The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes*
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1 Journal of Diabetes 4 (2012) ORIGINAL ARTICLE The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes* Wenying YANG, 1 Yanfen GUAN, 2 Yue SHENTU, 2 Zhi LI, 3 Amy O. JOHNSON-LEVONAS, 2 Samuel S. ENGEL, 2 Keith D. KAUFMAN, 2 Barry J. GOLDSTEIN 2 and Maria ALBA 2à 1 China Japan Friendship Hospital, Beijing, China, 2 Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey, USA and 3 MSD China, Shanghai, China Correspondence Samuel S. Engel, Merck Sharp & Dohme Corp., RY34A-232, 126 E. Lincoln Ave, Rahway, NJ 07065, USA. Tel: Fax: samuel.engel@merck.com *This study has been registered with Clinicaltrials.gov (registration no.: NCT ). Core Protocol for this paper can be found in Supporting Information Data S1. à Present address: Janssen R&D, Raritan, NJ, USA. Received 22 February 2012; revised 19 May 2012; accepted 1 June doi: /j x Abstract Background: The present study was conducted to evaluate the efficacy, safety and tolerability of sitagliptin added to ongoing metformin therapy in Chinese patients with type 2 diabetes (T2DM) who failed to achieve adequate glycemic control with metformin monotherapy. Methods: After a metformin titration stabilization period and a 2-week, single-blind, placebo run-in period, 395 Chinese patients with T2DM aged years (baseline HbA1c 8.5%) were randomized (1:1) to double-blind placebo or sitagliptin 100 mg q.d. added to ongoing open-label metformin (1000 or 1700 mg day) for 24 weeks. Results: Significant (P < 0.001) changes from baseline in HbA1c ()0.9%), fasting plasma glucose ()1.2 mmol L), and 2-h post-meal plasma glucose ()1.9 mmol L) were seen with sitagliptin compared with placebo. There were no significant differences between sitagliptin and placebo in the incidence of hypoglycemia or gastrointestinal adverse events. A small decrease from baseline body weight was observed in the placebo group compared with no change in the sitagliptin group (between-group difference 0.5 kg; P = 0.018). Conclusions: The addition of sitagliptin 100 mg to ongoing metformin therapy significantly improved glycemic control and was generally well tolerated in Chinese patients with T2DM who had inadequate glycemic control on metformin alone. Keywords: glycemic control, sitagliptin, type 2 diabetes. Significant findings of the study: Substantial and consistent placebo-adjusted reductions in HbA1c were observed across the study strata defined by concomitant use of metformin doses of 1000 or 1700 mg day, gender, age, baseline body mass index, duration of disease, baseline HbA1c, and prior use of antihyperglycemic medications. What this study adds: Treatment of T2DM with a combination of sitagliptin plus metformin has not been studied previously in Chinese patients. Sitagliptin 100 mg once daily added to metformin significantly improved glycemic control for Chinese patients with inadequate glycemic control on metformin monotherapy. Introduction Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that arises from insulin resistance, reduced insulin secretion, and increased hepatic glucose output. 1 Monotherapy with metformin, a biguanide agent that primarily acts to lower hepatic glucose output, 2,3 is the most widely prescribed first-line oral ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 227
2 Sitagliptin + metformin in Chinese patients W. YANG et al. antihyperglycemic agent (AHA). However, monotherapy with metformin is often unsuccessful at achieving or maintaining adequate glycemic control. 4,5 Indeed, patients who initially respond to metformin monotherapy frequently require additional agents over time to maintain glycemic control due to the progressive nature of T2DM. 5 9 The incretin peptide hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) stimulate glucose-dependent release of insulin. In addition, GLP-1 suppresses the release of glucagon from the pancreas. Under physiological conditions, these incretins are rapidly inactivated by the enzyme dipeptidyl peptidase (DPP) Sitagliptin is an orally active and highly selective DPP-4 inhibitor that prevents the enzymatic degradation and inactivation of GLP-1 and GIP Sitagliptin increases insulin release and lowers glucagon secretion in a glucose-dependent manner, thereby posing minimal risk for hypoglycemia when administered as either monotherapy or in combination with agents not known to cause hypoglycemia. 8,16 20 The combined use of sitagliptin and metformin has been shown to be an effective and well-tolerated treatment in patients with T2DM. 6,8,9,17,19,21 27 Several studies have demonstrated the additive glycemic efficacy of combination therapy with sitagliptin and metformin compared with metformin alone; 6,8,17,19 the glycemic effects were durable, and the combination with metformin was generally well tolerated for up to 2 years of treatment. 9,27 Over the past several decades, the prevalence of T2DM has increased rapidly in China and other Asian countries. 28 In addition, many patients in these regions do not achieve optimal glycemic control with currently available antihyperglycemic therapies. 29 A recent study demonstrated that sitagliptin as monotherapy is effective, well tolerated, and improves b-cell function in Chinese patients with T2DM. 30 Treatment of T2DM with a combination of sitagliptin and metformin has not been studied previously in patients from China. The purpose of the present study was to evaluate the efficacy, safety and tolerability of adding sitagliptin to ongoing metformin therapy in Chinese patients with T2DM who failed to achieve adequate glycemic control with metformin monotherapy. Methods Patients Eligible participants included Chinese men and women (18 78 years of age) with T2DM and inadequate glycemic control (i.e. HbA1c 7.5% and 11.0%) while taking metformin monotherapy at a stable dose of 1000 or 1700 mg day (500 or 850 mg twice daily) either at the time of entry into the study or after a metformin dose stabilization, AHA washout, run-in period. Patients who were taking metformin monotherapy or metformin-based dual combination therapy (i.e. metformin in combination with any AHA, except for a peroxisome proliferator-activated receptor [PPAR] c agent), were eligible to participate in the study if their HbA1c level met the screening criteria (i.e. HbA1c 7.5% and 11.0% for metformin monotherapy or 7.0% and 9.0% for metformin-based dual combination therapy). Key exclusion criteria included diagnosis of type 1 diabetes, a history of diabetic ketoacidosis, active liver or gallbladder disease, congestive heart failure, unstable coronary heart disease, elevated liver enzymes (i.e. more than twofold the upper limit of normal), pregnancy, breastfeeding, or any contraindication for the use of metformin. Other AHAs were prohibited during the study. Study design The present study was a multicenter, randomized, double-blind, parallel-group clinical trial (Merck Protocol MK-0431 P074; Clinicaltrials.gov: NCT ) consisting of a 1-week screening period (Visits 1 2), an up to 9-week metformin up-titration dose stabilization and diet exercise period (Visits 2 and 3), a 2-week single-blind placebo run-in period (Visit 3 4), and a 24-week placebo-controlled treatment period (Visits 4 8). The study was conducted between 13 January 2009 and 9 August 2010 at 17 sites in China in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All patients provided written informed consent before the initiation of any study procedures. The institutional review board or independent ethics committee for each study site approved the final protocol and informed consent form. Patients who were already taking a stable (i.e. 10 weeks prior to screening) metformin dose of 1000 or 1700 mg day and had a screening HbA1c 7.5% and 11% continued to receive their metformin dose in an open-label manner and directly entered the 2-week, single-blind, placebo run-in period. Patients taking metformin at doses other than 1000 or 1700 mg daily entered a metformin up-titration dose-stabilization, diet and exercise period of up to 9 weeks. Patients on metformin-based dual oral combination therapy were allowed to enter the metformin up-titration dose-stabilization period after discontinuation of the second oral AHA. 228 ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
3 W. YANG et al. Sitagliptin + metformin in Chinese patients After the metformin up-titration stabilization and diet exercise period, patients entered the 2-week placebo run-in period and were randomized if they continued to meet inclusion criteria. Eligible patients were stratified by metformin dose (1000 or 1700 mg daily) and randomized in a 1:1 ratio per a computer-generated schedule to receive either placebo or sitagliptin 100 mg once daily for 24 weeks in addition to their ongoing stable metformin dose. Approximately 49% and 51% of patients were taking 1000 and 1700 mg metformin daily, respectively. During the 24-week double-blind treatment period, patients continued to receive counseling on exercise and a weight management diet consistent with American Diabetes Association recommendations (see accessed 13 June 2012). Patients not meeting progressively stricter glycemic goals were required to initiate rescue therapy with open-label glipizide (titrated at the investigator s discretion) if fasting plasma glucose (FPG) exceeded specific criteria as follows: >15.0 mmol L after Day 1 and up to Week 6; >13.3 mmol L after Week 6 and up to Week 12; and >11.1 mmol L after Week 12. Study endpoints Efficacy assessments The primary efficacy endpoint was change from baseline at Week 24 in HbA1c in the entire cohort. Secondary endpoints included changes from baseline in HbA1c for the individual metformin dose strata and changes from baseline in 2-h post-meal glucose (2-h PMG) and FPG at Week 24 for the entire cohort. Other key endpoints for the entire cohort included the proportions of patients with HbA1c at the goals of <7.0% and <6.5%, changes from baseline in fasting insulin, homeostasis model assessment of insulin resistance of b-cell function (HOMA-b), homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI), as well as the percentage change from baseline in lipids (i.e. total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TG]) at Week 24. All laboratory assays were performed by technicians blinded to treatment assignment at a central laboratory (Covance Pharmaceutical R&D [Beijing], Shanghai, China). HbA1c was determined by HPLC; FPG was determined by the hexokinase method (Roche Diagnostics, Basel, Switzerland); serum insulin was determined using a chemiluminescence assay (Elecsys 2010; Roche Diagnostics); plasma TGs were measured by enzymatic determination of glycerol (Roche Diagnostics); and plasma TC was quantified enzymatically (Roche Diagnostics). After selective removal of apolipoprotein B-containing lipoproteins by heparin and manganese chloride precipitation for HDL isolation, plasma HDL-C was quantified enzymatically (Roche Diagnostics); LDL-C was calculated using the Friedewald equation. 31 Safety assessment Visits included assessment of vital signs, physical examinations, adverse events, and laboratory assessments. All adverse events were rated by the investigators as mild, moderate, or severe for intensity as well as for duration, outcome, and relationship to study drug. Predefined safety endpoints of interest included hypoglycemia, body weight, and selected gastrointestinal adverse events (i.e. abdominal pain, nausea, vomiting, diarrhea). Laboratory safety data were collected during the study and included blood chemistry measurements, complete blood cell count, and urinalysis. Patients were counseled to self-monitor their blood glucose levels and immediately notify investigators if they experienced symptoms of hypoglycemia, such as sweating, anxiety, and palpitations, for assessment of hypoglycemic events during the study. Hypoglycemia was assessed by the study site investigators by reviewing patient self-reports of signs and symptoms of hypoglycemia. A fingerstick blood glucose determination was not required to support the documentation of a symptomatic episode of hypoglycemia, but was required to report an episode of asymptomatic hypoglycemia. Patients were instructed to also report episodes of asymptomatic low blood glucose levels (i.e. 3.9 mmol L). Statistical analyses Efficacy analyses were performed on the full analysis set defined separately for each endpoint as all randomized patients who received at least one dose of study drug and who had both a baseline measurement and at least one post-baseline measurement of the respective endpoint prior to initiation of glycemic rescue medication. The change in HbA1c and percentage change in lipids from baseline at Week 24 were analyzed using an analysis of covariance (ancova) model, controlling for treatment, study center, metformin stratum (i.e or 1700 mg day), and the baseline value of the respective endpoint. The proportions of patients meeting HbA1c goals (<7.0% and <6.5%) at Week 24 were analyzed using ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 229
4 Sitagliptin + metformin in Chinese patients W. YANG et al. a logistic regression model analogous to the ancova model above. Percentage change from baseline in TG was analyzed using a non-parametric ancova model using ranks based on Tukey s normalized scores and model terms analogous to the ancova model above. Within-group effects for TG were estimated using medians, whereas between-group differences were estimated using the Hodges Lehmann estimate with a corresponding distribution-free 95% confidence interval (CI) based on Wilcoxon s rank sum test. The lastobservation-carried-forward method was used to impute missing data for all efficacy analyses. P < was considered significant. Multiplicity adjustments were made to control the type I error rate across the key efficacy endpoints. If the P-value for the test of change from baseline in HbA1c for the entire study cohort was <0.050 (twosided), then testing of change from baseline in HbA1c was to continue for each individual metformin stratum, using the Hochberg procedure, 32 and testing of change from baseline in 2-h PMG and FPG was to proceed using an ordered testing procedure. Prespecified subgroup analyses of change from baseline in HbA1c were performed to explore the consistency of the treatment effect across subgroups defined by gender, age (<65 or 65 years), metformin dose level, baseline body mass index (BMI; >median or median), baseline HbA1c (>median or median), prior AHA therapy, and known duration of T2DM. Safety analyses included the all-patients-as-treated population consisting of all patients who took at least one dose of study drug. Change from baseline in body weight was analyzed using the same ancova model used for efficacy analyses. For other adverse events and predefined limits of changes in laboratory variables, analyses of the proportions of patients with one or more events were performed using the method of Miettinen and Nurminen. 33 To avoid the confounding influence of glycemic rescue therapy, data obtained after the initiation of rescue therapy were treated as missing in all analyses. Results Patient demographics and disposition The overall patient disposition is shown in Figure 1. Of the 972 patients screened, 395 were randomized to the addition of either once-daily sitagliptin 100 mg (n = 197) or placebo (n = 198) to ongoing metformin therapy dose. The demographic, anthropometric, and disease characteristics of randomized patients were similar across the two treatment groups (Table 1). At Figure 1 Patient disposition. *Including one patient who discontinued due to an adverse experience that started before randomization. AE, adverse event. Table 1 Baseline demographics and disease characteristics of randomized patients Sitagliptin 100 mg Placebo n Age (years) 54.1 ± ± 9.8 Gender No. men 92 (47%) 108 (55%) No. women 105 (53%) 90 (45%) Body weight (kg) 67.9 ± ± 13.3 BMI (kg m 2 ) 25.3 ± ± 3.6 Known duration 6.4 ± ± 4.6 of T2DM (years) HbA1c % (range) 8.5 ± 0.9 ( ) 8.5 ± 0.9 ( ) HbA1c distribution at baseline <8% 72 (36%) 72 (36%) >8 to <9% 76 (39%) 69 (35%) >9% to <10% 33 (17%) 43 (22%) >10% 16 (8%) 14 (7%) FPG (mmol L) 9.6 ± ± h PMG (mmol L) 14.3 ± ± 3.5 Metformin dose 1000 mg day 95 (48%) 100 (51%) 1700 mg day 102 (52%) 98 (49%) Data are expressed as the mean ± SD or as the number of patients in each group with percentages given in parentheses. BMI, body mass index; FPG, fasting plasma glucose; PMG, post meal glucose; T2DM, type 2 diabetes mellitus. 230 ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
5 W. YANG et al. Sitagliptin + metformin in Chinese patients baseline, patients had an average HbA1c of 8.5% (range 6.2% 11.4%), with a mean ± SD baseline FPG of 9.6 ± 2.2 mmol L. Of the 395 randomized patients, 356 (90.1%) completed the 24-week study. The number of patients in the sitagliptin and placebo groups discontinuing prior to study completion was 23 (11.7%) and 16 (8.1%), respectively. Reasons for discontinuation were generally similar across treatment groups (Fig. 1). The rates of treatment compliance were similar in both groups, with an overall mean of 99% over the 24-week study. Glycemic efficacy At Week 24, the addition of sitagliptin 100 mg once daily to ongoing metformin monotherapy resulted in significant (P < 0.001) reductions in HbA1c compared with placebo (Table 2). For the entire cohort, the placebo-adjusted least squares (LS) mean change from baseline in HbA1c was )0.9% at Week 24. The time course of HbA1c reduction reached a nadir at Week 18 and was generally stable for the remainder of the study (Fig. 2a). The placebo-adjusted changes from baseline in HbA1c at Week 24 were )0.8% (95% CI )1.1, )0.5) and )0.9% (95% CI )1.2, )0.7) for the metformin 1000 and 1700 mg day strata, respectively (P < vs placebo for both metformin dose strata; Table 3). The placebo-adjusted reductions in HbA1c were generally consistent across other patient subgroups (Fig. 3). A significantly greater proportion of patients in the sitagliptin group met the HbA1c goals of <7.0% and <6.5% compared with the placebo group (P < for both HbA1c goals; Fig. 4). The odds ratios for the likelihood of meeting HbA1c goals <7.0% and <6.5% with sitagliptin compared with placebo were 6.2 (95% CI 3.2, 11.9) and 6.0 (95% CI 2.3, 15.5). The addition of sitagliptin to ongoing metformin therapy also resulted in significant between-group reductions from baseline in FPG and 2-h PMG at Week 24 (Table 2; P < for both parameters). The LS mean placebo-adjusted changes from baseline in FPG and 2-h PMG were )1.2 mmol L (95% CI )1.6, )0.7) and )1.9 mmol L (95% CI )2.5, )1.2), respectively. The FPG-lowering effect reached a nadir at Week 6 and remained generally stable for the remainder of the study (Fig. 2b). Indices of b-cell function and insulin sensitivity For fasting serum insulin and HOMA-b, numerically larger increases from baseline were observed in the Table 2 Baseline and change from baseline in glycemic endpoints at Week 24 Sitagliptin 100 mg Placebo HbA1c (%) n Baseline 8.5 ± ± 0.9 Change from baseline )1.0 ()1.2, )0.9) )0.1 ()0.3, 0.0) Difference vs placebo )0.9** ()1.1, )0.7) ) 2-h PMG (mmol L) n Baseline 14.1 ± ± 3.3 Change from baseline )2.4 ()2.9, )2.0) )0.6 ()1.0, )0.1) Difference versus placebo )1.9** ()2.5, )1.2) ) FPG (mmol L) n Baseline 9.6 ± ± 2.2 Change from baseline )1.1 ()1.5, )0.8) 0.0 ()0.3,0.4) Difference versus placebo )1.2** ()1.6, )0.7) ) Fasting serum insulin (pmol L) n Baseline 44.0 ± ± 51.6 Change from baseline 3.0 ()3.2, 9.2) )0.6 ()6.9,5.8) Difference versus placebo 3.5 ()4.8, 11.9) ) HOMA-b n Baseline 24.3 ± ± 43.8 Change from baseline 6.3 (0.4, 12.1) 1.7 ()4.3, 7.7) Difference versus placebo 4.6 ()3.3, 12.4) ) HOMA-IR n Baseline 2.7 ± ± 2.7 Change from baseline )0.1 ()0.4, 0.3) )0.1 ()0.5, 0.3) Difference versus placebo 0.0 ()0.5, 0.5) ) QUICKI n Baseline ± ± Change from baseline (0.001, 0.010) Difference versus placebo ()0.005, 0.007) (0.000, 0.010) Baseline data are expressed as the mean ± SD; changes from baseline and differences compared with placebo are given as the least squares mean with 95% confidence intervals in parentheses. **P < compared with placebo. Full analysis set population. FPG, fasting plasma glucose; HOMA-b, homeostatic model assessment of b-cell function; HOMA-IR, homeostasis model assessment of insulin resistance; PMG, post-meal glucose; QUICKI, quantitative insulin sensitivity check index. sitagliptin compared with the placebo group; however, the between-group difference was not statistically significant (Table 2). There were no meaningful within- or between-group differences in indices of ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 231
6 Sitagliptin + metformin in Chinese patients W. YANG et al. (a) (b) Figure 2 Changes from baseline in (a) HbA1c and (b) fasting plasma glucose (FPG) over time in the 100 mg sitagliptin + metformin (d) and placebo + metformin (,) groups. Data are the least squares mean ± SE. Figure 3 Difference in HbA1c (%) least squares (LS) mean change from baseline at Week 24 by subgroup categories relative to LS mean change for all patients (vertical line). The n values in parentheses show the number of patients in the sitagliptin group, number of patients in the placebo group. BMI, body mass index. group required rescue therapy compared with 20 of 198 (10%) in the placebo group. insulin sensitivity (i.e. QUICKI and HOMA-IR) at Week 24. Use of glycemic rescue therapy Consistent with the significantly greater improvement in glycemic control, patients in the sitagliptin group had a significantly (P < 0.001) lower rate of requiring glipizide rescue therapy compared with the placebo group. Three of 197 (2%) patients in the sitagliptin Lipids There were no significant between-group differences in any of the lipid parameters at Week 24 (see Table S1 available as Supplementary Material to this paper). Safety and tolerability The addition of sitagliptin to ongoing therapy with metformin was generally well tolerated in Chinese patients with T2DM. Over the 24-week treatment period, the Table 3 HbA1c levels according to metformin stratum Metformin 1000 mg day Sitagliptin 100 mg Placebo Metformin 1700 mg day Sitagliptin 100 mg Placebo HbA1c (%) n Baseline 8.3 ± ± ± ± 0.9 Change from baseline )0.8 ()1.1, )0.6) )0.0 ()0.2, 0.2) )1.1 ()1.4, )0.9) )0.2 ()0.4, 0.0) Difference versus placebo )0.8 ()1.1, )0.5)** )0.9** ()1.2, )0.7) Baseline data are expressed as the mean ± SD; changes from baseline and differences compared with placebo are given as the least squares mean with 95% confidence intervals in parentheses. **P < compared with placebo. 232 ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
7 W. YANG et al. Sitagliptin + metformin in Chinese patients Table 4 Adverse events, including Tier 1 adverse events, for the entire cohort No. patients (%) Sitagliptin 100 mg Placebo Difference versus placebo (95% CI) Figure 4 The percentage of patients in the entire cohort meeting specified HbA1c goals at Week 24. Numbers inside the columns represent the number of patients achieving the specified goal number of patients with data available. **P < compared with placebo. (n), 100 mg sitagliptin + metformin; (h), placebo + metformin. One or more AE 56 (28.4) 60 (30.3) )2.0 ()10.9, 7.0) Drug-related AE* 12 (6.1) 8 (4.0) 2.1 ()2.4, 6.8) SAE 7 (3.6) 5 (2.5) 1.0 ()2.7, 5.0) Drug-related SAE* 0 (0) 1 (0.5) à Deaths 0 (0) 0 (0) à Discontinued 8 (4.1) 4 (2.0) 2.0 ()1.5, 6.0) due to AE Discontinued due to 3 (1.5) 1 (0.5) à drug-related AE Discontinued 6 (3.0) 1 (0.5) 2.5 ()0.1, 6.0) due to SAE Discontinued due to 0 (0) 0 (0) à drug-related SAE Hypoglycemia 1 (0.5) 3 (1.5) )1.1 ()4.0,1.4) All gastrointestinal AE 8 (4.1) 5 (2.5) 1.5 ()2.4, 5.6) Prespecified gastrointestinal AE Abdominal pain 3 (1.5) 0 (0.0) 1.5 ()0.4, 4.4) Diarrhea 4 (2.0) 1 (0.5) 1.5 ()1.0, 4.6) Nausea 0 (0.0) 0 (0.0) à Vomiting 1 (0.5) 0 (0.0) 0.5 ()1.4, 2.8) *Drug-related adverse events (AE) and serious adverse events (SAE) are those considered by the study investigator to be possibly, probably, or definitely drug related. Includes lower abdominal pain, upper abdominal pain, abdominal pain, abdominal discomfort, and epigastric pain. à Estimate of difference versus placebo (95% CI) was not evaluated per the statistical analysis plan All hypoglycemic events reported in the present study were symptomatic (i.e. episode with clinical symptoms attributed to hypoglycemia, without regard to glucose level); none of these episodes was severe (i.e. none required medical or non-medical assistance). CI, confidence interval. incidence of overall adverse events was similar across both groups for the entire cohort (28% vs 30% for sitagliptin and placebo, respectively; Table 4). The incidence of adverse events classified by system organ class (SOC) was generally low and similar between the treatment groups (Table S2). The one exception was the finding of an overall higher incidence of adverse events in the Investigations SOC in the placebo group compared with the sitagliptin group, due mainly to a higher incidence of the specific adverse event of blood glucose increased. Drug-related adverse events (6% vs 4%), adverse events leading to discontinuation (4% vs 2%), and serious adverse events leading to discontinuation (3% vs 1%) were slightly higher in the sitagliptin group than in the placebo group (Table 4). All 95% CI around the between-group differences for these groupings of adverse events included zero. These numerical trends were driven mainly by patients in the metformin 1700 mg day stratum (Table S3). In contrast, similar incidences of these groupings of adverse events were observed across both treatment groups in the metformin 1000 mg day stratum. The overall percentage of adverse events was low and no particular pattern for any specific type of adverse event was identified either across the treatment groups or metformin strata. No deaths were reported during the 24-week treatment period. Hypoglycemia, regardless of whether designated as an adverse event by the study investigator, and selected gastrointestinal adverse events (abdominal pain, diarrhea, nausea, and vomiting) were prespecified as Tier 1 safety parameters of interest in the present study. The incidence of patients with at least one episode of hypoglycemia in the entire cohort was numerically lower in the sitagliptin group compared with the placebo group (Table 4). All reported hypoglycemic episodes occurred in the metformin 1700 mg day stratum (Table S3) and were mild in intensity, with none leading to discontinuation. None of the episodes required medical or non-medical assistance or exhibited signs of marked severity (e.g. markedly depressed level of consciousness, loss of consciousness, or seizures). The incidence of overall gastrointestinal adverse events was 4% in the sitagliptin group and 3% in the placebo group for the entire cohort (Table 4). The most frequently reported gastrointestinal adverse event in each group was diarrhea (Table 4). In the metformin 1000 mg day stratum, the incidence of selected ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 233
8 Sitagliptin + metformin in Chinese patients W. YANG et al. gastrointestinal adverse events was low, with one patient in the sitagliptin group and none in the placebo group experiencing abdominal pain, and one patient in each group experiencing diarrhea (Table S3). In the metformin 1700 mg day stratum, the incidence of selected gastrointestinal adverse events of abdominal pain and diarrhea was numerically higher in the sitagliptin group compared with the placebo group. No clinically meaningful differences between the groups were observed with respect to changes from baseline in blood pressure or other vital signs. At Week 24, a change from baseline in body weight of )0.5 kg (95% CI )0.9, )0.1) was observed in the placebo group compared with 0.0 kg (95% CI )0.3, 0.4) in the sitagliptin group, resulting in a between-group difference of 0.5 kg (95% CI 0.1, 0.9; P = 0.018) for the overall cohort. Within the metformin 1000 mg day stratum, small numerically similar changes from baseline were seen in body weight in both the sitagliptin ()0.1 kg) and placebo ()0.2 kg) groups at Week 24. Within the metformin 1700 mg day stratum, a small increase (0.2 kg) in body weight was observed in the sitagliptin group compared with a modest reduction ()0.7 kg) in the placebo group at Week 24. Discussion In the present study, Chinese patients with T2DM and inadequate glycemic control (defined as an HbA1c 7.5% and 11%; mean baseline HbA1c = 8.5%) while on a stable dose of metformin monotherapy (i.e or 1700 mg day) randomized to the addition of sitagliptin 100 mg to ongoing open-label metformin therapy had a significant, clinically meaningful reduction from baseline in HbA1c of 0.9% relative to the addition of placebo after up to 24 weeks of treatment. Consistent with the findings in the overall cohort, substantial placebo-adjusted reductions in HbA1c of 0.8% and 0.9% were observed across the study strata defined by the concomitant use of metformin at 1000 or 1700 mg day, respectively. In addition, the treatment effect was generally consistent across patient subgroups defined by gender, age, baseline BMI, duration of disease, baseline HbA1c, and prior use of AHA. The addition of sitagliptin compared with placebo to ongoing metformin therapy allowed a significantly greater proportion of patients to meet the HbA1c goal of <7% at Week 24. A smaller, but significant, proportion of patients treated with sitagliptin met the HbA1c goal of <6.5% at Week 24 compared with placebo. This finding was attributable, in part, to the relatively high mean baseline HbA1c values in both treatment groups (i.e. 8.5% and 8.6% in the sitagliptin and placebo groups, respectively), reflecting the entry inclusion criterion lower boundary of an HbA1c of 7.5%. Consistent with the significantly greater improvement in glycemic control observed in the sitagliptin group, a substantially smaller proportion of sitagliptin-treated patients compared with placebotreated patients required the initiation of glycemic rescue therapy (based upon protocol-defined glycemic rescue criteria) during the study. The addition of sitagliptin to ongoing metformin therapy also provided significant and clinically meaningful improvements in FPG (i.e. a 1.2 mmol L reduction) and 2-h PMG (i.e. a 1.9 mmol L reduction) compared with placebo, demonstrating that both fasting and post-meal glucose contributed to the overall improvement in glycemic control. The overall study findings are consistent with those of two similarly designed studies 6,8 (baseline HbA1c of 8.0% and 9.2%) conducted in predominantly non-asian populations in which significant reductions in HbA1c (placebo-adjusted changes from baseline of )0.7% 6 and )1.0%; 8 P < vs placebo), FPG (placebo-adjusted changes from baseline of )1.4 mmol L; 6,8 P < vs placebo) and 2-h PMG (placebo-adjusted changes from baseline of )3.0 mmol L; 8 P < vs placebo) were observed during studies of sitagliptin 100 mg added onto a stable dose of metformin 1500 mg day for up to 24 or 30 weeks. The addition of once-daily sitagliptin 100 mg to ongoing therapy with metformin was generally well tolerated in the entire cohort and among patients within each metformin dose stratum. Although the percentage of patients in the sitagliptin group who exhibited one or more adverse events was similar to that in the placebo group, a numerically higher incidence of drug-related adverse events, adverse events leading to discontinuation, and serious adverse events leading to discontinuation was observed in the sitagliptin group compared with the placebo group. These findings were predominantly observed in the metformin 1700 mg day stratum. The overall percentage of these particular adverse events was low, and no specific patterns or types of adverse events were identified. The addition of sitagliptin to ongoing metformin therapy did not lead to significant mean changes in body weight over the 24-week treatment period. However, a small, statistically significant, decrease from baseline in body weight of 0.5 kg observed in the placebo group may be related to the fact that patients with poorer glycemic control tend to lose weight. 34 The incidence of hypoglycemia in the present study was very low, with only one patient in the sitagliptin group reporting hypoglycemia compared with three 234 ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
9 W. YANG et al. Sitagliptin + metformin in Chinese patients patients in the placebo group. All episodes were mild in intensity and none led to discontinuation. Selected gastrointestinal adverse events occurred infrequently in both treatment groups. A numerically higher incidence of abdominal pain and diarrhea was observed in the sitagliptin group than in the placebo group, but differences between groups were not statistically significant. Most of these events occurred in the metformin 1700 mg day stratum, whereas the incidence of abdominal pain and diarrhea in the metformin 1000 mg day stratum was very low and similar to placebo. In conclusion, sitagliptin 100 mg once daily added to the treatment regimen for Chinese patients with T2DM who had inadequate glycemic control on metformin 1000 or 1700 mg day provided improved glycemic control, with reductions in HbA1c, FPG, and 2-h PMG, and was generally well tolerated. The improvements in glycemic control were not associated with a higher incidence of hypoglycemia and were generally consistent across the two metformin doses (i.e and 1700 mg day). In addition, treatment with sitagliptin did not result in an increase in weight from baseline. Acknowledgments The authors thank Kathleen NEWCOMB, Merck Sharp & Dohme Corp. (Whitehouse Station, NJ, USA) for editorial assistance with the preparation of this manuscript. The authors also thank the Investigators (see Appendix I) who assisted with the conduct of the clinical trial. Disclosure Funding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA. YG, YS, ZL, AOJ-L, SSE, KDK, BJG, and MA are all current or former employees of Merck Sharp & Dohme and may own stock or hold stock options in the company. WY has received consulting fees and payments for lectures, including serving on Speakers Bureaus, from Merck, Novo Nordisk, Bristol-Myers Squibb, and Bayer, and has received reimbursement from Merck for travel to congresses. References 1. DeFronzo RA. Lilly Lecture The triumvirate: Beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988; 37: Hundal RS, Krssak M, Dufour S et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000; 49: Inzucchi SE, Maggs DG, Spollett GR et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998; 338: Cook MN, Girman CJ, Stein PP, Alexander CM. Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with Type 2 diabetes in UK primary care. Diabet Med. 2007; 24: Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999; 281: Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29: Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: Scientific review. JAMA. 2002; 287: Raz I, Chen Y, Wu M et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008; 24: Seck T, Nauck M, Sheng D et al. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: A 2-year study. Int J Clin Pract. 2010; 64: Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes. 1998; 47: Herman GA, Stevens C, Van Dyck K et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: Results from two randomized, double-blind, placebocontrolled studies with single oral doses. Clin Pharmacol Ther. 2005; 78: Herman GA, Bergman A, Stevens C et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006; 91: Kim D, Wang L, Beconi M et al. (2R)-4-oxo-4-[3-(trifluo- romethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8h)- yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005; 48: Deacon CF, Ahren B, Holst JJ. 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10 Sitagliptin + metformin in Chinese patients W. YANG et al. betic humans. Am J Physiol Endocrinol Metab. 2004; 287: E Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006; 29: Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007; 30: Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006; 49: Reasner C, Olansky L, Seck TL et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011; 13: Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallelgroup study. Clin Ther. 2006; 28: Gallwitz B. Sitagliptin with metformin: Profile of a combination for the treatment of type 2 diabetes. Drugs Today. 2007; 43: Herman GA, Bergman A, Yi B, Kipnes M. Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes. Curr Med Res Opin. 2006; 22: Migoya EM, Miller JL, Larson PJ et al. Sitagliptin, a selective DPP-4 inhibitor, and metformin have complementary effects to increase active GLP-1 concentrations. Diabetologia. 2007; 50(Suppl. 1): S52 (Abstract). 24. Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008; 10: Williams-Herman D, Johnson J, Lunceford JK. Initial combination therapy with sitagliptin and metformin provides effective and durable glycemic control over 1 year in patients with type 2 diabetes: A pivotal phase III clinical trial. Diabetologia. 2007; 50(Suppl. 1): S52 3 (Abstract). 26. Williams-Herman D, Johnson J, Teng R et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: A 54-week study. Curr Med Res Opin. 2009; 25: Williams-Herman D, Johnson J, Teng R et al. Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. Diabetes Obes Metab. 2010; 12: Yoon KH, Lee JH, Kim JW et al. Epidemic obesity and type 2 diabetes in Asia. Lancet. 2006; 368: Chuang LM, Tsai ST, Huang BY, Tai TY. The status of diabetes control in Asia: A cross-sectional survey of patients with diabetes mellitus in Diabet Med. 2002; 19: Mohan V, Yang W, Son HY et al. Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract. 2009; 83: Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18: Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988; 75: Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985; 4: Chandalia HB, Lamba PS, Chandalia SH, Singh DK, Modi SV, Shaikh SA. Weight gain in type 2 diabetics with different treatment modalities. Metab Syndr Relat Disord. 2005; 3: Appendix I. List of investigators and institutions who participated in the present study Wenying YANG, China-Japan Friendship Hospital Xiaohui GUO, Peking University First Hospital Lixin GUO, Beijing Hospital Xiaofeng LV, the Military General Hospital of Beijing PLA Linong JI, Peking University People s Hospital Xiaoming LIU, the 1st Affiliated Hospital of Harbin Medical University Qiang LI, the 2nd Affiliated Hospital of Harbin Medical University Qiuhe JI, Xijing Hospital Qifu LI, the 1st Affiliated Hospital of Chongqing Medical University Zhongyuan WEN, People s Hospital of Wuhan University Yancheng XU, Zhongnan Hospital of Wuhan University Yanbing LI, the 1st Affiliated Hospital of Sun Yat-sen University Longyi ZENG, the 3rd Affiliated Hospital of Sun Yat-sen University Yuqian BAO, Shanghai 6th People s Hospital Zhimin LIU, Shanghai Changzheng Hospital Yongde PENG, Shanghai First People s Hospital Wei GU, Second Affiliated Hospital Zhejiang University College of Medicine Ruifang BU, Wu Xi People s Hospital Supporting Information Additional Supporting Information may be found in the online version of this article: Data S1 Core Protocol 236 ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
11 W. YANG et al. Sitagliptin + metformin in Chinese patients Table S1 Baseline and changes from baseline in lipid endpoints at Week 24 Table S2 Summary of adverse experiences by system organ class (SOC) occurring at an incidence of 2% in any treatment group Table S3 Adverse events by metformin stratum Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. ª 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd 237
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