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Diabetes Management DPP-4 Inhibitors
sitagliptin and metformin, alone or in combination.
52
Indeed, initial incidence rates of adverse experiences overall, serious adverse
combination therapy provided substantial and additive glycemic experiences, and discontinuation due to adverse experiences were
improvements with the most robust response—a placebo-subtracted similar between the sitagliptin and non-exposed groups (which
reduction in HbA
1c
from baseline of -2.07%—seen from maximum included both placebo and active controls).
60
There was a higher rate
dose combination therapy. Glycemic response was generally of drug-related adverse experiences in the non-exposed group,
sustained at 54 weeks and 104 weeks.
53,54
However, an important primarily due to the increased incidence rate of hypoglycemia in
limitation of these studies is that only patients who entered the studies in which a sulfonylurea was used as an active comparator.
28-week continuation period following the initial 26-week trial without
receiving glycemic rescue therapy were included in the analysis, Importantly, the small increases in nasopharyngitis and urinary tract
while the subsequent 52-week extension study included only those infections observed in the earlier meta-analyses were not confirmed in
subjects who chose to continue in the trial. Initial combination this larger study. Overall incidence of cardiovascular- and gastrointestinal-
therapy was generally well tolerated, with low rates of hypoglycemia. related adverse experiences, including rates of pancreatitis, did not
differ significantly between the sitagliptin and non-exposed groups.
The combination of sitagliptin and metformin in a single fixed-dose However, the US Food and Drug Administration (FDA) recently revised
combination tablet (Janumet) enhances convenience and may prescribing information for sitagliptin and Janumet (sitagliptin/
therefore improve adherence and overcome clinical inertia. Initial metformin) due to 88 post-marketing cases of acute pancreatitis
fixed-dose combination therapy resulted in a superior HbA
1c
reported between October 2006 and February 2009 in patients using
reduction and better glycemic goal attainment compared with these agents.
61
The nature of this association is not clear, particularly
metformin monotherapy at 18 and 44 weeks.
55,56
Over the 44-week as diabetes itself may be a risk factor for pancreatitis. In a recent,
treatment period, HbA
1c
reductions from a baseline of 9.9% were large, retrospective cohort study, patients with type 2 diabetes had an
-2.3% for sitagliptin/metformin and -1.8% for metformin alone, almost three-fold greater risk of pancreatitis compared with age- and
favoring initial combination therapy. Interestingly, rates of certain sex-matched controls without diabetes.
62
gastrointestinal adverse experiences such as abdominal pain and
diarrhea were lower with combination therapy, suggesting that the Saxagliptin and Vildagliptin
addition of sitagliptin may make metformin more tolerable, although a Saxagliptin (Onglyza) and vildagliptin (Galvus) are members of the
specific mechanism for this is lacking.
55
cyanopyrrolidine chemical class.
63,64
Saxagliptin was recently approved
for use in the US as an adjunct to diet and exercise in patients with
Initial combination therapy with sitagliptin and pioglitazone led to a type 2 diabetes.
65
Vildagliptin is available in Europe and some other
reduction in HbA
1c
at 24 weeks of -2.4% from a baseline of 9.5%, countries around the world, but not yet in the US.
compared with -1.5% with pioglitazone monotherapy.
57
Fasting plasma
glucose and measures of beta-cell function were also improved with Saxagliptin
initial combination therapy compared with pioglitazone alone. Monotherapy
In a dose-ranging study (dose range 2.5–40mg once daily) in drug-
Chronic Renal Insufficiency naïve patients with type 2 diabetes, saxagliptin significantly reduced
Dose adjustments are recommended for sitagliptin in patients with HbA
1c
by -0.7 to -0.9% from an average baseline of 7.9% compared
moderate to severe renal insufficiency (RI) or end-stage renal disease with a 0.3% reduction with placebo at 12 weeks.
66
Similar and clinically
(ESRD) (50mg daily if creatinine clearance (CrCl) ≥30 and <50ml/min meaningful reductions in HbA
1c
were achieved with all doses of
and 25mg daily if CrCl <30ml/min).
58
Since the fraction of sitagliptin saxagliptin, with no significant dose–response relationship. A
dose removed by dialysis is small, it can be administered without subsequent trial of saxagliptin monotherapy demonstrated mean
regard for timing of hemodialysis in patients with ESRD. changes in HbA
1c
(baseline 7.9%) over 24 weeks of -0.43, -0.46, and
-0.54% for saxagliptin 2.5, 5, and 10mg, respectively, versus +0.19%
In a study of patients with moderate to severe RI and a baseline HbA
1c
for placebo.
67
Improvements were also seen in fasting plasma glucose,
of 7.7%, patients were randomized to receive dose-adjusted sitagliptin post-prandial glucose–area under the curve (AUC), and the proportion
50mg (moderate RI, CrCl >30 and <50ml/min) or 25mg (severe RI, CrCl of patients achieving HbA
1c
<7%. There was no weight gain and the
<30ml/min, including patients on dialysis) or initial treatment for 12 occurrence of hypoglycemia was similar to that seen with placebo.
weeks with placebo followed by active treatment with glipizide.
59
At The recommended dose of saxagliptin is 2.5 or 5mg once daily,
12 weeks, the mean change in HbA
1c
from baseline with sitagliptin was although 5mg is the proposed usual clinical dose.
68
-0.7% (95% CI -0.9 to -0.4) compared with -0.2% (95% CI -0.4 to 0.1) in
the group receiving placebo. The observed reduction in HbA
1c
from A dose of 2.5mg once daily is recommended for patients with
baseline with sitagliptin was sustained at 54 weeks. Rates of adverse moderate to severe renal impairment (CrCl ≤50ml/min) or ESRD and
experiences were similar between groups, with the exception of when co-administered with medications that strongly inhibit
hypoglycemia, which occurred at a lower rate with sitagliptin. cytochrome P450 3A4/5 (CYP3A4/5), for example ketoconazole.
68
Safety Add-on Dual Combination Therapy
In a pooled analysis of 6,139 patients in 12 large, double-blind, When added to ongoing metformin therapy, saxagliptin 2.5, 5, and
randomized phase IIb and III studies of up to two years’ duration, the 10mg resulted in statistically significant adjusted mean decreases in
66 US ENDOCRINOLOGY
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