This document summarizes recent therapeutic approaches for dyslipidemia. It discusses lifestyle changes like smoking cessation, weight loss, improved diet, and increased physical activity. It also discusses pharmacological management including ATP III guidelines, novel therapies that block lipoprotein output or increase clearance like PCSK9 inhibitors. Therapies to raise anti-atherogenic lipoproteins by promoting ApoA1 production or cholesterol efflux are also covered, as well as therapies slowing HDL removal and dual PPAR agonists. Surgical modalities like partial ileal bypass and liver transplantation are mentioned for severe dyslipidemia cases.

1. Recent therapeutic approaches for
dyslipidaemia
Marwa oraby
April 2014

2. Dyslipidemia
• is a range of disorders that include both
abnormally high and low lipoprotein levels, as
well as disorders in the composition of these
particles.
• the term is applied to lipid levels for which
treatment has proven beneficial

3. ATP III Treatment Priorities
 Reduce LDL-C to goal
 Correct other lipid/lipoprotein abnormalities (
TG & HDL- C ) by non HDL-C goals (30 mg/dl
higher than LDL-C goals)
 Apo B 100 ? For residual CVR

4. ATP III Update(2004)
LDL-C goals (Recommendations)

7. Modalities of dyslipidaemia management
Non pharmacological ( Therapeutic life style
changes )
Pharmacological
Surgical

8. Therapeutic lifestyle changes
LIFESTYLE INTERVENTIONS
Smoking
Cessation
Weight
Loss
Improved
Diet
Habits
Increased
Physical
Activity

9. Smoking Cessation
 Advice all patients
not to smoke (A)
 Initiate cessation
counseling (B)
 Offer combined
pharmacological
and behavioral
interventions(B)

10. Weight Loss
 Moderate weight loss
(7%body weight) (A)
 Reduce caloric
intake(1200-1800
Kcal/day) (A)
 As a part of weight
loss program ;diet and
physical activity (A)

11. Improved dietary habits
 Dietary modifications( fat< 30 %, protein
< 20% CHO 50-60 % of total calories)
 Saturated fat intake should be < 7 % of
total calories (A)
 Polyunsaturated fat up to 10% total
calories
 Monounsaturated fat up to 20% total
calories
 Low cholesterol diet (< 200mg/day)
 Minimize intake of trans fat (B)
 Increase plant sterol and stanol intake
modestly lower LDL-C and serum
cholesterol

12. Dietary Management of Dyslipidemia
(ATP III Recommendations)
•

13. Increased physical activity
 Regular physical activity (
150 min / week ) (A)
“moderate-intensity aerobic
exercise“
 Resistance training ( 3
times / week ) unless
containdicated (A)
 Start gradually and slowly
build intensity

14. Benefits of Exercise
 Increased insulin
sensitivity
 Improved lipid levels
(↑HDL-c)
 Lower blood pressure
 Weight control
 Improved blood glucose
control
 Reduced risk of CVD
 Prevent/delay onset of
type 2 diabetes

16. PHARMACOLOGICAL MANAGEMENT

18. • SURGICAL MODALITIES
Partial ileal bypass that eliminates the
reabsorption of bile acids at the distal portion of
the ileum has been shown to be a viable treatment
in some cases of severe dyslipidemia
Portacaval shunt altering cholesterol hepatic and
lipoprotein metabolism
liver transplantation shown to be effective in
treating severe hypercholesterolemia in homozygos
familial hypercholestrolemia.

19. Novel Therapies for Lipid Management
Therapies for lowering levels of atherogenic
lipoproteins
Blocking Lipoprotein Output
ApoB Blockade(anti sense oligonucleotide) (Mipomersen)
MTP Inhibition (Lomitapide)
Increasing Lipoprotein Clearance
PCSK9 Inhibitors
LDL apheresis

20. Therapies for raising levels of anti atherogenic
lipoproteins
Therapies promoting Apo A I production
Autologus Apo A I (IV infusion)
Apo A I mimetic peptidase inhibitors (IV)
Apo A I mimetic peptidase inhibitors oral
Therapies promoting cholesterol efflux and RCT
PPAR alpha agonists
PPAR gamma agonists
DUAL PPAR agonists
Therapies slowing removal of HDL from blood
CETP Inhibitors
CETP vaccine
Gene therapy for LPL deficeincy
Alipogene tiparvovec )Glybera)

21. Therapies for lowering levels of
atherogenic lipoproteins
Blocking Lipoprotein Output
ApoB Blockade(anti sense oligonucleotide) (Mipomersen)
MTP Inhibition (Lomitapide)
Increasing Lipoprotein Clearance
PCSK9 Inhibitors
LDL apheresis

22. Blocking Lipoprotein Output

23. ApoB Blockade (Mipomersen)
(Anti sense oligonucleotides)

27. Mipomersen sodium (Kynamro)
 Approved January 30, 2013
 Antisense oligonucleotide that decreases secretion of apo B
containing lipoproteins from the liver by decreasing the number
of specific mRNA available for translation of the encoded protein
in the hepatic synthesis of apoB 100
 Approved to reduce LDL‐C, apo B, TC, non‐HDL‐C in patients with
homozygous familial hypercholesterolemia (HoFH)
 Dosing: 200 mg once weekly subcutaneous injection .
 Adverse effects:
 injection site reactions (84%),
 flu‐like symptoms (30%),
 elevated hepatic transaminases

28. MTP Inhibition Lomitapide (Juxtapid)
VLDL assembly as target of therapy

29. MTP Inhibition Lomitapide (Juxtapid)
 Approved December 24, 2012
 MTP inhibitor decreases lipoprotein production
 Microsomal Triglyceride Transfer Protein (MTP)
is responsible for transferring triglycerides onto
apolipoprotein B within the liver in the assembly of
(VLDL), the precursor to LDL.
 In the absence of functional microsomal triglyceride
transfer protein, as in the rare recessive genetic disorder
abetalipoproteinemia, the liver cannot secrete VLDL,
leading to the absence of all lipoproteins containing
apolipoprotein B in the plasma.
 used to reduce LDL‐C, TC, apo B, non‐HDL‐C in
homozygous familial hypercholesterolemia (HoFM)

30. Dosing: capsules 5 & 10 mg daily titrated to a
maximum of 60 mg daily
Adverse effects:
 hepatic steatosis,
elevated hepatic transaminases;
GI adverse reactions (93%)
decreased absorption of vitamin E, ALA, linoleic
acid, EPA, DHA (supplement recommended)

32. Increasing Lipoprotein Clearance

33. PCSK9 INHIBITOR (evolocumab)
• Function of LDL receptor and life cycle

34. The role of PCSK9 in the regulation of
LDL receptor expression

35. PCSK9 INHIBITOR (evolocumab)
the gene PCSK9 proprotein convertase subtilisin/kexin
type 9 , serine protease mainly expressed in the liver and
the intestine which regulates the levels of the LDL receptor
in the liver.
It acts by reducing the amount of LDL-R in hepatocytes by 2
ways;
- Circulating PCSK9 binds the LDL-R on the cell surface and
is co-internalised with the LDL-R promoting the
degradation of the receptor in the lysozyme.
- Intracellularly, it can also bind to the LDL-R increasing its
degradation rather than recycling to the plasma
membrane

36. • LAPLACE-2 is a large phase III study of PCSK9
INHIBITOR (evolocumab)
 The monoclonal antibody evolocumab produced
highly significant reductions in low-density
lipoprotein (LDL) cholesterol, the "bad cholesterol,"
as an add-on to statins in all treatment groups,
 Evolocumab was well tolerated, with adverse
event rates similar to those in placebo and
ezetimibe-treated groups and no sign of liver damage
or muscle problems.
• The ongoing FOURIER trial will assess whether
additional lowering of LDL cholesterol with
evolocumab, on top of high and moderate-intensity
statin therapy, reduces the number of cardiovascular
events over a period of years.

37. LDL apheresis

38. LDL apheresis
• type of 'extracorporeal' procedure to remove low-density
lipoprotein (LDL) cholesterol from the
blood
• removes the LDL cholesterol , lipoprotein (a) and
triglycerides but has only a small effect on high-density
lipoprotein (HDL).
• two needles (catheters) ,permanent catheters in the
chest or formation of a shunt in the arm
• lower LDL level by 50 to 65 % after a single
treatment.
• either every week or every two weeks

39. • Indications
refractory forms of homozygous familial
hypercholesterolaemia (FH)
preventing the progression of coronary
artery disease in heterozygotes and
others with severe dyslipidaemia who are
refractory to or intolerant of high doses
of lipid-lowering drugs , despite the
maximum amount of drug treatment and
a cholesterol lowering diet

40. Extracorporeal methods for elimination of
LDL cholesterol
1) Plasmapheresis
2) Cascade filtration
3) Immunoadsorption
4) Heparin-induced LDL precipitation (HELP)
5) Dextran sulfate LDL adsorption (liposorber-
LA 15)
6) LDL hemoperfusion the direct adsorption of
lipoproteins (DALI)

41. Side effects of LDL apheresis

42. •

48. Therapies for raising levels of anti-atherogenic
lipoproteins

49. Therapies for raising levels of anti
atherogenic lipoproteins
Therapies promoting Apo A1 production
Autologus Apo A1 (IV infusion)
Apo A1 mimetic peptidase inhibitors (IV)
Apo A1 mimetic peptidase inhibitors oral
Therapies promoting cholesterol efflux and RCT
PPAR alpha agonists
PPAR gamma agonists
DUAL PPAR agonists
Therapies slowing removal of HDL from blood
CETP Inhibitors
CETP vaccine

51. Therapies promoting Apo A1 production
Autologus Apo A1 (IV infusion)
Apo A1 mimetic peptidase inhibitors (IV)
Apo A1 mimetic peptidase inhibitors oral

52. Autologus Apo A1 (IV infusion)
• pateint’s own Apo A1
• Apo A1 is more effective at promoting
cholesterol efflux from macrophages than mature
HDL
• Selectively delipidate HDL in whole plasma ex
vivo generating lipid poor Apo A1 then reinfused
• Promote cholesterol efflux and RCT thus slowing
or regressing atherogenesis

53. Autologus Apo A I (IV infusion)
• Acute effects of bolus iv infusion of Apo A I in
humans
• 5 weekly infusions of recombinant Apo A I
milano
• Resulted in a significant reduction of coronary
atheroma volume as measured by IVUS.

54. rHDL (CSL-111)
• CSL-111 is an apolipoprotein A-I isolated from human plasma and
phosphatidylcholine derived from soybean at 1:150 mol/mol
• Effect of rHDL (CSL-111) on Atherosclerosis Safety and Efficacy
(ERASE) trial.
• patients needing coronary angiography were given infusions of
reconstituted HDL cholesterol isolated from human plasma as 4
weekly infusions at 2 different strengths or placebo.
• Use of the high-dose infusion was discontinued early in the trial
after biochemical and laboratory liver test abnormalities were
detected, and these patients were moved into the low-dose infusion
or placebo groups.
• At the end of the study, no significant differences in coronary
atheroma volume were found between the groups. Those receiving
the CLS-111 infusions also had significant changes in plaque
characterization index.

55. Apo A I mimetic peptidase inhibitors
(IV)
• small synthetic peptides having properties
similar to Apo A I including promotion of cellular
cholesterol efflux
• Injection of Apo A I mimetic peptide (L-5F) into
mice significantly reduced the progression of
atherosclerosis
• ETC-642 (RLT peptides) in early trials .
• Parenteral administration is a logistical barrier to
long term administration so in the clinical trials as
“ acute induction therapy” for rapid plaque
regression or stabilization in patients with ACS

56. Apo A I mimetic peptidase inhibitors
oral
• D-4F : oral Apo A I mimetic peptide
• Not recognized by gut peptidases so not
degraded
• Showed dramatic reduction of atherosclerosis
in mice
• Promoted macrophage RCT in vivo in mice

57. RVX-208 ( Resverlogix)
• a novel small molecule that increases production
of ApoA-1, taken orally which raises HDL levels
and is thought to enhance reverse cholesterol
transport
• the ASSURE (phase 2b multicenter, double-blind,
randomized, parallel group, placebo-controlled
trial ) had failed to meet its primary endpoint.
• the trial did meet the secondary endpoints of
regression of total (coronary) atheroma volume
(TAV) and increases in Apolipoprotein A-I (ApoA-I)
and HDL cholesterol The company said that
results in the placebo arm of the study were
stronger than expected.

58. Therapies promoting cholesterol
efflux and RCT
PPAR alpha agonists
PPAR gamma agonists
DUAL PPAR agonists

59. • macrophage cholesterol
efflux involves the ABCA1
transporter promoting
efflux to Apo A1
• Over expression of
ABCA1 in mice leads to
significant increase in
HDL-C levels associated
with significant reduction
in atherosclerosis
• The major regulator of
ABCA1 gene expression is
the nuclear receptor liver
X receptor (LXR) and
retinoid X receptor (RXR)

60. Pleiotropic actions of balanced PPAR-α/γ agonists. FA = fatty acids; FFA = free
fatty acids. Adapted from Fiévet et al, Balakumar et al, and Charbonnel

61. PPAR alpha agonists
• Clofibrate ,Fenofibrate, Bezafibrate, Gemfibrozil
• PPAR-α is metabolically active in the liver, heart, kidney,
skeletal muscle and brown fat.
• It is also present in all vascular cells, including endothelial
cells, smooth muscle cells and monocytes/macrophages.
• The effects of PPAR-α include hypolipidemic action,an anti-inflammatory
effect on the vascular wall and metabolic
effects on the myocardium
• clinical trials of fibrates have demonstrated their beneficial
effects on cardiovascular clinical outcomes, particularly in
patients suffering with metabolic syndrome and diabetes.
• Treatment of macrophages in vitro with fibrates led to
upregulation of ABCA1 and increased cholesterol efflux

62. selective PPAR-α agonist, LY518674
• (LY5) is similar to fenofibrate but pproximately
10 000 times more potent.
• LY518674 and fenofibrate demonstrated evidence
of increasing the serum creatinine levels; this
effect was substantial in some cases.
• The novel PPAR-α agonist was not better than
fenofibrate or statin monotherapy in achieving
the intended improvement of the lipid profile,
and it appeared to worsen renal function.

63. PPAR γ agonists
• macrophages also express PPAR - gamma
• Thiazolidendiones (TZDs) , agonists of PPAR –
gamma promote macrophage cholesterol efflux in
vitro
• Potentially also through up regulation of LXR ,
ABCA1 expression
• Troglitazone (Glaxo Smith Kline) Withdrawn from
Market.
• Rosiglitazone ,Pioglitazone

64. PPAR α and γ agonist (Dual PPAR agonists)
• targeting both PPAR- alpha and PPAR- gamma
promoting more macrophage cholesterol efflux
• Muraglitazar (Bristol Mayer, Merck) first
developed , but data analysis suggested incraesed
incidence of adverse CV events
• Naveglitazar increased risk of bladder cancer
• Tesaglitazar has risk of renal dysfunction
• Aleglitazar the latest and most promising ,
SYNCHRONY study showed decreased LDL ,
decreased glucose and incrased HDL.

65. Therapies slowing removal of HDL from
blood
CETP Inhibitors
CETP Vaccine

66. CETP inhibitors
• Cholesterol ester transport protein responsible for the
exchange of cholesterol for TG in mature HDL to be
changed into LDL and VLDL

67. cholesteryl ester transfer protein (CETP)
inhibitor
dalcetrapib, torcetrapib
• Torcetrapib (from Pfizer) not only failed to show
a reduction in risk when HDL was increased, but
actually showed an increase in cardiovascular risk.
• Dalcetrapib ( from Roche) was halted in May
2012 for lack of effectiveness.
• Both of these related drugs significantly increased
HDL levels, but doing so did not result in any
demonstrated clinical benefit.

68. Anacetrapib &evacetrapib
• cholesteryl ester transfer protein (CETP) inhibitor
• Produce dose-dependent increases in HDL-C
• When administered in combination with statin
therapy, evacetrapib, increased HDL-C levels and
resulted in greater reductions in LDL-C and non-
HDL-C
• Both evacetrapib and anacetrapib give a more
dramatic HDL elevation, and a sizeable LDL
reduction .

69. CETP vaccine
• novel strategy using CETP based peptide for
IMMUNIZATION to raise inhibiting auto
antibodies against CETP ( anti CETP antibodies)
• Single injection of the CETP peptide can develop
anti CETP antibodies
• Second injection of the active vaccine develop
significant levels of anti CETP antibodies
• Interesting approach with the advantage of
avoiding the need to take a daily pill

70. Gene therapy

71. Gene therapy
• The adeno-associated virus serotype 1 (AAV1)
viral vector delivers an intact copy of the
human lipoprotein lipase (LPL) gene
• In two Phase II/III clinical trials, LPLD patients
received a series of injections into the thigh
muscle, followed by several weeks of
immunosuppressive drugs to blunt immune
responses to the viral capsids
• fat concentrations in blood were reduced
between 3 and 12 weeks after injection(IM) , in
nearly all patients

72. • advantages of AAV include
 lack of pathogenicity,
 delivery to non-dividing cells,
 non-integrating in contrast to retroviruses,
which show random insertion with risk
of cancer
 very low immunogenicity, mainly restricted to
generating neutralizing antibodies, and little
well defined cytotoxic response.

73. Alipogene tiparvovec )Glybera)
• 2012 became the first gene therapy treatment to be
approved for clinical use in either EUROPE or the
United States after its endorsement by the
European Commission, as a treatment for a disease
caused by a defect in a single gene, lipoprotein
lipase.