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Dipeptidyl Peptidase-4 Inhibitors and the Management of Hyperglycemia
In a systematic review and meta-analysis of the early clinical trials on <7% with sitagliptin compared with 18.3% in the placebo-treated
the use of incretin-based therapy for type 2 diabetes, these agents arm.
42
Similarly, when added to ongoing treatment with pioglitazone,
lowered HbA
1c
compared with placebo: weighted mean difference sitagliptin resulted in a significant reduction in HbA
1c
at 24 weeks
-0.97% (95% confidence interval [CI] -1.13 to -0.81%) for GLP-1 analogs (-0.70%) and a greater proportion of patients reaching glycemic target
and -0.74% (95% CI -0.85 to -0.62%) for the DPP-4 inhibitors with no increased risk of hypoglycemia compared with placebo.
43
sitagliptin and vildagliptin.
34
DPP-4 inhibitors were associated with an
increased risk of infections such as nasopharyngitis and urinary tract Sitagliptin has similar glycemic efficacy to other oral agents such as
infection. Headaches were also reported more commonly, particularly rosiglitazone or glimepiride as add-on therapy to metformin.
44,45
with vildagliptin. However, the addition of rosiglitazone resulted in a significant
increase in bodyweight (+1.5kg) compared with sitagliptin (-0.4kg) or
In 2008, a Cochrane review was published that included 25 studies placebo (-0.8kg) over 18 weeks.
44
In addition, the incidence of
ranging from 12 to 52 weeks in duration with a total of 6,743 patients hypoglycemia was significantly higher with glipizide (32%) than with
randomized to sitagliptin and 6,121 patients to vildagliptin.
35
Sitagliptin sitagliptin (5%), and sitagliptin led to weight loss (-1.5kg) rather than
and vildagliptin therapy resulted in an HbA
1c
reduction compared with the weight gain (+1.1kg) seen with glipizide (p<0.001) over 52 weeks.
45
placebo of approximately 0.7 and 0.6%, respectively. Treatment did
not result in weight gain and was generally well tolerated with no Add-on Triple Combination Therapy
severe hypoglycemia. Of note, all-cause infection was significantly When combined with glimepiride, with or without metformin, the
increased with sitagliptin therapy, but did not reach statistical overall reduction in HbA
1c
at 24 weeks by sitagliptin was -0.74% (95%
significance for vildagliptin. Importantly, the majority of trials included CI -0.90 to -0.57; p<0.001) relative to placebo, with the greatest
in both of these reviews were of short duration, and therefore long- improvement, -0.89%, seen in those patients receiving the triple
term safety and efficacy could not be assessed. therapy.
46
In this study, an increase in adverse events was seen in the
sitagliptin group, largely due to a higher incidence of hypoglycemia.
Sitagliptin Therefore, sulfonylurea dose adjustment may be required when
Sitagliptin (Januvia) is a potent, orally available, highly selective DPP-4 adding sitagliptin to ongoing therapy. Another study of triple therapy
inhibitor. It was the first agent of its class to be available in the US and showed a significant reduction in HbA
1c
with sitagliptin compared
is approved for use as an adjunct to diet and exercise alone or in with placebo on background metformin and rosiglitazone. At 18
combination with another oral antihyperglycemic agent. weeks, sitagliptin lowered HbA
1c
by -0.7% compared with placebo, an
effect that continued out to 54 weeks.
47
Monotherapy
Several studies have evaluated sitagliptin for use as monotherapy in Add-on Therapy to Insulin
patients with type 2 diabetes and inadequate glycemic control Sitagliptin was recently evaluated as add-on therapy to stable-dose
despite diet and exercise.
36–38
Two studies examined the efficacy of insulin with or without metformin in patients with type 2 diabetes.
48
The
sitagliptin 100 and 200mg compared with placebo and showed average duration of diabetes was 12 years, with a baseline HbA
1c
of
clinically and statistically significant reductions in HbA
1c
ranging from 8.7% at entry, suggesting a population with more advanced disease.
-0.48 to -0.94%.
36,37
As is typically seen in trials of glucose-lowering Patients treated with sitagliptin achieved an additional reduction in
agents, patients with a higher baseline HbA
1c
(>9%) experienced HbA
1c
of -0.6% at 24 weeks, and significantly more patients achieved
greater reductions in HbA
1c
than those with better glycemic control at target glycemic control. Interestingly, no increase in bodyweight from
enrolment. Treatment with sitagliptin also resulted in significant baseline was observed. However, the incidence of hypoglycemia was
improvements in markers of insulin secretion and beta-cell function significantly greater with sitagliptin (15.5%) compared with placebo
compared with placebo. Key efficacy parameters did not differ (7.8%). This was likely a result of the study design, as investigators were
significantly between sitagliptin doses, and subsequent studies have discouraged from making insulin dose adjustments during the study
used 100mg daily. There does not appear to be a significant difference period unless the study subject had symptomatic hypoglycemia.
between once-daily (100mg once daily) and twice-daily (50mg twice
daily) dosing regimens.
39
In a pooled cohort of 147 patients in two Initial Combination Therapy
monotherapy trials, sitagliptin decreased mean HbA
1c
from 8.5% at Given what is known about the progressive nature of type 2 diabetes
baseline to 6.9% at two years.
40
Compared with initial therapy with and the eventual need for multiple antihyperglycemic medications, a
metformin titrated to a maximum of 2,000mg/day, sitagliptin 100mg strategy of early combination therapy has been advocated, using
daily was found to be non-inferior with respect to the primary end- agents that possess complimentary mechanisms of action to enable
point (reduction in HbA
1c
at 24 weeks).
41
more patients to achieve and sustain glycemic control.
49,50
Metformin
and sitagliptin may have synergistic effects on the incretin axis; in a
Add-on Dual Combination Therapy study of individuals with normal glucose tolerance, each agent alone
In a pooled cohort of 852 patients in two trials of sitagliptin added to increased post-meal active GLP-1 concentrations by 1.5- to two-fold,
ongoing metformin therapy, HbA
1c
decreased from a baseline of 8.0 while their combination raised levels by greater than four-fold.
51
to 6.9% at two years.
40
At 24 weeks, the addition of sitagliptin to
ongoing metformin therapy led to a significant, -0.65% reduction in In a 24-week study, 1,091 patients with a baseline HbA
1c
of 8.8% were
HbA
1c
compared with placebo; 47% of patients achieved an HbA
1c
randomized to one of six daily treatments involving varying doses of
US ENDOCRINOLOGY 65
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