Abstract Background Lower genetically predicted Lp(a) is not causally associated with increased T2DM risk. Development of T2DM itself may lower Lp(a). Low insulin-like growth factor-1 (IGF-1) is associated with insulin resistance (IR). Purpose To assess whether low normal IGF-1 alters the relation between Lp(a) and incident type 2 diabetes and outcome. Methods UK-Biobank cohort whose Lp(a) and IGF-1 were 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. Age- and sex- adjusted normal IGF-1, divided into quintiles. The association between time to incident T2DM and MACE in Lp(a) quartile in subjects in the low-normal IGF-1 and each of its quintiles is analysed by Kaplan-Meier method. Cox regression used to assess risk of incident T2DM/MACE in these Lp(a) quartiles. Results Lp(a) and IGF-1 measurements were available for 331761 non-diabetic subjects. 319139 had age- and sex-adjusted normal IGF-1 (Q1-63830, Q2-63833, Q3-63821, Q4-63834, Q5-63821). Over 11.9 years follow up, T2DM developed in 3168 (5.0%) in Q1, 2202 (3.4%) in Q2, 1904 (3.0%) in Q3, 1717 (2.7%) in Q4 and 1574 (2.5%) in Q5 (p0.0001). MACE occurred in 31076 (9.7%), 7880 (12.3%) in Q1, 6507 (10.2%) in Q2, 6061 (9.5%) in Q3, 5649 (8.8%) in Q4 and 4979 (7.8%) in Q5 (p0.0001). Inverse association between Lp(a) and T2DM was seen in the whole cohort of subjects with low-normal IGF-1 (Fig 1A) and in IGF-1 Q1-2 (Fig1BC) but not Q3-5 (Fig1DEF). After adjustment for risk factors for T2DM including preDM, Lp(a) quartiles was inverse related to incident T2DM in IGF-Q1 (Lp(a) Q4: HR 0.86, 0.77-0.95, p=0.0027) and IGF-Q2 (Lp(a) Q2: HR 0.82, 0.72-0.92, p=0.001; Q3: HR 0.85, 0.76-0.96, p=0.009; Q4 HR 0.88, 0.78-0.99, p=0.038) but not in Q3-5. Lp(a) and MACE were directly associated in all subjects with low normal IGF-1 and in all the IGF-1 quintiles (Fig 2ABCDEF). In a fully adjusted model MACE risk was higher in Lp(a) Q4 (but no Q2-3) compared to Q1 in all the IGF-1 quintiles (Q1: HR 1.09, 1.02-1.16, p=0.014; Q2: HR 1.14, 1.06-1.23, p0.001; Q3:HR 1.23, 1.14-1.32, p0.0001; Q4: HR 1.22, 1.13-1.32, p0.0001; Q5: HR 1.14, 1.05-1.24, p-0.002) Conclusion Inverse relation of Lp(a) and incident T2DM is seen only in the lowest 2 quintiles of subjects with low-normal IGF-1, a high IR state. Increased MACE in higher Lp(a) quartiles in all IGF-1 quintiles suggest that IGF-1 levels may not affect the relation between Lp(a) and MACE.
Sangha et al. (Sat,) studied this question.