TRAJECTORIES OF SERUM HIGH-SENSITIVITY CRP PRECEDING FATAL CVD
AND INCIDENT DM: THE WHITEHALL II STUDY [1050-P]
Tabák AG, Kivimaki M, Brunner EJ, Lowe GDO, Witte DR; London, Great Britain;
Budapest, Hungary; Glasgow, Great Britain; Gentofte, Denmark
C-reactive protein (CRP) is an acute phase reactant that increases markedly in response to
inflammation. Elevated serum CRP has been associated with an increased risk of both
type 2 diabetes and cardiovascular disease (CVD).1 However, CRP elevation has also
been linked with other risk factors for CVD and diabetes, such as obesity.2,3 It is therefore
unclear whether CRP directly contributes to increased risk of diabetes and CVD, or
whether CRP is merely a secondary marker for other causative factors.
The Whitehall II study is a prospective examination of factors that influence long-term
health outcomes that initially enrolled approximately 10 000 British civil servants
working in London.4 In this presentation, the investigators examined whether early CRP
assessments could be used to identify specific patterns of CRP change over time that
predicted fatal CVD outcomes or new-onset diabetes. Data from 7350 subjects were
included in this analysis (mean age, 51 years; 70% male). Over a 10-year follow-up
period, the investigators identified a total of 125 fatal CVD events and 559 new cases of
type 2 diabetes. They then examined the trajectories of CRP values over time for these 2
groups of patients using 2 CRP determinations 10 years apart.
The subjects who eventually developed fatal CVD events had significantly higher CRP
levels at baseline than those who did not develop CVD (median 1.49 vs 0.88 mg/L; P <.0001). Subjects who eventually developed type 2 diabetes also had higher baseline
CRP values than those who did not (1.43 vs 0.79 mg/L; P <.0001). However,
examination of CRP values over time revealed different patterns of CRP change for
patients who eventually developed CVD versus those with new-onset diabetes. After
statistically adjusting CRP values for age, sex, body mass index (BMI), ethnicity, and
employment, log CRP values gradually increased over the 10-year follow-up period in
both CVD and non-CVD subjects, with the 2 curves generally rising in parallel. In
contrast, adjusted log CRP values at baseline were higher among subjects who developed
diabetes than among those who did not, but the 2 groups gradually converged over time.
Thus, the difference in CRP values between individuals with and without diabetes
actually decreased as the subjects approached the point in time when the diagnosis was
made. The investigators concluded that it is unclear whether CRP elevation is causally
related to new-onset type 2 diabetes.
The relationship between CRP and incident diabetes has also been examined in recent
genetic studies. In one study that examined polymorphisms of the CRP gene and the
incidence of diabetes in this same patient dataset, different CRP phenotypes were not
significantly associated with the risk of new-onset diabetes.5 Studies such as these have
increasingly suggested that elevated CRP is not a causal factor in the development of
new-onset diabetes, and suggest that other inflammatory mediators (eg, interleukin-6, a
cytokine that regulates CRP production) may be more closely related to the pathogenesis
of diabetes.6
References
1. Dandona P. Effects of antidiabetic and antihyperlipidemic agents on C-reactive
protein. Mayo Clin Proc. 2008;83:333-342.
2. Mehta S, Farmer JA. Obesity and inflammation: a new look at an old problem. Curr
Atheroscler Rep. 2007;9:134-138.
3. Nesto RW. Obesity: a major component of the metabolic syndrome. Tex Heart Inst J.
2005;32:387-389.
4. Rael EG, Stansfeld SA, Shipley M, et al. Sickness absence in the Whitehall II study,
London: the role of social support and material problems. J Epidemiol Community
Health. 1995;49:474-481.
5. Brunner EJ, Kivimäki M, Witte DR, et al. Inflammation, insulin resistance, and
diabetes—mendelian randomization using CRP haplotypes points upstream. PLoS Med.
2008;5:e155.
6. Keavney B. More evidence against a causal association between C-reactive protein and
diabetes. PLoS Med. 2008;5:e174.
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