Sanofi-Aventis資助本研究，且和資深作者、Paul M. Ridker醫師有各種財務關係，Paul M. Ridker醫師也宣告和國家心臟肺臟暨血液研究中心、國家癌症研究中心、Donald W. Reynolds基金會、Leducq基金會、Astra-Zeneca、Novartis、Merck、Abbott、Roche、Merck-Schering Plough、ISIS, Dade-Behring與Vascular Biogenic等藥廠有各種財務關係。他也是布萊根婦女醫院擁有的心血管疾病和糖尿病發炎生物標記專利之共同發明者，該專利授權給Siemens和Astra-Zeneca。
Insulin or Metformin Therapy May Not Reduce Inflammatory Biomarkers in Diabetes
By Laurie Barclay, MD
Medscape Medical News
September 15, 2009 — In patients with recent-onset type 2 diabetes, treatment with insulin or metformin vs placebo improves glucose control but does not lower levels of inflammatory biomarkers, according to the results of a randomized controlled trial reported in the September 16 issue of the Journal of the American Medical Association.
"Proinflammatory mechanisms have been linked to the core metabolic defects of beta-cell insufficiency and insulin resistance, and elevations in levels of inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), IL-6 [interleukin 6], and soluble tumor necrosis factor receptor 2 (sTNFr2), predict incident type 2 diabetes among apparently healthy individuals," write Aruna D. Pradhan, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues. "Evidence is limited on whether improvement in glycemic control, insulin resistance, or both with antidiabetic agents such as insulin and metformin may beneficially change inflammation."
The goal of this 2 x 2-factorial trial of open-label insulin glargine and placebo-controlled metformin was to assess whether insulin alone or in combination with metformin would lower hsCRP, IL-6, and sTNFr2 levels in patients with recent-onset type 2 diabetes mellitus.
Between October 2006 and December 2008, a total of 500 adults with type 2 diabetes (median time from diagnosis, 2.0 years), suboptimal glycemic control, and elevated hsCRP levels were recruited from US office-based practices and randomly assigned to 1 of 4 treatments (placebo metformin only, placebo metformin and insulin glargine, active metformin only, or active metformin and insulin glargine). Dose titration was used to target fasting blood glucose levels less than 110 mg/dL.
The primary endpoint of the study was change in hsCRP level from baseline to 14 weeks. Other outcome measures were change in IL-6 and sTNFr2 levels.
Compared with the placebo group, active treatment groups had significantly lower levels of glucose and glycated hemoglobin (HbA1c; all P values < .001). All 4 groups had reduction in hsCRP levels. Reduction in hsCRP levels was not significantly different among those assigned to insulin (?11.8%; 95% confidence interval [CI], ?18.7% to ?4.4%), no insulin (?17.5%; 95% CI, ?23.9% to ?10.5%; P for difference = .25), 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).
Despite different effects on glucose control in the individual treatment groups, reductions in hsCRP levels were no different than reductions with placebo alone (?19.0%; 95% CI, ?27.8% to ?9.1%) in the metformin group (?16.1%; 95% CI, ?25.1% to ?6.1%; P = .67 vs placebo) and the metformin plus insulin group (?20.1%; 95% CI, ?28.8% to ?10.4%; P = .87 vs placebo). Compared with placebo, only insulin was associated with decreased hsCRP levels (?2.9%; 95% CI, ?13.2% to 8.6%; P = .03). Findings were similar for IL-6 and sTNFr2 levels.
"No consistent association was found between glucose reduction and improvement in inflammatory status ascertained by change in levels of hsCRP, IL-6, or sTNFr2," the study authors write. "Despite substantially improving glucose control, neither insulin nor metformin reduced inflammatory biomarker levels for the main effects evaluated or in comparisons between the individual treatment groups. An interaction between interventions was observed such that, compared with no pharmacologic intervention, those allocated to insulin alone had a significant attenuation of inflammation reduction, an effect not observed among those allocated to metformin and insulin or to metformin alone."
Limitations of this study include use of surrogate markers of cardiovascular disease risk, lack of data on change in visceral fat, and lack of generalizability to all individuals with type 2 diabetes.
"From a clinical perspective, until other end-point trial data become available, these data underscore the need to improve adherence with therapies that do reduce cardiovascular events among diabetic patients, including exercise; weight management; smoking cessation; blood pressure control; and, in appropriate patients, antiplatelet and statin therapy," the study authors conclude.
Sanofi-Aventis funded this study and has various financial relationships with senior author Paul M. Ridker, MD, MPH, who also has disclosed various financial relationships with the National Heart, Lung, and Blood Institute; the National Cancer Institute; the Donald W. Reynolds Foundation; the Leducq Foundation; Astra-Zeneca; Novartis; Merck; Abbott; Roche; Merck-Schering Plough, ISIS, Dade-Behring, and Vascular Biogenics. He is also listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes, which have been licensed to Siemens and Astra-Zeneca.
