Lipoprotein(A) and Diabetes Mellitus

Abstract

Lipoprotein(a), first described in human plasma by Berg (1) in 1963, is a distinct lipoprotein class with a structure similar to low-density lipoprotein (LDL). It differs from LDL in having a unique apolipoprotein, apo(a), attached to the apo B-100 of LDL by a disulfide bond. Apo(a) is a large glycoprotein with structural homology to plasminogen. Thus, investigators have proposed that this particle may form an important link between atherosclerosis and thrombosis. Indeed, lipoprotein(a) has been shown to compete with plasminogen for binding sites on the endothelium (2). In addition, lipoprotein(a) has been shown to interfere with endothelial cell fibrinolysis by inhibiting plasminogen binding and hence plasmin generation (3) and has been demonstrated in human atherosclerotic tissue (4). Increased plasma concentrations of lipoprotein(a) have been thought to be associated with atherosclerosis in subjects without diabetes mellitus. Although several prospective studies have demonstrated this finding in men (57), it has not been a universal observation (8). Less information is available about the role of lipoprotein(a) as a risk factor for coronary artery disease in women without diabetes mellitus. A recent cross-sectional study suggested that lipoprotein(a) is a determinant of coronary artery disease in both premenopausal and postmenopausal women (9). In addition, one prospective study has demonstrated that lipoprotein(a) is a risk factor for coronary artery disease in women (10). Thus, in subjects without diabetes mellitus, considerable evidence suggests that lipoprotein(a) is a risk factor for coronary artery disease. Because the reason for the increased risk of coronary artery disease in patients with diabetes mellitus cannot be fully explained by traditional risk factors, considerable interest has been focused on the potential role of lipoprotein(a) as a risk factor in these subjects. Most studies addressing the role of this particle in diabetes mellitus have been cross-sectional analyses and have yielded inconsistent results. Studies in patients with insulindependent diabetes mellitus (IDDM) have reported lipoprotein(a) levels to be similar (11,12) or increased (13,14) in comparison with the levels in control subjects without diabetes. In a follow-up study of the Diabetes Control and Complications Trial, lipoprotein(a) levels were similar in external control subjects and intensively treated subjects but significantly higher in the conventionally treated group (15). This suggests that lipoprotein(a) levels may be influenced by glycemic control in IDDM. In contrast to IDDM, most large cross-sectional studies have shown that lipoprotein(a) levels are similar in patients with non-insulin-dependent diabetes mellitus (NIDDM) and control subjects (16,17). Fewer published studies have compared lipoprotein(a) levels in patients who have NIDDM with and without coronary artery disease. Some cross-sectional studies have reported similar lipoprotein(a) levels in patients who have NIDDM with and without coronary artery disease (18,19). This is also the finding described by Ginier and Deedwania in this issue of Endocrine Practice(pages 276 to 280). Thus, on the basis of evidence available from cross-sectional studies, lipoprotein(a) has not been substantiated as a risk factor for coronary artery disease in patients with diabetes. Nevertheless, as pointed out by the authors of the current report, cross-sectional studies may yield inaccurate results because subjects with increased lipoprotein(a) levels and coronary artery disease may have died before the study. Therefore, prospective studies are necessary to evaluate whether lipoprotein(a) is a risk factor for coronary artery disease in diabetes mellitus. Thus, it is of interest that a recent prospective study from the Mayo Clinic found no relationship between lipoprotein(a) levels and the risk of coronary artery disease in patients with diabetes mellitus (20). This observation is consistent with the results of the cross-sectional studies. Further prospective studies must be conducted, however, to establish the consistency of these findings. The reason that lipoprotein(a) is not a risk factor for coronary artery disease in subjects with diabetes in contrast to those without diabetes is unclear. Perhaps numerous other risk factors for coronary artery disease present in diabetes mellitus may outweigh the effect of increased levels of lipoprotein(a). In addition, different apo(a) isoforms may be present in diabetes mellitus. Apo(a) is a heterogeneous protein, and lipoprotein(a) concentrations are influenced by the apo(a) isoform present. Further studies should be designed to address these issues. The relationship between lipoprotein(a) and microvascular complications in diabetes mellitus is unclear. Of interest, lipoprotein(a) levels were increased in subjects with diabetic retinopathy in the current study. This finding is consistent with that in another study, in which apo(a) levels were increased in patients with retinopathy who required laser therapy (21). As pointed out by the authors, studies of the relationship between lipoprotein(a) and renal disease have yielded inconsistent results. In the current study subjects, no difference in lipoprotein(a) levels was found between those with microalbuminuria and those with normoalbuminuria. The relationship between lipoprotein(a) levels and microvascular disease must be determined in larger prospective studies in the future.