Agents Used in Dyslipidemia

1. Agents Used in Dyslipidemia
Prepared by: Abraham Daniel C. Cruz, MD, MSc, FPSECP

2. Introduction
• Atherosclerosis - leading cause of death in the Western world
• Drugs to be discussed prevent the sequelae of atherosclerosis (heart attacks,
angina, peripheral arterial disease, ischemic stroke) and decrease mortality in
patients with a history of CVD and hyperlipidemia
• The drugs are generally safe and effective BUT can cause problems (drug-
drug interactions and toxic reactions in skeletal muscle and the liver)

4. HYPERLIPOPROTEINEMIA

5. Pathogenesis
• premature or accelerated atherosclerosis - strongly associated with ↑
concentrations of certain plasma lipoproteins, esp. low-density lipoproteins
(LDLs) that participate in cholesterol transport
• ↓ high-density lipoproteins (HDLs) - also associated with ↑ risk of
atherosclerosis
• hypertriglyceridemia - similarly correlated with atherosclerosis
• chylomicronemia - occurrence of chylomicrons in the serum while fasting;
recessive trait that is correlated with a high incidence of acute pancreatitis;
managed by restriction of total fat intake

7. • Regulation of plasma lipoprotein levels - complex interplay of dietary fat
intake, hepatic processing, and utilization in peripheral tissues
• Primary disturbances - genetic conditions (mutations in apolipoproteins, their
receptors, transport mechanisms, and lipid-metabolizing enzymes)
• Secondary disturbances - associated with a Western diet, certain endocrine
conditions, and diseases of the liver or kidneys
Pathogenesis

9. Treatment Strategies

10. Diet
• cholesterol and saturated fats - 1° dietary factors that contribute ↑ levels of
plasma lipoproteins; reduction of total intake  1st method of management;
and may be sufficient to reduce lipoprotein levels to a safe range
• alcohol - raises triglyceride and very-low-density lipoprotein (VLDL) levels;
should be avoided by patients with hypertriglyceridemia

11. Drugs
• Individualized treatment;
• Drug choice is based on the lipid abnormality
• HMG-CoA reductase inhibitors, resins, ezetimibe, and niacin - most effective
at lowering LDL cholesterol
• fibric acid derivatives (eg, gemfibrozil), niacin, and marine omega-3 fatty acids
- most effective at lowering triglyceride and VLDL concentrations and raising
HDL cholesterol concentrations

13. Sites of Action of Antilipemic Drugs

15. HMG-CoA REDUCTASE
INHIBITORS

16. Mechanism and Effects
• conversion of hydroxymethylglutaryl coenzyme A (HMG-CoA) to mevalonate
by HMG-CoA reductase - rate-limiting step in hepatic cholesterol synthesis
• statins - structural analogs of HMG-CoA  competitively inhibit HMG-CoA
reductase
• lovastatin and simvastatin - prodrugs
• atorvastatin, fluvastatin, pravastatin, and rosuvastatin - active as given

17. • ↓ hepatic cholesterol synthesis - contributes a small amount to the total
serum cholesterol-lowering effect
• greater effect is from the response to a reduction in the hepatic pool of
cholesterol
• liver compensates by ↑ number of high-affinity LDL receptors  clear
LDL and VLDL remnants from the blood
• functional LDL receptors are required to achieve a therapeutic LDL-
lowering effect
• Other MOA: direct anti-atherosclerotic effects and anti-inflammatory effects;
also prevent bone loss
Mechanism and Effects

18. Clinical Use
• dramatic ↓ of LDL cholesterol levels, especially if used with other
cholesterol-lowering drugs
• commonly used because of efficacy and general safety
• ↓ risk of coronary events and mortality in patients with ischemic heart disease
• ↓ risk of ischemic stroke

19. • rosuvastatin, atorvastatin, and simvastatin - greater maximal efficacy than
the other HMG-CoA reductase inhibitors
• also ↓ TG ↑ HDL cholesterol in patients with TG levels > 250 mg/dL and with
reduced HDL cholesterol levels
• fluvastatin - less maximal efficacy than the other drugs in this group
Clinical Use

20. Toxicity
• Common: mild elevations of serum aminotransferases, often not
associated with hepatic damage; more severe reactions in patients with
preexisting liver disease
• ↑ creatine kinase (released from skeletal muscle) in ~ 10% patients;
severe muscle pain and rhabdomyolysis may occur in a few
• metabolized by the cytochrome P450 system  drugs or foods (eg,
grapefruit juice) that inhibit cytochrome P450 activity increase the risk of
hepatotoxicity and myopathy
• Teratogenic  interfere with myelination

21. RESINS

22. Mechanism and Effects
• N - > 90% of bile acids (metabolites of cholesterol) are reabsorbed in the
gastrointestinal tract and returned to the liver for reuse
• cholestyramine, colestipol, and colesevelam – bile acid resins; large
nonabsorbable polymers
• bind bile acids and similar steroids in the intestine and prevent their absorption
 prevent recycling of bile acids  divert hepatic cholesterol to
synthesize new bile acids  ↓ cholesterol in the liver   compensatory
↑ in high-affinity LDL receptor synthesis   ↑ removal of LDL
lipoproteins from the blood

23. Mechanism and Effects
• cause modest reduction in LDL cholesterol
• little effect on HDL cholesterol or triglycerides
• In some patients with familial combined hyperlipidemia (predisposes to
hypertriglyceridemia and hypercholesterolemia) - resins increase triglycerides
and VLDL

24. Clinical Use
• used in patients with hypercholesterolemia
• reduce pruritus in patients with cholestasis and bile salt accumulation

25. Toxicity
• bloating, constipation, and an unpleasant gritty taste
• ↓ absorption of fat-soluble vitamins (eg, vitamin A, D, E, K, dietary folates)
and drugs (eg, thiazide diuretics, warfarin, pravastatin, fluvastatin)

26. EZETIMIBE

27. Mechanism and Effects
• Prodrug; converted in the liver to the active glucuronide form  inhibits a
transporter (sterol transporter NPC1L1) that mediates GI uptake of cholesterol
and phytosterols
• prevent absorption of dietary cholesterol and cholesterol excreted in bile
 ↓ cholesterol in the hepatic pool  compensatory ↑ synthesis of high-
affinity LDL receptors  ↑ removal of LDL lipoproteins from the blood
• monotherapy - reduces LDL cholesterol by about 20%
• more effective when combined with statins

28. Clinical Use
• treatment of hypercholesterolemia and phytosterolemia (rare genetic disorder
that results from impaired export of phytosterols)

29. Toxicity
• well tolerated
• ↑ risk of hepatic toxicity when combined with statins
• fibrates can increase serum concentrations of the glucuronide form
• cholestyramine can reduce serum concentrations of the glucuronide form

30. NIACIN (NICOTINIC ACID)

31. Mechanism and Effects
• multiple MOA; ↓ LDL, triglycerides, and VLDL; ↑ HDL
• liver: ↓ VLDL synthesis  ↓ LDL levels
• adipose tissue: activate a signaling pathway  ↓ hormone-sensitive lipase
activity  ↓ plasma fatty acid and triglyceride levels  ↓ LDL formation 
↓ LDL cholesterol
• lipoprotein lipase associated with capillary endothelial cells  ↑ VLDL
clearance  ↓ plasma triglyceride concentrations
• ↓ HDL catabolic rate
• ↓ circulating fibrinogen, ↑ tissue plasminogen activator

32. Clinical Use
• ↓ lowers serum LDL cholesterol and triglyceride concentrations
• ↑HDL cholesterol concentrations
• used in treating hypercholesterolemia, hypertriglyceridemia, and low levels of
HDL cholesterol

33. Toxicity
• Cutaneous flushing - common adverse effect; mediated by prostaglandin
release
• associated with pruritus
• aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs)
pretreatment reduces intensity
• tolerance to flushing develops within a few days
• Dose-dependent nausea and abdominal discomfort (common)
• Pruritus and other skin conditions (reports)

34. Toxicity
• Moderate elevations of liver enzymes and severe hepatotoxicity may occur
• Severe liver dysfunction - associated with an extended-release preparation
(not the same as the sustained-release formulation; *there are contradicting
studies stating that sustained-release formulations are more associated
with hepatotoxicity)
• Hyperuricemia occurs in ~ 20% of patients
• Carbohydrate tolerance - moderate impairment
• *possible increase risk of hepatotoxicity if combined with statins

35. FIBRIC ACID DERIVATIVES

36. Mechanism and Effects
• gemfibrozil, fenofibrate - ligands for the peroxisome proliferator-activated
receptor-alpha (PPAR-α) protein (receptor that regulates gene transcription
in lipid metabolism)
• adipose tissue: ↑ synthesis of lipoprotein lipase  associates with capillary
endothelial cells  ↑ clearance of triglyceride-rich lipoproteins
• liver:
• stimulate fatty acid oxidation  limits the supply of triglycerides and
decreases VLDL synthesis
• ↓ apoC-III expression  impedes VLDL clearance
• ↑ apoA-I and apoA-II expression  ↑ HDL levels

37. Mechanism and Effects
• little or no effect on LDL concentrations in most patients
• can ↑ LDL cholesterol in patients with familial combined
hyperlipoproteinemia (genetic condition associated with combined increase
in VLDL and LDL)

38. Clinical Use
• treatment of hypertriglyceridemia
• often combined with other cholesterol-lowering drugs for treatment of
patients with elevated concentrations of both LDL and VLDL because these
drugs have only a modest ability to reduce LDL cholesterol and can increase
LDL cholesterol in some patients

39. Toxicity
• nausea - most common adverse effect with all members
• skin rashes - common with gemfibrozil
• ↓ WBC count or Hct in some patients
• can potentiate the action of anticoagulants and antiplatelet drugs
• ↑ risk of cholesterol gallstones  used with caution in patients with a
history of cholelithiasis
• Significant ↑ risk of myopathy if combined with statins

40. COMBINATION THERAPY
• All patients with hyperlipidemia are treated first with dietary modification
• often insufficient  drugs must be added
• Drug combinations are often required to achieve:
• maximum lowering possible with minimum toxicity
• desired effect on the various lipoproteins (LDL, VLDL, and HDL)

41. COMBINATION THERAPY
• Certain combinations provide advantages
• Other combinations present specific challenges
• resins interfere with absorption of certain statins (pravastatin, cerivastatin,
atorvastatin, and fluvastatin)  give statins at least 1 h before or 4 h after
the resins
• statins + fibrates or niacin = ↑ risk of myopathy
• statin + ezetimibe = ↑ risk of hepatotoxicity

42. DRUGS RESTRICTED TO PATIENTS WITH HOMOZYGOUS
FAMILIAL HYPERCHOLESTEROLEMIA
• Lomitapide - microsomal triglyceride transfer protein (MTP) inhibitor
• MTP role: accretion (growth by gradual accumulation of layers) of
triglycerides to nascent VLDL in liver and to chylomicrons in the intestine
• inhibition decreases VLDL secretion  ↓ accumulation of LDL in plasma
• adverse effect: accumulation of triglycerides in the liver and elevations in
transaminases
• Mipomersen - antisense oligonucleotide that targets apoB-100, mainly in the
liver
• Adverse effects: mild to moderate injection site reactions and flu-like
symptoms

45. PCSK9 Inhibitors
• https://www.ncbi.nlm.nih.gov/books/NBK448100/
• PCSK9 - proprotein convertase subtilisin/kexin type 9; product of hepatocytes;
secreted into the plasma; binds to the LDL receptor  lysosomal
degradation of the receptor  ↓ expression of LDL receptors on the cell
membrane  ↓ clearance of LDL cholesterol
• Familial hypercholesterolemia - due to a genetic mutation of the LDL receptor,
rarely a mutation of the apoprotein B100 gene
• In 2003, a family in France had familial hypercholesterolemia without
identifiable mutation of the LDL receptor or apoprotein B100
• Discovered to have gain of function mutation of PCSK9

46. • Two pharmaceutical products available in the US: alirocumab and
evolocumab
• fully-humanized monoclonal antibodies injected subcutaneously at intervals of
every 2 to 4 weeks
• highly potent in lowering total and LDL cholesterol
• Whether used as monotherapy or in combination with a statin, they typically
reduce LDL cholesterol levels by 50% to 60%.
• The effect sustains as long as treatment continues
PCSK9 Inhibitors

48. PCSK9 Inhibitors
• FDA has approved alirocumab for adult patients:
• To reduce the risk of myocardial infarction, stroke, and unstable angina
requiring hospitalization in adults with established cardiovascular disease.
• As an adjunct to diet, alone or in combination with other lipid-lowering
therapies (e.g., statins, ezetimibe), for treating adults with primary
hyperlipidemia (including heterozygous familial hypercholesterolemia) to
reduce LDL cholesterol.

49. PCSK9 Inhibitors
• FDA has approved evolocumab for adult patients:
• To reduce the risk of myocardial infarction, stroke, and coronary
revascularization in adults with established cardiovascular disease.
• As an adjunct to diet, alone or in combination with other lipid-lowering
therapies (e.g., statins, ezetimibe), for treatment of adults with primary
hyperlipidemia (including heterozygous familial hypercholesterolemia) to
reduce LDL cholesterol.
• As an adjunct to diet and other LDL-lowering therapies (e.g., statins,
ezetimibe, LDL apheresis) in patients with homozygous familial
hypercholesterolemia who require additional lowering of LDL-C

50. THANK YOU!!!