MD Conference Express ADA 2013 - (Page 13)
creatinine, urinary ratio of albumin to creatinine, use
of angiotensin receptor blockers, educational status,
presence of integrated health plan, and presence of
certified diabetes educator on staff at randomization.
Model 2 added assignment to blood pressure or lipid trial,
treatment assignment within these, severe hypoglycemia,
and weight change. Model 3 added the updated average
HbA1C, and Model 4 added the glycemic treatment arm
assignment. Results from all 4 models by total, basal, and
bolus insulin are presented in Table 1.
Table 1. HRs for CV Mortality of Insulin Dose (per 1 unit/kg)
From Cox Proportional Hazards Model
Unadjusted
Insulin
HR
Categories (95% CI)*
Model 1*
Model 2*
Model 3*
Model 4*
Total
insulin
1.83
(1.45-2.31)
p<0.0001
1.21
(0.92-1.6)
p=0.1726
1.21
(0.91-1.61)
p=0.1912
1.12
(0.84-1.49)
p=0.4540
0.99
(0.74-1.34)
p=0.9693
Basal
insulin
2.29
(1.62-3.23)
p<0.0001
1.3
(0.87-1.94)
p=0.2073
1.29
(0.85-1.95)
p=0.2272
1.13
(0.74-1.72)
p=0.5636
0.94
(0.61-1.46)
p=0.7955
Bolus
insulin
3.36
(2.0-5.66)
p<0.0001
1.65
(0.88-3.11)
p=0.1172
1.63
(0.85-3.12)
p=0.1399
1.48
(0.77-2.84)
p=0.2365
1.23
(0.63-2.4)
p=0.5478
*For the unadjusted model, and Models 1 to 4, only a single insulin exposure was entered into
the model at a time. Thus, each cell represents the results for that insulin variable being the
only one within the model.
Based on the unadjusted HRs, a daily insulin dose
increase by 1 unit/kg of body weight was associated with
a 1.83- (total insulin), 2.29- (basal insulin) and 3.36-fold
increase in risk of CV mortality (all p<0.0001). However,
results from the four models did not confirm these findings.
After adjustment for baseline covariates in Model 1, the
HRs became nonsignificant indicating no association of
insulin dose with CV mortality. Additionally, no association
between insulin dose and CV mortality emerged after
adjustments were made for on-treatment factors.
Dr. Siraj concluded that these results do not support the
idea that insulin dose is an independent risk factor for CV
mortality in the ACCORD population.
Canagliflozin Reduces HbA1C in
Patients With Stage 3 CKD, With
the Change Greater in Patients
With Higher eGFR
Written by Wayne Kuznar
The
sodium
glucose
cotransporter-2
inhibitor
canagliflozin reduces HbA1C level in patients with type
2 diabetes mellitus (T2DM) and stage 3 chronic kidney
disease (CKD), an effect that is more pronounced with
higher levels of estimated glomerular filtration rate
(eGFR), according to the results of a pooled analysis.
Gary Meininger, MD, Janssen Research and Development
LLC, Raritan, New Jersey, USA, presented the results
of this pooled analysis of four randomized, doubleblind, placebo-controlled Phase 3 trials that compared
canagliflozin with placebo in patients with inadequately
controlled T2DM and stage 3 CKD.
Options for glycemic control in patients with T2DM and
impaired renal function are limited, said Dr. Meininger.
Canagliflozin has been approved in the United States as an
adjunct to diet and exercise to improve glycemic control in
adults with T2DM. However, its approved dosage is limited
to 100 mg QD in patients with moderate renal impairment
with an eGFR ≥45 and <60 mL/min/1.73 m2, and it is not
indicated in patients with an eGFR <45 mL/min/1.73 m2.
The present pooled analysis included 1085 patients with
T2DM and stage 3 CKD (eGFR ≥30 and <60 mL/min/1.73 m2)
who were randomized to canagliflozin 100 or 300 mg, or
placebo for 18 to 26 weeks.
In the overall study population, the mean change
from baseline to efficacy assessment in HbA1C was
-0.52% in the canagliflozin 100-mg group; -0.62% in the
canagliflozin 300-mg group; and -0.14% in the placebo
group (p<0.001 for both canagliflozin groups vs placebo).
When assessed by baseline eGFR, a greater reduction in
HbA1C with canagliflozin was observed in patients with
eGFR ≥45 mL/min/1.73 m2 and <60 mL/min/1.73 m2 than
in those with eGFR ≥30 and <45 mL/min/1.73 m2.
In the 88.2% of all participants who were on background
insulin or a sulfonylurea, the rates of documented episodes
of hypoglycemia were greater with canagliflozin 100 mg
and 300 mg (41.9% and 43.8%, respectively) than with
placebo (29.2%).
Weight loss was also greater in the canagliflozin groups
than in the placebo groups, and the effect was greater in
patients with eGFR ≥45 mL/min/1.73 m2 than in those with
eGFR ≥30 and <45 mL/min/1.73 m2.
Systolic blood pressure decreased more in the
overall study population in the canagliflozin groups
versus the placebo group. In the subgroup with eGFR
≥30 and <45 mL/min/1.73 m 2, systolic blood pressure
increased by 0.8 mm Hg in each canagliflozin group and
by 5.7 mm Hg in the placebo group.
The incidence of overall adverse events (AEs) was
higher with canagliflozin (74.0% with 100 mg and 75.3%
with 300 mg) than with placebo (70.4%). Intravascular
volume-related adverse events were also more common
with canagliflozin (5.0% and 8.5% in the 100- and 300mg groups, respectively) than with placebo (2.6%). The
percentage of these events in the canagliflozin groups was
greater in patients with eGFR ≥30 and <45 mL/min/1.73 m2
(6.6% and 11.1% in the 100- and 300-mg groups, respectively)
relative to placebo (1.7%) than in those with eGFR
≥45 mL/min/1.73 m2 (4.2% and 7.1% with 100-mg and 300-mg
Official Peer-Reviewed Highlights From the American Diabetes Association 73rd Scientific Sessions 2013
13
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