This a is a slide set (42 slides) covering clinically used drugs for lipid lowering. This is an updated version of the lecture series for the 2021-2022 academic year. Suitable for intermediate level learners

1. Drugs influencing lipid metabolism
DEPARTMENT OF PHARMACOLOGY AND PHARMACOTHERAPY
S E M M E L W E I S U N I V E R S I T Y
Dr. Zoltán Varga
Website: semmelweis.hu/pharmacology

2. Case study
A 67 years old male heavy smoker patient is
checking into your office as a new patient, and is
asking about prescriptions.
As with every new patient in your office, you are
performing the routine checkups (physical exam,
BP measurement, routine bloodwork).

3. • Height.:178cm, Body
weight.:90kg.
• Negative physical exam,
except observation of
yellowish nodules on
both hands of the
patient.
• BP: 185/105; HR: 81/min
Results
Test Result Unit Reference
Total cholesterol 9.75 mmol/l <5.2
LDL-cholesterol 7.8 mmol/l <2.6
HDL-cholesterol 1.3 mmol/l >1.5
Triglycerol 1.4 mmol/l <1.7

5. Atherosclerotic plaque development: the role of LDL-cholesterol
PGI2 and NO production
Endothelial dysfunction
Production of free radicals
LDL oxidation
Subendothelial migration
"Fatty streak" lesion Smooth muscle cell proliferation
Fibrosis initiation
PLAQUE development
Macrophage uptake of oxLDL via
scavanger receptors
Activation of monocytes
and other WBCs

6. Prevention of atherosclerosis
1. Physical exercise: increases HDL production
2. Healthy diet
• Omega-3 fatty acids
• Available as a drug also: Icosapent ethyl
• For the reduction of cardiovascular risk in patients with hypertriglycerolemia
• Adverse effects: bleeding, atrial fibrillation, GI symptoms, skin rashes,
musculoskeletal pain, peripheral edema, gout
• Restricted alcohol consumption (red wine)
• Folate, B6- and B12- vitamin: reduces homocysteine level
• Antioxidants
3. Ostrogen
4. Drugs
• Antihypertensive medications: improves endothelial function
• Antihyperlipidemic drugs

7. Acetil-CoA
cholesterol
Liver
LDL
IDL
VLDL
lipoprotein-lipase
Intestine
ApoB
mediated
uptake
Fat in food + cholesterol
Chilomicrones
FFA
FFA
lipoprotein-lipase
Bile acids
Chilomicrone
remnant
Peripheral
tissues
ApoE mediated uptake
ApoB mediated uptake
ApoE mediated uptake
lipoprotein-lipase
lipoprotein-lipase
FFA
Statins
Bile acid sequestrants
Ezetimibe
HDL
Niacin
Bempedoic acid
PCSK9 inhibitors
Fibrates

8. A HMG-CoA-reductase inhibitors: the statins
Drug names: lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, rosuvastatin
lovastatin
simvastatin
pravastatin

9. Pharmacodynamics – Mechanism of action:
• inhibition of the HMG-CoA – mevalonate conversion in the liver (a process thought to be more active during the night)
- Cholesterol synthesis decreases
increased hepatic LDL uptake from the circulation
- LDL-receptor upregulation
- Inhibition of farnesol synthesis
Clinical effects:
 better endothelial function
 plaque stabilization
 decreased LDL-oxidation
 inhibition of smooth muscle proliferation
 fibrinolytic, antithrombotic effect
 antiinflammatory effects
20-30% decrease in cardiovascular mortality (AMI, stroke, total cv. mortality)
A HMG-CoA-reductase inhibitors: the statins

10. HMG-CoA
Mevalonate
Isopentenyl-PP
Geranil-PP
Farnesyl-PP
Dolichol
HMG-CoA reductase
"Statin"
Cholesterol
Ubiquinone (Coenzyme Q10)
Protein prenylation
Cholesterol
Mechanism of action of statins: the mevalonate pathway
Citrate
ATP-citrate liase
Acetyl-Coa
Bempedoic acid

11. Originally isolated from mushrooms
–lovastatin is abundant in "oyster
mushroom"
LDL-C HDL-C Triglycerol Other effects
HMG-CoA
reductase
inhibitors -
statins
↓20-50% ↑10% ↓10-40% LDL receptor
expression
increases in the
liver
HMG-CoA-reductase inhibitors: statins

12. HMG-CoA-reductase inhibitors: statins
Pharmacokinetics:
• Good oral absorption
• Highly lipophylic character
• Extensive hepatic first pass metabolism
• Could be important in the pharmacological effect (cholesterol
synthesis occurs in the liver)
• Compounds bypassing the hepatic first pass metabolism seems to
be more toxic (e.g. cerivastatin that was withdrawn from the market in
2001)
• The CYP3A4 enzyme plays a central role in statin metabolism

13. HMG-CoA-reductase inhibitors: statins
Pharmacokinetics:
• Good oral absorption
• Highly lipophylic character
• Extensive hepatic first pass metabolism
• Could be important in the pharmacological effect (cholesterol synthesis occurs in the
liver)
• Compounds bypassing the hepatic first pass metabolism seems to be more toxic
(e.g. cerivastatin that was withdrawn from the market in 2001)
• The CYP3A4 enzyme plays a central role in statin metabolism
• Statins are excreted with the bile

14. HMG-CoA-reductase inhibitors: statins
Side effects:
• mild GI symptoms – diarrhoea, constipation
• distrubed sleep
• skin rash
• mild, transient proteinuria
• muscle related side effects:
rabdomyolysis (rare, 1000:1), myopathy- muscle pain (common, 10:1)
- mostly when other CYP3A4 substrates are given together with the
statins e.g. fibrates, macrolides, grapefruit – "statin intolerance"
• in case of statin intolerance: dose reduction, change to an other statin,
or discontinuation of statin therapy
Contraindication: pregnancy, severe liver failure

15. HMG-CoA-reductase inhibitors: statins
The statin type and dose has to be selected according to our therapeutic target.
Target:
Healthy individual LDL-C below 3.3 mmol/l
Patient with increased CV risk LDL-C below 2.6 mmol/l
Patient with CV disease (prior MI or stroke) LDL-C below 1.8 mmol/l
If we need to achive at least 50%-
reduction in LDL-C level or our patient
already has advanced atherosclerosis,
we need to use high intensity statin
therapy.

16. Misbeliefs and fake information on statins

17. Safety of statins: muscle
• Myopathy and rhabdomyolysis are important statin side
effects
• Increase serum creatine kinase (CK) might indicate
statin-induced muscle damage
• Muscle weakness and muscle pain alone (even without
CK increase) might indicate statin-induced muscle
damage
• Muscle damage is dose-dependent
• Drug interactions increase the risk of statin-induced
muscle damage – e.g. gemfibrozil and other CYP3A4
inhibitors
Thompson PD et al. Am J Cardiol. 2006;97:69C-76C

18. Safety of statins: liver
• Statin use often associates with increased liver enzyme
levels
• This does not necessarily indicate overt liver injury
• Testing liver function is not needed during statin therapy
• Liver failure is however, a contraindication of statin
therapy
Thompson PD et al. Am J Cardiol. 2006;97:69C-76C

19. Safety of statins: kidney
• Clinically used doses do not associate with significant
protein- or hematuria
• Some studies even suggest a protective role of statins in
certain kidney diseases
Thompson PD et al. Am J Cardiol. 2006;97:69C-76C

20. Safety of statins: CNS
• Statin use does not lead to peripheral nerve injury
• Statin use does not lead to memory issues, and
cognitive impairment
• According to clinical studies there is no association
between statin use and haemorrhagic strokes
Thompson PD et al. Am J Cardiol. 2006;97:69C-76C

21. Landmark statin trials
Preiss D et al. JACC. 2019;75:1945-1955

23. Niacin (nicotinic acid, Vitamin B3)
Mechanism of action:
• activates lipoprotein-lipase
• inhibits VLDL secretion
• most effectively increases HDL-C level
Dose: daily 2-3 g (!), stepwise increase of the dose is needed starting with 500-750 mg
Daily recommended dose of vitamin is – 14-16 mg/day
Side effects:
• flushing (XR – extended release form may decrease)
• dyspepsia (ulcer is a contraindication!)
• severe hepatotoxicity
• insulin resistance (diabetes is a contraindication!)
• urate elevation
• pregnancy is a contraindication
Chylomicron-, VLDL triglycerol
level (even 50% decrease)
XR niacin combined with statin
has been withdrawn from the
market in the US in 2016.

25. Bile acid sequestrantts (colesevelam, colestipol, colestiramin)
Mechanism of action:
After oral administration they bind to bile acids in the intestines
Interfere with the enterohepatic recirculation
Decreased cholesterol absorption
Increased bile acid synthesis
Side effects: - GI complaints (nausea, flatulence, constipation) – might be better with proper fluid intake
- inhibit the absorption of other drugs – avoid concomittant drug use for 4 hours
Clinical use: - isolated LDL-C increase, even during pregnancy
- children may also take

27. Drug that decrease intestinal cholesterol absorption: ezetimibe
Mechanism of action:
Selective inhibition of intestinal cholesterol absorption
- NPC1L1 sterol transporter is inhibited
- Cholesterol content is decreased in chylomicrons
- Hepatic LDL-R expression increases
Pharmacokinetics:
• glucuronidation is needed for its activation
• enterohepatic recirculation is characteristic
Side effect: concomittant statin use increases liver enzyme levels
Dose: daily 5-20 mg (recommended: 10 mg/day)

28. Drug that decrease intestinal cholesterol
absorption: ezetimibe + simvastatin
Common fixed dose synergistic combination product
Side effects:
- increased liver enzymes
- increased cancer risk – SEAS study (2008 – 1873 patients),
IMPROVE-IT study showed no cancer risk (2020 – 17708 patients)
Dose: Bedtime 1x: Ezetimibe 10 mg + Simvastatin 10-80mg
Not recommended to combine with niacin, amiodarone, or verapamil.
Contraindicated in liver diseases and pregnancy.

29. Bile acid sequestrants
IStalins I
;
Bempedoic acid
••••••••••
-c; • Fat in food + cholesterol
� • lipoprotein-lipase Chilomicrone
• , , , ► Ch1lom1crones ,
._ remnant -----.
-·I Ezetimibe I �� FFA
••••
... JI'
• •• ·••• FFA
• •• •••
• •• •••
• ••
: ..
• •• ·-...�
� .....
•
•
•
•
•
•
•
•
•
••
Peripheral �
tissues
iJ
0
iJ
0
::::J
I
C: 3 )> iJ
iJ (t) iJ ll)
Q) a. 0 (/)
""" -· OJ "'
(t) �
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(t)

30. Fibrates (fenofibrate, gemfibrozil)
Mechanism of action:
• PPARa agonists
• increases b-oxidation
• activates lipoprotein-lipase
(promotes urate excretion, can be used in diabetic patients as well)
Pharmacokinetics:
• 90% is well absorbed from the intestines, has strong plasma protein binding
• after hepatic glucuronidation, it is excreted in the urine
Side effects: rabdomyolysis (especially if combined with statins!), acute kidney failure,
gall stone production, hypoglycemia
Dose: daily 2x600 mg gemfibrozil, 45-145 mg/day fenofibrate
Interactions: statin + gemfibrozil not recommeded, careful combination with other fibrates
VLDL and
triglycerol level

31. PPAR alpha and gamma effects on VLDL, LDL
and HDL metabolism
* Peroxisome Proliferator Activated Receptor
PPAR alpha
Expressed: Liver, kideny, heart, skeletal
muscle
Ligands: fatty acids, fibrates
Effects: Increased production of Apo-AI,
and lipoprotein lipase
FFA uptake and breakdown is increased,
VLDL synthesis is decreased.
HYPERLIPIDEMIA
PPAR gamma
Expressed: Adipose and intestines.
Ligands: arachidonic acid, glitazones
Effects: ABCA-1 expression
increases,
FFA uptake inreases into adipocyts,
increases insulin sensitivity.
DIABETES

33. New drugs for the treatment of hyperlipidemia
(Mipomersen):
• antisense oligonucleotide (s.c.)
• decreases ApoB100 expression
Used for homozygotic familiar hypercholesterolemia treatment in the US.
Less often used due to the risk of liver steatosis.
Lomitapide:
• inhibitor of the microsomal triglycerole transfer protein (MTP)
• decreases ApoB levels and VLDL synthesisin the liver
Used for homozygotic familiar hypercholesterolemia treatment (EU as well).
Bempedoic acid:
Approved in 2020, inhibitor of the ATP-citrate lyase enzyme. Used for
heterozygotic familiar hypercholesterolemia treatment, and in case of severe
statin intolerance. SE: increased risk of gout?
VLDL, IDL, LDL
VLDL, IDL, LDL

34. • PCSK9 inhibitors:
- Therapeuticly used monoclonal antibodies against PCSK9 protein (Proprotein
convertase subtilisin/kexin type 9) - Evolocumab, Alirocumab
- Antisense RNA against hepatic PCSK9 production – Inclisiran
- PCSK9 inhibits LDL receptor recirculation in the liver – PCSK9 inhibition
therefore results in increased LDL receptor density on hepatocytes – more LDL is
taken up by hepatocytes – circulating LDL-C concentration decreases
- The highest reduction in LDL-C level (over 50%) can be achieved by PCSK9
inhibition
- Recent clinical studies also confirmed the reduction of cardiovascular events by
their use.
New drugs for the treatment of hyperlipidemia

35. Physiologic recirculation of LDL-receptors and the role of PCSK9
Figure: Daniel Kucsera

36. PCSK9 inhibition with monoclonal antibodies or antisense RNA
Figure: Daniel Kucsera

37. Clinical efficacy of LDL-C lowering drugs
Class of agent
LDL reduction efficacy
(%)
Event reduction Approval status
Statins 30–50 + +
Ezetimibe 15–20 + Combined with statin +
PCSK9 inhibitors 50–60 + For MoAb combined
with statin
+
Bempedoic acid 17–25 Outcome trial in
progress
+
Lale Tokgözoğlu, Peter Libby, The dawn of a new era of targeted lipid-lowering therapies, European Heart Journal, 2022;, ehab841

38. New therapeutic targets to reduce cardiovascular risk
Triglyceride-rich lipoproteins
Lp(a)
• Elevated Lp(a) is associated with increased CV risk
• Usual pharmacologic agents that lower LDL have little or no effect on Lp(a); PCSK9 inhibitors modestly reduce it!
• Difficult to target pharmacologically, however, there are ongoing clinical trials:
• Pelacarsen (anti-sense nucleotide)
• Olpasiran (silencing RNA)
• Volanesorsen
• anti-sense nucleotide
• Main target: apolipoprotein CIII
• Approved in familial chylomicronaemia
syndrome
• Evinacumab
• Monoclonal antibody
• Main target: Angiopoietin-like 3
• Approved in rare hypercholesterolemias Lale Tokgözoğlu, Peter Libby, European Heart Journal, 2022;, ehab841

39. New mechanisms to reduce cardiovascular risk
Lale Tokgözoğlu, Peter Libby, European Heart Journal, 2022;, ehab841

40. Drug choice might depend on the type of dyslipidaemia
•Increased LDL-C dominant:
Primarily statin, second choice ezetimibe/bile acid sequestrant,
third choice niacin
•Increase LDL-C and decreased HDL-C:
Primarily statin, second choice niacin
•Increased LDL-C, decreased HDL-C, increased triglycerol:
Niacin and statin, fibrates are second choice
•Increased triglycerol:
Primarily fibrates, niacin second choice
• Low HDL-C:
Niacin, second choice fibrates – OR nothing.

42. Thank you for your attention!