Effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the LANCET randomized trial.
BACKGROUND
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.


METHODS
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.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00366301.
Pradhan
Aruna D
AD
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215-1204, USA. apradhan@partners.org
Everett
Brendan M
BM
Cook
Nancy R
NR
Rifai
Nader
N
Ridker
Paul M
PM
D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose; D002097:C-Reactive Protein / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood
D015415:Biomarkers; D001786:Blood Glucose; D002097:C-Reactive Protein; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D015850:Interleukin-6; D008687:Metformin; D047889:Receptors, Tumor Necrosis Factor, Type II; C025617:glucosylated hemoglobin A