2. Introduction 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 given
homology to plasminogen and/or to be atherogenic given homology with LDL
Commercial assays not well standardized and sensitive to size of apo(a)

3. Epidemiology Lp(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:

4. 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
Cutoff Percentile
Lipoprotein(a) Level, mg/dL
25th
≥ 4.4
50th
≥ 10.6
75th
≥ 32.8
90th
≥ 65.5
95th
≥ 83
99th
≥ 130.7
Fully Adjusted HR (95% CI)*
P Value
1.05 (0.90–1.23)
.56
1.10 (0.96–1.27)
.15
1.48 (1.29–1.71)
<.001
1.66 (1.38–1.99)
1.87 (1.50–2.34)
1.99 (1.32–3.00)
.001
Suk Danik et al. JAMA 2006;296:

5. 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:

6. Lp(a) and Type 2 Diabetes
Common Soil” Hypothesis Common genetic and environmental antecedents
for CVD and type 2 diabetes
Prior Studies
Small 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:
Haffner SM et al Diabetes 1992;41:267-72

7. Question
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?

8. Materials and Methods Women’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

9. 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

10. Question
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)?

11. Results: Baseline Characteristics
Lp(a) concentrations were lower in cases compared with non-cases
Weak correlations of Lp(a) with other risk factors

12. 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

13. Lp(a) added predictive information to standard risk factors and
HbA1c concentrations within the normal range
Lp(a), mg/L
≥10
<10
5.36*
P for trend <0.001
3.50*
Adjusted Hazard Ratio
1.62
Ref.
5 to <6.5
HbA1c, %
Figure 2. Additive association of Lp(a) (mg/L) and HbA1c (%) concentrations with incident type 2 diabetes in WHS. * P < compared with reference (Ref.).

14. CCHS Confirmed WHS Findings
Lp(a) (mg/dL) was also inversely associated with diabetes in the CCHS
No significant interaction by sex

15. Question
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?

16. Discussion
Predicting risk of type 2 diabetes has mostly focused on glycemic factors
This prospective study demonstrates independent and additive
predictive value for Lp(a) in association with diabetes
Predicting type 2 diabetes vs CVD
While 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

17. 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