(Research Project 2) Type 2 diabetes mellitus (T2DM) is a progressive disease with many patients requiring insulin therapy. Treatment of patients with T2DM is challenging and many such patients remain uncontrolled, despite a high dosage of insulin, which itself tends to lead to weight gain. Tackling insulin resistance (IR) is critically important in the treatment of patients with T2DM, but effective treatment options are limited. Recent studies suggest that chronic inflammation, mediated by the IKKb/NF-kB pathway, may be implicated in the pathogenesis of IR and may provide new targets for its reversal. Salsalate (Disalcid) is a prodrug form of salicylate. The Targeting INflammation using SALsalate for Type 2 Diabetes Stage II (TINSAL-T2D) trial demonstrated the efficacy and safety of oral salsalate, given at a dose of 3.5 gm/day, in improving glycemic control in patients with T2DM who were not using insulin. Salsalate also suppresses inflammatory markers and may have beneficial effects on cardiovascular disease (CVD) risk factors. The benefit and safety of adjuvant therapy with salsalate in patients with T2DM using insulin are unknown. The efficacy of salsalate on glycated hemoglobin (HbA1c), insulin resistance, markers of inflammation and beta cell function has not been studied in such patients. Our hypothesis is that treatment with salsalate 3.5 gm/day will provide additional glycemic control in patients with T2DM on insulin and will improve markers of inflammation, beta cell function and surrogate markers of CVD risk. We propose to test this hypothesis by conducting a randomized, double-blind, placebo-controlled trial with the following specific aims: Determine whether the addition of oral salsalate, at a dose of 3.5 gm/day, in patients with T2DM on insulin therapy leads to improvement in: 1. glycemic control (HbA1c); 2. markers of inflammation, such as white cell count, high-sensitivity C-reactive protein, free fatty acids, adiponectin, interleukin-6, and serum uric acid, and 3. insulin sensitivity and beta cell function, based on the results of a mixed meal tolerance test with minimal model assessment. In addition, we will test for differences in quality of life using SF36 surveys; and differences in other CVD risk factors, including lipids and endothelial function and vascular compliance using noninvasive testing (EndoPAT). One hundred and forty patients with uncontrolled T2DM despite insulin therapy will be randomized to receive salsalate or placebo. We anticipate 90% statistical power to detect a 0.5% difference in HbA1c change between the salsalate treatment and placebo control groups over a 6 month period of intervention. The study will confirm proof of concept and provide important insight into the safety and efficacy of oral salsalate use in patients with T2DM on insulin therapy. The proposed COBRE program will provide the junior faculty investigator with the protected-time and funding necessary to conduct high quality clinical research and help her transition into a successful competitive independent NIH- funded investigator.
(Research Project 2) The proposed randomized, double-blind, placebo-controlled trial will test the efficacy of oral salsalate, an inexpensive anti-inflammatory drug, on glycemic control, biomarkers of inflammation, and other cardiovascular disease risk factors in patients with poorly controlled type 2 diabetes despite insulin use. The study will generate important information regarding the safety and efficacy of oral salsalate treatment on glycemic control among patients with type 2 diabetes being managed with insulin therapy. The proposed COBRE program will provide the junior faculty investigator the protected-time and funding necessary to conduct high quality clinical research and help her become a successful competitive independent NIH-funded investigator.
|Xu, Tan; Zhang, Yonghong; Bu, Xiaoqing et al. (2017) Blood pressure reduction in acute ischemic stroke according to time to treatment: a subgroup analysis of the China Antihypertensive Trial in Acute Ischemic Stroke trial. J Hypertens 35:1244-1251|
|Shou, Haochang; Hsu, Jesse Y; Xie, Dawei et al. (2017) Analytic Considerations for Repeated Measures of eGFR in Cohort Studies of CKD. Clin J Am Soc Nephrol :|
|Peacock, Erin; Krousel-Wood, Marie (2017) Adherence to Antihypertensive Therapy. Med Clin North Am 101:229-245|
|Grams, Morgan E; Yang, Wei; Rebholz, Casey M et al. (2017) Risks of Adverse Events in Advanced CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis 70:337-346|
|Mehta, Rupal; Cai, Xuan; Hodakowski, Alexander et al. (2017) Fibroblast Growth Factor 23 and Anemia in the Chronic Renal Insufficiency Cohort Study. Clin J Am Soc Nephrol 12:1795-1803|
|Zhang, Dingding; Gu, Dongfeng; He, Jiang et al. (2017) Associations of the Serum/Glucocorticoid Regulated Kinase Genes With BP Changes and Hypertension Incidence: The Gensalt Study. Am J Hypertens 30:95-101|
|Ahmad, Faraz S; Cai, Xuan; Kunkel, Katherine et al. (2017) Racial/Ethnic Differences in Left Ventricular Structure and Function in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort. Am J Hypertens 30:822-829|
|Khairallah, Pascale; Isakova, Tamara; Asplin, John et al. (2017) Acid Load and Phosphorus Homeostasis in CKD. Am J Kidney Dis 70:541-550|
|Bundy, Joshua D; Li, Changwei; Stuchlik, Patrick et al. (2017) Systolic Blood Pressure Reduction and Risk of Cardiovascular Disease and Mortality: A Systematic Review and Network Meta-analysis. JAMA Cardiol 2:775-781|
|Zhu, W; Shen, H; Zhang, J-G et al. (2017) Cytosolic proteome profiling of monocytes for male osteoporosis. Osteoporos Int 28:1035-1046|
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