Why do lipid soluble statins have increased risk of adverse effects? Which ones?
- Because they penetrate muscle
- Simvastatin, Lovastatin
Why is it good that statins are metabolized in the liver?
- This is also the site of action of statins, so very little statin ever leaves the liver, making these drugs pretty safe under normal circumstances
- Dangerous at periphery -> myositis
Why is the OATP transporter important for statin metabolism?
Primary method of liver uptake of statins
How dose renal insufficiency affect statin tx?
- Should reduce dosage in pts with renal insufficiency
- EXCEPT Atorvastatin, which is primarily secreted by fecal mechanisms
What are the bile acid sequestrants?
- Anionic (+ charge) ion exchange resins: interrupt enterohepatic recycling of cholesterol by binding (-) charged bile acids in the gut
- Among the oldest (and safest) hypolipidemic drugs
- Non-systemic (not absorbed from intestine), so can be safely used in children, pts with liver disease
- Available in both powder and pill formulations
- Lowers LDL-cholesterol by up to 25% at max doses
- Modest effect on HDL-C, but does NOT decrease TGs (may increase)
- GI side effects (bloating, constipation) can limit use
Which bile acid sequestrants are given only as a tablet, only as a powder, or both?
- Only tablet: Colesevelam (should be taken w/liquid)
- Only powder: Cholestyramine
- Both: Colestipol (powder should be mixed with OJ or applesauce)
What are the common AE's of bile acid sequestrants?
- Gritty texture (slurried powder, “sand”)
- GI: bloating, nausea, flatulence, constipation (premix-refrigerate), fecal impaction (take with water!)
- Paradoxical hypertriglyceridemia
What are the drug interactions and contraindications for the bile acid sequestrants?
- Drug interactions:
1. Prevents absorption of other drugs: digoxin, b-blockers, thyroxine, Warfarin
2. Take other meds 1 hour before or 3-4 hours after bile acid sequestrant
2. Complex drug regimens, critical meds
3. History of constipation (elderly patients)
What drugs lower TG's and raise HDL?
- Fibric Acid Derivatives (Fibrates)
- Nicotinic Acid (Niacin)
- Omega-3 Polyunsaturated fatty acids (Fish Oil)
What are the fibric acid derivatives? What is their MOA?
- Gemfibrozil, Fenofibrate
- MOA: ligand for the ligand-activated PPAR-alpha nuclear receptor (mimic fatty acids, the natural ligand)
1. INC transcription of LPL, DEC syn of ApoC-III, and ApoA-1 and -2 syn INC (increased HDL)
2. Increased oxidation of fatty acids bc enzymes involved also regulated by PPAR -> less FA available for synthesis of TG’s
3. Whole series of metabolic genes with this binding site on them
What are the lipoprotein effects of fibrates?
- Reduce VLDL, increase HDL
- TG's reduced up to 50%
- HDL-C increased up to 15%
- LDL-C unchanged or decreased modestly (may also increase)
What are the AE's of the fibrates?
- Gastroesophageal reflux, diarrhea, increased liver enzymes
- Fenofibrate: increased creatinine (reversible DEC in GFR; though to be related to PG syn), paradoxical HDL lowering
- Lithogenic bile: gallstones
- Teratogenic/Embryocidal in animals (no human data)
1. Pregnancy category C (use only if benefit outweighs risk)
What are the dosage, metabolism, and excretion differences between Gemfibrozil and Fenofibrate?
- Gemfibrozil (generic): 600 mg tablet
1. Extensively metabolized by liver (oxidation, glucuronidation by UGT1A1) -- UGT1A1 also used for statins -> reduces statin metabolism, so contraindicated or dosage of statin limited
2. Can be safely given to pts w/renal disease.
- Fenofibrate (Tricor®)
1. Hepatic metabolism: active metabolite fenofibric acid dependent on renal excretion
2. Accumulates with renal insufficiency (GFR < 50 ml/min) -> dosage reduction recommended
3. NOT recommended for advanced renal disease ie GFR < 30 ml/min
What are the chemistry and preparations of nicotinic acid?
- Pyridine-3-carboxylic acid (vitamin B3, aka niacin)
1. Immediate Release (IR) (Niacor®): requires slow up-titration to minimize flushing
2. Extended-Release (ER) (Niaspan®): less flushing, better tolerated
What are the adverse effects of nicotinic acid?
- Cutaneous flushing (common): give ASA; start low, INC slowly, use extended-release niacin (Niaspan)
- Elevated transaminases, hepatitis, hepatic failure (older slow release preps: SR dose limited to 2 g/d)
- GI irritation: nausea, activation of peptic ulcer disease, hyperuricemia, gout
- Conjunctivitis, cystoid macular edema, retinal detachment
- Myositis (rare)
- Dry skin, pruritis, icthyosis, acanthosis nigricans (if you give Niacin several times, you deplete mast cells of histamine)
- Insulin resistance: glu intolerance, hyperglycemia
- Pregnancy category C: use if benefit exceeds risk
HyperTGemia and low HDL are powerful risk predictors, but are they risk factors?
- When you do multivariate analysis, looking at risk with these, and take everything else out, very little risk remaining that can be attributed solely to these
- Somehow this moderates risk, however
- No trials showed added benefit of using these with statin therapy, which are main line of tx (exception people with high TG, low HDL, who did improve)
- Considered unproven add-on therapy
What are N-3 FA's, and how do they reduce TG's and CV risk?
What are some dietary sources of Omega-3 and -6 FA's?
- 3: walnuts, flaxseed, fatty fish, canola oil, fish oil, soybean
- 6: corn, cottonseed, sunflower oils, black currant seed oil,
How do N-3 FA's affect lipids?
- Reduce plasma TG's up to 35% and hepatic TG syn
- INC FA oxidation via PPAR
What are the potentially beneficial effects of N-3 FA's?
- Antiplatelet, hypotensive, hypolipidemic effects
- Dietary intake of one or more servings of fish/week reduces risk of heart attack or stroke
- Intake of fish oil capsules has not yet been shown to reduce risk
- Studies using concentrated fish oil (EPA and/or DHA) currently underway
How does HDL affect CHD risk?
- Epi observations:
1. CHD risk decreases by 50% for each 0.52 mmol/L INC in HDL-C
2. Epi association b/t low HDL-C level and CAD consistent across pops, and has been validated in all major epi studies
3. Still just an ASSOCIATION (does NOT imply causality)
What is CETP?
- Plasma protein that catalyzes transfer of CE (chol ester) from HDL to ApoB-containing lipoproteins (VLDL and LDL) in exchange for TG's
Will CETP inhibitors work?
- Higher HDL-C is good, but benefit of HDL-C raising has been harder to prove
- Anacetrapib and Evacetrapib dramatically increase HDL-C (10x that seen in HPS2), AND lower LDL by 30-40%
- Anacetrapib lowers Lp(a) by 35%
- TRIALS ARE ONGOING
A 55 year old male has Type II Diabetes and Coronary Heart Disease. His LDL-C is 105 mg/dl, TG is 300 mg/dl and HDLC is 32 mg/dl. What drug would be considered PRIMARY treatment to reduce his risk of recurrent coronary disease events?
What did the PROVE-IT study show?
That while there is a benefit to using intensive statin therapy, there is still residual risk