Treatment of Hyperlipidemia Flashcards Preview

Cardiology > Treatment of Hyperlipidemia > Flashcards

Flashcards in Treatment of Hyperlipidemia Deck (29):
1

Clinical Lipid Management

  • Average LDL cholesterol levels in mammals vs. in American adults
  • Primary goal
  • Candidates for drug therapy

  • Average LDL cholesterol levels in mammals vs. in American adults
    • Mammals: 50-70 mg/dl
    • American adults: 130 mg/dl
  • Primary goal
    • Reduce LDL cholesterol to lower coronary hear disease risk
  • Candidates for drug therapy
    • Patients who can't reduce LDl cholesterol via therapeutic lifestyle

2

Lipid Lowering Drugs

  • Statins
  • Intestinal acting agents
    • Ezetimibe
    • Bile acid resins
  • Nicotinic acid
  • Fish oil
  • Fibric acid derivatives

3

Treatment of Hyperlipidemia

  • Drug of choice
  • Alternative choices

  • Drug of choice
    • Statin
    • Lower LDL-C most effectively, reduce CHD risk, & safe
    • Able to achieve LDL-C treatment goals in most patients regardless of their risk category
  • Alternative choices
    • Ezetimibe, bilde acid resin, & niacin
    • Cosndiered b/c 5-10% fo patients can't tolerate a statin
    • Not as effective in lowering LDL-C, but effective in reducing CHD risk

4

Statins: Mechanism of Action

  • Mechanism
  • Net effect
  • Extra effect

  • Mechanism
    • Inhibit hepatic HMG-CoA reductase
      • HMG-CoA reductase catalyzes the rate-limiting step in hepatic cholesterol synthesis
    • Statins decrease cholesterol sysnthesis by the liver -->
      • Up-regulation of LDL receptors by hepatocytes
      • Increased removal of apoE- & apoB-containing lipoproteins from circulation
      • Reduction in synthesis & secretion of lipoproteins from the liver
  • Net effect
    • Lower plasma concentrations of cholesterol-carrying lipoproteins (esp LDL)
  • Extra effect
    • Increase the removal & reduce the secretion of remnant particles (VLDL, IDL)
    • Drug of choice in patients who have both elevated LDL & triglycerides (non-HDL)
      • Elevated triglycerides indicates increased triglyceride-rich VLDL & IDL remnants

5

Statins: Triglyceride-Lowing Effects

  • Statins vs. TGs
  • TG reduction is dependent on...
  • In patients w/ mixed hyperlipidemia...
  • Statins are best restricted to use in patients who...
  • In the rest of patients...

  • Statins vs. TGs
    • Statins have a moderate triglyceride-lowering efficacy when triglycerides exceed 150 mg/dl
  • TG reduction is dependent on...
    • Baseline triglyceride level (higher baseline --> greater reduction)
    • Dose of statin (higher dose --> greater reduction)
    • Amount of LDL-C reduction (more potent statins (atorvastatin & simvastatin) --> greater LDL-C reduciton --> greater TG reduction)
  • In patients w/ mixed hyperlipidemia...
    • LDL-C reduction w/ statin isn't as great as in patients w/ primary hypercholesterolemia
  • Statins are best restricted to use in patients who...
    • Have only a moderate TG elevation (150-300 mg/dl)
  • In the rest of patients...
    • W/ TG elevated above 300 mg/dl
    • Treat primary cause of hypertriglyceridemia (ex. diabetes, hypothyroidism)
    • Use triglyceride-lowering drugs: niacin, fibrates, fish oils

6

Statins: Reducing CHD Events

  • Statins reduce...
  • Statins that reduce CHD risk

  • Statins reduce...
    • CHD events in both primary & secondary prevention populations
    • Nonfatal myocardial infarction
    • CHD death
    • Ischemic events requiring hospitalization
  • Statins that reduce CHD risk
    • Lovastatin
    • Simvastatin
    • Pravastatin

7

Statins: CHD Risk Reduction

  • Clinical manifestations of atherosclerosis that statins reduce
  • Statins have not been associated w/...
  • Overall results

  • Clinical manifestations of atherosclerosis that statins reduce
    • Fatal & nonfatal myocardial infarction
    • Sudden CHD death
    • Unstable angina
    • Revascularization procedures
      • Percutaneous transluminal coronary angioplasty (PTCA)
      • Coronary artery bypass grafting (CABG)
    • Stroke
    • Symptoms of peripheral arterial disease
    • Total mortality
  • Statins have not been associated w/...
    • An increase in noncardiovascular events
  • Overall results
    • Statins improve quality of life by reducing nonfatal events
    • Statins length life by reducing total mortality

8

Statins: Time Course of CHD Risk Reduction

  • Weeks to months
    • Restored endothelial function
  • Months
    • Reduced inflammation & markers (ex. high-sensitiviey C-reactive protein)
  • Months to years
    • Reduced ischemic events
  • Years
    • Reduced rates of fatal & nonfatal myocardial infarction
  • Years
    • Stabilized vulnerable plaque
    • Lipid-rich core of plaque is replaced w/ connective tissue & matrix

9

Statins: Adverse Events

  • Overal safety
  • Common side effects
  • Liver enyzmes
  • Myopathy

  • Overall safety
    • Statins are very safe
    • 95% of patients can tolerate them, 5% can't
  • Common side effects
    • Headache
    • Fatigue
    • GI intolerance
    • Myalgia
    • Flu-like symptoms
  • Increased liver enzymes
    • In 0.5-2.5% of cases in dose-dependent manners
    • Serious liver problems are very rare
    • Manage by reducing statin dose or discontinuing until levels return to normal
  • Myopathy: muscle symptoms (weakness, aches, soreness) + elevated CK
    • In 0.2-0.4% of patients
    • Rare causes of rhabdomyolysis, myoglobinuria, acute renal necrosis, & death
    • Reduce by...
      • Cautiously using statins in patients w/ impaired renal function
      • Using the lowest effective dose
      • Cautiously combining statins w/ fibrates
      • Avoiding drug interactions
      • Carefully monitoring symptoms
    • Presence of muscle toxicity requires statin discontinuation

10

Mechanism of Intestinal-Acting Agents

  • Bile acid sequestrants
  • Plant stanols & sterols
  • Ezetimibe

  • Bile acid sequestrants
    • Inhibit bile acid reabosrption in the ilium --> hepatic bile acid deficiency
    • Compensatory increase in bile acid synthesis from hepatic cholesterol
      • Replenished through increased hepatic uptake of LDL/chylomicron from plasma & increased hepatic cholesterol synthesis
    • Reduce LDL-C through increased clearance of LDL particles by the liver
  • Plant stanols & sterols
    • Displace cholesterol from micelles
    • Prevent micelle uptake at the bruch border membrane
    • Reduce the amount of cholesterol transported to the liver
    • Reduced delivery of dietary/biliary cholesterol to the liver --> increased clearance of LDL & LDL-C particles from plasma
  • Ezetimibe
    • Inhibits the uptake of micellar cholesterol into intestinal epithelial cells
      • Selectively inhibits the putative sterol transporter on teh bruch border surface of intestinal epithelial cells
    • Reduces the amount of cholesterol from diet & bile that's transported to the liver
    • Compensatory increase in LDL clearance by the liver
    • Reduced plasma LDL-C levels

11

Ezetimibe

  • Drug class
  • Mechanism of action & selectivity
  • Pharmacology / localization
  • Clinical experience & role in management

  • Drug class
    • Selective cholesterol absorption inhibitor
  • Mechanism of action & selectivity
    • Blocks cholesterol absorption by selectively inhibiting the putative sterol transporter at the intestinal brush border membrane of intestinal epithelial cells
    • No effect on absorption of lipid-soluble vitamins b/c it's selective for cholesterol absorption
  • Pharmacology / localization
    • Intestinal wall localization as a glucuronidated metabolite
    • Enterohepatic circulation
      • Absorbed in the intestine --> transported to the liver --> circulated back to the intestinal lumen via bile
    • Minimal systemic exposure
  • Clinical experience & role in management
    • Monotherapy
    • Combination w/ other lipid-lowering agents (e.g., statins, fibrates)

12

Adding Ezetimibe to Ongoing Statin Therapy

  • Addition of ezetimibe to ongoing stable statin therapy in patients  who aren't at their goal produces a dramatic reduction in LDL-C vs. statin + placebo

13

Bile Acid Resins: Mechanism of Action

  • Bile acid resins...
  • Liver...
  • In patients who have an elevated TG level...

  • BIle acid resins bind bile acids in the intestine
    • Reduces enterohepatic recirculation of bile acids
    • Promotes the upregulation of 7-alpha hydroxylase
    • Promotes the conversion of more cholesterol in the hepatocyte into bile acids
    • Decreases cholesterol content in the hepatocyte
    • Enhances LDL-receptor expression
    • Increases the removal of LDL & VLDL remnant particles from the circulation
    • Lowers LDL-C
  • Liver also increases its synthesis of cholesterol
    • Partially negates the LDL-C-lowering eficacy of the bild acid resin
  • In patients who have an elevated TG level...
    • Resins increase hepatic VLDL production & raise serum TG levels

14

Effect of Colesevelam on LDL-C

  • Bile acid resins vs. LDL-C
  • Older bile acid resins: cholestyramine & colestipol
  • Newer bile acid resins: colesevelam

  • Bile acid resins vs. LDL-C
    • Bile acid resins reduce LDL-C in a dose-dependent manner
    • Lower LDL-C baseline levels --> greater % LDL-C reduction
  • Older bile acid resins: cholestyramine & colestipol
    • Lower LDL-C by 15-25% w/ moderate daily doses
    • Side effect: no or significantly increased effect on TG levels, esp in patients w/ high pretreatment TG levels
  • Newer bile acid resins: colesevelam
    • Lowers LDL-C by 15% w/ the standard daily dose
    • No side effect of increasing TG levels

15

Bile Acid Resins: Clinical Features

  • Available products
  • Beneficial events
  • Adverse events
  • Drug interactions

  • Available products
    • Cholesteryamine (Questran)
    • Colestipol (Colestid)
    • Colesevelam (WelChol)
  • Beneficial events
    • Reduce LDL-C
    • Reduce coronary events (nonfatal MI, CHD death)
  • Adverse events
    • GI intolerance: constipation, bloating, abdominal pian, flatulence
    • Lack systemic toxicity
  • Drug interactions
    • Occur with colestipol & cholestyramine, not colesevelam
    • Bind other negatively charged drugs
    • Impede the absorption of drugs &/or fat-soluble vitamins
    • Must give other drugs 1 hour before or 4-6 hours after

16

Nicotinic Acid (Niacin): Mechanism of Action

  • Mechanisms
  • Net result

  • Mechanisms
    • Inhibits lipoprotein synthesis
    • Decreases VLDL production by the liver
    • Inhibits peripheral mobilizaiton of free FAs
    • Reduces hepatic synthesis of TGs
    • Reduces VLDL secretion
    • Reduces apoB
    • Increases production of apoA-I --> increase HDL
  • Net result
    • Reduciton in VLDL particle secretion by teh liver
    • Less substrate availability to make LDL particles

17

Nicotinic Acid (Niacin): Effect on Lipoproteins

  • Niacin vs. LDL-C
  • To reduce the risk of hepatotoxicity...
  • Niacin vs. TGs & HDL-C
  • Niacin vs. apoA

  • Niacin vs. LDL-C
    • Niacin reduces LDL-C in a linear, dose-dependent manner (up to 25%)
  • To reduce the risk of hepatotoxicity...
    • The dose of extended- & sustained-release forms of niacin is limited to reduce LDL-C (15-20%)
    • Immediate-release niacin can be titrated to reduce LDL-C (20-25%)
  • Niacin vs. TGs & HDL-C
    • Niacin alters TGs & HDL-C in a curvilinear manner
    • Modest doses of niacin can significantly alter these lipid levels
    • Niacin is the most effective drug for raising HDL-C
  • Niacin vs. apoA
    • Niacin reduces apoA by 30%

18

Nicotinic Acid (Niacin): Clinical Features

  • Available products
  • Immediate vs. sustained
  • Immediate-release niacin
  • Niacin combinations
  • Niacin is the best agent available for...

  • Available products
    • Immediate-release (OTC)
    • Extended-release (prescription)
    • Sustained-release (OTC)
  • Immediate vs. sustained
    • Immediate-release is better at lowering LDL-C & raising HDL-C than sustained-release
  • Immediate-release niacin
    • Reduces fatal & nonfatal MI
    • Coronary Drug Project
      • 6-year, placebo-controlled, randomized clinical trial
      • Only sufficiently powered clinical trial comparing niacin to placebo in secondary prevention
  • Niacin combinations
    • Used in combination w/ bile acid resin to slow atherosclerosis progression
  • Niacin is the best agent available for...
    • Raising HDL-C
    • Shifting cholesterol from small to large LDL particles in patients w/ mixed hyperlipidemia
      • Converts these patients from the atherogenic pattern B to the less-atherogenic pattern A

19

Nicotinic Acid (Niacin): Clinical Features

  • Adverse effects
  • Contraindications

  • Adverse Effects
    • Flushing, itching, headache
      • Extended-release: dozed at bedtime to limit these effects
      • Take aspirin 30 minutes prior to the first daily dose to limit these effects
      • Take niacin w/ food to limit flushing
    • Hepatotoxicity, GI (sustained-release)
      • Manifests as asymptomatic increased liver transaminases, malaise, lethargy, anorexia, or hepatitis
      • Should monitor liver function
      • Use immediate- or extended- over sustained-release to avoid this risk
    • Activation of peptic ulcer
    • Hyperglycemia & reduced insulin sensitivity
      • Often worsens hyperglycemia in patients w/ type 2 diabetes
  • Contraindications
    • Active liver disease or unexplained LFT elevations
    • Peptic ulcer disease

20

Simvastatin Alone vs. w/ Colesevelam & LDL-C

  • Statin + bild acid resin
  • When combining a statin + bild acid resin

  • Statin + bild acid resin
    • Effective way to lower LDL-C
      • Limited by the GI side effects associated w/ older bile acid resins
    • Colesevelam: more tolerable, better for combination therapy
      • Simvastatin + colesevelam > 2x simvastatin dose in reducing LDL-C
  • When combining a statin + bild acid resin
    • Use the loewst effective doses of the drugs
    • No need to separate the statin from teh bile acid resin dose
    • If the combination isn't effective, consider adding niacin or replacing the bile acid resin with niacin

21

Effect of Adding Extended-Release Niacin to a Stable Dose of a Statin

  • Effects of extended-release niacin + statin
  • Combination is particularly good for...

  • Effects of extended-release niacin + statin
    • Accentuated LDL-C lowering
    • Accentuated HDL-C raising
    • Accentuated TG reduction
  • Combination is particularly good for...
    • Patients w/ mixed hyperlipidemia

22

Triple-Drug Regimen

  • Drugs
  • Patients that benefit most from a triple-drug regimen

  • Drugs
    • Lovastatin
    • Niaspan
    • Colestipol
  • Patients that benefit most from a triple-drug regimen
    • Patients w/ severe hypercholesterolemia (ex. familial hypercholesterolemia) that require substantial LDL-C reductions

23

Treatment of Mixed Hyperlipidemia

  • Initial management
  • Patients that require additional treatment to achieve their secondary treatment goal defined by non-HDL-C
  • Patients w/ diabetes or imparied fasting glucose

  • Initial management
    • TLC --> LDL-C reduction to the LDL-C goal
  • Patients that require additional treatment to achieve their secondary treatment goal defined by non-HDL-C
    • Intensified statin (or other LDL-C-lowing) therapy
    • Addition of TG-lowering drugs
  • Patients w/ diabetes or imparied fasting glucose
    • Aggressive glycemic control to address the cause fo the hypertriglyceridemia

24

Fish Oils

  • Indications
  • Efficacy (alone)
  • Efficacy (when combined w/ a statin)
  • Other effects of omega-3 FAs
  • Side effects
  • Intervention trials

  • Indications
    • Adjunctive therapy to diet
    • Hypertriglyceridemia (type IV & V)
    • W/ statins or other LDL-C-lowering drugs in mixed hyperlipidemia
  • Efficacy (alone)
    • Decrease TGs
    • LDL-C remains the same or increases
    • No change in HDL-C
  • Efficacy (when combined w/ a statin)
    • Decrease TGs
    • May blunt LDL-C lowering
  • Other effects of omega-3 FAs
    • Reduce fibrinogen levels
    • Reduce BP
    • Reduce cell proliferation
    • Protect against sudden death due to ventricular arrhythmias
    • Reduce CHD risk
  • Side effects
    • GI upset
    • "Fish burp"
  • Intervention trials
    • Lyon Heart Study (dietary)
    • GISSI Prevenzion Trial

25

Potential Triglyceride-Lowering Mechanisms of Omega-3 FA

  • Inhibit...
  • Stimulate...
  • End result

  • Inhibit...
    • Lipogenesis
    • Diacylglycerol acyltransferase (DGAT)
    • Phosphatidic acid (PA)
    • Hormone-sensitive lipase
  • Stimulate...
    • Beta-oxidation
    • Phospholipid synthesis
    • apoB degradation
  • End result
    • Reduce secretion of VLDL TG

26

Fibric Acid Derivatives

  • General
  • Indications
  • Mechanism of action
  • Efficacy
  • Side effects
  • Contraindications
  • Intervention trials

  • General
    • TG-lowering drugs used to reach non-HDL-C goals
  • Indications
    • Adjunctive therapy to diet
    • Hypertriglyceridemia (type IV & V)
    • Combined hyperlipidemia (type IIb) w/ low HDL-C who don't respond to nicotinic acid
  • Mechanism of action
    • Increase peripheral lipolysis
    • Decrease hepatic TG production
    • Increase nuclear transcription factor peroxisome proliferator-activated receptor alpha (PPAR-alpha) in liver, adipose, & other tissues
      • Downregulate apoC-III genes & up-regulate genes for apoA-I, FA transport protein, FA oxidation, & possibly lipoprotein lipase
      • Enhance catabolism of TG-rich lipoproteins
      • Reduce formation of VLDL TGs
      • Increase apoA-I synthesis --> raise HDL-C
  • Efficacy
    • Decrease TG
    • LDL-C decreases, remains the same, or increases
    • Increase HDL-C in hypertriglyceridemia
  • Side effects
    • GI upset
      • Increase litogenicity of bile
      • Increase likelihood of cholesterol gallstones
    • Cholelithiasis
    • Myositis
    • Abn LFTs
    • Increased anticoagulatn effects
      • Fibrates bind to serum albumin & may displace warfarin
  • Contraindications
    • Hepatic or renal dysfunction
    • Pre-existing gallbladder disease
  • Intervention trials
    • HHS, VA-HIT, BIP, LOCAT, BECAIT, DAIS

27

Steps to Minimize the Risk of Muscle Toxicity w/ Fibrate-Statin Combination Therapy

  • Use statin alone for non-HDL-C goals
  • Use fish oils or niacin instead of fibrates
    • If must used fibrate, use fenofibrate instead of gemfibrozil for lower risk
  • Keep doses of statin & fibrate low
  • Dose fibrate in the AM & the statin in the PM
  • Avoid (or cautiously use) combo in renal or hepatic impairment
  • Ensure no drug-drug interations
  • Monitor CK levels
  • Teach the patient to recognize muscle symptoms (weakness, tenderness, pain)
  • Discontinue therapy if muscle symptoms are present & CK > 10x the upper limit of normal

28

Statin Benefit Groups

  • 4 groups
    • Established ASCVD (secondary prevention)
    • LDL-C > 190 mg/dl
    • Adults 40-75 w/ diabetes & LDL-C = 70-189 mg/dl w/o clinical ASCVD
    • Adults 40-75 w/o diabetes or ASCVD w/ 10year calculated ASCVD risk > 7.5%
  • Factors that inform clinical decision making in individuals not in a statin benefit group
    • FH of premature ASCVD
    • Elevated lifetime risk of ASCVD
    • High LDL-C, hs-CRP, or CAC score
    • Low ABI
    • Statin use

29

ASCVD Risk Estimator

  • Enables providers to estimate 10-year risk & lifetime risk of CV events
    • Coronary death
    • Nonfatal MI
    • Fatal or nonfatal stroke
  • Quantitative assessment of risk based on representative populations (pooled cohorts)
  • While applied to individuals, the estimates are based on group averages
  • Takes into account...
    • Gender, age, race, total cholesterol, HDL, SBP, HTN treatment, diabetes, smoking