Inflammatory markers associated with development of diabetes in people taking HIV therapy

Low-level elevations in important markers of systemic inflammation are associated with the development of type-2 diabetes in people taking antiretroviral therapy (ART), investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes. The authors examined the relationship between baseline levels of high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and incident type-2 diabetes among people in two large HIV treatment strategy trials – the SMART and ESPRIT studies. The study participants were taking continuous ART without any adjunct therapy. Higher baseline hsCRP and IL-6 were associated with diagnosis with type-2 diabetes during follow-up.

“Inflammatory markers provide independent information for predicting the development of diabetes,” comment the authors. “Experimental studies aimed at reducing inflammation are needed to establish a causal relationship.”

Improvements in treatment and care mean that many people with HIV now have an excellent life expectancy. However, HIV infection – even in the context of effective ART – is associated with a higher risk of metabolic complications, including the development of type-2 diabetes. The reasons for this are unclear, but possible causes include the side-effects of some anti-HIV drugs and the inflammatory effects of HIV infection, which can persist at low levels even in the context of ART.

Results of several studies in the general population suggest that higher levels of hsCRP and IL-6 are associated with incident type-2 diabetes. But it is unclear if this is also the case in people living with HIV.

Investigators therefore conducted a retrospective analysis of the relationship between baseline hsCRP and IL-6 and incident type-2 diabetes in approximately 3700 people enrolled in the SMART and ESPRIT studies.

These strategy studies explored the safety and efficacy of CD4-guided structured interruptions in ART (SMART) and the use of IL-2 adjunct therapy (ESPRIT). The present analysis was restricted to people taking continuous ART who were not randomised to receive IL-2.

Average CD4 count at baseline was 523 cells/mm³ and participants were followed for an average of 4.6 years (2.9 years in SMART and 6.8 years in ESPRIT). Type-2 diabetes was diagnosed in 137 people (3.5), a rate of 8.18 per 1000 person-years.

The proportion of people with a CD4 count above 500 cells/mm³ and virologic suppression remained unchanged during follow-up.

Median hsCRP and IL-6 levels were significantly higher among people who developed type-2 diabetes compared to people who did not (hsCRP = 4.91 vs 3.29 μg/ml, p < 0.001; IL-6 = 3.45 vs 2.50 pg/ml, p < 0.001).

A doubling of baseline hsCRP levels increased the risk of type-2 diabetes by approximately a fifth (HR = 1.22; 95% CI, 1.10-1.36, p < 0.001), whereas a doubling of baseline IL-6 increased the risk by almost a third (HR = 1.29; 95% CI, 1.08-1.55, p = 0.005).

A number of traditional risk factors were also associated with the diagnosis of diabetes. These included higher body mass index (p < 0.001), older age (p = 0.0.013), co-infection with hepatitis B or C virus (p = 0.03) and the use of lipid-lowering medication (p = 0.008).

The authors believe their findings offer “clues” as to why people living with HIV remain at increased risk of cardiovascular disease and other chronic illness even when they are taking effective ART, and conclude, “our findings support the hypothesis that low-grade systemic inflammation is an underlying factor in the pathogenesis of type-2 diabetes.”