Dyslipidemia Management: An Evidence Based Approach

Types of Plasma Lipids

2013 ACC/AHA Guidelines: Statins without any lipid

“goals”

Circulation 2014; 129: S1-S45

• 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

Circulation. 2014;129[suppl 2]:S1-S45

LAI 2016 Statement: Both LDL-C/Non-HDL-C goals are important in Indian context

Journal of The Association of Physicians of India March 2016 supplement

2014 Indian Consensus statement also mentions LDL and Non-HDL-C goals

I n d i a n Hea rt Journal 6 6 ( 2 0 1 4 ) S 1-S 5 1

Clinical Conditions where Lipid Lowering therapy required

1. Patients with ASCVD2. Patients undergoing PCI3. Primary prevention of CVD for DM/HT4. Primary prevention of CVD for high hsCRP (> 2 mg/dl) 5. For patients with CKD6. For patients with very high LDL-C (> 190 mg/dl)7. Atherogenic (Mixed) Dyslipidemia with T2DM8. Atherogenic (Mixed) Dyslipidemia without T2DM9. Patients with IGT and High CV risk10. Patients with statin intolerance

1. Patients with ASCVDStatin for secondary prevention

• Current guidelines recommend moderate to high dose of statins for secondary prevention.

• Atorvastatin has multiple landmark trials for secondary prevention

TNT: High Vs Low Dose statin in Stable CAD

22% risk reduction by 80 mg Vs 10 mg atorvastatinp<0.001

Waters DD et al. N Engl J Med 2005;352:1425-35Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD),

nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke

High dose statin is more effective for CV protection in stable IHD patients

CV events in PROVE IT study

Cannon et al. NEJM 2004 Ray et al. Am J Cardiol 2006

Death/MACEDeath/MI/Urg. Revascu.

↓33%↓16%

Intensive statin Rx provides more benefits than moderate statin Rx

SATURN: CV events At 2 yrs

No difference between Rosuvastatin 40 mg and Atorvastatin 80 mg on CV events in CAD patients

N Engl J Med 2011;365:2078-87

2. Patients undergoing PCILoading High dose statin before PCI in ACS

reduces CV events: ARMYDA-ACS

%

5

17

P=0.01

JACC 2007:49:1272-78

171 NSTEACS patients randomized to atorvastatin (80 mg 12 h before PCI, with a further 40-mg pre-PCI or placebo. All patients received long-term atorvastatin thereafter (40 mg/day). Primary end point : 30-day incidence of MACE(death, myocardial infarction, or unplanned revascularization)

ARMYDA-RECAPTURE: loading 80 mg atorvastatin pre-PCI in those on statin already also reduces CV events

0

3

6

9

12

3.4

9.1

P=0.045

MA

CE

( %)

PlaceboAtorvastatin

JACC 2009:54:558-65

383 patients with stable angina (53%) or NSTMI(47%) and chronic statin therapy undergoing PCI were randomized to atorvastatin reload (80 mg 12 h before PCI , + 40-mg pre-PCI) or placebo. All patients received long-term atorvastatin thereafter (40 mg/day). Primary end point : 30-day MACE (cardiac death, myocardial infarction, or unplanned revascularization)

Atorvastatin Placebo0

4

8

12

5

13

Chart TitleP=0.046

Incidence of Contrast-Induced Nephropathy

CIN: Contrast induced Nephropathy Am J Cardiol, 2011;108:1-7

80 mg Atorvastatin before PCI reduces CINAnd inflammation: ARMYDA-CIN

241 Statin-naive ACS patients undergoing PCI randomised to atorvastatin (80 mg 12 hours before PCI, 40-mg preprocedure dose) or placebo. All patients had long-term atorvastatin thereafter (40 mg/day). Primary end point: incidence of CIN [post-intervention increase in serum creatinine >0.5 mg/dl or >25% from baseline].

Post-PCI peak CRP levels

Rosuvastatin loading in ACS

Loading dose of rosuvastatin: 40mgAll the patients received rosuvastatin 10mg/d after PCI

Primary endpoints:periprocedural MI as per CK-MB > 2 times

International Journal of Cardiology 146 (2011) 68–72

Rosuvastatin loading in ACSResults: MACE at 12 months

* P= 0.002 vs. control

Control Rosuvastatin0

5

10

15

20

2520.5

9.8*

Control Rosuvastatin

High dose rosuvastatin loading before PCI significantly improved 12-month clinical outcomes in ACS patients

undergoing PCI

International Journal of Cardiology 146 (2011) 68–72

Study Patients Follow up Results

ASCOT LLA * 2532 Atorvastatin 10 mg

3.3 yrs 23% risk reduction

CARDS 2838 Atorvastatin 10 mg

3.9 yrs 37% risk reduction

HPS * 2912 Simvastatin 40 mg

5 yrs 33% risk reduction

3. Primary prevention of CVD for DM/HTMajor Statin Primary Prevention Trials In DM

* sub-analysis

CARDS: Statin For Primary Prevention In T2DM

*Acute CHD event, coronary revascularization, stroke. RRR: Relative risk reduction

Colhoun HM et al. Lancet. 2004;364:685-696.

0

5

10

15

0 1 2 3 4 5 6

RRR=37% p=0.001

Cum

ulati

ve in

cide

nce

of e

vent

s (%

of p

atien

ts)

127 events

83 events

Time (years)

Atorvastatin 10 mg (n=1428)Placebo (n=1410)

median follow-up 3.9 years

VOYAGER Meta analysis in DM patientsEffect of statins on LDL-C 37 trials, > 32,000 patients

Rosuvastatin reduced LDL-C better than atorvastatin and simvastatin in DM patients

Nutrition, Metabolism & Cardiovascular Diseases (2012) 22, 697-703

HOPE-3: Primary Prevention with Rosuvastatin ACC-Chicago, 2nd April 2016

• 12,705 patients (without CVD + intermediate CV risk) randomised to rosuvastatin 10 mg/day or placebo.

• 1st coprimary outcome : Composite of CVD death, nonfatal myocardial infarction, or nonfatal stroke

• 2nd coprimary outcome: 1st coprimary outcome + revascularization, heart failure, and resuscitated cardiac arrest.

• CV Risk Feature: 87% Obese/overweight, 38% HT, 18% T2DM/IGT, 27% Smokers

• The median follow-up : 5.6 years.

This article was published on April 2, 2016, at NEJM.org.DOI: 10.1056/NEJMoa1600176

HOPE-3 Lipid Lowering CV Outcomes

Outcome Rosuvastatin N (%)

PlaceboN (%)

HR (95% CI) RRR % p

Co-Primary 1 235 (3.7) 304 (4.8) 0.76 (0.64-0.91) 24 0.002

Co-Primary 2 277 (4.4) 363 (5.7) 0.75 (0.64-0.88) 25 0.0004

CV Death 154 (2.4) 171 (2.7) 0.89 (0.72-1.11) 0.31

MI 45 (0.7) 69 (1.1) 0.65 (0.44-0.94) 35 0.02

Stroke 70 (1.1) 99 (1.6) 0.70 (0.52-0.95) 30 0.02

22This article was published on April 2, 2016, at NEJM.org.DOI: 10.1056/NEJMoa1600176

Rosuvastatin 20 mg (N=8901) MIStroke

Unstable Angina

CVD DeathCABG/PTCA

4-week run-in

Ridker PM et al, Circulation 2003;108:2292-2297

No Prior CVD or DMMen >50, Women >60

LDL <130 mg/dL hsCRP >2 mg/L

Placebo (N=8901)

Follow up: 1.9 yrs

4. Primary prevention of CVD for high hsCRP (> 2 mg/dl)

JUPITER study

Placebo 251 / 8901

Rosuvastatin 142 / 8901

Risk Reduction: 44 %

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulati

ve In

cide

nce

Follow-up (years)

Ridker PM et al, N Engl J Med 2008;359:2195-207

JUPITER : Primary Trial Endpoint

In patients with high hs-CRP (>2 mg/dl), rosuvastatin significantly reduces CV events by 44%

Rosuvastatin is the only statin approved by US FDA for primary prevention of CVD in patients with hsCRP > 2 mg/dl

• A sub analysis to evaluate CV benefits in patients who achieved LDL-C< 50mg/dl with rosuvastatin (n= 4154) Vs those on placebo

• Following benefits were seen those with LDL-C< 50 mg/dl vs those on placebo

JUPITER : LDL < 50 mg/dl Provides Maximum CV Protection

65% Risk reduction in Primary End Point

46% Risk reduction in All Cause Mortality

J Am Coll Cardiol 2011;57:1666–75

5. For patients with CKDDose of statins in patients with CKD

• Atorvastatin: No dose adjustment required• Rosuvastatin: In patients severe CKD with creatinine

clearance < 30 ml/min (not on hemodialysis), Maximum dose: 10 mg/day

• Pitavastatin: in patients with moderate/severe CKD (GFR: 15-59 ml/min) Maximum dose: 2 mg/day,

GFR: Glomerular Filtration Rate

• A meta-analysis of 5 clinical trials head to head comparing atorvastatin vs rosuvastatin

Atorvastatin Vs Rosuvastatin For Proteinuria: A Meta-analysis

Atorvastatin is better than rosuvastatin for reduction in proteinuria

Circ J 2012;76:1259-66

Effect of pitavastatin on eGFR in CKD patients eGFR<60

ml/min/1.73m2

J Atheroscler Thromb 2010;17:601-609

0 1 2 3 4 5 60

2

4

6

8

10

12

Pravastatin Placebo

Years in Study

Percentwith

Events

6. For patients with very high LDL-C (> 190 mg/dl)

WOSCOPS Study31% RiskReduction

P=0.0001

Shepherd J, et al, N Engl J Med 1995;333:1301-7

Statin therapy can reduce CV events in those without CVD and LDL-C > 190 mg/dl

WOSCOPS 20 years Legacy benefits of statin therapy-AHA 2014

Statin therapy has long term legacy effects in those with LDL-C > 190 mg/dl

Lipid Lowering with Various statins : VOYAGER Meta analysis-37 trials, > 32,000 patients

Am J Cardiol 2010;105:69 –76

Rosuvastatin is most effective for Lowering LDL-C and Non-HDL-C

7. Atherogenic (Mixed) Dyslipidemia with T2DMResidual CV risk: after using High dose statin

RRR=22% P=0.001

78% residual risk

TNT study

N Engl J Med 2005;352:1425-35

Non HDL-C : Responsible for Residual CV risk

Meta-analysis of 62154 patients data enrolled in 8 statin

trials (1994-2008)

JAMA. 2012;307(12):1302-1309Among statin-treated patients, non HDL-C is associated with risk of future major CV events,

Drug therapy for Non-HDL-C

As mentioned, in a patient on optimal statin therapy, TG lowering therapy is preferred for non-HDL-C reduction• Saroglitazar (Dual PPAR agonist)- For T2DM• Fibrates• Ezetimibe

Diabetes. 2005 Aug;54(8):2460-70

Saroglitazar – Mechanism of actionPPAR α action – reduces TG and non HDLPPAR γ action – improves insulin sensitivity

Effect of Saroglitazar 4 mg on TG and Non-HDL-C

Baseline 3 months Baseline 3 months0

50

100

150

200

250

300

350TG (mg/dL) Non-HDL-C (mg/dL)

312.3

188.7*

201.8

149.4*

- 35.8%

- 23.4%

* p-value < 0.0001

Indian Heart Journal 167 (2015) 23-26

2804 diabetic dyslipidemia patients treated with 4 mg saroglitazar and followed up for 3 months

Effect of Saroglitazar 4 mg on HbA1c after 3 months

Baseline 3 months6.8

77.27.47.67.8

88.28.4 8.3

7.4

HbA1c ( %)

- 0.9%

* p-value < 0.0001

Indian Heart Journal 167 (2015) 23-26

Saroglitazar 2016 Study

• The study was done to evaluate the effect of saroglitazar 4 mg OD in 108 diabetic dyslipidemia patients for 3 months

• mean duration of diabetes 5.65 years, mean age 51 years, mean body weight : 71.2 kg mean BMI: 26.8 kg/m2.

• Mean HbA1c value: 8.4 % , Mean TG : 322.3 mg/dl • saroglitazar 4 mg led to reduction of

– TG (34.7 %), total Cholesterol (18%), LDL-C (16.8 %) and non-HDL (22.8%).

– HbA1c reduction : 0.8%

INTERNATIONAL JOURNAL OF SCIENTIFIC RESEARCH 2016;5(4): 344-346

Saroglitazar vs. Fibrates in the management of high TG?

Saroglitazar FibrateEffect on blood Glucose

Reduction (PPAR γ agonist action)

No effect

Use with statin No specific adverse event Increased risk of myopathy

Liver enzymes decreases Increases

May be preferred in T2DM patients with hypertriglyceridemia

May be preferred in hypertriglyceridemia without T2DM

8. Atherogenic (Mixed) Dyslipidemia without T2DMMeta-analysis: in 6632 patients with highTG (> 200

mg/dl),

Cardiovasc Pharmacol 2011;57:267–272

fibrates reduced CV risk by 28% in patients with atherogenic dyslipidemia

Choline fenofibrate

Only fenofibrate that do not require activation from the liver Only fenofibrate with predictable bioavailability (81%) Dose is 135 mg/day, lower than micronized and nanoparticle

fenofibrate Can be taken with or without food

Long term choline fenofibrate + statin well tolerated

93% patients completed 116 wks study The combination resulted in sustained improvement in

HDL-C (+17.4%), TG (−46.4%) and LDL-C (−40.4%). No deaths/treatment-related serious adverse events Discontinuation due to adverse events was 2.9%. Rhabdomyolysis was not reported in any group. Conclusion: choline fenofibrate is safe for combination

with statin (moderate dose) for long term use

Clinical Drug Investigation 2010;30(1): 51-61

Indian Study of Choline Fenofibrate200 patients treated with 135 mg choline fenofibrate or 160 mg

fenofibrate for 12 weeks

Journal of The Association of Physicians of India August 2015;63:25-31

TG VLDL-C HDL-C LDL-C

-50

-40

-30

-20

-10

0

10

20

30

-37.9 -38

25.3

-7.8

-31.9 -31.8

20.9

-5.4

Choline Fenofibrate 135 mgFenofibrate 160 mg

% C

hang

eCholine fenofibrate is as effective as conventional fenofibrate for dyslipidemia in Indians

Indian Consensus statement on management of dyslipidemia

• Fibrates are considered first-line therapy for severe hypertriglyceridemia while as an adjunct to statins, they are a therapeutic option for combined dyslipidemia

• Choline salt of fenofibric acid does not have problems of erratic pharmacokinetics.

• It has good (~81%) and predictable bioavailability and can be taken regardless of meals.

• It is only preparation of fenofibric acid recommended for use at present.

Indian Heart Journal , 10 December 2014 dx.doi.org/10.1016/j.ihj.2014.12.001

13 statins trials included, 91140 participants.

Statins therapy is associated with 9% increase in the risk of new diabetes.

Conclusion: Statin therapy is associated with a slightly increased risk of development of diabetes

Lancet 2010;375:735-42

9.Patients with IGT and High CV risk

LIVES study: Pitavastatin does not disturb blood glucose in T2DM

patients over 2 years

Expert Opin Pharmacother. 2010;11(5):817–828.

Pitavastatin does not increase FPG and HbA1c in T2DM patients even in long term therapy (upto 2 years)

Pitavastatin is a good option for long term treatment in T2DM patients

Only large scale prospective study done to evaluate effect of statin therapy on new onset DM in IGT (impaired glucose tolerance) patients

1,269 IGT patients were randomized to lifestyle changes + pitavastatin or control (lifestyle changes only)

Patients are followed upto > 5 years

Primary End Point: % patients developing New onset DM

ADA 2013, Late breaking abstract No. 61-LB

J PREDICT: Effect of Pitavastatin on NOD in IGT patients

18%

Pitavastatin significantly reduces the new onset of DM by 18% in IGT patients

Pitavastatin prevents new onset DM in Acute MI patients

Conclusion – Pitavastatin did not increase the NODM development in AMI patients compared with placebo, rosuvastatin or atorvastatin. Presented in ACC-2016 conference

• In Florida, USA, 152 patients intolerant to > 2 previous statins due to myopathy (average 2.7 statins) were placed on pitavastatin therapy.

• Percentage (%) of patients tolerating pitavastatin and achieving NCEP ATP-III LDL-C goal non-HDL-C goal were measured

• 104 patients (76%) patients tolerated pitavastatin therapy and continued it for > 6 months

• 87% of patients with intermediate CV risk achieved their NCEP-ATP III LDL-C goals with pitavastatin therapy

10. Patients with statin intolerancePitavastatin For Statin Intolerant Patients

Journal of Clinical Lipidology 2012: 6(3) : 274

Pitavastatin is a good option fore those who cannot tolerate other statins

Minimum rise in CK enzymes with Pitavastatin

Adverse events

Pitavastatin Atorvastatin Rosuvastatin

CK elevation

1.41 2.19 2.29

Incidence of adverse effects (%)

Drug Design, Development and Therapy 2011:5 283–297

Pitavastatin-lesser incidence of CK elevation: Better tolerance?

Pitavastatin: Less change in CoQ10 levels

An open, randomized, four-phased crossover study using 4 mg of pitavastatin or 20 mg of atorvastatin was performed to compare their efficacy and safety, especially regarding plasma levels of coenzyme Q10 (CoQ10).

Results:Atorvastatin Pitavastatin

-26.1%

-7.7%

*

* P = 0.0007 vs. baseline

Change in plasma CoQ10 from baseline (%)

Clin Pharmacol Ther. 2008 May;83(5):731-9

Pitavastatin-lesser Change in Co-enzyme-Q10 : Better tolerance?

Take Home MessagePatient’s Profile Preferred OptionPatients with ASCVD Atorvastatin/Rosuvastatin?Patients undergoing PCI Atorvastatin/RosuvastatinPrimary prevention of CVD for DM/HT Atorvastatin/RosuvastatinPrimary prevention of CVD for hsCRP (> 2 mg/dl) Rosuvastatin

For patients with CKD Atorvastatin/PitavastatinFor patients with very high LDL-C (> 190 mg/dl) RosuvastatinAtherogenic (Mixed) Dyslipidemia with T2DM statin+ SaroglitazarAtherogenic (Mixed) Dyslipidemia without T2DM statin + FenofibratePatients with IGT and High CV risk PitavastatinPatients with statin intolerance Pitavastatin