Long-Term Efficacy of Sitagliptin

Just Accepted by Current Medical Research & Opinion
Original Article
Long-term Efficacy of Sitagliptin as Either Monotherapy or Add-on
Therapy to Metformin: Improvement in Glycemic Control Over 2 Years
in Patients with Type 2 Diabetes
HL Katzeff, D Williams-Herman, L Xu, G Golm, H Wang, Q Dong, JR
Johnson, EA O’Neill, KD Kaufman, SS Engel, BJ Goldstein
doi: 10.1185/03007995.2015.1037259
Abstract
Objective To evaluate the efficacy of once-daily sitagliptin 100 mg as
monotherapy or as add-on to metformin in patients with type 2 diabetes
mellitus (T2DM) over 2 years of treatment.
Research Design And Methods The monotherapy analysis used pooled
Curr Med Res Opin Downloaded from informahealthcare.com by Nyu Medical Center on 05/12/15
104-week data from 64 patients in two randomized, double-blind trials

evaluating the safety and efficacy of sitagliptin monotherapy. Data used
were from patients who were randomized to sitagliptin 100 mg/day, were
not on an antihyperglycemic agent at the screening visit, had baseline A1C
of 7.0%-10.0%, and had Week 104 A1C measurements. The add-on to
metformin analysis used pooled data from 347 patients in two randomized double-blind trials evaluating the
safety and efficacy of sitagliptin + metformin combination therapy. Data used were from patients who were
randomized to sitagliptin 100 mg/day + metformin ≥1500 mg/day, had baseline A1C of 7%-10%, and had
Week 104 A1C measurements. Excluded from either analysis were patients who discontinued prior to 2 years
(e.g., due to lack of efficacy, a need for rescue medications, or adverse experiences). Analysis endpoints were
For personal use only.
A1C, fasting plasma glucose (FPG), HOMA-β proinsulin/insulin (P/I) ratio, and for monotherapy, 2-hour post
meal plasma glucose (PMG).
Results For the pooled monotherapy cohort, after 2 years of treatment, mean A1C, FPG, and 2-hour PMG
decreased from baseline values of 7.9%, 156 mg/dL, and 223 mg/dL to 6.9%, 143 mg/dL, and 191 mg/dL,
respectively, while HOMA-β increased from 67% to 85% and P/I ratio improved from 0.57 to 0.28. For the
pooled add-on to metformin cohort, after 2 years of treatment, mean A1C and FPG decreased from baseline
values of 7.7% and 160 mg/dL to 6.9% and 140 mg/dL, respectively, while HOMA-β increased from 50% to
62% and P/I ratio improved from 0.33 to 0.28. These analyses are limited in that only patients who were able
to complete 104 weeks of study were included.
Conclusion In the subset of patients with T2DM who maintained and completed treatment for 2 years with
sitagliptin as monotherapy or as add-on to metformin, improvements in glycemic control and measures of β-
cell function were observed over the course of treatment.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon
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1
ORIGINAL ARTICLE
Long-term Efficacy of Sitagliptin as Either Monotherapy or Add-on Therapy to
Metformin: Improvement in Glycemic Control Over 2 Years in Patients with Type 2
Diabetes
HL Katzeff
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D Williams-Herman
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L Xu
G Golm
Merck & Co., Inc., Whitehouse Station, NJ USA
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H Wang
Current address: Sanofi, Bridgewater, NJ USA

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Q Dong
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Current address: Celgene, Summit, NJ USA

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JR Johnson
EA O’Neill
KD Kaufman
SS Engel
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Merck & Co., Inc., Whitehouse Station, NJ USA
BJ Goldstein
Current address: Covance, Inc., Princeton, NJ USA
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Address for correspondence: Harvey L Katzeff, MD, Merck Research Laboratories, 126 East
Lincoln Avenue, Mail Code: RY34-A254, Rahway, NJ 07065-0900 USA. Tel: +1 732 594
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4793; Fax: +1 732 594 3560; harvey_katzeff@merck.com
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[Short Title: Long term efficacy of sitagliptin]
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Key words: DPP-4, incretins, beta-cell function, HOMA-, P/I ratio, Type 2 diabetes disease
progression
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ABSTRACT
OBJECTIVE To evaluate the efficacy of once-daily sitagliptin 100 mg as monotherapy or as
add-on to metformin in patients with type 2 diabetes mellitus (T2DM) over 2 years of
treatment.
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RESEARCH DESIGN AND METHODS The monotherapy analysis used pooled 104-week
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data from 64 patients in two randomized, double-blind trials evaluating the safety and
efficacy of sitagliptin monotherapy. Data used were from patients who were randomized to
sitagliptin 100 mg/day, were not on an antihyperglycemic agent at the screening visit, had
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baseline A1C of 7.0%-10.0%, and had Week 104 A1C measurements. The add-on to
metformin analysis used pooled data from 347 patients in two randomized double-blind trials
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evaluating the safety and efficacy of sitagliptin + metformin combination therapy. Data used
were from patients who were randomized to sitagliptin 100 mg/day + metformin ≥1500
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mg/day, had baseline A1C of 7%-10%, and had Week 104 A1C measurements. Excluded
from either analysis were patients who discontinued prior to 2 years (e.g., due to lack of
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efficacy, a need for rescue medications, or adverse experiences). Analysis endpoints were
A1C, fasting plasma glucose (FPG), HOMA-proinsulin/insulin (P/I) ratio, and for
monotherapy, 2-hour post meal plasma glucose (PMG).

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RESULTS For the pooled monotherapy cohort, after 2 years of treatment, mean A1C, FPG, and 2-
hour PMG decreased from baseline values of 7.9%, 156 mg/dL, and 223 mg/dL to 6.9%, 143 mg/dL,
and 191 mg/dL, respectively, while HOMA-β increased from 67% to 85% and P/I ratio improved from
0.57 to 0.28. For the pooled add-on to metformin cohort, after 2 years of treatment, mean A1C and
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FPG decreased from baseline values of 7.7% and 160 mg/dL to 6.9% and 140 mg/dL, respectively,
while HOMA-β increased from 50% to 62% and P/I ratio improved from 0.33 to 0.28. These
analyses are limited in that only patients who were able to complete
104 weeks of study were included.
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CONCLUSION In the subset of patients with T2DM who maintained and completed treatment for
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2 years with sitagliptin as monotherapy or as add-on to metformin, improvements in glycemic
control and measures of β-cell function were observed over the course of treatment.
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INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a chronic disease, characterized by progressive cell
dysfunction, requiring long-term therapeutic intervention1. As observed in the UK
Prospective Diabetes Study, a majority of patients with T2DM will initiate
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treatment with monotherapy but eventually require combination therapy with two or more
antihyperglycemic agents2. The requirement for an increase in the number of antihyperglycemic

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agents is temporally associated with a linear decline in cell function, as assessed by HOMA-
Therefore it is important to understand the long-term effects of available antihyperglycemic agents
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on both glycemic regulation and -cell function.
The DPP-4 inhibitors comprise a relatively new class of medications that lower blood glucose
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in a glucose-dependent manner by increasing active levels of the incretins glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic peptide (GIP)3. In animal studies, incretin-based
therapies maintain -cell function and mass4, 5 but analogous data on the long-term effects of these
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therapies in humans are lacking.
Sitagliptin is a once-daily, oral, selective DPP-4 inhibitor6. Sitagliptin improves fasting and
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postprandial glycemic control in patients with T2DM7, 8 and is generally well tolerated in clinical trials
up to 2 years in duration9, 10. However, analysis of the long-term efficacy of sitagliptin, with regard
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to glycemic control and -cell function, has been limited. Therefore, we evaluated the relationship
between sitagliptin treatment and blood glucose, glycosylated hemoglobin levels and HOMA- in
patients with T2DM who maintained stable glucose control for 2 years duration.
PATIENTS AND METHODS

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For both the sitagliptin monotherapy and add-on to metformin therapy analyses, data from a
subgroup of individuals who met common glycemic A1C entry criteria were pooled from studies with
duration of 2 years. Below is a summary by treatment regimen of the studies used in the analyses.
Sitagliptin monotherapy Data were pooled from two multicenter, double-blind, randomized studies,
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one of 24-week and the other of 54-week initial duration (P021, ClinicalTrials.gov NCT00087516, and
P036, ClinicalTrials.gov NCT00103857)8, 11-13 that were continued for an additional 80 and 50 weeks
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respectively, to provide a total of 104 weeks (2 years) of assessment in each study. This analysis
includes results from the subgroup of patients who were not on an AHA at the screening visit, had
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A1C ≥7 and ≤10% at baseline, were randomized to treatment with sitagliptin 100 mg once daily, and
had Week 104 A1C measurements without receiving glycemic rescue medication .
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Sitagliptin add-on to metformin therapy Data were pooled from two multicenter, double-blind,
randomized, add-on to metformin therapy studies, one of 24 week initial duration that was
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continued for an additional 80 weeks, the other of 104 week duration (P020, Clinical Trials.gov
NCT0086515, and P024, Clinical Trials.gov NCT00094770)14-16. The analysis includes data from the
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subgroup of patients who were on metformin ≥1500 mg/day, had A1C ≥7 and ≤10% at baseline,
were randomized to treatment with sitagliptin 100 mg/day, and had Week 104 A1C
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measurements without receiving glycemic rescue medication.
Efficacy endpoints of interest In all studies from which data were pooled, blood was collected after
an overnight fast. A1C, fasting plasma glucose (FPG), insulin, and proinsulin were evaluated at
baseline and at various time points during the studies. Homeostasis model assessment--cell
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function (HOMA-) and the proinsulin/insulin (P/I) ratio were used to assess -cell function17, 18. In
the monotherapy studies, a standard meal tolerance test was administered at baseline (before the
first dose of study medication) and at Weeks 24, 54, and 104, with the endpoints analyzed as
previously described13. Meal tolerance tests were not done at common time points in the
metformin add-on studies; thus these data were not pooled for this analysis.
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Glycemic Rescue and Discontinuation Criteria The studies used in these analyses applied varying
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glycemic rescue and discontinuation criteria (Table 1). Patients meeting specific glycemic criteria
were either eligible for glycemic rescue medication or were discontinued from the study.
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Statistical Analysis For each efficacy endpoint the statistical analyses were performed using all
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observed values, restricted to patients who had 104-week A1C values without glycemic rescue.
Least-squares means for on-treatment efficacy measurements at each time point were computed
from an ANCOVA model with terms for treatment, trial, and corresponding baseline value. Sample
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means are reported at baseline.

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RESULTS
Long-term efficacy of sitagliptin monotherapy: Of the 184 patients meeting baseline criteria for
inclusion in the monotherapy analysis, 64 patients completed a trial with sufficient data to be
included. Data from 78 patients were not included in the analysis because the patients were either
rescued or discontinued without rescue due to lack of efficacy (Tables 1 and 2), and data from 9
patients were not included because the patients discontinued prior to the 2-year time point due to
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adverse experience (Table 2). Data for 33 others were unavailable for a variety of other reasons
(Table 2). Baseline characteristics of the pooled monotherapy cohort are shown in Table 3. Mean
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anthropometric characteristics for the pooled monotherapy cohort included baseline age of
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54 years, A1C of 7.9%, FPG of 156.0 mg/dL, and duration of T2DM of 2.8 years.
With sitagliptin monotherapy, substantial reductions from baseline were observed for A1C
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(Figure 1A), FPG (Figure 1B) and 2 hour post-meal glucose (PMG) (Figure 1C) at the first
measurements after treatment began. Improvements in each of these glycemic endpoints
diminished slightly during the course of the studies, but remained well below baseline at Week 104.
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The fasting P/I ratio (Figure 1D) decreased from baseline and HOMA-(Figure 1E) increased at the
first measurements after treatment began; for both endpoints, improvements from baseline were
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generally observed through Week 104.

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Long-term efficacy of sitagliptin as add-on to metformin: Of the 853 patients meeting the baseline
criteria for inclusion in the add-on to metformin analysis, 347 patients completed a trial with
sufficient data to be included. Data from 281 patients were not included in the analysis because the
patients were rescued or discontinued without rescue due to lack of efficacy (Tables 1 and 2),
and data from 48 patients were not included because the patients discontinued prior to the 2-year
time point due to adverse experience (Table 2). Data for 177 others were unavailable for a variety of
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other reasons (Table 2). Baseline characteristics of the pooled add-on cohort are shown in Table 3.
Mean anthropometric characteristics for the add-on therapy cohort included baseline age of
56.3 years, A1C of 7.7%, FPG of 159.7 mg/dL, and duration of T2DM of 6.5 years.
The addition of sitagliptin to ongoing metformin therapy resulted in substantial decreases in
A1C (Figure 2A) and FPG (Figure 2B) within weeks of treatment initiation. These improvements
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diminished slightly during the 2 year period of the analysis. The fasting P/I ratio decreased at 24
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weeks and remained below baseline through 104 weeks (Figure 2C), while increases in HOMA-
were observed through Week 1(Figure 2D).
DISCUSSION
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Given the chronic and progressive nature of T2DM, the long-

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term efficacy and safety of therapies used by patients with

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this disease are of increasing interest. Numerous clinical
studies have demonstrated the therapeutic benefit of

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sitagliptin as monotherapy or as add-on to a variety of

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antihyperglycemic agents. In placebo-controlled trials of up
to 30 weeks in duration, sitagliptin as monotherapy or as
add-on therapy improved A1C, FPG and postprandial
glycemic control11, 13, 14, 19-26. In a 52-week, active-comparator

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controlled trial comparing sitagliptin to glipizide when either
is added on to ongoing metformin therapy, sitagliptin
demonstrated similar efficacy, with a lower incidence of
hypoglycemia, and weight loss versus weight gain, compared
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with glipizide16. Previous publications reported analyses of
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pooled safety and tolerability data from randomized clinical
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trials of sitagliptin that were from 12 weeks to 2 years in
duration9, 10, 27. In this report, long-term efficacy of sitagliptin

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was evaluated as monotherapy or as add-on to metformin

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for 2 years. For both regimens, measures of glycemic control
and -cell function improved following initiation of sitagliptin

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treatment, with only slight lessening of glycemic efficacy

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observed during the 2 year period of study.
In the pooled data there appeared to be a trend toward
increasing A1C, FPG and PMG during the second year of
treatment. This may be the result of relaxed adherence to

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lifestyle modifications, progression of disease, and/or a
lessening of treatment efficacy. However, -cell function, as
assessed by HOMA-or P/I ratio, appeared stable for up to 2
years, suggesting that the effect of sitagliptin therapy,
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presumably resulting from stabilization of the actions of the
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incretins GLP-1 and GIP 3, 28, 29 was maintained. These results
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are consistent with a recent study which showed that HOMA-
 was improved by sitagliptin or metformin monotherapy,

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with greater improvement observed with the combination30.

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In the current analysis, when sitagliptin was added on to

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ongoing metformin treatment, the measured improvement
in the P/I ratio was less compared with the improvement

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observed with sitagliptin monotherapy. This finding possibly reflected a
reduced P/I ratio at baseline (as a result of ongoing metformin therapy), since the final values were
similar for both the monotherapy and add-on to metformin cohorts. Another potential explanation
is that the sitagliptin add-on to metformin therapy group had a longer duration of disease compared
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with the sitagliptin monotherapy group and may have had less -cell reserve to respond to the
incretin-based treatment.
These analyses are limited in that only patients who
maintained an adequate A1C value throughout the entire 104
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weeks were included. A source of data loss was the
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increasingly stringent criteria for glycemic rescue therapy or
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treatment discontinuation with time, preferentially
eliminating individuals who either did not respond well to

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therapy or whose baseline glycemic parameters were high
enough that even with significant improvement they

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remained above the thresholds for glycemic rescue or

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discontinuation from study. It is not clear why all patients do

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not respond equally to treatment with sitagliptin. In a
previous analysis of the relationship of patient age, gender, or body mass index at study
baseline with glycemic efficacy, no interactions between these baseline characteristics and
treatment outcomes were observed.31 It is not possible to determine how

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the elimination of patients from the study cohorts over time
affected assessment of the durability of treatment effects
based on the patients who had data available 2 years
following initiation of therapy.
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With respect to efficacy, it is currently unknown
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whether incretin-based therapies have durability similar to
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that of other classes of antihyperglycemic medications. The
ADOPT study compared the durability of efficacy of various

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therapies in patients with short duration of T2DM and

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observed that the sulfonylurea glibenclamide, compared to

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metformin or rosiglitazone, showed the most rapid decline in
A1C but also the poorest durability32. In the same study,

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rosiglitazone showed the best durability, but all 3 agents
showed decline in efficacy over the 4-year duration of the
study. One possible explanation for this decline with all 3
classes of agents is the natural history of T2DM, in which

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there is a steady decline in -cell function with increasing
duration of disease 1. A variety of mechanisms explaining the
progressive decline in -cell function associated with T2DM
have been proposed33. These include endoplasmic reticulum
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stress resulting from continuously increasing demand for
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insulin production in the face of rising insulin resistance,
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metabolic and oxidative stress due to increased glycolytic flux
resulting from an excessive nutritional state (glucotoxicity,

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lipotoxicity), and accumulation of amyloid plaques, all of

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which may eventually lead to chronic, islet-localized
inflammation. Therefore, even antihyperglycemic agents

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that work by decreasing the workload of -cells would be

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expected to become less effective as increasing age
associated peripheral or hepatic insulin resistance 34
continues to challenge -cells. In the current analysis, there
appears to be decreasing glycemic control despite stable -

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cell function. However, in the studies used for this analysis -
cell function was measured under fasting conditions and the
ability of -cells to respond to glycemic challenge was not
tested.
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With regard to the role that impairment of insulin
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secretion as a result of glucose toxicity plays in the durability
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of efficacy of an antihyperglycemic agent, studies have
shown that patients with high A1C values, despite being on

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antihyperglycemic agents, will become more responsive to

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these agents after short-term (4-6 weeks) intensive insulin

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therapy, once insulin therapy is withdrawn35, 36. Whether
incretin-based therapies would more effectively maintain

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lower blood glucoses levels after short-term, intensive
management with insulin, is largely unknown.

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CONCLUSIONS
Once-daily sitagliptin, used as monotherapy or as
add-on to metformin therapy, provided long-term
improvements in glycemic control and -cell function in a
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subset of patients with T2DM who maintained and
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completed treatment during 2-year clinical trials.
Transparency:
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Declaration of funding:
These analyses were funded by Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA
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Declaration of financial/other relationships:
All authors are, or were, employees of Merck & Co., Inc., Whitehouse Station, NJ USA at the time this
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study was conducted. CMRO Peer Reviewer 1 has disclosed that he has received grants from Eli Lilly,
Boehringer Ingelheim, Janssen and Merck. He has also disclosed that he is a consultant to and on the
Speakers’ Bureau of Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Janssen and Merck. CMRO Peer
Reviewer 2 has disclosed that he has received consulting fees or lecture fees from Sanofi, Novo
Nordisk, Eli Lilly, GlaxoSmithKline, Astellas, Takeda, Boehringer Ingelheim, Johnson & Johnson,
Becton Dickinson, AstraZeneca, Taisho Toyama and Taisho.

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Acknowledgments:
The authors gratefully acknowledge the assistance of Sheila Erespe in submission of the manuscript.
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Previous presentation:
Some of the material reported here was presented at the ADA Scientific Sessions, June 5 - 9, 2009;
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New Orleans, Louisiana and at the IDF World Congress October 18 - 22, 2009; Montreal, Canada
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and tolerability of sitagliptin in patients with type 2
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A
2008;8:14
ST
28. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the
two incretin hormones: Similarities and differences. J

JU
Diabetes Investig 2010;1:8-23
29. Seino Y, Yabe D. Glucose-dependent insulinotropic
polypeptide and glucagon-like peptide-1: Incretin actions
beyond the pancreas. J Diabetes Investig 2013;4:108-30

25
30. Williams-Herman D, Xu L, Teng R, et al. Effect of initial
combination therapy with sitagliptin and metformin on
beta-cell function in patients with type 2 diabetes.
Diabetes Obes Metab 2012;14:67-76
D
31. Williams-Herman D, Swern AS, Davies MJ, et al. In
TE
Patients with Type 2 Diabetes, Sitagliptin Effectively
Lowers A1C Regardless of Patient Age, Gender, or Body

EP
Mass Index. 2008; 57(suppl 1): 495-P
CC
32. Kahn SE, Haffner SM, Heise MA, et al. Glycemic
durability of rosiglitazone, metformin, or glyburide

A
monotherapy. N Engl J Med 2006;355:2427-43

ST
33. Halban PA, Polonsky KS, Bowden DW, et al. beta-cell
failure in type 2 diabetes: postulated mechanisms and

JU
prospects for prevention and treatment. J Clin Endocrinol
Metab 2014;99:1983-92
34. DeFronzo RA. Glucose intolerance and aging. Diabetes
Care 1981;4:493-501
26
35. Retnakaran R, Yakubovich N, Qi Y, et al. The response
to short-term intensive insulin therapy in type 2 diabetes.
Diabetes Obes Metab 2010;12:65-71
36. Retnakaran R, Qi Y, Opsteen C, et al. Initial short-term
D
intensive insulin therapy as a strategy for evaluating the
TE
preservation of beta-cell function with oral antidiabetic
medications: a pilot study with sitagliptin. Diabetes Obes

EP
Metab 2010;12:909-15
CC
A
ST
JU
27
Table 1. Glycemic rescue therapy or discontinuation
criteria, and numbers of patients excluded from the
pooled analysis due to rescue or discontinuation
according to these criteria (n), by week.
D
TE
FPG FPG FPG FPG A1C A1C
Study
Total
Protocol
> 270 mg/dL >240 mg/dL >220 mg/dL >200 mg/dL >8.0% >7.5%
Pooled Studies for Monotherapy Analysis
Weeks Weeks
EP Weeks Weeks Weeks
CC
P02113 0 to 6 > 6 to 12 - > 12 to < 38* 38 to < 54* 54 to 104* n = 38
n=0 n=0 n=6 n=5 n = 27
Weeks Weeks Weeks Weeks Weeks

A
P036 8, 11, 12 0 to 6 > 6 to 12 - > 12 to 24 > 24 to 54 > 54 to 104 n = 40
n=1 n=1 n=9 n = 14 n = 15

ST
Pooled Studies for Add-on to Metformin Analysis

JU
P020 14 0 to 6 > 6 to 12 - > 12 to < 38* 38 to < 54* 54 to 104* n = 118
n=1 n=3 n = 24 n = 21 n = 69

Weeks
P024 15, 16 0 to 6* > 6 to 12* > 12 to 18* > 18 to 30* > 30 to 52* n = 163
> 52 to
104*
n=1 n=5 n=7 n = 19 n = 53
28
n = 78
*Study P024 and Weeks 24-104 in studies P020 and P021 did not include glycemic rescue therapy. Patients who met the specified
glycemic criteria in study P024 and at these time points in studies P020 and P021 were discontinued from their respective study.
D
TE
EP
CC
A
ST
JU
29
Table 2. Accounting of patients available for the pooled analysis.
D
Monotherapy Add-on Therapy
TE
Randomized patients with baseline A1C ≥7.0% and ≤10% 184 853
Included in analysis 64 347
Excluded from analysis

EP 120 506
No A1C data at Week 104 3 8

CC
Initiated glycemic rescue 45 19
Discontinued without rescue 72 479

A
Due to: Lack of efficacy 33 262

ST
Adverse experience 9 48
Consent withdrawn 11 42
JU
Lost to follow-up 6 33
Protocol specified 2 20
Protocol deviation 4 12
Moved 0 7
Other
JU Site terminated
ST
A
7
0
CC
1
54
EP
TE
D
30
31
Table 3. Baseline demographic and anthropometric characteristics of patients included
Monotherapy Add-on Therapy

Parameter*
(N = 64) (N = 347)
D
TE
EP
CC
A
in the pooled analysis.

ST
JU
32
Age, years 54 (9.5) 56.3 (9.1)
Males, n (%) 40 (62.5) 200 (57.6)
Race, n (%)
White 33 (51.6) 234 (67.4)
Hispanic 15 (23.4) 32 (9.2)
D
Asian 8 (12.5) 43 (12.4)
TE
Black 0 (0.0) 19 (5.5)
Other 8 (12.5) 19 (5.5)
Duration of T2DM, years
Body Weight, kg
EP 2.8 (3.5)
82.9 (18.2)
6.5 (5.9)
86.1 (16.8)
CC
A1C, % 7.9 (0.7) 7.7 (0.6)
FPG, mg/dL 156.0 (35.1) 159.7 (32.5)

A
2
Body Mass Index, kg/m 29.6 (5.4) 30.6 (4.9)
ST
*All values are mean (standard deviation) except as noted.

JU
JU
ST
A
CC
EP
TE
D
33
34
Figure 1. Effect of sitagliptin monotherapy over 2 years on A1C (A, n ranges from 63 – 64); fasting
plasma glucose (B, n ranges from 63 – 64); 2-hour post meal plasma glucose (C, n ranges from 60 -
61); the proinsulin/insulin ratio (D, n ranges from 56 – 57); and HOMA-(E, n = 63)
A.
D
8.0
TE
7.8
7.6
7.4
(LS mean ± SE)
A1C, %
7.2
7.0
6.8
6.6
EP
6.4
CC
6.2
0 20 40 60 80 100 120
Week
A
ST
B.
JU
165
160
Fasting Plasma Glucose, mg/dL
155
150
(LS mean ± SE)
145
140
135
130
125
120
0 20 40 60 80 100 120
Week
JU
ST
A
CC
EP
TE
D
35
Proinsulin / Insulin Post-meal Glucose, mg/dL C.
D.
(LS mean ± SE) (LS mean ± SE)
0.0
0.2
0.4
0.6
0.8
0
50
100
150
200
250
0
0
JU
24
24
ST
Week
Week
54
54
A
104
104
CC
EP
TE
D
36
E.
HOMA-, %
(LS mean ± SE)
100
120
0
20
40
60
80
0
JU
24
ST
Week
54
A
104
CC
EP
TE
D
37
38
Figure 2. Effect of sitagliptin added on to metformin treatment over 2 years on A1C (A, n
ranges from 341 – 347); fasting plasma glucose (B, n ranges from 333 – 342); the proinsulin/insulin
ratio (C, n ranges from 317 – 328); and HOMA- (D, n ranges from 319 – 328).
A.
D
TE
8.0
7.8
7.6
7.4
(LS mean ± SE)
EP
A1C, %
7.2
7.0
6.8
6.6
CC
6.4
6.2
0 20 40 60 80 100 120
Week
A
ST
JU
C.
B.
Proinsulin / Insulin Fasting Plasma Glucose, mg/dL
D.
(LS mean ± SE) (LS mean ± SE)
0.0
0.2
0.4
0.6
0.8
120
125
130
135
140
145
150
155
160
165
0
JU
20
24
40
ST
Week
Week
60
54
A
80
104
100
120
CC
EP
TE
D
39
HOMA-
(LS mean ± SE)
0
20
40
60
80
100
JU
0
24
ST
Week
54
A 104
CC
EP
TE
D
40

Long-Term Efficacy of Sitagliptin

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Long-Term Efficacy of Sitagliptin

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Just Accepted by Current Medical Research & Opinion

104-week data from 64 patients in two randomized, double-blind trials

Long-term Efficacy of Sitagliptin as Either Monotherapy or Add-on Therapy to

Metformin: Improvement in Glycemic Control Over 2 Years in Patients with Type 2

Merck & Co., Inc., Whitehouse Station, NJ USA

Current address: Sanofi, Bridgewater, NJ USA

Current address: Celgene, Summit, NJ USA

Merck & Co., Inc., Whitehouse Station, NJ USA

Current address: Covance, Inc., Princeton, NJ USA

OBJECTIVE To evaluate the efficacy of once-daily sitagliptin 100 mg as monotherapy or as

monotherapy, 2-hour post meal plasma glucose (PMG).

104 weeks of study were included.

Type 2 diabetes mellitus (T2DM) is a chronic disease, characterized by progressive cell

dysfunction, requiring long-term therapeutic intervention1. As observed in the UK

Prospective Diabetes Study, a majority of patients with T2DM will initiate

antihyperglycemic agents2. The requirement for an increase in the number of antihyperglycemic

Therefore it is important to understand the long-term effects of available antihyperglycemic agents

(GLP-1) and glucose-dependent insulinotropic peptide (GIP)3. In animal studies, incretin-based

therapies in humans are lacking.

PATIENTS AND METHODS

measurements without receiving glycemic rescue medication.

means are reported at baseline.

measurements after treatment began. Improvements in each of these glycemic endpoints

generally observed through Week 104.

The addition of sitagliptin to ongoing metformin therapy resulted in substantial decreases in

were observed through Week 1(Figure 2D).

Given the chronic and progressive nature of T2DM, the long-

term efficacy and safety of therapies used by patients with

this disease are of increasing interest. Numerous clinical

studies have demonstrated the therapeutic benefit of

sitagliptin as monotherapy or as add-on to a variety of

antihyperglycemic agents. In placebo-controlled trials of up

to 30 weeks in duration, sitagliptin as monotherapy or as

add-on therapy improved A1C, FPG and postprandial

glycemic control11, 13, 14, 19-26. In a 52-week, active-comparator

controlled trial comparing sitagliptin to glipizide when either

is added on to ongoing metformin therapy, sitagliptin

demonstrated similar efficacy, with a lower incidence of

hypoglycemia, and weight loss versus weight gain, compared

duration9, 10, 27. In this report, long-term efficacy of sitagliptin

was evaluated as monotherapy or as add-on to metformin

for 2 years. For both regimens, measures of glycemic control

and -cell function improved following initiation of sitagliptin

treatment, with only slight lessening of glycemic efficacy

observed during the 2 year period of study.

In the pooled data there appeared to be a trend toward

increasing A1C, FPG and PMG during the second year of

treatment. This may be the result of relaxed adherence to

lifestyle modifications, progression of disease, and/or a

lessening of treatment efficacy. However, -cell function, as

assessed by HOMA-or P/I ratio, appeared stable for up to 2

years, suggesting that the effect of sitagliptin therapy,

 was improved by sitagliptin or metformin monotherapy,

with greater improvement observed with the combination30.

In the current analysis, when sitagliptin was added on to

ongoing metformin treatment, the measured improvement

in the P/I ratio was less compared with the improvement