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The LANCET Randomized Trial

Aruna D. Pradhan, MD, MPH; Brendan M. Everett, MD, MPH; Nancy R. Cook, ScD; Nader Rifai, PhD; Paul M Ridker, MD, MPH

JAMA. 2009;302(11):1186-1194.

Context  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).

Objective  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 x 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.

Intervention  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 end point) and change in IL-6 and sTNFr2 levels (secondary end points) from baseline to 14 weeks.

Results  Levels of glucose and glycated hemoglobin (HbA_1c) were significantly reduced with active treatment vs placebo (all P values <.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 metformin (–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.

Conclusion  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00366301

Author Affiliations: Center for Cardiovascular Disease Prevention (Drs Pradhan, Everett, Cook, and Ridker), Donald W. Reynolds Center for Cardiovascular Research (Drs Pradhan, Everett, Cook, and Ridker), Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (Dr Ridker), Divisions of Cardiovascular Medicine (Drs Everett and Ridker) and Preventive Medicine (Drs Pradhan, Everett, Cook, and Ridker), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Pathology (Dr Rifai), Children's Hospital Medical Center and Harvard Medical School, Boston; and Division of Cardiovascular Medicine (Dr Pradhan), Boston VA Medical Center, Boston.

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