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)

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;302:412-423

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: 1363-1370

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

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;44:369-374 Haffner SM et al Diabetes 1992;41:267-72

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?

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

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

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)?

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

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

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 < 0.001 compared with reference (Ref.).

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

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?

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

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