Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus (T2D), Inflammation, Obesity, Metabolic Syndrome, Salicylates
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. Enrollment in the first stage is complete. The primary objective of the first stage was to select a dose of salsalate that is both well-tolerated and demonstrates a trend toward improvement in glycemic control. 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.
Interventions
DRUGSalsalate
Salsalate 3.5 g/d orally, divided dosing
DRUGSalsalate Placebo
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 (including SFU, non-SFU, and dipeptidyl peptidase IV (DPP-4) inhibitors), alpha-glucosidase inhibitors, or bile acid sequestrants (dosed once per day such that study drug can be administered ≥ 4 hours prior to sequestrant); or a combination of up to two of these at maximal dose. Dosing must be stable for 8 weeks prior to screening. Participant must have been diagnosed with T2D at least 8 weeks before screening. 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. No prior participation in Stage I of TINSAL-T2D ; exception: a participant who failed screening for HbA1c in Stage I will be allowed to re-screen for Stage II. 2. Type 1 diabetes and/or history of ketoacidosis determined by medical history 3. History of severe diabetic neuropathy including autonomic neuropathy, gastroparesis or lower limb ulceration or amputation 4. History of long-term therapy with insulin (\>30 days) within the last year 5. Therapy with rosiglitazone (Avandia) or pioglitazone (Actos), alone or in combination in the previous 6 months; or exendin-4 (Byetta), alone or in combination in the previous 3 months 6. Pregnancy or lactation 7. Patients requiring oral corticosteroids within 3 months or recurrent continuous oral corticosteroid treatment (more than 2 weeks) 8. 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 9. Surgery within 30 days prior to screening 10. 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 11. History of chronic liver disease including hepatitis B or C 12. History of peptic ulcer or endoscopy demonstrated gastritis 13. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV) 14. 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 15. New York Heart Association Class III or IV cardiac status or hospitalization for congestive heart failure 16. History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack or any revascularization within 6 months 17. 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). If on blood pressure medications, dosing should be stable for 2 weeks prior to randomization. 18. History of drug or alcohol abuse, or current weekly alcohol consumption \>10 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed DCCktail containing 1 ounce of alcohol) 19. Hemoglobin \<12 g/dL (males), \<10 g/dL (females) at screening\* 20. Platelets \<100,000 cu mm at screening 21. AST (SGOT) \>2.50 x ULN or ALT (SGPT) \>2.50 x ULN at screening 22. Total Bilirubin \>1.50 x ULN at screening 23. Triglycerides (TG) \>500 mg/dL at screening 24. Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study 25. Previous allergy to aspirin 26. Chronic or continuous use (daily for more than 7 days) of nonsteroidal anti-inflammatory drugs within the preceding 2 months 27. Use of warfarin (Coumadin), clopidogrel (Plavix), dipyridamole (Persantine), heparin or other anticoagulants 28. Use of probenecid (Benemid, probalan), sulfinpyrazone (Anturane) or other uricosuric agents 29. Macroalbuminuria, defined as spot urine protein \>300 mcg/mg Cr at screening 30. Pre-existing chronic tinnitus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Outcome for the TINSAL-T2D Study is Change in HbA1c Level From Baseline to Week 48 From Baseline, Compared Between Treatment Groups. | 48 weeks from baseline | HbA1c (%, percentage of HbA1c) change from baseline. |
Secondary
| Measure | Time frame |
|---|---|
| Response Rates for Reduction in Fasting Glucose of ≥20 mg/dl, a Reduction in HbA1c of ≥0.5%, and a Reduction in HbA1c of ≥0.8% | 24 and 48 weeks |
| 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) | 48 weeks |
| Change From Baseline in Fasting Glucose Over Time. | 48 weeks from baseline |
| Response Rates for Exceeding Hyperglycemic Targets Between Active and Placebo Treated Groups; Need for Rescue Therapy; Need for Discontinuation of Study Medication | 24 and 48 weeks |
| Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy | 24 and 48 weeks |
| Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers | 24 and 48 weeks |
Countries
United States
Participant flow
Pre-assignment details
The Enrollment number in the protocol section (638) is higher than the number of participants Started in the Participant Flow module (286) due to screen failures and drop out prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo for salsalate, orally, divided dosing | 140 |
| Salsalate Salsalate, 3.5 g/d orally, divided dosing | 146 |
| Total | 286 |
Baseline characteristics
| Characteristic | Salsalate | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 28 Participants | 28 Participants | 56 Participants |
| Age, Categorical Between 18 and 65 years | 118 Participants | 112 Participants | 230 Participants |
| Age, Continuous | 55.8 years STANDARD_DEVIATION 9.2 | 55.8 years STANDARD_DEVIATION 10 | 55.8 years STANDARD_DEVIATION 9.6 |
| Region of Enrollment United States | 146 participants | 140 participants | 286 participants |
| Sex: Female, Male Female | 64 Participants | 65 Participants | 129 Participants |
| Sex: Female, Male Male | 82 Participants | 75 Participants | 157 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 64 / 140 | 85 / 146 |
| serious Total, serious adverse events | 6 / 140 | 10 / 146 |
Outcome results
Primary
The Primary Outcome for the TINSAL-T2D Study is Change in HbA1c Level From Baseline to Week 48 From Baseline, Compared Between Treatment Groups.
HbA1c (%, percentage of HbA1c) change from baseline.
Time frame: 48 weeks from baseline
Population: Participants with complete data at both Baseline and 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | The Primary Outcome for the TINSAL-T2D Study is Change in HbA1c Level From Baseline to Week 48 From Baseline, Compared Between Treatment Groups. | -0.04 HbA1c units are % |
| Salsalate | The Primary Outcome for the TINSAL-T2D Study is Change in HbA1c Level From Baseline to Week 48 From Baseline, Compared Between Treatment Groups. | -0.33 HbA1c units are % |
Secondary
Change From Baseline in Fasting Glucose Over Time.
Time frame: 48 weeks from baseline
Population: Participants with complete data at both Baseline and 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Fasting Glucose Over Time. | 2.0 mg/dl |
| Salsalate | Change From Baseline in Fasting Glucose Over Time. | -13.1 mg/dl |
Secondary
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)
Time frame: 48 weeks
Secondary
Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers
Time frame: 24 and 48 weeks
Secondary
Response Rates for Exceeding Hyperglycemic Targets Between Active and Placebo Treated Groups; Need for Rescue Therapy; Need for Discontinuation of Study Medication
Time frame: 24 and 48 weeks
Secondary
Response Rates for Reduction in Fasting Glucose of ≥20 mg/dl, a Reduction in HbA1c of ≥0.5%, and a Reduction in HbA1c of ≥0.8%
Time frame: 24 and 48 weeks
Secondary
Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy
Time frame: 24 and 48 weeks