residual risk reduction in insulin resistant patients

8/8/2019 Residual Risk Reduction in Insulin Resistant Patients

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TREATMENTOPTIONSPractical Pearls

Gregory S Pokrywka MD,

FACP, FNLA, NCMP

Director, Baltimore Lipid Center

Baltimore, MD

Residual Risk Reduction in Insulin

Resistant Patients

The clinical concept o residual risk is commonly dened

as risk or cardiovascular disease (CVD) events afterthe

patient has been treated with a statin medication. At theIAS meetings held recently in Boston, I was struck by a

more comprehensive denition, rom the International

Residual Risk Reduction Initiative (www.R3i.org): The

signicant residual risk o macrovascular events and

microvascular complications, which persists in most

patients despite current standards o care, including

achievement o low-density lipoprotein cholesterol

(LDL-C) goal and intensive control o blood pressure

and blood glucose. Given the increasing incidence o

insulin resistant syndrome (IRS) patients crowding our

waiting rooms and clinics, and the act that at least 2/3

o acute coronary events and strokes are occurring in

insulin resistant patients,1 it is imperative that we ocus

on residual risk reduction in insulin resistant patients. In

this Practical Pearl I will ocus on reduction o lipoprotein-

related residual risk. In addition, the reduction o

diabetes risk through aggressive liestyle modications

as well as the use o medications such as metormin and

thiazolidinediones must also be considered in all IRS

patients. While the concept o residual risk has largely

ocused on abnormalities o triglyceride (TG) and high-

density lipoprotein cholesterol (HDL-C) concentrations

(TG/HDL axis abnormalities), we oten orget what the

lipoprotein-related etiology o that risk is.

In order to adequately manage lipoprotein-related

residual risk, we need to properly assess the lipoprotein

status o individual patients. Although some studies in

lower-risk, noninsulin resistant populations have shown

LDL-C to have a high correlation with LDL-Particle counts

(LDL-P) in assessing CVD risk, several studies have shown

the two measures to be signicantly discordant. For

those with insulin resistance it is clear that traditional

lipid panel measurements are inadequate to assess

and manage this risk. Lipid concentrations as proxies

or lipoprotein risk oten signicantly under-represent

CVD (cardiovascular disease) risk. The 2008 ADA/ACC

consensus statement addresses these issues as the

rst truly lipoprotein-based consensus statement or

insulin resistant patients, stating that measurement o

apolipoprotein B (apoB) is warranted in patients with

cardiometabolic risk on pharmacologic treatment who

are in high or very high risk categories.2 The ACC/ADA

statement calls or the use o directly measured apoB to

guide adjustments in therapy and positions NMR-derived

LDL-P as equally inormative. Interestingly, as is noted ina more recent statement rom the American Association

o Clinical Chemistry (AACC), the lipoprotein (apoB)

goals cited in the ACC/ADA consensus statement do not

correlate as equivalents with the Framingham Ospring

Study (FOS) population cut-points that would correlatewith the lipid concentration goals advised by NCEP ATP

III guidelines. The NCEP ATP III LDL-C goals or high risk

and very high risk patients are 70 mg/dL (2nd percentile

population cut-point) and 100 mg/dL (20th percentile

cut-point) whereas ADA/ACC suggests apoB o 90 mg/dL

(40th percentile cut-point) and 80 mg/dL (20th percentile

cut-point) . In their revision, the AACC paper advises

consistent achievement o the 20th percentile o lipid

and lipoprotein levels).

Table 1 is my attempt to improve outcomes, using

both the 2nd percentile cut-point (or very high risk

TABLE 1


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Practical Pearls continued

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patients) and FOS 20th percentile cut-point (or high

risk patients).3 Further support or using a particle-

based approach comes rom the recent Best Practices

Statement o the AACC: In light o the mounting

evidence, the members o this working group o the

Lipoproteins and Vascular Diseases Division o the AACC

believe that apoB and alternate measures o LDL particle

concentration should be recognized and included

in guidelines, rather than continuing to ocus solely

on LDL-C.4 Although there is as yet no prospective

clinical outcome data supporting the lowering o

apoB to < 80 mg/dL, or LDL-P to < 1000 nmol/L, it is

my opinion that the clinician should recognize the

increased relative CVD risk o the NCEP ATP III very

high risk category, and treat beyond the AACC BestPractices groups recommendations to the population-

based lipoprotein goals in Table 1. Examination o the

Framingham Ospring epidemiologic data provides

support or this concept. In this study o CVD event-

ree survival o over 3000

participants (mean age

51; 53% women) , LDL-C

was not at all associated

with risk in men and

only weakly associated

with risk in women.5

Non-HDL-C provided risk prediction intermediate

between LDL-P and LDL-C. However, a substantial

subset (21%) o the individuals with discordant LDL-C

vs. LDL-P values had higher LDL-P, and these discordant

individuals had a higher CVD event rate. The corollary

to this was that those individuals with a low LDL-P had a

correspondingly lower CVD event rate than those with a

low LDL-C. A review o 17,000 patients on LDL loweringtherapy in 11 studies showed that Many patients

who achieve LDL-C and nonHDL-C target levels will

not have achieved correspondingly low population-

equivalent apoB or LDL-P targets. Reliance on LDL-C

and non-HDL-C can create a treatment gap in which the

opportunity to give maximal LDL-lowering therapy is

lost.6 These results suggest that at-goal apoB or LDL-P

is a better indicator o reduction o residual risk than

equivalently at-goal LDL-C or at-goal non-HDL-C values,

and could perhaps be better utilized to manage residual

LDL-related risk in IRS patients.

As o now, on-treatment clinical trial data supports the

use o 2 methodologies to assess lipoprotein associated

residual risk and establish therapeutic goals, non-HDL-C

and apoB.7,8 Non-HDL-C is a simple calculationo apoB

particle cholesterol content. Directly measured apoB

is undamentally dierent rom non-HDL-C in that it a

measure othe number of atherogenic apoB particles. As

per the AACC Best Practices groups recommendations,

Despite a high correlation, these markers are only

moderately concordant, indicating that one cannot simply

substitute a marker or another in classiying patients into

risk categories. Importantly, on-treatment non-HDL-C

concentrations may not refect residual risk associated

with increased LDL particle number.9,10 The use o LDL

particle counts by NMR is supported by epidemiologicdata. All 3 o these methodologies are superior to

traditional LDL-C assessment o LDL risk, especially in

IRS populations, where the presence o large numbers

o TG-rich lipoproteins and remnant particles, and small,

dense LDL particles create

a disconnect between the

traditional parameter or

assessment o LDL-related

risk, LDL-C (cholesterol

content), and the more

accurate determinant

o LDL risk, apoB or LDL-P, the number o atherogenic

particles. It should be noted, however, that FOS data

indicates that remnants and VLDL-P played almost no role

in CVD risk beyond LDL-P, and that non-HDL-C should

be viewed as a surrogate o LDL-P itsel.11 A recent meta-

analysis o multiple dierent techniques o lipoprotein

risk assessment concluded that there was no signicant

advantage to assessing LDL subfractions over standardlipid determinations.12 However, the meta-analysis showed

that in multiple studies the assessment oLDLparticle

number (LDL-P) was associated with CVD incidence.

Perhaps surprisingly to some, LDL particle size and small

LDL particle raction were not as consistently associated

with incident disease, conrming earlier analyses rom the

MESA study showing that once adjusted or LDL-P, LDL

particle size disappears as a predictor o risk (as assessed

by carotid IMT surrogate).

The second component o lipoprotein-associated residual

If we prevent the disease, we will

prevent the events and if we take

away the atherogenic particles, we

will take away the atherosclerosis.


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15

risk in insulin resistant patients is the risk beyond apoB

elevation inherent in abnormalities o HDL unction and

triglyceride elevation. Even modest pre- and postprandial

elevations o TG (> 130 mg/dL asting and > 150 mg/dL

2 hrs postprandial) are known to increase cardiovascular

risk through multiple mechanisms beyond apoB elevation,

including increases in blood viscosity, hypercoagulability,

endothelial dysunction, and infammation o atherogenic

plaque.13 Fibrates, high-dose niacin and very high dose

omega-3 atty acids

(N3FA) all help reduce

TG elevations in these

patients. The elevated

TG levels seen in IRS also

lead to the TG enrichmento HDL particles and the

accompanying drop in

HDL unctionality and

HDL particle numbers via

increased HDL catabolism.

Although readily available

tools to assess HDL

unctionality are lacking,

we must realize that HDL-C content is inadequate to

assess HDL unctionality, either in drug nave patients or

in patients on medication.14 Clinical trials with the HDL-C

increasing agents brates and niacin are associated with

CVD event reductions, in the brates case even with

only modest increases in HDL-C in VA-HIT and HHS, and

a negligible increase in FIELD. Fibrates and niacin (as well

as ezetimibe and colesevalam) improve HDL unctionality

by increasing the critical step o macrophage reverse

cholesterol transport. Niacin shits in HDL subpopulations

correlated with angiographic disease reduction in theHATS trial, and gembrozil shits in HDL-P (HDL particle

count) and HDL subractions predicted new CHD events

in VA-HIT. Gembrozil induced HDL subpopulation

changes in LOCAT predicted angiographic progression o

disease and similar results were ound with bezabrate

in BECAIT. Fibrates and niacin benecially aect HDL

proteomics (the protein makeup o HDL), likely improving

HDL unctionality. It is tempting to speculate that this

increased HDL unctionality will be associated with

residual risk reduction. It is important to realize that even

patients with seemingly isolated low HDL-C physiology

on examination o standard lipid panels oten have

signicantly increased numbers o (usually small

dense) LDL particles.15 Such low HDL-C states in IRS

are most oten simply surrogates or the presence

o a large amount o LDL-P associated risk. Evidence

rom small clinical trials (HATS, FATS, AFREGS, SANDS,

etc.) is beginning to accumulate that addressing the

LDL axis abnormalities andabnormalities o the HDL/

triglyceride axis with various combinations o statins,

niacin, brates, bile acid

sequestrants and ezetimibe,

provides superior CVD risk

reduction, as measured by

imaging procedures. Large

scale clinical trials such asACCORD, AIM-HIGH and

IMPROVE-IT will provide

additional data in this

regard.

How can we best manage

residual risk in insulin-

resistant patients? (See Table

2.) By realizing that it is

essential to go beyond traditional lipid concentration-based proxies as therapeutic goals in these patients,

we have the potential to accomplish this objective:

I we prevent the disease, we will prevent the events

and that i we take away the atherogenic particles,

we will take away the atherosclerosis.16 Even the

infammatory aspect o atherosclerosis is most likely

driven by excessive numbers o atherogenic particles.

Our top priority must then be to reduce atherogenic

particle numbers by reducing their ormation or

enhancing their clearance by upregulating LDL

receptors with agents such as statins, ezetimibe and

colesevelam, and then to monitor the ecacy o these

agents with achievement o a low risk (low LDL-P)

state. The eort to reduce atherogenic particles is

o course a partnership between the clinician and

patient: the patient can likely decrease LDL particle

production (through therapeutic liestyle changes)

at least as much as the clinician can increase LDL

clearance (through pharmacologic intervention).

17

We need to reduce the risk o TG-rich lipoproteins

continued on page 25

TABLE 2


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ARTICLESCONTINUED

Articles continued...

Practical Pearls cont. from page 15

and improve HDL unctionality by combining brates,

niacin, and N3FA with the aorementioned LDL-receptor

upregulating agents. Although NCEP ATP III encouragesreducing TG and increasing HDL-C,there are no specic

lipid goals or HDL-C or TG provided by clinical trial

data at this time. Fibrates have an impressive body

o evidence-based medicine or event reduction o

macrovascular disease in IRS patients (with triglycerides

> 200 mg/dL and low HDL-C). The microvascular event

reduction o peripheral amputations, retinopathy

and nephropathy in FIELD by enobrate makes this

a reasonable choice or addition to a statin or TG/

HDL axis manipulation in T2DM patients. Niacins most

impressive data is in the secondary reduction o CVD, and

it should be utilized in this population. Pharmacologic

dose o N3FAs have been shown to reduce CVD risk,

and the latest data rom the JELIS trial shows reduction

o CVD events to be superior in the impaired glucose

metabolism patients receiving the N3FA/statin

combination in that trial.18

Notes:Colesevelam may increase triglycerides, especially when

baseline triglycerides are elevated. The above algorithm

is my own personal attempt to improve risk reduction

beyond the NCEP ATP III guidelines and thus is not

consistent with those guidelines, nor does it represent

the views o the NLA or Lipid Spin.

References:

1. Plutzky J. A Cardiologists Perspective on Cardiometabolic Risk. AmJ Cardiol. 2007;100[suppl]:3P-6P

2. Brunzell JD, Davidson M, Furberg CD et al. LipoproteinManagement in Patients with Cardiometabolic Risk: ConsensusStatement rom the American Diabetes Association and theAmerican College o Cardiology Foundation. Diabetes Care.2008;31:811-822, J Am Coll Cardiol. 2008;51:1512-1524.

3. Contois JH, McConnell JP, Sethi AA et al. ApoB and CardiovascularDisease Risk: Position Statement rom the AACC Lipoproteins andVascular Diseases Division Working Group on Best Practices. ClinChem. 2009;55:407-419.

4. Ibid.

5. LDL particle number and risk o uture cardiovascular diseasein the Framingham Ospring StudyImplications or LDLmanagement. Cromwell C, Otvos J, Keyes M, et al. J Clin Lipidol2007;1:583-502

6. Dierential response o cholesterol and particle measureso atherogenic lipoproteins to LDL-lowering therapy:

implications or clinical practice. Sniderman, AD. Journal ofClinical Lipidology(2008) 2, 3642

7. Barter PJ, Sniderman A, Ballantyne CM et al. ApoB vs.cholesterol in estimating cardiovascular risk and guidingtherapy: report o the 30 person/10 countries panel.J InternMed. 259:247-2582.

8. Mudd J, Borlaug B, Johnston P, et al. Beyond Low-DensityLipoprotein Cholesterol: Dening the Role o Low-DensityLipoprotein Heterogeneity in Coronary Artery Disease.JACC.2007,50(18):1735-1741.

9. Contois JH, McConnell JP, Sethi AA et al. ApoB andCardiovascular Disease Risk: Position Statement rom theAACC Lipoproteins and Vascular Diseases Division WorkingGroup on Best Practices. Clin Chem. 2009;55:407-419.

10. Sniderman A.Targets or LDL-lowering therapy. Curr OpinLipidol. 2009;20(4):282-287.

11. Cromwell C, Otvos J, Keyes M et al. LDL particle numberand risk o uture cardiovascular disease in the FraminghamOspring Study: Implications or LDL management.J ClinLipid. 2007;1:583-502

12. Stanley LP, Lichtenstein AH, Chung M et al. SystematicReview: Association o Low-Density LipoproteinSubractions With Cardiovascular Outcomes.Ann Int Med.2009;150:474-484.

13. Toth P, Dayspring T, Pokrywka G. Drug Therapy orHypertriglyceridemia: Fibrates and Omega-3 Fatty Acids.Current Atherosclerosis Reports. 2009,11:71-79.

14. deGoma E, deGoma R, Rader D. Beyond High-DensityLipoprotein Cholesterol Levels: Evaluating High-DensityLipoprotein Function as Infuenced by Novel TherapeuticApproaches.

J Am Coll Cardiol. 2008;51:2199-211.

15. Kathiresan S, Otvos J, Sullivan L, et al. Increased Small Low-Density Lipoprotein Particle Number: A Prominent Featureo the Metabolic Syndrome in the Framingham Heart Study.Circulation. 2006;113(1):20-29.

16. Sniderman A. We Must Prevent Disease, Not Predict Events.JAm Coll Cardiol. 2008;52: 300-301.

17. William Cromwell, MD, lectures in risk reduction, 20082009.

18. Oikawaa S, Yokoyamab M, Origasac H. Suppressiveeect o EPA on the incidence o coronary events in

hypercholesterolemia with impaired glucose metabolism:Sub-analysis o the Japan EPA Lipid Intervention Study(JELIS).Atherosclerosis. 2009;doi:10.1016/j.atherosclerosis.2009.03.029 (article in press).

residual risk reduction in insulin resistant patients

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