Dyslipidemia Tx Options - Non-statin lipid lowering drugs Flashcards
Ezetimibe
MOA
reduces C absorption, reduces flux of C from intestine to liver
Because this C is packaged and resecreted by liver into blood as VLDL, reduced flux of C to VLDL particles will lowwer LDL-C
Ezetimibe
indication
dose
Ezetimibe Ezetrol® 10 mg
• Indicated to lower LDL‐C as adjunct to statin
• Lowers LDL‐C by additional 15‐20%
• Monotherapy if patient statin intolerant
• Modest reduction in CV events when used in
combination with a statin – no evidence with
monotherapy
Ezetimibe
Contraindications
• Drug interactions:
- Combination with statins in patients with active liver disease or unexplained liver enzyme elevation
- Hypersensitivity
- Pregnancy and lactation
- Cyclosporine (increase ezetimibe levels)
- Fibrates (increase ezetimibe levels)
- BAS (decrease ezetimibe levels
Fibrates
MOA
agonist of PPARa which are a class of intracellular receptors that modulate fat metabolism they increase genes transcription for lipoprotein lipase leading to increased breakdown TG in VLDL and chylomicrons
Fibrates
names and dose
Bezafibrate Bezalip® 400 mg
Fenofibrate Lipidil® 48 – 200 mg
Gemfibrozil Lopid® 600 – 1200 mg
- First line therapy to reduce TG (20‐50%)
- Goal is to reduce risk of pancreatitis
- Historical outcome data demonstrates a reduction in CV and coronary events – pre‐statins
Niacin
MOA
decrease sybtg if VLDL in liver, increased clearance in plasma, decreased mobilization of free fatty acids from adipose tissue
most common AEL cutaneous flushing, GI disturbacnes
Niacin
name and dose
Crystalline niacin ‐ 1 – 3 g
ER niacin Niaspan® 500 – 2000 mg hs
• Indicated for combined dyslipidemia
• Lowers LDL‐C by 20% in combination with statin
• Increases HDL‐C by 20%
• Reduced coronary stenosis in combination with simvastatin (HATS trial),
but no outcome studies
which niacin pdts are otc
- Crystalline niacin (OTC)
• Requires titration to develop tolerance to flushing - Extended‐release niacin (Niaspan®) (Rx‐only)
• Reduced incidence of flushing
• Associated with hepatotoxicity - Flush‐free niacin (OTC)
• Studied in rabbits
• Contains inositol no flushing but no absorption
• Do NOT recommend as alternative to niacin
Bile Acid Sequestrants (BAS) ‐‐ MOA
• Bile acids make cholesterol absorption easier form the intestine – both endogenous cholesterol (synthesized in the liver and enterohepatically recirculated) and exogenous cholesterol (ingested
and processed in the intestine)
• Bile acid sequestrants form an insoluable complex with bile acids and salts, preventing their reabsorption from the intestines. They disrupt enterohepatic recirculation of bile acids and reduce reabsorption of
endogenous and exogenous cholesterol
Bile Acid Sequestrants
names and dosse
AE?
Cholestyramine Questran® 2 – 24 g
Colestipol Colestid® 5 – 30 g
Colesvelam Lodalis® 1.25‐3.75 g
- Indicated to lower LDL‐C as adjunct to statin
- Lowers LDL‐C by additional 10‐15%
- Multiple GI adverse effects
- Multiple drug interactions
- interfere with drug absorption (Colesvelam has not been shown to do this)
- wait 1‐hr before or 3‐4 hrs after administration of BAS before other drugs
- No outcomes trial
PCSK9 Inhibitors (Proprotein Convertase Subtilisin/Kexin type 9)
MOA
see slide 105-107
PCSK = proprotein convertase subtilisin/kexin
• Serum PCSK9 is inversely related to density of LDL‐C receptors on hepatocytes
• More LDL‐C receptors = less circulating LDL‐C
• PCSK9 modulates formation of atherosclerosis
• PCSK9 knockout mice resistant to atherosclerosis
• Development of PCSK9 mAb inhibitors
Secreted PCSK9 binds to the LDLR on the surface of the hepatocyte, leading to the internalization and degradation of the LDLR in the lysosomes, and reducing the number of LDLRs on the cell surface.
Inhibition of secreted PCSK9 should therefore increase the number of available LDLRs on the cell surface and increase uptake of LDL‐C into the cell.
PCSK9 Inhibitors
names, route of admin
Alberta Blue Cross coverage under Special Authorization:
• Limited to patients with “definite” or “probable” diagnosis of Heterozygous Familial Hypercholesterolemia (HeFH) and other treatment limitations
• Covered, with conditions, by some third party drug plans
• Market access programs currently being offered with both agents for other patients
- Evolocumab (Repatha®) – Sanofi
- SQ injection q 2‐4 weeks (140 mg q 2 weeks or 420 mg q month); $7844 per year (vs. $100‐600 per year for statin)
- Alirocumab (Praluent®) – Sanofi/Regeneron
- SQ injections every 2 weeks: 75 or 150 mg q 2 weeks; ~$7800 per year
- Bococizumab – Pfizer
- was still in the pipeline – D/C’d further development of this drug as of Nov. 1, 2016 – attenuation of LDL‐C
PCSK9 Inhibitors
indications
• to lower LDL‐C in patients with HeFH without clinical ASCVD whose LDL‐C remains above the
target despite maximally tolerated statin therapy with or without ezetimibe
• for patients with HeFH and ASCVD whose LDL‐C remains above the threshold ≥ 1.8 mmol/L despite maximally tolerated statin therapy, with
or without ezetimibe.
• for all secondary prevention CVD patients in whom LDL‐C remains ≥ 1.8 mmol/L (or non‐HDL‐C
≥ 2.4 mmol/L or ApoB ≥ 0.7 g/L) on maximally tolerated statin dose
Icosapent Ethyl
vascepa
• Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA).
• reduces hepatic very low‐density lipoprotein triglycerides (VLDL‐TG) synthesis, and/or
secretion, and enhances TG clearance from circulating VLDL particles.
Icosapent Ethyl
vascepa
indication
Indication:
• 2021 CCS guidelines recommend the use of icosapent ethyl to lower the risk of CV events
in patients with ASCVD, or with diabetes and ≥1 CVD risk factors, who have an elevated
fasting TG level of 1.5‐5.6 mmol/L despite treatment with maximally tolerated statin
therapy. (Strong Recommendation; High‐Quality Evidence)
• Major outcome trial with IPE
•demonstrated a significant reduction in CV
events (RRR = 24.5% and ARR = 4.8%)
