"Current Approach for Dyslipidaemia

Management 2019"
 Treatment of Dyslipidemia is Important..!!!
CV benefits of lipid lowering
Cholesterol Treatment Trialists’ (CTT) collaborators – Meta-analysis

Reduction of 1 mmol per liter (38.7 mg per deciliter) in LDL cholesterol

levels yields a consistent 23% reduction in the risk of major coronary

events over 5 years

N Engl J Med 2015; 372:2448-2450

 Fail to Over 50 % of diabetic dyslipidemic
Achieve
Goal
Indian not achieving the LDL-C goal
High residual risk for recurrent
cardiovascular events

Residual Atherogenic
Risk dyslipidemia

Small dense LDL particles,

Challenges of High TG, Low HDL,
dyslipidemia common in South Asians.
Increasing the statin dose management
increases the risk of side effects
Statin
Concomitan
Intoleranc t diabetes
e

Concomitant diabetes,
Food metabolic syndrome modulate
Extensive use of fatty food centric
India the impact of dyslipidemia

Indian J Endocrinol Metab. 2014 Sep-Oct; 18(5): 642–647.

Indian heart journal 66 (2014) S1 eS51
DIDAC MAURICIO Molecular nutrition and diabetes a volume in the molecular nutrition series. 2016
Am J Cardiovasc Drugs (2018) 18:157–173
LDL C, Lower is better and more…..

190 mg/dl

140 mg/dl

70 mg/dl

50 mg/dl

30 mg/dl
Lipid Association of India Guideline 2016:
Treatment Goal Guidelines recommends ; LDL C,
Lower is better
Residual Risk
Known Cardiovascular Diseases

Patients remain at high

residual risk for
recurrent cardiovascular
events for different High Intensity statin
underlying
pathophysiologic
reasons even after
statin therapy
Residual Residual Residual Residual
Cholesterol Inflammatory Triglyceride Thrombotic
Risk Risk Risk Risk

Potential Targeted Targeted Targeted Targeted

Intervention LDL Reduction Inflammation Triglyceride Antithrombotic
Reduction Reduction Reduction

Ridker, P.M. J Am Coll Cardiol. 2018

 Failure for Goal attainment even after titration of statin

Analysis of Database
Percent attainment of LDL-C (100 mg/dL)
between November 1,
2002 and September 30, % Attainment of LDL-C (100mg/dl ) after Up titration of statins
2009
80

70
Patients who titrated(n = 69 70
392,878 60 62

50
50
Titration : 40 45
Initially received statin 38
30
monotherapy then titrated
20
to either a higher dose of
the same statin or switched 10

to a higher-potency dose 0
Atorvastatin Rosuvastatin Simvastatin
of another statin, Baseline Follow up

Vascular Health and Risk Management 2013:9 719–727

Now What is next to Lower LDL C and residual risk
for Indian pattern of dyslipidaemia ?
Life Style Modification

Statins
Ezetimibe
Ezetimibe - First Line
Non-Statin Therapy
 Back to basic Endogenous and Exogenous Sources of
Cholesterol

Dietary
Exogenous
cholesterol Fecal bile acids
Intestine and neutral sterols

Biliary
cholesterol

Liver
Synthesis

Endogenous

Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New
York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart
J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.
Ezetimibe blocks the absorption of dietary and biliary cholesterol

NPC1L1

NPC1L1
 Statin + Ezetimibe MOA


Target two sources of Ezetimibe
Statin
cholesterol • Action on small intestine :
• Action on Liver: HMG CoA Inhibits the dietary cholesterol
reductase inhibition leads simultaneously with a absorption
to reduced cholesterol • Increased expression of LDL
synthesis from liver complementary receptors and thereby enhance
LDL clearance
mechanism of action


Dual inhibition of both sources of cholesterol provides significantly greater LDL-C
reduction and subsequent goal attainment
 Rosuvastatin & Ezetimibe for Hypercholestelolemia (I-ROSETTE study)

The mean percent change in LDL-C level in Rosuvastatin

92.3% patients achieved LDL-C goal
+ Ezetimibe combination groups was - 57%

% Change in LDL-C, TG, TC and HDL-C % of patients with LDL-C goal

13.6
11.3
achievement at week 8

LDL C TC TG HDL C
-11.9 92.3
-19.2

-30.2
-38.8
-44.4
79.9
-57
• N= 396
patients
• Duration - 8
Rosuvastatin + Ezetimibe Rosuvastatin weeks
Rosuvastatin + Ezetimibe Rosuvastatin

Rosuvastatin + ezetimibe combinations significantly improved lipid profiles in patients with hypercholesterolemia
compared with rosuvastatin monotherapy.
Clinical Therapeutics/Volume40,Number2,2018
 Greater LDL-C
Greater LDL-C reduction with Rosuvastatin 10 + Ezetimibe 10 reduction with
Rosuvastatin 10 +
Ezetimibe 10 vs
titrated dose of
other Statin + Greater LDL-C
Estimated % LDL-C reduction Ezetimibe reduction with
combination Rosuvastatin 10 +
Ezetimibe 10 vs
Rosuvastatin 10 +Ezetimibe 10 61 titrated dose of Statin
monotherapy
60
Rosuvastatin 40

54
Rosuvastatin 20

56
Atorvastatin 40 + Ezetimibe 10

54
Atorvastatin 20 + Ezetimibe 10

55
Atorvastatin 80

50
Atorvastatin 40

44
Atorvastatin 20
0 10 20 30 40 50 60 70

Vascular Health and Risk Management 2013:9 US administrative managed-care database, (n = 17,830, retrospective, observational study
Who can be benefitted from Statin + Ezetimibe
• 52 year old patient of severe primary
hypercholesterolemia
• No Hypertensive
• No diabetes
• on statin, but not able to achieve LDL c goal

LDL : 156 mg/dl

HDL : 38 mg/dl,
BP : 128/ 80 mm of Hg

ACC/ AHA 2018 Lipid Guideline recommendation

 Who can be benefitted from Statin +
Ezetimibe

• 40 year old patient with heterozygous FH on

statin monotherapy therapy

• A total of 635 patients with premature CAD Total C ; 190 mg/dl

LDL : 130 mg/dl
were assessed for FH using the Dutch Lipid
BP : 138 / 84mm of Hg
Clinical Network (DLCN) criteria

• High prevalence of heterozygous

FH in premature CAD ~ 15% in ACC/ AHA 2018 Lipid Guideline recommendation
Ezetimibe plus a moderate-intensity statin is associated with
north India greater LDL-C reduction than statin monotherapy
 Primary Prevention Adults 40 to 75 Years of Age With
LDL-C Levels 70 to 189 mg/dL

• In intermediate-risk adults who would benefit from more aggressive

LDL-C lowering and in whom high-intensity statins are advisable but not
acceptable or tolerated, it may be reasonable to add a nonstatin drug
(ezetimibe or bile acid sequestrant) to a moderate-intensity statin

ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol, Journal of the American College of Cardiology (2018),
 Effects of glucose on NPC1L1 expression
Higher expression of the NPC1L1 in in intestinal epithelial cells.
Diabetes

• In diabetes higher expression of the NPC1L1 gene,

which facilitates the cholesterol absorption in the
small intestine

• NPC1L1 expression is increased in diabetic patients

and in animal models of diabetes mellitus. • The depletion of glucose or fasting in mice decreases
the expression and the promoter activity of NPC1L1.
• NPC1L1 appears to be a prime target for • The replenishment of glucose after depletion
stimulates NPC1L1 promoter activity in protein
therapeutic intervention to lower plasma phosphatase-dependent pathway.

EZITIMIBE acts
cholesterol in in NPC1L1
high-risk andasinhibits
patients such patients the cholesterol
• The increase inabsorption inresults
the promoter activity intestine
in an
increase in NPC1L1 mRNA and protein expression as
with diabetes mellitus
DIDAC MAURICIO Molecular nutrition and diabetes a volume in the molecular nutrition series. 2016
well as cholesterol uptake
 Who can be benefitted from Statin +
Ezetimibe
Age-Standardized, State-Level Prevalence of Diabetes and
Hypertension by Rural vs Urban Location Within Each State • 58 year old patient with known case of T2DM,
• Hypertensive
• Has quit smoking 3 years back
• on Rosuvastatin 10, Telmisartan 40 and
Metformin + Glimepiride

Total C ; 220 mg/dl ,

HDL : 38 mg/dl, LDL : 130 mg/dl
BP : 142/ 84 mm of Hg

• Prevalence of diabetes and hypertension in India are ACC/ AHA 2018 Lipid Guideline recommendation
high across all geographical settings and
socioeconomic groups in middle and old age.

• The crude prevalence of diabetes 7.5%

JAMA Intern Med. doi:10.1001/jamainternmed.2017.8094
Contributors to cardiovascular risk

Inflammatory markers of importance;

Infammation • Hs-CRP,
• Interlukin 6,
• Lipoprotein‑associated phospholipase A2
(Lp‑PLA2)

Lipids Cardiovascular Hemostasis

Diabetes Risk Thrombosis

Behavioral Genetic
Factors Factors
hs-CRP is a stronger marker for prediction of
cardiovascular disease
Comparisons of hs-CRP to other lipid parameters and
nonlipid risk factors for cardiovascular disease

Levels of • 60% greater risk of future

hsCRP >3 cardiovascular events
• 3.6% annual event rate
mg/L (3.6per 100 person-years)
associate even after accounting for
d with on-treatment LDL-C.

Inflammation modulation may offer additional opportunities

for cardiovascular risk reduction.
Circulation. 2018;138:141–149 Current Vascular Pharmacology, 2011, Vol. 9, No. 1 103
Clinical interpretation of hsCRP for cardiovascular risk prediction
 Ezetimibe Attenuates Inflammation
Ezetimibe reduces CRP levels in 887 Ezetimibe suppressed macrophage
patients with hypercholesterolemia accumulation in atherosclerotic
lesions

Multicenter Preclinical
double-blind, study :
placebo- macrophage
controlled, contents in
factorial study. lesions of
for 12 weeks. the mice

Current Vascular Pharmacology, 2011, Vol. 9, No. 1 103 PLOS ONE 10(11): e0142430. 2015
 Reduction in Inflammatory marker
135 patients of acute myocardial infarction (AMI). 106 patients with coronary atherosclerotic
heart disease and hyperlipidaemia

Changes in Interlukin 6

272

116 112

Interlukin 6
Baseline 6 Month 12 Month In Rosuvastatin + Ezetimibe

Combination of Rosuvastatin + Ezetimibe decreased hsCRP, IL-6, levels at six and

12 months after treatment
Heart, Lung and Circulation (2016) 25, 459–465 Ren Y et al Experimental and therapeutic medicine 14: 4942-4950, 2017
Heart, Lung and Circulation (2016) 25, 459–465
Lipoprotein‑associated phospholipase A2
(Lp‑PLA2)
• Lipoprotein‑associated phospholipase A2 (Lp‑PLA2) is excreted
predominantly from atherosclerotic plaques by macrophages and
neutrophils and subsequently circulates in the blood stream

• It has been demonstrated that Lp‑PLA2 is a potentially important

pathogenic factor participating in the progression of atherosclerosis

• Lp‑PLA2 is indicated to be positively correlated with an increased risk of

coronary artery disease and stroke
EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 4942-4950, 2017
 Reductions in Lp‑PLA2 were observed to be significantly greater with
Rosuvastatin + Ezetimibe compared with monotherapy

Net changes from baseline to 12 months in

Lp‑PLA2 for prespecified subgroups.

*P<0.05 vs. corresponding baseline levels; &P<0.05 vs. R10 group.

EXPERIMENTAL AND THERAPEUTIC MEDICINE 14: 4942-4950, 2017
 • The study group comprised 106 patients with coronary atherosclerotic heart disease and hyperlipidaemia.
• Two groups: (1) Ezetimibe (10 mg, once a night) plus rosuvastatin (10 mg, once a night) (n = 55) or (2)
Rosuvastatin alone (10 mg, once a night) (n = 51).

Ezetimibe and rosuvastatin reduces plaque burden and improves plaque stability, which is associated with
the potent inhibitory effects of ezetimibe and rosuvastatin on inflammatory cytokines
Heart, Lung and Circulation (2016) 25, 459–465
 Effect on Plaque
Intravascular ultrasonography Image IVUS Image after combined treatment
(IVUS) before combined treatment with with ezetimibe + rosuvastatin
At 12 months, ezetimibe + rosuvastatin.

significant reduction in

• Plaque burden
• Percentage of
necrotic plaque
composition

Heart, Lung and Circulation (2016) 25, 459–465

A significant
reduction in plaque
area and increase in
lumen area
were observed after
6 months. EZT/RSV
combination

Int Heart J 2015; 56: 278-285)

 IMPROVE-IT
CV Death, Non-fatal MI, or Non-fatal Stroke Reduction with
EZ/statin combination
• 18,144 patients who had been HR 0.90 CI (0.84, 0.97)
hospitalized for an acute p=0.003
Statin — 22.2%
coronary syndrome NNT= 56
1704 events

• Simvastatin40–ezetimibe 10) Vs
Simvastatin 40 monotherapy).

The combination of simvastatin EZ/Statin — 20.4%

1544 events
and ezetimibe also resulted in a
significantly lower risk of
7-year event rates
cardiovascular events than that
with statin monotherapy,

N Engl J Med 2015;372:2387-97.

Who can be benefitted from Statin + Ezetimibe

• 52 year old patient • 68 year old patient

• Underwent PCI 9 months before • Suffered with ischemic stroke 1 year
• Hypertensive and Diabetes since 5 years back
• Smoker
• on statin, but not able to achieve LDL goal Very High-Risk • Hypertensive and Diabetes since 8
of Future ASCVD years
Events • on statin, but not able to achieve LDL
goal
LDL : 90 mg/dl
HDL : 38 mg/dl, LDL : 94 mg/dl
BP : 128/ 80 mm of Hg HDL : 40 mg/dl,
BP : 138/ 80 mm of Hg

ACC/ AHA 2018 Lipid Guideline recommendation

At very high risk and have an LDL-C level of 70 mg/dL or higher, it is
reasonable to add ezetimibe therapy
 Who can be benefitted from
Very High-Risk* of Future ASCVD Events Statin + Ezetimibe
Very high risk includes a history of multiple major ASCVD events ACC/ AHA 2018
or 1 major ASCVD event and multiple high-risk conditions Lipid Guideline
recommends

• Recent ACS
• History of MI In very high-risk ASCVD patients, it is reasonable to add
Major ASCVD • History of ischemic stroke ezetimibe to maximally tolerated statin therapy when
Events • Symptomatic peripheral arterial disease (history of the LDL-C level remains ≥70 mg/dL.
claudication with ABI <0.85, or previous revascularization
or Amputation

• Age ≥65 y
• Heterozygous familial hypercholesterolemia Moderate-intensity statin therapy should be initiated or
• History of prior coronary artery bypass surgery or continued in patients with statin associated side effect
High-Risk percutaneous coronary intervention outside of the major
Conditions • ASCVD event(s)
• Diabetes mellitus, Hypertension , CKD
• Current smoking Moderate-intensity statin + ezetimibe could potentially
• History of congestive HF produce a level of ASCVD risk reduction similar to that
produced by high-intensity therapy alone.

ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol, Journal of the American College of Cardiology (2018),
Ezetimibe + Statin vs PCSK9i
Recommendations ~ Per month cost of therapy

Add Ezetimibe First,

If LDL C not under Ezetimibe + Statin -
control then PCSK9I Cost Effective
 Who can be benefitted from Statin + Ezetimibe
ACC/ AHA 2018 Lipid Guideline recommends

Primary Prevention: In
In heterozygous FH
In CKD with 10-year intermediate-risk adults
In severe primary Ezetimibe plus a In diabetes mellitus and
ASCVD risk of 7.5% or in whom high-intensity
hypercholesterolemia moderate-intensity 10-year ASCVD risk of
higher*, initiation of statins not acceptable or
when LDL-C level remains statin is associated with 20% or higher, it may be
moderate-intensity tolerated, it may be
≥100 mg/dL adding greater LDL-C reduction reasonable to add
statins combined with reasonable to add
ezetimibe+ is reasonable. than is statin ezetimibe +
ezetimibe can be useful ezetimibe to a moderate-
monotherapy
intensity statin

*CKD not treated with dialysis or kidney transplantation ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol,
Journal of the American College of Cardiology (2018),
+ to maximally tolerated statin therapy
 Meet the unmet need in dyslipidaemia management:

Rosuvastatin 10 + Ezetimibe 10

Ezetimibe - First Line Dual inhibition of both Addition reduction in

Reduces plaque burden
Non-Statin Therapy sources of cholesterol LDL

Greater reduction of
LDL C than up titration Recommended by
Improves plaque
Decreased hsCRP, IL-6, of other statin Global lipid and
stability
monotherapy and Diabetes guidelines
combination therapy