The Diabetologist #26

Even though IL-1 blockade was not effective in newonset
T1D (see Preservation section), use earlier in
the course of the autoimmune process may prove effective.
There is also interest in non-steroidal anti-inflammatories
and further assessment of omega-3 fatty
acids, possibly in combination with vitamin D. Nonspecific
immunostimulants, such as OM85 and BCG,
could also prove effective. Emerging evidence links the
intestinal micro-biome with mucosal immunity and T1D
risk. Probiotics, helminthes (such as trichuris suis ova),
and even lactobacillus modified to over-express IL-10
may alter T1D risk.23 As noted with antigen-based
therapies, optimizing dose, frequency, and timing of
administration in the disease course will be necessary
for success. It may be that a combination of drugs
working by different mechanisms is necessary to accomplish
the task. Investigators will continue to closely
monitor advances in related autoimmune diseases and
transplantation, in search of therapies that warrant assessment
in T1D prevention.
‏.‏III PRESERVATION
Preservation trials focus on halting further pancreatic
beta-cell destruction after T1D diagnosis. At the time of
diagnosis, it has been estimated that 15–40% of betacell
function remains. However, this remnant can serve
one well while it lasts, as evidenced by better overall
glycemic control during this remission or honey-moon
phase, with lower A1Cs, less glycemic variability, and
less hypoglycemia risk. For several decades, investigators
have attempted to define a safe and effective
means to preserve beta-cell function following diagnosis.
However, intervening late in the process poses the
challenge of daring to be aggressive enough to arrest
further destruction while finding an intervention that
is safe and tolerable. In those with long-standing disease,
such therapy could be used in conjunction with
a beta-cell replacement strategy: even if replacement
islets are generated from host stem cells, one must
control the chronic autoimmune response to enable
long-term cell survival. Over the past few decades, numerous
agents have been evaluated with varying levels
of success, with many efforts conducted with smaller
number of subjects and often lacking a contemporaneous
control group. A subset of these efforts is reviewed
herein, with a focus on the well-powered randomized,
placebo-controlled studies.
Antigen-Based Therapies
Antigen-based therapies have yielded disappointing
results in new-onset T1D patients. Given its known
role as a primary antigen in the NOD mouse and in
humans, it is not surprising that various forms of insulin
as an antigen- based therapy have been attempted
in new-onset T1D studies. While some have shown
early promise after disease onset, no large, placebocontrolled
study has shown efficacy to date (reviewed
in Prevention section). Animal studies and pilot human
clinical studies with glutamate decarboxylase (GAD)
were promising, but subsequent phase II and III trials
have shown no effect.24,25 As with the insulin antigen
experience, there may be numerous reasons for
the negative findings to date and opportunities to optimize
responses. These include 1) antigen use earlier
in the course of disease (as a preventive measure), 2)
use of specific peptides vs. whole molecules, 3) an
alternate dose or frequency of antigen administration,
4) an alternate route of administration, or 5) use
of an alternate adjuvant to improve efficacy.
‏,‏Diapep277‎ an epitope of heat shock protein 60, is
another antigen that may be involved in autoimmune
responses against the beta-cell, though it does not
appear to be one of the primary initial targets. Phase
II trials showed mixed results with statistically significant
preservation of -1-cell function in adults but not
in children, and there was no change in A1C and insulin
requirements.26 Results from a recently completed
randomized, double-blind, phase III trial for adults
with new-onset T1D reached the primary outcome,
showing modest improvement in glucagon stimulated
C-peptide at 24 months for the treated group, with improvement
in some secondary measures of metabolic
control (A1C, insulin use, hypoglycemia frequency),
yet there was no difference in stimulated C-peptide on
MMTT between the two groups (NCT01103284).27 A
follow-up phase III trial will soon be underway to confirm
these findings. None of the Diapep277 trials has
raised any safety concerns.
Anti-Inflammatory Agents
Beta-Cell destruction may result from inflammation as
well as autoimmunity, and thus another approach to
preserving beta-cell function is through use of antiinflammatory
agents. Recent focus has centered on
responses generated by the innate immune system,
and IL-1 has been implicated as a primary proinflammatory
cytokine and mediator of beta-cell destruction.
A TrialNet-sponsored phase II new-onset T1D clinical
trial with the IL-1beta receptor antagonist canakinumab
failed to demonstrate efficacy in the initial analysis
of the primary end point at 1 year (NCT00947427)
(Moran, submitted manuscript).28 Similarly, a phase II/
III study with the IL-1 receptor antagonist anakinra also
failed to reach the primary end point (NCT00711503)
(Mandrup-Poulsen, TR, submitted manuscript). As
with other therapies, it may be that dosing earlier in
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