dyslipidemia management an evidence based approach

Dr Vivek BaligaConsultant Internal Medicine

Director, HeartSenseTM

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

Clinical Conditions where Lipid Lowering therapy requiredA. Patients with ASCVDB. Patients undergoing PCIC. Primary prevention of CVD for DMD. Patients with low HDL-CE. For patients with CKDF. For patients with very high LDL-C (> 190

mg/dl)G. Patients with IGT and High CV riskH. Patients with statin intoleranceI. Residual risk with statin therapy:

a. Atherogenic (Mixed) Dyslipidemia with T2DMb. Atherogenic (Mixed) Dyslipidemia without T2DM

Statin For Secondary PreventionCurrent guidelines recommend moderate to high

dose of statins for secondary prevention.Atorvastatin has multiple landmark trials for

secondary prevention

Amongst all statins, Atorvastatin has robust evidence for secondary prevention of ASCVD

Higher dose atorvastatin has shown incremental benefits over and above those expected with lower dose statins

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;352:1425-35

Primary 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

PROVE IT trial randomly assigned 4,162 patients who had been hospitalized within the previous 10 days for ACS to receive pravastatin 40 mg vs intensive regimen of 80 mg atorvastatin.

NAME: REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering With Pitavastatin in CAD)

Objective To evaluate CVD prevention by moderate cholesterol lowering (pitavastatin 1mg/day) or aggressive cholesterol lowering pitavastatin 4mg/day in patients with stable CAD

Design Randomized, multicentric, Intervention, Parallel, Open Label, Prevention

No of Patients/ follow up

12,600 (3-6 years)

Inclusion criteria Age: 20-80 years, Stable CAD (with/without ACS, PCI, CABG in past)

Intervention Pitavastatin 1 mg daily Vs Pitavastatin 4 mg daily

Primary Outcome

Composite of: CV death, Non-fatal MI, Non-fatal Cerebral Infarction (CI), Unstable angina requiring urgent hospitalization)

Expected Time of completion

March 2017

Pitavastatin in Secondary Prevention : Ongoing Study

Clinical Conditions where Lipid Lowering therapy required

A. Patients with ASCVDB. Patients undergoing PCIC. Primary prevention of CVD for DMD. Patients with low HDL-CE. For patients with CKDF. For patients with very high LDL-C (> 190

Loading High dose statin before PCI in ACS reduces CV events: ARMYDA-ACS

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)

Among patients with ACS undergoing PCI, pretreatment with atorvastatin 80 mg improves clinical outcomes, driven mainly by reduction in periprocedural MI

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

P=0.045

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)

Reloading with high-dose atorvastatin resulted in 50% reduced risk of MACE at 30 days versus placebo

These findings support strategy of routine reload with high-dose atorvastatin early before intervention even in the background of chronic therapy.

Clinical Conditions where Lipid Lowering therapy required

A. Patients with ASCVDB. Patients undergoing PCIC. Primary prevention of CVD for DMD. Patients with low HDL-CE. For patients with CKDF. For patients with very high LDL-C (> 190 mg/dl)G. Patients with IGT and High CV riskH. Patients with statin intoleranceI. Residual risk with statin therapy:

Major Statin Primary Prevention Trials

Study Patients

Cohort Follow up

Results

ASCOT LLA *

2532 HT Atorvastatin 10 mg

3.3 yrs 23% risk reduction

CARDS 2838 DM Atorvastatin 10 mg

3.9 yrs 37% risk reduction

HPS * 2912 DM Simvastatin 40 mg

5 yrs 33% risk reduction

* sub-analysis

CARDS: Statin For Primary Prevention In T2DM (2838 patients)

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

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

0 1 2 3 4 5 6

RRR=37% RRR=37% pp=0.001=0.001

127 events

83 events

Time (years)Time (years)

Atorvastatin 10 mg (LDL 119) (n=1428)Atorvastatin 10 mg (LDL 119) (n=1428)Placebo (LDL 118) (n=1410)Placebo (LDL 118) (n=1410)

median follow-up 3.9 yearsmedian follow-up 3.9 yearsAtorvastatin 10 mg daily is safe and efficacious in reducing risk of first cardiovascular disease events, including stroke, in patients with T2DM without high LDL-C. The level of LDL should not dictate statin use.

Collaborative Atorvastatin Diabetes Study – Performed in patients without CVD

28th Feb 2012: FDA Drug Safety Communication:

Important safety label changes to cholesterol-lowering statin drugs Increases in HbA1c and fasting serum glucose

levels have been reported with statin use

www.fda.gov

EFFECT ON BLOOD GLUCOSE LEVELS

A 2016 analysis estimated that high-dose statin therapy (eg, atorvastatin 40 mg daily) would lead to 50 to 100 new cases of diabetes in 10,000 treated individuals.

Effect on Blood Sugar LevelsStatins could have effects on glucose

metabolism that might influence the development of diabetes mellitus in non-diabetics or affect glycemic control in patients with existing diabetes.

A 2011 meta-analysis of five randomized trials (N = 32,752) also found an increased risk of incident diabetes with intensive statin therapy compared with moderate statin therapy

Consider risk Vs benefit

Pitavastatin in T2DM:No glycemic disturbances

T2DM patients were treated by Atorvastatin 10 mg (n=99), pravastatin 10 mg (n=85) and pitavastatin 2 mg (n=95) for 3 months.

J Atheroscler Thromb. 2008;15(5):269–275

Pitavastatin does not increase FPG and HbA1c in T2DM patients unlike

Atorvastatin

LIVES study: 2 years of Pitavastatin in T2DM

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

B. Effect on HDL-CLIVES : Pitavastatin increases HDL-C upto 32.4%^

Effects of pitavastatin on HDL-cholesterol in the LIVES study according to the previous use of statins. *p < 0.05; **p < 0.01; ***p < 0.001 (vs baseline, one-sample t-test).

^ in patients with low HDL-CExpert Opin. Pharmacother. 2012;13(6): 859–865

Pitavastatin's ability to significantly and continually increase HDL-C levels over time suggests a particular benefit for patients with low baseline levels of HDL-C and/or those that fail to increase their HDL-C levels

using alternative statins.

Shifting from other statins to Pitavastatin further increases HDL-C

129 dyslipidemia patients (already on statin for 3 months were crossed over to other statins for 3 months

↑ 7.7% (p< 0.05)

↓5.5% (p< 0.05)

↑ 7.5% (p< 0.05)

↓2.9.%

Dose of statins in patients with CKDAtorvastatin: No dose adjustment requiredRosuvastatin: 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

Atorvastatin Vs Rosuvastatin For Proteinuria: A Meta-analysis

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

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

Pitavastatin 2 mg provides nephroprotective effects in CKD patients (eGFR 15-59 ml/min)

Effect of Pitavastatin on proteinuria

* P <0.01 Vs Control Diabetes Care 2005;28:2728–2732

20 T2DM patients were treated with pitavastatin or placebo for 12 months

Even at 1 mg/day dosage, pitavastatin reduces proteinuria in CKD patients

12-16 week treatment with pitavastatin (n=65) or control (n=40) ** p< 0.01Am J Cardiol 2011;107:1644 –1649

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

31% 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

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

Am J Cardiol 2010;105:69 –76

Rosuvastatin showed higher reduction in LDL-C & Non-HDL-C compared to other statins

13 statins trials included, 91140 participants. Statins therapy is associated with 9% increase in

the risk of new diabetes (usually in patients predisposed to developing T2DM).

Conclusion: Statin therapy is associated with a slightly increased risk of development of diabetes Lancet 2010;375:735-42

J PREDICT: Effect of Pitavastatin on NOD in IGT 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

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

patients

J-PREDICT Sub-analysis based on BMI: ADA 2015

Abstract No: 1199-P, June 7, 2015

Pitavastatin significantly reduces the new onset of DM by 39% in IGT patients with BMI < 23.4 kg/m2

Upto 29% of patients on statin develops muscle related symptoms

LAI estimate – 10 – 15%. 75% of cases in first 3 months, 90% in first 6 months

Re-challenge with different statin is important if symptoms disappear

Pitavastatin For Statin Intolerant Patients: Study 1In 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

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

Pitavastatin is a good option for those who cannot tolerate other

statins

Pitavastatin For Statin Intolerant Patients: Study 2

In a study, 148 patients who had history of > 2 statin intolerance were prescribed pitavastatin.

104 patients who tolerated pitavastatin > 6 weeks were followed up for 1 year to detect long term tolerance of pitavastatin

Results: 80.1% of the patients were still tolerating pitavastatin after 1 year use.

79% of patients who tolerated pitavastatin reached NCEP LDL goal

Journal of Clinical Lipidology 2013;7(3):264

Conclusions Pitavastatin is well tolerated by

majority of statin intolerant patients

Pitavastatin For Statin Intolerant Patients: Study 3

A study presented in ACC 2013 conference40 patients (USA) who were intolerant to other statins

were treated with pitavastatin 2 mg27 (68%) patients could tolerate pitavastatin for > 3

monthsLDL-C was reduced by 34% (from 147 mg/dl to 93

mg/dl)Conclusion: Low dose pitavastatin is an acceptable

alternative to abandoning statin among 2/3rd of patients documented to be intolerant to other statins, providing an average LDL-C reduction of 34%.

JACC 2013;61(10):E1465

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%

* 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

Clinical Conditions where Lipid Lowering therapy requiredA. Patients with ASCVDB. Patients undergoing PCIC. Primary prevention of CVD for DM D. Patients with low HDL-CE. For patients with CKDF. For patients with very high LDL-C (> 190

Residual 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

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

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

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

Efficacy and Safety of Saroglitazar in Indian diabetics - 2 year data (ADA-2016)

• Design: Observational, post-marketing surveillance study (phase 4 study).

• Eligibility: As per the approved indication and prescribing information of saroglitazar

• Medication: Saroglitazar 4mg OD

• Background Tx : Antidiabetics and statin therapy

• Outcome: Safety (adverse event monitoring) and effectiveness (lipid and glycemic parameters) at baseline and 2 years follow up

• Statistics: Significant differences in the means from baseline to post baseline were assessed by paired t-tests.

• P<0.05 was considered significant

Efficacy and Safety of Saroglitazar in Indian diabetics - 2 year data (ADA-2016)Results• 41% reduction (P < 0.001) in triglycerides • 12% reduction in LDL-C• 16.3% reduction in TC• 28% reduction in non HDL-C • Significant absolute reduction of 0.7 % in HbA1C• Significant improvement in Fasting and PP plasma glucose• Renal, hepatic and cardiac functions were monitored every 3

months and no serious adverse events were seen • No edema or weight gain was reported during 2 years follow-up

Efficacy of Saroglitazar in 4 studies presented at ADA 2016

Follow upPatients with dyslipidemia

6 months(N=40)

Prediabetes

10 months(N=74)

Diabetes

1 year(N=106)Diabetes

2 years(N=108)

Diabetes

Laboratory Parameters: Absolute reduction(% reduction)

Triglycerides (mg/dL) -131.5(-38.7%) * -193.56* -91.14* (-41%) *

LDL-C (mg/dL) -31.9(-15%) * -14.48* -55.25* (-12%) *

Non-HDL-C (mg/dL) -54.5(-19.9%) * -38.48* -57.33* (-28%) *

HbA1C(%) -0.7* -1.0* -1.4* -0.7*

Abbreviations: N = number of subjects in specified treatment; * -significant p value

Meta-analysis: in 6632 patients with high TG (> 200 mg/dl), fibrates reduced CV risk by 28%

Cardiovasc Pharmacol 2011;57:267–272

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 As per Indian consensus statement for dyslipidemia 2014, It

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

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

Primary Prevention – Who To Treat

• It may be most appropriate to view lipid-lowering therapy with statins as an intervention that can reduce relative cardiovascular (CV) risk by approximately 20 to 30 percent regardless of baseline low-density lipoprotein cholesterol (LDL-C)

• The absolute benefit of treatment will be proportional to the underlying absolute risk.

• Use a risk calculator like the Framingham Risk score.• Moderate intensity best – 20 mg Atorva, 5 – 10 mg

Rosuvastatin

Current LAI Guidelines – Key Points

Enas EA, Dharmarajan T S. The Lipid Association of India Expert Consensus Statement 2016: A sea change for management of dyslipidemia in Indians. J Clin Prev Cardiol 2016;5:62-6

Take Home Message

Patient’s Profile Preferred Option

Patients with ASCVD Atorvastatin

Patients undergoing PCI Atorvastatin/Rosuvastatin

Primary prevention of CVD for DM Atorvastatin

Patients with low HDL-C Pitavastatin/Rosuvastatin

For patients with CKD Atorvastatin/Pitavastatin

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

Patients with IGT and High CV risk Pitavastatin

Patients with statin intolerance Pitavastatin

Atherogenic (Mixed) Dyslipidemia with T2DM statin+ Saroglitazar

Atherogenic (Mixed) Dyslipidemia without T2DM statin + Fenofibrate

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