Pharmacology of Hyperlipidemia

LO 1: Describe the mechanism of action, clinically relevant pharmacokinetic parameters, adverse effects, contraindications, and major drug-drug interactions. LO2:

Statins MOA

 Competitive inhibition of the HMG-CoA reductase enzyme → ↓ hepatic cholesterol synthesis AND ↑ LDL receptors on liver

Statins adverse effects

1) Statin-associated muscle symptoms (SAMS) — myalgias, myopathy, rhabdomyolysis

2) Elevations in liver enzymes (usually released when liver is injured/stressed)

3) Elevations in creatine kinase (released when muscles are damaged)

4) Elevations in blood glucose levels (new onset diabetes in those w/ risk factors)

Contraindications for statins

1) Active liver disease or decompensated cirrhosis/hepatitis

2) Breastfeeding

3) Simvastatin and lovastatin are contraindicated with CYP3A4 inhibitors

Statins are metabolized by what enzyme?

CYP3A4/C29

When can statins with long half lives be taken? When can statins with short half lives be taken?

Statins with long half lives can be taken anytime of day

Statins with short half lives can be taken in the evening to coincide with peak nighttime cholesterol synthesis

Statin drug-drug interactions

1) Strong CYP3A4 inhibitors (i.e. -azole antifungals, cyclosporine, erythromycin, large amounts of grapefruit juice, etc)

2) Do not use concomitantly with gemfibrozil — a fibrate drug used to treat high TG and cholesterol (increased risk of statin-associated muscle symptoms (SAMS))

Bempedoic acid (Nexletol)

Bempedoic acid (Nexletol) MOA

1) prodrug activated by ACSVL1 in liver

2) active form inhibits Adenosine triphosphate-citrate lyase (ACL), a key enzyme in the cholesterol biosynthesis pathway that acts earlier/upstream of HMG-CoA reductase

3) Results in ↑ LDL receptors and ↓ plasma LDL

Bempedoic acid adverse effects

• Hyperuricemia (can exacerbate gout)

• Small increases in serum creatinine & liver function enzymes

• Increased risk of tendon rupture

Bempedoic acid drug-drug interactions

• Avoid concomitant use with simvastatin > 20 mg

• Avoid concomitant use with pravastatin > 40 mg

Bile acid sequestrants (BAS) MOA

• Binds bile acids in the intestinal lumen → disrupts enterohepatic circulation (↑ bile acid/cholesterol excretion) → ↑ conversion of hepatic cholesterol to bile acids

• ↑ LDL receptors on liver

Bile acid sequestrants (BAS) adverse effects

• GI complaints (i.e. constipation, bloating, abdominal pain, nausea, dyspepsia/indigestion)

• Increase in TG

Bile acid sequestrants (BAS) contraindications

BAS increase TG levels, so do not use if baseline TG ≥ 300 mg/dL

Bile acid sequestrants drug-drug interactions

• BAS can decrease the absorption of certain drugs that are administered concomitantly

  • Other drugs should be taken 1 hr before OR 4 hrs after BAS

• May decrease absorption of fat-soluble vitamins A, D, E, K

Ezetimibe (Zetia) MOA

Inhibits cholesterol transporter NPC1L1 → inhibition of cholesterol reabsorption at brush border of small intestine →↓↓ plasma LDL

Ezetimibe (Zetia) adverse effects

Minimal (usually GI related), usually well tolerated

Ezetimibe (Zetia) contraindications

• When used with statin, statin contraindications apply

• Not recommended to use with fibric acids (i.e. gemfibrozil) due to increased risk of myopathy and cholelithiasis

PCSK9 Inhibitors (alirocumab, evolocumab) MOA

Monoclonal antibodies that block circulating PCSK9 → ↑ LDL receptors

PCSK9 Inhibitor Inclisiran MOA

siRNA that blocks synthesis of PCSK9 by degrading PCSK9 mRNA → ↑ LDL receptors

PCSK9 Inhibitors (alirocumab, evolocumab, inclisiran) adverse effects

Injection site rxns

Nasopharyngitis and influenza sx 

Headache

Possible antibody development

Fibric acid/Fibrates MOA

• Activate peroxisome proliferator-activated receptor-alpha (PPAR-α)

  • ↓ ApoC-III and ↑ LPL

  • ↑ Apo A-I to make more HDL

  • ↑ VLDL lipolysis → lower TG

Flushing with niacin can be decreased with pretreatment with what?

aspirin

Fibric acid/Fibrates adverse effects

• Myopathy (gemfibrozil > fenofibrate)

• Dyspepsia/indigestion

• Transient LFT/liver enzyme elevations possible

• Increase risk of gallstones/Cholelithiasis

• reversible increase in serum creatinine (Scr) without a true decrease in glomerular filtration rate (eGFR)

Fibric acids/fibrates drug interactions

• Gemfibrozil has an increased risk of myopathy when used with statin therapy

• Gemfibrozil is a minor substrate of CYP3A4 and a strong inhibitor of CYP2C8 and CYP2C9; inhibitor of OATP1B1

Fibric acids/fibrates contraindications

- Severe renal dysfunction

- Active liver disease or persistently elevated LFTs

- History of gallbladder disease

Omega 3 fatty acids MOA

- MOA not fully known

-  In high doses, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) lower serum TG by reducing hepatic synthesis and secretion of TG-rich lipoproteins (VLDL) 

- ↑ lipoprotein lipase (LPL) activity → ↑ VLDL metabolism

Omega 3 fatty acids adverse drug effects

• GI upset/dyspepsia, belching

• Increased LDL-C (DHA containing products)

• Increased risk of atrial fibrillation/flutter (with higher doses)

Omega 3 fatty acids drug-drug interactions

May increase bleeding in those taking antiplatelet or anticoagulant therapy

Nicotinic acid/Niacin MOA

- Inhibits free fatty acid release from adipose tissue 

- ↑ lipoprotein lipase (LPL) activity → ↑ VLDL metabolism/↓ VLDL production

- ↑ HDL-C

Nicotinic acid/Niacin adverse effects

• Flushing (vasodilation)/itching

• Skin abnormalities

• GI intolerance

• Hyperuricemia or gout

• Hepatotoxicity (increased LFT, hepatic dysfunction)

• Blurred vision

• Hyperglycemia

Nicotinic acid/Niacin contraindications

• Significant/active hepatic disease

• Persistently elevated transaminases (liver enzymes)

• Active peptic ulcer

• Arterial hemorrhage

Microsomal Triglyceride Transfer Protein (MTP) Inhibitor MOA

Binds to and inhibits MTP, which prevents the assembly of apo-B lipoproteins in enterocytes and hepatocytes → ↓ production of chylomicrons and VLDL → ↓ LDL-C

MTP Inhibitor (lomitapide) adverse drug effects

• Hepatoxicity/hepatic steatosis (fatty liver)

• black box warning

• GI disturbances (diarrhea, nausea, constipation, etc)

MTP inhibitor (lomitapide) contraindications

• Pregnancy

• Co-administration with moderate or strong CYP3A4 inhibitors

• Moderate or severe hepatic impairment

Which currently available lipid-lowering therapies have been associated with a reduction in cardiovascular event outcomes?

• Statins

• Addition of Ezetimibe, omega-3 fatty acids, or PCSK9 Inhibitors (monoclonal antibodies) to statins

• Bempedoic acid (in statin-intolerant patients)