JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Transcription

1 Dear Health Care Professional: Merck is pleased to provide you with the enclosed article, Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial, by R. Arechavaleta et al, as published in Diabetes, Obesity and Metabolism, 2011, Volume 13, Issue 2, pages Important Information JANUVIA (sitagliptin) 25 mg, 50 mg, 100 mg tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA. Selected Important Risk Information JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiating JANUVIA, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA. Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. Caution should be used to ensure that the correct dose of JANUVIA is prescribed. There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. When JANUVIA was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. DIAB /16

2 Selected Important Risk Information (continued) The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 12.2% (0.59 episodes/patient-year) for JANUVIA 100 mg in combination with glimepiride (with or without metformin), 1.8% (0.24 episodes/patient-year) for placebo in combination with glimepiride (with or without metformin), 15.5% (1.06 episodes/patient-year) for JANUVIA 100 mg in combination with insulin (with or without metformin), and 7.8% (0.51 episodes/patient-year) for placebo in combination with insulin (with or without metformin). There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA. There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from 1 day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or with any other antidiabetic drug. In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in 5% of patients treated with JANUVIA as monotherapy and in combination therapy and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache. Before prescribing JANUVIA (sitagliptin) tablets, please read the accompanying Prescribing Information. The Medication Guide also is available. For additional copies of the Prescribing Information, please call , visit Januvia.com, or contact your Merck representative. Sincerely, Chris Allen, MD, FRCA, FFPM AVP, Global Medical Affairs Global Medical Information and Operations DIAB /16

3 original article Diabetes, Obesity and Metabolism 13: , Merck Sharp & Dohme Corp. original article Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial R. Arechavaleta 1,T.Seck 2,Y.Chen 2,K.J.Krobot 3,E.A.O Neill 2,L.Duran 2, K. D. Kaufman 2, D. Williams-Herman 2 &B.J.Goldstein 2 1 Hospital Especialidades Centro Medico de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico 2 Metabolism, Merck Sharp & Dohme Corp., Rahway, NJ, USA 3 Outcomes Research, Merck Sharp & Dohme Corp., Munich, Germany Aim: To evaluate the efficacy and safety of adding sitagliptin or glimepiride to the treatment regimen of patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin monotherapy. Methods: Patients with type 2 diabetes and an HbA 1c of % while on a stable dose of metformin ( 1500 mg/day) combined with diet and exercise for at least 12 weeks were randomized in a double-blind manner to receive either sitagliptin 100 mg daily (N = 516) or glimepiride (starting dose 1 mg/day and up-titrated, based upon patient s self-monitoring of blood glucose results, to a maximum dose of up to 6 mg/day) (N = 519) for 30 weeks. The primary analysis assessed whether sitagliptin is non-inferior to glimepiride in reducing HbA 1c at week 30 (based on the criterion of having an upper bound of the 95% CI less than the prespecified non-inferiority bound of 0.4%). Results: The mean baseline HbA 1c was7.5%inboththesitagliptingroup(n= 443) and the glimepiride group (n = 436). After 30 weeks, the least squares (LS) mean change in HbA 1c from baseline was 0.47% with sitagliptin and 0.54% with glimepiride, with a between-group difference (95% CI) of 0.07% ( 0.03, 0.16). This result met the prespecified criterion for declaring non-inferiority. The percentages of patients with an HbA 1c < 7.0% at week 30 were 52 and 60% in the sitagliptin and glimepiride groups, respectively. The LS mean change in fasting plasma glucose from baseline (95% CI) was 0.8 mmol/l ( 1.0, 0.6) with sitagliptin and 1.0 mmol/l ( 1.2, 0.8) with glimepiride, for a between-group difference (95% CI) of 0.2 mmol/l ( 0.1, 0.4). The percentages of patients for whom hypoglycaemia was reported were 7% in the sitagliptin group and 22% in the glimepiride group (percentage-point difference = 15, p < 0.001). Relative to baseline, sitagliptin was associated with a mean weight loss ( 0.8 kg), whereas glimepiride was associated with a mean weight gain (1.2 kg), yielding a between-group difference of 2.0 kg (p < 0.001). Conclusions: In patients with type 2 diabetes and inadequate glycaemic control on metformin monotherapy, the addition of sitagliptin or glimepiride led to similar improvement in glycaemic control after 30 weeks. Sitagliptin was generally well tolerated. Compared to treatment with glimepiride, treatment with sitagliptin was associated with a lower risk of hypoglycaemia and with weight loss versus weight gain (ClinicalTrials.gov: NCT ). Keywords: DPP-4 inhibitor, glimepiride, sitagliptin, type 2 diabetes Date submitted 5 August 2010; date of first decision 10 September 2010; date of final acceptance 1 November 2010 Introduction Type 2 diabetes mellitus is a progressive disease, which usually requires multiple antihyperglycaemic agents (AHAs) to attain or maintain glycaemic control [1]. Most current therapeutic guidelines recommend metformin as initial monotherapy for treatment of type 2 diabetes [2]. Insulin secretagogues, such as sulfonylureas, are frequently used as second-line therapy if metformin monotherapy does not achieve acceptable glycaemic control [2]. However, sulfonylureas can lead to an increased Correspondence to: Thomas Seck, Merck Sharp & Dohme Corp., 126 East Lincoln Avenue, RY34-A220, Rahway, NJ , USA. thomas seck@merck.com risk of hypoglycaemia and weight gain [3]. Therefore AHAs that provide similar glycaemic efficacy as sulfonylureas, but with less hypoglycaemia and weight gain, could improve the management of patients with type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an incretin-based therapy that is effective and well tolerated when used in addition to metformin therapy [4 6]. Furthermore, when added to metformin the risk of hypoglycaemia with sitagliptin is similar to that observed when placebo is added to metformin [5,7]. Treatment with sitagliptin has also been shown to be generally weight neutral relative to baseline [8,9]. A prior study showed that the glycaemic efficacy of the addition of sitagliptin to ongoing metformin monotherapy

4 DIABETES, OBESITY AND METABOLISM was non-inferior to the addition of glipizide [10]. To provide an additional comparison to another commonly used sulfonylurea, this study assessed the efficacy and safety of sitagliptin compared with glimepiride in patients with inadequate glycaemic control on metformin monotherapy. Patients and Methods Patients Patients 18 years of age, with type 2 diabetes and with inadequate glycaemic control (defined as HbA 1c 6.5 and 9.0%) while on a stable dose of metformin ( 1500 mg/day) as well as diet and exercise for at least 12 weeks prior to the screening visit, were eligible for this study if they met all screening criteria. Patients were excluded if they had a history of type 1 diabetes, used any AHA besides metformin within 12 weeks of the screening visit, had renal function impairment prohibiting the use of metformin or had a fasting fingerstick glucose of <6.1 or >13.3 mmol/l at randomization. Use of other AHAs was prohibited during the study. Concurrent lipid-lowering and antihypertensive medications, thyroid medications, hormone replacement therapy and birth control medications were allowed, but were expected to have been maintained at stable doses during the run-in period as well as during the active study itself. Patients received counselling on exercise and a diet consistent with American Diabetes Association recommendations throughout the study. Study Design This was a multinational, double-blind, randomized, parallelgroup, non-inferiority study. After a 2-week, placebo run-in period,eligiblepatientswererandomized1:1,usingaconcealed computer-generated allocation schedule, to either the sitagliptin or glimepiride group. Patients in the sitagliptin group were treated with sitagliptin 100 mg daily and matching glimepiride placebo; patients in the glimepiride group received a matching sitagliptin placebo tablet and started glimepiride 1 mg/day. The glimepiride dose could be up-titrated during the first 18 weeks of the treatment period to a maximum dose of 6 mg/day, based on patient s self-administered blood glucose monitoring, as considered appropriate by the investigator following their usual practice. In the event of up-titration, glimepiride or matching placebo was increased to 2 mg and then further increased in 1- or 2-mg increments. At any time during the study, glimepiride could be down-titrated to prevent recurrent hypoglycaemic events. Patients were to be discontinued from the study if they experienced repeated episodes of unexplained hypoglycaemia as defined by fasting plasma glucose (FPG) or fingerstick glucose <2.78 mmol/l with or without the symptoms of hypoglycaemia or <3.89 mmol/l with symptoms of hypoglycaemia. In addition, patients were to be discontinued from the study if they failed to meet prespecified, progressively stricter glycaemic control criteria. From randomization through week 12, patients were discontinued if FPG was consistently >13.33 mmol/l on at least 4 mg daily glimepiride/glimepiride placebo for at least 2 weeks; after week 12, patients were discontinued if their original article FPG was consistently >11.10 mmol/l on at least 4 mg daily glimepiride/glimepiride placebo for at least 2 weeks. The assessment of compliance was based on the patient s prime therapy records. The calculation was based on the following formula: 100 times (number of days when the patient took the correct number of tablets)/(number of days the patient was in the treatment period) (%). All patients provided written informed consent to participate. The study (Sitagliptin Protocol 803; ClinicalTrials.gov: NCT ) was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. Study Evaluations Efficacy Assessments The primary efficacy outcome was changed from baseline in HbA 1c at week 30. Secondary efficacy endpoints included the percentages of patients with HbA 1c values at goals of <7.0 and <6.5%, change from baseline in FPG and mean or median percent change from baseline in fasting lipid parameters [total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)]. At baseline (randomization, week 0), week 18 and week 30, each patient evaluated him or herself with the EQ-5D from the EuroQol Group ( Safety Assessments Safety and tolerability were assessed through the analysis of adverse experiences, laboratory evaluations, body weight and vital signs. All adverse experiences were rated by the study site investigators for intensity and relationship to study drug. Laboratory safety evaluations included blood chemistry, haematology and urinalysis. Patients were counselled regarding the symptoms of hypoglycaemia (e.g. weakness, dizziness, shakiness, increased sweating, palpitations or confusion) and requested to immediately perform a fingerstick glucose measurement if any symptoms occurred that may have been related to hypoglycaemia, but to avoid delay in treating these symptoms. To assist the investigator in assessing the severity of an event, patients were provided with, and instructed in the use of, a hypoglycaemia assessment log to document potential hypoglycaemia episodes and collect information on the severity of the events (such as the requirement for the assistance of another person or medical treatment). Events assessed by the investigator as hypoglycaemia were reported as adverse experiences of hypoglycaemia; documentation of a glucose determination at the time the patient had symptoms was not required for an event to be reported as hypoglycaemia. Events of symptomatic hypoglycaemia were analysed as follows: those not requiring assistance; those requiring non-medical assistance of others and those requiring medical intervention or exhibiting markedly depressed level of consciousness, including loss of consciousness or seizure. All laboratory efficacy and safety measurements were performed at central laboratories (PPD Global, Volume 13 No. 2 February 2011 doi: /j x 161

5 original article Central Labs, LLC, Highland Heights, KY, USA, and Zaventem, Belgium) by technicians who were blinded to treatment allocation. Statistical Analysis Efficacy The primary hypothesis test assessed whether sitagliptin is noninferior compared with glimepiride regarding change from baseline in HbA 1c at week 30. The primary analysis was conducted in the per-protocol (PP) population [11], defined as those patients with a baseline measurement, a measurement at week 30, and with no major protocol violations (drug compliance <85%, use of prohibited medications, change of metformin dose or incorrect administration of double-blind study medication) identified prior to unblinding the data. The criterion for declaring sitagliptin non-inferior to glimepiride was an upper bound of the two-sided 95% confidence interval (CI) for the between-treatment difference (sitagliptin and glimepiride) in least squares (LS) mean change from baseline in HbA 1c less than 0.4% based on an analysis of covariance (ANCOVA) with treatment, baseline HbA 1c, and country as covariates. The change (or percent change) from baseline in FPG and all lipid parameters except TG was analysed in a similar manner, substituting the relevant baseline measurement as a covariate. For the analysis of TG, within-group effects were estimated using medians and between-group effects were estimated using the Hodges Lehmann estimate [12] with a corresponding distribution-free 95% CI based on Wilcoxon s rank sum test. Between-group differences in the percentages of patients with an HbA 1c value <7.0 and <6.5% at week 30 were analysed using the method of Miettinen and Nurminen [13] stratified by country. To assess the robustness for the results in the PP population, analyses of HbA 1c and FPG were also performed in the full analysis set (FAS), defined as all randomized patients who took at least one dose of study medication and had both a baseline measurement and at least one postbaseline measurement of the respective efficacy outcome. In the event of missing outcome data, the ANCOVA model used the last observation carried forward (LOCF) method. The distribution of EQ-5D scores and change from baseline in VAS were summarized by treatment at weeks 18 and 30. Safety and Tolerability Safety and tolerability were assessed by a review of all safety parameters including adverse experiences, laboratory safety parameters, body weight and vital signs. The population for all safety endpoints except body weight consisted of all randomized patients who received at least one dose of study therapy (All Patients as Treated population). The method of Miettinen and Nurminen [13] was used to compute 95% CIs for betweentreatment differences in incidence percentages for AEs. The secondary hypothesis test assessed the between-group difference in the proportion of patients with at least one hypoglycaemic event via the method of Miettinen and Nurminen [13]. In addition, the hazards of hypoglycaemic DIABETES, OBESITY AND METABOLISM events occurring in patients receiving sitagliptin versus those receiving glimepiride were compared in a complementary log log regression model clustered by patient, with terms for treatment, most recent HbA 1c value prior to the event, time from randomization to the event, gender and age group (< or 65 years) in all models. In this modelling, the hazard for each subject was treated as a random effect and p < 0.2 was considered significant for keeping two-way interactions including squared terms for most recent HbA 1c value prior to the event and for time from randomization in the model. To maintain the type 1 error at p = 0.05, the four models of the four endpoints were tested in a fixed sequence: (1) symptomatic hypoglycaemia accompanied by a fingerstick blood glucose measurement 3.9 mmol/l, (2) symptomatic hypoglycaemia, whether or not blood glucose values were documented, (3) symptomatic hypoglycaemia accompanied by a fingerstick blood glucose measurement 2.8 mmol/l and (4) hypoglycaemia requiring the medical or non-medical assistance of others, or accompanied by the symptoms of neuroglycaemia. Random effects models were estimated using Stata 11 SE (StataCorp LP, College Station, TX, USA). The between-group difference in change from baseline in body weight was tested using the ANCOVA model described for HbA 1c, substituting baseline body weight for baseline HbA 1c as a covariate. This analysis included all patients with a body weight measurement at week 30. Results Patient Disposition and Characteristics Of the 1035 randomized patients, 936 completed the 30-week study: 468/516 (90.7%) in the sitagliptin group and 468/519 (90.2%) in the glimepiride group (figure 1). Approximately 85% (86% for the sitagliptin group and 84% for the glimepiride group) of randomized patients were included in the PP population. The most common reasons for exclusion from the PP population were no treatment data at week 30 (10.9 and 13.5% of the sitagliptin and glimepiride groups, respectively) and <85% drug compliance (3.1 and 3.3% of the sitagliptin and glimepiride groups, respectively). Baseline demographics and efficacy-related characteristics of the PP population were generally similar to those of the randomized cohort (Table 1). The mean dose of glimepiride after week 18 (at the end of the up-titration period) was 2.1 mg daily. Efficacy In the PP population, the LS mean change from baseline in HbA 1c at week 30 was 0.47% in the sitagliptin group and 0.54% in the glimepiride group (Table 2), with a betweengroup difference (95% CI) of 0.07% ( 0.03, 0.16). The upper-limit of the 95% CI for the between-group LS mean difference in change from baseline in HbA 1c met the prespecified criterion for declaring non-inferiority of sitagliptin to glimepiride. Results of the analysis in the FAS population were consistent with those observed in the primary PP population analysis (Table 2). Both treatment groups exhibited a rapid improvement in HbA 1c, with near-maximal reduction 162 Arechavaleta et al. Volume 13 No. 2 February 2011

6 DIABETES, OBESITY AND METABOLISM original article Screened (N = 1625) Excluded (n = 590) Randomized (n = 1035) Adverse event, n = 1 Lost to follow-up, n = 14 Protocol violation, n = 1 Screen failure, n = 528 Study terminated by sponsor, n = 3 Withdrawal by subject, n = 43 Sitagliptin 100 mg daily (n = 516) Glimepiride (n = 519) Discontinued, n = 48 Adverse event, n = 11 Lack of efficacy*, n = 5 Lost to follow-up, n = 9 Serum creatinine increased, n = 4 Hyperglycemia, n = 2 Required excluded medication, n = 1 Physician decision, n = 3 Protocol violation, n = 2 Withdrawal by subject, n = 11 Discontinued, n = 51 Adverse event, n = 3 Lack of efficacy*, n = 4 Lost to follow-up, n = 9 Serum creatinine increased, n = 5 Hyperglycemia, n = 3 Hypoglycemia, n = 2 Required excluded medication, n = 2 Physician decision, n = 4 Protocol violation, n = 3 Withdrawal by subject, n = 16 Completed: n = 468 Completed: n = 468 Figure 1. Patient disposition. One patient was randomized, but did not receive any study drug and was therefore not included in efficacy and safety analyses. One patient in each group discontinued due to an adverse experience with an onset before randomization; these events are not included in the safety analysis (Table 3). Patients who discontinued for lack of efficacy included patients not meeting the progressively stricter protocol-specified glycaemic criteria and/or not meeting the investigator s expectations of glycaemic improvement. by week 12 (figure 2). The reduction in HbA 1c remained stable over time in the sitagliptin group. Although a slightly larger reduction in HbA 1c wasobservedacrosstimepointsinthe glimepiride group, beginning at week 18 a slight increase in HbA 1c was observed. The percentage of patients with an HbA 1c < 7.0% at week 30 in the PP population was lower for the sitagliptin group (52.4%; n/n = 232/443) compared with the glimepiride group (59.6%; n/n = 260/436) [difference (95% CI) = 7.5 ( 13.8, 1.1)]. Similarly, in the sitagliptin group, 21.2% of patients (n/n = 94/443) had an HbA 1c < 6.5% at week 30 compared with 27.5% (n/n = 120/436) in the glimepiride group [difference (95% CI) = 6.7% ( 12.3, 1.1)]. The LS mean change from baseline in FPG at week 30 in the PP population was 0.8 mmol/l in the sitagliptin group and 1.0 mmol/l in the glimepiride group (Table 2), resulting in a between-group difference in LS means (95% CI) of 0.2 ( 0.0, 0.4). Results were similar in the FAS population. The LS mean percent change from baseline (95% CI) for HDL-C was 4.4% (1.8, 7.0) in the sitagliptin group and 0.9% ( 1.7, 3.5) in the glimepiride group, resulting in a betweengroup difference of 3.5% (0.6, 6.5) favouring sitagliptin. The median percent change from baseline (95% CI) in TG was 5.3% ( 9.0, 1.6) in the sitagliptin group and 2.1% ( 1.7, 5.9) in the glimepiride group, resulting in a between-group difference of 6.1% ( 10.4, 1.7), also favouring sitagliptin. No meaningful between-group differences in total cholesterol [ 0.8% ( 2.9, 1.3)], LDL-C [2.3% ( 1.9, 6.5)] or non-hdl-c [ 1.2% ( 4.3, 1.8)] were observed at week 30 of this study. With regard to the EQ-5D and the EQ-VAS, generally similar responses were observed in both treatment groups at baseline, with no meaningful between-group differences for changes from baseline in responses at week 18 or week 30. Safety and Tolerability Glimepiride treatment was associated with a higher incidence of overall adverse experiences and drug-related adverse experiences compared with sitagliptin (Table 3), largely because of a higher incidence of hypoglycaemia in the glimepiride group, as detailed below (Table 4). In the sitagliptin group and glimepiride group, serious adverse experiences were reported for 16 and 11 patients, respectively. The serious adverse experiences reported for the sitagliptin group were distributed across different System Organ Classes. One serious adverse experience that was considered drug-related by the investigator was reported in the study: a 61-year-old female in the sitagliptin group experienced a serious drug-related adverse experience of thrombocytopenia (platelet count of /μl) resulting in discontinuation from the study. The patient s platelet count had been normal ( /μl) on day 66, with the onset (day 109) of symptoms approximately 17 days following the onset Volume 13 No. 2 February 2011 doi: /j x 163

7 original article Table 1. Baseline demographics and baseline efficacy endpoint data for all randomized patients. Parameter Sitagliptin added to metformin (N = 516) Glimepiride added to metformin (N = 519) Age (years) 56.3 ± ± 10.1 Gender, n (%) Male 284 (55.0) 279 (53.8) Race, n (%) White 297 (57.6) 298 (57.4) Asian 109 (21.1) 111 (21.4) Multiracial 78 (15.1) 76 (14.6) Other 26 (5.0) 28 (5.4) Black or African American 6 (1.2) 6 (1.2) Ethnicity, n (%) Hispanic or Latino 196 (38.0) 196 (37.8) Not Hispanic or Latino 320 (62.0) 323 (62.2) Body weight (kg) 80.6 ± ± 16.7 Body mass index (kg/m 2 ) 29.7 ± ± 4.4 HbA 1c (%) 7.5 ± ± 0.8 (range) ( ) ( ) HbA 1c distribution, n (%) <7% 114 (22.1) 126 (24.3) 7and<8% 280 (54.3) 254 (48.9) (23.6) 139 (26.8) FPG (mmol/l) 8.0 ± ± 1.9 Duration of T2D (years) 6.8 ± ± 4.8 Data are expressed as mean ± standard deviation or frequency [n (%)] unless otherwise indicated. FPG, fasting plasma glucose. To convert FPG in mmol/l to mg/dl, multiply by 18. of a sinusitis treated with amoxicillin/clavulonate from days In addition to sitagliptin, the investigator considered the amoxicillin/clavulonate and another medication, pentoxifylline (started for dizziness on day 60), as suspect medications. Haemoglobin and white blood cell counts were within the normal range and a bone marrow biopsy did not show any abnormalities. The patient was treated with prednisone, and platelet counts returned to the normal range. Table 2. Key efficacy results. HbA 1c (%) DIABETES, OBESITY AND METABOLISM Sitagliptin 100 mg Glimepiride Week Figure 2. HbA 1c (mean ± s.e.), per-protocol (PP) population. One death occurred in this study: a patient in the glimepiride group died as a result of a haemorrhagic stroke that was not considered related to the study drug by the investigator. A higher incidence of discontinuations because of adverse experiences was observed in the sitagliptin group (Table 3) while overall discontinuations were similar in both groups. Hypoglycaemia was reported for 114 (22%) patients in the glimepiride group (total number of episodes in the glimepiride group = 460) and 36 (7%) patients in the sitagliptin group (total number of episodes in the sitagliptin group = 73). In the glimepiride group, eight patients had hypoglycaemic episodes requiring non-medical assistance (eight episodes) compared with one patient having one episode requiring non-medical assistance in the sitagliptin group. Furthermore, three patients in the glimepiride group had a total of six hypoglycaemic episodes requiring medical assistance or that were accompanied by neurological symptoms (six episodes), compared with one patient in the sitagliptin group having one episode. Patients in the glimepiride group were also more likely to experience multiple episodes of hypoglycaemia: in the glimepiride group, 4.4% of patients experienced 6 episodes of hypoglycaemia n Week 0 (baseline), mean (s.d.) Week 30, mean (s.d.) LS mean change from baseline (95% CI) Difference in LS mean change (95% CI) HbA 1c (%) Per-protocol population Sitagliptin added to metformin (0.68) 7.04 (0.83) 0.47 ( 0.55, 0.39) 0.07 ( 0.03, 0.16) Glimepiride added to metformin (0.74) 6.98 (0.89) 0.54 ( 0.62, 0.45) Full analysis set population Sitagliptin added to metformin (0.70) 7.09 (0.86) 0.46 ( 0.54, 0.38) 0.07 ( 0.02, 0.16) Glimepiride added to metformin (0.76) 7.02 (0.92) 0.52 ( 0.60, 0.45) FPG (mmol/l) Per-protocol population Sitagliptin added to metformin (1.8) 7.2 (1.7) 0.8 ( 1.0, 0.6) 0.2 ( 0.1, 0.4) Glimepiride added to metformin (1.9) 7.1 (1.8) 1.0 ( 1.2, 0.8) Full analysis set population Sitagliptin added to metformin (1.9) 7.3 (1.9) 0.8 ( 1.0, 0.6) 0.1 ( 0.1, 0.3) Glimepiride added to metformin (2.0) 7.3 (2.0) 0.9 ( 1.1, 0.8) CI, confidence interval; FPG, fasting plasma glucose; LS, least squares; s.d., standard deviation; to convert FPG in mmol/l to mg/dl multiply by Arechavaleta et al. Volume 13 No. 2 February 2011

8 DIABETES, OBESITY AND METABOLISM original article Table 3. Safety results. Sitagliptin added to metformin (N = 516) n(%) Glimepiride added to metformin (N = 518) n(%) Difference: sitagliptin versus glimepiride (%) (95% CI) One or more AEs 244 (47.3) 291 (56.2) 8.9 ( 14.9, 2.8) Drug-related AEs 47 (9.1) 116 (22.4) 13.3 ( 17.7, 8.9) SAEs 16 (3.1) 11 (2.1) 1.0 ( 1.0, 3.1) Drug-related SAEs 1 (0.2) 0 (0.0) 0.2 ( 0.5, 1.1) Deaths 0 (0.0) 1 (0.2) 0.2 ( 1.1, 0.6) Discontinuations as a result of AEs 10 (1.9) 2 (0.4) 1.6 (0.3, 3.2) Discontinuations as a result of drug-related AEs 2 (0.4) 2 (0.4) 0.0 ( 1.1, 1.1) Discontinuations as a result of SAEs 5 (1.0) 0 (0.0) 1.0 (0.2, 2.3) Discontinuations as a result of drug-related SAEs 1 (0.2) 0 (0.0) 0.2 ( 0.5, 1.1) AE, adverse experience; SEA, serious adverse experience. One patient was randomized, but did not receive any study drug and was therefore not included in the safety analyses. Considered by the investigator as possibly, probably or definitely related to study drug. Autonomicneuropathy,diabetes mellitus inadequatecontrol, lungsquamous cell carcinoma stage unspecified, pancreatic carcinoma, thrombocytopenia. Thrombocytopenia. Table 4. Cumulative incidence of hypoglycaemia. Treatment n/n (%) Sitagliptin added to metformin Glimepiride added to metformin Patients with at least one episode Number of patients with specific number of episodes Between-group difference in % versus (95% CI) p Value 0 (%) 1 (%) 2 (%) 3 (%) 4 (%) 5 (%) 6(%) 36/516 (7.0) 15.0 ( 19.3, 10.9) < (93.0) 21 (4.1) 7 (1.4) 3 (0.6) 2 (0.4) 1 (0.2) 2 (0.4) 114/518 (22.0) 404 (78.0) 37 (7.1) 23 (4.4) 16 (3.1) 7 (1.4) 8 (1.5) 23 (4.4) compared with 0.4% of patients in the sitagliptin group (Table 4). In the analysis assessing the risk of hypoglycaemia adjusted for key variables such as recent HbA 1c value, the hazard of having symptomatic hypoglycaemic events was substantially lower with sitagliptin compared with glimepiride across various event types and definitions (figure 3). The hazard was approximately 15-fold lower (p < 0.001) and 18-fold lower (p < 0.001) for symptomatic hypoglycaemic events accompanied by fingerstick blood glucose measurements 3.9 mmol/l (70 mg/dl) and 2.8 mmol/l (50 mg/dl), respectively. In multivariate analyses, the adjusted rate of hypoglycaemic events was substantially lower with sitagliptin relative to glimepiride across different event types and definitions of hypoglycaemia in all age groups and both genders (data not shown). Among patients with measurements at week 30, body weight decreased from baseline with sitagliptin [LS mean change (95% CI) = 0.8 kg( 1.1, 0.5)] and increased from baseline with glimepiride [1.2 kg (0.9, 1.5)], resulting in a significant between-group difference of 2.0 kg (p < 0.001) (figure 4). Apart from hypoglycaemia, the only other adverse event with an incidence of at least 5% in either treatment group was nasopharyngitis (4.8 and 6.9%, in the sitagliptin and glimepiride groups, respectively). For specific adverse experiences other than hypoglycaemia, the between-group differences in incidence were small (less than 3 percentage points). There were no clinically meaningful differences in the percentages of patients with values meeting predefined limits of change criteria for chemistry and haematology analytes. Discussion In this multicenter, double-blind, randomized study, patients with type 2 diabetes and inadequate glycaemic control (defined as an HbA 1c of 6.5 and 9.0%) on a stable dose of metformin were randomized to the addition of treatment with the DPP-4 inhibitor, sitagliptin, or the sulfonylurea agent, glimepiride. The results of the study show that the HbA 1c -lowering efficacy of sitagliptin is non-inferior to that of glimepiride. The demonstration of non-inferiority between sitagliptin and glimepiride was further supported by the finding of similar reductions in FPG observed in both treatment groups. As a consequence, the majority of patients in both groups had an HbA 1c value at the glycaemic goal of 7.0% at week 30. Compared with sitagliptin, a slightly higher percentage of patients in the glimepiride group had an HbA 1c goal of 7% at week 30, reflecting the slightly greater mean reduction in the HbA 1c observed in the glimepiride group. Compared to treatment with glimepiride, treatment with sitagliptin was associated with less hypoglycaemia and with weight loss versus weight gain over 30 weeks. The results of this study are consistent with the results of a prior study that showed the non-inferiority of sitagliptin and the sulfonylurea agent glipizide in a similar patient population after 1 year of therapy [10]. Glimepiride is another widely used second-generation sulfonylurea that purportedly has a lower risk of hypoglycaemia and weight gain relative to other medications in the same class [14,15]. The consistency of the Volume 13 No. 2 February 2011 doi: /j x 165

9 original article DIABETES, OBESITY AND METABOLISM Hypoglycemic episodes Sitagliptin (516 patients; patientyears) Glimepiride (518 patients; patientyears) Hazard Ratio (95% CI) p-value (1) Accompanied by a fingerstick blood glucose measurement 70 mg/dl (3.9 mmol/l) (0.030; 0156) < (2) All events, whether or not blood glucose values were documented * (0.048; 0.183) < (3) Accompanied by a fingerstick blood glucose measurement 50 mg/dl (2.8 mmol/l) (0.015; 0.217) < (4) Requiring the medical or non-medical assistance of others, or accompanied by neurological symptoms (0.028; 0.733) Sitagliptin better Glimepiride better 100 Figure 3. Hazard ratios for hypoglycaemic events. Model terms: Treatment, most recent HbA 1c value prior to the event, time from randomization to the event, gender, age group (< or 65 years), most recent squared HbA 1c valuepriortotheevent(model1only), and treatment-by-most recent HbA 1c interaction (model 2 only). Hazard ratio at a HbA 1c value of 6.5%. Fixed-sequence testing procedure (model 1 through model 4). Variances relaxed to account for clustering by patient; CI = confidence intervals. LS mean body weight change from baseline (kg) Sitagliptin Glimepiride Week Difference in LS Means at Week 30 = -2.0 kg; p<0.001 Figure 4. Body weight change from baseline [least squares (LS) mean ± s.e.] over time in the All Patients as Treated population, with body weight measurement at week 30, on ongoing metformin treated with sitagliptin or glimepiride. results observed across two studies enhances the robustness of the conclusion regarding non-inferiority of the glycaemic efficacy of sitagliptin compared with sulfonylurea agents in the population of patients with mild-to-moderate hyperglycaemia on metformin monotherapy. The results reported here are similar to a study that compared the safety and efficacy of another DPP-4 inhibitor with glimepiride when added to ongoing metformin treatment [16]. The HbA 1c inclusion criterion in this study of % was selected as many guidelines, including those from the International Diabetes Federation, suggest that an HbA 1c of less than 6.5% is an appropriate target for patients with diabetes [17]. In this study, the titration of glimepiride was designed to support a dose escalation that would avoid excessive hypoglycaemia a general concern with sulfonylurea agents. With the HbA 1c inclusion criterion for this study ranging from 6.5 to 9.0% many patients had relatively mild hyperglycaemia ( 76% of patients had a baseline HbA 1c < 8.0% and 23% of patients had a baseline HbA 1c < 7.0%). Therefore, it is not surprising that many patients were not up-titrated to the maximumallowed dose of glimepiride (6 mg/day), and that a substantial proportion of patients remained on glimepiride doses of 1 or 2 mg per day. The mean dose of glimepiride achieved in this study was 2.1 mg/day, which is similar to the mean daily dose of glimepiride used in clinical practice of about 2.3 mg (Independent analysis by Merck using IMS MIDAS, 4Q09). This finding may be because of the risk of hypoglycaemia associated with the use of glimepiride. As noted above, the proportion of patients for whom hypoglycaemia was reported, as well as the adjusted rate of reported hypoglycaemic episodes, was substantially higher with glimepiride than with sitagliptin treatment, and more glimepiride-treated patients had hypoglycaemic episodes that required assistance and/or were of marked severity. Further, although the risk of hypoglycaemia may be dose-dependent, the relationship between dose and glycaemic efficacy of sulfonylurea agents is not linear over the therapeutic dose range. In a dose-range finding study with glimepiride, a substantial reduction in HbA 1c was observed with 1 mg daily, whereas nearly full efficacy was reached with the 4 mg per day dose with little additional efficacy obtained with dose escalation through doses of 8 mg per day [13]. Therefore, while a higher mean dose of glimepiride might have resulted in modestly greater efficacy, such efficacy would probably have been associated with and offset by an increased risk of hypoglycaemia. Overall, clinical adverse experiences and drug-related adverse experiences were reported more frequently with glimepiride, primarily as a result of an increased incidence of hypoglycaemia. However, with the exception of the increased incidence of hypoglycaemia for patients treated with glimepiride, both sitagliptin and glimepiride were generally well tolerated over the 30 weeks of study, with few patients discontinuing treatment because of adverse events. In this study, clinically important differences in the percentages of patients experiencing at least one hypoglycaemic event and in the adjusted rate of hypoglycaemic events were 166 Arechavaleta et al. Volume 13 No. 2 February 2011

10 DIABETES, OBESITY AND METABOLISM observed. Throughout the course of this study 22% of the patients treated with glimepiride experienced at least one episode of hypoglycaemia, compared with 7% in the sitagliptin group. Patients in the glimepiride group compared with the sitagliptin group were also more likely to experience multiple episodes of hypoglycaemia. In multivariate analyses, the adjusted rate of hypoglycaemic events was substantially lower with sitagliptin relative to glimepiride across different event types and definitions of hypoglycaemia. Although the risk of hypoglycaemia in this study was substantially greater in the glimepiride group compared with the sitagliptin group, a number of patients did not report hypoglycaemic events. Thus, the absence of meaningful between-group differences in the EQ-5D or EQ-VAS does not contradict previous research that hypoglycaemia can be associated with increased worry, reduced quality of life [18], reduced treatment satisfaction and barriers to adherence [19]. For specific adverse experiences other than hypoglycaemia, the between-group differences in incidence were small. No meaningful between-group differences were observed in laboratory safety assessments. The increase in body weight associated with certain AHAs [3] is an undesired side effect in patients with type 2 diabetes. In this study, the pattern of body weight change differed between treatment groups over the 30-week study period: the addition of sitagliptin to ongoing metformin monotherapy was associated with weight loss, whereas the addition of glimepiride was associated with weight gain. This resulted in a clinically meaningful between-group difference of 2.0 kg following 30 weeks of treatment. The observation of weight loss when sitagliptin is added to metformin is consistent with similar observations in other studies that showed small ( 0.5 kg) reductions from baseline in body weight when sitagliptin is used in this treatment paradigm [5,10,20,21]. In summary, the addition of sitagliptin to ongoing metformin monotherapy provided similar HbA 1c -lowering efficacy after 30 weeks of treatment compared with the addition of glimepiride. Patients treated with sitagliptin had a substantially lower rate of hypoglycaemic events relative to those treated with glimepiride and experienced weight loss versus weight gain. Acknowledgements This study was funded by Merck Sharp & Dohme Corp., Whitehouse Station, NJ. The Merck employees, who are authors, developed the study design, collected and analysed the data and prepared and approved the manuscript. The authors thank Sheila Erespe of Merck for her help in preparing this manuscript. Conflict of Interest R. A. collected data, analysed the data and wrote manuscript. T. S. developed study design, collected data, analysed data and wrote manuscript. Y. C. collected data, analysed the data and wrote manuscript. K. J. K. and E. A. O. analysed data and wrote manuscript. L. D. did study design, data collection and original article wrotemanuscript.k.d.k.,d.w.andb.j.g.developedstudy design, analysed data and wrote manuscript. R. A. is a member of the advisory board for Merck, GSK and NOVO, and has received honoraria fees for lectures for Merck, GSKandNOVO.T.S.,Y.C.,K.J.K.,E.A.O.,L.D.,K.D.K.,D. W. and B. J. G. are Merck employees and may own stock/stock options in Merck. References 1. 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). JAMA 1999; 281: Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32: Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes scientific review. JAMA 2002; 287: Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9: 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: 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: 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: 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: 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: Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9: Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJW. Reporting of noninferiority and equivalence randomized trials an extension of the CONSORT Statement. JAMA 2006; 295: Hodges JL, Lehmann EL. The efficiency of some nonparametric competitors of the t-test. Ann Math Stat 2010; 27: Miettinen O, Nurminen M. Comparative-analysis of 2 rates. Stat Med 1985; 4: Davis SN. The role of glimepiride in the effective management of type 2 diabetes. J Diabetes Complications 2004; 18: Korytkowski MT. Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepiride. Pharmacotherapy 2004; 24: Volume 13 No. 2 February 2011 doi: /j x 167

11 original article 16. Matthews DR, Dejager S, Ahren B et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diabetes Obes Metab 2010; 12: IDF Clinical Guidelines Task Force. Global guideline for type 2 diabetes: recommendations for standard, comprehensive, and minimal care. Diabet Med 2006; 23: Vexiau P, Mavros P, Krishnarajah G, Lyu R, Yin D. Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in France. Diabetes Obes Metab 2008; 10(Suppl. 1): DIABETES, OBESITY AND METABOLISM 19. Alvarez GF, Tofe PS, Krishnarajah G, Lyu R, Mavros P, Yin D. Hypoglycaemic symptoms, treatment satisfaction, adherence and their associations with glycaemic goal in patients with type 2 diabetes mellitus: findings from the Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) Study. Diabetes Obes Metab 2008; 10(Suppl. 1): 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: 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: Arechavaleta et al. Volume 13 No. 2 February 2011