Lipids and Lp(a) Lipoprotein Levels and Coronary Artery Disease in Subjects With Non-Insulin-Dependent Diabetes Mellitus

doi:10.1016/S0025-6196(12)61638-3

Mayo Clinic Proceedings

Volume 69, Issue 5, May 1994, Pages 430-435

https://doi.org/10.1016/S0025-6196(12)61638-3 Get rights and content

Objective

To determine whether increased Lp(a) lipoprotein levels are associated with either non-insulin-dependent diabetes mellitus (NIDDM) or coronary artery disease (CAD) in patients with NIDDM and to examine the relationship between Lp(a) levels and glycemic control.

Design

We conducted a cross-sectional study of subjects with NIDDM who were participants in the Rochester Diabetic Neuropathy Study and healthy control subjects from the population of Rochester, Minnesota.

Material and Methods

Lipids and Lp(a) lipoprotein levels were compared in 227 subjects with NIDDM and 163 control subjects and, among the subjects with NIDDM, in those with (N = 96) and without (N = 131) CAD. The correlation between Lp(a) levels and glycosylated hemoglobin was investigated.

Results

Subjects with NIDDM had higher triglyceride and lower high-density lipoprotein cholesterol levels than did control subjects. Subjects with NIDDM and CAD had higher total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels and lower high-density lipoprotein cholesterol levels than did subjects with NIDDM without CAD. Subjects with NIDDM had significantly higher Lp(a) levels than did control subjects, but subjects with NIDDM and CAD did not have significantly higher Lp(a) levels than did those without CAD. Among subjects with NIDDM, the level of Lp(a) was not significantly correlated with glycosylated hemoglobin.

Conclusion

Although subjects with NIDDM have higher Lp(a) levels than do control subjects, Lp(a) does not seem to be associated with CAD in subjects with NIDDM. In this study, no association was found between Lp(a) level and glycemic control.

Section snippets

Study Subjects

Blood samples were obtained from 227 subjects (115 women and 112 men) with NIDDM who were participants in the Rochester Diabetic Neuropathy Study and 163 adult control subjects (85 women and 78 men) who were healthy persons from the general population of Rochester, Minnesota, without evidence of CAD on clinical examination and review of the medical history. All subjects were at least 35 years old. The diagnosis of diabetes was based on a fasting blood glucose level of more than 140 mg/dL on at

Lipoprotein Profiles in Subjects With NIDDM Versus Control Subjects

Lipid and Lp(a) lipoprotein profiles for subjects with NIDDM and control subjects are shown in Table 1. In comparison with control subjects, those with NIDDM had higher triglyceride levels (2.47 versus 1.34 mmol/L; P = 0.0001, ANCOVA) and lower HDL cholesterol levels (0.92 versus 1.21 mmol/L; P = 0.0001). Total and LDL cholesterol levels were approximately the same in NIDDM and control groups. Lp(a) levels were significantly higher in subjects with NIDDM than in control subjects without

DISCUSSION

Lp(a) lipoprotein is a risk factor for CAD in subjects without diabetes9, 10, 11 and seems to be related to the severity of CAD as assessed angiographically.¹⁰ The role of Lp(a) in atherogenesis in diabetes is unknown. Researchers have postulated that Lp(a) may, in part, explain the increased risk of vascular disease associated with diabetes mellitus that exists after controls have been imposed for conventional risk factors.

The role of Lp(a) in atherogenesis in NIDDM has not been addressed

CONCLUSION

Lp(a) lipoprotein levels are higher in subjects with NIDDM than in control subjects. Lp(a) levels in subjects with NIDDM and CAD, however, do not differ significantly from those without CAD. Furthermore, no significant association exists between Lp(a) levels and glycemic control or nephropathy. These findings do not support the conclusion that Lp(a) excess is independently atherogenic in NIDDM. The possibility exists that Lp(a) has a synergistic role in diabetes-related atherogenesis, but an

ACKNOWLEDGMENT

We acknowledge the expert technical assistance of Nina D. Bren, who performed the Lp(a) assays, and the help of Douglas W. Mahoney with statistical analysis.

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Lipoprotein (a) and comprehensive lipid tetrad index as a marker for coronary artery disease in NIDDM patients in South India
2006, Clinica Chimica Acta
Coronary artery disease (CAD) is reaching epidemic proportions in India, in the absence of traditional risk factors. Lipoprotein (a) (Lp(a)) concentrations are related to both atherogenesis and thrombogenesis and may be a key link between lipid and CAD. We studied the role of Lp(a) and comprehensive lipid tetrad index as markers for CAD in South Indian patients with non-insulin-dependent diabetes mellitus (NIDDM).
Lp(a) concentrations and lipid profile were estimated in 53 NIDDM patients with CAD (Group 1), 53 NIDDM patients without CAD (Group 2), and 52 control subjects (Group 3). Comprehensive lipid tetrad index was calculated in all patients and controls.
Lp(a) concentrations were significantly higher in Group 1 patients, when compared with Groups 2 and 3. In NIDDM patients with CAD, only total cholesterol and low-density cholesterol concentrations correlated significantly positively with lipoprotein (a) concentrations (r = 0.184, p = 0.03 and r = 0.168, p = 0.02). Mean comprehensive lipid tetrad index was 45,487 ± 2747 in Group 1, 10,866 ± 1163 in Group 2 and 4582 ± 348 in Group 3 subjects.
Based on the foregoing data, high Lp(a) concentrations show strong correlation with CAD in NIDDM patients of South India. High concentrations of Lp(a) and comprehensive lipid tetrad index, along with high prevalence of NIDDM, may render Indians particularly vulnerable to malignant atherosclerosis at a young age. As NIDDM is increasing in prevalence in India, the above observations have ominous dimensions in terms of total burden of CAD in India.
Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease: The Strong Heart Study
2002, Annals of Epidemiology
PURPOSE: To evaluate the distribution of lipoprotein(a) (Lp(a)) and assess its association to cardiovascular disease (CVD) in American Indians.
METHODS: Lp(a) was measured in 3991 American Indians (aged 45–74 years with no prior history of CVD at baseline) from 13 communities in Arizona, Oklahoma, and South/North Dakota. They were followed prospectively from 1989 to 1997 for CVD. The distribution of Lp(a) was examined by center, sex, and diabetic status. Spearman correlation coefficients and Cox regression models were used to evaluate the association of Lp(a) to CVD.
RESULTS: A total of 388 participants subsequently developed CVD. Median Lp(a) concentration in American Indians was 3.0 mg/dl. This was almost half of that in whites and one sixth in blacks from the CARDIA study measured by the same method. Nondiabetic participants had significantly higher Lp(a) levels than diabetic participants for both genders. Lp(a) levels were higher in women than in men for nondiabetic participants, but there was no gender difference for diabetic participants. Correlation analysis showed Lp(a) was significantly negatively correlated with the degree of Indian heritage, insulin, triglycerides (TG), fasting plasma glucose (FPG), and 2-hour plasma glucose (2hPG), and positively with low-density lipoproteins (LDL), apoprotein B (apoB), and fibrinogen (FIB). In Cox regression models, adjusting for other risk factors, Lp(a) was no longer a significant predictor of CVD in either diabetic or nondiabetic participants.
CONCLUSIONS: The lower concentration of Lp(a) in American Indians and the high correlation with Indian heritage confirm the concept that Lp(a) concentration is in large part genetically determined. Lp(a) concentration is not an independent predictor of CVD among American Indians; it is higher in those who develop CVD because of its positive correlation with LDL, apoB, and FIB.
Lack of association of serum lipoprotein (a) levels with type-2 diabetes mellitus in patients with angiographically defined coronary artery disease
2000, International Journal of Cardiology
Multiple studies have demonstrated that elevated serum lipoprotein (a) [Lp(a)] levels are independent predictors for coronary artery disease (CAD) in subjects without diabetes mellitus (DM). However, their contribution in patients with DM is controversial and still requires clarification. We determined serum Lp(a) levels in 355 consecutive Caucasian patients (271 men and 84 women) with angiographically documented CAD, and in 100 control subjects (58 men and 42 women) who were clinically free of cardiovascular disease. In addition, the association of serum Lp(a) levels with type-2 DM in patients with CAD was investigated after reassigning patients according to the diagnosis of type-2 DM (61 men and 40 women with type-2 DM and 210 men and 44 women without). No gender differences in Lp(a) levels were observed between men and women (patients and control subjects). Patients with CAD had higher Lp(a) levels than the control subjects (33 (14–74) vs. 13 (9–29) mg/dl, P<0.001). Elevated Lp(a) levels (defined as >90th percentile of controls) were significantly more prevalent in men and women with CAD (35% and 28%, respectively) than in control subjects (13% and 10%, respectively). Serum Lp(a) levels correlated with LDL cholesterol (r=0.22, P<0.001) and apo B levels (r=0.18, P<0.03) in patients and control subjects. Stepwise discriminant analysis revealed that Lp(a) was an independent risk factor for the presence of CAD, independent of smoking, hypertension, type-2 DM, LDL and HDL cholesterol or apo A1 and B levels. When patients were studied according to the spread of CAD (evaluated as the number of narrowed vessels), no differences in serum Lp(a) levels were observed, nor was there a higher prevalence of elevated Lp(a) levels. Finally, when patients were re-assigned according to the diagnosis of type-2 DM, no effect of apo B and LDL-C levels on Lp(a) was found (r=0.06, P=n.s. and 40.14, P=n.s., respectively) and serum Lp(a) levels neither associated nor contributed to the extent of CAD. Our results showed that serum Lp(a) levels are increased in patients with angiographically documented CAD, but there were no significant differences between diabetic and non-diabetic patients, which indicates that elevated Lp(a) levels are specifically associated with CAD but not with type-2 DM.
Glycation amplifies lipoprotein(a)-induced alterations in the generation of fibrinolytic regulators from human vascular endothelial cells
2000, Atherosclerosis
Increased lipoprotein(a) [Lp(a)] in plasma is an independent risk factor for premature cardiovascular diseases. The levels of glycated Lp(a) are elevated in diabetic patients. The present study demonstrated that glycation enhanced Lp(a)-induced production of plasminogen activator inhibitor-1 (PAI-1), and further decreased the generation of tissue-type plasminogen activator (t-PA) from human umbilical vein endothelial cells (HUVEC) and human coronary artery EC. The levels of PAI-1 mRNA and its antigen in the media of HUVEC were significantly increased following treatments with 5 μg/ml of glycated Lp(a) compared to equal amounts of native Lp(a). The secretion and de novo synthesis of t-PA, but not its mRNA level, in EC were reduced by glycated Lp(a) compared to native Lp(a). Treatment with aminoguanidine, an inhibitor for the formation of advanced glycation end products (AGEs), during glycation normalized the generation of PAI-1 and t-PA induced by glycated Lp(a). Butylated hydroxytoluene, a potent antioxidant, inhibited native and glycated Lp(a)-induced changes in PAI-1 and t-PA generation in EC. The results indicate that glycation amplifies Lp(a)-induced changes in the generation of PAI-1 and t-PA from venous and arterial EC. This may attenuate fibrinolytic activity in blood circulation and potentially contributes to the increased incidence of cardiovascular complications in diabetic patients with hyperlipoprotein(a). EC-mediated oxidative modification and the formation of AGEs may be implicated in glycated Lp(a)-induced alterations in the generation of fibrinolytic regulators from vascular EC.
High lipoprotein(a) concentrations are associated with lower type 2 diabetes risk in the Chinese Han population: a large retrospective cohort study
2021, Lipids in Health and Disease
Lipoprotein (a) is not significantly associated with type 2 diabetes mellitus: cross-sectional study of 1604 cases and 7983 controls
2017, Acta Diabetologica

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: This study was supported in part by a grant from the American Diabetes Association, Minnesota Affiliate, and Grant NS 14304 from the National Institutes of Health, Public Health Service. Dr. O'Brien is supported in part by the W. L. Stephenson Fellowship in Clinical Nutrition.

^*: Current address: University of Florida, Gainesville, Florida.

^†: Current address: The Watson Clinic, Lakeland, Florida.

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Lipids and Lp(a) Lipoprotein Levels and Coronary Artery Disease in Subjects With Non-Insulin-Dependent Diabetes Mellitus

Objective

Design

Material and Methods

Results

Conclusion

Section snippets

Study Subjects

Lipoprotein Profiles in Subjects With NIDDM Versus Control Subjects

DISCUSSION

CONCLUSION

ACKNOWLEDGMENT

Am J Clin Nutr

J Biol Chem

Clin Chim Acta

Atherosclerosis

Metabolism

Atherosclerosis

Metabolism

Atherosclerosis

Morbidity and mortality in diabetics in the Framingham population: sixteen year follow-up study

Diabetes

A new serum type system in man—the Lp system

Acta Pathol Microbiol Scand

Angina of effort and an extra pre-beta lipoprotein fraction

Acta Med Scand Suppl

Plasma pre-beta lipoprotein sub-fractions in diagnosis of coronary artery disease [abstract]

Circulation

Lp(a) lipoprotein/pre-β1-lipoprotein in Swedish middle-aged males and in patients with coronary heart disease

Clin Genet

Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography

Circulation

Lp(a) lipoprotein as a risk factor for myocardial infarction

JAMA

Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen

Proc Natl Acad Sci U S A

cDNA sequence of human apolipoprotein(a) is homologous to plasminogen

Nature

Lp(a) lipoprotein/pre-β₁-lipoprotein in Swedish middle-aged males and in patients with coronary heart disease