Treatment of Hyperlipidemia Flashcards
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
Lipid Lowering Drugs
- Statins
- Intestinal acting agents
- Ezetimibe
- Bile acid resins
- Nicotinic acid
- Fish oil
- Fibric acid derivatives
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
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
- Inhibit hepatic HMG-CoA reductase
- 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

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
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
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
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

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
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
- Inhibits the uptake of micellar cholesterol into intestinal epithelial cells

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)
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
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

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
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
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

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%
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
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
- Flushing, itching, headache
- Contraindications
- Active liver disease or unexplained LFT elevations
- Peptic ulcer disease
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
- Effective way to lower 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
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
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
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

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
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

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
- GI upset
- Contraindications
- Hepatic or renal dysfunction
- Pre-existing gallbladder disease
- Intervention trials
- HHS, VA-HIT, BIP, LOCAT, BECAIT, DAIS
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
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
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