Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: A multinational 24-week, randomized clinical trial*† Weiqing WANG,1 Jinkui YANG,2 Gangyi YANG,3 Yan GONG,4 Sanjay PATEL,5 Candice ZHANG,6 Toshiyasu IZUMOTO7 and Guang NING1 1 Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 6Boehringer Ingelheim International Trading, Shanghai, 2Beijing Tongren Hospital, Capital Medical University, Beijing, 3The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China, 4Boehringer Ingelheim Pharma, Ingelheim, Germany, 5Boehringer Ingelheim, Bracknell, UK, and 7Nippon Boehringer Ingelheim, Tokyo, Japan
Correspondence Weiqing Wang, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin 2nd Road, Shanghai 200025, China. Tel: +86 138 1783 6184 Fax: 86 21 64373514 Email: [email protected] *This trial has been registered with ClinicalTrials.gov (ID NCT01215097). † All decisions regarding this paper, coauthored by the Editor-in-Chief, were made by Professor Zachary Bloomgarden. Received 22 April 2014; revised 12 January 2015; accepted 20 February 2015. doi: 10.1111/1753-0407.12284
Abstract Background: Despite the increasing prevalence of type 2 diabetes mellitus (T2DM) in Asia, clinical trials for glucose-lowering therapies are often dominated by Caucasian and/or Western populations. The present Phase III randomized placebo-controlled double-blind, 24-week study evaluated the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin added to metformin in Asian T2DM patients. Methods: In all, 306 patients (n = 265 Chinese; n = 24 Malaysian; n = 17 Filipino), aged 18–80 years with HbA1c between ≥7.0 and ≤10.0% and on metformin therapy were randomized (2:1) to either linagliptin 5 mg daily or placebo added to metformin. Antidiabetes drugs other than metformin were washed out prior to randomization. The primary endpoint was change in mean HbA1c from baseline after 24 weeks. Results: Baseline characteristics were well-matched between the groups (overall mean [±SD] HbA1c 8.0 ± 0.8%). Adjusted mean (±SE) HbA1c decreased in the linagliptin and placebo groups by −0.66 ± 0.05 and −0.14 ± 0.07%, respectively (placebo-corrected difference −0.52 ± 0.09%; 95% confidence interval [CI] −0.70, −0.34; P < 0.0001). In patients with baseline HbA1c ≥8.5%, the placebo-corrected decrease in HbA1c was −0.89 ± 0.17% (P < 0.0001). Adverse events occurred in similar proportions in the linagliptin and placebo patients (27.3% and 28.0%, respectively) and few were considered drug-related (2.4% and 0.0%, respectively). Hypoglycemia occurred in 1.0% of patients in both groups. Linagliptin therapy was weight neutral. Conclusions: Linagliptin 5 mg was efficacious and well tolerated over 24 weeks in Asian patients with T2DM inadequately controlled by metformin. Keywords: Asian patients, dipeptidyl peptidase-4 inhibitor, linagliptin.
Introduction Among Asian individuals, type 2 diabetes mellitus (T2DM) is commonly characterized by early pancreatic β-cell dysfunction and diminishing insulin secretion.1,2 In East Asians in particular, T2DM occurs in people who are younger and who are less obese compared with Caucasian patients of European descent.3 Risk for T2DM begins to appear in this population at a body mass index (BMI) of approximately 23 kg/m2.4 For most patients with T2DM, international guidelines recommend the biguanide metformin as first-line therapy.5,6 As the disease progresses, combination therapy with an additional oral antidiabetes drug (OAD) or basal insulin may be needed to achieve or maintain an HbA1c target.5,6 The paradigm of treatment endorsed jointly by the European Association for the Study of Diabetes and the American Diabetes Association includes five potential two-drug treatment strategies, namely supplementing metformin with either a sulfonylurea, a thiazolidinedione (TZD), a dipeptidyl peptidase (DPP)-4 inhibitor, a glucagon-like peptide (GLP)-1 receptor agonist, or basal insulin, depending on individual patient needs and risk factors.6 In addition, α-glucosidase inhibitors are widely used in Asia despite their association with gastrointestinal side effects. A DPP-4 inhibitor has certain advantages that make it a rational treatment option: unlike GLP-1 agonists and insulin, they are orally administered; unlike sulfonylureas and insulin, they are associated with a low risk for hypoglycemia; and, unlike TZDs and insulin, they are not associated with weight gain.6 Linagliptin is a potent and selective DPP-4 inhibitor that prolongs the half-life of the incretin hormone GLP-1, thereby promoting insulin secretion in a glucose-dependent manner.7 Because linagliptin is eliminated primarily via the bile and gut, it can be used without dose adjustment in patients with chronic kidney disease.8 No dose adjustment is required for patients with impaired liver function. In multinational Phase III clinical trials that included Asian patients, linagliptin as monotherapy or in combination with other glucose-lowering drugs reduced hyperglycemia with a low risk of hypoglycemia and did not cause weight gain.9–12 A pooled analysis of data for South and East Asian patients from these studies suggested that linagliptin was an efficacious and well-tolerated treatment option for Asian patients with inadequately controlled T2DM.13 In a global Phase III trial, linagliptin added to metformin reduced HbA1c by a placeboadjusted mean of −0.64 ± 0.07% (95% confidence interval [CI] −0.78, −0.50; P < 0.0001) over 24 weeks.11 Linagliptin has also been evaluated in combination 230
with metformin plus a sulfonylurea.12 A subgroup analysis of that trial has provided evidence for the efficacy and tolerability of linagliptin and metformin plus sulfonylurea in Chinese patients.14 The present dedicated study was undertaken to evaluate the efficacy and safety of linagliptin 5 mg added to metformin in Asian patients with T2DM.
Methods Study overview The present study was a randomized double-blind placebo-controlled parallel-group multicenter Phase III trial (ClinicalTrials.gov ID: NCT01215097). Prior to randomization, patients on metformin and one other OAD discontinued the other OAD treatment only and underwent a wash-out period of 4 weeks. This patient group was then subjected to a 2-week placebo run-in period. Patients pretreated with metformin alone directly entered the 2-week placebo run-in period. The trial was performed in compliance with the principles laid down in the Declaration of Helsinki, in accordance with the International Conference of Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice, and in accordance with applicable regulatory requirements. All participants provided informed written consent.
Patients The patient population in this study originated from 19 centers in three countries (China, The Philippines, and Malaysia). Eligible patients were men and women aged 18–80 years with inadequately controlled T2DM who had been treated with metformin (stable dose ≥1500 mg/ day or maximum tolerated dose) alone or with one other OAD. Additional inclusion criteria were HbA1c 7.0%– 10.0% at the start of the placebo run-in and BMI ≤45 kg/m2 at screening. Patients were ineligible to participate if they had experienced myocardial infarction, stroke, or transient ischemic attack ≤6 months prior to informed consent; had unstable or acute congestive heart failure; had impaired hepatic function at screening; or confirmed hyperglycemia (glucose ≥240 mg/dL) after overnight fasting during the wash-out or run-in periods. Other key exclusion criteria were treatment with a TZD, insulin, GLP-1 agonist, DPP-4 inhibitor, or anti-obesity drugs; recent alcohol and/or drug abuse; current treatment with systemic steroids; renal failure or impairment at screening; and participation in another trial ≤2 months prior to informed consent.
Treatments Patients who met the entry criteria at the end of the run-in period were randomized to linagliptin 5 mg or matching placebo in a 2:1 ratio. The randomization was stratified by HbA1c (<8.5% or ≥8.5%) at the beginning of the placebo run-in and by previous antidiabetes treatment (metformin monotherapy or combination therapy). Randomization sequence was computer generated using an interactive voice-response system. At the time of treatment allocation, the investigator was blinded to which treatment the next patient would receive. During the randomization period, both the patient and the investigator were blinded to the identity of the treatment. Rescue medication (glimepiride) could be initiated with a confirmed fasting plasma glucose (FPG) level of >240 mg/dL during the first 12 weeks and >200 mg/dL during the last 12 weeks of treatment, or a glucose level >400 mg/dL at a randomly performed measurement. A patient was to be discontinued from the study if his or her FPG remained uncontrolled despite rescue therapy initiated as described above. Endpoints The primary endpoint of the study was change from baseline in HbA1c after 24 weeks. Secondary endpoints were change from baseline in HbA1c in Chinese patients, occurrence of target HbA1c efficacy responses (<7.0% or <6.5%) and a relative efficacy response (−0.5%), change in HbA1c from baseline over time, change in FPG after 24 weeks, and change in FPG from baseline by visit over time. Change from baseline in HbA1c in patients with baseline HbA1c ≥8.5% and changes in lipid profiles and body weight were evaluated as additional efficacy endpoints. Safety was evaluated by the incidence and intensity of adverse events (AEs), including hypoglycemia. Serious AEs were defined as events that resulted in death or were immediately life threatening, resulted in persistent or significant disability, required or prolonged patient hospitalization, led to congenital anomalies or birth defects, or were considered to be an important medical event that may have jeopardized the patient and required medical or surgical intervention to prevent one of the other outcomes. Investigator-defined hypoglycemia was categorized as asymptomatic with plasma glucose ≤70 mg/dL, documented symptomatic with glucose 54–70 mg/dL, documented symptomatic with glucose <54 mg/dL without need for external assistance, and severe (requiring another person’s assistance for active administration of resuscitative actions). Cardiovascular events were adjudicated by an independent clinical event committee
Linagliptin added to metformin in Asians
(CEC). Study sites provided documentation for any event believed to meet the adjudication criteria (nonfatal myocardial infarction, other cardiac ischemia, stroke, transient ischemic attack, or death). Statistical analysis A total of 231 patients was calculated to be necessary to detect a between-group difference of 0.5% in change from baseline in HbA1c with 90% power (two-sided, α = 0.05, SD assumed 1.1%). With estimated drop-out rates of 8% for Chinese patients and 12% for patients from the other countries, sample sizes of ≥190 and ≥95 patients for the linagliptin and placebo groups, respectively, were determined (giving a total population of ≥285). The primary evaluation was performed on the full analysis set (FAS), which included all randomized patients who received at least dose of study drug and had a baseline and at least one on-treatment HbA1c measurement. The primary analysis of change in HbA1c from baseline to Week 24 was assessed using an analysis of covariance, with baseline HbA1c as a linear covariate and prior use of antidiabetes agents and treatment as fixed classification effects. Missing values were imputed using last observation carried forward (LOCF) by assuming that patients with missing values had failed to achieve the response. Adjusted mean change from baseline in FPG was assessed on an LOCF basis with continuous baseline FPG as an additional covariate. Categorical HbA1c responses and changes in HbA1c and FPG were assessed without imputation of missing data. Lipids were analyzed on an observed cases basis in the FAS. Safety data were analyzed descriptively on the treated set, which consisted of all randomized patients who received at least one dose of study drug.
Results The trial was conducted between 11 November 2010 and 16 April 2012. In all, 306 Asian patients with T2DM were randomized to linagliptin or placebo (n = 265 Chinese; n = 24 Malaysian; n = 17 Filipino). One patient randomized to the placebo group was not treated. Thus, the treated set comprised 205 and 100 patients in the linagliptin and placebo groups, respectively, whereas the FAS consisted of 203 and 97 patients, respectively, meeting the specified criteria. Of the treated patients, 93.2% of patients randomized to linagliptin and 88.0% of those randomized to placebo completed the trial (Fig. 1). Baseline demographics and clinical characteristics were well matched between treatment groups, with mean
Figure 1 Disposition of randomized patients. *Note, 101 patients were randomized, but only 100 patients received treatment.
(±SD) baseline HbA1c of 7.99 ± 0.83% and 8.00 ± 0.80% in the linagliptin and placebo groups, respectively (Table 1). In the overall population, 49.5% of participants had a BMI ≤25 kg/m2. Most patients (90%) had a mean daily metformin dose >1500 mg at baseline. Approximately one-third of the overall population had been receiving two OADs prior to randomization. Efficacy After 24 weeks, treatment with linagliptin was superior to placebo at reducing hyperglycemia. Adjusted mean (±SE) HbA1c decreased by −0.66 ± 0.05% in the linagliptin group compared with −0.14 ± 0.07% in the placebo group, for a placebo-corrected difference of −0.52 ± 0.09% (95% CI −0.70, −0.34; P < 0.0001; Fig. 2). Results for the predefined Chinese subgroup were similar to those for the overall Asian population (adjusted mean change in HbA1c after 24 weeks −0.69 ± 0.06% and −0.17 ± 0.08% for linagliptin and placebo, respectively). Significantly greater HbA1c reductions were observed with linagliptin versus placebo in patients with baseline HbA1c <8.5% or ≥8.5% (Fig. 3). More patients in the linagliptin than placebo group achieved an HbA1c of <7.0% or <6.5%, or a reduction in HbA1c of ≥0.5%. Among patients with baseline HbA1c ≥7.0%, the glycemic target of <7.0% was attained by 37.3% and 10.1% in the linagliptin and placebo groups, respectively. The target of <6.5% was attained by 12.9% and 3.1% of patients in the linagliptin and placebo groups, respectively (one patient in each treatment group had a baseline HbA1c measurement <6.5%). Reductions in HbA1c ≥0.5% were achieved in 59.1% and 34.0% of linagliptin- and placebo-treated patients, respectively. There was a significant reduction in FPG in the linagliptin compared with placebo group. Adjusted mean (±SE) FPG decreased by −10.7 ± 2.5 and −1.1 ± 3.5 mg/dL in the linagliptin and placebo groups, respec232
Figure 2 Adjusted mean change in HbA1c from baseline (a) at Week 24 and (b) over time (full analysis set – last observation carried forward) with linagliptin or placebo as add-on therapy to metformin. The model includes treatment, baseline HbA1c, and previous antidiabetes medication. Data are the mean ± SE.
Baseline demographics and clinical characteristics Linagliptin 5 mg
No. patients (treated set) Age (years) Gender Male Female Country China Malaysia Philippines Body weight (kg) BMI (kg/m2) eGFR (mL/min per 1.73 m2) ≥90 60 to <90 30 to <60 <30 No. patients (full analysis set) HbA1c (%) FPG (mg/dL) Time since diagnosis (years) ≤1 >1–5 >5 Total daily metformin dose <1500 mg ≥1500 mg No. OADs prior to washout 1 2 Antidiabetes drugs at enrolment Metformin only Metformin + sulfonylurea Metformin + α-glucosidase inhibitor Metformin + other antidiabetes drugs
Data are given as the mean ± SD or as the number of subjects in each group, with percentages in parentheses. BMI, body mass index; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; OAD, oral antidiabetes drug.
tively (placebo-corrected difference −9.6 ± 4.2 mg/dL [95% C: −17.8, −1.3]; P = 0.02; Fig. 4). Similarly, across visits, the adjusted mean decrease in FPG over time was significantly greater with linagliptin than placebo. Mean lipid profiles, assessed on observed cases only, were within normal to slightly above normal ranges at baseline and remained mostly unchanged with both linagliptin and placebo after 24 weeks (Table 2). No clinically relevant trends in laboratory parameters or vital signs were observed. Mean (±SD) body weight decreased slightly in both the linagliptin and placebo groups (–0.12 ± 2.83 and −0.67 ± 2.64 kg at Week 24, respectively) with no significant difference between treatments. No increases in BMI or waist circumference were observed in either group.
Safety Linagliptin was well tolerated, with AEs occurring in a similar proportion of patients as in the placebo group (27.3% vs 28.0%, respectively; Table 3). Drug-related AEs were reported for 2.4% and 0.0% of linagliptin- and placebo-treated patients, respectively. Small proportions of patients in both groups discontinued therapy due to AEs (2.9% of linagliptin patients and 1.0% of placebo patients). Serious AEs were experienced by four patients in the linagliptin group. One patient had an alanine transaminase increase that was considered drug related. The other serious AEs (one case of gastric cancer, one of prostatic hyperplasia, and one of comminuted fracture) were not
Figure 3 Adjusted mean change in HbA1c from baseline at Week 24 in patients with baseline HbA1c <8.5% and ≥8.5% (full analysis set – last observation carried forward). The model includes categorical baseline HbA1c, number of previous antidiabetes drugs, treatment group, and the treatment × baseline HbA1c (categorical) interaction. Data are the mean ± SE.
Table 2 Changes in lipid levels from baseline at Week 24 (full analysis set – observed cases)
Total cholesterol n Baseline (mmol/L) Week 24 (mmol/L) HDL-C n Baseline (mmol/L) Week 24 (mmol/L) LDL-C n Baseline (mmol/L) Week 24 (mmol/L) Triglycerides n Baseline (mmol/L) Week 24 (mmol/L)
Linagliptin 5 mg
188 4.72 ± 0.07 4.76 ± 0.07
85 4.78 ± 0.11 4.89 ± 0.10
188 1.28 ± 0.02 1.31 ± 0.02
85 1.34 ± 0.04 1.34 ± 0.04
188 2.59 ± 0.06 2.64 ± 0.06
85 2.67 ± 0.10 2.72 ± 0.10
188 1.96 ± 0.10 1.92 ± 0.14
85 1.80 ± 0.14 1.99 ± 0.23
Data are given as the mean ± SE. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
considered drug related. The unrelated case of gastric cancer was discovered on Day 49 of randomized therapy, and the patient discontinued linagliptin 37 days later. Two patients in the placebo group had serious AEs (one case of lacunar infarction and one of choleocystitis). Neither event was considered drug related by the investigators. No cases of pancreatitis or pancreatic cancer were observed in either treatment group, and no patient 2344 4
Figure 4 Adjusted mean change in fasting plasma glucose (FPG) from baseline (a) at Week 24 and (b) over time (full analysis set – last observation carried forward) with linagliptin or placebo as add-on therapy to metformin. The model includes treatment, baseline HbA1c, baseline FPG, and previous antidiabetes medication. Data are the mean ± SE.
experienced renal failure. No patients were hospitalized for heart failure, and no cases of worsening heart failure were reported. One instance of suspected myocardial ischemia was observed in the linagliptin group. That, along with the instance of lacunar infarction in the placebo group, was referred to the CEC for adjudication. The CEC determined that the patient on linagliptin did not experience a prespecified cardiovascular event, and the patient on placebo was not assessable because of insufficient information. Hypoglycemic events were rare: investigator-defined hypoglycemia was experienced by 1.0% of patients in the linagliptin and placebo groups (n = 2 and 1, respectively), and none of the events was considered severe. Discussion In the present Phase III randomized clinical trial of Asian patients with T2DM and insufficient glycemic
Number of patients experiencing adverse events over 24 weeks (treated set)
Any AE AE by MedDRA-preferred term with an incidence >2.5% Hyperglycemia Hyperlipidemia Upper respiratory tract infection Drug-related AEs* Gastrointestinal disorders Investigations Metabolism and nutrition disorders Skin and subcutaneous tissue disorders AEs leading to discontinuation Serious AEs Fatal Requiring hospitalization Other Investigator-defined hypoglycemia Confirmed adjudicated cardiovascular events
Data show the number of subjects in each group, with percentages in parentheses. *Listed by system organ class in alphabetical order. †Alanine aminotransferase increased. AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities (version 15.0).
control with metformin alone, once-daily add-on treatment with linagliptin 5 mg was superior to placebo at reducing hyperglycemia over 24 weeks. The incidence of hypoglycemia with linagliptin added to metformin was very low, and treatment did not increase mean body weight. Overall, linagliptin was well tolerated in Asian patients in the present study. No clinically relevant safety issues arose during the evaluation period, and no cases of pancreatitis or pancreatic cancer were observed. These results support the findings of a previous 24-week Phase III trial in a mixed, multinational population.11 That trial randomized 701 patients with T2DM inadequately controlled by metformin to linagliptin add-on to metformin or placebo in a 3:1 ratio. With linagliptin, HbA1c was reduced by a placebo-corrected −0.64 ± 0.07% (95% CI −0.78, −0.50; P < 0.0001) with a very low incidence of hypoglycemia and without weight gain. Both FPG and postprandial glucose (PPG) were significantly reduced with linagliptin compared with placebo. Linagliptin has previously been compared with glimepiride as add-on therapy to metformin in a 2-year non-inferiority trial.15 Results from that trial showed linagliptin was similar to glimepiride in managing hyperglycemia, but linagliptin was associated with a lower incidence of hypoglycemia (7% vs 36%) and severe hypoglycemia (1% vs 2%). In addition, in that study linaglip-
tin was found to have a lower risk of cardiovascular events than glimepiride (odds ratio 0.46 [95% CI 0.23, 0.91]; P = 0.0213). Other DPP-4 inhibitors have been evaluated as addons to metformin therapy in Asian populations.16–18 These 24-week trials showed glucose-lowering benefits that were comparable to the findings of the present study. In the present trial, we observed that one-third of patients in the placebo plus metformin group experienced an HbA1c reduction ≥0.5% (compared with 59.1% of linagliptin plus metformin patients). This response suggests the occurrence of a placebo effect that is similar in magnitude to the results of trials with saxagliptin plus metformin and vildagliptin plus metformin in Asian T2DM populations.17,18 The result may reflect the more rigorous adherence to diet and exercise of a clinical trial setting. In the present study, 35% of participants had mild-tomoderate renal impairment (none had severe impairment). Although efficacy and safety results were not analyzed for the subpopulation with kidney disease, linagliptin has previously been shown to be efficacious and well tolerated in T2DM populations with moderate-tosevere renal impairment.19,20 Importantly, no dose adjustments are needed when administering linagliptin to patients with reduced renal function.8
This trial did not include assessment of the effects of linagliptin on PPG, which is an important consideration for Asian patients with T2DM. Asian diets tend to be high in carbohydrates, making control of prandial glucose excursions a challenge. Previous multinational trials with linagliptin have included meal-tolerance testing, and have shown significant reductions in 2-h PPG.9,11 These findings are in line with the mode of action of DPP-4 inhibition, which promotes PPGdependent insulin secretion through preservation of GLP-1. A pooled analysis of Asian patient data from the linagliptin clinical trials program showed a placebocorrected reduction in 2-h PPG of −56.9 mg/dL (95% CI −85.17, −28.52).13 Homeostatic model assessments of β-cell function were not measured in the present trial, but they were included in previous trials and showed improvements with linagliptin.9–12 We acknowledge several other limitations affecting the interpretation of our study findings. The trial duration was 24 weeks, which does not permit a long-term safety evaluation of linagliptin in Asian patients. The study was also not powered to evaluate clinical outcomes in this population, such as impact on cardiovascular events. The present study was a robustly conducted randomized clinical trial in a population that has been underrepresented in clinical research of T2DM therapies. In the absence of studies such as this one, treatment decisions for Asian patients with T2DM have often been based on extrapolations of data derived in mostly Caucasian populations. However, potentially relevant pathophysiological differences exist between Asians and Caucasians with T2DM, so the present dataset provides clinically important information for Asian patients. In summary, the findings of the present trial provide evidence that add-on therapy with linagliptin once daily is efficacious and well tolerated over 24 weeks in Asian patients with T2DM inadequately controlled on metformin. Acknowledgements This work was supported by Boehringer Ingelheim Pharma GmbH & Co. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Mark Poirier (Envision Scientific Solutions) during the preparation of this manuscript. Disclosure WW, JY, GY, and GN have no financial interests to disclose. YG, SP, and TI are employees of Boehringer 2366
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