Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00330733
• Collaborator: Joslin Diabetes Center (Other)
• Enrollment: 71
• Location: 1
• Arms: 2
• Duration (Months): 44
• Patients Per Site Per Month: 1.6

Study Details

Study Description

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

1. 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.

Condition or Disease	Intervention/Treatment	Phase
Atherosclerosis; Cardiovascular Disease; Inflammation; Insulin Resistance; Noninsulin-dependent Diabetes Mellitus	Drug: Salsalate; Drug: Placebo	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching placebo	Drug: Placebo; Participants were randomized to 12-week treatment matching the active salsalate arm.
Active Comparator: Salsalate Therapy Salsalate	Drug: Salsalate; Participants were randomized to 12-week treatment with up to 4 g/day.; Other Names: Amigesic Anaflex Argesic-SA Disalcid Marthritic Mono-Gesic Salflex Salsitab

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Glucose Area Under the Curve in These Subjects [3 months]

2. 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.

3. Endothelial Function [Baseline and 12 weeks]

   Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel).

4. 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.

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Carl T. Hayden VA Medical Center	Phoenix	Arizona	United States	85012

Sponsors and Collaborators

• VA Office of Research and Development
• Joslin Diabetes Center

Investigators

• Principal Investigator: Peter Reaven, MD, Carl T. Hayden VA Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00330733
• Other Study ID Numbers: CLIN-011-05F
• First Posted: May 29, 2006
• Last Update Posted: Jan 21, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by VA Office of Research and Development: Cardiovascular Disease; Inflammation; Insulin Resistance; Type 2 DM
• Additional relevant MeSH terms: Cardiovascular Diseases; Atherosclerosis; Insulin Resistance; Diabetes Mellitus, Type 2; Inflammation; Salicylsalicylic acid

Study Results

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 Detail	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.

Arm/Group Title	Placebo	Salsalate
Arm/Group Description	Matching placebo	Salsalate therapy (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.
Period Title: Overall Study
STARTED	37	34
Received Study Medication	36	34
COMPLETED	30	29
NOT COMPLETED	7	5

Baseline Characteristics

Arm/Group Title	Placebo	Salsalate Therapy	Total
Arm/Group Description	Matching placebo	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.	Total of all reporting groups
Overall Participants	36	34	70
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (9)	60 (6)	58 (8)
Sex: Female, Male (Count of Participants)
Female	1 2.8%	2 5.9%	3 4.3%
Male	35 97.2%	32 94.1%	67 95.7%
Region of Enrollment (Count of Participants)
United States	36 100%	34 100%	70 100%
Insulin sensitivity (mg/ kg . min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/ kg . min]	4.08 (1.46)	3.8 (1.0)	3.93 (1.27)
Oral Glucose Tolerance Test (mg/dl. min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl. min]	167 (21)	165 (17)	166 (19)
Fasting glucose (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	105 (12)	103 (10)	104 (11)

Outcome Measures

1. Primary Outcome

Title	Change in Systemic Glucose Disposal- Glucose Infusion Rates
Description	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

Outcome Measure Data

Analysis Population Description

analysis was performed on all participants with available baseline and final clamp studies

Arm/Group Title	Placebo	Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo	Salsalate: Salsalate therapy
Measure Participants	29	29
Median (95% Confidence Interval) [percent change from baseline]	1	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Salsalate Therapy
	Comments	Paired comparisons (follow-up vs baseline) and unpaired group comparisons were performed by Student's t tests or Wilcoxon signed rank tests.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Glucose Area Under the Curve in These Subjects
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

analysis was performed on all participants with available baseline and final clamp studies

Arm/Group Title	Placebo	Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo	Salsalate: Salsalate therapy
Measure Participants	30	28
Mean (Standard Deviation) [mmol/l/hr]	8.98 (1.19)	8.74 (1.33)

3. Secondary Outcome

Title	Plasma CRP
Description	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

Outcome Measure Data

Analysis Population Description

Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication

Arm/Group Title	Placebo	Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo	Salsalate: Salsalate therapy
Measure Participants	36	34
Change in CRP at 8 weeks	0	-0.8
Change in CRP at 12 weeks	-0.1	-.3

4. Secondary Outcome

Title	Endothelial Function
Description	Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel).
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on all participants with available baseline and final clamp studies

Arm/Group Title	Placebo	Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo	Salsalate: Salsalate therapy
Measure Participants	26	27
Pat Index baseline	1.8 (.5)	1.9 (.5)
Pat Index 12 week	1.7 (.5)	1.7 (.6)

5. Secondary Outcome

Title	Plasma Interleukin 6
Description	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

Outcome Measure Data

Analysis Population Description

Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication

Arm/Group Title	Placebo	Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo	Salsalate: Salsalate therapy
Measure Participants	36	34
Change in IL-6 at 8 weeks	0.1	0
Change in IL-6 at 12 weeks	0.2	0

6. Secondary Outcome

Title	Plasma sVCAM
Description	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

Outcome Measure Data

Analysis Population Description

Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication

Arm/Group Title	Placebo	Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo	Salsalate: Salsalate therapy
Measure Participants	36	34
Change in sVCAM at 8 weeks	-12	-5
Change in sVCAM at 12 weeks	9	171

7. Secondary Outcome

Title	Plasma Adiponectin
Description	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

Outcome Measure Data

Analysis Population Description

Seventy-eight individuals entered the placebo run-in phase. Of these, 71 were randomised and 70 returned to receive study medication

Arm/Group Title	Placebo	Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo	Salsalate: Salsalate therapy
Measure Participants	36	34
Change in adiponectin at 8 weeks	-0.5	1.3
Change in adiponectin at 12 weeks	-0.1	1.2

Adverse Events

Time Frame	14 weeks (12 weeks active treatment + 2-week follow-up).
Arm/Group Title	Placebo		Salsalate Therapy
Arm/Group Description	Placebo: Matching placebo The frequency of tinnitus was relatively low (n=4 for salsalate, n= 2 for placebo), only one instance was graded > mild. Gastrointestinal complaints did not differ between groups (n= 8 for salsalate, n=5 for placebo). No hypoglycaemia occurred.		Salsalate: Salsalate therapy The frequency of tinnitus was relatively low (n=4 for salsalate, n= 2 for placebo), only one instance was graded > mild. Gastrointestinal complaints did not differ between groups (n= 8 for salsalate, n=5 for placebo). No hypoglycaemia occurred.
All Cause Mortality
	Placebo		Salsalate Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Salsalate Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Salsalate Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/36 (19.4%)		12/34 (35.3%)
Ear and labyrinth disorders
tinnitus	2/36 (5.6%)	2	4/34 (11.8%)	4
Gastrointestinal disorders
nausea	5/36 (13.9%)	5	8/34 (23.5%)	8

Limitations/Caveats

Since we did not measure endogenous glucose production and lipolysis, the effects on hepatic glucose and lipid metabolism deserve further study. Sufficient numbers of women were not included, with which to confidently extend these results to women

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.