Hyperlipidemia Flashcards
Hyperlipidemias consist of an elevation of 1 (or more) of what?
Cholesterol
Phospholipids
Triglycerides
What are the consequences of hyperlipidemia?
- Development of atherosclerosis leading to coronary heart disease (CHD) and cerebrovascular disease (CVD)
- 1 death every 39 seconds (From CVD)
- CHD caused 1 of every 6 deaths, mortality was 405,309
What are the three major lipids in the body?
Cholesterol
Triglycerides
phospholipids
What are the three major classes of lipoproteins found in serum?
LDLs
HDLs
And very low density lipoproteins (VLDLs)
What are cholesterol and triglycerides essential for?
the synthesis of cell membranes, bile acids and steroid molecules
What is plasma cholesterol regulated by?
by absorption (extrinsic), hepatic production (intrinsic), and hepatic & bile acid excretion (intrinsic)
What accounts for the majority of cholesterol in the body?
Cholesterol synthesis
Where is cholesterol synthesis the greatest?
Occurs in all cells but is the greatest in the liver and intestinal mucosal
What do intestinal mucosa and the liver secrete?
Intestinal mucosa secretes TG-rich chylomicrons (produced primarily from dietary lipids); liver secretes TG-rich VLDL particles
Chylomicron remnants bind to liverendocytosed inhibiting synthesis VLDL
What does extra cellular lipoprotien degrade into?
Extracellular (adipose) lipoprotein lipase (LPL) degrades:
TG ->FFA + phospholipids (transferred to HDL)
VLDL -> IDL ->LDL
What do LDLs bind to and cause?
LDLs bind to specific receptors on extrahepatic tissues and liver-> endocytosed and degraded
What does increased intracellular cholesterol resulting from LDL catabolism do?
- Inhibits activity of HMG-CoA reductase- the rate limiting enzyme for intracellular cholesterol biosynthesis
- Reduces synthesis LDL receptors
- Accelerates activity ACAT to facilitate cholesterol storage within cells
What type of hyperlipidemia results from a single inherited gene defect or is caused by a combo of genetic and environmental factors?
Primary
What type of hyperlipidemia results from generalized metabolic disorders ie., DM, excessive ETOH, hypothyroidism, primary biliary cirrhosis?
Secondary
What is the treatment for secondary hyperlipidemia?
treattment: dietary intervention + drugs to treat cause of hyperlipidemia
What are the primary hyperlipidemais?
Familial hypercholesterolemia (FH)
Familial hypertriglyceridemia (FHTG)
Familial combined hyperlipidemia (FCHL)
Hypoalphalipoproteinemia
What is Familial hypercholesterolemia (FH)?
1 in 500 people in the US
Defect = dysfunctional or absent LDL receptors
Manifest = increased LDL (250-450mg/dl)
What is Familial hypertriglyceridemia (FHTG)?
Defect = decreased LPL activity leading to decreased TG removal
If not able to remove the TG then they elevate.
Manifest = increased TG (200-500mg/dl)
What is familial combined hyperlipidemia (FCHL)?
Defect = Increased apoB and VLDL production Manifest = increased LDL (160-250mg/dL), increased TG (200-800mg/dL)
What is hypoalphalipoproteinemia?
Defect = increased HDL catabolism Manifest = isolated HDL < 35
What drugs might alter lipid profiles?
Thiazide diuretics
Beta blockers
OCPs
How do thiazide diuretics alter lipid profiles?
Increase TG’s 30-50%, Increase TC
How do beta blockers alter lipid profiles?
Increase TG 20-50%, decrease HDL 5-15%
Nonselective beta blockers > selective
How do OCPs alter lipid profiles?
Increase cholesterol 5-20%
Increase TG 10-45%
What is the pathogenesis of atherosclerosis?
-Develops in response to altered endothelial integrity or injury. (usually resulting from HTN)
Injury can be from mechanical forces, or nonmechanical agents (exp. homocysteine, CO)
-Monocytes adhere to vessel surface & become macrophages.
-Macrophages highly oxidize LDL and then take up the LDL creating foam cells
-Oxidized LDL is dangerous
Oxidation of LDL may be cytotoxic
all cell types within vessel wall able to oxidize
Oxidized LDL induces expression of adhesive cell-surface proteins (exp. VCAM)- these allow other stuff to accumulate
-Lipid accumulates in SMC, macrophages, and extracellular matrix
-Ultimately get build up of SMC, macrophages, fibrous tissue and lipid to form plaque.
-Platelets adhere to site of injury and secrete growth factors
-HDL promotes “reverse cholesterol transport”
What is primary prevention?
Preventing the development of atherosclerosis and cardiovascular disease
What is secondary prevention?
Prevent the progression of cardiovascular disease and recurrence of cardiovascular events
What are the goals of cholesterol lowering therapy?
Decrease morbidity and mortality
Achieve target goals for each lipid
What is the bottom line for screening for cholesterol?
Cholesterol reduction decreases progression, increases regression, & decreases formation of new lesions.
Cholesterol reduction decreases CV events, revascularization, and mortality
Cholesterol reduction in some instances decreases all cause mortality
What is the LDL-C (mg/dL) classification?
LDL-C ( mg/dL) < 100 Optimal 100-129 Above, near optimal 130-159 Borderline High 160-189 High ≥190 Very high
What is the HDL-C(mg/dL) classification?
HDL-C (mg/dL)- want it between 40-60
60 High
What is TC(mg/dL) classification?
TC (mg/dL)
< 200 Desirable
200-239 Borderline High
≥240 High
What is the serum triglyceride classification?
Triglycerides (mg/dL) < 150 Normal 150-199 Borderline high 200-499 High ≥ 500 Very high
What are the treatment goals for those with low risk?
Low Risk (0-1risk Factors): LDL < 160mg/dL
What are the treatment goals for those with moderate-high risk?
Moderate-High Risk: LDL < 130mg/dL
Optional: LDL < 100mg/dL for patients with 10-20% 10 year risk
What are the treatment goals for those with DM?
DM:LDL < 100 mg/dL Optional: LDL < 150 mg/dL HDL: > 40 mg/dL for males > 50 mg/dL for females
What are the major risk CHD risk factors other than LDL-C?
Cigarette smoking
Hypertension: BP ≥140/90 mm Hg or on antihypertensive medication
Low HDL-C: <65 years
Age
male ≥45 years
female ≥55 years
*HDL-C ≥60 mg/dL is a negative risk factor and negates one other risk factor.
What are the CHD risk equivalents?
- Myocardial infarction, unstable or stable angina, post-CABG, s/p angioplasty or other PCI
- Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease)
- Diabetes
- Multiple risk factors that confer a 10-year risk for CHD >20%
What is the framingham scoring based on?
Age Total cholesterol HDL cholesterol SBP Smoking status
What are antihyperlipidemic drugs always used in conjunction with?
Diet, exercise, and weight reduction
LDL>160mg/dL + 1 risk factor = drug candidate
When should antihyperlipidemic drugs be reevaluated after baseline labs?
After baseline labs – reevaluate after 4-8 weeks and then after changes
Fasting Lipid Panel every 1-2 years
How do antihyperlipidemic drugs work?
- Decrease synthesis VLDL and LDL
- Enhance VLDL clearance
- Enhance LDL catabolism
- Decrease cholesterol absorption
- Elevate HDL
- Or some combination of action
Niacin (nicotinic acid, niaspan)- MOA
- Inhibits mobilization of FFA’s from adipose tissue => results in decreased VLDL synthesis by the liver
- Lowers TG (20-50%), LDL (5-25%) and increases HDL (15-30%)
- Reduces major coronary events and possibly mortality
Niacin (nicotinic acid, niaspan)- therapeutic uses
Mixed hyperlipoproteinemias
Adjunct to increase HDL (most effective agent)
Adjunct to decrease TG
Niacin (nicotinic acid, niaspan)- adverse effects
Vasodilation => flushing, itching & HA
Slow realease niacin doesn’t cause as much flushing but it doesn’t work as well, But you can also have them take it with an ASA will avoid these side effects.
GI => N, dyspepsia, activation of PUD
Hyperuricemia
Worsen glucose tolerance- therefore a problem in DM patients and there might be better choices.
Hepatotoxicity => LFTs > 3X normal
More severe cases = fatigue, nausea, anorexia
Dose dependent and more common with SR products
Baseline LFTs and monitor q6-8 weeks x 1 year
Niacin (nicotinic acid, niaspan)- monitoring
Glucose, uric acid at baseline and dose threshold
LFTs (AST/ALT)
Baseline
monthly until dose stable for SR
Q 3 months for first year on SR niacin
Check once at dose threshold for IR and ER (4-8 weeks)
For all forms check LFTs Q 6 months
Niacin (nicotinic acid, niaspan)- contraindications
Relative: DM, gout, peptic ulcer
Absolute: Liver disease
Niacin (nicotinic acid, niaspan)- drug interactions
- Hypotension with BP lowering drugs
- Diabetic meds may need adjusting secondary to hyperglycemia
- Increased risk of hepatotoxicity with HMG-CoA reductase inhibitors (statins)
What is the best choice antihyperlipidemic drug for raising HDL?
Niacin
What are the antihypelipidemic drug fibrates?
Gemfibrozil (Lopid)
Clofibrate (Atromid-S)
Fenofibrate (Tricor)
Fibrates –Gemfibrozil (Lopid®)- MOA
MOA: inhibits lipolysis and increases lipoprotein lipase; decreasing serum VLDL and increasing HDL
Effects on lipoproteins: Decreases TGs by 30-50% and increases HDL by 10-20%; may increase LDL (increase in LDL is not something we could like to see)
Reduce major coronary events; inconclusive data regarding increase CV, non-CV, & total mortality
In several trials the decrease in CHD deaths were offset by increased mortality secondary to gallstones and pancreatitis
Fibrates –Gemfibrozil (Lopid®)- Indication
Approved indication = lowering of TG in patients with hypertriglyceridemia
Also used for combined increased cholesterol and TG (in combination)
Fibrates –Gemfibrozil (Lopid®)- adverse effects
-Most common – GI (decrease with time)
-Myopathy – sx: muscle soreness pain
Increased risk if on statin
Baseline CPK => 10X normal d/c
Decreased renal function = increases risk
-Hepatoxicity
-Neutropenia
-Gallstones and pancreatitis
Avoid in high risk groups – women, Native Americans, obese patients.
What are the bile acid binding resins?
Cholestyramine (Questran)
Colestipol (Colestid)
Cholestyramine (Questran) & Colestipol (Colestid)- MOA
Bile acid binding resins
By inhibiting enterohepatic recycling of bile acids and salts, the liver is stimulated to convert stored cholesterol to bile acids
Forms insoluble complex
Increases expression of LDL receptors and LDL uptake in peripheral circulation
Reduces total cholesterol and LDL in a dose-dependent manner
15-30% reduction in LDL; 15-18% with colesevelam; increase HDL 3-10%; and increase TGs 0-12% (this is the problem so need to make sure pt doesn’t already have problems with TG)
Reduce major coronary events and CHD deaths
Cholestyramine (Questran) & Colestipol (Colestid)- Adverse effects
Primarily GI
Constipation, bloating, gas, nausea
Avoid in patients with diverticulosis, swallowing difficulties, GI motility disorders
↑ TGs
Cholestyramine (Questran) & Colestipol (Colestid)- ADRs
warfarin, thyroid, digoxin
Separate all meds by at least 2 hrs, if you have taken it wait 4 hours to take it.
Cholestyramine (Questran) & Colestipol (Colestid)- Contraindications
Absolute: Biliary obstruction, fasting TGs > 500mg/dL
Relative: fasting TGs > 200 mg/dL
What are the HMG-CoA reducatase inhibitors?
Lovastatin (Mevacor), Pravastatin (Pravachol), Fluvastatin (Lescol), Simvastatin (Zocor), Rosuvistatin (Crestor), Atorvastatin (Lipitor)
HMG-CoA reducatase inhibitors (Lovastatin (Mevacor), Pravastatin (Pravachol), Fluvastatin (Lescol), Simvastatin (Zocor), Rosuvistatin (Crestor), Atorvastatin (Lipitor))- MOA
Competitively inhibit the rate-limiting enzyme (HMG-CoA Reductase) necessary for cholesterol synthesis results in an increase in hepatic LDL receptors
Decreased cholesterol concentration within cell
Low intracellular cholesterol stimulates synthesis of LDL receptors and LDL clearance from peripheral circulation
Low intracellular cholesterol decreases secretion of VLDL
HMG-CoA reducatase inhibitors (Lovastatin (Mevacor), Pravastatin (Pravachol), Fluvastatin (Lescol), Simvastatin (Zocor), Rosuvistatin (Crestor), Atorvastatin (Lipitor))- effects on lipoproteins
Decreases LDL 20-60%
Decreases TGs 10-30%
Increases HDL 5-10%
HMG-CoA reducatase inhibitors (Lovastatin (Mevacor), Pravastatin (Pravachol), Fluvastatin (Lescol), Simvastatin (Zocor), Rosuvistatin (Crestor), Atorvastatin (Lipitor))- Proven efficacy to reduce
Major coronary events and stroke
CV-related and total mortality
Coronary procedures (PCI/CABG)
Statins pleiotropic effects- cardiovascular
Stabilize atherosclerotic plaques
Enhance vascular nitric oxide production
Attenuate inflammation due to vascular injury
Decrease oxidative stress
Statins pleiotropic effects- renal
Modulate glomerular mesangial and interstitial inflammatory processes
Statins pleiotropic effects- endocrine
Improve insulin sensitivity (beneficial in type II DM)
Statins pleiotropic effects- skeletal
Inhibit bone resorption
When do statins work the best?
Efficacy greatest if given with dinner or at bedtime to coincide with peak cholesterol biosynthesis (due to peaking cholesterol in the middle of the night)
Statins- Adverse effects
Few side effects, excellent patient acceptance
Most common = HA, myalgias, GI (dyspesia)
Hepatotoxicity = LFTs > 3X normal
Check LFTs every 4-6 weeks for 1 year
Alcohol and prior liver disease increase risk
Myopathy = muscle aches, soreness, weakness and CPK > 10X normal
Increased levels = increased risk
Doses should not exceed those required to attain ATP III goals
Risks are associated with the higher levels.
Statins- Drug interactions
-Drug interactions: (few)
-Cyp450 3A4 Inhibitors:
Cyclosporine, grapefruit juice, macrolides, triazole antifungals, fluoroquinolones, SSRIs, diltiazem, verapamil, amiodarone, omeprazole, protease inhibitors
-Pravastatin, Fluvastatin (2C9) and Rosuvastatin (2C9 minor) not metabolized by 3A4
-Lovastatin increases warfarin effects
-Drugs that cause myopathy
Gemfibrozil and niacin
Statins- Monitoring
AST/ALT before and 12 weeks after initiation of statin or after dosage increase then periodically (every 6 months), CK at baseline and if symptoms
Statins- cautions and contraindications
Liver and renal disease
Contraindicated in pregnancy
What is the best drug for lowering LDL?
HMG-CoA reductase inhibitors (statins)
Advicor® (Niacin ER/Lovastatin)
Increased risk of myopathy and hepatotoxicity
Monitor LFT’s baseline, Q 6-12 weeks x 6 months then periodically
Ezetimbe (Zetia®)- MOA
Cholesterol absorption inhibitor
- Inhibits absorption of cholesterol at the brush border of SI->decreased delivery of cholesterol to liver
- Decreased total cholesterol, LDL-C and TG; increased HDL-C
- Decreases LDL-C by 15-20%, TGs by 5-10% and increases HDL by 4-9% in monotherapy and as add-on
- No data on CV morbidity or mortality
- No effect on blood levels of fat soluble vitamins
Ezetimbe (Zetia®)- ADRs
May increase risk of AST/ALT elevation when used in combination with statins
ADRs: HA, GI, arthralgia, sinusitis
Vytorin® (simvastatin + ezetibmbe)
Should only be used when other therapies are not working
Estrogen- effects of CVD
- Decrease CVD risk by ~ 35% from epidemiologic studies
- Decrease LDL 15-20%, Increase HDL 5-20%, -Increase TG’s 10-25%,
- Decrease Lp (a) 20-30%
Estrogen- WHI/HERS/ACC/AHA recommendations
- WHI and HERS study demonstrated no benefit on CV risk and increased risk of breast CA
- ACC/AHA recommends that estrogen/progesterone not be initiated or continued to prevent CAD in postmenopausal women.
Fish oil (omega-3 fatty acids)
- Effective at lowering TG’s (25-30%); can increase LDL (5-10%) esp at higher doses (> 3 gm/day), minimal effects on HDL
- MOA: Not understood, one possible mechanism is increased plasma lipoprotein lipase activity.
- Supplementation demonstrated to decrease CHD events (MI, death, nonfatal stroke)- in trials
Lovaza® (formally Omacor®)
- Decrease TG’s by 45% (baseline TGs > 500 mg/dL)
- Side Effects: Higher doses (> 3 gm/day) can effect bleeding time and may impair insulin secretion, GI (nausea, diarrhea, taste disturbance)
Psyllium husk (Metamucil)
Good (↓ LDL 10-15%)
Garlic
Probably good (↓ TC 5-15%)
Olestra (sucrose polyester) “WOW, Olean”
Not so good (↓ TC 5-8%)
Made patients leak out fatty stuff from butt
Red yeast rice
Has activity against HMG Co-A reductase
↓ LDL 20 - 25%
Alcohol
–Moderate alcohol consumption is associated with lower mortality
Most evidence with red wine
–Moderate consumption (< 2 drinks/day; 20 gm/day alcohol) associated with:
~ 12% increase in HDL-C
decreased LDL oxidation
decreased platelet aggregation
–Higher consumption associated with increased mortality
Increased BP, arrhythmia, TG, stroke, and MI
How do you select an agent for treatment of hyperlipidemia?
Based on goal LDL and % reduction required
Initiate therapeutic lifestyle changes
Smoking cessation
Diet, including plant stanols/sterols, fish oils, & fiber
Weight reduction, physical activity
What selection of agent is used if LDL-C >20% above goal or patient is high or moderately high risk?
If LDL-C > 20% above goal or patient is high or moderately high risk, statins should be the initial drug choice
What selection of agent is used if LDL-C <20% above goal?
If LDL-C < 20% above goal, then a statin, niacin, ezetimibe, or BAR are good choices
What selection of agent is used if TGs>500?
IF TGs > 500, then initiate TG lowering therapy (fibrate or niacin) to reduce risk of pancreatitis
What is the goal when initiating drug therapy for patients at very high risk, high risk, or moderately high risk?
When initiating drug therapy for patients at very high risk, high risk, or moderately high risk the intensity of therapy should be such to achieve a 30 – 40% LDL reduction
When should a repeat fasting lipid profile be done?
Repeat fasting lipid profile in 4 – 6 weeks
If not at goal, intensify statin dose
OR
Add ezetimibe, BAR (bile acid resin), or niacin
Once LDL goal is acheived what should be assessed?
Once LDL goal achieved, assess TGs and HDL
If TG > 200 mg/dL, achieve non-HDL-C (TC – HDL-C) goal (LDL goal + 30 mg/dL)
Intensify therapy with LDL-lowering drug
OR
Add niacin or fibrate
If TG < 200 mg/dL, HDL < 40 mg/dL, & CHD or equivalent, consider fibrate or niacin
What is considered low HDL-C?
Low HDL-C: <40 mg/dL (no specific goal defined for raising HDL-C)
What is the targets of therapy for management of low HDL-C?
- All persons with low HDL-C: achieve LDL-C goal; then ↓ weight, ↑ physical activity (if metabolic syndrome is present)
- Those with TG 200–499 mg/dL: achieve non–HDL-C goal* as secondary priority
- Those with TG <200 mg/dL: consider drugs for raising HDL-C (fibrates, niacin)
What is considered very high LDL-C?
LDL-C ≥190 mg/dL usually traced to genetic forms of hypercholesterolemia
What are the recommendations for management of very high LDL-C?
- Early detection in young adults through cholesterol screening to prevent premature CHD
- Family cholesterol testing to identify affected relatives
- Combination drug therapy usually required to achieve target LDL-C levels
What is considered borderline high TG and how should it be managed?
Borderline high 150–199
↓ weight, ↑ physical activity
What is considered high TG and how should it be managed?
High 200-499
↓ weight, ↑ physical activity, consider drug treatment to reach non–HDL-C goal-‡
What is considered very high TG and how should it be managed?
Very High > 500
Very low-fat diet, ↓ weight, ↑ physical activity, nicotinic acid or fibrate
What is the management of diabetic dyslipidemia?
- -Primary target of therapy: identification of LDL-C; goal for persons with diabetes: <100 mg/dL
- -Therapeutic options:
- -LDL-C 100–129 mg/dL: increase intensity of TLC; add drug to modify atherogenic dyslipidemia (fibrate or nicotinic acid); intensify risk factor control
- -LDL-C ≥130 mg/dL: simultaneously initiate TLC and LDL-C–lowering drugs
- -TG ≥200 mg/dL: non–HDL-C* becomes secondary target
What characterizes dyslipidemia in diabetes?
Increased TG
Decreased HDL
LDL concentrations do not significantly differ from concentrations in non-DM patients
However, DM LDL is predominately small, dense LDL
