MD Conference Express ADA 2013 - (Page 12)
CLINICAL TRIAL HIGHLIGHTS
Participants were ~47 years of age, with duration of
diabetes of ~5 months, and an initial mean HbA1C of
8.6% (range, 6.6% to 14.0%). HbA1C decreased sharply in
both treatment groups by the 6-month time point. HbA1C
remained below 6.5% for the triple-therapy armDiabetes 6 to 24
7. Abdul Gahni Figures 1 and 2; Figure 1. Change in HbA1C Over Time in Patients With Newly Diagnosed from
months, but it gradually increased to 6.6% at 24 months in
the conventional-therapy arm (Figure 1).
Figure 1. Change in HbA1C Over Time
Conventional therapy
Insulin Dose Not Linked to
Cardiovascular Mortality
in the ACCORD Trial
Triple therapy
9
Hb1AC (%)
8
Written by Muriel Cunningham
7
*
*
†
†
*
†
6.6%
p<0.001
6
-
-
6
-
-
-
6.0%
0
18
12
24
Months
*p<0.05; †p<0.01.
Reproduced with permission from M Abdul-Ghani, MD, PhD.
Additional analyses indicated that 60% of patients in the
triple-therapy group achieved an HbA1C <6.0% versus 27%
in the conventional-therapy group (p<0.001). At 24 months,
significantly fewer Figure 2. Time toin the triple-therapy group (17%)
patients Treatment Failure
7. Abdul Gahni Figures 1 and 2;
were considered treatment failures compared with the
conventional-therapy group (42%; p<0.001; Figure 2).
Figure 2. Time to Treatment Failure
Conventional therapy
Triple therapy
1.0
Cumulative Survival
0.9
17%
0.8
p<0.001
0.7
42%
0.6
0
6
12
Months
18
24
Reproduced with permission from M Abdul-Ghani, MD, PhD.
Patients in the triple-therapy group lost a mean of 1.2 kg
whereas those in the conventional-therapy group gained a
mean of 4.1 kg at 24 months (p<0.001). Significantly fewer
12
hypoglycemic events occurred in the triple-therapy group
(15%, 0.27 events per patient-year) versus the conventionaltherapy group (46%, 2.1 events per patient-year; p<0.0001).
Dr. Abdul-Ghani concluded that initiating triple
therapy with metformin/pioglitazone/exenatide at diagnosis
achieves a greater and more durable reduction in HbA1C
with less risk of hypoglycemia compared with the stepwise
add-on conventional therapy.
August 2013
Previously published results from the Action to Control
Cardiovascular Risk in Diabetes study [ACCORD; ACCORD
Study Group. N Engl J Med 2008] showed an increased risk of
all-cause and cardiovascular (CV) mortality in the intensive
control group (HbA1C target, <6.0%) compared with the less
intensive group (HbA1C target, 7.0% to 7.9%). “This brought
a huge puzzle to the diabetes community, to figure out why
we were seeing this result,” said Elias S. Siraj, MD, Temple
University School of Medicine, Philadelphia, Pennsylvania,
USA. Several post hoc analyses have been conducted to
date to determine what factors may have influenced this
outcome [ACCORD Study Group. N Engl J Med 2008; Bonds
DE et al. BMJ 2010; Riddle MC et al. Diabetes Care 2010;
Seaquist ER et al. Diabetes Care 2012]. These analyses did
not find a conclusive link between the ACCORD results and
factors such as hypoglycemia, low HbA1C, the rapid decline
in HbA1C during the first year of the study, weight gain, and
specific medication use.
To better understand the findings of this study,
ACCORD investigators hypothesized that higher doses of
exogenous insulin may be associated with the CV mortality
results from the ACCORD trial. To investigate this idea, data
for insulin exposure and CV mortality from 10,163 patients
were analyzed. HRs and 95% CIs were calculated, and
multivariable Cox regression performed to choose the most
appropriate baseline covariates and models.
The updated average total, basal, and bolus insulin
doses were significantly higher in the intensive-control
arm (all p<0.0001). In addition, there was a significant
linear association between the updated average HbA1C
level and updated average insulin dose in both groups
(both p<0.0001). Four different Cox proportional hazards
models were employed to determine HRs for CV mortality.
The first model controlled for the following 14 baseline
covariates: age, history of CV disease, heart failure, QTindex, baseline HbA1C value, high-density lipoprotein,
amputation, presence of peripheral neuropathy, serum
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