SA JOURNAL OF DIABETES & VASCULAR DISEASE ADA WATCH
2010 UPDATE FROM ORLANDO, USA
American Diabetes Association 25–29June2010
Contributors:J Aalbers, Dr F Mahomed, Prof WF Mollentze
CliniCaltrialupdates brate or placebo. The remaining 4 733 par- glycaemic-control arm due to an increased
ticipants were randomly assigned to either rate of death from any cause after a mean
aCCOrdretinopathystudyshows the intensive blood-pressure control (< 120 of 3.5 years has influenced the retinopa-
intensiveglycaemiccontrol,and mmHg systolic blood pressure) or standard thy results in this arm, potentially underes-
combinationdyslipidaemiatherapy therapy (< 140 mmHg). timating the retinopathy benefits of good
withfenofibratereducesretinopa- In this ACCORD eye study, participants glycaemic control.
thyprogression with retinopathy at baseline were excluded; The beneficial effect of fenofibrate ther-
those included were comprehensively eval- apy on the progression of diabetic retinopa-
A study group of the ACCORD study has
uated at baseline and at year four of the thy at four years (6.3 vs 10.2% on placebo)
shown that targeting glycaemic control at
study. Progression of diabetic retinopathy provides further support to the findings of
the 6% HbA1c level and lipid therapy with
was defined as at least three steps on the the FIELD study, which also showed visual
fenofibrate instead of placebo significantly
EDTRS severity scale or development of benefits with fenofibrate.
reduced the rate of progression of diabetic
retinopathy requiring photocoagulation
retinopathy.1 Intensive blood pressure con- 1. The ACCORD study group and ACCORD Eye study
therapy or vitrectomy.
trol did not reduce progression. group. Effects of medical therapies on retinopathy
Results of the progression to retinopa- progression in type 2 diabetes. N Engl J Med
The ACCORD study was an independ-
thy and moderate vision loss are summa- 10.1056/NEJM oa1001288. Pub 29/6/2010.
ent study sponsored by the National Heart,
rised in Table 1.
Lung and Blood Institute and companies
The early stoppage of the intensive
did not participate in the study design or
conduct, data accrual or analysis, or manu-
script preparation, providing only the study taBleOFCOntents
CliniCAl triAl uPDAtes Once-daily liraglutide lowers systolic blood
The more than 10 000 ACCORD patients ACCOrD retinopathy study shows intensive pressure (sbP) in treated and untreated
with type 2 diabetes and HbA1c higher than glycaemic control, and combination hypertensive patients ����������������������������������������3
7.5% were randomly assigned to either dyslipidaemia therapy with fenofibrate
reduces retinopathy progression ����������������������1 Dietary omega-3 polyunsaturated fatty acid
the intensive glycaemic-control arm or (fish oil capsules) reduced atherosclerosis
standard control. Of these participants, Optimising glucose control in iCu patients progression in type 2 diabetes ��������������������������3
reduces costs (triuMPH three-year results) �����2
5 518 with dyslipidaemia were also ran- Costs of continuing sulphonylureas with
domly assigned in a two-by-two factorial VADt study: further analysis of results shows insulin therapy in type 2 diabetes: more
intensive glycaemic control offered some hypoglycaemia and weight gain but less
design to receive simvastatin and fenofi- renal protection to patients with more insulin needed����������������������������������������������������3
advanced microvascular disease �����������������������2
reDuCing COMPliCAtiOns OF DiAbetes
VADt trial: intensive glycaemic control did infliximab treatment improves visual acuity
not prevent progression of calcified in diabetic macular oedema that does not
table.1. Progression to retinopathy and moderate atherosclerosis in patients with long- respond to laser photocoagulation ������������������4
vision loss standing type 2 diabetes �����������������������������������2
Point-of-care testing of diabetic keto-acidosis
Once-weekly exenatide injection improves avoids unnecessary DKA work-ups in
progressionof Moderate blood sugar control more than daily oral hyperglycaemic patients presenting at
retinopathy visionloss sitagliptin or pioglitazone and induces emergency departments �����������������������������������4
more weight loss (DurAtiOn-2 study)�������������2
treatment n (%) n (%) rotating glucometer usage after achieving
PAtHOgenesis OF tyPe 2 DiAbetes glucose control in the first patient improves
Glycaemic therapy intramyocellular lipid accumulation does not HbA1c levels in resource-constrained settings
Intensive 104/1429 (7.3) 266/1629 (16.3) occur in pre-diabetes, but only after in Kenya��������������������������������������������������������������4
manifestation of hyperglycaemia ���������������������2
Standard 149/1427 (10.4) 273/1634 (16.7) Poor glycaemic control slows wound healing ������4
insulin resistance study (irAs) shows problems
Dyslipidaemia for HbA1c levels as diagnostic tool ��������������������2 encouraging and educating physicians can
With fenofibrate 52/806 (6.5) 145/908 (16) result in earlier insulin prescription with
new metabolic syndrome definition and value enhanced HbA1c control�������������������������������������4
With placebo 80/787 (10.2) 136/893 (15.2) of waist circumference evaluated in type 2
diabetes ��������������������������������������������������������������3 Cardiovascular outcomes trial initiated for
Antihypertensive liraglutide �����������������������������������������������������������4
Intensive 67/647 (10.4) 145/749 (19.4) DiAbetes tHerAPy
Metformin protects against antidepressant
Standard 54/616 (8.8) 113/13 (15.8) diabetes risk? �����������������������������������������������������3
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ADA WATCH SA JOURNAL OF DIABETES & VASCULAR DISEASE
OptimisingglucosecontroliniCu Vadttrial:intensiveglycaemiccon- sitagliptin group and 1.2% in the pioglita-
patientsreducescosts(triuMpH troldidnotpreventprogressionof zone group.
three-yearresults) calcifiedatherosclerosisinpatients Patients in the exenatide group lost on
withlong-standingtype2diabetes average 2.3 kg, compared with a mean
Targeting lower glucose levels (9.18 mg/dl,
weight loss of 0.8 kg in the sitagliptin
AACE guideline) in ICU patients has been The VADT trial was able to show reduced
group and a mean weight gain of 2.8 kg in
shown to reduce length of stay (LOS) and cardiovascular events in participants with
the pioglitazone group. No major episodes
ICU costs ($8 000) in the extended three- low levels of calcified coronary athero-
of hypoglycaemia (abnormally low blood
year period of the TRIUMPH study involving sclerosis at baseline. This newly presented
sugar) occurred in any group.
more than 11 000 patients. study evaluated 197 patients with calcified
The most frequent adverse events with
The use of intensive insulin therapy (IIT) atherosclerosis at baseline, as measured
exenatide and sitagliptin were nausea (24
also reduced complications and improved by CT scan and after 4.6 years in both the
and 10%, respectively) and diarrhoea (18
outcomes. The benefit of IIT was confirmed intensive glycaemic-control arm and the
and 0%, respectively); while upper respira-
in this study, which compared intervention normal control group.
tory tract infection (10%) and peripheral
ICUs to control ICUs, which did not apply These scans showed no treatment ben-
oedema (fluid retention/swelling in the
the intensive insulin therapy protocol. efit of intensive versus standard therapy
legs) (18%) were the most frequent events
with regard to either pre-existing coronary
Source: Presidents Poster, 0433-PP. Sadhu AR, Ang AC, with pioglitazone.
Ingram-Drake LA, et al. Length of stay – cost-savings of artery calcium (CAC) or abdominal aortic
intensive insulin therapy in ICU patients – 3-year results artery calcium (AAC). Source: Oral presentation, ADA
of the TaRgeted InsUlin therapy to iMProve Hospital
outcomes (TRIUMPH) program. Source: Presidents Poster 0405-PP. Saremi A, Anderson
RJ, Duckworth WC, et al. Intensive glucose lowering
therapy and progression of coronary (CAC) and patHOgenesisOFtype2
Vadtstudy:furtheranalysisof abdominal aortic artery calcium (AAC) in the Veterans
resultsshowsintensiveglycae- Affairs Diabetes Trial (VADT). diaBetes
protectiontopatientswithmore Once-weeklyexenatideinjection doesnotoccurinpre-diabetes,but
advancedmicrovasculardisease improvesbloodsugarcontrolmore onlyaftermanifestationofhyperg-
The Veterans Affairs Diabetes Trial (VADT) thandailyoralsitagliptinorpiogli- lycaemia
in type 2 diabetes, although not able to tazoneandinducesmoreweight
Using prior gestational diabetes (GDM) as a
show reduced cardiovascular events com- loss(duratiOn-2study)
model to study early changes in the devel-
pared to average control in this further A convenient, once-weekly injection of opment of type 2 diabetes, the researchers
analysis of renal outcomes, provided data exenatide in patients with type 2 diabe- used magnetic resonance imaging (MRI)
not yet published on the microvascular pro- tes was more effective at improving blood and MR spectroscopy to measure left ven-
tection achieved by intensive control (INT). sugar control and inducing weight loss tricular function and myocardial lipid accu-
In the VADT trial, the average age of than were either daily oral sitagliptin or mulation in the cardiac septum of women
patients was 60 years, duration of diabe- pioglitazone. with prior GDM with normal glucose toler-
tes was 11 years, with HbA1c levels of 9.4% In this 26-week, randomised trial, the ance, in women with prior DGM and type
at the outset of the study. With regard to patients included all had type 2 diabetes 2 diabetes, and controls without GDM and
renal function, patients were excluded if and had been treated with metformin. with normal glucose tolerance.
the serum creatinine was above 1.6 mg/dl. The mean baseline glycosylated haemo- There was no difference in left ventricu-
Renal progression was evaluated in terms globin (HbA1c) concentration in the cohort lar function between the groups except
of worsening urine albumin:creatinine ratio was 8.5%, the mean fasting plasma glu- for stroke volume, which was decreased in
(ACR) and sustained worsening of esti- cose was 9.1 mmol/l, and the mean body women with type 2 diabetes. Also, these
mated glomerular filtration rate (eGFR). weight was 88.0 kg. women showed increased intramyocellu-
It was found that INT did not independ- The study included patients from the lar lipid content compared to the women
ently attenuate ACR or eGFR progression USA, India and Mexico. Patients were ran- with GDM and normal glucose toler-
but did retard ACR progression by 72% in domly assigned to exenatide 2 mg injected ance and decreased levels of high-density
those who had photocoagulation, and by once weekly plus daily oral placebo (170 lipids, which were inversely related to the
95% in those requiring cataract surgery. patients); daily oral sitagliptin 100 mg plus intramyocellular lipid content.
The beneficial effect of INT was also more placebo injected once weekly (172); or
evident in patients with a BMI ≥ 34 kg/m2. daily oral pioglitazone plus placebo injected Source: Abstract ADA, 0014-OR. Winhofer Y, Krissak
In conclusion, INT had no independent once weekly (172). All patients continued M, Anderwald C, et al. Cardiac function and lipid
beneficial renal effect but afforded some metabolism in women with prior gestational diabetes.
their metformin treatment throughout the
protection in those with more advanced study.
microvascular disease, lower baseline BP or Four hundred and ninety-one patients
higher baseline BMI. received at least one dose of the study showsproblemsforHBa1clevelsas
drug and were included in the final analysis diagnostictool
Source: Presidents Poster 0412-PP. Agrawal L, Azad N,
Emanuele N, et al. Renal outcomes in Veterans Affairs (160 exenetide, 166 sitagliptin, 165 piogli- The IRAS study of some 417 patients at
Diabetes Trial. tazone). Treatment with exenatide reduced risk of developing diabetes has shown that
HbA1c by 1.5%, compared with 0.9% in the the 6.5 and 5.7% HbA1c thresholds have
130 E-PUBLICATION • TUESDAY 20 JULY 2010
SA JOURNAL OF DIABETES & VASCULAR DISEASE ADA WATCH
a low sensitivity of detecting the onset of diabetes in the 10 years of the extended in patients receiving fish oil capsules, com-
both diabetes and pre-diabetes, as defined Diabetes Prevention Programme Outcomes pared to patients following the diet recom-
by previous definitions of diabetes, using Study (DPPOS) in those patients not receiv- mended by ESC/EASD.
fasting glucose values (≥ 11.1 mmol/l), ing metformin. There was no association The dosage of omega-3 was 1 g EPA,
impaired glucose tolerance (IGT) (2-h glu- between antidepressant medication usage 1 g DHA and 0.1 g alpha-tocopherol ace-
cose: 7.8–11.0 mmol/l) and impaired fast- and diabetes risk in patients receiving met- tate. Interestingly, total cholesterol, HDL
ing glucose (IFG) (fasting glucose: 5.6–6.9 formin. cholesterol and triglyceride levels improved
mmol/l). This ADA-sponsored research confirms
The sensitivity and specificity of HbA1c ≥ the strong positive and statistically signifi-
6.5% for detecting incident diabetes was cant association between continuous anti-
table.1. Change in SBP from baseline to week 26
22 and 99.5%, respectively. The low sen- depressant medication use and increased (mmHg)
sitivity of these HbA1c cut-off points could diabetes risk found in the three-year fol-
jeopardise the timely implementation of low-up period of the DPP in those patients difference
protective lifestyle and pharmacological on the placebo and intensive lifestyle arm. between
interventions. The researchers noted that this association
was still significant when controlled for patientgroup 1.8mg placebo placebo
Source: Presidents Poster, 0424-PP. Haffer SM,
Wagenknecht LE, Hanley AJ, et al. HbA1c and fasting
depression symptom level.
Overall –2.55 0.19 –2.37
and 2-h glucose concentrations for detecting worsening While acknowledging that this find-
of glucose tolerance status in individuals with normal ing does not allow the interpretation of a AH treat at week 26 –2.03 0.76 –2.79
glucose tolerance at baseline: the Insulin Resistance protective effect of metformin, it does alert No AH treat –3.07 –1.13 –1.95
clinicians to the higher diabetes risk facing
patients who are being treated also for
newmetabolicsyndromedefinition long-term depression. in those patients on the fish oil capsules.
andvalueofwaistcircumference Source: Presidents Poster. Abstract No 0479-PP. Rubin Source: Abstract 0193-OR. Dragomir AD, Radulian
evaluatedintype2diabetes RR, Marrero DG, Yong MA, et al. Antidepressant G, Rosu E, et al. One-year administration of dietary
medication use and risk of developing diabetes during omega-3 polyunsaturated fatty acid decreases oxidative
The recent consensus definition of the stress and atheroscerlosis progression in type 2
the Diabetes Prevention Program and the Diabetes
metabolic syndrome allows for both the Prevention Programme Outcomes study. diabetes.
IDF and NCEP ATP III cut-off points for the
diagnosis of a large waist in Caucasians. Its Costsofcontinuingsulphonyl-
value in predicting type 2 diabetes has not Once-dailyliraglutidelowers ureaswithinsulintherapyintype2
yet been assessed. systolicbloodpressure(sBp)in diabetes:morehypoglycaemiaand
This prospective study assessed and fol- treatedanduntreatedhypertensive weightgainbutlessinsulinneeded
lowed up for eight years, more than 500 patients There is no consensus on whether insulin
non-diabetic Caucasians undergoing coro-
A meta-analysis of six randomised, control- secretagogues should be maintained when
nary angiography for evaluation of stable
led trials (n = 3 967) has shown that the analogue insulin therapy is added to the
CAD. At baseline, 50% of the patients met
reduction in SBP with liraglutide was inde- type 2 diabetes regimen, while metformin
the novel consensus metabolic syndrome
pendent of concomitant antihypertensive is continued.
definition but the predictability of this defi-
treatment (AH), and that this reduction This multinational study of almost 1 000
nition was enhanced when the NCEP ATP
was additive to concomitant antihyper- insulin-naïve patients tracked diabetes
III waist circumference cut-off values of
tensive therapy. The evaluation was done control when basal insulin (glargine once
more than 102 cm for men and more than
using an ANCOVA model, which included daily or detemir twice daily) was added and
88 cm in women were used.
randomised treatment effect, use of AH sulphonylureas and glinides were retained/
The eight-year incidence of type 2 diabe-
therapy at 26 weeks and interaction with stopped.
tes was 32% in patients defined according
liraglutide/placebo at 26 weeks. Glucose control was not statistically
to these criteria, compared to 15% using
significantly different but patients who
the smaller waist circumference measure. Source: Abstract 0296-OR. Fonseca V, Plutzky J,
Montanya E, et al. Liraglutide, a once-daily human
continued with sulphonylureas had more
Source: Abstract 0381-OR. Saely CH, Vonbank A, GLP-1 analog, lowers systolic blood pressure (SBP) hypoglycaemia (40 vs 24.5%) and gained
Rein P, et al. Prediction of type 2 diabetes with the independently or concomitant antihypertensive treat- significantly more weight (1.5 vs 0.4 kg).
novel metabolic syndrome consensus definition: The ment. End-of study daily insulin doses were how-
importance of waist circumference.
ever significantly lower in patients continu-
ing secretagogues than in those stopping
dietaryomega-3polyunsaturated these agents (0.6 vs 0.8 units/kg/day).
atherosclerosisprogressionintype Source: Abstract 0037-OR. Swinnen SG, Dain MP,
Mauricio D, et al. Continuation versus discontinuation
Metforminprotectsagainstanti- 2diabetes of insulin sceretagogues when initiating insulin in type
depressantdiabetesrisk? This one-year study of 300 patients with 2 diabetes.
Continuous use of antidepressant medi- type 2 diabetes showed that carotid
cation increased the risk of developing intima–media thickness did not progress
E-PUBLICATION • TUESDAY 20 JULY 2010 131
ADA WATCH SA JOURNAL OF DIABETES & VASCULAR DISEASE
reduCingCOMpliCatiOnsOF diabetic ketoacidosis at emergency department triage: encouragingandeducatingphysi-
beta hydroxybutyrate vs urine dip.
firstpatientimprovesHBa1clevels Using the updated ADA/EASD consen-
oedemathatdoesnotrespondto sus statement, which includes earlier use
of insulin in patients not achieving HbA1c
This small phase III study suggested that goals on metformin and lifestyle, this cer-
larger and long-term trials should be under- A home glucose-monitoring programme tified diabetes educator (CDE) programme
taken to assess the efficacy of the systemic for Kenyan patients with an HbA1c above increased insulin use rates from 25 to 39%.
or intravitreal anti-TNF monoclonal anti- 10% and a cell phone has shown a mean Patient HbA1c values improved with the
body, infliximab, to improve the vision of drop in HbA1c of 3% in a remotely managed proportion of diabetics with HbA1c > 8.5%
patients with diabetic macular oedema cost-effective process of diabetes care. dropping from 36 to 24%.
refractory to laser therapy. Patients are given a glucometer and pro- The intervention was not too labour
This single-centre, double-blind, ran- vided with glucose testing strips. They are intensive, and was conducted over six
domised, placebo-controlled, crossover called weekly by community workers, who months and included three main compo-
study in 11 patients showed that intrave- record their results and relay the informa- nents: office-based education, print and
nous infliximab (5 mg/kg) at weeks zero, tion to clinicians, who then adjust the insu- monthly e-mail reminders.
two, six and 14, followed by placebo to lin dose based on a standardised protocol.
Once a patient achieves good control, Source: Abstract 0108-OR. Endsley S, Leal S, Choi J,
32 weeks, improved visual acuity by 24% Martinez AN. An office-based physician education
compared to placebo-treated eyes. he/she returns the glucometer, which is program to enhance the earlier initiation of insulin: An
then given to another patient. The research- evaluation of an academic detailing intervention in the
Source: Presidents Poster 0416-PP. Tentolouris IV, ers plan to extend this model to rural areas US.
Grigcropoulos V, Emfietzoglou I, et al. Infliximab for of Kenya.
diabetic macular edema refractory to laser photo-
coagulation. Source: Presidents Poster, Abstract No 0432-PP. Ouma
MN and Pastakia SK. A comprehensive collaborative Cardiovascularoutcomestrialiniti-
point-of-caretestingofdiabetic enhanced diabetes care program in the rural resource atedforliraglutide
constrained setting of Eldoret (western) Kenya.
keto-acidosisavoidsunnecessary Novo Nordisk announced at the ADA meet-
dKawork-upsinhyperglycaemic ing details of the company’s cardiovascular
patientspresentingatemergency poorglycaemiccontrolslows outcomes trial for liraglutide, which is set
departments woundhealing to start in the autumn of 2010.
The LEADER™ trial (Liraglutide Effect and
The poor specificity of urine dipstick tests This evaluation of raw data from several Action in Diabetes: Evaluation of cardiovas-
for diabetic ketones resulted in a high false- multi-centre, randomised, FDA-approved cular outcome Results) aims to assess and
positive rate with increased hospital costs. clinical trials among similar populations confirm the cardiovascular safety of the
This study used the point-of-care (POC) incorporated 411 diabetic patients with company’s new once-daily human GLP-1
capillary beta-hydroxybutyrate test (the neuropathic foot ulcerations and evaluated analogue and potentially show its ability to
Precision Xtra meter, Abbott Laboratories) the clinical and laboratory data during a improve cardiovascular outcomes. The trial
to obviate these additional costs. 12-week period of wound healing. also satisfies the new FDA guideline for
Five hundred hyperglycaemic patients The relationship between HbA1c and type 2 diabetes treatments.
admitted to the emergency department successful wound healing over 12 weeks The protocol has been designed in close
were enrolled in the study and 53 met all of standardised treatment was then evalu- collaboration with an international expert
ADA criteria for DKA. The urine dipstick ated. After adjusting for covariates (dura- steering committee as well as US and EU
had a sensitivity of 98%, but a specificity tion of diabetes, age, gender, race, etc), regulatory authorities, and with assistance
of 40%, whereas use of the Precision Xtra the evaluation showed that the odds of from the Population Health Research Insti-
meter had an equal sensitivity but a specifi- healing decreased by 15% for every 1% tute (PHRI) at McMaster University, Canada.
city of 80%, thereby significantly reducing increase in HbA1c during the preceding 12 Furthermore, an independent data-moni-
unnecessary DKA work-ups in hyperglycae- weeks of wound care. toring committee will monitor progress of
Source: Abstract 0189-OR. Cook EA, Cook JJ, Henao the trial and ensure that it meets the high-
Source: Presidents Poster 0386-PP. Arora S, Peters AL, M, et al. The importance of sustained glycaemic control est standards of ethics and patient safety.
Long T, et al. Utilising point-of-care testing to identifiy during wound healing.
132 E-PUBLICATION • TUESDAY 20 JULY 2010