Obat Lipidemik

Dept of Pharmacology and Therapeutics

FK Undip
Oktober , 2018
 Case # 1
A 55-year-old woman without symptoms of CAD seeks
assessment and advice for routine health maintenance.
Her blood pressure is 135/85 mm Hg. She does not
smoke or have diabetes and has been postmenopausal
for 3 years. Her BMI is 24. Lipoprotein analysis shows a
total cholesterol level of 240 mg/dL, an HDL level of 55
mg/dL, a triglyceride level of 85 mg/dL and a LDL level is
180 mg/dL. The patient has no family history of
premature CAD.

What is the goal LDL in this woman?

What would you do if exercise/diet change do not improve cholesterol after 3
months?
How would your management change if she complained of claudication with
walking?
 Case # 2
A 50- year-old man just had a “heart attack” and
implanted with 1 stent in his left anterior descending
(LAD) coronary artery. He is a current smoker and has a
23-pack year history of tobacco use. A fasting lipid panel
reveals a LDL 170 mg/dL and an HDL of 35 mg/dL. Serum
Triglycerides were 140 mg/dL. Serum chemistries
including liver panel are all normal.

What is this patient’s goal LDL?

Would you start medication, and if so, what?
 Cholesterol and Lipprotein Pathway

1-4
 29-5

Hypolipidemic Drugs

• There are six groups – HMG-CoA reductase

of drugs used in the inhibitors (statin)
management of – Cholesterol absorption
inhibitors
hyperlipidemia:
– Bile acid sequestrants
– Fibric acid derivatives
– Nicotinic acid
– PCSK9 inhibitor
 Mechanism Action
Hypolipidemic Drugs

1-6
 Serum Cholesterol and
Cardiovascular Risk
18
6 year CHD death rate per 1,000 men

16
14
12
10
8
6
4
2
0
140 160 180 200 220 240 260 280 300 mg/dL
4.5 5.5 6.5 7.5 mmol/L
Serum cholesterol
Martin. Lancet 1986;933–936
 29-9

1. HMG-CoA Reductase Inhibitors

• Also referred to as statins
• MOA—inhibit enzyme that causes
cholesterol synthesis

• IND—adjunct to dietary treatment to

decrease total serum and LDL cholesterol:
– Reduce LDL level up to 30%
– Raise HDL level up to 20%
 1-10

HMG-CoA Reductase Inhibitors

• The liver
makes two-
thirds of the
daily
cholesterol
requirement
.

• An early, very important step in this process is the conversion of

acetyl-CoA molecules into HMG-CoA, which is then converted to
mevalonic acid by HMG-CoA reductase. Mevalonic acid is a rate-
limiting pivotal step in steroid and cholesterol biosynthesis
Fundamental & Clinical Pharmacology 19 (2004) 117–125
Robert H. Knopp, M.D. N Engl J Med 1999; 341:498-511
 4 Statin Benefit Groups
• Clinical ASCVD*
• LDL-C ≥190 mg/dL, Age ≥21 years
• Primary prevention – Diabetes: Age 40-75 years, LDL-C 70-189
mg/dL
• Primary prevention - No Diabetes†: ≥7.5%‡ 10-year ASCVD
risk, Age 40-75 years, LDL-C 70-189 mg/dL

*Atherosclerotic cardiovascular disease

†Requires risk discussion between clinician and patient before statin initiation

‡Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk

calculator
 Intensity of Statin Therapy

*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There
might be a biologic basis for a less-than-average response.
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not
recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.
Side Effects Statin
 Management of Muscle
Symptoms on Statin Therapy
• It is reasonable to evaluate and treat muscle
symptoms including pain, cramping, weakness, or
fatigue in statin-treated patients according to the
management algorithm

• To avoid unnecessary discontinuation of statins,

obtain a history of prior or current muscle symptoms
to establish a baseline before initiating statin therapy
 Management of Muscle
Symptoms on Statin Therapy (cont.)
If unexplained severe muscle symptoms or fatigue
develop during statin therapy:
• Promptly discontinue the statin
• Address possibility of rhabdomyolysis with:
• CK
• Creatinine
• Urinalysis for myoglobinuria
 Management of Muscle
Symptoms on Statin Therapy (cont.)
If mild-to-moderate muscle symptoms develop during
statin therapy:
• Discontinue the statin until the symptoms are
evaluated

• Evaluate the patient for other conditions* that might

increase the risk for muscle symptoms

• If after 2 months without statin Rx, muscle

symptoms or elevated CK levels do not resolve
completely, consider other causes of muscle
symptoms
*Hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as
polymyalgia rheumatica, steroid myopathy, vitamin D deficiency or primary muscle diseases
Robert H. Knopp, M.D. N Engl J Med 1999; 341:498-511
 29-21

2. Bile Acid Sequestrants

• MOA—bind bile salts and cholesterol in the
GI tract, preventing absorption of both

• Cholestyramine, Colestipol, Colesevelam

• IND—hyperlipidemia:
– Increased elimination of bile salts, cholesterol, and
other fats in the faeces.
– Adverse effects include GI disturbances, severe
constipation, and fecal impaction.
– Most serious adverse effect is intestinal obstruction.
Side Effects

Robert H. Knopp, M.D. N Engl J Med 1999; 341:498-511

 29-23

3. Cholesterol Absorption Inhibitors

• Ezetimibe:
– MOA—blocks absorption of cholesterol in
the intestines
• Decreases VLDL
• Decreases circulating LDL cholesterol
– IND—treatment of hyperlipidemia in
conjunction with diet alteration
 29-24

Cholesterol Absorption Inhibitors

• Ezetimibe:
– Modestly reduces total cholesterol, LDL,
and triglyceride blood levels
– Ideal to combine with other hypolipidemic
drugs
– Adverse effects—abdominal pain, fatigue,
coughing, diarrhea, back pain, and
arthralgia
 29-25

4. Fibric Acid Derivatives (Fibrates)

• Gemfibrozil:
– MOA—inhibits breakdown of fat into
triglycerides, and limits liver production of
triglycerides
– IND—to decrease triglycerides
– Adverse effects—nausea, vomiting, diarrhea,
and flatulence
• Gemfibrozil, Benafibrate, Fenofibrate,
Ciprofibrate
 4. Activators of lipoprotein lipase (Fibrates)

Fibrates enhance the oxidation of fatty acids (FA) in liver and muscle and reduce the
rate of lipogenesis in the liver, thereby reducing hepatic secretion of very-low-
density lipoprotein (VLDL) triglycerides (TG).
The increased uptake of triglyceride-derived fatty acids in muscle cells results from
an increase in lipoprotein lipase (LPL) activity in adjacent capillaries and a decrease
in the apolipoprotein CIII (Apo CIII) concentration mediated transcriptionally by
peroxisome proliferator-activated receptor a (PPARa).
Side Effects
 5. Inhibitor of VLDL secretion and
lipolysis
• Niacin (Nicotinic acid)

Miscellaneous: Gugulipid and fish oil derivatives

 29-29

Nicotinic Acid
• MOA—affects cholesterol synthesis through a
G proteins coupled receptor:
– Inhibits triglyceride lipase
– Stimulates lipoprotein lipase
– Decreases free fatty acid release and removes
triglycerides
• IND—hyperlipidemia
• Adverse effects—flushing, nausea, vomiting,
and diarrhea
Nicotinic acid inhibits the mobilization of free fatty acids (FFA) from peripheral
adipose tissue to the liver. As a consequence of this decrease or an additional
hepatic effect, the synthesis and secretion of very-low-density lipoprotein (VLDL)
are reduced, and theconversion of VLDL to low-density lipoprotein (LDL) is
decreased.

Nicotinic acid can also increase serum high-density lipoprotein (HDL) cholesterol
concentrations by up to 30 percent; the mechanism responsible for this effect is
unknown.
Robert H. Knopp, M.D. N Engl J Med 1999; 341:498-511
Side Effects
 Fish oil derivative
• Omega-3-fatty acids
• Eicosa-pentanoic and docosa-hexanoic acid
• Prophylaxis use in high risk patient of CAD
• Usually formulated with vit.E
 Combination drug therapy
• Bile acid binding resins+Fibrates
• Bile acid binding resins+Niacin
• Bile acid binding resins+Statins
• Bile acid binding resins+Niacin+ Statins
• Niacin+Statin (Atorva 10+ Nia 500)
• Statins+Ezetimibe (OK)
• Statins+Fibrate (Careful, better avoid)
 6. PCSK9 inhibitor

Aust Prescr. 2016 Oct; 39(5): 164–167.

 Inhibiting PCSK9
means that more
LDL receptors
will be recycled
to the surface of
the cell.

This should
increase the
clearance of LDL
cholesterol from
the circulation.

Eur Heart J. 2015 Sep 21;36(36):2415-24.

 DESCARTES: % Change in UC LDL-C
From Baseline - FAS
20
6.0%
from Baseline, Mean (± SE)

10
UC LDL-C Percent Change

0
-10
-20 Treatment difference
57%
-30
-40
-50
-60 -51.5%
-70
Number of patients:
-80
302 294 264
599 582 542

Baseline Week 12 Week 52

Study Week

Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599)

FAS = Full analysis set, UC = ultracentrifugation
29-38