Aruna D. Pradhan, MD, MPH Brendan M. Everett, MD, MPH Nancy R. Cook, ScD Nader Rifai, PhD Paul M Ridker, MD, MPH
As diabetes is in part an inflammatory condition,the initiation of insulin and/or metformin may beneficially reduce levels of inflammatory biomarkers such as high- sensitivity C-reactive protein (hsCRP).
To determine whether insulin alone or combined with metformin lowers levels of hsCRP, IL-6, and soluble tumor necrosis factor receptor 2 (sTNFr2) in patients with recent-onset type 2 diabetes mellitus.
Design, Setting, and Participants:
Randomized 2×2 factorial trial of open-label insulin glargine and placebo-controlled metformin in 500 adults with type 2 diabetes (median time from diagnosis, 2.0 years), suboptimal glycemic control, and elevated hsCRP levels. Patients were recruited from US office-based practices between October 2006 and December 2008.
Random allocation to 1 of 4 treatments(placebo metformin only,placebo metformin and insulin glargine, active metformin only, or active metformin and insulin glargine) with dose titration targeting fasting blood glucose less than 110 mg/dL.
Main Outcome Measures: Change in hsCRP level(primary endpoint)and change in IL-6 and sTNFr2 levels (secondary end points) from baseline to 14 weeks.
Levels of glucose and glycated hemoglobin(HbA1c)were significantly reduced with active treatment vs placebo (all P values less than .001). Levels of hsCRP were reduced in all 4 groups. There was no significant difference in hsCRP reduction among those allocated to insulin (−11.8%; 95% CI, −18.7% to −4.4%) or to no insulin (−17.5%; 95% CI, −23.9% to −10.5%) (P for difference = .25), or among those allocated to active met- formin (−18.1%; 95% CI, −24.4% to −11.1%) or placebo metformin (−11.2%; 95% CI, −18.1% to −3.7%) (P for difference=.17). In the individual treatment groups, despite a differential impact on glucose control, reductions in hsCRP in the metformin (−16.1%; 95% CI, −25.1% to −6.1%) and metformin plus insulin (−20.1%; 95% CI, −28.8% to −10.4%) groups were no different than reductions with placebo alone (−19.0%; 95% CI, −27.8% to −9.1%; P=.67 and .87 vs placebo, respectively). By contrast, hsCRP reduction was attenuated with insulin alone (−2.9%, 95% CI, −13.2% to 8.6%; P = .03 vs placebo). Similar findings were noted for levels of IL-6 and sTNFr2.
In patients with recent-onset type 2 diabetes, treatment with insulin or metformin compared with placebo did not reduce inflammatory biomarker levels despite improving glucose control.