LIPID GUIDELINES: 2015 D P Mikhailidis

BSc MSc MD FCPP FCP FRSPH FFPM FRCP FRCPath

Academic Head

Dept. of Clinical Biochemistry

(Vascular Disease Prevention Clinics)

Royal Free campus

University College London (UCL)

DECLARATION OF INTEREST

• Attended conferences and gave talks sponsored

by MSD and Genzyme

DECLARATION OF INTEREST

• Lead: Guidelines for Medical Management of

Carotid Artery Stenosis (Eur Soc Vasc Surg)

• Chairperson: Expert Panel on Small Dense

Low Density Lipoprotein

• Co-chairperson: Expert Panel on Post-Prandial

Hypertriglyceridaemia

DECLARATION OF INTEREST

Editor-in-Chief of several journals, including:

• Curr Med Res Opin

• Expert Opin Pharmacother

• Angiology

• Curr Vasc Pharmacol

• Open Cardiovasc Med J

American College of Cardiology (ACC) and American Heart Association (AHA) guidelines November 2013

Stone, N. J. et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation http://dx.doi.org/10.1161/01.cir.0000437738.63853.7a.

• ACC/AHA 2013: Mention the use of statins almost exclusively. Risk calculation and threshold controversial. “Rejected” by the EAS, IAS, NLA and ADA. They are “statin” guidelines, not lipid guidelines.

• IAS guidelines 2013: Mention the use of bile acid sequestrants or ezetimibe for patients not getting to LDL-C target or unable to tolerate a high dose statin or any statin dose.

• National Institute for Clinical Excellence (NICE) 2014: Similar to IAS, EAS.

GUIDELINE LDL TARGETS

USA (2001) ≤ 2.6 mmol/l (100 mg/dl) UK (2004) ≤ 2.0 mmol/l (80 mg/dl) USA (2004) ≤ 1.8 mmol/l (70 mg/dl) (optional) very high risk patients UK JBS2 (2005) ≤ 2.0 mmol/l (80 mg/dl) (total cholesterol 4.0 mmol/l; 160 mg/dl) European (2007) ≤ 2.5 mmol/l (96 mg/dl) Canada (2009) ≤ 2.0 mmol/l (80 mg/dl) ESC/EAS (2011) ≤ 1.8 mmol/l (70 mg/dl)

ACC/AHA GUIDELINES 2013 1] A new pooled equation to calculate risk.

This equation seems to overestimate risk leading to more patients being treated with statins. We should consider that the cost effectiveness of such an initiative, if very low risk patients are treated, may be offset by new onset diabetes (NOD) and other adverse effects (e.g. cataracts) associated with statin use.

Aspirin analogy

“Healthy volunteer effect”

Who will be (over)calculated as high risk?

Limited to USA population

ACC/AHA GUIDELINES 2013 1] A new pooled equation to calculate risk.

This threshold for intervention is set at 7.5%. The authors maintain that there is evidence even at 5%! They state that it is reasonable to consider moderate intensity statin therapy at a risk of 5 – 7.5%.

ACC/AHA GUIDELINES 2013 1] A new pooled equation to calculate risk.

Vaucher et al. Eur Heart J 2014:35: 958-59

Ray K et al. Eur Heart J 2014:35: 960-68

Ridker PM, Cook NR. Lancet 2013; 382:1762-65

Seth B et al. Metabolism 2014; in press

Banerjee S et al. Expert Rev Cardiovasc Ther 2014; 12: 285-90

ACC/AHA GUIDELINES 2013

2] No specific low density lipoprotein cholesterol (LDL-C) targets. Instead the percentage reduction in LDL-C in different risk categories is specified. For example, high-intensity statin therapy, that lowers LDL-C by ≥50%, is recommended mainly for secondary prevention and in some patients with diabetes.

Do you leave a high risk patient who has an LDL-C at target without drug administration? Do you lower and LDL-C of 2.6 to 1.3 mmol/l (100 to 50 mg/dl)?

ACC/AHA GUIDELINES 2013

3] There is no guidance regarding the use of non-statin lipid lowering drugs. The International Atherosclerosis Society (IAS) 2013 position paper specifies that these drugs (e.g. ezetimibe and bile acid sequestrants) can be used in addition to statins or in statin intolerant patients.

The NICE guidelines (2014) also specify the same as the IAS guidelines and focus on atorvastatin as first choice statin.

Hypertension example – do we have trials for every combination we use?

SHARP trial for ezetimibe? IMPROVE-IT trial?

ACC/AHA GUIDELINES 2013

4] Some conditions (e.g. rheumatoid arthritis) that are accepted as high risk by other guidelines are only mentioned in parenthesis in the ACC/AHA text.

ACC/AHA GUIDELINES 2013

5] No follow up checks needed.

GFR decline with age and risk of hypothyroidism? Unrecognised drug interactions? NAFLD/NASH?

CHD EQUIVALENTS

• Diabetes

• Peripheral arterial disease

• Symptomatic carotid disease

• Abdominal aortic aneurysm • Chronic kidney disease (eGFR <60 ml/min/1.73m2

• Rheumatoid arthritis (?psoriasis + arthritis, SLE)

Potential CHD Equivalents

• Non-Alcoholic Fatty Liver Disease (NAFLD), especially NASH (Non-Alcoholic Steatohepatitis)

• Metabolic Syndrome, Impaired Fasting Glucose, Impaired Glucose Tolerance

• Obstructive Sleep Apnoea (OSAS)

• Erectile Dysfunction (ED)

• Periodontitis

• Chemotherapy (e.g. anthracyclines) and Radiotherapy (chest)

• Inflammatory Bowel Disease

Jafri H, Alsheikh-Ali AA, Karas RH. Meta-analysis: statin therapy does

not alter the association between low levels of high-density lipoprotein

cholesterol and increased cardiovascular risk. Ann Intern Med 2010

21;153:800-8

20 RCTs: 543 210 person-years of follow-up; 7 838 MIs

After adjustment for on-treatment LDL-C levels, age, hypertension,

diabetes, and tobacco use, there was a significant inverse association

between HDL-C levels and risk for MI in statin-treated patients and

control participants.

In Poisson meta-regressions, every 0.26 mmol/L (10 mg/dL) decrease in

HDL-C was associated with 7.1 (95% CI 6.8 - 7.3) and 8.3 (8.1 - 8.5)

more MIs per 1000 person-years in statin-treated patients and control

participants, respectively.

TG LEVELS AND VASCULAR

DISEASE

Risk of vascular events was increased in a meta-

analysis of 262,525 participants (10,158 events).

Increase in risk was in the range of 19 – 27% for every

1.0 mmol/l (88 mg/dl) increase in TG levels from the

baseline value after a follow up of 4 – 12 years.

N Sarwar et al. Circulation 2007; 115: 450-8

TG LEVELS AND VASCULAR

DISEASE

Links with:

HDL (inverse relationship; quality of HDL?)

LDL (dense LDL – more atherogenic)

Coagulation (e.g. factor VII)

Insulin resistance (e.g. metabolic syndrome,

IFG, IGT, DM)

Obesity (NAFLD and vascular risk)

Whatever the guidelines “shared decision-

making framework” is the way forward

SUMMARY

1] Who to treat:

Calculating risk; CHD equivalents; risk engines

2] Targets:

Absolute levels vs % fall of LDL-C

3] What to use to achieve targets:

Statins and what else? PSCK-9?

Athyros VG, Katsiki N, Karagiannis A, Mikhailidis DP. The 2013 American

College of Cardiology/American Heart Association guidelines for the treatment of

dyslipidemia: mind the gaps! Curr Med Res Opin 2014;30:1701-5.

Mikhailidis DP, Athyros VG. Dyslipidaemia in 2013: New statin guidelines and

promising novel therapeutics. Nat Rev Cardiol 2014;11:72-4.