Hyperlipidemia Flashcards
what is hyperlipidemia
-Elevation of lipids (fatty substances) in the bloodstream
-Can include:
-cholesterol
-cholesterol esters
-phospholipids
-triglycerides
hyperlipidemia: primary vs secondary
-primary- familial disorder
-secondary:
-ds risk factor- DM, hypothyroid, alcohol, cushing, kidney failure
-dietary risk factor
-drug induced- hormones, steroids, diuretics, beta blockers
-MC in men than women**
cholesterol
-produced by liver- endogenous
-we consume from meat and dairy- exogenous
lipoproteins
-chylomicrons- triglycerides, cholesterol, protein -> LARGEST
-very low density lipoproteins (VLDL)
-intermediate density lipoproteins (IDL)
-low density lipoproteins (LDL)
-high density lipoproteins (HDL)- good
atherosclerosisb
-slow, progressive disease
-deposition of fatty substances (mainly cholesterol), fibrous tissue and calcium on the intimal lining of blood vessels (mainly arteries)
-aim is to lower total cholesterol and LDL or raising HDL to slow the progression of the disease and possibly reverse it.
-Atherosclerosis increases risk of CAD
-Treat with diet, drugs and exercise
lipoprotein levels
-12 hours fast
-focus on numbers that we like -> desirable
triglyceride levels
-<150 - normal
-150-199 - borderline high
-200-499 - high
-=> 500 - very high
therapeutic lifestyle changes
-Dietary Modifications
-Weight reduction
-Exercise
-Quit smoking
-increase soluble fiber*
dietary modifications
-Attempt TLC & dietary modifications first (depending on LDL levels and risk factors)
-Diet should be:
-Low in cholesterol (< 200 mg/day)
-Low in saturated fat (calories < 7% of total fat)
-Low in calories
-Avoid trans fat
-avoid alcohol
-decrease wt
“good” fat
-Monounsaturated fatty acids (MUFA)
-Aka oleic acid
-found in olive oil, canola oil, safflower oil and sunflower oil
-Also found in walnuts, almonds, peanuts and sesame seeds and olives and avocados
-Polyunsaturated fatty acids (PUFA)
-Linoleic acid (omega-6) – found in vegetable oils (soybean, safflower, sunflower and corn)
-alpha-linoleic acid (omega-3) – found in certain fish, marine oils, flaxseed and linseed oils
CHD major risk factors
-age- men > 45; women > 55
-diabetes mellitus
-family hx of early CHD- male < 55; female < 65
-HTN
-smoking
-low HDL <40
-others:
-obesity
-sedentary lifestlye
-atherogenic diet
ASCVD risk calculator
-risk factors used in calculation:
-10 year risk
-Sex
-Age
-Race
-Total Cholesterol
-HDL
-Systolic BP
-Treated for HBP
-Diabetes
-Smoker
classes of drugs
-HMG-CoA Reductase inhibitors
-Bile sequestering agents
-Fibric acid derivatives
-Nicotinic acid
-Miscellaneous
HMG-CoA reductase inhibitors
-(HMG CoA = 3-hydroxy-3-methylglutaryl-CoA)
-Aka “statin drugs”
-MOA - block the rate-limiting step in cholesterol biosynthesis (conversion of HMG CoA to mevalonic acid) thereby lowering LDL and TC levels -> Also lower TGs and raise HDL
-Lipid-lowering efficacy: Reduce LDL by 20-60%, TG by 15-60% and raise HDL 3-15% -> robust
-Efficacy increases with higher doses and more potent statins- start high
-lowers cholesterol at first step
Therapeutic Benefit:
-Plaque stabilization
-Improvement of coronary endothelial dysfunction
-Inhibition of platelet thrombus formation
-Anti-inflammatory activity- less chance of plaque attaching and building
-Evidence-based data in following patient populations
-Patients with CHD with or without hyperlipidemia
-Men w/ hyperlipidemia but no known CHD
-Men and women with average total and LDL cholesterol levels and no known CHD
-Per guidelines: First line to reduce LDL
statins ADR and pregnancy
-Contraindicated in ACTIVE hepatic disease and pregnancy
-Hepatic disease – Safe to use in non-alcoholic fatty liver disease and probably safe in Hepatitis C
-Precautions: Dose adjustments if DDIs
-GI (n,v,d)
- high LFTs, hepatotoxicity
-myopathy - myalgia, rhabdomyolosis (rare)
-CNS: ↓ cognitive function, memory loss -> Reversible upon d/c of drug, tinnitus
-CNS symptoms can just be from old age so maybe test hearing before starting
-New data on small incidence of hyperglycemia and increase HbA1C, but benefit»_space; risk in DM
Pregnancy Category X, also contraindicated in Breast Feeding
-Fetal Abnormalities include:
-Spontaneous abortion
-Congenital anomalies:
-Polydactyly
-Cleft lip
-Trisomy 18
-Club foot
-A-V septal defects
-Fetal skeletal malformations
HMG-CoA Reductase Inhibitors- Risk Factors for myopathy: patient factors and drug properties
PATIENT FACTORS
-Age > 80
-Female gender
-Small body frame
-↓ hepatic/renal Fn
-Hypothyroidism
-Diet (grapefruit juice)
-polypharmacy
DRUG PROPERTIES
-Lipophilicity (pravastatin and rosuvastatin least likely)
-High F
-Limited protein binding
-CYP substrate
statins DDIs
-dose adjustment of statin based on DDI -> this is a precaution NOT a CI
-CYP 450 3A4 substrates: Lovastatin & Simvastatin»_space; Atorvastatin
-Significant 3A4 inhibitors: grapefruit juice, amiodarone, azole antifungal, macrolides
-Significant 2C9 inhibitors: amiodarone, cimetidine, azole antifungals, SSRIs, zafirlukast
-Fluvastatin is a CYP2C9 substrate.
-Pravastatin and Rosuvastatin have least DDIs.
HMG-CoA Reductase Inhibitors: monitoring parameters
-Lipid profile: Baseline, then 4-8 weeks after initiation of therapy or dose changes, then q6-12 months thereafter
-LFTs: Baseline, then periodically thereafter or if signs or symptoms of liver disease (Updated in 2012 that routine LFT monitoring is no longer required)
-CPK: Consider at baseline, then if pt has myalgia symptoms (rhabdo)
HMG-CoA Reductase Inhibitors: examples
atorvastatin (Lipitor)
fluvastatin (Lescol)
lovastatin (Mevacor)
pravastatin (Pravachol)
rosuvastatin (Crestor)
simvastatin (Zocor)
pitavastatin (Livalo)
HMG-CoA Reductase Inhibitors: dosing implications
-Best to dose at bedtime (HS) to mimic normal circadian rhythm
-Atorvastatin and Rosuvastain (newer drugs) have > 24 hr half-lives, so DOESNT MATTER WHEN YOU TAKE
-RULE OF 6’s – Initial doses produce the most substantial reduction in LDL, so must start patient on the highest necessary dose to get to goal -> Each doubling of dose after only produces an additional 6-7% reduction in LDL
-Ex: Pt with an LDL of 200 mg/dL needs to get to LDL goal of < 100 mg/dL. Atorvastatin will reduce LDL by 50% with the max dose of 80mg -> If start pt on lower dose (i.e 40 mg), they may not get to goal
PCSK9 Mab Inhibitors: indications
-newest
-Alirocumab (Praluent) – SC Injection
-Evolocumab (Repatha) – SC Injection
-Indications
-Familial hypercholesterolemia - homozygous, in combo with other lipid-lowering therapies
-Primary heterozygous familial hypercholesterolemia, in combo with statin
-Primary hypercholesterolemia, Atherosclerotic cardiovascular disease; in combo with statin
-usually used for pts who maxed out on oral meds
PCSK9 Mab inhibitors MOA
-monoclonal antibody that inhibits the binding of Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) to low-density lipoprotein receptors (LDLRs) on hepatocytes, thus reducing degradation of the LDLR.
-Increased LDLRs are then available to clear LDL-C from circulation and lower LDL-C levels
-Repatha – 140mg SC q2weeks or 140mg q4weeks
-Praulent – 75mg SC q2weeks or 300mg q4weeks
PCSK9 Mab inhibitors ADR
-injection site reactions
-nasopharyngitis
-influenza
-allergic reactions
PCSK9 siRNA inhibitors
-inclisiran (leqvio)
-indications- adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low- density lipoprotein cholesterol (LDL-C)
-By binding to the messenger RNA (mRNA) precursor ofPCSK9, inclisiran inhibits the PCSK9 gene expression, resulting in increased hepatocyte recycling and membrane expression of LDL receptors and decreased levels of LDL-c
-2x yearly injection
ASCVD tx recommendation
-Age ≤ 75yo & no safety concern -> High-intensity Statin tx
-Age > 75yo or safety concern -> Moderate-intensity Statin tx
-Primary Prevention – Diabetes 40-75yo & LDL-C 70-189 mg/dL -> Moderate intensity statin tx -> Consider high intensity statin if ≥ 7.5% 10y ASCVD risk
-Primary Prevention – NO diabetes 40-75yo & LDL-C 70-189 mg/dL -> Estimate 10y ASCVD risk
-Primary Prevention – Primary LDL-C ≥ 190 mg/dL
-R/O secondary causes
-Age ≥ 21yo
-High intensity statin
-Achieve min of 50% ↓ in LDL-C
-LDL-C lowering non-statin tx
statin intensity
bile sequestering agents
-MOA – binds to bile acids and forms a complex which is excreted, therefore less bile acids available to emulsify fats in GI tract, increase conversion of cholesterol to bile acid -> decrease LDL by 10-20%, but increase TG by 20%.
-Contraindicated in hypertriglyceridemia (TG > 400)*
-Pharmokinetic: not absorbed from gut, excreted in feces -> steatorrhea
-ADRs - Primarily GI effects (n,v, constipation, flatulence, steatorrhea*, anorexia, heartburn), increase TGs
-DDI - will bind with and prevent absorption of almost all drugs, so take 1 hr before or 4 hrs after, esp. digoxin, thyroxin, and warfarin
-Per guidelines: Can add when pts don’t reach LDL goal with statins or if cant tolerate statins
bile sequestering agents: examples
-cholestyramine (Questran) (C): Give QID TO Q4H, available as a powder
-colestipol (Colestid)(B): Give BID, available as tabs or granule pkts
-colesevelam (WelChol)(B) Give Daily - BID, available as tabs, take w/ meals May also have a glucose lowering effect in Type 2 DM
-All can take several weeks for maximal effect
-Questran and Colestid may also be used for treatment of overdose w/ toxicological agents
fibric acid derivatives
-MOA- Complex MOA involving activation of peroxisome proliferator activator receptors PPARs:
-Activates lipoprotein lipase (leads to decreased TGs)
-decrease expression of apo CII (leads to decreased TGs)
-increase expression of apo AI, and apo AII (leads to increased HDL)
Lipid lowering efficacy:
-increase HDL (6-15%), decrease TG (20-50%), LDL (variable)!!!!!!
-Indications: Primarily used to treat hypertriglyceridemia or marked HDL deficiency
-Contraindicated in severe renal/hepatic failure, biliary and gallbladder disease
-ADRs - GI, dyspepsia, rash, urticaria, alopecia, fatigue, headache, impotence, LFT, myopathy and rhabdomyolosis, gallstones.
-DDIs: Compete with warfarin and sulfonylureas for protein binding sites. Monitor appropriately.
-Examples
-gemfibrozil (Lopid) (C): Give BID,
-fenofibrate (Tricor, Lipofen, Fibricor, etc. )(C): Give once a day
nicotinic acid (niacin)
-MOA: AT HIGH DOSES: Inhibits lipolyis → decrease circulating free fatty acids → decrease TG synthesis → decrease hepatic VLDL production and secretion -> Also raises HDL.
-Lipid-lowering efficacy: decrease LDL (10-15%) and decrease TG (20-50%) and increase HDL (5-10%).
-Causes vasodilation & flushing, pruritis (face and upper body – less w/ SR form). Reduce this ADR w/ ASA pretreatment or slowly increase dose!!
-Other ADRs- GI (take with food to minimize), PUD, increase LFTs - hepatic dysfunction (more w/ SR form), hyperuricemia, hyperglycemia.
-Available alone or in combination with lovastatin (Advicor)
-Per guidelines: 2nd line choice to add when pts don’t reach LDL goal with statins or if cant tolerate statins
ezetimibe (zetia): miscellaneous
-Unique MOA – Inhibits absorption of cholesterol at brush border of small intestine, leading to decrease delivery of cholesterol to liver, increase cholesterol clearance
-TC (decrease 13%), LDL (decrease 15-18%), TG (decrease 9%) and very small increases in HDL
-ADRs – Chest pain, dizziness, fatigue, headache, GI effects – diarrhea and abdominal pain, arthralgia
-DDIs – cyclosporine, fibric acid derivatives
-Conflicting data on benefit in reducing CV events
-benefits pt in combo with other drugs
combination products
-ezetimibe/ simvastatin (Vytorin)
-nicotinic acid/lovastatin (Advicor)
-nicotinic acid/simvastatin (Simcor)
-amlodipine/atorvastatin (Caduet)
-pravastatin/asa (Pravigard)
-ezetimibe/atorvastatin (Liptruzet)
miscellaneous- probuchol (Lorelco)
-Rarely used today b/c of increased effectiveness of statins
-lowers both LDL AND HDL - therefore generally limited to certain types of hereditary high cholesterol and/or to cases in which other cholesterol-lowering medications have been ineffective.
-ADRs - diarrhea, bloating, nausea, and dizziness.
miscellaneous therapies
-Vitamin E
-Garlic
-HDL infusions
-Alternative therapies – see next slide
-Dietary supplements – see next slide
summary: alternative tx for hyperlipidemia
-artichoke extract lower LDL -> doesnt help anything else
-fish oil -> lowers triglycerides
-plant stanols/sterols
-fiber
fish oils (omega-3 fatty acids)
-Contain 2 PUFAs [eicosapentaenoic acid (EPA) and docosahexaenoic acid(DHA)]
-Available as RX product Lovaza -> both EPA and DHA
-MOA: Decrease synthesis and secretion of VLDL, reduce TG transport.
-Efficacy:
-Several studies supporting use
-2 grams 2x day can reduce triglycerides 20-50%
-Only effective for high TGs. Does not lower total cholesterol or LDL
-reduces the risk of cardiovascular and all-cause mortality
-Fish oils 1 gm/day: Decrease risk of MI, stroke and progression of atherosclerosis
-23% reduction in overall mortality and 32% reduction in death from cardiovascular causes in people with or without CVD
-16% reduction in overall mortality and 24% reduction in death due to MI
-Similar efficacy to some studies evaluating statins’ effects on mortality and CVD
fish oils dosing
-Considered safe in doses of < 3 grams per day
-2g 2x day
-Mostly GI (flatulence, diarrhea, dyspepsia), body odor. RX product (Lovaza) has less ADRs than OTCs
-Higher doses may have anticoagulant effect and increase risk of bleeding and/or suppress immune response
-Dosing: 2-4 g per day for hypertriglyceridemia
- Rx product is 2 g bid
fish oils from dietary sources
-Large amounts of fatty fish may have high amounts of toxins (mercury, PCB, dioxin)
-ADRs can include tremor, numbness, tingling, difficulty concentrating and vision problems
-Fatty fish include shark, swordfish, king mackerel, tilefish and farm-raised salmon
