Type 2 Diabetes
Conditions
Keywords
Type 2 Diabetes, Inflammation, Obesity, Metabolic Syndrome
Brief summary
Growing evidence over recent years supports a potential role for low grade chronic inflammation in the pathogenesis of insulin resistance and type 2 diabetes. In this study we will determine whether salsalate, a member of the commonly used Non-Steroidal Anti-Inflammatory Drug (NSAID) class, is effective in lowering sugars in patients with type 2 diabetes. The study will determine whether salicylates represent a new pharmacological option for diabetes management. The study is conducted in two stages. The first stage is a dose ranging study, administering salsalate compared to placebo over three months. The primary objective of Stage 2 of the study is to evaluate the effects of salsalate on blood sugar control in diabetes; the tolerability of salsalate use in patients with type 2 diabetes (T2D); and the effects of salsalate on measures of inflammation, the metabolic syndrome, and cardiac risk. The second stage is a second trial and posted under alternate registration.
Detailed description
The primary objective of the first stage of the TINSAL-T2D trial is to select a dose of salsalate that is both well-tolerated and demonstrates a trend toward improvement in glycemic control. The trial is a multicenter, single mask lead-in, double masked placebo controlled dose ranging study, comparing salsalte to placebo over 3 months.
Interventions
DRUGSalsalate
Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided
DRUGPlacebo
Placebo to Salsalate
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Joslin Diabetes Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Type 2 diabetes on diet and exercise therapy or monotherapy with metformin, insulin secretagogue, or alpha-glucosidase inhibitors, or a low-dose combination of these at ≤ 50% maximal dose (see Appendix). Dosing is stable for 8 weeks prior to randomization. 2. FPG ≤ 225 mg/dL and HbA1c\>7% and ≤9.5% at screening 3. Age ≥18 and \<75 4. Women of childbearing potential agree to use an appropriate contraceptive method (hormonal, IUD, or diaphragm)
Exclusion criteria
1. Type 1 diabetes and/or history of ketoacidosis determined by medical history 2. History of severe diabetic neuropathy including autonomic neuropathy, gastroparesis or lower limb ulceration or amputation 3. History of long-term therapy with insulin (\>30 days) within the last year 4. Therapy with rosiglitazone (Avandia) or pioglitazone (Actos), or extendin-4 (Byetta), alone or in combination in the previous 6 months 5. Pregnancy or lactation 6. Patients requiring corticosteroids within 3 months or recurrent continuous oral corticosteroid treatment (more than 2 weeks) 7. Use of weight loss drugs \[e.g., Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanol-amine), or similar over-the-counter medications\] within 3 months of screening or intentional weight loss of ≥ 10 lbs in the previous 6 months 8. Surgery within 30 days prior to screening 9. Serum creatinine \>1.4 for women and \>1.5 for men or eGFR \<60 \[possible chronic kidney disease stage 3 or greater calculated using the Modification of Diet in Renal Disease (MDRD) equation. 10. History of chronic liver disease including hepatitis B or C 11. History of peptic ulcer or endoscopy demonstrated gastritis 12. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV) 13. History of malignancy, except participants who have been disease-free for greater than 10 years, or whose only malignancy has been basal or squamous cell skin carcinoma 14. New York Heart Association Class III or IV cardiac status or hospitalization for congestive heart failure 15. History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack or any revascularization within 6 months 16. Uncontrolled hypertension (defined as systolic blood pressure \>150 mmHg or diastolic blood pressure \>95 mmHg on three or more assessments on more than one day) 17. History of drug or alcohol abuse, or current weekly alcohol consumption \>10 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 ounce of alcohol) 18. Hemoglobin \<12 g/dL (males), \<10 g/dL (females) at screening 19. Platelets \<100,000 cu mm at screening. 20. AST (SGOT) \>2.50 x ULN or ALT (SGPT) \>2.50 x ULN at screening 21. Total Bilirubin \>1.50 x ULN at screening 22. Triglycerides (TG) \>500 mg/dL at screening 23. Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study 24. Previous allergy to aspirin 25. Chronic or continuous use (daily for more than 7 days) of nonsteroidal anti-inflammatory drugs within the preceding 2 months 26. Use of warfarin (Coumadin), clopidogrel (Plavix) or other anticoagulants 27. Use of probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1 | 14 week | The primary outcome for the TINSAL-T2D study is change in HbA1c level from baseline to week 14 (stage 1) in the intent-to-treat (ITT) population with last observation carried forward. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline and Trends in Fasting Glucose Over Time | 14 week | — |
| Change in Lipids | 14 week | Change in lipids (low-density lipoprotein cholesterol \[LDL-C\], non-high-density lipoprotein cholesterol \[non-HDL-C\], triglycerides \[TG\], total cholesterol \[TC\], high-density lipoprotein cholesterol \[HDL C\], TC/HDL-C ratio, and LDL-C/HDL-C ratio) LDL-C/HDL-C ratio not calculated |
| Change in HbA1c | 14 week | Change from baseline to either 14 or 26 weeks, or last HbA1c measurement prior to rescue therapy |
| Safety and Tolerability | 14 weeks | See adverse event module for details. Safety and tolerability of salsalate compared to placebo as assessed by adverse events. |
| Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index | Baseline, week 14 | HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in C-peptide from Baseline to Week 14 is in the data table below |
| Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index | Baseline, week 14 | HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in insulin from Baseline to Week 14 in data table below. |
Countries
United States
Participant flow
Recruitment details
3 private practices and 14 universities. First patient recruited February 2007; last patient end of study visit, May 2008
Pre-assignment details
Screening, followed by 4-week single mask placebo lead-in. 277 participants signed screening consent. Some participants were ineligible, some withdrew consent, and some had treatment side effects during placebo lead-in.
Participants by arm
| Arm | Count |
|---|---|
| 3 Gram Salsalate 3.0 g daily, divided | 27 |
| 3.5 Gram Salsalate 3.5 g daily, divided | 27 |
| 4 Gram Salsalate 4.0 g daily, divided | 27 |
| Placebo matched to active drug | 27 |
| Total | 108 |
Baseline characteristics
| Characteristic | 3.5 Gram | 4 Gram | 3 Gram | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 3 Participants | 4 Participants | 5 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 24 Participants | 23 Participants | 22 Participants | 91 Participants |
| Age, Continuous | 56.7 years STANDARD_DEVIATION 9.8 | 55.0 years STANDARD_DEVIATION 10.2 | 55.4 years STANDARD_DEVIATION 9.4 | 55.9 years STANDARD_DEVIATION 8.2 | 56 years STANDARD_DEVIATION 9 |
| Region of Enrollment United States | 27 participants | 27 participants | 27 participants | 27 participants | 108 participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 13 Participants | 12 Participants | 45 Participants |
| Sex: Female, Male Male | 18 Participants | 16 Participants | 14 Participants | 15 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 27 | 0 / 27 | 0 / 27 |
| other Total, other adverse events | 27 / 27 | 27 / 27 | 27 / 27 | 25 / 27 |
| serious Total, serious adverse events | 1 / 27 | 2 / 27 | 0 / 27 | 1 / 27 |
Outcome results
Primary
Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1
The primary outcome for the TINSAL-T2D study is change in HbA1c level from baseline to week 14 (stage 1) in the intent-to-treat (ITT) population with last observation carried forward.
Time frame: 14 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 3.0 g/d | Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1 | -0.36 % (units of HbA1c) |
| 3.5 g/d | Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1 | -0.34 % (units of HbA1c) |
| 4.0 g/d | Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1 | -0.49 % (units of HbA1c) |
| Placebo | Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1 | -0.01 % (units of HbA1c) |
p-value: <0.05Mixed Models Analysis
Secondary
Change From Baseline and Trends in Fasting Glucose Over Time
Time frame: 14 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 3.0 g/d | Change From Baseline and Trends in Fasting Glucose Over Time | 13 mg/dl |
| 3.5 g/d | Change From Baseline and Trends in Fasting Glucose Over Time | -19 mg/dl |
| 4.0 g/d | Change From Baseline and Trends in Fasting Glucose Over Time | -14 mg/dl |
| Placebo | Change From Baseline and Trends in Fasting Glucose Over Time | -15 mg/dl |
Secondary
Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index
HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in insulin from Baseline to Week 14 in data table below.
Time frame: Baseline, week 14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 3.0 g/d | Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index | -3.0 pmol/l |
| 3.5 g/d | Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index | 15 pmol/l |
| 4.0 g/d | Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index | 7.6 pmol/l |
| Placebo | Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index | 27 pmol/l |
Secondary
Change in HbA1c
Change from baseline to either 14 or 26 weeks, or last HbA1c measurement prior to rescue therapy
Time frame: 14 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 3.0 g/d | Change in HbA1c | 0 % HbA1c |
| 3.5 g/d | Change in HbA1c | -0.4 % HbA1c |
| 4.0 g/d | Change in HbA1c | -0.3 % HbA1c |
| Placebo | Change in HbA1c | -0.5 % HbA1c |
Secondary
Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index
HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in C-peptide from Baseline to Week 14 is in the data table below
Time frame: Baseline, week 14
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 3.0 g/d | Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index | 0.10 C-peptide in nmol/l |
| 3.5 g/d | Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index | -0.07 C-peptide in nmol/l |
| 4.0 g/d | Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index | -0.03 C-peptide in nmol/l |
| Placebo | Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index | 0.03 C-peptide in nmol/l |
Secondary
Change in Lipids
Change in lipids (low-density lipoprotein cholesterol \[LDL-C\], non-high-density lipoprotein cholesterol \[non-HDL-C\], triglycerides \[TG\], total cholesterol \[TC\], high-density lipoprotein cholesterol \[HDL C\], TC/HDL-C ratio, and LDL-C/HDL-C ratio) LDL-C/HDL-C ratio not calculated
Time frame: 14 week
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 3.0 g/d | Change in Lipids | LDL | 0 mg/dl |
| 3.0 g/d | Change in Lipids | Cholesterol | 0 mg/dl |
| 3.0 g/d | Change in Lipids | TG | 15 mg/dl |
| 3.0 g/d | Change in Lipids | HDL | 0 mg/dl |
| 3.0 g/d | Change in Lipids | Total to HDL ratio | 0 mg/dl |
| 3.5 g/d | Change in Lipids | LDL | 15 mg/dl |
| 3.5 g/d | Change in Lipids | HDL | 3 mg/dl |
| 3.5 g/d | Change in Lipids | TG | -34 mg/dl |
| 3.5 g/d | Change in Lipids | Cholesterol | 8 mg/dl |
| 3.5 g/d | Change in Lipids | Total to HDL ratio | 0.1 mg/dl |
| 4.0 g/d | Change in Lipids | TG | -22 mg/dl |
| 4.0 g/d | Change in Lipids | Cholesterol | -1 mg/dl |
| 4.0 g/d | Change in Lipids | HDL | 1 mg/dl |
| 4.0 g/d | Change in Lipids | LDL | 3 mg/dl |
| 4.0 g/d | Change in Lipids | Total to HDL ratio | -0.1 mg/dl |
| Placebo | Change in Lipids | TG | -16 mg/dl |
| Placebo | Change in Lipids | HDL | 2 mg/dl |
| Placebo | Change in Lipids | Cholesterol | 6 mg/dl |
| Placebo | Change in Lipids | Total to HDL ratio | 0.2 mg/dl |
| Placebo | Change in Lipids | LDL | 8 mg/dl |
Secondary
Safety and Tolerability
See adverse event module for details. Safety and tolerability of salsalate compared to placebo as assessed by adverse events.
Time frame: 14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 3.0 g/d | Safety and Tolerability | 17 participants |
| 3.5 g/d | Safety and Tolerability | 16 participants |
| 4.0 g/d | Safety and Tolerability | 16 participants |
| Placebo | Safety and Tolerability | 14 participants |