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
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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 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 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 βcell function were observed over the course of treatment.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
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
L Xu G Golm
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Merck & Co., Inc., Whitehouse Station, NJ USA
H Wang
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Current address: Sanofi, Bridgewater, NJ USA
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Q Dong
Current address: Celgene, Summit, NJ USA
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D Williams-Herman
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HL Katzeff
JR Johnson EA O’Neill
KD Kaufman SS Engel
2 Merck & Co., Inc., Whitehouse Station, NJ USA
BJ Goldstein
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Address for correspondence: Harvey L Katzeff, MD, Merck Research Laboratories, 126 East
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Lincoln Avenue, Mail Code: RY34-A254, Rahway, NJ 07065-0900 USA. Tel: +1 732 594 4793; Fax: +1 732 594 3560; [email protected]
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[Short Title: Long term efficacy of sitagliptin]
Key words: DPP-4, incretins, beta-cell function, HOMA-, P/I ratio, Type 2 diabetes disease
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progression
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Current address: Covance, Inc., Princeton, NJ USA
3 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
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treatment.
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
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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
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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
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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 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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RESEARCH DESIGN AND METHODS The monotherapy analysis used pooled 104-week
RESULTS For the pooled monotherapy cohort, after 2 years of treatment, mean A1C, FPG, and 2hour 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
4 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
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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
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control and measures of β-cell function were observed over the course of treatment.
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104 weeks of study were included.
5 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
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Prospective Diabetes Study, a majority of patients with T2DM will initiate
antihyperglycemic agents2. The requirement for an increase in the number of antihyperglycemic
agents is temporally associated with a linear decline in cell function, as assessed by HOMA-
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Therefore it is important to understand the long-term effects of available antihyperglycemic agents on both glycemic regulation and -cell function.
The DPP-4 inhibitors comprise a relatively new class of medications that lower blood glucose 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
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therapies maintain -cell function and mass4, 5 but analogous data on the long-term effects of these therapies in humans are lacking.
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Sitagliptin is a once-daily, oral, selective DPP-4 inhibitor6. Sitagliptin improves fasting and
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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treatment with monotherapy but eventually require combination therapy with two or more
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
6 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.
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Sitagliptin monotherapy Data were pooled from two multicenter, double-blind, randomized studies,
P036, ClinicalTrials.gov NCT00103857)8, 11-13 that were continued for an additional 80 and 50 weeks respectively, to provide a total of 104 weeks (2 years) of assessment in each study. This analysis
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includes results from the subgroup of patients who were not on an AHA at the screening visit, had
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 .
Sitagliptin add-on to metformin therapy Data were pooled from two multicenter, double-blind,
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randomized, add-on to metformin therapy studies, one of 24 week initial duration that was continued for an additional 80 weeks, the other of 104 week duration (P020, Clinical Trials.gov
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NCT0086515, and P024, Clinical Trials.gov NCT00094770)14-16. The analysis includes data from the 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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one of 24-week and the other of 54-week initial duration (P021, ClinicalTrials.gov NCT00087516, and
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
7 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
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Glycemic Rescue and Discontinuation Criteria The studies used in these analyses applied varying glycemic rescue and discontinuation criteria (Table 1). Patients meeting specific glycemic criteria
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were either eligible for glycemic rescue medication or were discontinued from the study.
Statistical Analysis For each efficacy endpoint the statistical analyses were performed using all 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
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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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metformin add-on studies; thus these data were not pooled for this analysis.
8 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
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patients were not included because the patients discontinued prior to the 2-year time point due to
(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 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 (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
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diminished slightly during the course of the studies, but remained well below baseline at Week 104. The fasting P/I ratio (Figure 1D) decreased from baseline and HOMA-(Figure 1E) increased at the
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first measurements after treatment began; for both endpoints, improvements from baseline were generally observed through Week 104.
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adverse experience (Table 2). Data for 33 others were unavailable for a variety of other reasons
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
9 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
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A1C (Figure 2A) and FPG (Figure 2B) within weeks of treatment initiation. These improvements
weeks and remained below baseline through 104 weeks (Figure 2C), while increases in HOMA-
DISCUSSION
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were observed through Week 1(Figure 2D).
Given the chronic and progressive nature of T2DM, the long-
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term efficacy and safety of therapies used by patients with this disease are of increasing interest. Numerous clinical
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studies have demonstrated the therapeutic benefit of sitagliptin as monotherapy or as add-on to a variety of
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diminished slightly during the 2 year period of the analysis. The fasting P/I ratio decreased at 24
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
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with glipizide16. Previous publications reported analyses of
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pooled safety and tolerability data from randomized clinical 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 for 2 years. For both regimens, measures of glycemic control
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and -cell function improved following initiation of sitagliptin treatment, with only slight lessening of glycemic efficacy
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hypoglycemia, and weight loss versus weight gain, compared
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
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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 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 ongoing metformin treatment, the measured improvement in the P/I ratio was less compared with the improvement
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years, suggesting that the effect of sitagliptin therapy,
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
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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 treatment discontinuation with time, preferentially eliminating individuals who either did not respond well to therapy or whose baseline glycemic parameters were high
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enough that even with significant improvement they
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remained above the thresholds for glycemic rescue or discontinuation from study. It is not clear why all patients do
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maintained an adequate A1C value throughout the entire 104
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
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With respect to efficacy, it is currently unknown
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whether incretin-based therapies have durability similar to
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 metformin or rosiglitazone, showed the most rapid decline in A1C but also the poorest durability32. In the same study,
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following initiation of therapy.
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
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stress resulting from continuously increasing demand for
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insulin production in the face of rising insulin resistance,
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 which may eventually lead to chronic, islet-localized
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inflammation. Therefore, even antihyperglycemic agents that work by decreasing the workload of -cells would be
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have been proposed33. These include endoplasmic reticulum
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
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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 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 therapy, once insulin therapy is withdrawn35, 36. Whether incretin-based therapies would more effectively maintain
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tested.
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
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subset of patients with T2DM who maintained and
Transparency:
Declaration of funding:
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completed treatment during 2-year clinical trials.
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These analyses were funded by Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA
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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improvements in glycemic control and -cell function in a
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.
17
Acknowledgments:
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The authors gratefully acknowledge the assistance of Sheila Erespe in submission of the manuscript.
Some of the material reported here was presented at the ADA Scientific Sessions, June 5 - 9, 2009;
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27. Williams-Herman D, Round E, Swern AS, et al. Safety and tolerability of sitagliptin in patients with type 2
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diabetes: a pooled analysis. BMC Endocr Disord
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2008;8:14
28. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J
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tolerability of the dipeptidyl peptidase-4 inhibitor
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.
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Diabetes Obes Metab 2012;14:67-76
Patients with Type 2 Diabetes, Sitagliptin Effectively
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Lowers A1C Regardless of Patient Age, Gender, or Body Mass Index. 2008; 57(suppl 1): 495-P
32. Kahn SE, Haffner SM, Heise MA, et al. Glycemic
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durability of rosiglitazone, metformin, or glyburide
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monotherapy. N Engl J Med 2006;355:2427-43 33. Halban PA, Polonsky KS, Bowden DW, et al. beta-cell failure in type 2 diabetes: postulated mechanisms and
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31. Williams-Herman D, Swern AS, Davies MJ, et al. In
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
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36. Retnakaran R, Qi Y, Opsteen C, et al. Initial short-term
preservation of beta-cell function with oral antidiabetic
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medications: a pilot study with sitagliptin. Diabetes Obes
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Metab 2010;12:909-15
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intensive insulin therapy as a strategy for evaluating the
27
Table 1. Glycemic rescue therapy or discontinuation criteria, and numbers of patients excluded from the pooled analysis due to rescue or discontinuation
FPG
FPG
FPG
FPG
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Study
A1C
A1C
Total
> 270 mg/dL
>240 mg/dL
>220 mg/dL
>200 mg/dL
>8.0%
>7.5%
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Protocol
Pooled Studies for Monotherapy Analysis
P036 8, 11, 12
Weeks
0 to 6
> 6 to 12
n=0
n=0
Weeks
Weeks
0 to 6
> 6 to 12
-
n=1
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n=1
-
A
P02113
Weeks
Weeks
Weeks
Weeks
> 12 to < 38*
38 to < 54*
54 to 104*
n=6
n=5
n = 27
Weeks
Weeks
Weeks
> 12 to 24
> 24 to 54
> 54 to 104
n=9
n = 14
n = 15
Weeks
Weeks
Weeks
> 12 to < 38*
38 to < 54*
54 to 104*
n = 24
n = 21
n = 69
n = 38
n = 40
Pooled Studies for Add-on to Metformin Analysis
Weeks
Weeks
0 to 6
> 6 to 12
n=1
n=3
Weeks
Weeks
Weeks
Weeks
Weeks
0 to 6*
> 6 to 12*
> 12 to 18*
> 18 to 30*
> 30 to 52*
n=1
n=5
n=7
n = 19
n = 53
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according to these criteria (n), by week.
P020 14
P024 15, 16
-
n = 118
Weeks
> 52 to 104*
n = 163
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
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glycemic criteria in study P024 and at these time points in studies P020 and P021 were discontinued from their respective study.
29
Monotherapy
Add-on Therapy
184
853
64
Excluded from analysis
347
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Included in analysis
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Randomized patients with baseline A1C ≥7.0% and ≤10%
120
506
3
8
45
19
72
479
33
262
Adverse experience
9
48
Consent withdrawn
11
42
Lost to follow-up
6
33
Protocol specified
2
20
Protocol deviation
4
12
Moved
0
No A1C data at Week 104 Initiated glycemic rescue
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Discontinued without rescue
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Due to: Lack of efficacy
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Table 2. Accounting of patients available for the pooled analysis.
7
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Site terminated 0 1
Other 7 54
31
Table 3. Baseline demographic and anthropometric characteristics of patients included Monotherapy
Add-on Therapy
(N = 64)
(N = 347)
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in the pooled analysis.
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Parameter*
32 Age, years
54 (9.5)
56.3 (9.1)
Males, n (%)
40 (62.5)
200 (57.6)
White
33 (51.6)
234 (67.4)
Hispanic
15 (23.4)
32 (9.2)
Asian
8 (12.5)
Black
0 (0.0)
Other
8 (12.5)
Body Weight, kg A1C, %
2
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Body Mass Index, kg/m
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2.8 (3.5)
6.5 (5.9)
82.9 (18.2)
86.1 (16.8)
7.9 (0.7)
7.7 (0.6)
156.0 (35.1)
159.7 (32.5)
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FPG, mg/dL
43 (12.4)
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Duration of T2DM, years
29.6 (5.4)
*All values are mean (standard deviation) except as noted.
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Race, n (%)
30.6 (4.9)
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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)
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8.0 7.8
7.4 7.2 7.0 6.8 6.6 6.4 6.2 0
20
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A1C, % (LS mean ± SE)
7.6
40
60
80
100
120
100
120
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B.
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A
Week
165 160
Fasting Plasma Glucose, mg/dL (LS mean ± SE)
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A.
155 150 145 140 135 130 125 120
0
20
40
60
Week
80
ST
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35
ST
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0.4
D.
0.8
0.6
50
0 0
0
24 54
24
Week 54
104
Week
0.2
0.0
104
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Post-meal Glucose, mg/dL (LS mean ± SE)
36
C.
250
200
150
100
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40
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E.
120
100
80
60
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A
37
20
0
0
24
Week
54 104
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).
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8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 0
20
40
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A1C, % (LS mean ± SE)
60
80
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A
Week
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A.
100
120
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D. Week
C.
0.8 145
140
135
130
125
120 0 20
0 40 60
24
Week 80
54 100
0.4
0.2
0.0
104 120
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Fasting Plasma Glucose, mg/dL (LS mean ± SE)
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B.
165
160
155
150
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0 0 24 54
Week 104
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HOMA- (LS mean ± SE)
40
100
80
60
40
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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 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 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 βcell function were observed over the course of treatment.
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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
L Xu G Golm
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Merck & Co., Inc., Whitehouse Station, NJ USA
H Wang
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Current address: Sanofi, Bridgewater, NJ USA
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Q Dong
Current address: Celgene, Summit, NJ USA
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D Williams-Herman
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HL Katzeff
JR Johnson EA O’Neill
KD Kaufman SS Engel
2 Merck & Co., Inc., Whitehouse Station, NJ USA
BJ Goldstein
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Address for correspondence: Harvey L Katzeff, MD, Merck Research Laboratories, 126 East
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Lincoln Avenue, Mail Code: RY34-A254, Rahway, NJ 07065-0900 USA. Tel: +1 732 594 4793; Fax: +1 732 594 3560; [email protected]
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[Short Title: Long term efficacy of sitagliptin]
Key words: DPP-4, incretins, beta-cell function, HOMA-, P/I ratio, Type 2 diabetes disease
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progression
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Current address: Covance, Inc., Princeton, NJ USA
3 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
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treatment.
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
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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
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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
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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 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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RESEARCH DESIGN AND METHODS The monotherapy analysis used pooled 104-week
RESULTS For the pooled monotherapy cohort, after 2 years of treatment, mean A1C, FPG, and 2hour 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
4 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
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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
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control and measures of β-cell function were observed over the course of treatment.
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104 weeks of study were included.
5 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
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Prospective Diabetes Study, a majority of patients with T2DM will initiate
antihyperglycemic agents2. The requirement for an increase in the number of antihyperglycemic
agents is temporally associated with a linear decline in cell function, as assessed by HOMA-
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Therefore it is important to understand the long-term effects of available antihyperglycemic agents on both glycemic regulation and -cell function.
The DPP-4 inhibitors comprise a relatively new class of medications that lower blood glucose 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
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therapies maintain -cell function and mass4, 5 but analogous data on the long-term effects of these therapies in humans are lacking.
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Sitagliptin is a once-daily, oral, selective DPP-4 inhibitor6. Sitagliptin improves fasting and
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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treatment with monotherapy but eventually require combination therapy with two or more
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
6 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.
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Sitagliptin monotherapy Data were pooled from two multicenter, double-blind, randomized studies,
P036, ClinicalTrials.gov NCT00103857)8, 11-13 that were continued for an additional 80 and 50 weeks respectively, to provide a total of 104 weeks (2 years) of assessment in each study. This analysis
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includes results from the subgroup of patients who were not on an AHA at the screening visit, had
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 .
Sitagliptin add-on to metformin therapy Data were pooled from two multicenter, double-blind,
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randomized, add-on to metformin therapy studies, one of 24 week initial duration that was continued for an additional 80 weeks, the other of 104 week duration (P020, Clinical Trials.gov
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NCT0086515, and P024, Clinical Trials.gov NCT00094770)14-16. The analysis includes data from the 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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one of 24-week and the other of 54-week initial duration (P021, ClinicalTrials.gov NCT00087516, and
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
7 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
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Glycemic Rescue and Discontinuation Criteria The studies used in these analyses applied varying glycemic rescue and discontinuation criteria (Table 1). Patients meeting specific glycemic criteria
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were either eligible for glycemic rescue medication or were discontinued from the study.
Statistical Analysis For each efficacy endpoint the statistical analyses were performed using all 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
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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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metformin add-on studies; thus these data were not pooled for this analysis.
8 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
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patients were not included because the patients discontinued prior to the 2-year time point due to
(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 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 (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
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diminished slightly during the course of the studies, but remained well below baseline at Week 104. The fasting P/I ratio (Figure 1D) decreased from baseline and HOMA-(Figure 1E) increased at the
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first measurements after treatment began; for both endpoints, improvements from baseline were generally observed through Week 104.
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adverse experience (Table 2). Data for 33 others were unavailable for a variety of other reasons
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
9 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
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A1C (Figure 2A) and FPG (Figure 2B) within weeks of treatment initiation. These improvements
weeks and remained below baseline through 104 weeks (Figure 2C), while increases in HOMA-
DISCUSSION
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were observed through Week 1(Figure 2D).
Given the chronic and progressive nature of T2DM, the long-
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term efficacy and safety of therapies used by patients with this disease are of increasing interest. Numerous clinical
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studies have demonstrated the therapeutic benefit of sitagliptin as monotherapy or as add-on to a variety of
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diminished slightly during the 2 year period of the analysis. The fasting P/I ratio decreased at 24
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
10
controlled trial comparing sitagliptin to glipizide when either is added on to ongoing metformin therapy, sitagliptin demonstrated similar efficacy, with a lower incidence of
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with glipizide16. Previous publications reported analyses of
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pooled safety and tolerability data from randomized clinical 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 for 2 years. For both regimens, measures of glycemic control
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and -cell function improved following initiation of sitagliptin treatment, with only slight lessening of glycemic efficacy
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hypoglycemia, and weight loss versus weight gain, compared
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
11
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
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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 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 ongoing metformin treatment, the measured improvement in the P/I ratio was less compared with the improvement
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years, suggesting that the effect of sitagliptin therapy,
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
12
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
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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 treatment discontinuation with time, preferentially eliminating individuals who either did not respond well to therapy or whose baseline glycemic parameters were high
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enough that even with significant improvement they
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remained above the thresholds for glycemic rescue or discontinuation from study. It is not clear why all patients do
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maintained an adequate A1C value throughout the entire 104
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
13
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
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With respect to efficacy, it is currently unknown
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whether incretin-based therapies have durability similar to
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 metformin or rosiglitazone, showed the most rapid decline in A1C but also the poorest durability32. In the same study,
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following initiation of therapy.
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
14
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
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stress resulting from continuously increasing demand for
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insulin production in the face of rising insulin resistance,
metabolic and oxidative stress due to increased glycolytic flux resulting from an excessive nutritional state (glucotoxicity,
A
lipotoxicity), and accumulation of amyloid plaques, all of which may eventually lead to chronic, islet-localized
ST
inflammation. Therefore, even antihyperglycemic agents that work by decreasing the workload of -cells would be
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have been proposed33. These include endoplasmic reticulum
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 -
15
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
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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 of efficacy of an antihyperglycemic agent, studies have shown that patients with high A1C values, despite being on
A
antihyperglycemic agents, will become more responsive to
ST
these agents after short-term (4-6 weeks) intensive insulin therapy, once insulin therapy is withdrawn35, 36. Whether incretin-based therapies would more effectively maintain
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tested.
lower blood glucoses levels after short-term, intensive management with insulin, is largely unknown.
16
CONCLUSIONS Once-daily sitagliptin, used as monotherapy or as add-on to metformin therapy, provided long-term
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subset of patients with T2DM who maintained and
Transparency:
Declaration of funding:
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completed treatment during 2-year clinical trials.
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A
These analyses were funded by Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA
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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improvements in glycemic control and -cell function in a
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.
17
Acknowledgments:
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The authors gratefully acknowledge the assistance of Sheila Erespe in submission of the manuscript.
Some of the material reported here was presented at the ADA Scientific Sessions, June 5 - 9, 2009;
References
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New Orleans, Louisiana and at the IDF World Congress October 18 - 22, 2009; Montreal, Canada
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11. Goldstein BJ, Feinglos MN, Lunceford JK, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on
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18. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and
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22. Nonaka K, Kakikawa T, Sato A, et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract
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24. Hermansen K, Kipnes M, Luo E, et al. Efficacy and
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23. Brazg R, Xu L, Dalla MC, et al. Effect of adding
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25. Rosenstock J, Brazg R, Andryuk PJ, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with
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27. Williams-Herman D, Round E, Swern AS, et al. Safety and tolerability of sitagliptin in patients with type 2
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diabetes: a pooled analysis. BMC Endocr Disord
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28. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J
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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
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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.
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32. Kahn SE, Haffner SM, Heise MA, et al. Glycemic
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durability of rosiglitazone, metformin, or glyburide
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monotherapy. N Engl J Med 2006;355:2427-43 33. Halban PA, Polonsky KS, Bowden DW, et al. beta-cell failure in type 2 diabetes: postulated mechanisms and
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31. Williams-Herman D, Swern AS, Davies MJ, et al. In
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
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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
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36. Retnakaran R, Qi Y, Opsteen C, et al. Initial short-term
preservation of beta-cell function with oral antidiabetic
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Metab 2010;12:909-15
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intensive insulin therapy as a strategy for evaluating the
27
Table 1. Glycemic rescue therapy or discontinuation criteria, and numbers of patients excluded from the pooled analysis due to rescue or discontinuation
FPG
FPG
FPG
FPG
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Study
A1C
A1C
Total
> 270 mg/dL
>240 mg/dL
>220 mg/dL
>200 mg/dL
>8.0%
>7.5%
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Protocol
Pooled Studies for Monotherapy Analysis
P036 8, 11, 12
Weeks
0 to 6
> 6 to 12
n=0
n=0
Weeks
Weeks
0 to 6
> 6 to 12
-
n=1
ST
n=1
-
A
P02113
Weeks
Weeks
Weeks
Weeks
> 12 to < 38*
38 to < 54*
54 to 104*
n=6
n=5
n = 27
Weeks
Weeks
Weeks
> 12 to 24
> 24 to 54
> 54 to 104
n=9
n = 14
n = 15
Weeks
Weeks
Weeks
> 12 to < 38*
38 to < 54*
54 to 104*
n = 24
n = 21
n = 69
n = 38
n = 40
Pooled Studies for Add-on to Metformin Analysis
Weeks
Weeks
0 to 6
> 6 to 12
n=1
n=3
Weeks
Weeks
Weeks
Weeks
Weeks
0 to 6*
> 6 to 12*
> 12 to 18*
> 18 to 30*
> 30 to 52*
n=1
n=5
n=7
n = 19
n = 53
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according to these criteria (n), by week.
P020 14
P024 15, 16
-
n = 118
Weeks
> 52 to 104*
n = 163
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
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glycemic criteria in study P024 and at these time points in studies P020 and P021 were discontinued from their respective study.
29
Monotherapy
Add-on Therapy
184
853
64
Excluded from analysis
347
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Included in analysis
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Randomized patients with baseline A1C ≥7.0% and ≤10%
120
506
3
8
45
19
72
479
33
262
Adverse experience
9
48
Consent withdrawn
11
42
Lost to follow-up
6
33
Protocol specified
2
20
Protocol deviation
4
12
Moved
0
No A1C data at Week 104 Initiated glycemic rescue
A
Discontinued without rescue
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Due to: Lack of efficacy
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Table 2. Accounting of patients available for the pooled analysis.
7
ST
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30
Site terminated 0 1
Other 7 54
31
Table 3. Baseline demographic and anthropometric characteristics of patients included Monotherapy
Add-on Therapy
(N = 64)
(N = 347)
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in the pooled analysis.
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Parameter*
32 Age, years
54 (9.5)
56.3 (9.1)
Males, n (%)
40 (62.5)
200 (57.6)
White
33 (51.6)
234 (67.4)
Hispanic
15 (23.4)
32 (9.2)
Asian
8 (12.5)
Black
0 (0.0)
Other
8 (12.5)
Body Weight, kg A1C, %
2
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Body Mass Index, kg/m
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2.8 (3.5)
6.5 (5.9)
82.9 (18.2)
86.1 (16.8)
7.9 (0.7)
7.7 (0.6)
156.0 (35.1)
159.7 (32.5)
A
FPG, mg/dL
43 (12.4)
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Duration of T2DM, years
29.6 (5.4)
*All values are mean (standard deviation) except as noted.
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Race, n (%)
30.6 (4.9)
ST
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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)
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8.0 7.8
7.4 7.2 7.0 6.8 6.6 6.4 6.2 0
20
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A1C, % (LS mean ± SE)
7.6
40
60
80
100
120
100
120
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B.
ST
A
Week
165 160
Fasting Plasma Glucose, mg/dL (LS mean ± SE)
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A.
155 150 145 140 135 130 125 120
0
20
40
60
Week
80
ST
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35
ST
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0.4
D.
0.8
0.6
50
0 0
0
24 54
24
Week 54
104
Week
0.2
0.0
104
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A
Post-meal Glucose, mg/dL (LS mean ± SE)
36
C.
250
200
150
100
ST
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40
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E.
120
100
80
60
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A
37
20
0
0
24
Week
54 104
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).
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8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 0
20
40
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A1C, % (LS mean ± SE)
60
80
ST
A
Week
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A.
100
120
ST
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D. Week
C.
0.8 145
140
135
130
125
120 0 20
0 40 60
24
Week 80
54 100
0.4
0.2
0.0
104 120
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A
Fasting Plasma Glucose, mg/dL (LS mean ± SE)
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39
B.
165
160
155
150
ST
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0 0 24 54
Week 104
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A
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HOMA- (LS mean ± SE)
40
100
80
60
40
