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IPFC 3 Final > Dyslipidemia Therapeutics > Flashcards

Dyslipidemia Therapeutics Flashcards

1
Q

Define marginal patients. How much % of patients are in this categary.

A

For marginal patients their outcome is dependant on their expose
- 20%

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2
Q

What conditions are high CV risk where treatment is recommended? (4)

A
  • Atherosclerotic CV disease (all 2ndary prevention)
  • CKD
  • DM
  • LDL 5+
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3
Q

What are common conditions of secondary dyslipidemia? (6)

A
  • Excess alcohol
  • Renal failure/Nephrotic syndrome
  • Hypothyroidism
  • Liver disease
  • Pregnancy
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4
Q

What are common drugs of secondary dyslipidemia? (7)

A
  • B-blockers that are NON-selective (propanolol, pindol, labetolol, carvedilol, nadolol)
  • Corticosteroids
  • Antiviral therapy
  • hormone replacement therapy
  • COCs
  • Thiazide diuretics
  • Cyclosporine, carbramazepine, Isotretinoin
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5
Q

In the observational studies, how much did healthy behaviours lower risk of CVD outcomes

A

60-80%

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6
Q

What are the non-pharmacological choices for dyslipidemia

A
  1. Smoking cessation
  2. Healthy diet (mediterranean diet, no trans, saturated fat)
  3. Increase physical activity
  4. 2 or less standard drinks/day or max 9/week for females
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7
Q

What did the nurses’ health study say about having low-risk factors?
Population studied?
Outcome studied?

A

The more healthy lifestyle choices = lower risk of CV outcomes
Population: All women
Outcome: Deaths from coronary heart disease and nonfatal infractions (major coronary events)

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8
Q

What is the % chance of getting an MI if smoking 1 cigarette/day

A

50% higher

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9
Q

Smoking cessation
Studied in primary/secondary prevention?
RRR of CVD risk?
RRR of mortality?
Life expectancy increase by?

A

Studied in secondary prevention, can apply to primary
RRR of CVD risk? 50%
RRR of mortality? 35%
Life expectancy increase by? 10 years

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10
Q

What happens within 1 year of smoking cessation?

A

Risk of Coronary heart disease is about half than a smoker’s

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11
Q

Define surrogate endpoint

A

Certain measurements (physiological, lab results) that are ASSOCIATED with events but are NOT the outcomes themselves

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12
Q

Are CV outcomes dependant on LDL levels?

A

No, only associated
Statins reduced both CV outcomes and LDL

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13
Q

If you target LDL levels without touching the metabolic disorder that caused the high LDL,
decrease/not reduce risk of heart disease? What must you do?

A

not reduce risk of heart
- You must reduce LDL in a WAY that improves the metabolic disorder that caused the high LDL

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14
Q

Which drug is the best for:
Decreasing LDL
Increasing HDL
Decreasing triglycerides

A

Decreasing LDL: Statins, PCSK9s
Increasing HDL: Niacin, fibrates
Decreasing triglycerides: Niacin, Fibrates

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15
Q

Which statins are CYP3A4 inhibitors? (3)

A

Atorvastatin
Simvastatin
Lovastatin

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16
Q

Which statins have the longest half-life? (2)

A

Atorvastatin
Rosuvastatin

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17
Q

Which drug has the lowest risk of interactions?

A

Rosuvastatin

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18
Q

Which drug is metabolized by CYP2C9

A

Fluvastatin
Rosuvastatin (limited)

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19
Q

What are some CYP3A4 inducers and inhibitors?

A

Inducers:
- Carbamazepine
- phenytoin
- omeprazole
- rifampin

Inhibitors:
- Amiodarone
- Diltiazem
- Verapamil
- Azole, grapefruit
- cyclosporine

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20
Q

Which drugs are high-intensity statins?

A

Rosuvastatin 20-40
Atorvastatin 40-80
Simvastatin 80mg

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21
Q

Know a specific dose for primary prevention

A

Know a specific dose for PRIMARY prevention: ROSUVASTATIN 20MG

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22
Q

ASCOT-LLA trial
PICO
RRR

A

Population: Mostly men with HTN + 3 CVD risk factors (total cholesterol over 6.5)

Intervention: Atorvastatin 10mg

O: non-fatal MI and fatal CHD

RRR: 37% reduction in CVD

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23
Q

What are the effects on statins when baseline risk changes such as CV risk score, hypertension, renal dysfunction, diabetes?
What differs?

A

Effects of statins are consistent
- ARR and NNT differs according to baseline risk

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24
Q

What do the trials say for comparing statin treatment dose titrated to cholesterol levels vs fixed-dose treatment

A

In secondary prevention (patients with coronary artery disease, target lipid of 50-70 mg/dL), it is NOT INFERIOR to fixed dose high-intensity statin

no evidence for primary prevention

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25
Q

What do trials say for using low dose vs high dose statins in PRIMARY prevention?

A

no evidence to show advantage

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26
Q

JUPITER trial
PICO
primary/secondary

A

P: high sensitivity CRP patients (intermediate risk but high risk) -> have good LDL

I: Rosuvastatin 20 (high dose)

Primary prevention
GOOD FOR PATIENTS WITH HIGH CR PROTEIN

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27
Q

What is the relationship between incidence of diabetes vs statin in both primary and secondary prevention

A

Slight increase in diabetes incidence
- OR is 1.09 (overestimation)
- 6% risk of diabetes with statin

Overall: Ok to use statin since for every 1 patient that gets diabetes from statin, we save 11 from CVD

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28
Q

What are the 3 types of ADRs of statins
HMG

A

H Hepatic effects
M Muscular effects
G Gastrointestinal effects

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29
Q

Is statin hepatotoxicity dose dependant?
Solution?
effect on patients with liver disease?

A

Yes dose dependant
- inc hepatic transaminases

Solution: reduce dose or change statin

Statins actually improves fatty liver transaminase

30
Q

How do we monitor statin hepatotoxicity? How often?

A

Measure ALT/AST at baseline
- then at 12 weeks after starting therapy
- then annually

31
Q

Define
Myalgia
Myositis
Rhabdomyolysis

A

Myalgia:
- muscle pain/weakness with NO creatinine kinase CK elevation

Myositis:
- muscle symptoms with inc CK levels

Rhabdomyolysis
- muscle symptoms with HIGHLY INC CK levels (10x+ upper limit)
- SCr elevation
- urine may be brown due to existence myoglobin

32
Q

What are risk factors for statin induced myopathy?

A
  • Age 80+
  • Female
  • LOW BMI
  • DM
  • Liver/renal dysfunction
  • Hypothyroidism untreated
  • Trauma/surgery/heavy exercise
  • Drugs (fibrates, CCB, cyclosporine, amiodarone) (CYP inhibitions)
  • Genetics
33
Q

Is it recommended to get baseline CK?

A

No

34
Q

When to monitor for muscle symptoms in statins?
What to do if symptomatic?

A

6-12 weeks after starting
- then at each follow-up visit

If symptomatic obtain a CK measurement

35
Q

How to manage myopathy steps?

A
  1. Reduce statin dose
  2. switch statin
  3. Alternate day dosing statins (surrogate data suggests similar effects)
  4. Non-statin alternatives
  5. Coenzyme q10 supplementation (no evidence)
36
Q

When should LDL be monitored?

A

For estimating risk at baseline
- maybe for adherence

NOT FOR LIPID EFFICACY

37
Q

Time of administration for statins

A

HS: for short acting (lovastatin, simva, fluva)
- surrogate outcomes not clinical

Any time in day: does not matter for long-acting

38
Q

When are statins considered “not tolerated”

A

After trying at least 2 agents

39
Q

Which non-statin agents have evidence in primary prevention? (2)

A
  1. Gemfibrozil (fibrate)
  2. Cholestryamine (Bile acid resin)
40
Q

Which non-statin agents have NO evidence in primary prevention? (4)

A
  • Ezetimibe
  • Niacin
  • PCSK9 inhibitors
  • CETP inhibitors
41
Q

Helsinki Heart study
PICO

A

P: high cholesterol MEN with non-HDL cholesterol of 5.2+
I: Gemfibrozil 600mg po BID
C: Placebo
O: MI (fatal, non-fatal), Sudden cardiac death

42
Q

What are the limitations to the Helsinki Heart study?

A
  • Studied long time ago
  • only men
  • Different population, back then people had higher cholesterol, large % of smokers
43
Q

What is the most common ADR with gemfibrozil?

A

LOTS of GI symptoms
- Better to try “4 statins” before gemfibrozil

44
Q

What are fibrates good for in primary prevention?

A

Reduce risk for pancreatitis but no change CVD events vs placebo

45
Q

LRC-CPPT trial
PICO

A

P: primary prevention for men with total cholesterol over 6.8

I: Cholestyramine

C: placebo
O: Non-fatal MI and CHD

moderate improvement in composite outcomes, NO improvement in mortality

46
Q

How to administer Cholestryamine

A

Suspension (water or juice), not in dry form
- should not be sipped or held in mouth (can cause tooth discolouration, or enamel decay)
- administer with meal
- needs to be titrated up from low dose

47
Q

Cholestyramine safety

A

68% within the first year had mod-severe GI side effects
- lowered to 29% pre-entry

48
Q

Ezetimibe MOA
What is efficacy based on?

A

inhibits intestinal absorption of cholesterol
- 20% reduction in LDL
- Efficacy based on surrogate markers (LDL, carotid intima-media thickness

49
Q

What does data show about carotid intima media thickness CIMT?

A

CIMT is shown to be a significant predictor of future CVD event
- however, slow regression in CIMT due to drugs was not found to be associated CVD outcomes

50
Q

IMPROVE-IT
PICO

A

P: patients with an acute coronary syndrome within the previous 10 days (SECONDARY)

I: Simva 40mg + ezetimibe 10mg

C: Simva 40

O: MI + stroke (non-fatal) and CHD death

51
Q

IMPROVE-IT
Outcome

A

Improved composite outcomes and not mortality

52
Q

IMPROVE-IT
Limitations

A

Did not use a high intensity simva in secondary trial

53
Q

Can we use ezetimibe in primary prevention? As monotherapy in secondary?

A

No

54
Q

Niacin MOA of HDL, LDL, Lpa

A

inc HDL at lower doses
Dec LDL at higher doses
Dec Lpa

55
Q

AIM-HIGH trial
PICO

A

P: Patients with CVD and low HDL (SECONDARY)

I: Simva (40-80) + ER niacin (2000mg/day)

C: Simva 40-80 + placebo (100-200mg of niacin)

O: nonfatal MI, schemic stroke, hospitilzaation for an ACS, revascularization, Death from CHD

56
Q

AIM-HIGH trial
Limitations

A

Stopped early due to increased ischemic stroke in treatment group.

More use of 80mg simva in placebo, higher HDL than expected
- showed no benefits vs placebo

Increase in mortality? Laropiprant effect?

57
Q

Niacin safety?

A

Concerns for: Increased infections, myopathy, BG, Hepatic issues, hypotension, nigricans

  • 80% experienced flushing, poorly tolerated
  • must titrate dose
  • may need to premedicate with ASA or ibuprofen before dose
58
Q

When do we consider Niacin?

A

Considered VERY LAST LINE in high risk patients (familial hypercholesterolemia), who still have HIGH LDL despite being on max statin dose + ezetimibe/bile resin

59
Q

MOA of PCSK9

A

Increases LDL receptors, lowers LDL antibodies

60
Q

Which drugs are PCSK9 inhibitors?

A

Monoclonal antibodies
- Evolocumab
- Alirocumab
- Inclisiran

61
Q

FOURIER trial (evolocumab)
Population
Outcome
Side effect?

A

Population:
- with atherosclerotic CV disease (previous MI, stroke or PAD) (SECONDARY)
- LDL 1.8 mmol/L or higher
- On a statin

Outcome:
- reduced LDL levels as add-on, NO improvement in mortality

Side effect
- injection site reaction was most significant

62
Q

ODYSSEY Outcomes trial (Alirocumab)
Population
Outcome

A

Population
- ASCVD disease (SECONDARY)
- LDL over 1.8 mmol/l
- HIGH intensity statins

Outcome
- better composite outcomes, mortality slightly improved (but insignificant)

63
Q

Evolocumab injection indications (3)

A
  1. Homo/heterozygous and familial hypercholesterolemia (in addition to max tolerated statins + other meds)
  2. Clinical atherosclerotic CVD (in addition to max tolerated statins + other meds)
  3. Off label use: high risk patients (in addition to max tolerated statins + other meds)
64
Q

Inclisiran trials
Outcome assessed?
Surrogate outcome?

A

Outcome assessed? % change in LDL
Surrogate outcome?
- 50% change in LDL

Still ongoing

65
Q

Evacetrapib ACCELERATE trial outcome?
Available in Canada?
Class?

A

Cholestyeryl ester transfer protein (CETP) inhibitors
- Not available in canada
- Does not work

66
Q

Cholestyeryl ester transfer protein (CETP) inhibitors
MOA

A

block the transfer of cholesterol to VLDLs and HDLs
- less cholesterol in periphery

67
Q

CLEAR trials
PICO

A

Population:
- high risk primary (reynorlds risk score over 30%, type I or II diabetes aged, coronary artery calcium)
- statin-intolerant
- mixture of primary and secondary

I: bempedoic acid vs placebo

68
Q

Which combination studies showed improvement

A

Statin + omega-3 fatty acids (icosapent ethyl)

69
Q

Icosapent Ethyl
PICO

A

Population
- INCREASED Triglycerides 1.52-5.63
- on a statin (mod-high dose)
- PRIMARY AND SECONDARY

Significant in reducing clinical outcomes in patients with decent statin dose

70
Q

When do we consider ezetimibe vs PCSK9 inhibitor

A

PCSK9
- LDL 2.2+ mmol/L
- ApoB 0.8+
- non-HDL 2.9+

Ezetimibe
- all lower

IPFC 3 Final (6 decks)

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