Lipids/Triglycerides Flashcards
Genetically deficient/defective hepatic LDL receptors
* no receptors produced
* receptors don’t migrate to surface of cell
* defective LDL binding
* internalization defect
Autosomal dominant/co-dominant
* Elevated total & LDL cholesterol levels from birth
* heterozygotes = 325-450mg/dL
* homozygotes= 500-1000mg/dL
Familal hypercholesterolemia
what are some physical findings in hypercholesterolemia?
- Tendon Xanthomata
- xanthelasmas, arcus corneus
In a patient with familial hypercholesterolemia, when would cardiac events (MI, SCD, Aortic Stenosis) be seen?
Homozygotes: 1st decade of life
heterozygotes: men- 3rd, women-4th decades of life, especially aggressive with tobacco abuse, low HDL-C, high lipoprotein
What medications mainly lower LDL-C?
- Statins (HMG-CoA reductase inhibitors)
- Azetidinone (ezetimibe)
- Resins (bile acid binding resins or sequestrants)
- PCSK9 inhibitors
- Best evidence for CVD reduction and safety
- major effect is reduction in LDL-C: 20-60% (modest lowering of TG, modest increase HDL-C)
- Seven on the market in U.S (potency and and metabolism vary by agent)
- MOA: inhibition of HMG-CoA reductase–> reduce intrahepatic cholesterol pool–> upregulation of hepatic LDL receptors and removal of LDL from bloodstream
Statins
what are major side effects/contraindications to statin medications?
Major side effects:
* myalgia/ myopathy
* abnormal liver function tests
Contraindications
* Liver disease
* pregnancy
* caustion in combination with fibrates
What are high intensity statins?
- atorvastatin 40-80mg
- rosuvastatin 20-40mg
what is considered moderate intensity statins?
Atorvastatin 10-20mg
rosuvastatin 5-10mg
- reduces CVD risk in combination with statins; safety demonstrated over medium-term use
- major effect is reduction in LDL-C: 14-20%
- minimal decrease in TG, minimal increase in HDL-C
- MOA: Blocks absorption of cholesterol in the small intestine by inhibiting the Niemann-pick C1 like protein—> reduce intrahepatic cholesterol pool–> increases hepatic LDL receptors +LDL removal
- compensatory increase HMG-CoA–> best with statins
- well tolerated; avoid w/ severe liver disease
Azetidinones (Ezetimibe)
- MOA: block absorption of bile salts in the terminal ileum–> reduce intrahepatic cholesterol pool–> upregulation of hepatic LDL receptors + removal of LDL from blood
- major effect is reduction in LDL-C: 15-30% (modest increase in TG and increase HDL-C)
- woerks best with statins
Bile Acid binding resins
what are side effects/contraindications of Bile acid binding resins?
side effects:
* Abdominal discomfort and constipation
* decrease absorption of other durgs
* reduce absorption of fat solube vitamins
Contraindications
* Elevated TG (Especially > 200mg/dL)
* multiple, complex medicatin regimens
* bowel or biliary obstruction
- Reduce CVD risk; short-term safety only
- two on the market; both injectables
- MOA: secreted from hepatocytes–> binds LDL–> receptor–>endocytosis–> lysosomal degradation. Prevents LDL receptor degradation + preserves recycling to hepatocyte surface–> increase receptor density–> increase LDL-C clearance
- Very well tolerated (expensive)
- makes liver twice as effective at removing LDL
Proprotein Convertase Subtilisin/ Kexin Type- 9 (PCSK9) Inhibitors
Nutritious way to lower LDL-C
- Reduce dietary cholesterol to < 200mg/day–> decrease LDL-C by 3-5%, depending on baseline intake
- reduce saturated fats and trans fat to 5-6% of daily calories –> this reduces LDL-C by 8-10%, depending on baseline intake
- Dietary soluble fiber is weak bile acid binder (adding psylllium 6-12g/day)–> decrease LDL-C by 5-10%
- plant sterols block cholesterol absorption- adding plant stanol/sterol margarines (2g/day)–> decrease LDL-C by 7-15%
- varying patterns of LDL-C and VLDL-C levels in families with high apo-B-100 levels
- overproduce apo B-100: increase VLDL + LDL
- 1/3 with LPL abnormality (leads to increased TGs)
- increased atherogenicity (LDL: small and dense; VLDL: cholesterol-enriched; HDL: low, less anti-oxidant/inflammatory)
- genetic predisposition, acquired due to overweight
- Commonly associated with HTN, type II diabetes mellitus, obesity in families
Familial combined hyperlipidemia
which medications primarly lower triglycerides and increase HDL-C?
- Fibrates (fibric acid derivatives)
- omega-3 fatty acids (fish oils)
- niacin (nicotinic acid; also lowers LDL-C)
- Modest evidence for CVD reduction as monotx; limited benefit when added to statins + side effects
- best in TG> 400-500mg/dL to prevent pancreatitis
- MOA: complex mechanism: main is to activate LPL and reduce apo CIII (LPL inhibitor)
- 2 on the market, differ in clearance pathways and interactions with statins
- major effects (used if very high TGs): ( decreased TG by 20-50%, increased HDL 10-20%, increased LDL-C by 5-10% but often increase if high TG)
Fibrates
What are side effects and contraindications of fibrates?
Side Effects
* Abdominal pain
* gall stones
* increased creatinine (secretion, not GFR reduction)
* DVT/ pulmonary embolism (uncommon)
* myalgia/myopathy, especially with statins
Contraindications
* Liver disease
* severe kidney disease (Especially fenofibrate)
* gall stones
* caution with statins (fenofibrate may be safer)
* pregnancy
- decreases triglycerides by 20-50%
- modest increase in HDL-C, related to TG reduction
- LDL-C may increase or not change
- non-lipid effects: platelets, membrane stabilization
- both low and high dose have weak evidence for CVD risk reduction
Omega-3 Fatty Acids (fish Oils)
What are complex mechanisms, major side effects and major contraindications of omega-3 fatty acids?
Complex Mechanisms
* Decrease VLDL production
* Decrease lypolysis in adipocytes
* Decrease TG synthesis
Major side effects
* eructation
* flatulence
* abdominal pain
* bruising/bleeding
* atrial fibrillation
No major contraindications
- Modest evidence for CVD reduction as monotx, limited benefit when added to statins + side fx
- increases HDL-C by 15-30%
- decreases TG by 20-50%
- decreases LDL-C by 10-30% (at higher doses)
- Complex mechanisms: Decreases lypolysis from adiopcytes, VLDL syntheses, decrease APO A-1 catabolism, but not increase cholesterol removal from HDL
Niacin (Nicotinic Acid, Vitamin B3)
what are side effects/contraindications to niacin?
Side effects
* flushing and itching- reduced with aspirin
* abdominal pain, ulcers
* insulin resistance/hyperglycemia
* hepatotoxicity
* gout
* myalgia/myopathy- especially with statins
Contraindications
* Liver disease
* Gout
* Uncontrolled type II diabetes mellitus
* pregnancy
Nutrition to lower TGs?
- Achieve healthy weight (decrease insulin resistance)
- avoid alcohol
- limit simple carbohydrates and sweets
- fat intake should be 25-30%/day of total calories
- limit saturated fatty acids
- emphasize polyunsaturated fats and monounsaturated fats
- TGs> 500-1000mg/dl
- usually acquired, but can be genetic
- acquired- obesity, alcohol abuse, high fat diet, uncontrolled diabetes mellitus, non-compliance
- genetic- LPL deficiency, decrease apo CII, orin increase APO CIII
- main risk is pancreatitis due to hyperviscosity
- also get fatigue, impaired cognition and memory, paresthesias, hepatosplenomegaly
- may have eruptive xanthomata, lipemia retinalis
Chylomicronemia syndrome
how to treat hyperlipidemia (LDL-D: If TG< 500mg/dL)
appropriate dose statin to prevent ASCVD
* Add ezetimibe
* consider adding bile acid binding resin
* add PCSK9 inhibitor
how to treat hyperlipidemia if triglycerides are > 400-500mg/dL to prevent pancreatitis?
- Fenofibrate (or gemfibrozil, but limits statin use)
- optimize glycemic control
- add fish oils
- consider: niacin
