E3Hyperlipidemia Drugs Flashcards
This deck covers the pharmacologic agents associated with hyperlipidemia management.
1
Q
Lipoproteins
A
Proteins used in the transportation of lipids through the extracellular fluid around the body.
2
Q
Examples of Lipoportiens.
A
VLDL
IDL
LDL
HDL
3
Q
LDL
A
Low Density Lipoprotein.
4
Q
LDL is predominantly _________.
A
Cholesterol
5
Q
Apolipoprotein B is a precursor to _________
A
Low Density Lipoprotein (LDL)
6
Q
VLDL
A
Very Low Density Lipoprotein
7
Q
VLDL is mostly comprised of ___________.
A
Triglycerides.
Excess leads to plaque build up which leads to restricted blood flow.
8
Q
IDL
A
Intermediate Density lipoprotein
Formed when muscle and fat tissues take TGs from VLDL.
High Cholesterol Content
9
Q
HDL
A
High Density Lipoprotein
10
Q
Role of HDL
A
Take cholesterol back to the liver to be recycled.
11
Q
HDL is mostly ________
A
protein
12
Q
Apolipoprotein A is a precursor for ________
A
HDL
13
Q
Rank Lipoproteins by size relative to a chylomicron.
A
Chylomicron (largest)
VLDL
LDL
HDL (smallest)
14
Q
Chylomicrons are predominantly ___________
A
Triglycerides.
15
Q
All adults should have a lipid panel screened when?
A
All adults greater than 20 years old should be screened every 5 years.
16
Q
Lipid panels should be tested after a _________.
A
9-12 hour fast.
17
Q
What is measured on a lipid panel?
A
- Total Cholesterol (associated with CHD risk)
- LDL (reduction leads to decreased CHD risk)
- HDL (strong independent predictor of CHD)
- Triglycerides (Not consistently linked to CHD risk)
- Friedewald Equation (estimates LDL)
18
Q
Friedewald Equation
A
Estimates LDL
LDL = TC - HDL - (TG/5)
This formula is only accurate with TG under 400 mg/dL. If it is greater than this we can just measure LDL directly.
19
Q
When is the Friedewald equation not reliable?
A
Triglycerides >400 mg/dL.
if it is higher than this we should simply measure LDL directly.
20
Q
What are lifestyle modifications to reduce ASCVD risk?
A
- Heart Healthy Diet
- Regular, Moderate Intensity Exercise
- Smoking Cessation
- Healthy Weight Managment
21
Q
What are the major ASCVD risk factors? [7]
(6/7 needed for good)–> perfect 7 for perfect.
A
- Cigarette Smoking
- HTN
- Diabetes
- Advanced Age
- Lipid Panel Abnormalities
- CKD.
- Family ASCVD history
22
Q
What are current recommendations for a heart healthy diet?
A
DASH DIET
-Vegetables, Fruits, Whole Grains
- Low Fat Dairy Products, Poultry, Fish, Legumes
- Limit Intake of sweets, sugary beverages, and red meats.
- Reduce intake of saturated fat (5-6 % of calories)
- Limit intake of trans fat
23
Q
What are the current exercise recommendations to reduce ASCVD risk?
A
Moderate to Vigorous physical activity 3-4 times a week lasting at least 40 minutes per session.
24
Q
What guidelines were utilized in class to review non-statin cholesterol lowering therapies?
A
2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk.
25
Who are non-statin therapies indicated in? (3 answers)
High Risk Patients who:
1. Have less than anticipated response to statins.
2. Unable to tolerate recommended intensity of statin.
3. Completely intolerant to statin therapy.
26
What patients should be referred to a lipid specialist and RDN?
Those who are at high risk, that either do not tolerate statin therapy or don't receive optimal effect and have either:
1. LDL 250 mg/dL +
2. HoFH
27
Generic Name for Nexletol
Bempedoic Acid (Note this drug is brand name only currently)
28
Nexletol Dose
180 mg PO QD
With or without food.
29
Nexletol Mechanism of Action.
(slide 19 of Hyperlipidemia 1)
Adenosine Triphosphate-Citrate Lyase (ACL) Inhibitor.
*ACL is an enzyme which is upstream in the cholesterol synthesis pathway.*
Bempedoic acid and its active metabolite require CoA activation by a very long chain acyl-CoA synthetase 1 (ASCVL1).
Inhibition of ACL leads to:
1. Lowered Cholesterol synthesis
2. Lower LDL by upregulating LDL receptors in the liver.
30
What enzyme is responsible for the activation of Nexletol? Where is this enzyme primarily expressed?
ASCVL1 (Very Long Chain Acyl-CoA Synthetase 1). This is primarily expressed in the liver.
Note: Nexletol is a PRO DRUG!!!
31
What is the primary effect of Nexletol?
Lowers LDL.
32
What was the outcome of the CLEAR Harmony Trial?
Showed Nexletol increased LDL reduction by ~17-20 % in patients already taking max statin therapy.
33
What did the Clear Wisdom trial determine?
Evaluated patients taking maximum tolerated statin vs non statin at all and the additional benefit of Nexletol.
Found that Nexletol had a ~17-19% reduction of LDL in patients on statin therapy.
34
What did the CLEAR Tranquility Trial determine?
The clear tranquility trial evaluated the benefit of Nexletol for statin intolerant patients who were currently taking ezetimibe.
This found Nexletol to further reduce LDL levels by approximately 29%.
35
What did the CLEAR SERENITY trial determine.
This trial evaluated the use of Nexletol in statin intolerant patients to reduce LDL.
This trial found Nexletol to reduce LDL by 21%. However, there was also an increased incidence of adverse events compared to placebo.
36
Nexletol ADEs
1. Gout with prior history or Hyperuricemia
2. Tendon Rupture
3. Myopathy w/ concomitant use of simvastatin or pravastatin. --> these statins have a max daily dose with nexletol. (Note myopathy was not reported to occur with Nexletol monotherapy.)
37
Which statins have a max daily dose with nexletol?
Simvastatin and Pravastatin.
38
Brand Name for Ezetimibe
Zetia
39
Zetia Dose
10 mg PO QD
With or without food.
40
Zetia Mechanism
Inhibits absorption of cholesterol at the brush border of the small intestine.
41
Zetia Beneficial Effects
1. Decrease LDL (up to 25% additional reduction with statin therapy, 18% without.)
2. Decreased TC
3. Decreased TG
4. Increased HDL.
42
Zetia ADEs
1. URTI
2. Diarrhea
3. Arthralgias
4. Sinusitis
5. Pain in Extremities
Myopathy when used in conjunction with statins. (rare without concomitant statin use.)
43
What was the outcome of the IMPROVE-IT trial?
The addition of ezetimibe to moderate-intensity statin in patients with recent ACS resulted in lower LDL-C and reduced the primary cardiovascular composite endpoint.
44
What was the outcome of the SHARP trial?
This trial evaluated simvastatin and ezetimibe dual therapy. It found it to reduce LDL-C and reduce the primary endpoint of first major ASCVD benefit.
45
T or F: Zetia has CV benefit?
True!
46
T or F: Nexletol has CV benefit?
False: At least not studied.
47
What is the combinational therapy consisting of Bempedoic Acid and Ezetimibe?
Nexlecet
48
What is the mechanism of action of a PCSK9 inhibitor?
PCSK9 inhibitors are monoclonal antibodies which bind to PCKS9 to increase the number of LDL receptors that are available to clear circulating LDL.
49
What is the physiologic role of PCSK9 in the body?
See Slide 23/37 in Hyperlipidemia Part I notes
PCSK9 is an enzyme which binds to LDL receptors on the liver and degrades them. This leads to a decrease in hepatic clearance of LDL, causing an overall systemic increase in LDL.
50
What type of drug is Praluent
PCSK9 Inhibitor
51
Generic Name for Praluent
Alirocumab
52
Praluent Indication
1. HeFG, HoFG
2. Clinical ASCVD who need more LDL reduction
53
Praluent Dosing
1. ASCVD of HeFG:
75 mg SQ Q2W (may increase to 150)
OR
300 mg SQ QW
2. HoFH
150 mg SQ Q2W
54
Praluent Efficacy
With statin it lowers LDL by an additional 45% (75 mg dose) and 58% (150 mg dose)
55
What type of drug is Repatha?
PCSK9 Inhibitor
56
Repatha Generic Name
Evolocumab
57
Repatha Indication
1. HeFH
2. HoFH
3. Clinical ASCVD who need more LDL reduction
58
Repatha Dosing
1. ASCVD or HeFH
140 mg SQ Q2W or 420 mg SQ Q month
2. HoFH
420 mg SQ Q month
420 mg dose needs to be given as 3 injections (140 mg each) consecutively within 30 minutes.
59
Repatha Efficacy
With a statin, Repatha lowers LDL by an additional 64 % (140 mg Q2W) and 58% (420 mg Q month)
60
PCSK9i ADEs
1. Nasopharyngitis
2. Injection Site Reactions
3. Influenza
4. URTI
5. Back Pain
Evolucumab (Repatha) Only----> Self-Reported Cognitive ADEs
61
PCSK9i drug interactions
None, ha made you look.
62
What did the ODYSSEY OUTCOMES trial investigate and what were the outcomes.
Showed use of Alirocumab (Praluent) reduced ischemic events (including all-cause mortality, MI) compared with placebo among patients with an ACS event within the preceding 1-12 months in combination with statin therapy.
63
What did the FOURIER trial investigate and what did it conclude.
Showed Evolocumab (Repatha) demonstrated reduced primary end point of CV death, MI, Stroke, Revascularization or hospiutalization for UA in patients with PRIOR MI, storke, or PAD on atorvastatin greater than or equal to 20 mg or equivalent.
64
What is the mechanism of action of bile acid sequestrants?
Binds with bile acids in the small intestine to form an insoluble complex that is eliminated in the feces to prevent reabsorption.
Normally bile acids undergo hepatic recirculation. Therefore, when they are bound by resins, this interferes with this process stimulating HMG-CoA reductase activity. However, in this case this does not promote LDL production b/c cholesterol is shunted into the bile acid pathway.
The hepatocyte responds by increasing uptake of LDL, which drops plasma cholesterol concentrations.
65
What type of drug are Cholestyramine and Colestipol?
Bile Acid Sequestrant Powders
66
What kind of drug is Colesevelam?
Bile Acid Sequestrant (powder or tablet)
67
What is dose of colesevelam? (Welchol)
1. 6 tablets by mouth once daily. (can split to 3 tablets twice daily)
68
What other disease state is Colesevelam indicated for?
TIIDM
69
What is the therapeutic effect of bile acid sequestrants?
1. Reduce LDL
2. Increases VLDL (do not use in patients with hypertriglyceridemia)
----
1. Colesevelam Monotherapy (reduces LDL 15%--> 10-16% with statin therapy)
2. Colestipol Monotherapy (reduces LDL 16 to 27%)
3. Cholestyramine Monotherapy (reduces LDL 10.4%)
70
Who should Bile Acid Sequestrants not be used in and why?
Bile Acid Sequestrants should not be used in individuals with high triglycerides (>300 mg/dL).
This is because BAS can increase VLDL which are primarily composed of triglycerides--> worsening pre-existing hypertriglyceridemia.
71
Bile Acid Sequestrant ADE
1. Constipation
2. Dyspepsia
3. Nausea
4. Bowel Obstruction
5. Dysphagia
6. Hypertriglyceridemia
7. Pancreatitis
8. Increased Transaminases
72
Bile Acid Sequestrant Drug Interactions
1. Phenytoin (decrease concentration---> increased seizure activity.)
2. Warfarin (decreased INR--> increased clot risk)
3. Levothyroxine/THR--> Increase TSH levels
73
How long should you separate bile acid sequestrants from other medications?
At least 4 hours.
74
What was the result of the CV outcomes trials involving bile acid sequestrants?
19% reduction in CHD death or nonfatal MI in patients who took cholestyramine for an average of 7.4 years
However, it should be noted this data is not particularly strong and is falling out of favor. These are still occasionally sued for those who are ezetimibe intolerant and have high triglycerides.
75
Niacin is Vitamin ___________
B3 or Nicotinic Acid
76
Niacin Mechanism of Action
1. Reduces Hepatic Synthesis of VLDL ---> Lowers LDL
2. Inhibits Diacyl-glycerol acetyl transferase -2 and inhibits hepatic catabolism of HDL. (This leads to increased HDL.)
---------------------------------------
*It also acts on the peripheral circulation causing vasodilation which increases BF to the face, chest, neck. This is what causes "niacin flushing" ---> This does not happen with Nicotinamide.
77
Which drug in this section causes flushing?
Niacin
78
What are the therapeutic effects of niacin?
1. Reduces LDL 5-25%
2. Increase HDL 15-35%
3. Decreases TG 20-50%
79
Niacin ADEs
1. Cutaneous Flushing (prostaglandin mediated)-> occurs in 88% of patients.
2. headache, diarrhea, dyspepsia, abdominal pain
3. Increase blood glucose (due to increase in fatty acids)
80
How can we pretreat to avoid niacin flushing?
- take with food
-titrate dose slowly
- give aspirin 325 mg 30 minutes prior to administration.
81
What were the results of the CV outcomes trials for niacin?
Trick question! There were none. Made you look!
82
What is the mechanism of action for Omega-3-Fatty Acids
1. Hepatic Inhibition of Triglyceride Synthesis (lowered triglycerides)
2. Decreased LDL-C Secretion (increased LDL)
3. Increased VLDL-C metabolism (decreased VLDL)
83
What are the therapeutic effects of Omega-3 Fatty Acids?
1. Triglycerides: decreased 25-45%
2. HDL--> increase <10%
3. May increase LDL (due to DHA component)
84
How can we avoid LDL increase with Omega-3-Fatty Acids?
Avoid those with DHA.
Remember Vascepa is EPA purified (no DHA component.)
85
what type of drug is Lovaza
Omega-3-Fatty Acid
86
what type of drug is Vascepa
EPA Purified Omega-3-Fatty-Acid
87
what type of drug is Epanova
Omega-3-Fatty Acid
88
what type of drug is Omtryg
Omega-3-Fatty Acid
89
What is the typical dose of Omega-3-Fatty Acids?
1-3 grams of EPA + DHA daily in divided doses.
90
What are the ADEs of Omega-3-Fatty Acids?
1. GI upset
2. Aftertaste/Belching
3. Bleeding Risk--> only when used with other drugs which promote bleeding.
91
What was the conclusion of the REDUCE-IT trial?
Found Patients with the following:
CVD or DM
Fasting TG: 135-499 mg/dL
LDL: 41-100 mg/dL
-> Had significant risk reduction (25%) with Vascepa and statin dual therapy in primary endpoint of first occurrence of a major adverse cardiovascular event.
---------------------------------------
In other words, there was a relative risk reduction in the incidence of a first major cardiovascular event even in those with healthy triglycerides in those with CVD or diabetes.
92
Fenofibrate Drug Class
Fibric Acid Derivative
93
Gemfibrozil Drug Class
Fibric Acid Derivative
94
Gemfibrozil Typical Dose
600 mg PO BID
95
Fibric Acid Derivative Mechanism of Action
Peroxisome Proliferator-Activated receptor alpha agonists.
---------------------------------------
This receptor:
1. Increase Fatty Acid oxidation of free fatty acids.
2. Increases Metabolism of TG rich lipoproteins (VLDL, Chylomicrons)
3. Increase affinity of LDL for LDL receptor (decreases LDL C mildly)
4. Increases hepatocyte production of Apo A ---> leads to HDL-R formation.
96
What are the therapeutic effects of fibric acid derivatives.
1. LDL: decrease 5-20%
2. TGL Decrease 20-50%
3. HDL: Increase 10-20%
97
What is the most significant benefit to fibric acid derivatives?
Decreases TG by 20-50%
98
What is the indication of fibric acid derivatives?
Primarily for patients with triglycerides above 500 mg/dL.
99
What drug is contraindicated with gemfibrozil, and should be used with caution with fenofibrate?
Statins--> increased risk of myagia.
100
Do Fibric Acid derivatives have CV outcomes data?
Not enough to support use with statins.
101
Fibric Acid Derivative ADEs
1. Abdominal Pain
2. Diarrhea
3. Arthralgia
4. Myalgia
5. Myopathy
102
What did the AIM HIGH and ACCORD trials determine?
Adding Niacin and Fenofibrate to statin therapy did not increase ASCVD risk reduction.
Therefore, the risk of using these drugs together exceeds the benefit.
103
Leqvio Generic Name
Inclisiran
104
What is the mechanism of action of Inclisiran?
DS small interfering RNA. Prevents translation of PCSK9 in the liver. (synthesis is dependent on RNA).
This leads to an overall increase in LDL-R expression, causing a decrease in LDL as more can be hepatically cleared.
105
How is Inclisiran Dosed?
1. Initial Dose
2. 2nd Dose 3 months Later
3. Continuous dosing every 6 months.
106
What were the conclusions of the ORION-9 Trial?
Showed Inclisiran reduced LDL cholesterol levels by almost 50% with twice yearly administration in:
- patients with HeFH who had been receiving maximally tolerated statin therapy.
107
What were the conclusions of the ORION-10 and ORION-11 Trials?
1. A regimen of Inclisiran every 6 months was feasible and significantly reduced LDL cholesterol levels by approximately 50%.
2. More injection site ADE ocurred with Inclisiran than placebo.
108
What is the mechanism of statins?
Inhibit HMG-CoA reductase, the rate limiting step in cholesterol synthesis.
-----------------------------------
1. Decrease cholesterol synthesis (decrease LDL, TC, TG)
2. Increase LDL-R expression (decrease LDL)
3. Decrease C-Reactive protein (Anti-Inflammatory Effect)
4. Pleotropic Effects
109
What are the pleiotropic effects of statin therapy.
1. Improve endothelial function
2. Atherosclerotic plaque stabilization.
3. Decrease oxidative stress and inflammation.
4. Inhibition of thrombogenic response.
----------------------------------
These effects are the reason we continue statin therapy even if cholesterol levels return to normal.
110
HMG-CoA Reductase
Enzyme which catalyzes the rate limiting step of cholesterol synthesis. Converting HMG-CoA to Mevalonate.
111
High Intensity Statins decrease LDL by _____________
50%+
112
Moderate intensity statins decrease LDL by ____________
30-49%
113
Low Intensity Statins decrease LDL by _______
<30%
These are really only used for those who can not tolerate statin.
114
How do we decide statin strength to use?
Based on our goal for LDL reduction.
115
High Intensity Statins
1. Atorvastatin 40-80 mg
2. Rosuvastatin 20-40 mg
116
Moderate Intensity Statins
1. Atorvastatin 10-20 mg
2. Rosuvastatin 5-10 mg
3. Simvastatin 20-40 mg
4. Pitavstatin 40-80 mg
5. Lovastatin 40 mg
6. Fluvastatin 80 mg
7. Pitavastatin 2-4 mg
117
Low Intensity Statins
1. Simvastatin 10 mg
2. Pravastatin 10-20 mg
3. Lovastatin 20 mg
4. Fluvastatin 20-40 mg
5. Pitavastatin 1 mg
118
Rosuvastatin 20-40 mg Intensity
High Intensity Statin
119
Atorvastatin 40-80 mg Intensity
High Intensity
120
Atorvastatin 10-20 mg Intensity
Moderate Intensity Statin
121
Rosuvastatin 5-10 mg Intensity
Moderate Intensity
122
Simvastatin 20-40 mg Intensity
Moderate intensity
123
Pravastatin 40-80 mg Intensity
Moderate intensity
124
Lovastatin 40 mg Intensity
Moderate Intensity
125
Fluvastatin 80 mg Intensity
Moderate Intensity
126
Pitavastatin 2-4 mg Intensity
Moderate intensity
127
Simvastatin 10 mg intensity
Low Intensity
128
Pravastatin 10-20 mg intensity
Low Intensity
129
Lovastatin 20 mg intensity
Low Intensity
130
Fluvastatin 20-40 mg intensity
Low Intensity
131
Pitavastatin 1 mg intensity
Low intensity
132
The amount of ASCVD risk reduction with a statin is directly related to __________
Amount of LDL-C lowering achieved as a percentage of the baseline.
--------
This is associated with statin "intensity"
133
Which Statins are metabolized by CYP3A4?
1. Atorvastatin
2. Lovastatin
3. Simvastatin
134
Which Statins are Hydrophillic?
1. Rosuvastatin
2. Pravastatin
135
Which statins have a prolonged half-life allowing for morning dosing if needed for adherence purposes?
1. Atorvastatin
2. Pitavastatin
3. Rosuvastatin
-----
The other statins should ideally be taken at bedtime.
136
Which statins are less likely to cause myalgia?
Hydrophilic statins (rosuvastatin and pravastatin)
137
Statin ADEs
>10%
Diarrhea| Arthralgia| Nasopharyngitis
-----------------------------------
2-10%
Insomnia| New Onset Diabetes| Nausea| Dyspepsia|UTI|Myalgia| musculoskeletal pains
-----------------------------------
138
What are the severe ADE of statin therapy? (rare too)
1. Hepatotoxicity
2. Cognitive Dysfunction/Confusion (reversible)
3. Drug Induced Skin reactions (SJS/TEN)
139
Can statins be used in pregnancy?
No--> they are teratogenic.
140
What are the absolute contraindications to statin therapy?[4]
1. Active Liver Disease (elevated liver enzymes)
2. Unexplained elevated transaminases. (3x ULN)
3. Pregnant or nursing women.
4. Major drug-drug interactions.
141
What are the precautions/warnings of statin therapy?
1. Substantial Alcohol consumption.
2. Liver Disease Hx
3. Significant drug-drug interactions.
142
How does myalgia with statin therapy typically present? When?
1. Typically it involves large, proximal muscle groups in a symmetrical manner.
2. Typically occurs within 4 to 6 weeks after initiation. (NOT ALWAYS)
143
Differentiate:
-Myalgia
-Myopathy
-Rhabdomyolysis
1. Myalgia| Pain ( no creatine kinase elevation)
2. Myopathy| objective muscle weakness/loss of function.
3. Rhabdomyolysis| Emergent--> muscle breakdown--> requires immediate intervention.
144
How should a patient who experiences mild to moderate muscle pain with statin therapy be managed?
1. Hold statin for 2 to 4 weeks to evaluate for other causes.
If **muscle pain resolves**--> rechallenge with the same statin at the same or lower dose.
If **muscle pain re-merges**--> discontinue original statin. Once muscle symptoms resolve, use a low dose of a different statin.
When selecting a different statin a hydrophilic one is preferred. (rosuvastatin or pravastatin.)
-----------------------------------
**If muscle pain persists** without statin therapy:
Evaluate other causes, resume statin therapy at original dose.
145
How should a patient with unexplained, severe muscle symptoms while on a statin be managed?
1. Discontinue the statin and evaluate for rhabdomyolysis or other causes of myopathy.
once resolved. DO NOT REINITIATE statin therapy unless discussed by a specialist.
146
Define statin intolerance.
Muscle related symptoms which:
1. Resolve upon statin discontinuation
2. Occur with re-challenge
3. Occur with at least 2-3 statins, preferably ones that use different metabolic pathways and lipophilicity profiles. At least 1 statin should have been prescribed at the lowest approved dose.
147
How should statin intolerance be managed?
1. Lower Dose
2. Different statin
3. Alternative dosing strategy (TIW for statins with long half-lives--> however this has not been studied in RCTs yet.)--> However, remember some statin is better than no statin at all.
148
How should patients on statin therapy be monitoried?
1. Fasting Lipid Panel:
-4-12 weeks after initiation or therapy change.
-3-12 months as clinically indicated after.
2. Transaminases (ALT, AST)
-may measure in patients with symptoms of hepatotoxicity.
3. Monitor for obesity onset.
-note: statins due not cause diabetes.
149
Per the 2013 AACE guidelines, at what LDL should decreasing statin therapy be considered upon reviewing the fasting lipid panel?
2 consecutive LDL values below 40 mg/dL.
Note: these are old guidelines.
Now we typically, continue statin therapy for the pleiotropic effects mentioned earlier.
