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Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on Glycemic Control in Patients With Type 2 Diabetes PABLO ASCHNER, MD1

MARK S. KIPNES, MD2

JARED K. LUNCEFORD, PHD3

MATILDE SANCHEZ, PHD3

CAROLYN MICKEL, MS3

DEBORA E. WILLIAMS-HERMAN, MD3

FOR THE SITAGLIPTIN STUDY 021 GROUP*

OBJECTIVE — To examine the efficacy and safety of once-daily oral sitagliptin as mono- therapy in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS — In a randomized, double-blind, placebo- controlled study, 741 patients (baseline HbA1c [A1C] 8.0%) were randomized to sitagliptin 100 or 200 mg or placebo for 24 weeks.

RESULTS — Sitagliptin 100 and 200 mg produced significant (P � 0.001) placebo- subtracted reductions in A1C (�0.79 and �0.94%, respectively) and fasting plasma glucose (�1.0 mmol/l [�17.1 mg/dl] and �1.2 mmol/l [�21.3 mg/dl], respectively). Patients with baseline A1C �9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (�1.52 and �1.50%, respectively) than those with baseline A1C �8% (�0.57 and �0.65%) or �8 to �9.0% (�0.80 and �1.13%, respectively). In a meal tolerance test, sitaglip- tin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG �2.6 mmol/l [�46.7 mg/dl] and �3.0 mmol/l [�54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Ho- meostasis model assessment of �-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (�0.2 kg) or 200 mg (�0.1 kg). The body weight change with placebo (�1.1 kg) was significantly (P � 0.01) different from that observed with sitagliptin.

CONCLUSIONS — In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of �-cell function, and was well tolerated in patients with type 2 diabetes.

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T reatments that mimic or enhance the incretin axis are therapeutic ap- proaches for managing type 2 diabe-

tes (1). In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and, in turn, stimulate insulin and sup- press glucagon release (both in a glucose- d e p e n d e n t m a n n e r ) , d e l a y g a s t r i c emptying, and increase satiety (2–5). These incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4) (6). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents (OHAs) (7). By slowing incretin degradation, DPP-4 in- hibitors enhance meal-stimulated active GLP-1 and GIP levels by two- to threefold (8 –10). Studies in animal models of, and in patients with, type 2 diabetes demon- strated that treatment with DPP-4 inhibi- tors improves measures of �-cell function (8,11–13). In rodent models of type 2 di- abetes, both GLP-1 and DPP-4 inhibitors led to �-cell neogenesis and survival (14,15). Long-term studies are required to determine whether these �-cell effects occur in patients with type 2 diabetes.

Sitagliptin, a once-daily, oral, potent, and highly selective DPP-4 inhibitor, in- hibits plasma DPP-4 activity �80% over 24 h with single doses of �100 mg (10). In patients with type 2 diabetes, �80% inhibition of plasma DPP-4 activity with single doses of sitagliptin produced two- to threefold increases in active GLP-1 and GIP levels, increased insulin and C- peptide levels, reduced plasma glucagon levels, and reduced glycemic excursion following an oral glucose tolerance test (9). Two 12-week studies in patients with type 2 diabetes demonstrated that sita- gliptin dose-dependently reduced HbA1c (A1C) and fasting plasma glucose (FPG), with a neutral effect on body weight and incidences of hypoglycemia and gastroin- testinal adverse experiences similar to placebo (16,17).

Sitagliptin 100 mg q.d. was the most effective dose and was selected for contin- ued development. In the present study, we tested once-daily sitagliptin 100 and

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From the 1Colombian Diabetes Association, Bogotá, Colombia; the 2Diabetes & Glandular Disease Research Associates, San Antonio, Texas; and 3Merck Research Laboratories, Rahway, New Jersey.

Address correspondence and reprint requests to Debora Williams-Herman, MD, Merck Research Labo- ratories, RY34-A232, Rahway, NJ 07065. E-mail: [email protected].

Received for publication 31 March 2006 and accepted in revised form 18 September 2006. *A complete list of the Study 021 investigators can be found in the online appendix at http://

care.diabetesjournals.org. Abbreviations: ANC, absolute neutrophil count; APT, all-patients-treated; AUC, area under the glucose

concentration–time curve; DPP-4, dipeptidyl peptidase-4; ECG, electrocardiogram; FPG, fasting plasma glucose; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; HOMA-�, ho- meostasis model assessment of �-cell function; HOMA-IR, HOMA of insulin resistance; OHA, oral antihy- perglycemic agent; PPG, postprandial glucose; QUICKI, quantitative insulin sensitivity check index; WBC, white blood cell.

A table elsewhere in this issue shows conventional and Système Intenational (SI) units and conversion factors for many substances.

DOI: 10.2337/dc06-0703. Clinical trial reg. no. NCT00087516, clinicaltrials.gov. © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby

marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s O R I G I N A L A R T I C L E

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200 mg as monotherapy to explore toler- ability and potential dose-dependent effi- cacy in patients with inadequately controlled type 2 diabetes.

RESEARCH DESIGN AND METHODS — Patients, 18 –75 years of age, on and not on an OHA were eligi- ble. Patients with type 1 diabetes, unsta- ble cardiac disease, significant renal impairment (creatinine clearance �50 ml/min), or elevated (more than twofold the upper limit of normal) alanine amino- transferase, aspartate aminotransferase, or creatine phosphokinase were ex- cluded. Patients received counseling on exercise and a weight-maintenance diet consistent with American Diabetes Asso- ciation recommendations throughout the study.

Patients provided written informed consent. The protocol was reviewed and approved by the appropriate committees and authorities and performed in accor- dance with the Declaration of Helsinki.

This was a multinational, random- ized, double-blind, placebo-controlled study. At screening, patients with an A1C of 7–10% and not on an OHA for �8 weeks were eligible to directly enter a 2-week single-blind placebo run-in pe- riod; patients with A1C �10% and not on an OHA entered a run-in period of up to 6 weeks; patients with an A1C of 6 –10% and on an OHA discontinued the agent and entered a wash-out period of 6 –10 weeks (8 –12 weeks for those on thiazo- lidinediones). If A1C was 7–10% after the wash-out period, patients were eligible to enter the placebo run-in period. Patients with adequate compliance (�75%) dur- ing the placebo run-in period underwent baseline evaluation and were randomized to sitagliptin 100 or 200 mg q.d. or pla- cebo (1:1:1) for 24 weeks.

During the study, patients not meet- ing progressively stricter glycemic goals were provided rescue therapy (met- formin) until study completion. Glycemic rescue criteria were FPG �15.0 mmol/l (270 mg/dl) between randomization (day 1) and week 6, FPG �13.3 mmol/l (240 mg/dl) after week 6 through week 12, or FPG �11.1 mmol/l (200 mg/dl) after week 12 through week 24. The study in- cludes a long-term treatment period be- yond week 24, the results of which will be the subject of a subsequent report.

Study evaluations Efficacy assessments. After an over- night fast, A1C, FPG, insulin, proinsulin,

and fasting lipids were measured at base- line (randomization visit) and during the study. Proinsulin-to-insulin ratio and ho- meostasis model assessment of �-cell function (HOMA-�) assessed �-cell func- tion (18,19); HOMA of insulin resistance (HOMA-IR) and quantitative insulin sen- sitivity check index (QUICKI) assessed insulin resistance (18,20).

A standard meal tolerance test was administered at baseline (before the first dose of study medication) and at weeks 12 and 24. Patients took study medica- tion 30 min before the standard meal, which was ingested within 15 min and consisted of two nutrition bars and one nutrition drink (�680 kcal; 111 g carbo- hydrate, 14 g fat, 26 g protein). Plasma glucose, insulin, and C-peptide concen- trations were measured at 0, 60, and 120 min from the meal start for the determi- nation of 2-h postprandial glucose (PPG), area under the glucose concentration– time curve (AUC), insulin AUC, C- peptide AUC, and the insulin AUC–to– glucose AUC ratio. Safety assessments. Data on adverse ex- periences, physical examinations, vital signs, electrocardiograms (ECGs), and body weight were collected. All adverse experiences were rated by investigators for intensity and relationship to study drug. Laboratory evaluations included complete blood chemistry, hematology, and urinalysis.

Laboratory measurements and ECGs were performed at central laboratories (PPD Global Central Labs, Highland Heights, KY, and Zaventem, Belgium and Covance Central Diagnostics, Reno, NV, respectively) by technicians blinded to treatment group.

Statistical analysis Efficacy analyses were based on the all- patients-treated (APT) population, con- sisting of all randomized patients who received at least one dose of study treat- ment and who had both a baseline and at least one postbaseline measurement. AN- COVA was used to compare treatment groups for continuous efficacy parame- ters, focusing on change from baseline at week 24, with baseline values and prior OHA status as covariates. The between- group differences for efficacy end points were assessed by testing the difference in the least-squares mean change (or per- centage of change) from baseline at week 24. Missing data were handled using the last observation carried forward method. To avoid the confounding influence of

rescue therapy on efficacy comparisons, data collected after initiation of rescue therapy were treated as missing.

The proportion of patients achieving A1C �7% was compared among groups using a logistic regression analysis. Time- to-rescue analysis was performed using the Kaplan-Meier estimate and the log- rank test, and the proportion of patients rescued in each group was summarized. Prespecified subgroup analyses for the primary efficacy end point (A1C) were performed to explore whether treatment effects were consistent among subgroups, which included OHA status at screening (on or not on an OHA), baseline A1C (�8, 8 to �9, or �9%), sex, age (� or �65 years), race, baseline BMI (less than or equal to or more than the median), du- ration of diabetes (less than or equal to or m o r e t h a n t h e m e d i a n ) , b a s e l i n e HOMA-IR (less than or equal to or more than the median), and baseline HOMA-� (less than or equal to or more than the median).

Safety and tolerability were assessed in patients who received at least one dose of study medication by review of safety parameters. For body weight change and the prespecified clinical adverse experi- ences of hypoglycemia and specific gastro- intestinal adverse experiences (abdominal pain, nausea, vomiting, and diarrhea), in- ferential testing was performed for be- tween-group comparisons. Data for body weight change and the incidence of gas- trointestinal adverse experiences ex- cluded data obtained after initiation of rescue therapy.

RESULTS — T h e d i s p o s i t i o n o f screened and randomized patients is shown in online appendix Fig. 1 (avail- able at http://care.diabetesjournals.org). For the 741 patients randomized to treat- ments, groups were generally well- balanced for baseline demographics and efficacy variables. Patients had mild to moderate hyperglycemia with an average baseline A1C of 8.0% (range 6.3–10.9; �54% of patients �8.0%) and FPG of 9.6 mmol/l (173.7 mg/dl). The average dura- tion of known diabetes was 4.4 years; 51% were not on an OHA at screening. After randomization, 639 (86.2%) com- pleted 24 weeks of treatment, and 711 patients (96.0%) were included in the APT analysis. Of 30 patients excluded from the APT analysis, 2 had no baseline data, and 28 had no on-treatment data. More patients in the placebo group (52 [20.6%]) required rescue therapy than in

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the sitagliptin 100-mg (21 [8.8%]) or 200-mg (12 [4.8%]) groups (P � 0.001 for sitagliptin vs. placebo). Time to rescue was significantly longer with sitagliptin versus placebo.

At week 24, sitagliptin 100 and 200 mg significantly (P � 0.001) reduced A1C compared with placebo (between- group differences �0.79% [95% CI �0.96 to �0.62] and �0.94% [�1.11 to �0.77], respectively) (Table 1) without deterioration in the sitagliptin effect throughout 24 weeks (Fig. 1A). The per- centage of patients achieving A1C �7% was 41% with 100 mg and 45% with 200 mg versus 17% for placebo (P � 0.001 for sitagliptin vs. placebo). The effect of sita- gliptin on A1C was consistent across sub- g r o u p s d e fi n e d b y d e m o g r a p h i c , anthropometric, and disease characteris- tics. A significant interaction between baseline A1C and treatment effect was ob- served (P � 0.001), which was consistent with the finding of greater efficacy in pa- tients with higher baseline A1C. In pa- tients with baseline A1C �9%, placebo- subtracted reductions of �1.52 and �1.50% were observed for the 100- and 200-mg treatment groups, respectively (Fig. 1B).

At week 24, sitagliptin treatment led to significant (P � 0.001) between- treatment differences versus placebo in FPG change from baseline of �1.0 mmol/l (�17.1 mg/dl) and �1.2 mmol/l (�21.3 mg/dl) for the 100- and 200-mg

Figure 1—A: A1C (means � SE) over time during the 24-week treatment period for patients treated with sitagliptin 100 or 200 mg q.d. or with placebo. B: Placebo-subtracted least-squares (LS) mean change in A1C from baseline (�SE) by baseline A1C at study end point.

Table 1—Baseline and week 24 mean A1C, FPG, proinsulin-to-insulin ratio, and HOMA-� and least-squares mean change from baseline to study end point with sitagliptin or placebo treatment

n Week 0 (baseline)

mean � SD Week 24

mean � SD Least-squares mean change

from baseline (95% CI)

A1C (%) Placebo 244 8.03 � 0.82 8.20 � 1.37 0.18 (0.06 to 0.30) Sitagliptin 100 mg q.d. 229 8.01 � 0.88 7.39 � 1.15 �0.61 (�0.74 to �0.49)* Sitagliptin 200 mg q.d. 238 8.08 � 0.94 7.31 � 1.14 �0.76 (�0.88 to �0.64)*

FPG (mmol/l) Placebo 247 9.8 � 2.3 10.0 � 3.1 0.3 (�0.0 to 0.5) Sitagliptin 100 mg q.d. 234 9.5 � 2.4 8.8 � 2.5 �0.7 (�1.0 to �0.4)* Sitagliptin 200 mg q.d. 244 9.7 � 2.5 8.7 � 2.6 �0.9 (�1.2 to �0.7)*

Proinsulin-to-insulin ratio Placebo 220 0.44 � 0.30 0.44 � 0.28 �0.01 (�0.04 to 0.02) Sitagliptin 100 mg q.d. 210 0.47 � 0.82 0.37 � 0.25 �0.08 (�0.11 to �0.05)† Sitagliptin 200 mg q.d. 217 0.44 � 0.48 0.34 � 0.22 �0.11 (�0.14 to �0.07)*

HOMA-� Placebo 235 55.8 � 52.1 56.3 � 61.5 0.3 (�6.0 to 6.5) Sitagliptin 100 mg q.d. 218 57.6 � 71.7 70.9 � 91.8 13.2 (6.7 to 19.7)† Sitagliptin 200 mg q.d. 228 55.2 � 53.4 68.4 � 66.3 13.1 (6.8 to 19.5)†

*P � 0.001 for least-squares mean difference for sitagliptin 100 or 200 mg vs. placebo; †P � 0.01 for least-squares mean difference for sitagliptin 100 or 200 mg vs. placebo. P � NS for sitagliptin at 200- vs. 100-mg comparisons. (To convert glucose values from mmol/l to mg/dl, divide by 0.05551.)

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groups, respectively (Table 1). The effects on FPG were maintained over 24 weeks with a slight upward trend starting at week 12 (Fig. 2A).

Both proinsulin-to-insulin ratio and HOMA-� were significantly improved with sitagliptin versus placebo after 24 weeks (Table 1). There were no statisti- cally significant effects on fasting C- peptide, insulin, proinsulin, HOMA-IR, or QUICKI. Sitagliptin had no significant effects on fasting lipids.

At week 24, the reduction in 2-h PPG from baseline was significantly (P � 0.001) greater with sitagliptin 100 mg (�2.7 mmol/l [�48.9 mg/dl]) and 200 mg (�3.1 mmol/l [�56.3 mg/dl]) than with placebo (�0.1 mmol/l [�2.2 mg/ dl]) (online appendix Table 1 and Fig. 2B). Additionally, glucose total AUC was significantly (P � 0.001) decreased with sitagliptin versus placebo. Sitagliptin treatment significantly (P � 0.05) in- creased insulin total AUC, C-peptide total AUC, and ratio of insulin AUC to glucose AUC versus placebo (online appendix Table 1).

Safety and tolerability There were no meaningful differences be- tween groups in incidences of overall clin- ical adverse experiences or of those assessed as serious, drug-related, or lead- ing to discontinuation (Table 2). Three patients had a serious drug-related ad- verse experience (one on placebo [discon- tinued for cholecystitis] and two on sitagliptin 100 mg, including one with

Figure 2—Change in plasma glucose with treatments. A: Fasting plasma glucose (means � SE) over time during the 24-week treatment period for patients treated with sitagliptin 100 or 200 mg q.d. or placebo. B: Plasma glucose response during a meal tolerance test at baseline and week 24 by treatment group (means � SE).

Table 2—Safety summary of adverse experiences

Placebo Sitagliptin 100 mg q.d. Sitagliptin 200 mg q.d.

n 253 238 250 One or more clinical AE 167 (66.0) 157 (66.0) 160 (64.0) Drug-related clinical AE* 19 (7.5) 23 (9.7) 27 (10.8) Clinical SAE 9 (3.6) 12 (5.0) 12 (4.8) Drug-related clinical SAE* 1 (0.4) 2 (0.8) 0 (0) Discontinuation due to AE 4 (1.6) 5 (2.1) 4 (1.6) Discontinuation due to drug-related AE 2 (0.8) 1 (0.4) 0 (0) Discontinuation due to SAE 3 (1.2) 3 (1.3) 3 (1.2) Discontinuation due to drug-related SAE 1 (0.4) 0 (0) 0 (0) Hypoglycemia 2 (0.8) 3 (1.3)† 2 (0.8) Overall gastrointestinal AE‡ 29 (11.5) 39 (16.4) 41 (16.4) Prespecified selected gastrointestinal AE‡

Abdominal pain§ 4 (1.6) 5 (2.1) 3 (1.2) Nausea§ 3 (1.2) 5 (2.1) 10 (4.0) Vomiting§ 3 (1.2) 3 (1.3) 2 (0.8) Diarrhea§ 6 (2.4) 11 (4.6) 10 (4.0)

Data are n (%). *Considered by investigator as possibly, probably, or definitely related to study drug; †includes one hypoglycemia episode occurring after initiation of glycemic rescue therapy (metformin); ‡excludes adverse experiences after initiating glycemic rescue therapy (metformin). §P � 0.05 for sitagliptin (100 or 200 mg) vs. placebo. AE, adverse experience; SAE, serious adverse experience.

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mild nonalcoholic steatohepatitis with in- creased hepatic enzymes noted at discon- tinuation and one with mild diarrhea meeting criteria for a serious event due to temporal association with an overdose of two 100-mg tablets). Two other patients were discontinued for drug-related ad- verse experiences (one on placebo [tachy- cardia] and one on sitagliptin 100 mg [depression]).

The incidence of specific adverse ex- periences was generally similar across treatment groups. For specific adverse ex- periences with an incidence �2% in any treatment group, relatively few (constipa- tion, nasopharyngitis, pharyngitis, phar- y n g o l a r y n g e a l p a i n , u r i n a r y t r a c t infection, myalgia, arthralgia, hyperten- sion, and dizziness) had a slightly higher incidence in one or both sitagliptin groups versus placebo (online appendix Table 2). None of the above adverse experiences re- sulted in study drug discontinuation.

The incidence of hypoglycemia was similar among groups (Table 2). No epi- sode of hypoglycemia exhibited marked severity (i.e., loss of consciousness or re- quirement for medical assistance). The proportion of patients reporting gastroin- testinal adverse experiences was slightly higher with sitagliptin versus placebo, but for the prespecified specific gastrointesti- nal adverse experiences, the incidences were not statistically significant between groups (Table 2).

For laboratory adverse experiences, there were no statistically or clinically meaningful differences among groups, and only a few specific laboratory adverse experiences had an incidence �2% in any treatment group (online appendix Table 2). At 24 weeks, mean percentages of change in white blood cells (WBCs) were 4.7, 4.2, and 0.6% in the 100-mg treat- ment, 200-mg treatment, and placebo groups, respectively. These small, non- progressive increases in WBCs were mainly accounted for by small increases in absolute neutrophil counts (ANCs) (mean change � SD) of 330 � 91, 255 � 89, and 36 � 85 cells/�l in the 100-mg treatment, 200-mg treatment, and pla- cebo groups, respectively. The incidence of patients with laboratory values meeting predefined limits of change for increases in ANC (last measured value on treatment with increase �20% above the upper limit of normal) was similar in the 100- and 200-mg treatment groups versus pla- cebo (0.9, 0.8, and 0.4%, respectively). A small mean decrease in alkaline phospha- tase was found with sitagliptin treatment

(�3.8 and �3.3 IU/ml with 100 and 200 mg, respectively) versus placebo. A small mean increase from baseline of �0.2 mg/dl in uric acid was observed with sita- gliptin versus placebo. No meaningful differences among groups were observed in mean changes or occurrences of pre- specified elevations in alanine amino- transferase, aspartate aminotransferase, or creatine phosphokinase. No meaning- ful differences were observed in vital signs or in mean changes in ECG data.

After 24 weeks, sitagliptin 100 and 200 mg had a neutral effect on body weight relative to baseline (change from baseline � SE �0.2 � 0.2 and �0.1 � 0 . 2 k g , r e s p e c t i v e l y ) . T h e c h a n g e (�1.1 � 0.2 kg) in the placebo group was significantly (P � 0.01) different from that observed with sitagliptin.

CONCLUSIONS — This study was performed to provide an assessment of the efficacy and tolerability of sitagliptin at doses of 100 and 200 mg once daily as monotherapy in patients with type 2 dia- betes with inadequate glycemic control on diet and exercise. Treatment with sita- gliptin provided clinically meaningful re- ductions in A1C, FPG, and 2-h PPG compared with placebo. Results for these key efficacy parameters were not signifi- cantly different between sitagliptin doses. A general persistence of response for both A1C and FPG reduction over 24 weeks was observed in both sitagliptin groups. The improvements in 2-h PPG and glu- cose AUC after a standard meal, com- bined with the improvement in FPG, show that sitagliptin provides clinically important glucose lowering in both the fasting and postprandial states.

Sitagliptin treatment increased the proportion of patients achieving the gly- cemic goal of A1C �7% (21), led to fewer patients requiring glycemic rescue ther- apy, and extended the time to rescue ver- sus placebo. Sitagliptin lowered A1C consistently across subgroups defined by demographic, anthropometric, and dis- ease characteristics. As with other antihy- perglycemic agents, sitagliptin lowered A1C more in patients with higher baseline A1C, with a 1.5% reduction in patients with a baseline A1C �9%.

The increases in HOMA-� and in the amount of insulin secreted relative to glu- cose levels during a meal tolerance test and the reduction in the proinsulin-to- insulin ratio support the conclusion that sitagliptin improved �-cell function. Poorly functioning �-cells in patients

with type 2 diabetes secrete greater amounts of proinsulin relative to insulin, and a decline in this ratio has been sug- gested to be a marker of improved �-cell function (22). Other DPP-4 inhibitors have also been reported to improve �-cell function in patients with type 2 diabetes (8,11) and in animal models (12–14).

Sitagliptin had no effect on indexes of i n s u l i n r e s i s t a n c e a n d s e n s i t i v i t y (HOMA-IR and QUICKI), consistent with incretin studies demonstrating small, in- consistent effects on insulin sensitivity (23). Studies using more sensitive, direct measures are needed to further evaluate these findings.

Increased body weight observed with OHAs (24) is generally an undesired ef- fect. After 24 weeks, treatment with sita- gliptin had a neutral effect on body weight relative to baseline, consistent with re- sults from earlier studies (16,17). The small, significant weight loss observed with placebo likely reflected less adequate glycemic control.

Overall assessment of safety demon- strated that both sitagliptin doses were well tolerated in this study. No meaning- ful differences were found in the adverse experience profiles between sitagliptin and placebo treatments. There was a very low incidence of hypoglycemia with sita- gliptin that was similar to placebo and consistent with the glucose-dependent ef- fects of incretins (2). Slightly higher, but not statistically significant, incidences of nausea, constipation, diarrhea, and naso- pharyngitis/pharyngitis were reported with sitagliptin, but these events were generally mild or moderate, self-limited, and not temporally related to initiation of study medication.

Sitagliptin did not lead to changes in hepatic or muscle enzymes. A small de- crease in alkaline phosphatase was ob- served, which is unlikely to be clinically meaningful. Very small increases in WBCs and ANCs were observed. These changes were nonprogressive, not associ- ated with increased reports of laboratory adverse experiences, and were thus un- likely to be clinically meaningful. Sitaglip- tin had no effect on fasting lipids.

Lastly, while efficacy end points in this study generally showed trends toward greater improvement in the 200- compared with the 100-mg group, treat- ment with 200 mg tended to be less effective than with 100 mg in a similarly designed 18-week monotherapy study (25). Collectively, these data suggest the 100- and 200-mg doses are similarly effi-

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2636 DIABETES CARE, VOLUME 29, NUMBER 12, DECEMBER 2006

cacious. This conclusion is supported by modeling of pharmacokinetic and phar- macodynamic data in patients with type 2 diabetes predicting that sitagliptin 100 mg would provide optimal 24-h inhibi- tion of DPP-4 activity (i.e., �80%) in or- der to increase active incretin levels greater than twofold and produce signifi- cant glucose lowering following an oral glucose tolerance test (9).

In conclusion, in this 24-week study, once-daily sitagliptin monotherapy pro- vided effective glycemic control in both the fasting and postprandial states in pa- tients with type 2 diabetes. Sitagliptin produced significant improvements in in- dexes of insulin release and �-cell func- tion. Sitagliptin was generally well tolerated, with a rate of hypoglycemia similar to placebo and a neutral effect on body weight relative to baseline.

Acknowledgments — This study was spon- sored by Merck, Whitehouse Station, New Jer- sey.

The authors thank Dr. Michael J. Davies (Merck Research Laboratories) for his contri- bution in writing this article.

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