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The Effects of Salsalate on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Trial

Allison B. Goldfine, MD; Vivian Fonseca, MD; Kathleen A. Jablonski, PhD; Laura Pyle, MS; Myrlene A. Staten, MD; Steven E. Shoelson, MD, PhD, TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team
[+] Article and Author Information

For a list of all study investigators, see the Appendix.


From Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts; Tulane University, New Orleans, Louisiana; The George Washington University, Rockville, Maryland; and the National Institute of Diabetes and Digestive and Kidney Diseases, Washington, DC.


Acknowledgment: The authors thank Elizabeth Tatro, Joslin Diabetes Center, for her coordinating role in the trial; Laura Coombs, American College of Radiology, for assistance with trial design; Drs. Masumi Ai and Ernst J. Schaefer, Tufts University, for laboratory measurements; and Dr. Joshua Barzilay, for editorial assistance.

Grant Support: By National Institutes of Health grants U01 DK74556 and P50 HL83813, National Institutes of Health General Clinical Research Center and Clinical and Translational Science Award grants at multiple sites, and the Tullis-Tulane (Dr. Fonseca) and Helen and Morton Adler (Dr. Shoelson) Chairs. Caraco Pharmaceuticals (Detroit, Michigan) supplied drug and placebo, Lifescan (Miltipas, California; a division of Johnson & Johnson) supplied home glucose-monitoring kits, and Mercodia (Uppsala, Sweden) supplied insulin assay kits.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1361.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Goldfine (allison.goldfine@joslin.harvard.edu).

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. Pyle: The George Washington University, The Biostatistics Center, 6110 Executive Boulevard, Suite 750, Rockville, MD 20852.

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, V. Fonseca, K.A. Jablonski, L. Pyle, M.A. Staten, S.E. Shoelson.

Analysis and interpretation of the data: A.B. Goldfine, V. Fonseca, K.A. Jablonski, L. Pyle, M.A. Staten, S.E. Shoelson.

Drafting of the article: A.B. Goldfine, 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, L. Pyle, M.A. Staten, S.E. Shoelson.

Provision of study materials or patients: A.B. Goldfine, V. Fonseca.

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

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

Administrative, technical, or logistic support: A.B. Goldfine, V. Fonseca, K.A. Jablonski, L. Pyle, M.A. Staten, S.E. Shoelson.

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


Ann Intern Med. 2010;152(6):346-357. doi:10.7326/0003-4819-152-6-201003160-00004
Text Size: A A A

Background: Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies.

Objective: To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes.

Design: Parallel randomized trial with computer-generated randomization and centralized allocation. Patients and investigators, including those assessing outcomes and performing analyses, were masked to group assignment. (ClinicalTrials.gov registration number: NCT00392678)

Setting: 3 private practices and 14 universities in the United States.

Patients: Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% treated by diet, exercise, and oral medication at stable doses for at least 8 weeks.

Intervention: After a 4-week, single-masked run-in period, patients were randomly assigned to receive placebo or salsalate in dosages of 3.0, 3.5, or 4.0 g/d for 14 weeks (27 patients each) in addition to their current therapy.

Measurements: Change in HbA1c was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes.

Results: Higher proportions of patients in the 3 salsalate treatment groups experienced decreases in HbA1c levels of 0.5% or more from baseline (P = 0.009). Mean HbA1c changes were −0.36% (P = 0.02) at 3.0 g/d, −0.34% (P = 0.02) at 3.5 g/d, and −0.49% (P = 0.001) at 4.0 g/d compared with placebo. Other markers of glycemic control also improved in the 3 salsalate groups, as did circulating triglyceride and adiponectin concentrations. Mild hypoglycemia was more common with salsalate; documented events occurred only in patients taking sulfonylureas. Urine albumin concentrations increased in all salsalate groups compared with placebo. The drug was otherwise well tolerated.

Limitation: The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for type 2 diabetes at this time.

Conclusion: Salsalate lowers HbA1c levels and improves other markers of glycemic control in patients with type 2 diabetes and may therefore provide a new avenue for treatment. Renal and cardiac safety of the drug require further evaluation.

Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Figures

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Figure 1.
Study flow diagram.

* Participant who did not receive medication was excluded; participant who withdrew because of tinnitus was included in analysis.

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Figure 2.
Changes in circulating metabolic measures, by study group.

All data are provided as unadjusted mean changes. Each data point represents the mean value for all patients examined. We analyzed 27 patients at baseline in each group. This decreased to 26 patients in the 4.0-g/d group at 4 weeks; 26 and 25 patients in the 3.5- and 4.0-g/d groups, respectively, at 8 weeks; and 26 patients in the placebo and 3.5-g/d groups and 25 in the 4.0-g/d group at 14 weeks (Figure 1). We used the Holm procedure to adjust for multiple comparisons in all cases. FBG = fasting blood glucose; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein. A. Trends in HbA1c level over time. The F test for the overall effect of treatment group was significant (P = 0.003) as was each pairwise test between placebo and salsalate (P = 0.02, 0.02, and 0.001 for the 3.0-g/d, 3.5-g/d, and 4.0-g/d groups, respectively). B. Trends in FBG concentration over time. To convert results from mg/dL to mmol/L, multiply by 0.0555. C. Trends in glycated albumin level over time. D. Trends in adiponectin concentration over time. The F test for each overall effect in panels B, C, and D was significant (P < 0.001), as was each pairwise test between placebo and salsalate (P < 0.001 for all doses). E. Trends in triglyceride concentration over time. The F test for the overall effect of treatment group was significant (P = 0.005). Each pairwise test between placebo and salsalate was significant (P = 0.002, 0.02, and 0.03 for the 3.0-g/d, 3.5-g/d, and 4.0-g/d groups, respectively). To convert results from mg/dL to mmol/L, multiply by 0.0113. F. Trends in total–HDL cholesterol ratio over time. This ratio did not change (P = 0.55).

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Summary for Patients

The Effects of Salsalate on Blood Sugar Control in People With Type 2 Diabetes

The summary below is from the full report titled “The Effects of Salsalate on Glycemic Control in Patients with Type 2 Diabetes. A Randomized Trial.” It is in the 16 March 2010 issue of Annals of Internal Medicine (volume 152, pages 346-357). The authors are A.B. Goldfine, V. Fonseca, K.A. Jablonski, L. Pyle, M.A. Staten, and S.E. Shoelson, for the TINSAL-T2D (Targeting Inflammation using Salsalate in Type 2 Diabetes) Study Team.

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