Updated: 1/7/2019

Lipid Lowering Drugs

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Snapshot
  • A 45-year-old man presents for management of hypercholesterolemia. His past medical history includes type 2 diabetes, hyperlipidemia, and hypertension. A few months ago, he started a new medication for his elevated LDL cholesterol. On laboratory evaluation, he is found with elevated liver enzymes. He is switched to another medication in the same class, as it is the most effective medication for lowering LDL levels. (HMG-CoA reductase inhibitors)
Introduction
  • Key enzymes in lipid physiology
    • lipoprotein lipase (LPL)
      • degrades triglycerides (TG) that are circulating around the bloodstream in chylomicrons and very low-density lipoproteins (VLDL)
    • hormone-sensitive lipase
      • degrades TG stored in adipose tissues
    • HMG-CoA reductase
      • converts HMG-CoA into mevalonate, a precursor of cholesterol
    • peroxisome proliferator-activated receptor-α (PPAR-α)
      • activated during starvation and catabolizes fatty acids
      • increases synthesis of LPL, causing a reduction in TG
      • raises high-density lipoprotein (HDL)
  • Lipid-lowering agents
    • acts on the liver
      • HMG-CoA reductase inhibitors
      • PCSK9 inhibitors
    • acts peripherally
      • fibrates
      • niacin
    • acts on intestinal absorption
      • bile acid resins
      • ezetimibe
 
Relative Effects of Lipid-Lowering Agents on LDL, HDL, and TG
Drug LDL HDL TG
HMG-CoA Reductase Inhibitors
↓↓↓*
PCSK9 Inhibitors ↓↓↓
Fibrates ↓↓↓*
Niacin ↓↓ ↑↑*
Bile Acid Resins ↓↓
Ezetimibe ↑/-
↓/-
* = best therapy
 
HMG-CoA Reductase Inhibitors
  • Drugs
    • lovastatin, pravastatin, simvastatin, rosuvastatin, and atorvastatin 
  • Mechanism
    • prevents synthesis of mevalonate, a cholesterol precursor, by inhibiting HMG-CoA reductase
    • this is the rate-limiting step of cholesterol synthesis 
  • Clinical use
    • ↓ mortality in patients with coronary artery disease
    • primarily lowers low-density lipoproteins (LDL)
      • most effective drug for lowering LDL
    • statin therapy should be initiated in patients > 40 years of age with no history of cardiovascular disease (CVD), CVD risk factors, and a calculated 10-year risk of a CVD event ≥ 10% 
  • Toxicity
    • elevated AST/ALT  
    • hepatotoxicity
    • myopathy
      • especially when used in combination with fibrates & niacin
    • inhibitors of P450 can ↑ serum concentration 
PCSK9 Inhibitors
  • Drugs
    • alirocumab and evolocumab
  • Mechanism
    • these drugs are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9)
      • PCSK9 destroys LDL-receptor on hepatocytes, which results in decreases clearance of LDL
    • inhibition of PCSK9 improves clearance of LDL
  • Clinical use
    • primarily decreases LDL
  • Toxicity
    • myopathy
    • neurocognitive effects
      • delirium
      • dementia
Fibrates
  • Drugs
    • gemfibrozil, bezafibrate, and fenofibrate
  • Mechanism
    • activates PPAR-α and upregulates lipoprotein lipase
      • reduces levels of triglycerides
    • induces HDL synthesis
  • Clinical use
    • primarily decreases TG
      • most effective drug for lowering TG
  • Toxicity 
    • myopathy
    • cholesterol gallstones
    • can ↑ LDL so, so fibrates are not often used as monotherapy
Niacin (Vitamin B3)
  • Mechanism
    • inhibits hormone-sensitive lipase
    • inhibits hepatic VLDL synthesis
  • Clinical use
    • primarily increases HDL
      • most effective drug for increasing HDL levels
  • Toxicity
    • red and flushed face/upper body
      • thought to be due to a release of prostaglandins and histamine 
      • treat with non-steroidal anti-inflammatory drugs (NSAIDs) 
    • ↑ glucose
    • ↑ uric acid
    • acanthosis nigricans
    • pruritus
Bile Acid Resins
  • Drug
    • cholestyramine, colestipol, and colesevelam
  • Mechanism 
    • binds to bile acids and prevents reabsorption of bile acids in the distal ileum
      • this forces the liver to make more bile acids by using the available cholesterol in the body
  • Clinical use
    • primarily decreases LDL
  • Toxicity
    • gastrointestinal upset
    • malabsorption, especially of fat-soluble vitamins
Ezetimibe
  • Mechanism
    • inhibits sterol transporter at small intestine’s brush border, preventing the absorption of cholesterol
    • this decreases the liver’s stores of cholesterol
  • Clinical use
    • primarily decreases LDL
    • primarily used in combination with a statin
  • Toxicity
    • rare hepatotoxicity
      • when used in combination with statins
    • gastrointestinal upset
 

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Questions (4)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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