Atherosclerosis, Cardiovascular Disease, Inflammation, Insulin Resistance, Noninsulin-dependent Diabetes Mellitus
Conditions
Keywords
Cardiovascular Disease, Inflammation, Insulin Resistance, Type 2 DM
Brief summary
The hypothesis is that salsalate therapy may be an effective and safe method to modulate inflammation in metabolically-critical tissues and thus reduce insulin resistance and its related complications. The objectives of the study are to (1) determine whether salsalate therapy improves insulin resistance in subjects with IGT and changes in glucose area under the curve following a standard oral glucose tolerance test (OGTT); (2) determine whether salsalate therapy reduces a) plasma levels of a variety of well established inflammatory proteins and b) mononuclear cell inflammatory activity to provide evidence of reduced systemic and tissue inflammation, respectively; and (3)also determine whether salsalate therapy improves parameters of cardiovascular disease risk, including features of metabolic syndrome (fasting glucose, triglycerides, HDL, and blood pressure) as well as endothelial dysfunction.
Detailed description
Recent studies demonstrate an important role for sub-acute, chronic inflammation in the development of insulin resistance, type 2 diabetes mellitus (T2 DM) and cardiovascular disease (CVD). A broad body of data indicate that obesity and high fat or Western diets activate sub-acute inflammatory processes in fat and liver tissue as well as in mononuclear cells. The inflammatory mediators produced by these tissues and cells promote the development of insulin resistance both locally and at distant sites such as skeletal muscle. These same inflammatory mediators may also increase the risk for CVD. Work from our labs indicate that Nuclear Factor-kappa B (NF-kB), an inflammatory master switch for a multitude of proinflammatory genes and pathways, is activated in fat and liver by obesity and high fat diets. We have also noted similar NF-kB activation in monocytes and macrophages in similar conditions of nutritional excess. It has become evident that salicylates inhibit the NF-kB regulatory protein IKKB (inhibitor of Kappa B Kinase) and we have subsequently demonstrated their ability to downregulate NF-kB activation in each of these above tissues in animals. Moreover, by inhibiting the IKKB/NF-kB pathway, salicylates appear to ameliorate insulin resistance and its associated metabolic abnormalities and potentially provide a new approach for pharmacologic treatment of T2 DM as well as individuals with conditions such as impaired glucose intolerance (IGT) to prevent their progression to diabetes. Preliminary results from a two-week trail is T2 DM patients indicated that high-dose aspirin(ASA,\ 7g/day) improved glucose metabolism and associated risk factors. While this was as important first step towards proof-of-principle, the risk of severe gastrointestinal bleeding associated with high-dose ASA precludes broader use. Salicylate in its prodrug form of salsalate(Disalcid), is much safer than ASA(as it does not irritate the gastric mucosa nor alter bleeding times). We have now conducted several preliminary short-term in individuals with IGT or T2 DM as well in obese insulin resistant subjects and have demonstrated that salsalate in doses of 3.5-4.5g/d provides similar blood salicylate levels as high dose ASA and induces similar clinical and metabolic benefits over the 2-4 weeks study duration. Therefore, in vitro, animal and human clinical studies all support the concept that inhibiting the IKKB/NF-kB pathway with salsalate is a feasible approach to reducing insulin resistance. This study will more fully characterize the metabolic benefits of high dose salsalate therapy.
Interventions
DRUGSalsalate
Participants were randomized to 12-week treatment with up to 4 g/day.
DRUGPlacebo
Participants were randomized to 12-week treatment matching the active salsalate arm.
Sponsors
Joslin Diabetes Center
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female veterans between the age of 21-75 who have IFG (impaired fasting glucose) and/or IGT
Exclusion criteria
* any diabetes therapy in the prior 12-months period * any acute illness * Ongoing high dose aspirin or Salsalate Therapy * history of GI bleeding * hearing problems * poor vascular access, prior pancreatitis, uncontrolled hypertension, pregnancy, renal disease or anemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systemic Glucose Disposal- Glucose Infusion Rates | 3 months | Participants were admitted to the Clinical Research Units at 06:00-08:00 hours after an overnight fast. Euglycaemic-hyperinsulinaemic clamps were conducted at baseline and at the end of the study. Because salsalate therapy appears to decrease insulin clearance leading to higher circulating insulin levels during the clamp, we reduced the infusion rate of insulin in the active treatment arm by 20% (from 100 to 80 mUm-2 min-1) at the study end. Insulin solutions were prepared by the site pharmacist so that study staff remained blinded to drug assignment. Whole-body insulin sensitivity was estimated from glucose infusion rate (GIR) during last 30 min of insulin infusions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma CRP | 8 and 12 weeks | Plasma C-reactive protein was measured by PVAHS clinical laboratory. Data are reported as change from baseline at 8 and 12 weeks. |
| Endothelial Function | Baseline and 12 weeks | Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel). |
| Glucose Area Under the Curve in These Subjects | 3 months | — |
| Plasma sVCAM | 8 and 12 weeks | Plasma soluble VCAM was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks. |
| Plasma Adiponectin | 8 and 12 weeks | Plasma soluble Adiponectin was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks. |
| Plasma Interleukin 6 | 8 and 12 weeks | Plasma IL-6 was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks. |
Countries
United States
Participant flow
Recruitment details
Participants were veterans aged 21-75 years with impaired fasting glucose (i.e. ≥5.6 but \<7 mmol/l) or impaired glucose tolerance (2 h glucose values ≥7.8 but \<11.1 mmol/l) during a standard 2 h 75 g OGTT. Study participants were recruited from clinics and hospitals throughout the Phoenix and Boston VA Health Care systems.
Pre-assignment details
After enrolment there were 1 week screening, 3 week single-masked placebo run-in (to assess compliance) and 12 week randomised, double-masked treatment periods, with participants randomised 1:1 to receive salsalate or placebo. 78 individuals entered the run-in phase.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo | 36 |
| Salsalate Therapy Salsalate therapy, double-masked. Salsalate (Caraco Pharmaceutical Labs, Detroit, MI, USA) was initiated at 3.0 g/day and increased at weeks 2 and 4 of the treatment period to 3.5 and 4.0 g/day, respectively, in divided doses twice daily, as tolerated for 12 weeks total. | 34 |
| Total | 70 |
Baseline characteristics
| Characteristic | Placebo | Salsalate Therapy | Total |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 9 | 60 years STANDARD_DEVIATION 6 | 58 years STANDARD_DEVIATION 8 |
| Fasting glucose | 105 mg/dl STANDARD_DEVIATION 12 | 103 mg/dl STANDARD_DEVIATION 10 | 104 mg/dl STANDARD_DEVIATION 11 |
| Insulin sensitivity | 4.08 mg/ kg . min STANDARD_DEVIATION 1.46 | 3.8 mg/ kg . min STANDARD_DEVIATION 1 | 3.93 mg/ kg . min STANDARD_DEVIATION 1.27 |
| Oral Glucose Tolerance Test | 167 mg/dl. min STANDARD_DEVIATION 21 | 165 mg/dl. min STANDARD_DEVIATION 17 | 166 mg/dl. min STANDARD_DEVIATION 19 |
| Region of Enrollment United States | 36 Participants | 34 Participants | 70 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 35 Participants | 32 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 36 | 12 / 34 |
| serious Total, serious adverse events | 0 / 36 | 0 / 34 |
Outcome results
Primary
Change in Systemic Glucose Disposal- Glucose Infusion Rates
Participants were admitted to the Clinical Research Units at 06:00-08:00 hours after an overnight fast. Euglycaemic-hyperinsulinaemic clamps were conducted at baseline and at the end of the study. Because salsalate therapy appears to decrease insulin clearance leading to higher circulating insulin levels during the clamp, we reduced the infusion rate of insulin in the active treatment arm by 20% (from 100 to 80 mUm-2 min-1) at the study end. Insulin solutions were prepared by the site pharmacist so that study staff remained blinded to drug assignment. Whole-body insulin sensitivity was estimated from glucose infusion rate (GIR) during last 30 min of insulin infusions.
Time frame: 3 months
Population: analysis was performed on all participants with available baseline and final clamp studies
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Systemic Glucose Disposal- Glucose Infusion Rates | 1 percent change from baseline |
| Salsalate Therapy | Change in Systemic Glucose Disposal- Glucose Infusion Rates | 6 percent change from baseline |
Comparison: Paired comparisons (follow-up vs baseline) and unpaired group comparisons were performed by Student's t tests or Wilcoxon signed rank tests.p-value: <0.05t-test, 2 sided
Secondary
Endothelial Function
Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel).
Time frame: Baseline and 12 weeks
Population: Analysis was performed on all participants with available baseline and final clamp studies
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Endothelial Function | Pat Index baseline | 1.8 index | Standard Error 0.5 |
| Placebo | Endothelial Function | Pat Index 12 week | 1.7 index | Standard Error 0.5 |
| Salsalate Therapy | Endothelial Function | Pat Index baseline | 1.9 index | Standard Error 0.5 |
| Salsalate Therapy | Endothelial Function | Pat Index 12 week | 1.7 index | Standard Error 0.6 |
Secondary
Glucose Area Under the Curve in These Subjects
Time frame: 3 months
Population: analysis was performed on all participants with available baseline and final clamp studies
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Glucose Area Under the Curve in These Subjects | 8.98 mmol/l/hr | Standard Deviation 1.19 |
| Salsalate Therapy | Glucose Area Under the Curve in These Subjects | 8.74 mmol/l/hr | Standard Deviation 1.33 |
Secondary
Plasma Adiponectin
Plasma soluble Adiponectin was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
Time frame: 8 and 12 weeks
Population: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Plasma Adiponectin | Change in adiponectin at 8 weeks | -0.5 μg/ml |
| Placebo | Plasma Adiponectin | Change in adiponectin at 12 weeks | -0.1 μg/ml |
| Salsalate Therapy | Plasma Adiponectin | Change in adiponectin at 8 weeks | 1.3 μg/ml |
| Salsalate Therapy | Plasma Adiponectin | Change in adiponectin at 12 weeks | 1.2 μg/ml |
Secondary
Plasma CRP
Plasma C-reactive protein was measured by PVAHS clinical laboratory. Data are reported as change from baseline at 8 and 12 weeks.
Time frame: 8 and 12 weeks
Population: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Plasma CRP | Change in CRP at 8 weeks | 0 mg/l |
| Placebo | Plasma CRP | Change in CRP at 12 weeks | -0.1 mg/l |
| Salsalate Therapy | Plasma CRP | Change in CRP at 8 weeks | -0.8 mg/l |
| Salsalate Therapy | Plasma CRP | Change in CRP at 12 weeks | -.3 mg/l |
Secondary
Plasma Interleukin 6
Plasma IL-6 was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
Time frame: 8 and 12 weeks
Population: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Plasma Interleukin 6 | Change in IL-6 at 8 weeks | 0.1 pg/ml |
| Placebo | Plasma Interleukin 6 | Change in IL-6 at 12 weeks | 0.2 pg/ml |
| Salsalate Therapy | Plasma Interleukin 6 | Change in IL-6 at 8 weeks | 0 pg/ml |
| Salsalate Therapy | Plasma Interleukin 6 | Change in IL-6 at 12 weeks | 0 pg/ml |
Secondary
Plasma sVCAM
Plasma soluble VCAM was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
Time frame: 8 and 12 weeks
Population: Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Plasma sVCAM | Change in sVCAM at 8 weeks | -12 ng/ml |
| Placebo | Plasma sVCAM | Change in sVCAM at 12 weeks | 9 ng/ml |
| Salsalate Therapy | Plasma sVCAM | Change in sVCAM at 8 weeks | -5 ng/ml |
| Salsalate Therapy | Plasma sVCAM | Change in sVCAM at 12 weeks | 171 ng/ml |