Wake PA Unit 3: (PHARM) Dyslipidemia

What is the mechanism of statins?

competitively inhibit HMG-CoA to inhibit conversion early in cholesterol synthesis

increases expression of LDL receptor gene (more LDL will bind to and be taken out of blood stream)

What is the effect of statins?

decreased LDL

What is the counseling for statins?

Take with or without food any time of the day

Simvastatin and lovastatin should be taken in the evening

what class of medications does atorvastatin belong to? What "intensity" level is it?

statin (high intensity, moderate intensity, low intensity)

what class of medication does rosuvastatin belong to? What "intensitiy" level is it?

statin (high intensity, moderate intensity)

what class of medications does simvastatin belong to? What "intensity" level is it?

statin (moderate intensity, low intensity)

what class of medications does fluvastatin belong to? What "intensity" level is it?

statin (moderate intensity, low intensity)

what class of medications does lovastatin belong to? What "intensity" level is it?

statin (moderate intensity, low intensity)

what class of medications does pravastatin belong to? What "intensity" level is it?

statin (moderate intensity, low intensity)

what class of medications does pitavastatin belong to? What "intensity" level is it?

statin (moderate intensity, low intensity)

What are the contraindication for statins?

pregnancy

What are the common adverse reactions to statins? When/how should we monitor these?

transient hepatotoxicity (not recommended to routinely screen LFTs unless clinical symptoms are suggestive of hepatic injury)

myalgias and myopathies (feeling of muscle soreness/weakness, rhabdomyolysis - check creatine kinase if suspecting rhabdo)

Precautions: which patients should use caution when using statins?

age > 80,

hepatic or renal dysfunction,

perioperative perio untreated hypothyroidismds,

small body size

untreated hypothyroidism

How are statins metabolized? (enzyme system)

CYP3A4

Which statins are less likely to cause myopathy?

pravastatin, rosuvastatin ( and fluvastatin)

At what point can you characterize a patient as having a "statin intolerance?"

1. tried at least 2 different statins

2. including either pravastatin or rosuvastatin (lipophilic less associated with myopathies)

3. at lowest dose or using alternate dosing strategies (i.e. QOD dosing)

How can we prevent statin intolerance?

•Switching statin therapies to a more hydrophilic statin

•Mitigation of drug interactions​ (Avoiding CYP3A4 inhibitors)

•Drinking fluids​ for adequate hydration

What is the "rule of 7" for statins?

every doubling of statin dose only reduces LDL by an additional 7% if pt is already taking a statin

i.e. atorvastatin 10mg to atorvastatin 20 mg = 7% reduction

i.e. rosuvastatin 10mg to rosuvastatin 40 mg = 14% reduction

When is maximum benefit seen when using statins?

When initiating statin therapy (i.e. statin naive patients)

What is the mechanism of action for ezetimibe?

inhibit cholesterol absorption at the brush border of the small intestine via inhibition of transport protein

—> Reduction of delivery of cholesterol to the liver (54%)

—> Reduction of hepatic cholesterol store and an increased clearance of cholesterol from the blood

What are the indications for ezetimibe?

reduction of LDL-C, especially in patients who are statin-intolerant (lower incidence of myalgias).

can also be used with a statin

What are the side effects of ezetimibe?

transient hepatotoxicity

myalgia (less), myopathy, rhabdo

What are the side effects of ezetimibe?

Transient hepatotoxicity

Myalgia, myopathy, rhabdomyolysis

List the PCSK9-inhibitors

evolocumab (IV)

alirocumab (IV)

enlicitide (PO)

What is the mechanism of action for PCSK9-inhibitors?

binds to PCSK9 (which normally degrades LDL receptors). prevents the degradation of the LDL receptors on hepatocytes and therefore allows the liver to remove cholesterol

What are the indications of PCSK9-inhibitors?

LDL-C reduction in the setting of homozygous familial hypercholesterolemia

Hyperlipidemia (primary or in CVD)

**can be used concurrently with statins without increased risk of myopathy

What is the mechanism of action for bempedoic acid?

targets the cholesterol biosynthesis pathway in the liver. inhibits ATP-citrate-lyase (ACL), which is 2 steps upstream from HMG CoA reductase.

*non-statin, statin pathway drug

What is the indication for bempedoic acid?

LDL-c reduction (especially in statin intolerance, great results with ezetimibe)

What are the side effects of bempedoic acid?

Hyperuricemia, gout symptoms

*no statin like myopathy (prodrug)

What is the mechanism of action for inclisiran?

TAKEN AS INJECTION:

small interfering RNA (siRNA) that blocks the production of PCSK9 in the liver. Reducing PCSK9 levels, it increases LDL receptor recycling and uptake of LDL cholesterol, which lowers LDL-C in the blood

What are the indications for inclisiran?

heterozygous familial hypercholesterolemia

ASCVD

Adjunct to diet and maximally tolerated statin

What are the side effects for inclisiran?

Injection site reactions

GI effects

UTI

arthralgias

What is the counseling for inclisiran?

Administered within a clinic setting by a provider

refer to a lipid specialist

What is the mechanism of action for bile acid sequestrants?

Bind with bile acids which inhibits their lipid solubilizing activity and blocks cholesterol absorption (increased fecal loss of bile acid-bound LDL cholesterol)

what class of medications does cholestyramine belong to

bile acid sequestrants

what class of medications does colestipol belong to

bile acid sequestrants

What are the side effects of bile acid sequestrants?

GI distress (higher doses)

what is the indication for bile acid sequestrants?

LDL-C reduction

potentially useful in younger patients with statin related myopathy

What is the counseling for bile acid sequestrants?

multiple doses per day

separate from other medications (1 hour before, 3-4 hours after)

What is the mechanism of action for fibric acid derivatives?

exact mechanism is unknown, but:

- dereases serum triglycerides

- decreases total cholesterol and serum LDL

- increases serum HDL

When are fibric acid derivatives indicated?

hypertriglyceridemia (TG > 500 mg/dL)

what class of medications does gemfibrozil belong to

fibric acid derivative

what class of medications does fenofibric acid belong to

fibric acid derivative

What are the indications for fibric acid derivatives?

hypertriglyceridemia (no benefit to add to statin therapy without proper indication)

What are the side effects of fibric acid derivatives?

minimal if monotherapy, primarily GI related

Increased risk of myopathy if used with statins

What is the counseling for fibric acid derivatives?

take 30 min prior to eating

What is the mechanism of omega-3 fatty acids?

exact mechanism unknown, but:

- inhibition of acyl CoA which is a group that metabolized fatty acids.

- reduction in hepatic production of triglyceride-rich, very low density lipoproteins

What is the indication for omega-3 fatty acids?

hypertriglyceridemia (adjunctive treatment)

What are the side effects of omega-3 fatty acids?

increased bleeding risk

can increase LDL levels

What is the counseling for omega-3 fatty acids?

may cause breath with fishy odor

may cause dyspepsia

What is the MOA of ANGPTL-3 inhibitors?

binds to and inhibits angiopoietin-like protein 3 preventing inhibition of LPL and endothelial lipase —> increased lipid metabolism —> decreased LDL-C, HDL-C, and TG

What class of drug does evinacumab belong to?

ANGPTL-3 inhibitors

What are the indications of ANGPTL-3 inhibitors?

homozygous familial hypercholesterolemia (adjunct treatment for patients 12 or older)

What are the side effects of ANGPTL-3 inhibitors (evinacumab)?

anaphylaxis

What is the counseling for ANGPTL-3 inhibitors (evinacumab)?

monthly IV infusion

Notify doctor if pregnant or considering becoming pregnant

What is the MOA of MTP inhibitor (lomitapide)?

inhibits microsomal triglyceride transfer protein (which helps package triglycerides and cholesterol into chylomicrons) and reduces transfer of chylomicrons and VLDL to blood stream

What is the indication for lomatapide?

LDL, TC, apoB reduction in patients with homozygous familial hypercholesterolemia (adjunct treatment)

What are the side effects of lomitapide?

hepatotoxicity (boxed warning)

chest pain

what is the counseling for lomitapide?

take 2 hours before evening meal, can cause GI upset