Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Pathophysiology/Complications

Lipoprotein(a) as a Risk Factor for Cardiovascular Mortality in Type 2 Diabetic Patients

A 10-year follow-up study

  1. Cristina Hernández, MD1,
  2. Gemma Francisco, MD1,
  3. Pilar Chacón, MD2 and
  4. Rafael Simó, MD1
  1. 1Diabetes Research Unit, Endocrinology Division, Hospital Universitari Vall d’Hebron, Barcelona, Spain
  2. 2Department of Biochemistry, Hospital Universitari Vall d’Hebron, Barcelona, Spain
  1. Address correspondence and reprint requests to Dr. Rafael Simó, Diabetes Research Unit, Endocrinology Division, Hospital Universitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail: rsimo{at}vhebron.net
Diabetes Care 2005 Apr; 28(4): 931-933. https://doi.org/10.2337/diacare.28.4.931
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading

A 10-year follow-up study

  • CHD, coronary heart disease
  • CVD, cardiovascular disease
  • WHO, World Heath Organization

Although patients with type 2 diabetes have a high risk of death from cardiovascular disease (CVD), the traditional risk factors do not fully explain this excess of mortality. In this regard, it would be of great interest to assess the role of nontraditional risk factors such as lipoprotein(a) in cardiovascular mortality in diabetic patients.

Danesh et al. (1), in a meta-analysis including the prospective studies published before 2000, concluded that there was a clear association between lipoprotein(a) and CVD in the general population. Further prospective reports have demonstrated that lipoprotein(a) is an independent predictor of the development of CVD (2–5). However, little data exist on the clinical importance of lipoprotein(a) in the diabetic population. We herein report a prospective study to evaluate the relationship between lipoprotein(a) levels and cardiovascular mortality in type 2 diabetic patients of Caucasian origin.

RESEARCH DESIGN AND METHODS

One hundred twenty-two consecutive type 2 diabetic outpatients of Caucasian origin attending the outpatient diabetic unit of a university hospital between April and May of 1993 were enrolled for a 10-year prospective study. To avoid the possible transient increase of lipoprotein(a) after starting insulin treatment (6), all patients in whom insulin treatment was initiated in the months before the study were excluded. Patients with renal failure were also excluded. To assess evidence of macroangiopathy, we used the World Health Organization (WHO) protocol, which includes a detailed questionnaire and a 12-lead electrocardiogram (7,8). By the end of the study, data were available from 100 patients. Of these, 29 had died (23 from CVD).

Metabolic parameters were evaluated in venous blood drawn after overnight fasting. Lipoprotein(a) was measured by enzyme-linked immunosorbent assay using a monoclonal lipoprotein(a) antibody technique (Macra Terumo, Newark, DE).

Statistical analysis

The Student’s t test for continuous variables and the χ2 test for categorical variables were used. In view of their skewed distribution of lipoprotein(a), triglycerides and albumin excretion rate results were logarithmically transformed. Correlations were studied by linear regression analysis. The event studied was death from vascular disease, e.g., coronary heart disease (CHD) or stroke event. Curves of event-free survival were estimated by the Kaplan-Meier method. To further explore the variables independently associated with cardiovascular mortality (dependent variable), a logistic regression analysis was performed taking into account lipoprotein(a), age, sex, BMI, smoking habit, HbA1c, creatinine, albumin excretion rate, LDL cholesterol, HDL cholesterol, triglycerides, and the presence of hypertension, macroangiopathy, and retinopathy (independent variables). In the present study, the cutoff point was lowered to 20 mg/dl because this enabled us to obtain a sufficient cohort of patients (top quarter) at risk of cardiovascular mortality due to lipoprotein(a) levels. The data were analyzed with SPSS.

RESULTS

The clinical characteristics and cardiovascular risk factors at baseline for patients in the study are shown in Table 1. During follow-up total mortality was 29% (n = 29), and 23 of 29 (79.3%) diabetic patients died due to CVD (18 from CHD and 5 from stroke). The lipoprotein(a) concentration was higher in patients who died from CVD (median 15.5 mg/dl [range 0.5–75]) than those who remained alive or those who died from non-CVD causes (6 mg/dl [0.5–85], P = 0.03). The coefficient of correlation between baseline lipoprotein(a) and final lipoprotein(a) performed in the subjects who were still alive at the end of follow-up (n = 71) was 0.88 (P < 0.001).

In the cross-sectional statistical analysis at the beginning of the study, diabetic patients with macroangiopathy had higher lipoprotein(a) concentrations than those without macroangiopathy (Table 1). There were no differences at baseline in the classic cardiovascular risk factors between patients with high (≥20 mg/dl) or low (<20 mg/dl) concentrations of lipoprotein(a) except for total cholesterol (Table 1). Among patients with serum lipoprotein(a) ≥20 mg/dl, 38.4% (n = 10) died of CVD during the study, whereas only 17.5% of patients (n = 13) with lipoprotein(a) <20 mg/dl died of CVD (P = 0.03). The survival rate from cardiovascular events calculated by means of Kaplan-Meier curves showed that it was lower in those patients in whom lipoprotein(a) was ≥20 mg/dl (log-rank test = 5.1, P = 0.02). The logistic regression analysis showed that both lipoprotein(a) concentration (log transformed) and the presence of macroangiopathy at baseline were independent risk factors for cardiovascular mortality (risk ratio 6.7 [1.3–20], P = 0.018 and 5.4 [1.3–27.9], P = 0.017, respectively). Furthermore, a lipoprotein(a) level ≥20 mg/dl was independently associated with a more than sixfold greater risk of cardiovascular mortality (6.6 [1.6–26.8], P = 0.008).

CONCLUSIONS

In this prospective study, we found for the first time that lipoprotein(a) concentration is an independent risk factor for cardiovascular mortality in type 2 diabetic patients. Although lipoprotein(a) serum concentration >30 mg/dl has generally been considered a cardiovascular risk factor, in the present study the cutoff point of 20 mg/dl was selected because it was the lowest lipoprotein(a) level that allowed us to identify those diabetic patients at risk for cardiovascular mortality.

To our knowledge there are only three prospective studies in which the predictive value of lipoprotein(a) on CVD in the diabetic population has been evaluated (9–11). Hiraga et al. (9) demonstrated that lipoprotein(a) was an independent risk factor for CVD in Japanese type 2 diabetic patients. However, the follow-up was short, and plasma lipoprotein(a) was semiquantified by a rapid electrophoretic method that only discriminates high from low serum lipoprotein(a) at 20 mg/dl. Abu-Lebdeh et al. (10), using a similar method of lipoprotein(a) measurement, found no relationship between lipoprotein(a) and CVD. This study was performed in a cohort of type 2 diabetic patients with a short duration of diabetes (one-third were enrolled within 1 year of diagnosis of diabetes) and without CVD at baseline. By contrast, in our study a large percentage of patients (36%) presented macroangiopathy at baseline, the mean duration of diabetes was 10.4 ± 8.1 years, and lipoprotein(a) was assessed by enzyme-linked immunosorbent assay. All of these differences could explain, in part, why these authors did not find a relationship between lipoprotein(a) and CVD. In this regard, it should be noted that the deleterious effect of lipoprotein(a) on CVD is higher in subjects with other risk factors (2,3). Finally, the study published by Simons et al. (11) was performed in elderly patients. It has been shown that the impact of elevated lipoprotein(a) on CHD appears to decrease with age (12). Therefore, the lack of relationship between lipoprotein(a) and CHD observed by these authors could be due to this selection bias.

Our findings suggest that the assessment of lipoprotein(a) concentration could contribute to the identification of diabetic patients with high risk of death due to CVD. However, only patients attending the outpatient clinic of a hospital (high-risk patients) have been included, and, therefore, one should be cautious about extrapolating our results to the general type 2 diabetic population. In addition, this study was not controlled for treatments that could influence cardiovascular mortality. With these caveats in mind, it is proposed that in those patients in whom lipoprotein(a) is ≥20 mg/dl, a strict follow-up to achieve the goals recommended by the American Diabetes Association should be a priority. Further studies to evaluate whether the treatment of cardiovascular risk factors in diabetic patients with high lipoprotein(a) should be more aggressive than currently recommended are needed. In addition, studies including a larger cohort of diabetic patients and control subjects for treatments influencing survival are necessary to confirm the findings of the present report.

View this table:
  • View inline
  • View popup
Table 1—

Univariate analyses comparing clinical features at baseline according to both lipoprotein(a) concentration and cardiovascular mortality

Acknowledgments

This study was supported by a grant from Novo Nordisk Pharma S.A. (01/0066) and the Instituto de Salud Carlos III (G03/212 and C03/08).

Footnotes

  • A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted December 21, 2004.
    • Received September 21, 2004.
  • DIABETES CARE

References

  1. ↵
    Danesh J, Collins R, Peto R: Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies. Circulation 102:1082–1085, 2000
    OpenUrlAbstract/FREE Full Text
  2. ↵
    von Eckardstein A, Schulte H, Cullen P, Assmann G: Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Col Cardiol 37:434–439, 2001
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    Luc G, Bard JM, Arveiler D, Ferrieres J, Evans A, Amouyel P, Fruchart JC, Ducimetiere P, the PRIME Study Group: Lipoprotein(a) as a predictor of coronary heart disease: the PRIME study. Atherosclerosis 163:377–384, 2002
    OpenUrlCrossRefPubMedWeb of Science
  4. Ariyo AA, Thach C, Tracy R, the Cardiovascular Health Study: Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 349:108–2115, 2003
    OpenUrl
  5. ↵
    Rifai N, Ma J, Sacks FM, Ridker PM, Hernandez WJ, Stampfer MJ, Marcovina SM: Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of angina pectoris with evidence of severe coronary atherosclerosis in men: the Physicians’ Health Study. Clin Chem 50:1364–1371, 2004
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Simó R, Hernández C, Chacón P, Martí R, Mesa J: Effect of insulin administration on serum lipoprotein(a) and its phenotypes in new-onset IDDM patients (Letter). Diabetes Care 21:866–867, 1998
    OpenUrlFREE Full Text
  7. ↵
    Jarret RJ, Keen H, Grabauskas V: The WHO multinational study of vascular disease in diabetes. 1. General description. Diabetes Care 2:175–186, 1979
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Keen H, Jarret J: The WHO multinational study of vascular disease in diabetes. 2. Macrovascular disease prevalence. Diabetes Care 2:187–195, 1979
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Hiraga T, Kobayashi T, Okubo M, Nakanishi K, Sugimoto T, Ohashi Y, Murase T: Prospective study of lipoprotein(a) as a risk factor for atherosclerotic cardiovascular disease in patients with diabetes. Diabetes Care 18:241–244, 1995
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Abu-Lebdeh HS, Hodge DO, Nguyen TT: Predictors of macrovascular disease in patients with type 2 diabetes mellitus. Mayo Clin Proc 76:707–712, 2001
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    Simons L, Friedlander Y, Simons J, McCallum J: Lipoprotein(a) is not associated with coronary heart disease in the elderly: cross-sectional data from the Dubbo study. Atherosclerosis 99:87–95, 1993
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    Sunayama S, Daida H, Mokuno H, Miyano H, Yokoi H, Lee YJ, Sakurai H, Yamaguchi H: Lack of increased coronary atherosclerotic risk due to elevated lipoprotein(a) in women > or = 55 years of age. Circulation 94:1263–1268, 1996
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
Diabetes Care: 28 (4)

In this Issue

April 2005, 28(4)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Lipoprotein(a) as a Risk Factor for Cardiovascular Mortality in Type 2 Diabetic Patients
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Lipoprotein(a) as a Risk Factor for Cardiovascular Mortality in Type 2 Diabetic Patients
Cristina Hernández, Gemma Francisco, Pilar Chacón, Rafael Simó
Diabetes Care Apr 2005, 28 (4) 931-933; DOI: 10.2337/diacare.28.4.931

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Lipoprotein(a) as a Risk Factor for Cardiovascular Mortality in Type 2 Diabetic Patients
Cristina Hernández, Gemma Francisco, Pilar Chacón, Rafael Simó
Diabetes Care Apr 2005, 28 (4) 931-933; DOI: 10.2337/diacare.28.4.931
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • RESEARCH DESIGN AND METHODS
    • RESULTS
    • CONCLUSIONS
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Insulin Resistance Is Associated With Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort
  • Restoration of Hypoglycemia Awareness Alters Brain Activity in Type 1 Diabetes
  • Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study
Show more Pathophysiology/Complications

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.