Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy

Diabetic neuropathy (DN) is the most common chronic complication of diabetes, affecting up
to50% of individuals with type 1 diabetes (T1DM). DN is a progressive disease, leading to
severe morbidity and staggering health care costs. Patients experience poor quality of life
due to pain, loss of sensation leading to poor balance, falls and eventual foot deformities
with high rates of ulcerations and amputations. While not as commonly diagnosed as DN,
cardiovascular autonomic neuropathy (CAN) carries equal morbidity with patients experiencing
orthostasis, arrhythmias and premature death).

Despite the high morbidity associated with DN, most randomized clinical trials evaluating
therapies for established DN have been disappointing. To date there is no pathogenetic
treatment for this condition. The Diabetes Control and Complications Trial (DCCT)
demonstrated that intensive control designed to achieve near-normal glycemia is essential in
reducing the risk of DN development in type 1 diabetes (8, 9). However, attainable intensive
glycemic control, although necessary, is insufficient to prevent adverse nervous system
effects, justifying a therapeutic need to identify new drug targets to treat DN early in its
course. One such new therapeutic target is inflammation. Multiple pre-clinical and clinical
studies demonstrate a pathogenic role for inflammation, especially cytokine production, in
the disease course of DN and CAN. This suggests that agents with known anti-inflammatory
properties, such as salicylates, may prevent the development of DN and the pain associated
with DN. Salsalate, a pro-drug form of salicylate, is a FDA approved drug commonly indicated
for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related
rheumatic disorders. In vitro and in vivo studies and human trials have shown that salicylate
therapy is effective in controlling low grade inflammation in diabetes by inhibition of the
inhibitor of the κB kinase (IKKβ)/NF-κB pathway. It has a large margin of safety (unlike
other salicylates), and a low cost. There is also extensive experience with long-term human
use of salsalate.

Several studies show that salsalate causes no greater intestinal occult blood loss than
placebo and has no suppressive effects on renal prostaglandin production in contrast to
aspirin or NSAIDs. The recently published NIDDK-funded "Targeting Inflammation Using
Salsalate in Type 2 Diabetes (TINSAL-T2D)" trial confirmed salutary effects of 3.5 gram/day
salsalate on markers of inflammation, glucose control and overall safety after 48 weeks
patients with type 2 diabetes. The Investigators' initial NIDDK funded R03 (DK 094499) grant
confirmed the safety and feasibility of targeting inflammation with salsalate treatment in
T1DM subjects with DN. The Investigators' current study builds upon and expands their initial
promising results and will either confirm or refute the therapeutic efficacy of salsalate in
a larger T1DM cohort.

Inclusion Criteria:

- Type 1 diabetes with mild to moderate peripheral neuropathy

- stable insulin treatment regimen

- willing to take study medication 3 times per day by mouth for 12 months

- women of child-bearing potential must use an approved method of contraception during
study.

Exclusion Criteria:

- history of severe DN, active lower limb ulceration or lower limb amputation or risk
factors for any other causes of neuropathy (e.g. active hepatitis C, end stage renal
disease, systemic lupus erythematosus or a known hereditary neuropathy) as determined
through medical history, family history, history of medications, occupational history,
history of exposure to toxins, physical and neurological examinations);

- history of recent severe hypoglycemia (within prior 6 months) as defined by
hypoglycemia resulting in coma or seizure or a history of recurrent diabetic
ketoacidosis (DKA) or any diabetic ketoacidosis within the last three months.

- history of persistent macroalbuminuria (urine albumin > 300 mg/24 hours).
Microalbuminuria up to 300 mg/24 hours is acceptable if serum creatinine is < 1.4 for
women, < 1.5 for men AND estimated GFR (eGFR) is > 60);

- 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];

- pregnancy or lactation, or intention to become pregnant in next 12 months;

- history of previous lung, kidney, pancreas, liver, cardiac or bone marrow transplant;

- history of drug or alcohol abuse within the previous 5 years, or current weekly
alcohol consumption >10 units/week;

- use of warfarin (Coumadin), clopidogrel (Plavix), dipyridamole (Persantine), heparin
or other anticoagulants, probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or
other uricosuric agents; Subjects must agree to not use high-dose aspirin during the
course of the study. Daily low-dose aspirin treatment (not more than 81 mg per day)
may be continued if currently prescribed.

- requiring long-term glucocorticoid therapy or chronic immunosuppressive therapy;
Inhaled steroid use for management of asthma is not an absolute exclusion.

- use of lithium

- participation in an experimental medication trial within 3 months of starting the
study;

- current therapy, or treatment within prior 5 years for malignant disease other than
basal- cell or squamous-cell skin cancer;

- history of gastrointestinal bleeding or active gastric ulcer; screening laboratory
abnormalities including AST (SGOT) and or ALT (SGPT) > 2.5 x the upper limit of normal
(ULN), total bilirubin > 1.5 x ULN, platelets < 100,000;

- history of keloid scarring. Keloids are large, thick masses of scar tissue. These are
more common among dark-skinned people.

- presence of any condition that, in the opinion of the investigator would make it
unlikely for the subject to complete 12 months of study participation, e.g., history
of non- adherence to therapeutic regimens, presence of conditions likely to limit life
expectancy, living situation that would interfere with study visit schedules such as a
job requiring frequent or extended travel

- known hypersensitivity to salsalate. Patients who have experienced asthma, hives, or
other allergic-type reactions to aspirin or other NSAIDs are excluded from
participation.

- Patients with known or suspected aspirin or NSAID-sensitive asthma are excluded.

- Patients with concurrent chicken pox, influenza, flu-like symptoms or other
symptomatic viral illnesses should not be enrolled in the study until the illness or
condition has resolved.

- Subjects with known or suspected hypersensitivity to lidocaine or epinephrine may not
be able to participate as these agents are used for local anesthesia during skin
biopsies. The study investigators should consider the nature and severity of past
reported reactions to these agents, and may consider alternative anesthesia options
for local anesthesia on a case by case basis.