© Copyright 2009 by the American Association for Clinical Chemistry

Lipoprotein(a) and Risk of Type 2 DiabetesLipoprotein(a) and Risk of Type 2 Diabetes

S. Mora, P.R. Kamstrup, N. Rifai, B.G. Nordestgaard, J.E. Buring, and P.M. Ridker

August 2010

http://www.clinchem.org/cgi/reprint/56/8/1252

© Copyright 2010 by the American Association for Clinical Chemistry

Journal ClubJournal Club

© Copyright 2009 by the American Association for Clinical Chemistry

IntroductionIntroduction

Lipoprotein(a) [Lp(a)]

LDL particle with apoB-100 linked with apo(a)

Lp(a) concentration dependent on apo(a) size, highly dependent on genetics

Biologic function uncertain; thought to be thrombogenic givenhomology to plasminogen and/or to be atherogenic given homology with LDL

Commercial assays not well standardized and sensitive to size of apo(a)

© Copyright 2009 by the American Association for Clinical Chemistry

EpidemiologyEpidemiologyLp(a) and CVD

Consistent positive association of Lp(a) and CVD: the odds ratios below are minimal estimates because of the aforementioned variability in assays from study to study.

Meta-analysis 126,634 participants, 36 prospective studies

Odds ratio for coronary disease 1.13 per 1-SD increase in Lp(a)

Odds ratio for ischemic stroke 1.10 per 1-SD increase in Lp(a)

Emerging Risk Factors Collaboration JAMA 2009;302:412-423

© Copyright 2009 by the American Association for Clinical Chemistry

Epidemiology (cont)Epidemiology (cont)Lp(a) and CVD for Extreme Levels of Lp(a)

In Women’s Health Study (WHS) Lp(a) levels ≥ 90th and ≥ 95th percentile (vs. <90th and <95th) had hazard ratios for CVD events of 1.7 and 1.9

Suk Danik et al. JAMA 2006;296: 1363-1370

Cutoff Percentile

Lipoprotein(a) Level, mg/dL

25th ≥ 4.450th ≥ 10.675th ≥ 32.890th ≥ 65.595th ≥ 8399th ≥ 130.7

Fully Adjusted HR (95% CI)*

P Value

1.05 (0.90–1.23) .561.10 (0.96–1.27) .151.48 (1.29–1.71) <.0011.66 (1.38–1.99) <.0011.87 (1.50–2.34) <.0011.99 (1.32–3.00) .001

© Copyright 2009 by the American Association for Clinical Chemistry

Epidemiology (cont)Epidemiology (cont)Lp(a) and MI for Extreme Levels of Lp(a)

In the Copenhagen City Heart Study (CCHS) Lp(a) levels >95th vs. <22nd percentile had hazard ratio for myocardial infarction of 2.6

Kamstrup et al. JAMA 2009;301: 2331-2339

Figure II-3

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Lp(a) and Type 2 DiabetesLp(a) and Type 2 Diabetes

Common Soil” HypothesisCommon genetic and environmental antecedents for CVD and type 2 diabetes

Prior StudiesSmall case-control studies inconsistent

Case-control studies susceptible to bias since the disease may alter Lp(a) concentrations

Prospective studies are better for determining risk factor associations Stern Diabetes 1995;44:369-374

Haffner SM et al Diabetes 1992;41:267-72

© Copyright 2009 by the American Association for Clinical Chemistry

QuestionQuestion

Given prior positive association of Lp(a) with CVD and the “common soil” hypothesis, what would be the expected association of Lp(a) with type 2 diabetes?

© Copyright 2009 by the American Association for Clinical Chemistry

Materials and MethodsMaterials and MethodsWomen’s Health Study (WHS) Prospective study

Apparently healthy U.S. women N=26 746

Baseline Lp(a): immunoturbidimetric assay (Denka Seiken) not affected by number of kringle-IV type 2 repeats

Follow-up 13.3 years

Outcome: Incident clinical diagnosis of type 2 diabetes N=1670 cases

© Copyright 2009 by the American Association for Clinical Chemistry

Materials and Methods (cont)Materials and Methods (cont)Copenhagen City Heart Study (CCHS)

Replication study, cross-sectional design

General population of Danish men and women N=9652

Baseline Lp(a): immunoturbidimetric assay (Dako)

Outcome: Prevalent diagnosis of type 2 diabetes N=419 cases

© Copyright 2009 by the American Association for Clinical Chemistry

QuestionQuestion

How does the number of kringle-IV type 2 repeats affect the accuracy of laboratory measurement of Lp(a) concentration? How may the size of apo(a) affect the measurement of Lp(a)?

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Results: Baseline CharacteristicsResults: Baseline Characteristics

Lp(a) concentrations were lower in cases compared with non-casesWeak correlations of Lp(a) with other risk factors

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Results (cont)Results (cont)

Lp(a) was inversely associated with diabetes in the WHS

In fasting individuals, threshold effect of ≈20% lower relative risk in quintiles 2–5 vs quintile 1

Stronger association in non-fasting individuals Up to 50% lower risk for quintile 5 vs 1, more linear effect

© Copyright 2009 by the American Association for Clinical Chemistry

Figure 2. Additive association of Lp(a) (mg/L) and HbA1c (%) concentrations with incident type 2 diabetes in WHS. * P < 0.001 compared with reference (Ref.).

0

2

4

6

<5 >5

Lp(a), mg/L

<10≥10

Ad

just

ed H

azar

d R

atio

P for trend <0.001

HbA1c, %5 to <6.5

Ref.

1.62

3.50*

5.36*

Lp(a) added predictive information to standard risk factors and HbA1c concentrations within the normal range

© Copyright 2009 by the American Association for Clinical Chemistry

CCHS Confirmed WHS FindingsCCHS Confirmed WHS Findings

Lp(a) (mg/dL) was also inversely associated with diabetes in the CCHS

No significant interaction by sex

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QuestionQuestion

What may be the mechanism(s) for the inverse association of Lp(a) with type 2 diabetes? What are possible explanations for why the association of Lp(a) with type 2 diabetes differs from its association with CVD?

© Copyright 2009 by the American Association for Clinical Chemistry

DiscussionDiscussionPredicting risk of type 2 diabetes has mostly focused on glycemic factors

This prospective study demonstrates independent and additivepredictive value for Lp(a) in association with diabetes

Predicting type 2 diabetes vs CVDWhile there is overlap in risk factors, not all risk factors for CVD are risk factors for type 2 diabetes

LDL cholesterol is risk factor for CVD but not diabetes

Family history of diabetes is risk factor for diabetes but not CVD

© Copyright 2009 by the American Association for Clinical Chemistry

Discussion (cont)Discussion (cont)

Potential Mechanisms?Less likely to be related to insulin resistance, inflammation, or other standard risk factors for diabetes

Possible mechanisms include hormonal regulation (insulin-like growth factors), post-transcriptional effects on apo(a), other effects

Deserves further investigation