The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

Salicylate (Salsalate) in Patients With Type 2 Diabetes: A Randomized Trial

Allison B. Goldfine, MD; Vivian Fonseca, MD; Kathleen A. Jablonski, PhD; Yii-Der Ida Chen, PhD; Laura Tipton, MS; Myrlene A. Staten, MD; Steven E. Shoelson, MD, PhD, for the Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team*
[+] Article, Author, and Disclosure Information

* For a list of contributors for the Targeting Inflammation Using Salsalate in Type 2 Diabetes Study, see Appendix 1.

From Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts; Tulane University, New Orleans, Louisiana; George Washington University, Rockville, Maryland; Cedars-Sinai Medical Center, Los Angeles, California; and National Institute of Diabetes and Digestive and Kidney Diseases, Washington, DC.

Acknowledgment: The authors thank Elizabeth Tatro for her coordinating roles in the trial and Yeheng Liu, MPH, Cedars-Sinai Medical Center, for laboratory measurements.

Grant Support: By National Institutes of Health (U01 DK74556, P50 HL83813, P30 DK03836, and General Clinical Research Center and Clinical and Translational Science Award at several sites) and the Tullis-Tulane (Dr. Fonseca) and Helen and Morton Adler (Dr. Shoelson) Chairs. Caraco Pharmaceutical Laboratories (Detroit, Michigan) supplied the salsalate and placebo, LifeScan (Milpitas, California) supplied the home glucose-monitoring kits, and Mercodia (Uppsala, Sweden) supplied the insulin assay kits.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2782.

Reproducible Research Statement: Study protocol: Available from Dr. Goldfine (e-mail, allison.goldfine@joslin.harvard.edu). Data set and statistical code: Not available.

Requests for Single Reprints: Steven E. Shoelson, MD, PhD, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215; e-mail, steven.shoelson@joslin.harvard.edu.

Current Author Addresses: Drs. Goldfine and Shoelson: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215.

Dr. Fonseca: Tulane University Health Sciences Center, Department of Medicine, Section of Endocrinology, 1430 Tulane Avenue, SL 53, New Orleans, LA 70112.

Dr. Jablonski and Ms. Tipton: The George Washington University, The Biostatistics Center, 6110 Executive Boulevard, Suite 750, Rockville, MD 20852.

Dr. Chen: Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.

Dr. Staten: National Institute of Diabetes and Digestive and Kidney Diseases, Division of Diabetes, Endocrinology, and Metabolic Diseases, Building 2 DEM, Room 6107, 6707 Democracy Boulevard, Bethesda, MD 20892.

Author Contributions: Conception and design: A.B. Goldfine (conception), V. Fonseca, K.A. Jablonski, M.A. Staten, S.E. Shoelson (conception).

Analysis and interpretation of the data: A.B. Goldfine, V. Fonseca, K.A. Jablonski, Y.D.I. Chen, L. Tipton, M.A. Staten, S.E. Shoelson.

Drafting of the article: A.B. Goldfine, K.A. Jablonski, S.E. Shoelson.

Critical revision of the article for important intellectual content: A.B. Goldfine, V. Fonseca, K.A. Jablonski, M.A. Staten, S.E. Shoelson.

Final approval of the article: A.B. Goldfine, V. Fonseca, K.A. Jablonski, M.A. Staten, S.E. Shoelson.

Provision of study materials or patients: A.B. Goldfine.

Statistical expertise: K.A. Jablonski, L. Tipton.

Obtaining of funding: A.B. Goldfine, V. Fonseca, S.E. Shoelson.

Administrative, technical, or logistic support: A.B. Goldfine, V. Fonseca, K.A. Jablonski, Y.D.I. Chen, L. Tipton, M.A. Staten.

Collection and assembly of data: A.B. Goldfine, V. Fonseca, K.A. Jablonski, S.E. Shoelson.

Ann Intern Med. 2013;159(1):1-12. doi:10.7326/0003-4819-159-1-201307020-00003
Text Size: A A A

Chinese translation

Background: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM).

Objective: To assess 1-year efficacy and safety of salsalate in T2DM.

Design: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643)

Setting: 3 private practices and 18 academic centers in the United States.

Patients: Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes.

Intervention: 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146).

Measurements: Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures.

Results: The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, −0.53% to −0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged.

Limitation: Trial duration and number of patients studied were insufficient to determine long-term risk–benefit of salsalate in T2DM.

Conclusion: Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted.

Primary Funding Source: National Institutes of Health.


Grahic Jump Location
Figure 1.

Study flow diagram.

All data were used through trial completion or point of withdrawal for patients with a baseline HbA1c measurement. Two participants withdrew after randomization but before the blood draw; 1 additional participant did not have baseline HbA1c measurement from the laboratory. Percentages may not sum to 100 due to rounding. HbA1c = hemoglobin A1c.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Glycemic effects of salsalate.

HbA1c (A) and FBG (C) levels are graphed as unadjusted means and 95% CIs. In panel A, the numbers of participants analyzed for the primary end point of HbA1c levels at each time point are displayed below study week. Mild hypoglycemia events (B) and notifications for hyperglycemia (D) sent to the primary caregivers are based on HbA1c levels >10.5% before week 24 and >9.5% after week 24. Participants could have >1 mild hypoglycemic event or exceed the hyperglycemic threshold >1 time during the trial. FBG = fasting blood glucose; HbA1c = hemoglobin A1c.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Mean values and 95% CIs for leukocyte count (A), hematocrit (B), neutrophil count (C), adiponectin level (D), lymphocyte count (E), and LDL cholesterol level (F).

LDL = low-density lipoprotein.

Grahic Jump Location
Grahic Jump Location
Figure 4.

Renal effects of salsalate.

ACR = albumin–creatinine ratio; DC = discontinued; eGFR = estimated glomerular filtration rate; IQR = interquartile range; MDRD = Modification of Diet in Renal Disease; NS = not significant. A. Median changes and IQRs for urinary ACR. Error bars represent the IQRs. The 2.3-µg/mg between-group difference in ACR reported in the text and values reported in Table 2 were obtained by back-transformation of log-transformed data for ACR because ACR was not normally distributed. B. Mean changes and 95% CIs in circulating uric acid levels. C and D. ACRs for the 23 participants receiving placebo (C) and 33 receiving salsalate (D) who were asked to return at week 56, after 8-week washout period, because ACR or blood pressure was elevated at week 48. Lines are median values; shaded areas are 25th through 75th quartiles. E and F. Mean changes and 95% CIs for eGFRs, using creatinine concentrations and the MDRD equation (E) or cystatin C concentrations (F).

Grahic Jump Location




Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


Submit a Comment/Letter
Submit a Comment/Letter

Summary for Patients

Salsalate for Type 2 Diabetes Mellitus

The full report is titled “Salicylate (Salsalate) in Patients With Type 2 Diabetes. A Randomized Trial.” It is in the 2 July 2013 issue of Annals of Internal Medicine (volume 159, pages 1-12). The authors are A.B. Goldfine, V. Fonseca, K.A. Jablonski, Y.D.I. Chen, L. Tipton, M.A. Staten, and S.E. Shoelson, for the Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team.


Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.


Buy Now for $32.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.