Treatment of Hyperlipidemia Flashcards
1
Q
Clinical Lipid Management
- Average LDL cholesterol levels in mammals vs. in American adults
- Primary goal
- Candidates for drug therapy
A
- 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
Q
Lipid Lowering Drugs
A
- Statins
- Intestinal acting agents
- Ezetimibe
- Bile acid resins
- Nicotinic acid
- Fish oil
- Fibric acid derivatives
3
Q
Treatment of Hyperlipidemia
- Drug of choice
- Alternative choices
A
- 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
Q
Statins: Mechanism of Action
- Mechanism
- Net effect
- Extra effect
A
- 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
5
Q
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…
A
- 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
Q
Statins: Reducing CHD Events
- Statins reduce…
- Statins that reduce CHD risk
A
- 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
Q
Statins: CHD Risk Reduction
- Clinical manifestations of atherosclerosis that statins reduce
- Statins have not been associated w/…
- Overall results
A
- 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
Q
Statins: Time Course of CHD Risk Reduction
A
- 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
Q
Statins: Adverse Events
- Overal safety
- Common side effects
- Liver enyzmes
- Myopathy
A
- 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
Q
Mechanism of Intestinal-Acting Agents
- Bile acid sequestrants
- Plant stanols & sterols
- Ezetimibe
A
- 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
11
Q
Ezetimibe
- Drug class
- Mechanism of action & selectivity
- Pharmacology / localization
- Clinical experience & role in management
A
- 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
Q
Adding Ezetimibe to Ongoing Statin Therapy
A
- 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
Q
Bile Acid Resins: Mechanism of Action
- Bile acid resins…
- Liver…
- In patients who have an elevated TG level…
A
- 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
Q
Effect of Colesevelam on LDL-C
- Bile acid resins vs. LDL-C
- Older bile acid resins: cholestyramine & colestipol
- Newer bile acid resins: colesevelam
A
- 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
Q
Bile Acid Resins: Clinical Features
- Available products
- Beneficial events
- Adverse events
- Drug interactions
A
- 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
Q
Nicotinic Acid (Niacin): Mechanism of Action
- Mechanisms
- Net result
A
- 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
23
Q
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
A
- 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
25
Q
Potential Triglyceride-Lowering Mechanisms of Omega-3 FA
- Inhibit…
- Stimulate…
- End result
A
- 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
