Antihyperlipidemics Notes

FNM [VM 060] Antihyperlipidemics

Intended Learning Outcomes

By the end of this session, you should be able to:

• List the different classes of antihyperlipidemic.
• Understand the mechanism of action of antihyperlipidemic.
• Know the therapeutic effects and clinical uses of antihyperlipidemic.
• Understand the common side effects of each class and their contraindication.

Lipids

• Types: Cholesterol, Phospholipids, Triglycerides.
• Functions: Energy storage, Cell membrane, Hormones.
• Hyperlipidemia:
  • Hypertriglyceridemia and Hypercholesterolemia.
  • Metabolic syndrome.
  • Fatty liver leading to cirrhosis/HCC or extrahepatic manifestations (Diabetes or CVD).
  • Atherosclerosis.

Dyslipidemia Causes

• Primary causes:
  • Combination of diet and genetics (usually polygenic).
• Secondary causes:
  • Uncontrolled diabetes mellitus.
  • Hepatic disease.
  • Nephrotic syndrome.
  • Excessive alcohol consumption.
  • Hypothyroidism.
• Dyslipidemia usually resolves if the underlying cause is treated.

Lipid Circulation

• Exogenous TG.
• Endogenous TG.
• Bad cholesterol (LDL).
• LDLR.
• Ox-LDL → Atherosclerosis.
• Good cholesterol (HDL).

Frederickson Classification

• Type I (Familial Hyperchylomicronemia):
  • Massive fasting hyperchylomicronemia, even following normal dietary fat intake, resulting in greatly elevated serum TG levels.
  • Deficiency of lipoprotein lipase or deficiency of normal apolipoprotein Cll (rare).
  • Not associated with an increase in coronary heart disease.
  • Treatment: Low-fat diet. No drug therapy is effective.
• Type IIA (Familial Hypercholesterolemia):
  • Elevated LDL with normal VLDL levels due to a block in LDL degradation.
  • Increased serum cholesterol but normal TG levels.
  • Caused by defects in the synthesis or processing of LDL receptors.
  • Ischemic heart disease is greatly accelerated.
  • Treatment: Diet.
    • Heterozygotes: Cholestyramine and niacin, or a statin.
• Type IIB (Familial Combined [Mixed] Hyperlipidemia):
  • Similar to Type IIA except that VLDL is also increased, resulting in elevated serum TG as well as cholesterol levels.
  • Caused by overproduction of VLDL by the liver.
  • Relatively common.
  • Treatment: Diet. Drug therapy is similar to that for Type IIA.
• Type III (Familial Dysbetalipoproteinemia):
  • Serum concentrations of IDL are increased, resulting in increased TG and cholesterol levels.
  • Cause is either overproduction or underutilization of IDL due to mutant apolipoprotein E.
  • Xanthomas and accelerated vascular disease develop in patients by middle age.
  • Treatment: Diet. Drug therapy includes niacin and fenofibrate, or a statin.
• Type IV (Familial Hypertriglyceridemia):
  • VLDL levels are increased, whereas LDL levels are normal or decreased, resulting in normal to elevated cholesterol, and greatly elevated circulating TG levels.
  • Cause is overproduction and/or decreased removal of VLDL and TG in serum.
  • Relatively common disease.
  • Few clinical manifestations other than accelerated ischemic heart disease. Patients are frequently obese, diabetic, and hyperuricemic.
  • Treatment: Diet. If necessary, drug therapy includes niacin and/or fenofibrate.
• Type V (Familial Mixed Hypertriglyceridemia):
  • Serum VLDL and chylomicrons are elevated. LDL is normal or decreased.
  • Elevated cholesterol and greatly elevated TG levels.
  • Cause is either increased production or decreased clearance of VLDL and chylomicrons. Usually, it is a genetic defect.
  • Occurs most commonly in adults who are obese and/or diabetic.
  • Treatment: Diet. If necessary, drug therapy includes niacin, and/or fenofibrate, or a statin.

Lipids Pathway

• ApoB100.
• ApoA.
• Exogenous.
• Endogenous.
• Bad (LDL).
• Good (HDL).

Ultimate Aim

• Lower: LDL, Total cholesterol (TC), Triglycerides (TG).
• Raise: HDL.

Potential Sites of Action for Antihyperlipidemics

• Before starting treatment, secondary causes of dyslipidaemia should be addressed.
• Treatment should be accompanied by lifestyle modifications (diet, exercise & weight reduction).

Drugs for Hyperlipidemia

• HMG CoA reductase inhibitors (statins).
• Fibrates.
• Niacin.
• Bile acid binding resins.
• Cholesterol absorption inhibitors.
• Omega-3 fatty acids.

Reductase Inhibitors “Statins”

• Most effective in lowering LDL.
• First-line drug treatment if lifestyle modifications are inappropriate or ineffective.
• Examples: Atorvastatin, Rosuvastatin, Lovastatin, Fluvastatin, Pravastatin, Simvastatin, and Pitavastatin.
• Clinically proven to reduce the risk of cardiovascular disease (mortality & morbidity).
• First choice for primary and secondary prevention of cardiovascular disease.
• Other benefits than cholesterol lowering: stabilization of plaque, improvement of coronary endothelial function, inhibition of platelet thrombus formation, and anti-inflammatory activity.
• Serum LDL cholesterol reduction produced (%):
  • Atorvastatin: 55.
  • Fluvastatin: 29.
  • Lovastatin: 34.
  • Pitavastatin: 43.
  • Pravastatin: 34.
  • Rosuvastatin: 60.
  • Simvastatin: 41.
• Serum triglyceride reduction produced (%):
  • Atorvastatin: 10
  • Fluvastatin: 16
  • Lovastatin: 18
  • Pitavastatin: 24
  • Pravastatin: 24
  • Rosuvastatin: 18
  • Simvastatin: 18
• Serum HDL cholesterol increase produced (%):
  • Atorvastatin: 6
  • Fluvastatin: 8
  • Lovastatin: 9
  • Pitavastatin: 8
  • Pravastatin: 12
  • Rosuvastatin: 8
  • Simvastatin: 12
• Plasma half-life (h):
  • Atorvastatin: 14
  • Fluvastatin: 1-2
  • Lovastatin: 2
  • Pitavastatin: 12
  • Pravastatin: 1-2
  • Rosuvastatin: 19
  • Simvastatin: 1-2
• Penetration of central nervous system:
  • Lovastatin: Yes
  • Pitavastatin: Yes
  • Simvastatin: Yes
  • Others: No
• Renal excretion of absorbed dose (%):
  • Atorvastatin: 2
  • Fluvastatin: <6
  • Lovastatin: 10
  • Pitavastatin: 15
  • Pravastatin: 20
  • Rosuvastatin: 10
  • Simvastatin: 13
• Reduction in low-density lipoprotein cholesterol.
  • High-intensity
    • Atorvastatin
      • 20 mg (43%)
      • 40 mg (49%)
      • 80 mg (55%)
    • Rosuvastatin
      • 10 mg (43%)
      • 20 mg (48%)
      • 40 mg (53%)
  • Medium-intensity
    • Atorvastatin
      • 10 mg (37%)
    • Fluvastatin
      • 80 mg (33%)
    • Rosuvastatin
      • 5 mg (38%)
    • Simvastatin
      • 20 mg (32%)
      • 40 mg (37%)
  • Low-intensity
    • Fluvastatin
      • 20 mg (21%)
      • 40 mg (27%)
    • Pravastatin
      • 10 mg (20%)
      • 20 mg (24%)
      • 40 mg (29%)
    • Simvastatin
      • 10 mg (27%)
• Advice from the MHRA: there is an increased risk of myopathy associated with high-dose (80 mg) simvastatin. The 80 mg dose should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.

Reductase Inhibitors “Statins” - Mechanism of Action

• Inhibits the rate limiting step of cholesterol synthesis.
• Analogs of HMG-CoA → competitive inhibitors.
• Main action → Plasma LDL decreases due to:
  1. Decreased intracellular cholesterol synthesis.
  2. Increased LDL catabolism.
• Minor action:
  1. Modest TG decrease.
  2. Slight HDL increase.

Reductase Inhibitors “Statins” - Therapeutic Uses and Dosage

• Lower plasma cholesterol levels effectively in almost all types of hyperlipidemia.
• Homozygous familial hypercholesterolemia benefit much less from statins due to lack of LDLR.
• Could be used alone or in combination with resins, niacin or ezetimibe to reduce LDL.

Pharmacokinetics (ADME):

• Absorption: Reductase inhibitors are mostly given at night, since cholesterol synthesis occurs mainly at night, (except atorvastatin, rosuvastatin, and pitavastatin).
• $T_{\frac{1}{2}}$: Long half lives for atorvastatin, pitavastatin & rosuvastatin.
• Metabolism: by CYP3A4 or CYP2C9 → Drug-Drug interaction (DDI).
• Drug-Food interactions: Some statins levels are elevated in plasma if more than 1L grape juice was ingested.

Reductase Inhibitors “Statins” - Toxicity & Precautions

• Liver failure.
  • Serum aminotransferase (AST/ALT) should be measured at :
    • Baseline.
    • At 1-2 months.
    • Then every 6-12 months (if stable).
    • Elevation (up to 3x) with no signs of hepatotoxicity→ therapy may be continued if aminotransferase levels are monitored & stable
    • Elevation (more than 3x) and asymptomatic → therapy should be discontinued
• Myopathy.
  • Creatinine kinase (CK) should be measured at :
    • Baseline
    • If muscle pain, weakness or tenderness occurs →CK should be assessed immediately.
    • Treatment discontinued if CK levels are significantly higher than baseline.
  • Myopathy might occur with:
    • Monotherapy →reverses upon treatment cessation with no CK elevation.
    • Rarely: Marked CK elevation accompanied by generalized discomfort or weakness in skeletal muscles→ if therapy was not discontinued, myoglobinuria might occur leading to renal injury.
    • Autoimmune myopathy → severe muscle pain and weakness (doesn’t remit upon treatment cessation). It is HMG-CoA reductase antibody positive and requires immunosuppressants.

Reductase Inhibitors “Statins” - Contraindication (C/I)

• Pregnancy, lactation or likely to become pregnant women.
• Active liver disease.
• Coadministration with strong CYP3A4 inhibitors (DDI).
• Caution:
  • Patients with liver disease, north Asian and the elderly.
  • Small but significant increase in type 2 diabetes incidence in statin treated patients, who were prediabetic at treatment initiation.
  • Reductase inhibitors may increase the effect of warfarin (DDI) → evaluate international normalized ratio (INR) frequently.
  • Concomitant use with cyclosporin, macrolides and some antivirals require “dose adjustment” (DDI).
  • Factors that increase myopathy risk:
    • Dose related.
    • Lean-body mass.
    • Hypothyroidism.
    • Renal impairment.
    • Genetic variants.
    • Concomitant drug administration such as erythromycin, gemfibrozil, or niacin or CYP3A4 inhibitors.

Fibric Acid Derivatives (Fibrates)

• Fibrates are mainly used to lower serum TG.
• Examples: Bezafibrate, Ciprofibrate, Gemfibrozil, Fenofibrate and Clofibrate.
• Effects:
  • Markedly decrease circulating VLDL hence TG.
  • Modestly increase HDL.
  • Effect on LDL is debatable.
• Mechanism of action (MOA): ligands/agonist for nuclear transcription receptor PPARα
  • Increase LPL expression → increases lipolysis of lipoprotein TG.
  • Increase apoA-I & apoA-II expression → increases HDL.
  • Decrease apo C-III concentration (an inhibitor of lipolysis).
  • Decreased intracellular lipolysis in adipose tissue & decreased VLDL secretion from the liver.

Fibric Acid Derivatives (Fibrates) - Therapeutic Uses & Dosage

• Useful in hypertriglyceridemia where VLDL predominates.
• Useful in type III hyperlipidemia (dysbetalipoproteinemia) where IDL accumulate.
• Toxicity:
  • Mostly GI disturbances → lessens as therapy progresses.
  • Possible potentiation of anticoagulants actions (c.f statins) (DDI) → dose adjustment & INR frequent monitoring.
  • Fibrates increase biliary cholesterol excretion: Modest risk of cholesterol gallstones, Caution with biliary tract disease.
  • Myopathy: Risk should be evaluated frequently especially in patients with renal insufficiency.
    • Risk of myopathy increases when co-administered with reductase inhibitors (gemofibrizil CI with simvastatin). Therefore, fibrates/statins combination are inadvisable, however, if necessary, transaminases and CK should be monitored frequently.
  • Should be avoided in patients with hepatic or renal impairment and patients with preexisting gall bladder disease

Niacin (Nicotinic Acid, Vit.B3)

• At gram doses, Niacin is the most effective in raising HDL, it modestly decreases LDL and TG.
• MOA:
  • As a vitamin (B3), niacin is converted in the body to amide, which is then incorporated in NAD, therefore has a critical role in energy metabolism.
  • However, its role in lipid metabolism at pharmacological doses is poorly understood.
  • Niacin inhibits lipolysis in adipose tissue (by inhibiting intracellular lipase in adipose), and thus reduces the production of free fatty acids. Circulating free fatty acids (FFAs) are a major source for TG synthesis in the liver. Therefore, reduced TG synthesis decreases VLDL production and thus LDL.
  • Other pleiotropic effects:
    • Increased neutral sterols in stool due to increased cholesterol mobilization from tissues.
    • Decreased catabolism of HDL.
    • Fibrinogen level decrease, tissue plasminogen activator increase.

Niacin (Nicotinic Acid, Vit.B3) - Therapeutic Uses & Dosage

• Usually used in combination with reductase inhibitors or resin.
• Most effective in increasing HDL.
• Toxicity:
  • Harmless intense cutaneous vasodilation. This is accompanied by uncomfortable feeling of warmth. Administering aspirin 30 min before niacin administration reduces the flush that is prostaglandin mediated.
  • Niacin should be avoided in patients with significant peptic or hepatic disease (especially active peptic ulcer).

Niacin (Nicotinic Acid, Vit.B3) - Caution

• Aminotransferases may rise → liver function should be measured at baseline and monitored frequently. Rare true hepatotoxicity might occur and requires discontinuation.
• Carbohydrate tolerance might occur especially in obese patients. Diabetics receiving insulin and some oral agents can use niacin, but insulin resistance might increase → can be overcome by increase the dose of insulin or oral agents).
• Niacin decrease uric acid tubular secretion → predisposes patients to hyperuricemia and gout.
• Red cell macrocytosis (similar to deficiency of folate or vit B12) that doesn't require treatment discontinuation.
• Significant platelet deficiency can occur → reversible upon treatment cessation.
• Rare association with arrythmias that needs treatment cessation.
• Patients should be instructed to report any blurred distance vision.
• Niacin can potentiate antihypertensive drugs → requiring dose adjustments.

Bile Acid-Binding Sequestrants (Resins)

• Can significantly decrease LDL, but to a lesser extent than statins.
• Examples: Colestipol, Cholestyramine, and Colesevelam are useful only for isolated increases in LDL.
• MOA: Large polymeric anion exchange resins that are insoluble in water→ they bind negatively charged bile acids & bile salts in the small intestine and prevent their reabsorption → The resin/ bile acid complex is secreted in the feces, lowering bile acid concentration → Therefore, hepatocytes increase the conversion of cholesterol to bile acids, lowering intracellular cholesterol → This activates hepatic uptake of cholesterol containing LDL through upregulating LDLR → This ultimately leads to a drop in plasma LDL:
  • Decreased absorption of exogenous cholesterol.
  • Increased metabolism of endogenous cholesterol into bile acids in the liver.
  • Increased expression of LDL receptors on hepatocytes, and hence increased clearance of LDL from the blood and a reduced concentration of LDL in plasma.
  • Decrease activation of the FXR receptor by bile acids → may slightly increase TG but can also improve glucose metabolism in patients with diabetes (increase VLDL).

Bile Acid-Binding Sequestrants (Resins) - Therapeutic Uses

• Used in primary hypercholesterolemia→ 20% LDL reduction at maximum dose.
• Not really effective in rare homozygous type IIA dyslipidemia patients lacking LDLR.
• Cholestyramine can relieve pruritis caused by bile acid accumulation in patients with biliary stasis.
• Could be useful in type II diabetes for its glucose lowering effect (Can improve glucose metabolism in diabetics (due to increased incretin glucagon-like peptide-1 from the intestine, thus increasing insulin secretion).
• Phramacokinetics: They are bulky, unpalatable and insoluble in water with large molecular weights → neither absorbed nor metabolically altered
  • Totally excreted in feces.

Bile Acid-Binding Sequestrants (Resins) - Side Effects (SE) & Toxicity

• GI disturbances (e.g.: constipation, nausea and flatulence) → could be relieved by increased dietary fibers.
• Steatorrhea may occur with patients with preexisting bowel disease or cholestasis.
• May impair absorption of fat soluble vitamins (A,D,E,K), supplements of vitamins A, D, K, and folic acid may be required when treatment is prolonged.
• Decreased vit K absorption → might lead to hypoprothrombinemia; Prothrombin time should be monitored in patients taking resins with anticoagulants.
• Interferes with absorption of some oral drugs (e.g: warfarin, thiazide diuretics, thyroid hormone and digoxin), other drugs should be administered 1-2 hrs before or 4-6 hrs after bile acid sequestrants. Additional medication (except niacin) should be given.
• May increase TG, so they are contraindicated in patients with significant hypertriglyceridemia ($\geq$400 mg/dL).
• Contraindication (C/I):
  • TG more than 300-500 mg/dl.
  • Biliary/bowel obstruction.
  • History of TG induced pancreatitis.

Cholesterol Absorption Inhibitors (Ezetimibe)

• MOA: selectively inhibits intestinal absorption of dietary & biliary cholesterol (through NPC1L1 transport protein), without affecting the absorption of fat-soluble vitamins, TG or bile acids → This decreases the delivery of intestinal cholesterol to the liver →This leads to a reduction in cholesterol liver stores → and thus increases the clearance of cholesterol from blood.
• Modestly decrease LDL, therefore it is usually used as adjunct therapy.
• Fibrates increase its plasma concentration, while bile acid sequestrants decrease its absorption (DDI).
• Toxicity: Adverse effects are uncommon
  • Low rate of reversible impaired hepatic function → they should not be used with moderate to severe hepatic insufficiency.
  • Myositis rarely reported.
  • C/I for breastfeeding women.

Omega-3

• Omega-3 polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) & docosahexaenoic acid (DHA) are used to lower TG.
• They are found in in marine sources such as tuna, halibut, and salmon.
• Essential fatty acids inhibit VLDL & TG synthesis in the liver.
• 4 gm marine-derived omega-3 can lower TG by 25-30%, with small increases in LDL-C & HDL-C → relatively contraindicated in patients with type IIa hyperlipoproteinaemia.
• Products containing EPA only do not significantly raise LDL-C.
• MOA on TG concentration is unknown, but PUFA can also inhibit platelet function, prolong bleeding time, act as anti-inflammatory and reduce plasma fibrinogen.
• Therapeutic uses: As adjunct treatment for patients with significantly high TG ($\geq$500 mg/dL).
• Although they are effective in lowering TG, they were not shown to be effective in reducing cardiovascular morbidity & mortality. (Plasma triglyceride concentrations are less strongly associated with coronary artery disease than is cholesterol). However, they improve survival of patients who recently had myocardial infarction.
• SE: Mostly GI disturbances & fish aftertaste; Bleeding risk increases in patients concomitantly administering anticoagulants or antiplatelets.

Characteristics of Antihyperlipidemics - Summary

New Therapies

• MTP inhibitors:
  • Microsomal triglyceride transfer protein (MTP) is needed for the addition of TG to VLDL in liver and to chylomicrons in intestine → MTP inhibitors decrease VLDL and thus LDL. Loptamide is available but confined to homozygous familial hypercholesterolemia, Might cause TG accumulation for some patients and transaminase elevation. Patients should follow low fat diet to avoid steatorrhea and should minimize deficiency of essential fat-soluble vitamins. Because of hepatotoxic risk , it is available through restricted access program and it is C/I in pregnancy>
• PCSK9 Inhibition:
  • PCSK9 is a protease that degrades LDLR in the liver, resulting in decreased LDL clearance and its elevation in the serum. Humanized antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9)(evolocumab, alirocumab ) reduced LDL. Use is restricted to familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease that requires further reduction of LDL. Small molecules and antisense oligonucleotides are being developed, however, PCSK9 inhibition should be addressed cautiously due to its important role in cell biology.
    • Expensive.
• ACL inhibitors (bempedoic acid):
  • Adenosine triphosphate-citrate lyase (ACL) inhibitors lower LDL-C by inhibiting cholesterol synthesis in the liver upstream of HMG-CoA reductase. Caution: might elevate uric acid and risk of tendon rupture or injury
• ANGPTL inhibitors:
  • Recombinant monoclonal antibody that binds and inhibits angiopoietin-like 3 (ANGPTL-3). Lipoprotein lipase and endothelial LPL are inhibited by ANGPTL3. Inhibition of ANGPTL by evinacumab increases lipid metabolism decreasing LDL-C, HDL-C and TG

New Therapies

• Small interfering RNA (siRNA) therapy:
  • Inclisiran is a double stranded small interfering RNA that is uptaken by hepatocytes. Inclisiran degrade PCSK9 mRNA in hepatocytes → This allows the increase of LDLR with increased LDL clearance.
• Apo B-100 antisense:
  • Mipomersen is antisense oligonucleotides against Apo B-100 (principal apolipoprotein of LDL and its metabolic precursor VLDL), that acts mainly in the liver. CI: hypersensitivity, moderate to severe hepatic impairment or active liver disease. Drug is available only for patients with homozygous familial hypercholesterolemia. Apo B-100 is synthesized in retina and cardiomyocytes. Caution: might increase liver transaminases and increase hepatic steatosis. Due to risk of hepatotoxicity, its use is restricted through access program and confined to homozygous familial hypercholesterolemia.
    • Accepted for use in USA but refused by EMA

Agents Under Development

• CETP Inhibition (Obicetrapib):
  • Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from mature HDL particles to triglyceride rich lipoproteins which eventually deliver the esters to liver where both cholesterol and bile acids can be eliminated into the intestine. Inhibition of CETP accumulates mature HDL particles and reduce the transport of cholesteryl esters to liver. Accumulation of HDL didn’t have the expected cardioprotective effect based on epidemiologic studies. Thus far no drug (eg, torcetrapib, anacetrapib) in this class has been approved
• AMP kinase activation:
  • AMP-activated protein kinase acts as a sensor of energy status in cells. When increased ATP is required, AMP kinase enhances fatty acid oxidation and insulin sensitivity, and inhibits cholesterol and triglyceride biosynthesis. Shows potential in treatment of metabolic syndrome & diabetes. Agent with combined effect as AMP kinase activator and ATP citrate lyase inhibitor is currently under clinical trial.
• Cyclodextrin (CD):
  • CD are cyclic oligosaccharides composed of glucose units. CD have hydrophobic pores, where they solubilize cholesterol. Animal studies showed the ability of CDs to regress atherosclerotic plaques

Treatment Options

• Hypercholesterolemia:
  • Lifestyle changes (diet, exercise & weight reduction) → modest decrease in LDL-C. HMG-CoA reductase inhibitors (statin) is the primary treatment (recommended in four major groups)
• Hypertriglyceridemia:
  • Lifestyle changes is a primary mode of treatment. If indicated, niacin and fibrates are most effective in lowering TG. Omega-3 could also be beneficial. TG lowering is secondary benefit of statins (LDL reduction is the primary benefit of statins).

Treatment Guidelines

*Definitions of high- and moderate-intensity statin therapy
*High
* daily dose
* lowers LDL-C by >=50%
*Moderate
* daily dose
* lowers LDL-C by 30%-50%
*Algorithm
*Clinical
*ASCVD
*YES
*Age

• Evaluate baseline lipid panel and patient history (e.g., established ASCVD, diabetes, or risk factors for ASCVD)
  *If baseline TG >= 500 mg/dL, initiate TG lowering therapy (fibrates, niacin)
  *Follow-up in 4-12 wk
  *Evaluate fasting lipid panel and medication adherence
  *Anticipated therapeutic response
  *Reinforce adherence
  *Less than anticipated response or intolerance to therapy
  *Reinforce adherence and lifestyle
  *Exclude secondary causes of dyslipidemia
  *Consider non-statin therapy in higher risk individuals or those who cannot tolerate statin therapy

Combination Therapy

• Drug combination is needed when:
  1. VLDL & LDL levels are initially high
  2. LDL or VLDL levels are not normalized with a single agent
  3. High Lp(a) or HDL deficiency coexists with other hyperlipidemia
  4. VLDL significantly increase when treating hypercholesterolemia with resins
• Caution:
  • Lowest possible dose should be used
  • Patient should be monitored closely for signs of toxicity
  • When combination therapy includes resin, other oral agents should be administered separately to ensure absorption (except with niacin).

Summary

• Endogenous pathway:
  • Statins decrease synthesis of C.
  • Fibrates decrease secretion.
  • Fibrates enhance HDL.
• Exogenous pathway:
  • Statins, resins, fibrates increase uptake.
  • Ezetimibe reduces absorption of C.
  • Resins bind Bile acids

References

• Rang, H., Ritter, J., Flower, R., Henderson, G. and Dale, M., 2016. Rang and Dale's pharmacology. 8th edition
• Bertram G. Katzung. eds. Basic & Clinical Pharmacology, 14e. McGraw Hill; 2017.
• Karen whalen. Lippincott illustrated reviews, Pharmacology. 6th edition
• British national formulary (BNF)