Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2015.1010638
Vol. 31, No. 3, 2015, 503–512
Article ST-0341.R1/1010638 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Original article Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus Wayne H.-H. Sheu Taichung Veterans General Hospital, Taichung, Taiwan School of Medicine, National Yang-Ming University Hospital, Taipei, Taiwan School of Medicine, National Defense Medical Center, Taipei, Taiwan
Sung Woo Park Kangbuk Samsung Hospital, Seoul, South Korea
Yan Gong Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
Sabine Pinnetti Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Sudipta Bhattacharya Formerly Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany AstraZeneca GmbH, Wedel, Germany
Sanjay Patel Boehringer Ingelheim Ltd, Bracknell, UK
Thomas Seck Hans-Juergen Woerle Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany Address for correspondence: Wayne H.-H. Sheu, Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Taichung, Taiwan (ROC). Tel.: +886 4 23592829; Fax: +886 4 23592728; [email protected]
Abstract Objective: To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents. Research design and methods: This was a post hoc analysis of Asian patients from a global 52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator’s discretion to improve glycemic control. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) from baseline to 24 weeks. Results: Data were available for 154 Asian patients (80 linagliptin, 74 placebo). Baseline HbA1c (standard deviation [SD]) was 8.6 (0.9)% (70 [10] mmol/mol). The placebo-corrected mean change (standard error [SE]) in HbA1c from baseline was 0.9 (0.1)% (10 [1] mmol/mol) (95% confidence interval [CI]: 1.2, 0.7; p50.0001) at Week 24 and 0.9 (0.1)% (10 [1] mmol/mol) (95% CI: 1.1, 0.6; p50.0001) at Week 52. The frequency of adverse events (linagliptin 81.3%, placebo 91.9%) and hypoglycemia (Week 24: linagliptin 25.0%, placebo 25.7%; treatment end: linagliptin 28.8%, placebo 35.1%) was similar between groups. By Week 52, changes (SE) in mean body weight were similar in both groups (linagliptin 0.67 [0.26] kg, placebo 0.38 [0.25] kg). Conclusions: This study was limited by the post hoc nature of the analysis and the small number of patients in the subgroup. However, the results suggest that linagliptin significantly improves glycemic control in Asian patients with T2DM inadequately controlled by basal insulin, without increasing the risk for hypoglycemia or weight gain. ClinicalTrials identifier: NCT00954447.
Introduction Keywords: Asian patients – Basal insulin – Linagliptin – Type 2 diabetes mellitus Accepted: 14 January 2015; published online: 13 February 2015 Citation: Curr Med Res Opin 2015; 31:503–12
! 2015 Informa UK Ltd www.cmrojournal.com
The geographical region comprising South-East Asia and Western Pacific includes more than half of the total number of patients diagnosed with diabetes mellitus1. In recent decades, Asia has undergone vast socioeconomic development, accounting for changes in dietary patterns, decreases in physical activity, and increases in obesity, as well as the implementation of screening programs at the national or community level2. The incidence and detection of type 2 Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
503
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 3
March 2015
diabetes mellitus (T2DM) in Asia has therefore increased rapidly. Epidemiologic data have shown that the onset of T2DM occurs in Asian patients at a relatively young age and low body mass index compared with individuals in Western countries3. The underlying pathophysiology in the development of T2DM in Asian patients is believed to be dominated by the deterioration of b-cell function in both obese and non-obese patients2,4–6, which might relate to higher postprandial hyperglycemia7,8. Among Asian patients, T2DM is also associated with a high risk of complications. Chronic kidney disease, which can progress to end-stage renal disease, is considered a potentially serious complication, which can also affect the pharmacologic responses to commonly used oral antidiabetes drugs (OADs)9,10. Moreover, the incidence of hypoglycemia has been found to be high in the AsiaPacific region, with one study showing that 35.8% of patients receiving OADs have experienced hypoglycemic symptoms11. Concerns about hypoglycemia often prevent patients with T2DM and their physicians from initiating or up-titrating basal insulin treatment, allowing uncontrolled hyperglycemia to remain above their goal. Taken together, these findings suggest an important clinical need to establish the efficacy and safety of new OADs in combination with insulin. In this regard, linagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors may supplement basal insulin therapy because they specifically target postprandial glucose concentration in a glucose-dependent manner, although fasting glucose control is also improved12. DPP-4 inhibitors therefore have a low risk for hypoglycemia if used in monotherapy or with oral agents that by themselves do not increase the risk for hypoglycemia or weight gain13, which are the major limitations of other OADs. Linagliptin is an oral DPP-4 inhibitor that is now licensed in a large number of countries, including numerous Asian countries, for the treatment of T2DM in a once daily dose regimen. Linagliptin is unique since it is primarily excreted via the bile and gut, and therefore does not require dose adjustment in patients with declining renal function10,14. In multinational phase III clinical trials, including several in patients from Asian countries, linagliptin was well tolerated and achieved clinically meaningful improvements in glycemic control when administered alone15,16, in combination with metformin17 or pioglitazone18, as add-on therapy to a combination of metformin and sulfonylurea19, or as add-on therapy to a number of different OADs including biguanide, glinide, glitazone, sulfonylurea, or a-glucosidase inhibitors20. Treatment with linagliptin was associated with a low risk of hypoglycemia, except when used in combination with sulfonylurea, and was weight neutral. In an additional phase III study, upon which the present subgroup analysis is based, linagliptin added to basal insulin therapy in inadequately controlled patients elicited clinically meaningful 504
Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
reductions in glycated hemoglobin (HbA1c) and was well tolerated without an increased risk for hypoglycemia compared with placebo21. In the present analysis, the efficacy and safety of linagliptin as add-on therapy to basal insulin alone, or in combination with metformin and/or pioglitazone, was evaluated in the subgroup of Asian patients with T2DM from the global study assessing linagliptin as add-on to basal insulin21.
Patients and methods This was a post hoc analysis of a phase III clinical trial in patients with inadequate glycemic control who were randomized to receive double-blind treatment with linagliptin 5 mg or placebo for 52 weeks as add-on therapy to basal insulin alone, or in combination with metformin and/or pioglitazone (ClinicalTrials.gov identifier NCT00954447)21. The background dose of basal insulin was kept stable for the first 24 weeks of treatment, after which adjustments could be made according to the investigator’s discretion to improve glycemic control (Figure 1). The dose of background OADs remained stable throughout the study. The design and methodology of this trial have previously been described in detail21. The trial protocol was carried out according to the principles of the Declaration of Helsinki and International Conference on Harmonization Guideline for Good Clinical Practice. The trial protocol was reviewed and approved by the independent ethics committees or institutional review boards of all participating centers. This analysis included data for all patients of Asian race. As in the parent study, the primary efficacy endpoint was the mean HbA1c change from baseline after 24 weeks of treatment. Secondary endpoints included the change from baseline in HbA1c, the proportion of patients achieving HbA1c 57.0% (53 mmol/mol) and reduction in HbA1c of 0.5% (6 mmol/mol), fasting plasma glucose (FPG) over time, and change from baseline in FPG after 52 weeks. Other endpoints were the change from baseline in mean basal insulin dose over time and after 52 weeks of treatment, the use of rescue medication, and the change from baseline in body weight to the end of treatment. Safety and tolerability assessments included the frequency and intensity of adverse events (AEs), including hypoglycemia, clinically relevant new or worsening findings in physical examination, 12-lead electrocardiogram, vital signs, lipid parameters, and clinical laboratory assessments. Other safety endpoints included treatment-emergent fatal events and suspected events of stroke or cardiac ischemia (including myocardial infarction), hospitalization for heart failure, stent thrombosis, and revascularization procedures, reviewed by an independent external clinical event committee. www.cmrojournal.com ! 2015 Informa UK Ltd
Placebo run-in period (2 weeks)
Assessment of eligibility
Free basal insulin dose
Linagliptin 5 mg qd n = 631 (80 Asian)
Linagliptin 5 mg qd n = 631 (80 Asian)
R
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Placebo qd n = 630 (74 Asian)
Primary efficacy endpoint
Assessment of eligibility
Stable basal insulin dose
24 weeks
Placebo qd n = 630 (74 Asian)
March 2015
Main safety endpoint
Current Medical Research & Opinion Volume 31, Number 3
≥28 weeks FPG target 6.1 mmol/L
Treatment duration: ≥52 weeks
Figure 1. Study design. FPG, fasting plasma glucose; qd, once daily; R, randomization.
Efficacy endpoints were evaluated using the full analysis set, defined as all randomized patients treated with 1 dose of study medication, with a baseline HbA1c measurement and 1 on-treatment HbA1c measurement within the first 24 weeks of treatment. Continuous data were analyzed using either last observation carried forward or observed cases, while categorical data (the percentage of patients who achieved HbA1c 57.0% or 0.5% reduction in HbA1c at week 24 and week 52) were analyzed with a non-completers considered failure approach (e.g. patients who did not complete 24 or 52 weeks of treatment were counted as not having achieved an HbA1c of 57% or a 0.5% reduction in HbA1c). The change from baseline in HbA1c at Week 24 was compared between the linagliptin and placebo groups with an analysis of covariance (ANCOVA) model at the level of ¼ 0.025 (onesided). This model was used to derive adjusted values that accounted for between-group differences in the following baseline covariates, which may have influenced treatment response: treatment, concomitant OADs (none, metformin only, pioglitazone only, or metformin þ pioglitazone), baseline renal function impairment category (normal renal function, mild impairment, moderate impairment, or severe impairment), and baseline HbA1c. Secondary endpoints were also analyzed using an ANCOVA model. The impact of treatment on the occurrence of hypoglycemia was investigated using logistic regression and Kaplan–Meier analysis. Safety endpoints were summarized using descriptive statistics.
Results Patient disposition, demographics, and baseline clinical characteristics Of the 1261 patients randomized in the parent study21, 154 were Asian (linagliptin n ¼ 80, placebo n ¼ 74). Of these, ! 2015 Informa UK Ltd www.cmrojournal.com
15 patients in the linagliptin group and 12 patients in the placebo group prematurely discontinued trial medication. Baseline demographics and clinical characteristics in the Asian subgroup for linagliptin and placebo were similar between treatment groups (Table 1). Most patients had either normal renal function (50.0%) or mild renal impairment (44.2%), and had been diagnosed with diabetes for 45 years (84.3%). All patients were receiving basal insulin at study entry and the majority of patients were also receiving metformin (81.5%). Approximately 4% of patients received metformin and pioglitazone combination therapy in addition to insulin. No patients in this study were taking pioglitazone in addition to insulin.
Efficacy outcomes Treatment with linagliptin resulted in a statistically significant improvement in HbA1c, with a placebo-corrected adjusted mean change (standard error [SE]) of 0.9 (0.1)% (10 [1] mmol/mol) at 24 weeks (Table 2 and Figure 2). A treatment effect was maintained up to Week 52. More patients in the linagliptin group compared with the placebo group reached the HbA1c target of57.0% (53 mmol/ mol) both at Week 24 and Week 52 (Table 3). Compared with the placebo group, patients in the linagliptin group were also more likely to achieve a reduction in HbA1c of 0.5% (6 mmol/mol) after 24 and 52 weeks of treatment (Table 3). At Week 24, following the stable basal insulin period, only the linagliptin group showed a decrease in the adjusted mean change in FPG from baseline, resulting in a significant placebo-corrected adjusted change from baseline (Figure 3). By Week 52 (when basal insulin titration was allowed in both groups), FPG levels were not lower than baseline in either group. However, as at Week 24, there was a significant placebo-corrected adjusted change from baseline in FPG at Week 52. Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
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Table 1. Baseline demographics and clinical characteristics.
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Demographics Patients (treated set*), n Males, n (%) Age, years, mean (SD) Age group, n (%) 565 years 65 years Body mass index, kg/m2, mean (SD) Renal function (eGFR) according to MDRD, n (%) Normal (90 mL/min) Mild impairment (60 to 590 mL/min) Moderate impairment (30 to 560 mL/min) Severe to end-stage impairment (530 mL/min) Clinical characteristics Patients (full analysis sety), n HbA1c, %, mean (SD) HbA1c, mmol/mol, mean (SD) FPG, mmol/L, mean (SD) Time since diagnosis of diabetes, mean (SD) 1 year, n (%) 41 to 5 years, n (%) 45 years, n (%) Type of basal insulin, n (%) Insulin glargine Insulin detemir NPH Concomitant OADs, n (%) None Metformin only Pioglitazone only Metformin þ pioglitazone
Linagliptin
Placebo
80 40 (50.0) 57.5 (10.1)
74 33 (44.6) 56.7 (9.6)
57 (71.3) 23 (28.8) 25.6 (3.6)
61 (82.4) 13 (17.6) 26.2 (3.4)
40 (50.0) 33 (41.3) 6 (7.5) 1 (1.3)
37 (50.0) 35 (47.3) 1 (1.4) 1 (1.4)
79 8.5 (0.9) 69 (10) 7.3 (2.3)
74 8.6 (0.9) 70 (10) 7.5 (2.2)
4 (5.1) 12 (15.2) 63 (79.7)
4 (5.4) 4 (5.4) 66 (89.2)
46 (58.2) 15 (19.0) 18 (22.8)
51 (68.9) 15 (20.3) 8 (10.8)
7 (8.9) 69 (87.3) 0 (0.0) 3 (3.8)
15 (20.3) 56 (75.7) 0 (0.0) 3 (4.1)
*All patients who were treated with 1 dose of study medication. yAll patients who had a baseline and 1 on-treatment HbA1c measurement. eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; MDRD, modification of diet in renal disease; NPH, neutral protamine Hagedorn; OADs, oral antidiabetes drugs; SD, standard deviation.
Table 2. Adjusted mean change in HbA1c from baseline at Week 24 and Week 52*.
Week 24 Patients*, n Mean at baseline, % (SE) (mmol/mol [SE]) Change from baseline, % (SE) (mmol/mol [SE]) Adjustedy mean Difference vs. placebo Adjustedy mean, % (SE) (mmol/mol [SE]) 95% CI p-value Week 52 Change from baseline, % (SE) (mmol/mol [SE]) Adjustedy mean Difference vs. placebo Adjustedy mean, % (SE) (mmol/mol [SE]) 95% CI p-value
Linagliptin
Placebo
79 8.5 (0.1) (69 [1])
74 8.6 (0.1) (70 [1])
0.9 (0.2) (10 [2])
0.0 (0.2) (0 [2])
0.9 (0.1) (10 [1]) 1.2, 0.7 50.001 0.6 (0.2) (7 [2])
0.2 (0.2) (2 [2])
0.9 (0.1) (10 [1]) 1.1, 0.6 50.001
*Full analysis set – all patients who had 1 baseline and 1 on-treatment HbA1c measurement. yAdjusted model includes treatment, baseline HbA1c, categories of renal function impairment, and concomitant oral antidiabetes drugs. Last observation carried forward analysis. CI, confidence interval; HbA1c, glycated hemoglobin; SE, standard error. Based on observed cases (i.e. patients who completed 24 and 52 weeks of treatment) mean HbA1c values were 7.48 (n ¼ 67) (linagliptin) and 8.52 (n ¼ 68) (placebo) at Week 24, and 7.52 (n ¼ 55) (linagliptin) and 8.40 (n ¼ 49) (placebo) at Week 52.
506
Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 3
0.50
Linagliptin 5 mg qd
Week 52 Placebo-corrected difference = −0.9% (95% CI: −1.1, −0.6; p
Vol. 31, No. 3, 2015, 503–512
Article ST-0341.R1/1010638 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Original article Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus Wayne H.-H. Sheu Taichung Veterans General Hospital, Taichung, Taiwan School of Medicine, National Yang-Ming University Hospital, Taipei, Taiwan School of Medicine, National Defense Medical Center, Taipei, Taiwan
Sung Woo Park Kangbuk Samsung Hospital, Seoul, South Korea
Yan Gong Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
Sabine Pinnetti Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Sudipta Bhattacharya Formerly Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany AstraZeneca GmbH, Wedel, Germany
Sanjay Patel Boehringer Ingelheim Ltd, Bracknell, UK
Thomas Seck Hans-Juergen Woerle Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany Address for correspondence: Wayne H.-H. Sheu, Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Taichung, Taiwan (ROC). Tel.: +886 4 23592829; Fax: +886 4 23592728; [email protected]
Abstract Objective: To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents. Research design and methods: This was a post hoc analysis of Asian patients from a global 52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator’s discretion to improve glycemic control. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) from baseline to 24 weeks. Results: Data were available for 154 Asian patients (80 linagliptin, 74 placebo). Baseline HbA1c (standard deviation [SD]) was 8.6 (0.9)% (70 [10] mmol/mol). The placebo-corrected mean change (standard error [SE]) in HbA1c from baseline was 0.9 (0.1)% (10 [1] mmol/mol) (95% confidence interval [CI]: 1.2, 0.7; p50.0001) at Week 24 and 0.9 (0.1)% (10 [1] mmol/mol) (95% CI: 1.1, 0.6; p50.0001) at Week 52. The frequency of adverse events (linagliptin 81.3%, placebo 91.9%) and hypoglycemia (Week 24: linagliptin 25.0%, placebo 25.7%; treatment end: linagliptin 28.8%, placebo 35.1%) was similar between groups. By Week 52, changes (SE) in mean body weight were similar in both groups (linagliptin 0.67 [0.26] kg, placebo 0.38 [0.25] kg). Conclusions: This study was limited by the post hoc nature of the analysis and the small number of patients in the subgroup. However, the results suggest that linagliptin significantly improves glycemic control in Asian patients with T2DM inadequately controlled by basal insulin, without increasing the risk for hypoglycemia or weight gain. ClinicalTrials identifier: NCT00954447.
Introduction Keywords: Asian patients – Basal insulin – Linagliptin – Type 2 diabetes mellitus Accepted: 14 January 2015; published online: 13 February 2015 Citation: Curr Med Res Opin 2015; 31:503–12
! 2015 Informa UK Ltd www.cmrojournal.com
The geographical region comprising South-East Asia and Western Pacific includes more than half of the total number of patients diagnosed with diabetes mellitus1. In recent decades, Asia has undergone vast socioeconomic development, accounting for changes in dietary patterns, decreases in physical activity, and increases in obesity, as well as the implementation of screening programs at the national or community level2. The incidence and detection of type 2 Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
503
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 3
March 2015
diabetes mellitus (T2DM) in Asia has therefore increased rapidly. Epidemiologic data have shown that the onset of T2DM occurs in Asian patients at a relatively young age and low body mass index compared with individuals in Western countries3. The underlying pathophysiology in the development of T2DM in Asian patients is believed to be dominated by the deterioration of b-cell function in both obese and non-obese patients2,4–6, which might relate to higher postprandial hyperglycemia7,8. Among Asian patients, T2DM is also associated with a high risk of complications. Chronic kidney disease, which can progress to end-stage renal disease, is considered a potentially serious complication, which can also affect the pharmacologic responses to commonly used oral antidiabetes drugs (OADs)9,10. Moreover, the incidence of hypoglycemia has been found to be high in the AsiaPacific region, with one study showing that 35.8% of patients receiving OADs have experienced hypoglycemic symptoms11. Concerns about hypoglycemia often prevent patients with T2DM and their physicians from initiating or up-titrating basal insulin treatment, allowing uncontrolled hyperglycemia to remain above their goal. Taken together, these findings suggest an important clinical need to establish the efficacy and safety of new OADs in combination with insulin. In this regard, linagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors may supplement basal insulin therapy because they specifically target postprandial glucose concentration in a glucose-dependent manner, although fasting glucose control is also improved12. DPP-4 inhibitors therefore have a low risk for hypoglycemia if used in monotherapy or with oral agents that by themselves do not increase the risk for hypoglycemia or weight gain13, which are the major limitations of other OADs. Linagliptin is an oral DPP-4 inhibitor that is now licensed in a large number of countries, including numerous Asian countries, for the treatment of T2DM in a once daily dose regimen. Linagliptin is unique since it is primarily excreted via the bile and gut, and therefore does not require dose adjustment in patients with declining renal function10,14. In multinational phase III clinical trials, including several in patients from Asian countries, linagliptin was well tolerated and achieved clinically meaningful improvements in glycemic control when administered alone15,16, in combination with metformin17 or pioglitazone18, as add-on therapy to a combination of metformin and sulfonylurea19, or as add-on therapy to a number of different OADs including biguanide, glinide, glitazone, sulfonylurea, or a-glucosidase inhibitors20. Treatment with linagliptin was associated with a low risk of hypoglycemia, except when used in combination with sulfonylurea, and was weight neutral. In an additional phase III study, upon which the present subgroup analysis is based, linagliptin added to basal insulin therapy in inadequately controlled patients elicited clinically meaningful 504
Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
reductions in glycated hemoglobin (HbA1c) and was well tolerated without an increased risk for hypoglycemia compared with placebo21. In the present analysis, the efficacy and safety of linagliptin as add-on therapy to basal insulin alone, or in combination with metformin and/or pioglitazone, was evaluated in the subgroup of Asian patients with T2DM from the global study assessing linagliptin as add-on to basal insulin21.
Patients and methods This was a post hoc analysis of a phase III clinical trial in patients with inadequate glycemic control who were randomized to receive double-blind treatment with linagliptin 5 mg or placebo for 52 weeks as add-on therapy to basal insulin alone, or in combination with metformin and/or pioglitazone (ClinicalTrials.gov identifier NCT00954447)21. The background dose of basal insulin was kept stable for the first 24 weeks of treatment, after which adjustments could be made according to the investigator’s discretion to improve glycemic control (Figure 1). The dose of background OADs remained stable throughout the study. The design and methodology of this trial have previously been described in detail21. The trial protocol was carried out according to the principles of the Declaration of Helsinki and International Conference on Harmonization Guideline for Good Clinical Practice. The trial protocol was reviewed and approved by the independent ethics committees or institutional review boards of all participating centers. This analysis included data for all patients of Asian race. As in the parent study, the primary efficacy endpoint was the mean HbA1c change from baseline after 24 weeks of treatment. Secondary endpoints included the change from baseline in HbA1c, the proportion of patients achieving HbA1c 57.0% (53 mmol/mol) and reduction in HbA1c of 0.5% (6 mmol/mol), fasting plasma glucose (FPG) over time, and change from baseline in FPG after 52 weeks. Other endpoints were the change from baseline in mean basal insulin dose over time and after 52 weeks of treatment, the use of rescue medication, and the change from baseline in body weight to the end of treatment. Safety and tolerability assessments included the frequency and intensity of adverse events (AEs), including hypoglycemia, clinically relevant new or worsening findings in physical examination, 12-lead electrocardiogram, vital signs, lipid parameters, and clinical laboratory assessments. Other safety endpoints included treatment-emergent fatal events and suspected events of stroke or cardiac ischemia (including myocardial infarction), hospitalization for heart failure, stent thrombosis, and revascularization procedures, reviewed by an independent external clinical event committee. www.cmrojournal.com ! 2015 Informa UK Ltd
Placebo run-in period (2 weeks)
Assessment of eligibility
Free basal insulin dose
Linagliptin 5 mg qd n = 631 (80 Asian)
Linagliptin 5 mg qd n = 631 (80 Asian)
R
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Placebo qd n = 630 (74 Asian)
Primary efficacy endpoint
Assessment of eligibility
Stable basal insulin dose
24 weeks
Placebo qd n = 630 (74 Asian)
March 2015
Main safety endpoint
Current Medical Research & Opinion Volume 31, Number 3
≥28 weeks FPG target 6.1 mmol/L
Treatment duration: ≥52 weeks
Figure 1. Study design. FPG, fasting plasma glucose; qd, once daily; R, randomization.
Efficacy endpoints were evaluated using the full analysis set, defined as all randomized patients treated with 1 dose of study medication, with a baseline HbA1c measurement and 1 on-treatment HbA1c measurement within the first 24 weeks of treatment. Continuous data were analyzed using either last observation carried forward or observed cases, while categorical data (the percentage of patients who achieved HbA1c 57.0% or 0.5% reduction in HbA1c at week 24 and week 52) were analyzed with a non-completers considered failure approach (e.g. patients who did not complete 24 or 52 weeks of treatment were counted as not having achieved an HbA1c of 57% or a 0.5% reduction in HbA1c). The change from baseline in HbA1c at Week 24 was compared between the linagliptin and placebo groups with an analysis of covariance (ANCOVA) model at the level of ¼ 0.025 (onesided). This model was used to derive adjusted values that accounted for between-group differences in the following baseline covariates, which may have influenced treatment response: treatment, concomitant OADs (none, metformin only, pioglitazone only, or metformin þ pioglitazone), baseline renal function impairment category (normal renal function, mild impairment, moderate impairment, or severe impairment), and baseline HbA1c. Secondary endpoints were also analyzed using an ANCOVA model. The impact of treatment on the occurrence of hypoglycemia was investigated using logistic regression and Kaplan–Meier analysis. Safety endpoints were summarized using descriptive statistics.
Results Patient disposition, demographics, and baseline clinical characteristics Of the 1261 patients randomized in the parent study21, 154 were Asian (linagliptin n ¼ 80, placebo n ¼ 74). Of these, ! 2015 Informa UK Ltd www.cmrojournal.com
15 patients in the linagliptin group and 12 patients in the placebo group prematurely discontinued trial medication. Baseline demographics and clinical characteristics in the Asian subgroup for linagliptin and placebo were similar between treatment groups (Table 1). Most patients had either normal renal function (50.0%) or mild renal impairment (44.2%), and had been diagnosed with diabetes for 45 years (84.3%). All patients were receiving basal insulin at study entry and the majority of patients were also receiving metformin (81.5%). Approximately 4% of patients received metformin and pioglitazone combination therapy in addition to insulin. No patients in this study were taking pioglitazone in addition to insulin.
Efficacy outcomes Treatment with linagliptin resulted in a statistically significant improvement in HbA1c, with a placebo-corrected adjusted mean change (standard error [SE]) of 0.9 (0.1)% (10 [1] mmol/mol) at 24 weeks (Table 2 and Figure 2). A treatment effect was maintained up to Week 52. More patients in the linagliptin group compared with the placebo group reached the HbA1c target of57.0% (53 mmol/ mol) both at Week 24 and Week 52 (Table 3). Compared with the placebo group, patients in the linagliptin group were also more likely to achieve a reduction in HbA1c of 0.5% (6 mmol/mol) after 24 and 52 weeks of treatment (Table 3). At Week 24, following the stable basal insulin period, only the linagliptin group showed a decrease in the adjusted mean change in FPG from baseline, resulting in a significant placebo-corrected adjusted change from baseline (Figure 3). By Week 52 (when basal insulin titration was allowed in both groups), FPG levels were not lower than baseline in either group. However, as at Week 24, there was a significant placebo-corrected adjusted change from baseline in FPG at Week 52. Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
505
Current Medical Research & Opinion Volume 31, Number 3
March 2015
Table 1. Baseline demographics and clinical characteristics.
Curr Med Res Opin Downloaded from informahealthcare.com by Yale Dermatologic Surgery on 05/14/15 For personal use only.
Demographics Patients (treated set*), n Males, n (%) Age, years, mean (SD) Age group, n (%) 565 years 65 years Body mass index, kg/m2, mean (SD) Renal function (eGFR) according to MDRD, n (%) Normal (90 mL/min) Mild impairment (60 to 590 mL/min) Moderate impairment (30 to 560 mL/min) Severe to end-stage impairment (530 mL/min) Clinical characteristics Patients (full analysis sety), n HbA1c, %, mean (SD) HbA1c, mmol/mol, mean (SD) FPG, mmol/L, mean (SD) Time since diagnosis of diabetes, mean (SD) 1 year, n (%) 41 to 5 years, n (%) 45 years, n (%) Type of basal insulin, n (%) Insulin glargine Insulin detemir NPH Concomitant OADs, n (%) None Metformin only Pioglitazone only Metformin þ pioglitazone
Linagliptin
Placebo
80 40 (50.0) 57.5 (10.1)
74 33 (44.6) 56.7 (9.6)
57 (71.3) 23 (28.8) 25.6 (3.6)
61 (82.4) 13 (17.6) 26.2 (3.4)
40 (50.0) 33 (41.3) 6 (7.5) 1 (1.3)
37 (50.0) 35 (47.3) 1 (1.4) 1 (1.4)
79 8.5 (0.9) 69 (10) 7.3 (2.3)
74 8.6 (0.9) 70 (10) 7.5 (2.2)
4 (5.1) 12 (15.2) 63 (79.7)
4 (5.4) 4 (5.4) 66 (89.2)
46 (58.2) 15 (19.0) 18 (22.8)
51 (68.9) 15 (20.3) 8 (10.8)
7 (8.9) 69 (87.3) 0 (0.0) 3 (3.8)
15 (20.3) 56 (75.7) 0 (0.0) 3 (4.1)
*All patients who were treated with 1 dose of study medication. yAll patients who had a baseline and 1 on-treatment HbA1c measurement. eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; MDRD, modification of diet in renal disease; NPH, neutral protamine Hagedorn; OADs, oral antidiabetes drugs; SD, standard deviation.
Table 2. Adjusted mean change in HbA1c from baseline at Week 24 and Week 52*.
Week 24 Patients*, n Mean at baseline, % (SE) (mmol/mol [SE]) Change from baseline, % (SE) (mmol/mol [SE]) Adjustedy mean Difference vs. placebo Adjustedy mean, % (SE) (mmol/mol [SE]) 95% CI p-value Week 52 Change from baseline, % (SE) (mmol/mol [SE]) Adjustedy mean Difference vs. placebo Adjustedy mean, % (SE) (mmol/mol [SE]) 95% CI p-value
Linagliptin
Placebo
79 8.5 (0.1) (69 [1])
74 8.6 (0.1) (70 [1])
0.9 (0.2) (10 [2])
0.0 (0.2) (0 [2])
0.9 (0.1) (10 [1]) 1.2, 0.7 50.001 0.6 (0.2) (7 [2])
0.2 (0.2) (2 [2])
0.9 (0.1) (10 [1]) 1.1, 0.6 50.001
*Full analysis set – all patients who had 1 baseline and 1 on-treatment HbA1c measurement. yAdjusted model includes treatment, baseline HbA1c, categories of renal function impairment, and concomitant oral antidiabetes drugs. Last observation carried forward analysis. CI, confidence interval; HbA1c, glycated hemoglobin; SE, standard error. Based on observed cases (i.e. patients who completed 24 and 52 weeks of treatment) mean HbA1c values were 7.48 (n ¼ 67) (linagliptin) and 8.52 (n ¼ 68) (placebo) at Week 24, and 7.52 (n ¼ 55) (linagliptin) and 8.40 (n ¼ 49) (placebo) at Week 52.
506
Linagliptin þ insulin in Asian patients with T2DM Sheu et al.
www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 3
0.50
Linagliptin 5 mg qd
Week 52 Placebo-corrected difference = −0.9% (95% CI: −1.1, −0.6; p
