The mixed benefit of low lipoprotein(a) in type 2 diabetes

Abstract

Background: Lipoprotein(a) (Lp(a)), a variant low-density lipoprotein (LDL), is a major genetic risk factor for cardiovascular disease. It is unknown whether an inverse relationship exists between Lp(a) and β-cell function (BCF), as for LDL-cholesterol (LDL-C) lowering by statins. We therefore assessedthe cardiometabolic phenotype of 340 men with type 2 diabetes mellitus (T2DM) in relation to Lp(a), focusing on BCF and hyperbolic product [BxS], which adjusts BCF to insulin sensitivity and secretion. Methods: Two groups were analyzed according to Lp(a) quartiles (Q): a (very-)low Lp(a) (Q1;n = 85) vs a normal-to-high Lp(a) group (Q2-Q4;n = 255). Results: In the overall cohort, mean Lp(a) was 52 nmol.L-1. Median Lp(a) was 6 nmol.L-1 (Q1) vs 38 nmol.L-1 (Q2-Q4). There were no differences between groups regarding age; education; diabetes duration; body mass index; body composition and smoking. Q1 had significantly worse glycemic control, higher systolic blood pressure, more severe metabolic syndrome, and more frequent hepatic steatosis. Insulin sensitivity was significantly lower (- 37%) in Q1, who also had lesser hyperbolic product (- 27%), and higher [BxS] loss rate (+ 15%). Q1 also had higher frequency (+31%) and severity (+20%) of atherogenic dyslipidemia. Microangiopathy and neuropathy were higher in Q1 (+ 34% and + 48%, respectively), whereas Q2-Q4 patients had increased macroangiopathy (+ 51%) and coronary artery disease (CAD; + 94%). Conclusions: Low Lp(a) appears both beneficial and unhealthy in T2DM. It is associated with unfavourable cardiometabolic phenotype, lesser BCF, poorer glycemic control, and increased microvascular damage despite being linked to markedly reduced CAD, suggesting that Lp(a)-related vascular risk) follows a J-shaped curve.