The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial.

Abstract

Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies.
To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes.
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)
3 private practices and 14 universities in the United States.
Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (< or = 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.
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.
Change in HbA1c was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes.
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.
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.
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.
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Full text

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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; and
Steven E. Shoelson, MD, PhD, for the TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team*
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 dif-
ferent doses in patients with type 2 diabetes.
Design: Parallel randomized trial with computer-generated ran-
domization and centralized allocation. Patients and investigators,
including those assessing outcomes and performing analyses, were
masked to group assignment. (ClinicalTrials.gov registration num-
ber: 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 hemo-
globin A1c(HbA1c) levels of 7.0% to 9.5% treated by diet, exer-
cise, 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 HbA1cwas the primary outcome. Ad-
verse 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 HbA1clevels of 0.5% or more
from baseline (P ? 0.009). Mean HbA1cchanges 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 pla-
cebo. 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 HbA1clevels 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 Diges-
tive and Kidney Diseases, National Institutes of Health.
Ann Intern Med. 2010;152:346-357.
For author affiliations, see end of text.
* For a list of all study investigators, see the Appendix (available at
www.annals.org).
www.annals.org
C
ish glycosuria in older diabetic patients. More recently, in-
flammation and innate immunity have been implicated in the
pathogenesis of insulin resistance and type 2 diabetes (3, 4).
Obesity activates the transcription factor nuclear factor–?B
(NF-?B), which promotes insulin resistance and risk for both
type 2 diabetes and cardiovascular disease (5–7). High-dose
sodium salicylate inhibits NF-?B (8–10). These findings may
explain the original observations and provide potential new
avenues for intervention in type 2 diabetes (5).
ase reports published more than a century ago (1, 2)
suggested that high-dose sodium salicylate could dimin-
A pilot trial that used aspirin, approximately 7 g/d (11), also
demonstrateddecreasesinglucoseconcentrations(12,13).How-
ever, aspirin at high doses is associated with risk for bleeding,
whichlimitsclinicalutility.Sodiumsalicylatedoesnotirreversibly
inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2) (14, 15)
and is thus not antithrombotic, but it also irritates the gastroin-
testinal tract. We therefore initiated pilot studies of salsalate, a
prodrugofsalicylatethatiswelltoleratedandconsideredsafeafter
years of use for arthritis. Salsalate reduced blood glucose, triglyc-
eride, free fatty acid and C-reactive protein concentrations; im-
proved glucose utilization; and increased circulating insulin and
adiponectin concentrations in small proof-of-concept studies
(16, 17). The TINSAL-T2D (Targeting Inflammation Using
Salsalate in Type 2 Diabetes) trial evaluates whether this generic
and inexpensive drug is safe, tolerated, and efficacious in patients
with type 2 diabetes.
METHODS
Trial Design
The TINSAL-T2D trial was a single-mask lead-in,
randomized, double-masked placebo-controlled, dose-ranging
See also:
Print
Editors’ Notes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-40
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Appendix
Conversion of graphics into slides
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Article
346 © 2010 American College of Physicians

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multicenter clinical trial conducted at 17 sites in the
United States (3 private practices and 14 university or ac-
ademic centers). The protocol, approved by human subject
institutional review boards at each institution, included 1
week of screening, a 4-week single-masked placebo run-in,
pretreatment baseline evaluation, and a 14-week treatment
period with visits at 2, 4, 8 and 14 weeks after random
assignment. Study patients, site investigators and staff,
steering committee members, and members of the data
coordinating center responsible for clinical activities were
masked to treatment assignment. We recruited patients
through physician referral and advertisement. The single-
masked placebo run-in period provided an interval for
metabolic stabilization, which may accompany participa-
tion in a clinical trial because of potential changes in life-
style or adherence to therapies. Patients with 80% or more
adherence to masked placebo, assessed by pill count, were
eligible for random assignment, which we conducted in
clinic blocks by using central computer assignments. We
assigned equal numbers to receive either salsalate, in dos-
ages of 3.0, 3.5, or 4.0 g/d, or an identical-appearing pla-
cebo, divided into 3 daily doses. Randomization codes
were secured at the data coordinating center. We escalated
the dosages by 0.5 g/d over 2-week intervals for patients
randomly assigned to receive higher dosages. We assessed
adherence by pill count.
We systematically assessed adverse events with a ques-
tionnaire given at each follow-up visit. Patients were in-
structed to monitor daily fasting glucose and symptomatic
events by using glucometers. The postdosing safety evalu-
ation, conducted 2 weeks after therapy, included a system-
atic medical history. Staff evaluated vital signs and labora-
tory chemistries for patients with systolic or diastolic blood
pressure greater than 160 or 95 mm Hg, respectively;
change from baseline in systolic or diastolic blood pressure
greater than 10 mm Hg; decrease from baseline in esti-
mated glomerular filtration rate (GFR) by 20 mL/min per
1.73 m2; or serum creatinine levels above normal. We re-
duced dosages for patients with tinnitus, who continued
receiving the maximum tolerable dose nearest the original
assignment. We also reduced concurrent diabetes therapies
for patients with hypoglycemia, either documented by
home glucose monitoring or with recurrent consistent
symptoms; concurrent oral therapies were increased for
documented hyperglycemia at the discretion of the primary
care provider. We assessed quality of life by using the total
scale and 9 subscales of the Short Form-36 (SF-36) survey,
which reflects aspects of physical and mental health and
well-being.
Criteria for terminating treatment included patient de-
cision to withdraw consent; pregnancy or lactation; a new
diagnosis of an exclusionary medical condition; an intoler-
able adverse event, as judged by the investigator and the
patient; and hospitalization or surgical procedures deemed
probably related to the use of the study drug.
Study Population
Eligible adult patients were younger than 75 years;
received their diagnosis of type 2 diabetes 8 or more weeks
previously; had 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% at screening; and were
treated by diet and exercise alone or with metformin, an
insulin secretagogue, or a dipeptidyl peptidase-4 inhibitor,
either as monotherapy or in combination. Concomitant
diabetes medication had to have been at stable dosages for
at least the past 8 weeks. Patients who received low-dose
aspirin (81 to 325 mg/d) were eligible for the trial.
Exclusion criteria included treatment with insulin,
thiazolidinedione (because of the potential overlap in
mechanism), or exenatide (because of association with
weight loss); intentional weight loss of 4.5 kg or more in
the previous 6 months; receipt of weight-loss drugs or cor-
ticosteroids in the previous 3 months; or recent long-term
nonsteroidal anti-inflammatory drug therapy. We also ex-
cluded patients who were receiving uricosuric agents or
anticoagulants other than low-dose aspirin or had aspirin
allergy, severe diabetic neuropathy, peptic ulcer disease
or gastritis, unstable cardiovascular disease, uncontrolled
hypertension, anemia or thrombocytopenia, hypertriglycer-
idemia, stage 3 or greater chronic kidney disease or pro-
teinuria, hepatic dysfunction, or other conditions likely to
interfere with the conduct of the trial. We added preexist-
ing chronic tinnitus as an exclusion criterion early in the
course of the trial.
Study End Points
The primary outcome was change in HbA1clevel. Im-
portant secondary outcomes included changes in various
other metabolic parameters, to determine the effect of sal-
salate on glucose and lipid homeostasis and coronary risk.
Context
Salsalate has been shown to reduce blood glucose concen-
tration in small studies.
Contribution
In this randomized trial, salsalate reduced hemoglobin A1c
levels and improved measures of metabolic and coronary
risk. Adverse effects included increased urinary albumin
levels. Other effects were minor and did not seem to dif-
fer by salsalate dose.
Caution
The trial’s small sample size and short follow-up make use
of the drug for treatment of diabetes premature.
Implication
Salsalate may be useful for treatment of type 2 diabetes.
The drug’s long-term safety in this population, especially
its effects on renal function, requires further investigation.
—The Editors
Article
Salsalate and Glycemic Control in Patients With Diabetes
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16 March 2010 Annals of Internal Medicine Volume 152 • Number 6 347

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We classified hypoglycemia as mild if symptoms were re-
lieved by food or if documented blood glucose concentra-
tion was less than 3.3 mmol/L (?60 mg/dL) and as severe
if patients required assistance.
Laboratory Measures
Unless otherwise noted, laboratory measurements were
performed at Quest Diagnostics (Chantilly, Virginia).
Commercial immunoassays for insulin, C-peptide, adi-
ponectin, high-sensitivity C-reactive protein, free fatty
acid, and glycated albumin were performed according to
assay instructions. Serum cystatin C concentration and cysta-
tin C GFR were measured as described elsewhere (17–19).
Statistical Analysis
The trial was designed to detect a 15% difference in
the proportion of patients with an absolute difference in
HbA1clevel of at least 0.5% from baseline to 14 weeks
between placebo and at least 1 treatment group, with sta-
tistical power of 90% and an ? level of 0.05. We closed the
data set before initiating analyses, which followed the
intention-to-treat principle. We compared baseline charac-
teristics among groups by using the chi-square test, Fisher
exact test, and parametric and nonparametric analysis of
variance. We evaluated the primary outcome by using chi-
square analyses to compare the proportion of patients in
each treatment group whose HbA1clevel decreased by
0.5%. We evaluated differences between active treatment
groups and placebo after adjusting the ? level for multiple
comparisons by using the Holm–Bonferroni method (20).
For continuous, normally distributed secondary out-
comes, we estimated between-group differences by using
linear mixed models adjusted for baseline levels, clinical
center, and follow-up. For secondary outcomes that were
continuous but not normally distributed, we examined
changes from baseline to week 14 by using the Kruskal–
Wallis test for an overall treatment effect and, when signif-
icant, used the Wilcoxon test to compare active treatment
Figure 1. Study flow diagram.
Screened (n = 277)
Ineligible (n = 149 [54%])
Entered run-in phase
(n = 128 [46%])
Excluded (n = 20 [16%])
Treatment side effects: 3
Medical issues: 2
Study burden: 8
Family issues: 2
Nonadherence: 1
Lost to follow-up: 4
Random assignment
(n = 108 [84%])
Placebo
(n = 27 [25%])
Analysis and
Safety Visit
Follow-up
Allocation
Enrollment
Moved
(n = 1 [4%])
Analyzed (n = 26)
Postdose visit:
Phone: 19
Clinic: 6
None: 1
Salsalate, 3.0 g/d
(n = 27 [25%])
Analyzed (n = 27)
Postdose visit:
Phone: 16
Clinic: 11
Salsalate, 3.5 g/d
(n = 27 [25%])
Analyzed (n = 26)
Postdose visit:
Phone: 14
Clinic: 10
None: 1
Salsalate, 4.0 g/d
(n = 27 [25%])
Excluded (n = 2 [7%])
Lost to follow-up: 1
Moved: 1
Analyzed (n = 25)
Phone: 16
Clinic: 8
None: 1
Changed mind and did
not receive medication
(n = 1 [4%])
Another left study
because of tinnitus*
* Participant who did not receive medication was excluded; participant who withdrew because of tinnitus was included in analysis.
Article
Salsalate and Glycemic Control in Patients With Diabetes
348 16 March 2010 Annals of Internal Medicine Volume 152 • Number 6
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Table 1. Baseline Characteristics of Study Patients
CharacteristicPlacebo (n ? 27)Salsalate, 3.0
g/d (n ? 27)
Salsalate, 3.5
g/d (n ? 27)
Salsalate, 4.0
g/d (n ? 27)
Mean age (SD), y
55.9 (8.2) 55.4 (9.4)56.7 (9.8) 55.0 (10.2)
Women, n (%)
12 (44.4)13 (48.1) 9 (33.3)11 (40.7)
Mean weight (SD), kg
99.1 (22.1)92.9 (22.2) 97.7 (18.8)102.2 (20.7)
Mean body mass index (SD), kg/m2
34.0 (6.1)32.3 (6.8)32.9 (6.5) 35.0 (6.5)
Mean waist circumference (SD), cm
104 (22.7)103 (15.6)106 (18.7)109 (23.0)
Mean time since diabetes diagnosis (SD), y
5.1 (3.7)6.4 (5.2)6.9 (6.0)6.4 (4.4)
Race or ethnicity, n (%)
White
Black
Other
15 (55.6)
9 (33.3)
3 (11.1)
12 (44.4)
12 (46.2)
2 (7.4)
14 (51.9)
10 (37.0)
3 (11.1)
14 (51.9)
10 (37.0)
1 (3.7)
Medical history, n (%)
Cardiovascular disease*
Hypertension†
1 (3.7)
20 (74.1)
1 (3.7)
19 (70.4)
1 (3.7)
19 (70.4)
4 (14.8)
18 (66.7)
Physical findings
Mean systolic blood pressure (SD), mm Hg
Mean diastolic blood pressure (SD), mm Hg
Mean heart rate (SD), beats/min
125 (14)
76 (8)
74 (11)
125 (13)
79 (7)
72 (9)
124 (13)
77 (10)
74 (13)
128 (12)
76 (9)
72 (7.1)
Laboratory values
Mean hemoglobin A1clevel (SD), %
Mean fasting glucose concentration (SD)
mmol/L
mg/dL
Mean glycated albumin level (SD), %
Median insulin concentration (IQR)
pmol/L
?U/mL
Mean C-peptide concentration (SD)
nmol/L
ng/mL
Median TSH level (IQR), mU/L
Mean total cholesterol level (SD)
mmol/L
mg/dL
Mean HDL cholesterol level (SD)
mmol/L
mg/dL
Mean LDL cholesterol level (SD)
mmol/L
mg/dL
Mean triglyceride concentration (SD)
mmol/L
mg/dL
Mean total–HDL cholesterol ratio (SD)
Median FFA concentration (IQR), mmol/L
Mean creatinine level (SD)
?mol/L
mg/dL
Mean MDRD eGFR (SD), mL/min per 1.73 m2
Mean cystatin C concentration (SD), mg/L
Mean CC eGFR (SD), mL/min
Mean uric acid level (SD), ?mol/L
Median albumin–creatinine ratio (IQR), ?g/mg Cr
Median ALT concentration (IQR), U/L
Median AST concentration (IQR), U/L
Median GGT concentration (IQR), U/L
Median CRP level (IQR), nmol/L
Mean hematocrit (SD), %
Mean leukocyte count (SD), ?109cells/L
Mean adiponectin concentration (SD), ?g/mL
7.8 (0.8)7.9 (1.1)7.4 (0.7)7.6 (0.9)
8.49 (2.22)
153 (40)
4.4 (0.3)
8.55 (2.33)
154 (42)
4.5 (0.2)
8.27 (2.16)
149 (39)
4.4 (0.3)
7.99 (2.00)
144 (36)
4.4 (0.2)
87.5 (121.5)
12.6 (17.5)
95.8 (73.6)
13.8 (10.6)
75.0 (40.3)
10.8 (5.8)
102.1 (110.4)
14.7 (15.9)
1.2 (0.79)
3.6 (2.4)
1.6 (0.6)
1.0 (0.36)
2.9 (1.1)
1.5 (1.5)
1.0 (0.5)
3.0 (1.5)
1.7 (0.9)
1.0 (0.6)
3.0 (1.8)
1.5 (0.9)
4.7 (1.3)
180 (49)
4.3 (1.3)
164 (50)
4.8 (1.4)
186 (54)
4.4 (0.7)
170 (27)
1.2 (0.4)
48 (14)
1.2 (0.3)
46 (12)
1.2 (0.3)
46 (11)
1.2 (0.3)
45 (12)
2.8 (1.1)
109 (44)
2.4 (0.8)
92 (32)
3.0 (1.2)
117 (46)
2.6 (0.7)
101 (25)
2.1 (1.1)
183 (93)
3.9 (1.3)
0.60 (0.30)
2.1 (2.0)
184 (178)
3.7 (1.1)
0.60 (0.32)
1.7 (0.9)
151 (76)
4.2 (1.5)
0.61 (0.29)
1.8 (0.9)
160 (81)
4.0 (1.3)
0.60 (0.21)
74.26 (17.68)
0.84 (0.20)
98.2 (19.9)
0.79 (0.15)
27.1 (4.2)
345 (72)
8 (23)
22 (13)
18 (10)
32 (25)
30.5 (51.4)
40.8 (4.2)
6.6 (1.7)
5.2 (4.2)
76.91 (23.87)
0.87 (0.27)
97.5 (24.4)
0.76 (0.12)
28.2 (4.2)
333 (95)
8 (28)
23 (21)
19 (8)
32 (18)
27.6 (31.4)
41.8 (3.0)
7.3 (2.2)
5.0 (4.1)
80.44 (17.68)
0.91 (0.20)
93.9 (23.8)
0.79 (0.18)
27.7 (6.3)
321 (77)
9.5 (9)
22 (11)
20 (7)
29 (18)
21.9 (20.0)
43.1 (3.9)
6.4 (1.7)
5.1 (4.9)
69.84 (14.14)
0.79 (0.16)
108.4 (26.2)
0.78 (0.12)
26.9 (3.5)
345 (83)
10 (25)
23 (18)
17 (9)
21 (22)
32.4 (81.9)
41.6 (4.2)
6.7 (1.9)
6.0 (6.2)
Continued on following page
Article
Salsalate and Glycemic Control in Patients With Diabetes
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16 March 2010 Annals of Internal Medicine Volume 152 • Number 6 349

Page 5

groups with placebo. We compared each active group with
placebo; we used the Holm procedure to adjust P values
for multiple comparisons and report the adjusted ? levels.
We also report nominal P values for the overall test of
difference among treatment groups, unadjusted for multi-
ple statistical testing of the secondary hypotheses. All P
values were 2-sided; we considered values less than 0.05 to
be statistically significant. We conducted post hoc analyses
to determine whether changes in albumin and creatinine
levels at week 14 were associated with changes in baseline
variables by using analysis of variance for estimated GFR,
blood pressure, and weight and the Fisher exact tests for
aspirin and angiotensin modulators.
Role of the Funding Source
The TINSAL-T2D trial is supported by the National
Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health (Bethesda, Maryland). The
funding agency was involved in study design and interpre-
tation of the data. Caraco Pharmaceuticals (Detroit, Mich-
igan) provided study drug and placebo, LifeScan (Miltipas,
California) provided glucometers and test strips, and Mer-
codia (Uppsala, Sweden) provided insulin assay materials.
No private company had a role in the design or conduct of
the trial, data analysis, or manuscript preparation.
RESULTS
Baseline Characteristics
Of the 277 patients screened, 128 entered the 4-week
placebo run-in phase (Figure 1). Most (72%) of the pa-
tients excluded at screening had HbA1clevels outside of
inclusion criteria. Differences in baseline characteristics
among treatment groups were not clinically significant
(Table 1).
Study Adherence
Median drug adherence rates, as assessed by pill count,
were 94% to 98%. No patients were unmasked during the
trial. Of the 27 patients randomly assigned to each treat-
ment group, 25 to 27 per group completed the study.
HbA1cLevel and Glycemic Control
Higher proportions of patients in the 3 salsalate treat-
ment groups experienced decreases in HbA1clevel of 0.5%
or more from baseline; the difference was statistically sig-
nificant overall (P ? 0.009) and in pairwise comparisons
with placebo for each salsalate dose (Table 2 and Figure 2,
A). Mean changes in HbA1clevel for the salsalate groups
were ?0.36% at 3.0 g/d (P ? 0.02), ?0.34% at 3.5 g/d
(P ? 0.02), and ?0.49% at 4.0 g/d (P ? 0.001) com-
pared with placebo.
Table 1—Continued
Characteristic Placebo (n ? 27)Salsalate, 3.0
g/d (n ? 27)
Salsalate, 3.5
g/d (n ? 27)
Salsalate, 4.0
g/d (n ? 27)
Ongoing diabetes therapies, n (%)
Metformin
Insulin secretagogue
?-Glucosidase inhibitor
Dipeptidyl peptidase-4 inhibitor
?2 diabetes drugs
Lifestyle modification only
22 (81.5)
13 (48.1)
0 (0)
1 (3.7)
12 (44.4)
4 (14.8)
22 (81.5)
10 (37.0)
0 (0)
1 (3.7)
10 (37.0)
4 (14.8)
18 (66.7)
12 (44.4)
0 (0)
0 (0)
8 (29.6)
5 (18.5)
23 (85.2)
12 (44.4)
0 (0)
0 (0)
11 (40.7)
3 (11.1)
Other relevant drugs, n (%)
Low-dose aspirin
ACE inhibitor or ARB
Other antihypertensive medication‡
HMG-CoA reductase inhibitor (statin)
Other lipid-lowering medication§
6 (22)
21 (77)
18 (67)
17 (63)
2 (7)
10 (37)
18 (67)
15 (56)
20 (74)
4 (15)
7 (26)
13 (48)
17 (63)
14 (52)
3 (11)
11 (41)
15 (56)
12 (44)
14 (52)
0 (0)
ACE ? angiotensin-converting enzyme; ALT ? alanine aminotransferase; ARB ? angiotensin-receptor blocker; AST ? aspartate aminotransferase; CC eGFR ? glomerular
filtration rate estimated by using cystatin C level; CRP ? C-reactive protein; FFA ? free fatty acid; GGT ? ?-glutamyltransferase; HDL ? high-density lipoprotein;
HMG-CoA ? 3-hydroxy-3-methylglutaryl coenzyme A; IQR ? interquartile range; LDL ? low-density lipoprotein; MDRD eGFR ? glomerular filtration rate estimated
by using the Modification of Diet in Renal Disease equation; TSH ? thyroid-stimulating hormone.
* Defined as coronary heart disease, heart attack, percutaneous transluminal angioplasty, coronary artery bypass surgery, or stroke.
† Defined as systolic blood pressure ?140 mm Hg; diastolic blood pressure ?90 mm Hg; or receiving medication, such as diuretics, calcium-channel blockers, peripheral
?-blockers, central ?-adrenergic agonists, ?-blockers, vasodilators, or reserpine.
‡ Diuretics, calcium-channel blockers, peripheral ?-blockers, central ?-adrenergic agonists, ?-blockers, vasodilators, or reserpine.
§ Bile-acid sequestrants, fibrates, cholesterol absorption inhibitors, niacin, or nicotine acid.
Table 2. Response Rates for Decreasing HbA1cLevel by
More Than 0.5%
Treatment GroupAll Patients,
n
Patients With >0.5%
Decrease in HbA1c
Level, n
Proportion
(95% CI)*
Placebo
Salsalate, 3.0 g/d
Salsalate, 3.5 g/d
Salsalate, 4.0 g/d
26
27
26
25
4 0.15 (0.02–0.30)
0.44 (0.26–0.63)
0.54 (0.35–0.73)
0.60 (0.42–0.78)
12
14
15
HbA1c? hemoglobin A1c.
* Calculated by using the chi-square test (P ? 0.009).
Article
Salsalate and Glycemic Control in Patients With Diabetes
350 16 March 2010 Annals of Internal Medicine Volume 152 • Number 6
www.annals.org