There are many ways to lower triglycerides in humans: Which are the most relevant for pancreatitis and for CV risk?

Michael Davidson M.D. FACC,

Diplomate of the American Board of Lipidology

Professor, Director of Preventive Cardiology

The University of Chicago

Pritzker School of Medicine

Justification for lowering Non-HDL-c to reduce CHD Risk Reduction

Assertions

Hypertriglyceridemia is correlated with increased CV risk

Risk of hypertriglyceridemia is contained within non-HDL-C rather

than triglycerides per se

TRL-C – triglyceride risk lipoprotein cholesterol – is an atherogenic

component of non-HDL-C

Reduced TRL-C is associated with decreased CV events

Pharmacologic treatment of high TRL-C has potential to reduce CV

risk

HDL LDL IDL VLDL Chylomicron remnant

Apo AI Apo B Apo B Apo B Apo B48

CholesterolTriglyceride

All atherogenic lipoproteins

Non-HDL

TRL-C = Non-HDL-C – LDL-C

Triglyceride Rich Lipoproteins

Non-HDL Cholesterol

Triglyceride Rich Lipoproteins (TRL)

CHD Risk for TG Elevation is Contained within Non-HDL-C and HDL-C

Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000

Analyses of loge TG were adjusted for HDL-C and non-HDL-C.

Analyses of HDL-C were adjusted for non-HDL-C and loge TG.

Analyses of non-HDL-C were adjusted for HDL-C and loge TG.

When discordant, risk follows non-HDL-C,not LDL-C

Discordance Meta-AnalysisRisk of Major CV Events during Statin Therapy

Boekholdt SM, et al. JAMA. 2012;307:1302-1309

HRs adjusted for sex, age, smoking, diabetes, systolic BP and trial

Low

High

TG Production

Large

VLDLRemnants

slow

LPL/HLLPL

ApoB

ApoB

ApoE

ApoE

ApoC-IIIApoC-III

Small

LDL

ApoBApoC-III

Very SmallLDL

ApoB ApoC-III

Non-HDL-C

Remnant Cholesterol LDL-C

LPL

ApoB ApoE

VerySmallVLDL

Large

LDL

ApoB

Non-HDL-C

Remnant Cholesterol LDL-C

Cholesterol Triglycerides

sHDLHDL

TGCE

TG

CETP

HL

Renal clearance

TG

HL

ApoA5

The greater the level of triglycerides the more VLDL-C and less LDL-C within non-HDL-C associated with Increasing CV Risk

Varbo A, et al. J Am Coll Cardiol. 2013;61:427-436.

(VLDL-C)

VLDL-C Compared to LDL-C on a Continuous Scale and Hazard Ratios of Ischemic Heart Disease

Copenhagen Heart Study; Varbo A, et al. Clin Chem. 2015;61:533-543.

(VLDL-C)

Lipoprotein Cholesterol Levels and IHD

Copenhagen Studies (n = 73,513): Risk of

Ischemic Heart Disease By Lipoprotein

Cholesterol Levels

Varbo et al. JACC 2013;61:427-436.

Lipoprotein Genotypes and IHD

Copenhagen Studies: Causal vs Observational Risk

Estimates

Varbo et al. JACC 2013;61:427-436.

HRs for 1 mmol/l or a 1 ratio unit increase or decrease in plasma lipoprotein levels

VLDL-C is causal for atherosclerosis greater than LDL-C:Each VLDL particle carries 5-20X more cholesterol than LDL with unregulated uptake by macrophages

Adapted from Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

VLDL VLDL

Cumulative incidence curves for risk of coronary heart disease (CHD) by small dense low-

density lipoprotein-cholesterol (sdLDL-C) and large buoyant LDL-C (lbLDL-C) quartiles,

adjusted for age, race, and sex.

Hoogeveen R C et al. Arterioscler Thromb Vasc Biol.

2014;34:1069-1077

Copyright © American Heart Association, Inc. All rights reserved.

Adjusted hazard ratios (HRs) for incident coronary heart disease by small dense low-density

lipoprotein-cholesterol (sdLDL-C) quartiles stratified by LDL-C risk categories, adjusted for

age, sex, and race, smoking, body mass index, hypertension, diabetes mellitus, diabetes

mellitus medications, and log high-sensitivity C-reactive protein.

Hoogeveen R C et al. Arterioscler Thromb Vasc Biol.

2014;34:1069-1077

Copyright © American Heart Association, Inc. All rights reserved.

Cumulative incidence of cardiovascular events in subgroups with low-density lipoprotein-

cholesterol (LDL-C) <100 mg/dL (<25th percentile) and small dense LDL-C (sdLDL-C) <27.8

mg/dL (<25th percentile), from proportional hazards models adjusted for age, sex, and race.

Hoogeveen R C et al. Arterioscler Thromb Vasc Biol.

2014;34:1069-1077

Copyright © American Heart Association, Inc. All rights reserved.

Fibrates, EPA, Niacin – CV Outcome Trials

Larger Risk Reductions in Hypertriglyceridemia

Trial (drug) Entire cohort

HR (95% CI)

Subgroup Subgroup

HR (95% CI)

HHS

(gemfibrozil)

0.66 (0.47, 0.92) TG ≥184 mg/dL

BMI >27.5 kg/m2

0.30 (0.15, 0.58)

BIP

(bezafibrate)

0.91 (NR) TG ≥200 mg/dL 0.60 (NR)

VA-HIT

(gemfibrozil)

0.78 (0.65, 0.93) TG ≥151 mg/dL 0.73 (0.58, 0.93)

FIELD

(fenofibrate)

0.89 (0.75, 1.05) TG ≥204 mg/dL

HDL-C <42 mg/dL

0.73 (0.58, 0.91)

ACCORD

(fenofibrate)

0.92 (0.79, 1.08) TG ≥204 mg/dL

HDL-C ≤34 mg/dL

0.69 (NR)

JELIS

(ethyl-EPA)

0.81 (0.69, 0.95) TG >150 mg/dL

HDL-C <40 mg/dL

0.47 (0.23, 0.98)

AIM-HIGH

(niacin)

1.02 (0.87, 1.21) TG >198 mg/dL

HDL-C <33 mg/dL

0.74 (0.50, 1.09)

Maki et al. J Clin Lipidol. 2012;6:413. Guyton et al. JACC 2013;62:1580.

Relationship Between Change in VLDL-C with Fibrates(Estimated from TG Responses) and CV Outcomes

Change in VLDL-C

(mg/dL)

HR (95% CI)

HHS (1987) -15.1 0.66 (0.47, 0.92)

SIHD (1988) -14.2 0.70 (NR)

VA-HIT (1999) -9.2 0.78 (0.65, 0.93)

BIP (2000) -6.1 0.91 (NR)

FIELD (2005) -8.5 0.89 (0.75, 1.05)

ACCORD (2010) -8.4 0.92 (0.79, 1.08)

Calculated from: Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635. Maki KC, et al. J Clin Lipidol.

2012;6:413-426. Carlson LA, Rosenhamer G. Acta Med Scand. 1988;223:405-418.

Abbreviations: ACCORD = Action to Control Cardiovascular Risk in Diabetes; BIP = Bezafibrate

Infarction Prevention; FIELD = Fenofibrate Intervention and Event Lowering in Diabetes; HHS = Helsinki

Heart Study; NR = not reported; SIHD = Scandinavian Ischaemic Heart Disease Secondary Prevention

Study (Carlson and Rosenhamer); VA-HIT = Veterans Affairs HDL Intervention Trial

Meta-regression Demonstrates that VLDL-C Lowering is Highly Correlated with a Reduction in the Hazard Ratio for a Major CV Event

Each 8.9 mg/dL reduction in VLDL-C (equivalent to 0.5 mmol/L for TG) in the fibrate

outcome trials is associated with a reduction of 26% in the hazard for a CV event

Y = -0.02955*X + 1.113; r = -0.93, P = 0.006

Calculated from: Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635. Maki KC, et al. J Clin Lipidol. 2012;6:413-426.

SIHD is Carlson LA, Rosenhamer G. Acta Med Scand. 1988;223:405-418.

0 5 10 15 200.6

0.7

0.8

0.9

1.0

VLDL-C Reduction (mg/dL)

HR

fo

r C

V E

ve

nts

HHS

BIP

VA-HIT

FIELD

ACCORD

SIHD

Y = -0.02955*X + 1.113; r = -0.93, P = 0.006

In ACCORD MACE Risk was Reduced 31% in Patients with TG ≥ 204 mg/dL and HDL ≤ 34 mg/dL

Adapted from ACCORD Study Group, NEJM 2010; 362:1563.

Pre-specified subgroup analysis (baseline TG levels ≥ 204 mg/dL + HDL-C

≤ 34 mg/dL) suggested favorable risk reduction for MACE with fenofibrate

(HR 0.69; 95%CI 0.49 – 0.97; p=0.032 within subgroup, p=0.06 for

interaction).

VLDL-C and LDL-C Changes in ACCORD in Subgroups with Dyslipidemia vs. Others

Change in VLDL-C with

Fenofibrate (mg/dL)

Change in LDL-C with

Fenofibrate (mg/dL)

High TG/Low

HDL-C

Others High TG/Low

HDL-C

Others

Fenofibrate -25.4 -5.2 -11 -20

Placebo -16.8 -0.6 -20 -21

Difference -8.6 -4.6 +9 +1

High TG was defined as TG ≥204 mg/dL and low HDL-C was defined as HDL-C ≤34

mg/dL.

High TG/Low HDL-C subgroup: fenofibrate n = 316 and placebo n = 287

Others: fenofibrate n = 1465 and placebo n = 1495

8.6 mg/dL reduction in VLDL-C is associated with a reduction of 31% in the hazard

for a CV event

Fenofibric Acid + High-Dose Statin Does Not Provide Incremental Non-HDL-C Reduction

Fillippatos TD. Cardiovasc Drugs Ther. 2012;26:245-55.

21

Davidson et ATVB

2013

FIRST Trial: Fenofibric Acid plus statin vs statin monotherapy; Rate of Change in CIMT by Baseline Lipids

-0.02 -0.01 0 0.01 0.02 0.03-0.03

Between Group Difference in Rate of Change

in Posterior wall IMT (mm/year)

Trilipix Better Placebo Better

Within Group Difference Between Group Difference

Trilipix + atorva Placebo + atorvaBaseline Lipids (mg/dL) by

tertiles n

Rate of change

(mm/yr) n

Rate of change

(mm/yr) Interaction P value

LDL-C

≤75 100 -0.007 96 0.000 0.814

>75 and ≤92 96 -0.004 103 0.005>92 85 -0.008 92 -0.006

HDL-C

≤36 98 -0.001 104 0.005 0.864

>36 and ≤42 88 -0.005 90 0.000

>42 95 -0.012 97 -0.003

Triglycerides

≤169 92 0.006 96 -0.009 0.016

>169 and ≤235 97 -0.018 105 0.005

>235 92 -0.007 90 0.005

non-HDL-C

≤106 105 -0.005 92 -0.004 0.835

>106 and ≤126 85 -0.004 105 0.006

>126 91 -0.010 94 -0.002

Table 14.2_7.9.1.1; 14.2_7.9.3.1;14.2_7.9.4.1

22

LDL Particle Number Significantly Increased in Patients on Statins

in Combination with Fenofibric Acid

Fenofibrate Significantly Increases PCSK9, Which Correlates with LDL-C Increase

Trout JS, et al. J Lipid Res. 2010;51:345-351.

Atherogenic Dyslipidemia Study: Absolute and Percentage

Changes in Laboratory Parameters and Blood Pressure

From Baseline Until Follow-Up Visit

24

AIM-HIGH – Subgroup Data for Elevated TG/Low HDL-C Targeted Therapy Consistent with the Pattern of 7 Other Trials

*TG≥198 mg/dL and HDL-C < 33

mg/dL

• In a subgroup of patients (n=522;15.3% of trial population) in the highest TG tertile (≥ 198 mg/dL) and lowest HDL-C tertile (<33

mg/dL), there was suggestion of a 26% reduction in risk with niacin ER, compared with placebo, added on to statin treatment,

but this did not reach nominal statistical significance (HR 0.74; 95% CI 0.50 – 1.09; p=0.07).

• In an even smaller group of patients (n=439 12.9% of population) with mixed dyslipidemia (TG > 200 mg/dl and HDL-C < 32

mg/dl), the treatment effect in the niacin group was larger (HR 0.64, p = 0.032).

Adapted from Guyton, Slee, JACC, Volume 62, Issue 17, 22 October 2013

AIM-HIGH: Relationship of CV events to baseline and in-trial lipoprotein variables

Guyton JR, et al. J Am Coll Cardiol. 2013;62:1580-

84.

ERN = extended-release niacin

LLT = LDL-C lowering therapy

• AIM-HIGH – Atherogenic lipoproteins correlated positively with

CV events in the control group but niacin might have caused

harm

• The top tertile for baseline (on-statin) non-HDL-C in HPS2-

THRIVE had values >=97 mg/dL, a very low value

AIM-HIGH and HPS-2 Results Should Be Interpreted with Caution

-26,6

-7,7

-3,5

-19

-4,5

108

0

14

-3

-30

-20

-10

0

10

20

30Icosapent ethyl 4 g mineral oil

-26,5

-8

7,5

-27

1916

-4

2,5 2

-9

3 4

-30

-20

-10

0

10

20

30OM-3 FFA 2 g olive oil

LS M

ean

ch

ange

fro

m b

asel

ine

(%)

<0.05* <0.01** <0.001***

Non-HDL-C HDL-C LDL-CVLDL-C LDL-C/ApoB

*

***

**

**

*

**

Med

ian

ch

ange

fro

m b

asel

ine

(%)

***

EVOLVE MARINE

*

Comparison of lipid changes with omega-3 FFA 2g dose containing

both EPA and DHA to a pure ethyl ester EPA 4g dose in patients with

severe hypertriglyceridemia

TG

*p ≤ 0.05, **p < 0.01, **p < 0.001

Non-HDL-C HDL-C LDL-CVLDL-C LDL-C/ApoBTG

***

**

NR

N=399 N=229

EPA and DHA modify the composition of VLDL

particles differently in patients with severe HTG

ApoC-II

ApoC-III

ApoE

ApoC-II ApoC-III

ApoE

ApoC-II

ApoE

Severe HTG Severe HTG

Treated with EPA

Severe HTG

Treated with EPA + DHA

Decreased TG compositionDecreased ApoC-III

improves lipolysis

ApoC-III reduction may help explain the differences between EPA

and DHA on lipoprotein changes

Adapted: Vrablik et al. Physiological Research (2009); von Schacky, Vascular Health and Risk Management (2006)

EPA DHA

Triglycerides

Non-HDL-C

VLDL-C

LDL-C

LDL Size

HDL

The Effects of 10 lbs of weight loss

STRENGTH (EPA+DHA) vs. REDUCE-IT (EPA only): STRENGTH Targets Patients Most Likely to Benefit

from Non-HDL-C Reduction

Clinical factors STRENGTH REDUCE-IT

Number of patients ~13,000 ~8,000

Inclusion criteria TG ≥200 mg/dL, <500 mg/dL

HDL-C <40 mg/dL (men)

HDL-C <45 mg/dL (women)

TG ≥200 mg/dL, <500 mg/dL

(started with TG ≥150 mg/dL)

≥4 weeks on statin ≥4 weeks on statin

Established CVD or at high

risk for development of CVD

Established CVD or at high

risk for development of CVD

Primary endpoint MACE MACE

Dosing regimen 4 g/d 4 g/d

Placebo Corn oil Mineral oil

Risk Reduction with Fenofibrate (ACCORD) or Niacin (AIM-HIGH) Added to Statin Therapy in Subjects with

High TG and Low HDL-C

Active

Events

Placebo

Events

Relative Risk

Reduction

Median

Follow-up

Placebo

Event Rate/y

ACCORD 12.4% 17.3% 28.3% 4.7 y 3.7%

AIM-HIGH 17.0% 22.4% 24.1% 3.0 y 7.5%

In 1,000,000 people with high TG and low HDL-C, a 26% risk reduction would prevent

the following numbers of events each year with annual event rates of 3.7% and 7.5%,

respectively:

• 1,000,000 x 0.0369 x (1 – 0.26) = 27,306 events prevented

• 1,000,000 x 0.0747 x (1 – 0.26) = 55,278 events prevented

• Midpoint of the above estimates is 41,292 events prevented

Conclusions

• New epidemiological and interventional data show a relationship

between VLDL-C and CVD risk (stronger than LDL-C), supporting the use

of non-HDL-C as an approvable surrogate.

• Triglyceride lowering also improves causal factors for CHD such as

remnant cholesterol and small dense LDL-c

• Fibrate and niacin appear to have CV benefits in the patients with high

TG/Low HDL-c but may cause harm in other dyslipidemic subgroups

• Patients with elevated TGs paired with low HDL-C, on optimal statin

therapy, are still at very high CV risk.

• STRENGTH, targeting this high risk population with omega-3 therapy, is

not expected to complete until 2020.