Raising HDL-cholesterol

the controversyShashikiran Umakanth MBBS MD

Professor & Head, Department of Internal MedicineDr. TMA Pai Hospital, Udupi

Melaka Manipal Medical CollegeManipal University, India

Brief history of HDL cholesterol…

Framingham Heart Study First to suggest importance of HDL Reduced HDL-c is an independent cardiovascular risk

factor Total-c/HDL-c is a predictor of CVD in all women and

men between 65-80 years For any given level of LDL-c, a HDL-c ranging from

high to low increased CVD risk by 10-fold

Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol 1992;2:23-82

HDL-c as a CVD Risk Factor

HDL-c (mg/dL) Men Women

<35 1.46 2.08

35-59 1.00 1.00

>59 0.61 0.64

Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998 May 12;97(18):1837-47.

Relative Risk

Raising HDL-C was seen as a viable & promising way to further reduce the risk of CV mortality

Raising HDL-c

Raising HDL-c was a daunting task Exercise and lifestyle modifications Food like nuts, seafood, olive oil, avocado etc.

Many studies showed elevation of HDL-c with statins, niacin and fibrates

Trials showing some CVD benefit

Trial Treatment regimen Duration (years)CHD event reduction (%)

1. NHLBI,type II Diet plus resin 533

2. STARS Diet plus resin 389*

3. CLAS Diet plus resin plus niacin 225

4. CLAS II Diet plus resin plus niacin 443

5. FATS Diet plus resin plus niacin 2.580*

6. FATS Diet plus resin plus lovastatin 2.570

7. MARS Diet plus lovastatin 228

8. CCAIT Diet plus lovastatin 222

9. SCRIP Diet plus drugs plus lovastatin 450*

10. PLAC I Diet plus pravastatin 362*

11. PLAC II Diet plus pravastatin 360

12. REGRESS Diet plus pravastatin 242*

13. MAAS Diet plus pravastatin 422

14. 4S Diet plus simvastatin 5.434*

We got a little too optimistic and enthusiastic that any increase in HDL will be good

Trials showing no CVD benefit

AIM HIGH (Niacin) dal-OUTCOMES (with Dalcetrapib) ILLUMINATE (Investigation of Lipid Level Management

to Understand its Impact in Atherosclerotic Events) with Torcetrapib

CHI-SQUARE (Can HDL Infusions Significantly QUicken Atherosclerosis Regression)

…fast forward to 2014

BMJ, July 2014 A meta-analysis of more than 117,000 patients

Increasing the HDL-c levels pharmacologically DID NOT generally reduce cardiovascular events

Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014 Jul 18;349:g4379.

No CV risk benefit

Drugs like torcetrapib and niacin could raise HDL-C levels by 25–60%.

But still, no change in cardiovascular mortality was detected.

In addition, atheroma size, by IVUS, was not affected which could support the notion that raising HDL-C levels may not be as beneficial as once thought

What do we know?

Reduced HDL-c is a CVD risk factor

Pharmacological elevation of HDL-c does NOT have clinical benefits

HDL cholesterolSome Basics

Basics of HDL-cholesterol

Made of many apolipoproteins mainly Apo-A1

Vehicle for cholesterol From blood vessels back

to liver Reverse Cholesterol

Transporter

HDL particles Vs HDL-cholesterol

Historically, HDL-cholesterol has been equated with HDL itself

But, it’s only a surrogate measurement for HDL-P

HDL particle subpopulations

2-D gel electrophoresis

Apo-A1 containing HDL subpopulations

Asztalos BF, de la Llera-Moya M, Dallal GE, et al. Differential effects of HDL subpopulations on cellular ABCA1- and SR-BI-mediated cholesterol efflux. J Lipid Res 2005;46:2246-2253

Life Cycle of HDL

Acceptors of free cholesterol and

phospholipid from cellular ABCA1

Via SRB-1, transfers the cholesterol to the hepatocytes,

and excreted in bile

CETP mediated transfer of

cholesterol to LDL, VLDL particles

Acted upon by L-CAT, and accept more cholesterol via ABCG1 transporter on

macrophages on atherosclerotic plaques

Asztalos BF, de la Llera-Moya M, Dallal GE, et al. Differential effects of HDL subpopulations on cellular ABCA1- and SR-BI-mediated cholesterol efflux. J Lipid Res 2005;46:2246-2253

“Dump Truck – HDL” analogy

HDL-particles or HDL-cholesterol?

Which should be tested? Traditionally – HDL-c

Only 20% of the HDL mass is cholesterol Does not determine the actual HDL particle mass Pre-β forms are not well represented, but they are

the “functional” HDL particles! HDL-P are not routinely tested

Davidson WS. HDL-C vs HDL-P: How Changing One Letter Could Make a Difference in Understanding the Role of High-Density Lipoprotein in Disease. Clin Chem. 2014 Nov;60(11):e1-3

HDL-P & HDL-c

Scatterplot of HDL-P with HDL-c

Mackey RH, Greenland P, Goff DC Jr, et al. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2012 Aug 7;60(6):508-16

HDL-P outperforms HDL-c in predicting CVD

Mackey RH, Greenland P, Goff DC Jr, et al. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2012 Aug 7;60(6):508-16

Carotid intima-medial thickness by HDL-P and HDL-c tertiles

HDL Quality Vs Quantity

HDL-c levels, usually acquired by ultracentrifugation determining the amount of cholesterol in HDL particles/ 100 mL of plasma, give no hint on composition of HDL particles nor their functionality

HDL-C may be a suboptimal parameter for assessing cardiovascular risk

Measures to raise HDLTraditional Statins Fibrates Niacin Cetrapibs

Experimental HDL infusion Apo-A1 infusion Delipidated HDL HDL-mimetic agents

CER-001 Miscellaneous

LXR agonists PPAR gamma agonists Lipase inhibitors sPLA2 inhibitors Endothelial lipase inhibitors LpPLA2 inhibitors SR-BI inhibitors

Traditional

Raising HDL-cholesterol by using Fibrates Niacin, or CETP inhibitors (dalcetrapib, torcetrapib, anacetrapib)

has not lowered CVD risks

Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014 Jul 18;349:g4379.

2013 ACC/AHA Guidelines

Importance to non-HDL-cholesterol reduction

No importance given to HDL-raising therapies

Stone NJ, Robinson JG, Lichtenstein AH 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. 2014 Jun 24;129(25 Suppl 2):S1-45.

Is HDL-targeted therapy dead?

Newer methods HDL infusion – not encouraging Apo-A1 infusion – not encouraging Delipidated HDL infusion – looks encouraging, but

time will tell CER-001 – not encouraging

Delipidated HDL

What are we doing?

Measuring HDL-cholesterol but not HDL-particles

Raising HDL-cholesterolbut not lowering CVD risks

In conclusion

HDL-c is a good biomarker May NOT be a good target for treatment

Confidence in HDL raising therapy is lowering But newer methods may hold promise in future

It's not what you do, it's the way you do it…?

Thank you