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Dipeptidyl Peptidase-4 Inhibitors and the Management of Hyperglycemia
HbA
1c
from a baseline of 8.0% of -0.59, -0.69, and -0.58%, respectively, using vildagliptin 100mg daily in 1,469 patients produced an adjusted
compared with placebo (+0.13%).
69
Reductions were seen at week mean change in HbA
1c
of -1.0% at 24 weeks, from a baseline of 8.6%.
78
four, the earliest time-point assessed, reached a maximum at 12 Vildagliptin has similar glycemic efficacy whether given as 50mg twice
weeks, and were sustained through 24 weeks of treatment. A greater daily or 100mg once daily.
76
An excess in abnormal liver function tests
percentage of patients achieved target glycemic control without an was observed with the 100mg daily dosage, however, and the current
increase in hypoglycemia or weight gain. Clinically meaningful recommendation in Europe is 50mg twice daily.
glycemic improvements were sustained up to 102 weeks.
70
The
addition of saxagliptin to metformin remained well tolerated with an In drug-naïve patients with type 2 diabetes and mild hyperglycemia
overall adverse event profile consistent with that seen at 24 weeks. (HbA
1c
6.2-7.5%), treatment with vildagliptin 50mg once daily resulted
in a modest but significant reduction in HbA
1c
compared with placebo
A study by Chacra et al. compared the safety and efficacy of adding of -0.3% at one year
79
and -0.5% at two years.
80
Improvements were also
saxagliptin to a submaximal dose of the sulfonylurea glyburide versus seen in fasting and post-prandial glucose, as well as insulin-secretory
uptitration of sulfonylurea monotherapy in a group of subjects with a rate relative to glucose (ISR/G), a reflection of beta-cell function. Thus,
mean baseline HbA
1c
of 8.4%.
71
Patients received either saxagliptin 2.5 vildagliptin appeared to attenuate the progressive deterioration in
or 5mg plus glyburide 7.5mg or glyburide titrated to a maximum of glycemic control seen in patients treated with lifestyle counseling only,
15mg/day as necessary. Combination therapy resulted in a significantly possibly through protective effects on beta-cell function.
greater reduction in HbA
1c
than maximum sulfonylurea monotherapy,
with more than twice as many patients achieving an HbA
1c
<7%. In fact, Comparative studies have examined the efficacy and tolerability of
HbA
1c
increased by 0.08% from baseline with uptitrated glyburide vildagliptin relative to monotherapy with acarbose, rosiglitazone,
compared with decreases in HbA
1c
of -0.54% and -0.64% with metformin, and gliclazide.
81–85
Vildagliptin and acarbose decreased
submaximal sulfonylurea plus saxagliptin 2.5mg and 5mg, respectively. HbA
1c
to a similar extent during 24-week treatment, meeting criteria for
An increased risk of hypoglycemia, often seen with combination non-inferiority.
81
Although bodyweight decreased with acarbose,
therapy, particularly involving a sulfonylurea or insulin, was not vildagliptin was weight-neutral (-1.7 versus -0.4kg; p<0.001) and
observed despite greater glycemic efficacy. resulted in fewer gastrointestinal adverse events compared with
acarbose. Vildagliptin was also found to be as effective as rosiglitazone,
In a recently published study conducted in patients inadequately improving HbA
1c
by -1.1 and -1.3%, respectively, at 24 weeks.
82
controlled on thiazolidinedione monotherapy (baseline HbA
1c
8.3%), However, rosiglitazone increased bodyweight and was associated with
the addition of saxagliptin 2.5 or 5mg resulted in statistically more edema than vildagliptin.
significant reductions in HbA
1c
at 24 weeks of -0.66 and -0.94%,
respectively, compared with -0.30% with placebo (p<0.0001).
72
In a 52-week study comparing treatment with vildagliptin (100mg daily)
versus metformin (titrated to 2,000mg daily) in drug-naïve patients, both
Initial Combination Therapy agents produced rapid, sustained reductions in HbA
1c
from a baseline of
Initial combination therapy in treatment-naïve patients was evaluated 8.7% of -1.0 and -1.4%, respectively; however, statistical non-inferiority
using metformin 500mg plus saxagliptin 5 or 10mg compared with of vildagliptin was not established.
83
These results were sustained in an
monotherapy with saxagliptin 10mg or metformin 500mg plus extension study at 104 weeks, suggesting durability of response for both
placebo. At 24 weeks, combination therapy resulted in statistically agents.
84
Of note, metformin resulted in weight loss compared with
significant improvements in glycemic parameters such as HbA
1c
, vildagliptin, but was associated with significantly worse gastrointestinal
fasting plasma glucose, and post-prandial glucose AUC, and a similar tolerability (45.6 versus 25.0%; p<0.001). The incidence of hypoglycemia
tolerability profile to monotherapy with either agent.
73
was similarly low in both groups (<1%).
Safety Another study compared monotherapy with vildagliptin versus
Clinical trials have shown saxagliptin to be safe and well tolerated gliclazide in treatment-naïve patients over two years.
85
Although the
thus far; however, experience with this agent is more limited. Of note, mean reduction in HbA
1c
from baseline to week 104 was similar, at
small, reversible, dose-dependent reductions in mean absolute -0.5% in the group receiving vildagliptin and -0.6% with gliclazide
lymphocyte count have been observed in studies of saxagliptin. monotherapy, vildagliptin did not meet the criteria for non-inferiority as
To date this has not been associated with adverse clinical the upper limit of the associated 95% CI for the between-group
consequences. Similar to vildagliptin, adverse skin toxicology was difference in mean change HbA
1c
of -0.13% (-0.06 to 0.33%) was just
reported in studies of saxagliptin in monkeys, although not in human above the cut-off of 0.3%.
clinical trials. There are no published studies to date of saxagliptin in
patients taking insulin. Add-on Dual Combination Therapy
When added to ongoing metformin therapy in patients with inadequate
Vildagliptin glycemic control, vildagliptin was well tolerated and produced
Monotherapy clinically meaningful reductions in HbA
1c
in studies of up to one
Monotherapy trials of vildagliptin in drug-naïve patients have shown year.
86–88
In a 24-week study, patients with a baseline HbA
1c
of 8.4%
significant reductions in HbA
1c
.
74–77
Pooling of data from phase III were treated with vildagliptin 50mg daily, 100mg daily, or placebo and
monotherapy trials, including placebo or active comparator controls, continued a stable metformin dose regimen. Placebo-adjusted mean
US ENDOCRINOLOGY 67
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