A brief insight into the management of Atherosclerosis - Malaysian CPG

1. PHARMACOTHERAPY POINTERS
[ATHEROSCLEROSIS]

2.  Statins
 Cholesterol Absorption Inhibitors
 PCSK9 Inhibitors
 Fibric Acid derivatives (Fibrates)
 Bile Acid Sequestrants
 Nicotinic Acid (Niacin) derivatives
 Combination therapies

3.  Cardiovascular diseases (CVDs) are an important cause of
morbidity and mortality in Malaysia.
 Major CV risk factors include dyslipidaemia, hypertension,
smoking, diabetes, obesity, and physical inactivity.
 Dyslipidaemia is highly prevalent in the Malaysian population and
is one of the main risk factors for Atherosclerotic CVD (ASCVD).
 Low-density lipoprotein cholesterol (LDL-C) is recognised as the
primary target of lipid-lowering therapy to reduce the disease
burden of ASCVD.

4. Atherosclerosis – an introduction
 Is a condition in which fatty material (atheromas) collects
along the walls of medium-sized and large arteries.
 These plaques contain lipids, inflammatory cells, smooth
muscle cells, and connective tissues.
 This fatty material thickens, hardens (forms calcium
deposits), and may eventually block the arteries.
 Atherosclerosis can affect many different organ systems,
including the heart, lungs, brain, intestines, kidneys, and
limbs (extremities).

5. Risk Factors for Atherosclerosis
Major Minor
NON-modifiable Modifiable
Increasing age Obesity
Male gender Physical inactivity
Family history Stress
Genetic abnormalities Postmenopausal estrogen deficiency
High carbohydrate intake
Modifiable Alcohol
Hyperlipidemia Lipoprotein Lp(a)
Hypertension Hardened (trans)unsaturated fat intake
Cigarette smoking Chlamydia pneumoniae
Diabetes

6. Risk factors
 DM
 Heavy alcohol use
 High BP
 High blood cholesterol levels; High LDL, Dense LDL; Low HDL
 High-fat diet; Obesity
 Increasing age
 Personal or family history of HD
 Smoking, Etc.

7. Dyslipidaemia is characterized by the following lipid levels:
TC > 5.2 mmol/L
HDL-C < 1.0 mmol/L (males) < 1.2 mmol/L (females)
TG > 1.7 mmol/L
LDL-C levels - will depend on the patient’s CV risk

8.  LDL-C is atherogenic .
 There is a direct relationship between levels of LDL-C (or TC) and
the rate of new onset CHD in men and women who were
initially free from CHD.
 In people with established CHD, elevated LDL-C correlates with
recurrent cardiac events.
 Lowering of LDL-C reduces CVD events.
 LDL-C should be the primary target for in atherosclerosis.

9.  Atherogenic dyslipidaemia comprises a triad of low HDL-C,
high TG and increased levels of LDL-C.
 Regular exercise reduces the risk of CVD mortality in both
healthy individuals and CVD patients.
 Dietary modification can result in an improvement in
atherogenic dyslipidaemia.
 Total Lifestyle Change (TLC) forms an integral component in
management.

10.  Most individuals at Low Risk and Intermediate (Moderate)
Risk can be managed by TLC alone.
 Lipid modifying agents may be necessary to achieve target
lipid levels.
 Statins are safe, reduce CV events, well-tolerated, and cost
effective.

11. Major Lipid Modifying Drug Classes

12. Major Lipid Modifying Drug Classes

13. HMG CoA Reductase Inhibitors (Statins)
 Statins inhibit HMG CoA reductase (the enzyme involved in
hepatic cholesterol synthesis).
 LDL-C reduction with statin treatment remains the cornerstone
of lipid lowering therapy to reduce risk of CVD.
 Statins have moderate effect in lowering TG and in elevating
HDL-C.
 Treatment is initiated at the recommended starting dose with
the evening meal or at bed time.

14.  Since cholesterol is biosynthesized in the early morning
hours,
statins with shorter half-lives (lovastatin 2 hrs., simvastatin
<5 hrs., and fluvastatin < 3 hrs.) should be administered in
the evening.
statins with longer half-lives (atorvastatin 14 hrs.,
rosuvastatin 19 hrs., and pravastatin 22 hrs.) can be
administered during the day.

15.  Statin therapy is contraindicated in pregnancy and
lactation.
 It should not be prescribed to women of child bearing
potential, unless adequate contraception is taken.
 If pregnancy is planned, then statins should be
discontinued.

16. Monitoring Statin Therapy
 Statin therapy is lifelong. Counsel the patient regarding this.
 It is very important to regularly monitor patients for response
to therapy and achievement of lipid targets.
 The degree of LDL-C reduction is dose-dependent and varies
between the different statins.

17. Monitoring Statin Therapy
 There is considerable inter-individual variation in LDL-C
reduction with the same dose of drug.
 Inadequate response to statin treatment may be due to poor
compliance and/or genetic variations of cholesterol and statin
metabolism in the liver.

18. Monitoring Statin Therapy (contd’.)
 Lipid profile should be measured at 1 - 3 months following
initiation and following a change in the dose of statin therapy.
 Then adjust the dose accordingly to achieve LDL-C levels.
 If LDL-C targets have been achieved, the same dose of statin
should be maintained.
 The drug should not be stopped.
 The lipid profile can be repeated at 6 - 12 month intervals.

19. Monitoring Statin Therapy (contd’.)
 If LDL-C target is not achieved, the dose of statin can be up-titrated
to the maximal tolerated dose.
 If target level still not achieved, then a non-statin drug can be
added.
 The frequency of repeat testing depends on the patients’
adherence to therapy and lipid profile consistency (if adherence is
a concern or the lipid profile is unstable, then more frequent
assessment may be necessary).

20. Monitoring Statin Therapy (contd’.)
Safety/Adverse Effects
 Liver Function
• Mild elevation of ALT is not associated with hepatotoxicity or
changes in liver function.
 Diabetes
• Statins have been associated with a slight increase in new-onset
diabetes. It occurs with all statins and may be dose-related.
 Muscle Symptoms
• Statin-associated muscle symptoms (SAMS) includes myalgia
[normal creatine kinase (CK)], myositis (CK > ULN) and
rhabdomyolysis (CK > 10x of ULN).

21. Monitoring Statin Therapy (contd’.)
Safety/Adverse Effects
 Statin intolerant patients: Patients unable to tolerate at least 2
different statins due to unexplained skeletal muscle-related
symptoms (pain, aches, weakness, or cramping) that began or
increased during statin therapy and returned to baseline when
statin therapy was discontinued;
 Discontinue the statin(s) for 2-3 weeks when statin myopathy is
suspected.

22. Optimizing Statin Therapy

23. Optimizing Statin Therapy
 High-intensity statin therapy produces a greater percentage of
LDL-C reduction (reduces CV events more than moderate-
intensity statin therapy).
 Lower-intensity statin therapy reduces CV events, but to a lesser
degree.
 Very High Risk and High Risk individuals should be treated with the
maximum appropriate intensity of a statin that does not cause
adverse effects.

24. Cholesterol Absorption Inhibitors
 Ezetimibe 10 mg daily
 Selectively blocks intestinal absorption of both dietary and biliary
cholesterols and other phytosterols.
 This leads to a reduction in hepatic cholesterol delivery
(complements the action of statins).
 It is used in combination with any dose of any statin to further
lower LDL-C if targets are not achieved.

25. PCSK9 Inhibitors
 A new class of lipid-lowering drugs that target the proprotein
convertase subtilisin kexin type 9 (PCSK9).
 It inhibits PCSK9 binding to the LDL-receptors.
Recommended Doses:
 Evolocumab: 140 mg SC every two weeks or 420 mg SC monthly
 Alirocumab: 75 - 150 mg SC every two weeks

26. Fibric Acid Derivatives (Fibrates)
 They reduce serum TG effectively and increase HDL-C modestly.
 The recommended dosages are:

27. Fibric Acid Derivatives (Fibrates)
 Doses of fibrates need to be adjusted in the presence of CKD.
 Serum ALT should be monitored when starting therapy or
when doses are increased.

28. Bile Acid Sequestrants (Anion exchange resins)
 Recommended Dose:
Cholestyramine: 4 g/day increased by 4g at weekly intervals to
12-24 g/day in 1-4 divided doses, Max. dose : 24 g/day

29. Nicotinic Acid (Niacin) and it’s Derivatives
 Decreases mobilization of free fatty acids from adipose tissues.
 Increases HDL-C and lowers TG levels.
 Recommended Dosages:
 Nicotinic acid (Niacin): available as 50mg tabs., 100 and 250 mg
caps.
 Starting dose: 150-300 mg daily in divided doses;
 It should be taken with meals to reduce gastrointestinal side
effects.

30. COMBINATION THERAPIES

31. To achieve LDL-C target levels
 Statin + cholesterol absorption inhibitors (ezetimibe)
 Statin + bile acid exchange resins
 Statin + PCSK-9 inhibitors

32. Considerations when using a combination of
statins and fibrates
Fibrates increase the risk of myopathy with statins, and the
risk is highest for gemfibrozil.
The combination of statins and gemfibrozil is discouraged.
The risk of myopathy when combining statins with
fenofibrate is small.
Fibrates should preferably be taken in the morning and
statins in the evening to minimize peak dose
concentrations and decrease the risk of myopathy.

33. THE END

34. REFERENCE:
MALAYSIAN CLINICAL PRACTICE GUIDELINES - Stable
Coronary Artery Disease 2018,
2ND EDITION (2018);
Published By:
National Heart Association of Malaysia