Abstract Background Lower genetically predicted Lp(a) is not causally associated with increased T2DM risk. High atherogenic index of plasma (AIP) is associated with insulin resistance (IR). Purpose To assess whether high AIP alters the relation between Lp(a) and incident T2DM and outcome. Methods UK-Biobank cohort whose Lp(a) and AIP is available; known and undiagnosed T2DM (from baseline HbA1c) excluded. Major adverse cardiovascular event (MACE) - death, non-fatal myocardial infarction (MI), revascularisation or ischaemic stroke after entry obtained from Death Register and hospital episode statistics data. AIP was divided into quartiles. Incident T2DM after enrolment and MACE events were captured using ICD-10 codes and OPCS-4 codes from the linked HES data. Deaths were identified from the linked Death Register. The association between time to incident T2DM and MACE in Lp(a) quartile in each quartile of AIP is analysed by Kaplan-Meier method. Cox regression used to assess risk of incident T2DM/MACE in these Lp(a) quartiles. The risk of incident diabetes and MACE between the AIP quartiles is compared. Results Lp(a) and AIP measurement was available for 305286 non-diabetic subjects (Q1: -1.0593 to -0.1880, n=76322; Q2: -0.1881 to 0.0134, n=76322; Q3: 0.0135 to 0.2240, n=76321; Q4: 0.2241 to 1.259, n=76321). Over 11.9 years follow up, T2DM developed in 795 (1.04%) subjects in Q1, 1577 (2.07%) in Q2, 2781 (3.64%) in Q3 and 4954 (6.49%) in Q4 (p0.0001). MACE occurred in 5011 (6.57%) in Q1, 6501 (8.52%) in Q2, 8223 (10.77%) in Q3 and 10029 (13.14%) in Q4 (p0.0001). A direct association between Lp(a) and T2DM was seen in AIP Q1-2 while the relation inverts in Q4 (Fig1A-D). After adjustment for risk factors for T2DM including preDM, Lp(a) quartiles were inversely related to incident T2DM only in AIP Q4 (Lp(a) Q2: HR 0.85, 0.78-0.92, p0.0001, Q3: HR 0.86, 0.80-0.94, p=0.0003; Q4: HR 0.86, 0.80-0.93, p=0.0002) but not in Q1-3. Unadjusted MACE was higher in higher Lp(a) quartiles (Fig2A-D). In AIP Q4, MACE in Lp(a) Q3 (HR 1.08, 1.02-1.15, p=0.006) and Q4 (HR 1.19, 1.13-1.26, p0.0001) were higher compared to Q1. In AIP Q3, MACE was higher in Lp(a) Q4 (HR 1.15, 1.08-1.22, p0.0001) only compared to Q1. Similar relation seen in AIP Q2 (Lp(a) Q4 HR 1.18, 1.10 to 1.26, p0.0001). there was no relation between Lp(a) and MACE in AIP Q1. Conclusion Inverse relation of Lp(a) and incident T2DM is seen only in highest AIP quartile, a high IR state. Compared to Lp(a) Q1, increased MACE in Lp(a) Q4 only in AIP Q2-3 and in all quartiles in AIP Q4. .Fig 1 Fig 2
Sangha et al. (Sat,) studied this question.