We read with great interest the study by Sharif et al. (1) of 1,829 patients with type 2 diabetes (T2D) from the Second Manifestations of ARTerial disease (SMART) cohort. Here, we would like to suggest a different interpretation of their findings in light of the results from our ongoing cohort of Iranian patients with T2D (2). We believe that the chameleon behavior of HDL cholesterol (HDL-c) might be ascribed to the chronic systematic inflammatory status. Hence, we investigated the association of serum C-reactive protein (CRP), a marker of chronic low-grade inflammation, with HDL-c, LDL cholesterol (LDL-c), and cardiovascular events.
In our cohort of 2,607 patients with T2D who were followed for an average of 8.5 years (2), we recorded 299 (11.5%) hard incident cardiovascular events. Patients with LDL-c >2.5 mmol/L had significantly higher serum CRP compared with their peers with LDL-c <2 mmol/L (2.46 ± 2.10 vs. 2.16 ± 2.13, P = 0.047), pointing to the role of inflammatory status in predisposing patients with T2D to incidence of cardiovascular events. Cox regression was used to investigate the risk of HDL-c on cardiovascular events similar to the model used by Sharif et al. (1), with the exception of the addition of baseline CRP into the model. In contrast with Sharif et al., we found that high HDL-c is associated with a reduced risk of cardiovascular events in T2D patients with LDL-c <2 mmol/L (crude hazard ratio [HR] 0.929 [95% CI 0.869–0.993], adjusted HR 0.771 [0.664–0.895], P < 0.05). This association was not significant in LDL-c strata of >2.5 mmol/L (crude HR 0.938 [0.879–1.001], adjusted HR 0.957 [0.885–1.035], P > 0.05).
The recent report from the Framingham Offspring cohort sheds light on the modulation of the association of HDL-c with the risk of cardiovascular events by other components of the lipid profile, including LDL-c. High HDL-c was associated with 40% lower risk of cardiovascular events except when LDL-c was elevated (3). Sharif et al. (1) addressed the lipid component in this scenario but did not include inflammation as a possible confounder. Here, we added to the results of Sharif et al. by investigating an inflammatory marker (CRP) in the link of HDL-c to cardiovascular events and found higher inflammatory status in those with LDL-c >2.5 mmol/L than in those with LDL-c <2 mmol/L. HDL-c acts as a shuttle whose contents are variable based on inflammatory status. HDL-c is enriched with serum amyloid A in inflammatory status and thereby becomes a proinflammatory particle (4). Proinflammatory HDL-c does not induce the production of endothelial nitric oxide and also triggers production of oxidized lipids (5). Hence, inflammation may untangle the dual behavior of HDL-c in risk estimation of cardiovascular events but not in the serum LDL-c range observed by Sharif et al. (1). Accordingly, HDL-c does not appear to be a residual risk factor when LDL-c is not elevated.
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Acknowledgments. The authors would like to thank Fahimeh Azimi, of the Endocrinology and Metabolism Research Institute, who helped in gathering the raw data. This work was partially funded by the Tehran University of Medical Sciences and Health Services.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
