Inflammation Inhibition in Prediabetic Humans
Condition: Prediabetes; Obese
MeSH terms: Prediabetic State; Glucose Intolerance; Inflammation
Intervention: Salsalate; Placebo
Intervention MeSH terms: Salicylsalicylic acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Maximum age: 79 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Endothelial Function; Arterial Stiffness; Inflammation; Muscle Sympathetic Nervous System; Prediabetes; Autonomic function

Summary:

      Prediabetes, characterized by elevated fasting blood sugar or exaggerated blood sugar
      response to sugar ingestion, effects over 79 million adult Americans and is a precursor to
      the development of Type 2 diabetes. Importantly, approximately 42% of Iowans (950,000) have
      diabetes and 32% (670,000) have prediabetes with the majority of those with prediabetes going
      undiagnosed. Adults with prediabetes demonstrate early signs of cardiovascular and nervous
      system abnormalities and are at high risk for developing overt diabetes unless aggressive
      lifestyle (weight loss, exercise) or pharmacological interventions are employed.
      Interestingly, data in recent years has linked obesity and diabetes to chronic inflammation
      of the blood vessels and brain areas that regulate blood pressure. Therefore, the current
      study will test whether a commonly used aspirin-like anti-inflammatory drug called salsalate,
      will improve blood vessel health and nervous system dysfunction in adults with prediabetes.
      Eligible subjects will have measurements of blood pressure, blood vessel function in the arms
      and eyes, assessments of nerve activity, and blood samples taken before and after 4 weeks of
      ingesting an FDA approved aspirin-like drug called salsalate. The study is important because
      it will identify a potentially new pharmacological strategy to treat vascular and nervous
      system abnormalities in overweight and obese adults with early stage type 2 diabetes using an
      inexpensive, generically available drug with an excellent safety record that has been used
      for decades to treat chronic inflammatory conditions such as rheumatoid arthritis. If proven
      effective, this will provide preliminary support for the concept of targeting inflammation as
      a new clinical approach to treating early diabetes related complications. Furthermore, the
      current pilot study will provide support for developing a larger clinical trial using
      salsalate that could potentially then be extended to patients with type 2 diabetes and
      cardiovascular disease, as well as lead to the development of new anti-inflammatory agents
      with greater specificity for selective inflammatory pathways.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Willing and able to provide written, signed informed consent after the nature of the
             study has been explained, and prior to any research-related procedures.

               -  Age is > or = 18 and < or = 49 years (older)

               -  Obese defined as body mass index > or = 30 kg/m2

               -  Prediabetic defined as fasting blood glucose 100-126 mg/dl, blood glucose between
                  140-199 mg/dl at 120 min of oral glucose tolerance test

               -  healthy, as determined by health history questionnaire, medical history and
                  physical examination by physician or nurse practitioner, blood chemistries,
                  resting blood pressure and exercise 12-lead ECG

               -  blood chemistries indicative of normal renal function (creatinine <2.2 mg/dl),
                  liver (<3 times upper limit for ALT, AST), and thyroid function (TSH between 0.4
                  - 5.0 mU/L)

               -  If currently receiving treatment with or taking any of the following supplements,
                  be willing and able to discontinue taking them for 2 weeks prior and throughout
                  the treatment period: Vitamin C, E or other multivitamins containing vitamin C or
                  E; nutraceuticals containing vitamin C or E

               -  No history of cardiovascular disease (e.g., heart attack, stroke, heart failure,
                  valvular heart disease, cardiomyopathy), Type 1 or 2 diabetes mellitus, or
                  peripheral arterial disease

               -  Sedentary or recreationally active defined as performs regular aerobic exercise
                  (30 min or more of vigorous walking, jogging, swimming, cycling, etc) less than 2
                  days/week or less than 12 days/month over the last year

               -  Non-smokers, defined as no history of smoking, no smoking for at least the past 1
                  year

               -  Normal resting 12-lead ECG.

        Exclusion Criteria:

          -  History of cardiovascular disease such as myocardial infarction, stroke, heart failure
             with or without LV ejection fraction <40%, cardiomyopathy, valvular heart disease,
             cardiomyopathy, heart transplantation, Type 2 diabetes and Type 1 diabetes

               -  Smoking or history of smoking within past one year

               -  History of gastric ulcers, bleeding disorders, dyspepsia, severe gastroesophageal
                  reflux disease (GERD), or metabolic acidosis

               -  History of asthma or lung disease (chronic obstructive pulomonary disease, COPD)

               -  Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left
                  ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block,
                  atrial fibrillation/flutter)

               -  Serious neurologic disorders including seizures

               -  History of renal failure, dialysis or kidney transplant

               -  Serum creatinine > 2.2 mg/dL, or hepatic enzyme concentrations > 3 times the
                  upper limit of normal

               -  History of HIV infection, hepatic cirrhosis, other preexisting liver disease, or
                  positive HIV, Hepatitis B or C test at screening.

               -  Use of any investigational product or investigational medical device within 30
                  days prior to screening, or requirement for any investigational agent prior to
                  completion of all scheduled study assessments.

               -  History of recent chicken pox, shingles or influenza (ie., risk of Reye's
                  syndrome) Recent flu-like symptoms within the past 2 weeks

               -  Pregnant or breastfeeding at screening, or planning to become pregnant (self or
                  partner) at any time during the study. A urinary pregnancy test will be done on
                  all females. If test is positive, the subject will be excluded.

               -  Women with history of hormone replacement therapy within the past 6 months

               -  History of rheumatoid arthritis, Grave's disease, systemic lupus erythamatosis,
                  and Wegener's granulomatosis;

               -  Taking medications for diabetes mellitus, kidney disease, liver disease, asthma,
                  sepsis or seizure disorders;

               -  Taking lipid lowering (e.g., statins, niacin), glycemic control (e.g. metformin,
                  insulin), anticoagulation, anti-seizure, anti-depression or antipsychotic agents

               -  History of co-morbid condition that would limit life expectancy to < 6 months.

               -  It is unknown if Salsalate is transferred in seminal fluid of men. However, it is
                  recommended that proper protection such as a condom be used during intercourse
                  during the study.

               -  Concomitant treatment with: aspirin, baby aspirin, indomethacin, naproxen
                  (Aleve), acetaminophen (Tylenol), ibuprofen (Advil, Motrin), any other
                  non-steroidal anti-inflammatory drugs; cox-2 inhibitors (Celebrex, Vioxx, etc);
                  allopurinol (Zyloprim, Lopurin, Alopurin; coumadin (Wafarin), enoxaparin
                  (Lovenox); clopidogrel (Plavix); dypyridamole (Persantine); heparin; diabetic
                  medications (Metformin, glyburide, insulin, etc), TZDs (Avandia, Rezulin, Actos);
                  corticosteroids (prednisone); methotrexate, infliximib (Remicade), etaneracept
                  (Enbrel); levothyroxine (Levoxyl, Synthroid, Levoxyl, Unithroid); Levodopa;
                  Phosphodiesterase (PDE) 5 inhibitors (e.g., Viagra®, Cialis®, Levitra®, or
                  Revatio®); PDE 3 inhibitors (e.g., cilostazol, milrinone, or vesnarinone);
                  lithium

               -  May participate if use of the following medications are discontinued 2 weeks
                  prior to participation: salicylate medications, aspirin, antioxidants, herbal
                  supplements, vitamins, omega-3 fatty acids; cox-2 inhibitors (Celebrex, Vioxx,
                  etc)

               -  May participate if no use of the following medications in the 48 hours prior to
                  experimental visits: naproxen (Aleve), acetaminophen (Tylenol), ibuprofen (Advil,
                  Motrin), other any non-steroidal anti-inflammatory drugs

               -  Vulnerable populations (prisoners, etc.) are not included in this study because
                  we are studying healthy middle-aged/older adults.

               -  Any condition that, in the view of the PI, places the subject at high risk of
                  poor treatment compliance or of not completing the study.

               -  Hemoglobin <12 mg/dl for men; < 10 mg/dl for women

               -  History of alcohol abuse or >10 alcoholic units per week (1 unit= 1 beer, 1 glass
                  of wine, 1 mixed cocktail containing 1 oz alcohol)

               -  Low platelets (<100,000 cu mm)

               -  On weight loss drugs (e.g., Xenical (orilistat), Meridia (sibutramine), Acutrim
                  (phenylpropanol-amine), or similar over-the-counter medications) within 3 months
                  of screening

               -  Any surgery within 30 days of screening