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News From the 45th European
Association for the Study of Diabetes
(EASD) Annual Meeting
September 29 TO October 2, 2009
Vienna
Glucose Targets and Diabetes TreatmentFor patients with type 1 diabetes, who are generally very
young at the time of diagnosis, there is clear evidence of a
positive effect when blood glucose is lowered to a near-normal
range. In contrast, the evidence for most type 2 diabetic
patients is much less clear, wrote Andrea Siebenhofer-
Kroitzsch, MD, from the Medical University Graz, Austria, in
a press statement. Epidemiological studies in type 2 diabetes
have shown an association between higher blood glucose
values and higher incidence of severe diabetes related complications.
1-5 Even if this association is true, however, it does
not guarantee that strict glucose lowering benefits patients
with type 2 diabetes. Adherence to this strict regimen is
demanding and often burdensome. Most patients would
have to take a combination of two or more antidiabetic
drugs and would need to prick their fingers several times a
day to check their blood glucose and need multiple injections.
And there is a risk that an overly intensive therapy
might do more harm than good, Dr. Siebenhofer-Kroitzsch
wrote.
Clinical relevance of strict glucose control: benefits
and harm.
Treating patients with type 2 diabetes to nearnormal
range means aiming to treat them to a level as close
as possible to that of a nondiabetic patient. To date, seven
large, long-term randomized controlled studies have tested
whether more intensive glucose lowering strategies lead to
fewer complications in comparison to a treatment strategy
with standard glucose therapy.6-14 When all available studies
are combined into a meta-analysis, the results are as follows:
The only benefit of a more intensive treatment was a reduction
of nonfatal MIs, Dr. Siebenhofer-Kroitzsch wrote. Apart
from that, the number of deaths could not be reduced by
treating patients more intensively; one of the seven trials
even had to be terminated early due to an increased death
rate in the intensively treated group. No benefit was seen for
any further patient relevant endpoint such as stroke, blindness,
renal failure, amputation or quality of life.
So the benefit is not very great, Dr. Siebenhofer-Kroitzsch
wrote. One can estimate that some some 100 type 2 diabetic
patients would have to be treated very strictly for several
years to save one patient from an MI. And it comes with a
price: one would have to accept a higher risk for hypoglycemia,
which was at least doubled for patients in the
intensively treated group. In addition, patients in the strictly
controlled group put on more weight. It so far remains
unproven that lowering blood glucose to approximate the
normal range of a nondiabetic individual has an advantage
over standard care. When the studies were examined in further
detail, it could be seen that the best results were found
for newly diagnosed and young type 2 diabetic patients
without any severe complications. The intensity of blood
glucose treatment should very much depend on the age of
the patient, whereby younger patients might have greater
benefits from strict blood glucose control. In contrast, for
older patients less stringent values might be appropriate, Dr.
Siebenhofer-Kroitzsch stated.
Properties of certain antidiabetic drugs. In addition,
antidiabetic therapies differ in their effects and some of them
appear to be more beneficial than others, even when the
blood glucose level is decreased to the same extent.7,8 It
does not suffice for an antidiabetic drug to lower blood glucose;
the way it does so makes a difference, Dr. Siebenhofer-
Kroitzsch said.
It makes more sense to treat high blood pressure or
lipids. Most type 2 diabetes patients are quite old when diabetes
is diagnosed and generally suffer from further co-morbidities
and have risk factors such as high blood pressure and
high lipids as well. The main therapeutic aim of the treatment
of type 2 diabetes is to reduce the rates of deaths and
diabetes related complications like MI, blindness, renal failure
or amputation. Dr. Siebenhofer-Kroitzsch wrote that a comparison
of the potential effects that can be obtained by
increasing the intensity of blood pressure and lipid therapy
with statins shows that these treatments—easy to perform
with a few side effects—are at least 50% more effective than
a very complicated blood glucose treatment.
Self-management might be the key. Nevertheless there
is good news: when patients participate in training courses and practice self-management, severe hypoglycemic episodes
can be minimized.15 Instead of paying more and more
money for glucose related drug treatment, more emphasis
should be placed on patient education to overcome the
notorious problem of noncompliance with prescribed therapies,
Dr. Siebenhofer-Kroitzsch wrote. Informed patients
define their treatment goals themselves, choose their therapeutic
strategies and are prepared to weigh risk and benefit
of more or less tight glucose control on their own.
New Insights: Pathogenesis of Type 1 and 2 Diabetes
Type 1 diabetes is an autoimmune disease that develops
against insulin-secreting pancreatic beta-cells. Lymphocytes
invade the islet of Langerhans along the disease process; antibeta-
cell autoantibodies and T lymphocytes are detected in
patient with type 1; and the disease only occurs in individuals
carrying a restricted set of human leukocyte antigen
genes and a long list of other gene variant modulating
immune responses or beta-cell function.
Writing in an EASD press statement, Prof. Christian
Boitard, Vice-President, EASD, said that proinsulin is a major
autoantigen in the disease process, but other autoantigens
are likely involved. Type 1 diabetes is a health challenge due
to high incidence in northern countries and steadily increasing
incidence in all countries under observation, disease
onset at an age that is progressively decreasing, and the
absence of treatment other than palliative in the form of
multiple daily insulin injections. Despite major advances in
understanding immune mechanisms involved in type 1 diabetes,
critical issues remain unanswered.
- What are the initial events triggering type 1 diabetes?
- How do viral infections and other environmental factors
initiate or modulate the development of diabetes?
- Are defects in key regulatory immune cells part of the
disease process?
- What are the epitopes of beta-cell antigens recognized by
different T lymphocyte subsets?
- Can manipulation of T lymphocytes be a basis for
immunotherapy?
Etiology. Mechanisms that initiate the failure of immune
tolerance to beta-cells remain elusive, Prof. Boitard wrote,
but type 1 diabetes is considered a multifactorial disease in
which environmental factors concur with a highly multigenic
susceptibility background. Impressive progress has been
made in defining gene variants involved and their biological
consequences. Epidemiological evidence suggests that environmental
exposures that are likely to intervene early in
development have a role in susceptibility. A metabolic signature
of early changes is seen.
Pathogenesis. While proinflammatory T cells are key
effector players, other T-cell subsets play a regulatory role in
inhibiting the pathogenic immune response against pancreatic
beta-cells. The long delay between the first indication of
autoreactivity against beta cells, evidenced by the presence
of autoantibodies, and the actual onset of diabetes suggests
that regulatory mechanisms are controlling the destructive
immune process. The predominant role of T lymphocytes in
type 1 diabetes underscores the need for characterizing the
beta-cell antigens and developing T-cell assays for human
type 1 diabetes. Defining type 1-related epitopes is likely to
be a prerequisite to further studies of the natural history of
type 1 diabetes and to peptide-based strategies in
immunotherapy of type 1 diabetes. Significant advances
have been made in this field, he wrote.
Early diagnosis. There are obvious limitations in the use
of autoantibody detection in the immunological diagnosis of
type 1 diabetes. Following characterization of major epitopes
recognized by T lymphocytes along the disease process, Tcell
assays are currently developed but will need careful evaluation
of their diagnostic accuracy.
Immunotherapy. Immunosuppressive approaches in diabetes
treatment have not reached the milestone of clinical
application. Progress is to be expected from vaccination-type
approaches based on characterization of beta-cell autoantigens
and epitopes recognized. Prof. Boitard concluded that
expansion of regulatory lymphocytes is also being developed
as an intermediate approach to restore the physiological tolerance
of lymphocytes to beta-cell autoantigens.
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