Elsevier

American Heart Journal

Volume 170, Issue 2, August 2015, Pages 380-389.e4
American Heart Journal

Clinical Investigation
Prevention and Rehabilitation
Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality

https://doi.org/10.1016/j.ahj.2015.04.017Get rights and content

Background

Single measurements of elevated high-sensitivity C-reactive protein (hs-CRP) are associated with increased risk of diabetes, cardiovascular disease, and mortality. Large increases or sustained elevations in hs-CRP may be associated with even greater risk of these outcomes. The objective of this study was to characterize the association of 6-year change in hs-CRP with incident diabetes, incident cardiovascular events (heart disease, stroke, and heart failure), and mortality.

Methods

We included 10,160 ARIC participants with hs-CRP measured at visits 2 (1990-1992) and 4 (1996-1998). Change in hs-CRP was categorized as sustained low/moderate (<3 mg/L at both visits), decreased (≥3 mg/L at visit 2 and <3 mg/L at visit 4), increased (<3 mg/L at visit 2 and ≥3 mg/L at visit 4), and sustained elevated (≥3 mg/L at both visits). Cox proportional hazards models were used to assess the association of 6-year change in hs-CRP with incident diabetes, cardiovascular events, and death during ~15 years after visit 4.

Results

Compared with persons with sustained low/moderate hs-CRP, those with increased or sustained elevated hs-CRP had an increased risk of incident diabetes (hazard ratios [95% CIs] 1.56 [1.38-1.76] and 1.39 [1.25-1.56], respectively), whereas those with deceased hs-CRP did not. Persons with sustained elevated hs-CRP had an increased risk of coronary heart disease, ischemic stroke, heart failure, and mortality (hazard ratios [95% CIs] 1.51 [1.23-1.85], 1.70 [1.32-2.20], 1.60 [1.35-1.89], and 1.52 [1.37-1.69], respectively) compared with those with sustained low/moderate hs-CRP. Associations for sustained elevated hs-CRP were greater than for those with increased hs-CRP over 6 years.

Conclusions

Large increases or sustained elevations in hs-CRP over a 6-year period were associated with a subsequent increased risk of diabetes, and persons with sustained elevations in hs-CRP were at the highest risk for cardiovascular disease and mortality. Two measurements of hs-CRP are better than one for characterizing risk, and large increases are particularly prognostic.

Section snippets

Study population

The Atherosclerosis Risk in Communities (ARIC) study is a community-based cohort of 15,792 participants who were originally recruited from 1987 to 1989 from 4 field centers in the United States: Forsyth County, NC; Jackson, MS; suburban Minneapolis, MN; and Washington County, MD.29 Participants were invited to return for 4 follow-up examinations in 1990 to 1992, 1993 to 1995, 1996 to 1998, and 2011 to 2013 (response rates were 93%, 86%, 80%, and 65%, respectively). All procedures were approved

Results

The mean age of participants was approximately 57 years at visit 2 and 63 years at visit 4. Nearly half of the study population had sustained low/moderate hs-CRP, and 29% had sustained elevated hs-CRP during the 6-year period (Table I). Of the 6,385 persons with low/moderate hs-CRP at visit 2, 76% also had low/moderate hs-CRP at visit 4, 6 years later. Of the 3,775 persons with elevated hs-CRP at visit 2, 77% also had elevated hs-CRP at visit 4. Visit 2 and visit 4 hs-CRP were highly correlated

Discussion

We observed that hs-CRP measured at a single time point was associated with an approximately 40% to 50% increased risk of diabetes, cardiovascular events, and death for nearly 15 years of follow-up. Furthermore, persons with sustained elevations in hs-CRP were at the highest relative risk for CVD and mortality. Large increases in and sustained elevations in hs-CRP that surpassed the 3-mg/L threshold were strongly associated with increased risk of future diabetes. Similarly, the more proximal

Disclosures

Dr Ballantyne received support from Roche Diagnostics and is a coinvestigator on a provisional patent filed by Roche for use of biomarkers in heart failure prediction. Drs Selvin and Ballantyne have served on a Roche Advisory Board.

Acknowledgements

The authors thank the staff and participants of the ARIC study for their important contributions. Reagents for the C-reactive protein assays in visit 2 samples were donated by Roche Diagnostics.

References (44)

  • M.Y. Donath et al.

    Type 2 diabetes as an inflammatory disease

    Nat Rev Immunol

    (2011)
  • G.S. Hotamisligil

    Inflammation and metabolic disorders

    Nature

    (2006)
  • F. Montecucco et al.

    New evidences for C-reactive protein (CRP) deposits in the arterial intima as a cardiovascular risk factor

    Clin Interv Aging

    (2008)
  • T.A. Pearson et al.

    Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association

    Circulation

    (2003)
  • D.I. Buckley et al.

    C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force

    Ann Intern Med

    (2009)
  • J. Danesh et al.

    Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies

    JAMA

    (1998)
  • S. Ahmadi-Abhari et al.

    Seventeen year risk of all-cause and cause-specific mortality associated with C-reactive protein, fibrinogen and leukocyte count in men and women: the EPIC-Norfolk study

    Eur J Epidemiol

    (2013)
  • A. Dregan et al.

    Chronic inflammatory disorders and risk of type 2 diabetes mellitus, coronary heart disease, and stroke: a population-based cohort study

    Circulation

    (2014)
  • X. Wang et al.

    Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis

    Diabetes Care

    (2013)
  • B.B. Duncan et al.

    Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study

    Diabetes

    (2003)
  • J.I. Barzilay et al.

    The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study

    Diabetes

    (2001)
  • D.J. Freeman et al.

    C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study

    Diabetes

    (2002)
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    This work was presented at the American Heart Association Epidemiology and Prevention and Nutrition, Physical Activity and Metabolism 2014 Scientific Sessions, held in San Francisco, CA; March 18-21, 2014.

    C.M. Parrinello is supported by National Institutes of Health/National Heart, Lung, and Blood Institute Cardiovascular Epidemiology Training Grant T32HL007024. This research was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant R01DK089174. The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C).

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