants Drug therapy for dyslipidemias Cholesterol absorption inhibitor Ezetimibe ❑ ADR ❖ A well-tolerated agent ❖ Rhabdomyolysis has been reported…. ▪ With monotherapy and ▪ With the addition of agents known to be associated with increased risk (e.g., fibrates, statins) Drug therapy for dyslipidemias Cholesterol absorption inhibitor Ezetimibe ❑ Contraindication ❖ Combination therapy contraindicated in pregnancy Drug therapy for dyslipidemias Cholesterol absorption inhibitor Ezetimibe ❑ DDI ❖ Bile acid sequestrants…. ▪ Inhibit absorption of ezetimibe; ▪ Avoid concurrent use Drug therapy for dyslipidemias Bile acid–binding resins (bile acid sequestrants) ❑ Bile acid–binding resins (bile acid sequestrants) ❖ Cholestyramine ❖ Colestipol ❖ Colesevelam Drug therapy for dyslipidemias Bile acid–binding resins (bile acid sequestrants) ❑ Preparations available. ❖ Cholestyramine………Oral: 4 g packets granules ❖ Colestipol: Oral: ▪ 5 g packets granules (for oral suspension) ▪ 1 g tablets ❖ Colesevelam: Oral ▪ Packets powder………..1875 mg, 3750mg ▪ Tablets…………………….625 mg Drug therapy for dyslipidemias Bile acid–binding resins (bile acid sequestrants) ❑ Mechanism of action ❑ BASs…. ❖ Highly positively charged ❖ Bind negatively charged bile acids. ❑ Resins ❖ Large in size ❖ Not absorbed ❖ The bound bile acids are excreted in the stool. ❑ ↑ Hepatic bile acid synthesis ❖ Cholesterol content ▪ LDL receptors ▪ Upregulation of HMG-CoA⊢ statins Drug therapy for dyslipidemias Bile acid–binding resins (bile acid sequestrants) ❑ Therapeutic uses ❖ Safest lipid-lowering drugs (absorption) ❖ Considered 1st line during pregnancy* ▪ Absorption ❖ Colesevelam: T2DM** Drug therapy for dyslipidemias Bile acid–binding resins (bile acid sequestrants) ❑ Common GI side effects: ❖ Bloating ❖ Dyspepsia ❖ Constipation Drug therapy for dyslipidemias Bile acid–binding resins (bile acid sequestrants) ❑ Contraindication ❖ Severe hypertriglyceridemia*… ▪ Cholestyramine and colestipol ▪ ↑ TAG ― Hepatic cholesterol biosynthesis → VLDL (TG) ― FXR ▪ Colesevelam (Insufficient data) Drug therapy for dyslipidemias Bile acid–binding resins (bile acid sequestrants) ❑ DDI ❖ bile acid sequestrants…. ▪ Interfere with absorption of many drugs; ▪ E.g. ― Fat-soluble vitamins A, D, E, and K; ― Warfarin ― Thyroid hormones ▪ 1 h before or 3–4 h after dose of a bile acid resin ❖ Bile acid sequestrants…. ▪ Inhibit absorption of ezetimibe→ do not combine* D Properties promoting DI Clinically documented interaction ❖ Resins may bind with ❖ Acetaminophen: [NE] ↓ GI absorption of acetaminophen. orally administered drugs ❖ Digitalis glycosides: [NE] ↓ GI absorption of digitoxin in GIT (possibly also digoxin). ❖ Resins may bind in ❖ Methotrexate: [NE] ↓ GI absorption of methotrexate. Bile acid binding resins ❖ Mycophenolate: [P] ↓ GI absorption of mycophenolate. gastrointestinal tract with ❖ Furosemide: [P] ↓ GI absorption of furosemide. drugs that undergo ❖ Thiazide diuretics: [P] ↓ GI absorption of thiazides. enterohepatic circulation, ❖ Thyroid hormones: [P] ↓ thyroid absorption. even if the latter are given ❖ Anticoagulants, oral: [P] ↓ absorption of anticoagulant. parenterally. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. Drug therapy for dyslipidemias Nicotinic acid ❑ Nicotinic acid ❑ Niacin Drug therapy for dyslipidemias Nicotinic acid ❑ Dosage form and strength ❖ Tablet: 50mg, 100mg, 250mg, 500mg* ❖ Tablet, ER: 250mg, 500mg, 750mg, 1000mg ❖ Capsule, ER: 250mg, 500mg Drug therapy for dyslipidemias Nicotinic acid ❑ Niacin ❖ Vitamin B3* ❖ Two formulations : ▪ Crystalline niacin (immediate or regular, IR) ― Dissolve quickly ― Half life: 20-48 min ― 2-3 times daily. ▪ Extended release (ER) ― ER: Developed to reduce flushing & itching of regular niacin** ❖ Excretion: Urine (60-88% as unchanged drug)** Drug therapy for dyslipidemias Nicotinic acid ❑ MOA ❖ Adipose tissue ▪ GPR109A (Gi, ↓cAMP>PKA) ▪ HSL → Hepatic TG synthesis ❖ Liver ▪ TG synthesis → ↓ VLDL secretion→ ↓ LDL* ❖ LPL activity → chylomicrons and VLDL TGs. ❖ ↑ HDL-C (apo A-I) ❖ Lp(a) ▪ The only Oral lipid-lowering drug Drug therapy for dyslipidemias Nicotinic acid ❑ MOA Figure 22.8 Niacin inhibits lipolysis in adipose tissue, resulting in decreased hepatic very–low-density lipoprotein (VLDL) synthesis and production of low-density lipoprotein (LDL) in the plasma. Drug therapy for dyslipidemias Nicotinic acid Therapeutic uses ❑ Therapeutic uses ❖ Dietary supplement (OTC labeling)* ❖ Dyslipidemia ▪ Niacin….favorably affects all lipid parameters; ― ↑ HDL-C→ Most effective agent** ― ↓ TG and ― ↓ LDL-C Drug therapy for dyslipidemias Nicotinic acid Therapeutic uses Drug or Drug Group LDL Cholesterol HDL Cholesterol TGs Statins ❖ Atorvastatin, rosuvastatin, simvastatin -25 to -50% +5 to +15% ↓↓ ❖ Lovastatin, pravastatin -25 to -40% +5 to +10% ↓ ❖ Fluvastatin -20 to -30% +5 to +10% ↓ ❖ Resins -15 to -25% +5 to +10% ±a ❖ Ezetimibe -20% +5% ± ❖ Niacin * -15 to -25% +25 to +35% ↓↓ ❖ Gemfibrozil -10 to -15%b +15 to +20% ↓↓ ❖ PCSK9 inhibitors -50 to -60 % +4 to +8% ↓ LDL, low-density lipoprotein; HDL, high-density lipoprotein; ±, variable, if any. aResins can increase triglycerides in some patients with combined hyperlipidemia. bGemfibrozil and other fibrates can increase LDL cholesterol in patients with combined hyperlipidemia. Drug therapy for dyslipidemias Nicotinic acid ADR ❑ Cutaneous effects: ❖ Flushing and associated pruritus ▪ Limit patient compliance ▪ Prostaglandin ▪ Aspirin (30 min before) ▪ Flushing: ― Low doses (250–500 mg QD) ― After a meal. ― Hot beverages or alcohol. ❖ Dry skin → skin moisturizers ❖ Acanthosis nigricans → salicylic acid. ❑ GI effects: ❖ Dyspepsia (rarer N/V/D)→ Meal. Figure 1: Acanthosis nigricans and skin tags over (A) neck, (B) left axillae before surgery. Darker and thicker skin* Drug therapy for dyslipidemias Nicotinic acid ADR ❑ ADR ❑ Other common and serous SE ❖ Hepatotoxicity ▪ Manifested as ↑ serum transaminases ▪ More likely to occur with the use of ER (vs. IR form) ❖ Hyperglycemia and niacin-induced insulin resistance; ▪ Known or suspected DM ▪ Blood glucose levels (at least weekly until stable) ❖ Hyperuricemia (gout). Drug therapy for dyslipidemias Nicotinic acid ADR ❑ Rarer ❖ Toxic amblyopia ❖ Toxic maculopathy ❖ Atrial tachyarrhythmias and atrial fibrillation (elderly). Drug therapy for dyslipidemias Nicotinic acid Niacin ❑ Contraindication: ❖ Pregnancy ▪ Birth defects in experimental animals ❖ Peptic ulcer disease ❖ Concurrent use of statins ▪ Cause myopathy ▪ No further reduction in ASCVD risk ▪ FDC are removed* ❖ Gout Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ Fibric acid derivatives (fibrates) Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ Drugs: ❖ Gemfibrozil ❖ Fenofibrate (isopropyl ester) ❖ Not in the U.S: ▪ Clofibrate ▪ Ciprofibrate ▪ Bezafibrate Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ Dosage forms & strengths ❑ Gemfibrozil: Tablet………..600mg ❑ Fenofibrate ❖ TriCor tablet: 48mg, 145mg ❖ Fenoglide tablet: 40mg, 120mg ❖ Lipofen capsule: 50mg, 150mg ❖ Lofibra tablet: 54mg, 160mg ❖ Triglide tablet: 160mg ❑ Fenofibrate is available in ❖ Tablets of 48 and 145 mg or ❖ Capsules containing 67, 134, or 200 mg. ❑ The choline salt of fenofibric acid is available in caps of 45 & 135 mg. ❑ Equivalent doses of fenofibrate formulations are… ❖ 135 mg of choline salt ❖ 145 mg of fenofibrate, and ❖ 200 mg of micronized fenofibrate (available in capsule form). Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ ADME ❑ Absorption: ❖ With a meal→ Rapidly & efficiently (>90%) ❖ Empty stomach ❑ Plasma protein binding : 95% (albumin) ❑ Prodrugs: ❖ Clofibrate→ clofibric acid ❖ Fenofibrate → Fenofibric acid ❖ Gemfibrozil (active) ❑ Metabolism ❖ Clofibrate, fenofibrate → Hydrolysis →Active ❖ Gemfibrozil (active)→ Inactive Figure 19.13 Metabolic pathways for gemfibrozil and fenofibrate. Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ ADME ❑ Half life: ❖ 1.1 h (gemfibrozil) ❖ 20 h (fenofibrate) ❑ Excretion ❖ Urine (60-90%, glucuronide conjugates) ❖ Feces (Smaller amounts) ❖ Renal failure Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ MOA ❑ Bind to PPARα ❖ PPARα (nuclear receptor) ❖ ↓ TGs through… PPARα-mediated… ▪ Stimulation of FA oxidation ▪ ↑ LPL synthesis (TG-rich lipoproteins) ▪ ↓ expression of apo C-III→ ― An inhibitor of LPL* ― VLDL ❖ ↑ HDL ▪ PPARα→apo A-I and apo A-II expression ▪ Fenofibrate > gemfibrozil ❖ LDL-C (NC,↑ )* (in pts with combined hyperlipidemia) * Figure 35–4 Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor- 𝛼, which decreases the secretion of VLDL and increases its peripheral metabolism. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins. Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) Drug or Drug Group LDL Cholesterol HDL Cholesterol TGs Statins ❖ Atorvastatin, rosuvastatin, simvastatin -25 to -50% +5 to +15% ↓↓ ❖ Lovastatin, pravastatin -25 to -40% +5 to +10% ↓ ❖ Fluvastatin -20 to -30% +5 to +10% ↓ ❖ Resins -15 to -25% +5 to +10% ±a ❖ Ezetimibe -20% +5% ± ❖ Niacin -15 to -25% +25 to +35% ↓↓ ❖ Gemfibrozil -10 to -15%b +15 to +20% ↓↓ ❖ PCSK9 inhibitors -50 to -60 % +4 to +8% ↓ LDL, low-density lipoprotein; HDL, high-density lipoprotein; ±, variable, if any. aResins can increase triglycerides in some patients with combined hyperlipidemia. bGemfibrozil and other fibrates can increase LDL cholesterol in patients with combined hyperlipidemia. Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ Therapeutic uses ❑ Usual DOC for treating…. ❖ Type III hyperlipoproteinemia (dysbetalipoproteinemia) ▪ Most sensitive responders. ― ↓ TG and cholesterol levels ― Tuberoeruptive and palmar xanthomas ― Angina and intermittent claudication ❖ Chylomicronemia and ❖ Severe hypertriglyceridemia (>1000 mg/dL) ❖Primary therapy: ▪ Alcohol ▪ Dietary fat intake ▪ Weight ▪ Physical activity Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ Clinical pharmacology and tips ❖ Myopathy syndrome ▪ Fibrates alone ▪ Statins + gemfibrozil ― Hepatic uptake of statins ▸ OATP1B** and ▸ CYP2C8** ― Fenofibrate-statin combinations→ less likely ― The FDA has withdrawn approval for coadministration of fibrates with statins ❖ Increased risk of gallstone formation* ❖ Antithrombotic effects→ INR Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ Contraindicated ❖ Children ❖ Pregnancy Drug therapy for dyslipidemias Fibric acid derivatives (fibrates) ❑ Relative contraindications ❖ Gallbladder disease ❖ Renal failure ❖ Hepatic dysfunction Drug therapy for dyslipidemias Omega-3 fatty acid ethyl esters ❑ Omega-3 fatty acid ethyl esters ❖ Omega-3 FAs ▪ Mixtures containing both EPA and DHA ▪ Icosapent ethyl (does not contain DHA) Drug therapy for dyslipidemias Omega-3 fatty acid ethyl esters ❑ Dosage forms ❑ Capsule, Oral: 200, 300 mg, 500 mg, 1000 mg, 1200 ❑ Capsule Delayed Release, Oral: ❖ Pro Nutrients Omega 3: 332.5 ❖ Generic: 1000 mg ❑ Tablet Chewable, Oral: 240 mg ❑ Brands: Epanova; Lovaza; Vascepa Drug therapy for dyslipidemias Omega-3 fatty acid ethyl esters ❑ ADME ❖ Absorption: small intestine ❖ Metabolism: liver ▪ Oxidized similar to FAs derived from dietary sources. ❖ Half life→ 50-80 h. Drug therapy for dyslipidemias Omega-3 fatty acid ethyl esters ❑ MOA ❖ Similar to fibrates ▪ Reduce VLDL triglycerides etc Drug therapy for dyslipidemias Omega-3 fatty acid ethyl esters ❑ Therapeutic uses ❖ Adjunct for treating severe hypertriglyceridemia (TG>1000 mg/dL) ❖ Icosapent ethyl ▪ Adjunct to maximally tolerated statin therapy to reduce risk of CV events in adults with TG levels ≥150 mg/dL ▪ Adjunct to diet in adults with severe hypertriglyceridemia (TGs ≥500 mg/dL) Drug therapy for dyslipidemias Omega-3 fatty acid ethyl esters ❑ Clinical pharmacology and tips ❖ AEs may include…. ▪ Arthralgia ▪ Nausea ▪ Fishy burps ▪ Dyspepsia ❖ Mixtures containing both EPA and DHA ▪ Increased LDL* ▪ Icosapent ethyl does not ❖ Prolong bleeding time ▪ pts taking anticoagulants should be monitored ❖ Icosapent ethyl → risk of atrial fibrillation and flutter. Drug therapy for dyslipidemias PCSK9 Inhibitors (mAbs) ❑ Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Drug therapy for dyslipidemias PCSK9 Inhibitors (mAbs) ❑ Drugs ❖ Monoclonal antibodies ❖ Drugs ― Alirocumab ― Evolocumab Drug therapy for dyslipidemias PCSK9 Inhibitors (mAbs) ❑ Dosage forms & strengths ❑ Alirocumab ❑ Injection, solution ❖ Prefilled, single-dose pen for SC injection ❖ 75mg/mL ❖ 150mg/mL ❑ Evolocumab ❑ Solution for SC injection ❖ 140mg/mL in a single-use prefilled syringe OR single-use SureClick autoinjector ❖ 420mg/3.5mL in a single-use Pushtronex system (on-body infusor with prefilled cartridge) Drug therapy for dyslipidemias PCSK9 Inhibitors (mAbs) ❑ MOA ❑ Inhibiting PCSK9 ❖ LDL-R recycling → ▪ ↑ LDL-C clearance ▪ Large LDL-C reductions (to