Emerging Treatments and Technologies ORIGINAL ARTICLE Salsalate Improves Glycemia and Inflammatory Parameters in Obese Young Adults 1,2,3 1,2 AMY FLEISCHMAN, MD, MMSC RAQUEL BERNIER, BS been reinvestigated, and the molecular 1,2 1,2 STEVEN E. SHOELSON, MD, PHD ALLISON B. GOLDFINE, MD target was identified to be the I␬B kinase complex ␤ (IKK␤)/nuclear factor ␬B (NF- ␬B) pathway (8,9), a central integrator of OBJECTIVE — Sedentary lifestyle and a western diet promote subacute-chronic inflamma- proinflammatory signals (2). The thera- tion, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the peutic potential of high-dose aspirin is efficacy of the anti-inflammatory drug salsalate to improve glycemia by reducing systemic in- limited by bleeding risk. Salsalate, a dimer flammation in obese adults at risk for the development of type 2 diabetes. of salicylic acid, has an established safety profile after decades of use for rheumatic RESEARCH DESIGN AND METHODS — In a double-masked, placebo controlled pain. As a nonacetylated salicylate, sal- trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or salate is an equipotent inhibitor of NF-␬B placebo. but has a lower bleeding risk than aspirin RESULTS — Compared with placebo, salsalate reduced fasting glucose 13% (P Ͻ 0.002), (10,11). glycemic response after an oral glucose challenge 20% (P Ͻ 0.004), and glycated albumin 17% To our knowledge, this is the first (P Ͻ 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test study to assess metabolic changes with C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P Ͻ 0.03), administration of salicylates to obese in- consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin dividuals without diabetes. We hypothe- clearance. Adiponectin increased 57% after salsalate compared with placebo (P Ͻ 0.003). Ad- sized that salicylates administered for 1 ditionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein month would improve glycemia in obese Ͻ were reduced by 34% (P 0.05). young adults. CONCLUSIONS — This proof-of-principle study demonstrates that salsalate reduces gly- cemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. RESEARCH DESIGN AND These data support the hypothesis that subacute-chronic inflammation contributes to the patho- METHODS — The Joslin Diabetes genesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeu- Center institutional review board ap- tic route for diabetes prevention. proved the double-masked, placebo- controlled study. Written informed Diabetes Care 31:289–294, 2008 consent was obtained. Subjects were Ͻ30 years and obese, with BMI Ն30 kg/m2. besity, occurring at epidemic rates opment of insulin resistance (1,2). Thus, Participants were excluded for recent worldwide, is a major risk factor for targeting the inflammatory pathway may blood donation, change in weight Ͼ5% in O diabetes and cardiovascular dis- be a novel pharmacologic intervention for the preceding 6 months, use of medica- ease. Thus, there is an urgent need for diabetes prevention and treatment. tion known to alter glucose metabolism, effective interventions to prevent diabetes Salicylates are among the most com- acute febrile illness, biochemical evidence in obese populations. The importance of monly used nonsteroidal anti-inflamma- of renal or hepatic dysfunction, aspirin lifestyle modification in obesity and dia- tory drugs. The benefits of salicylates for allergy, history of gastritis or gastrointes- betes is well recognized. However, disap- treatment of diabetes have long been rec- tinal bleeding, or diabetes. Women were pointing long-term results of these ognized (3,4). High doses of the salicylate excluded for pregnancy, lactation, or lack treatments have led to increased interest aspirin (4–7 g/day) improve fasting and of contraception use. in pharmaceutical intervention. Obesity postprandial hyperglycemia in patients Participants were instructed to con- and high-fat western diets activate inflam- with diabetes (5–7). In recent studies, the sume a high-carbohydrate diet (250–300 matory processes, which promote devel- hypoglycemic actions of salicylates have g/day) and abstain from strenuous exer- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● cise for 3 days before evaluations and not to alter dietary or exercise habits during From the 1Harvard Medical School, Boston, Massachusetts; the 2Joslin Diabetes Center, Boston, Massachu- setts; and the 3Children’s Hospital Boston, Boston, Massachusetts. the study. Blood pressure was measured Address correspondence and reprint requests to Allison B. Goldfine, MD, Joslin Diabetes Center, One twice (DINAMAP PRO-100; General Joslin Place, Boston, MA 02215. E-mail: allison.goldfi[email protected]. Electric Healthcare) with the patient su- Received for publication 5 September 2007 and accepted in revised form 18 October 2007. pine for 10 min. Fasting lipids and cyto- Published ahead of print at http://care.diabetesjournals.org on 24 October 2007. DOI: 10.2337/dc07- 1338. Clinical trial reg. no. NCT00258115, clinicaltrials.gov. kines were measured, and oral glucose Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; tolerance tests (OGTTs) were performed FFA, free fatty acid; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-IRC-peptide, with glucose, insulin, and C-peptide lev- homeostasis model assessment of insulin resistance calculated using C-peptide; IKK␤,I␬B kinase complex els measured before and 30, 60, 90, and ␤ ␬ ␬ ; NF- B, nuclear factor- B; OGTT, oral glucose tolerance test. 120 min after a 75-g glucose load. All sub- © 2008 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby jects were nondiabetic on the basis of marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. American Diabetes Association guidelines DIABETES CARE, VOLUME 31, NUMBER 2, FEBRUARY 2008 289 Salsalate improves glycemia in obesity (12). Insulin resistance was determined Table 1—Baseline subject characteristics using homeostasis model assessment of insulin resistance (HOMA-IR) for insulin Salsalate therapy Placebo and HOMA-IR calculated using C- peptide (HOMA-IRC-peptide), as described Sex (male/female) 1/8 2/9 by the modified formula HOMA-IR Ethnicity (W/H/B/other) 5/3/1 5/1/4/1 C- Ϯ Ϯ peptide ϭ (fasting C-peptide ϫ fasting glu- Age (years) 23.5 1.1 24.1 1.0 cose)/22.5 (13). BMI (kg/m2) 36.3 Ϯ 2.2 38.9 Ϯ 2.5 Subjects were randomly assigned by a Waist circumference (cm) 106 Ϯ 5 116 Ϯ 6 research pharmacist to receive salsalate, Current smoking 3 of 9 2 of 11 4.0 g/day (Caraco Pharmaceutical Labo- Cholesterol (mmol/l) 4.0 Ϯ 0.3 4.6 Ϯ 0.2 ratories, Detroit, MI) divided in two Triglycerides (mmol/l) 1.0 Ϯ 0.1 1.1 Ϯ 0.2 doses, or identical placebo for 4 weeks. Systolic blood pressure 121 Ϯ 4 123 Ϯ 4 Participants and study personnel were Diastolic blood pressure 67 Ϯ 371Ϯ 3 blinded to the treatment assignment. The Fasting glucose (mmol/l) 5.0 Ϯ 0.2 4.8 Ϯ 0.1 starting dose was selected on the basis of 120-min glucose (mmol/l) 6.7 Ϯ 0.4 6.8 Ϯ 0.4 tolerability data in patients with arthritis Data are means Ϯ SEM. There were no significant differences in the baseline characteristics between the (14). A dose-reduction plan was specified salsalate and placebo groups. W, white, non-Hispanic; H, Hispanic; B, African-American. a priori with stepped reductions of 500 mg for symptoms related to salicylate use, such as tinnitus or headache. Compliance min (a), partial enzymatic digestion of al- pants. There were no significant changes was evaluated by salicylate levels. bumin at glycated sites (b), reassessment in weight, systolic or diastolic blood pres- Twenty-seven subjects were enrolled. of albumin (c), and a Ϫ c. sure, or standard lipid profiles in either One subject became ineligible because of group (Table 2). blood donation after screening. Three sub- Statistical analysis jects withdrew consent because of personal The primary end point was change from Glucose metabolism conflicts and were considered noninforma- baseline in glycemic measures between Fasting glucose decreased 13% in the sal- tive; two had been randomly assigned to salsalate and placebo groups. Secondary salate group compared with the placebo placebo and one to salsalate. Three subjects outcomes were also assessed as change group after 1 month (Ϫ0.4 Ϯ 0.2 vs. were withdrawn because of rash. from baseline within group. Data are pre- ϩ0.2 Ϯ 0.1 mmol/l, respectively, P Ͻ sented as mean Ϯ SEM. Unpaired (sal- 0.002) (Fig. 1A, left). The glucose area Assays salate versus placebo) and paired (before under the curve after a 75-g OGTT was Glucose was measured by glucose oxida- versus after treatment) Student’s t tests also significantly reduced in salsalate tion, cholesterol and HDL were measured were performed. Treatment effects were compared with placebo-treated subjects Ϫ by a cholesterol esterase assay, triglycer- determined by calculating percent change (Ϫ130 Ϯ 53 vs. ϩ38 Ϯ 15 mmol ⅐ min 1 Ϫ ides were measured via hydrolysis to glyc- for each participant. Repeated measures ⅐ l 1, P Ͻ 0.004) (Fig. 1A, center). Like- erol and free fatty acids (FFAs) (Beckman and area under the curve analyses were wise, within groups the glycemic re- Synchron CX3 Delta and CX9; Beckman performed to compare response to OGTT sponse to an OGTT improved after Coulter, Brea, CA), and glycohemoglobin before and after treatment. Completer salsalate treatment (repeated-measures was measured by high-performance liq- analysis was prespecified. Multiple re- analysis P Ͻ 0.01) but not placebo (Fig.