High density lipoprotein cholesterol (HDL-c), often termed “good cholesterol”, is one of the major targets of cardiovascular risk reduction. Constant attempts have been made over the past 3 decades to increase their level in the blood in an attempt to reduce cardiovascular risk. In spite of these efforts, raising HDL-c still remains an enigma. While several methods are known to raise HDL-c, they are not as dramatic as reduction of low density lipoprotein cholesterol (LDL-c). Statins, fibrates, niacin and cholesteryl-ester transfer protein (CETP) inhibitors are useful in increasing HDL-c. However, it was recently demonstrated that raising HDL-c using these pharmacological means did not have any significant effect on reducing clinical cardiovascular events. The 2013 ACC/AHA guidelines on managing blood cholesterol did not give much importance to HDL-c management too. An important question is the method with which HDL-c is tested. Is HDL-cholesterol more important or HDL lipoprotein particle number? Are HDL-based therapies dead? Are there newer ongoing techniques that raise HDL cholesterol as well as reduce cardiovascular risk? Shashikiran Umakanth presented this at the Egyptian Association of Endocrinology, Diabetes & Atherosclerosis (EAEDA) 2014 conference at Alexandria, Egypt. This conference was help in association with Endocrine Society, USA and the European Association for the Study of Diabetes (EASD).

1. Raising HDL-cholesterol
the controversy
Shashikiran Umakanth MBBS MD
Professor & Head, Department of Internal Medicine
Dr. TMA Pai Hospital, Udupi
Melaka Manipal Medical College
Manipal University, India

2. 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

3. 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

4. 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

5. Trials showing some CVD benefit
Trial Treatment regimen Duration (years) CHD event reduction (%)
1. NHLBI,type II Diet plus resin 5 33
2. STARS Diet plus resin 3 89*
3. CLAS Diet plus resin plus niacin 2 25
4. CLAS II Diet plus resin plus niacin 4 43
5. FATS Diet plus resin plus niacin 2.5 80*
6. FATS Diet plus resin plus lovastatin 2.5 70
7. MARS Diet plus lovastatin 2 28
8. CCAIT Diet plus lovastatin 2 22
9. SCRIP Diet plus drugs plus lovastatin 4 50*
10. PLAC I Diet plus pravastatin 3 62*
11. PLAC II Diet plus pravastatin 3 60
12. REGRESS Diet plus pravastatin 2 42*
13. MAAS Diet plus pravastatin 4 22
14. 4S Diet plus simvastatin 5.4 34*

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

7. 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)

8. …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.

9. 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

10. What do we know?
 Reduced HDL-c is a CVD risk factor
 Pharmacological elevation of HDL-c does NOT
have clinical benefits

11. HDL cholesterol
Some Basics

12. Basics of HDL-cholesterol
 Made of many
apolipoproteins
 mainly Apo-A1
 Vehicle for cholesterol
 From blood vessels back
to liver
 Reverse Cholesterol
Transporter

13. HDL particles Vs HDL-cholesterol
 Historically, HDL-
cholesterol has been
equated with HDL itself
 But, it’s only a surrogate
measurement for HDL-P

14. 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

15. Life Cycle of HDL
Via SRB-1, transfers the
cholesterol to the hepatocytes,
and excreted in bile
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

16. “Dump Truck – HDL” analogy

17. 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

18. 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

19. 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

20. 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

21. Measures to raise HDL
Traditional
 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

22. 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.

23. 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.

24. 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

25. Delipidated HDL

26. What are we doing?
 Measuring HDL-cholesterol
 but not HDL-particles
Raising HDL-cholesterol
but not lowering CVD risks

27. 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…?

28. Thankyou