Current Controversies in Dyslipidemia Management:

LDL Cholesterol : How Low Should You Go?

Magdy El-MasryProf. of CardiologyTanta University

Current Controversies in Dyslipidemia Management: A Point-Counterpoint Discussion

FraminghamMRFIT

LRC-CPPTCoronary Drug

ProjectHelsinki HeartCLAS (angio)

Angiographic Trials (FATS, POSCH, SCOR, STARS, Ornish, MARS)Meta-Analyses

(Holme, Rossouw)

4S, WOSCOPS, CARE, LIPID,

AFCAPS/TexCAPS, VAHIT, others

1970s

NCEPATP IGuidelines1988

NCEPATP II

Guidelines1993

NCEPATP III

Guidelines2002

ATP III UPDATE

2004

HPS, PROVE-IT, ASCOT, ALLHAT, PROSPER

National Cholesterol Education ProgramAdult Treatment Panel

LDL-C Goals (ATP-III)Risk category Goal LDL (mg/dl) CAD & CAD risk equivalent <100 high risk

<70 optional

2 or more major risk factors + 10 yr risk >20%

<100 high risk <70 optional

2 or more major risk factors +10 yr risk 10-20%

<130 moderately high risk <100 optional

2 or more major risk factors +10 yr risk <10%

0-1 major risk factor

<130 moderate risk

<160 low risk

Keep it Simple : Start the Statin or Not ?

To Statin or Not to Statin?

Statins for everyone?

Put statins in the drinking water?

Identified 4 statin benefit groups ----- Focus efforts to reduce ASCVD events

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol toReduce Atherosclerotic Cardiovascular Risk in Adults

Secondary  Prevention

Primary  prevention

http://clincalc.com/Cardiology/ASCVD/PooledCohort.aspx

This is the new equation

Statin DoseBenefit Group

The guideline identifies high- and

moderate-intensity statin

therapy for use in primary and secondary prevention

Non-statin therapies

• For hyperlipidemia, non statin therapies, alone or in combination with statins, do not provide acceptable risk reduction benefits compared to adverse effects.

• These include:–Ezetimibe–Fibrates–Fish oil–Niacin

• For the most part, these should be avoided with few exceptions

What has changed compared to ATP-III guideline?

• Initiate either moderate-intensity or high-intensity statin therapy for patients who fall into the four categories

• Unlike ATP-III, Do not titrate to a specific LDL cholesterol target

• Measure lipids during follow-up to assess adherence to treatment, not to achieve a specific LDL target

Evidence to support controversy in 2013 ACC/AHA Guideline 

Recommendations for statin and combination treatment in people with diabetes

*In addition to lifestyle therapy.

**ASCVD risk factors include LDL- C ≥100 mg/dL, high BP, smoking, CKD, albuminuria, and family history of premature ASCVD.

2017ADA

2 Studies Support Guidelines for Wider Use of Statins

2016

Does HOPE-3 give hope?

This finding was independent of the cholesterol levels when patient started the trial. You “set it and forget it”

Importantly, the results show the benefits of using statins based on risk factors for disease, rather than the traditional approach of looking at lipid levels to guide decisions.

Statins reduce the risk of cardiovascular disease in intermediate risk patients

Four Major Statin Benefit Groups

Case 1

50 year old white female• Total cholesterol 180• HDL: 50• SBP: 130• taking anti-hTN meds• +diabetic• +smoker• Calculated 10 yr ASCVD: 9.8%

Dosing Statins

Case 2

22 yo white male• LDL: 195• SBP: 120• Not taking anti-HTN meds• Non-diabetic• Non-smoker

Dosing Statins

Case 3

62 year old AA male • Total cholesterol: 140• Low HDL: 35• SBP: 130 mmHg• Not taking anti-hypertensive medications• Non-diabetic• Non-smoker• Calculated 10 yr risk of ASCVD : 9.1%

Dosing Statins

Case 4

48 yo white female• Total cholesterol 180• HDL: 55• SBP: 130• Not taking anti-hTN meds• +diabetic• Non-smoker• Calculated 10 yr risk ASCVD : 1.8%

Dosing Statins

Case 5

66 yo white female • High Total cholesterol: 230• HDL: 55• SBP: 150• taking anti-HTN meds• Non-diabetic• Non-smoker• Calculated 10 yr risk of ASCVD : 2.0 %

What’s changed ? Yet another new ESC lipid guidelines

Total Cardiovascular Risk Estimation

CV risk in the context of these guidelines means the likelihood of a person developing a fatal or non-fatal

atherosclerotic CV event over a defined period of time.

Systemic Coronary Risk Estimation (SCORE) System

SCORE not used for Diabetic patients , Patient with documented CVD or CKD patients

They already Very high risk or High risk

4 Risk categories

I A

IIa A

IIa C

Recommendations for treatment targets for LDL-C

ESC 2016 Risk Categories & LDL Goal

Continental Divide on Lipid GuidelinesThe U.S. guidelines recommend giving a statin to all high-risk patients, even those with low cholesterol, but the ESC/EAS guidelines do not do that (no tx if low LDL despite high risk).The American approach would mean considerably more people in Europe being on a statin.

While the ACC/AHA guidelines do not specify a numeric goal, the ESC/EAS guidelines set a target of a reduction in LDL

Fasting is no longer required before screening for lipid levels in Europe due to "new evidence that non-

fasting blood samples give similar results for cholesterol." However, fasting is recommended in

the U.S. the guidelines.

ESC comes out in favor of LDL targets This raises the question: How will we reach these goals?

If we do not reach our goals with diet alone, we are recommending the prescription of a statin as the first step.

In the few cases where there is true statin intolerance, then the second step would be to use either ezetimibe or a bile acid sequestrant.

If, with a statin at the highest tolerable dose, we do not reach the goal, then we have to think of combinations. Nowadays, we know that by combining ezetimibe

and a statin, we can achieve a better result in terms of cardiovascular disease prevention.

In patients at very high risk, with persistent high LDL-C levels despite treatment with the maximal tolerated statin dose, even in combination with ezetimibe, or in

patients who really are completely statin intolerant, then this new family of drugs, the PCSK9 inhibitors, may be considered.

Statins inhibit cholesterol synthesis in the liver, ezetimibe blocks cholesterol absorption in the intestine, and PCSK9 inhibitors block the PCSK9-mediated degradation of LDL receptors.

Statins, ezetimibe, and PCSK9 inhibitors all increase the expression of LDL receptors and reduce LDL-cholesterol levels (by percentages shown).

Ezetimibe and PCSK9 inhibition join the mainstream of lipid‑lowering therapy

LDL-C The debate goes on

Schematic Depiction of the Statin Hypothesis.The reduction in LDL- C with lipid-modifying agents is plotted against the reduction in cardiovascular events under either the LDL hypothesis or the statin hypothesis. The putative added “pleiotropic” effects of statins (effects that are un-related to their lipid-lowering effects) are represented by the shaded area. The IMPROVE-IT trial provides im-portant new evidence in favor of the LDL hypothesis.

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial

A Multicenter, Double-Blind, Randomized Study to Establish the

Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-

Risk Subjects Presenting With Acute Coronary Syndrome

IMPROVE-IT

Patients stabilized post ACS ≤ 10 days:LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)

Standard Medical & Interventional Therapy

Ezetimibe / Simvastatin 10 / 40 mg

Simvastatin 40 mg

Follow-up Visit Day 30, every 4 months

Duration: Minimum 2 ½-year follow-up (at least 5250 events)

Primary Endpoint: CV death, MI, hospital admission for UA,coronary revascularization (≥ 30 days after randomization), or stroke

N=18,144

Uptitrated to Simva 80 mg if LDL-C > 79(adapted per

FDA label 2011)

Study Design *3.2mM **2.6mM

Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

90% power to detect ~9% difference

Conclusions

IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy:

YES: Non-statin lowering LDL-C with ezetimibereduces cardiovascular events

YES: Even Lower is Even Better(achieved mean LDL-C 53 vs. 70 mg/dL at 1 year)

YES: Confirms ezetimibe safety profile

Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events

Results could be considered for future guidelines

Proprotein convertase subtilisin/kexin type 9 (PCSK9)

PCSK9 inhibitors

A Patient Journey Through Statin Intolerance