Long-Term Efficacy and Safety of Linagliptin in a Japanese Population with Type 2 Diabetes Aged ≥ 60 Years Treated with Basal Insulin: A Randomised Trial

Abstract

Introduction: An estimated 4.3 million people aged ≥ 65 years with diabetes live in Japan. We evaluated the efficacy and safety of linagliptin in older Japanese patients with poorly controlled type 2 diabetes (T2DM).

Methods: In this phase 4, randomised, placebo-controlled national study (part of a global study) conducted in Japan over a period of 52 weeks, 102 patients on stable treatment with basal insulin ± metformin/alpha-glucosidase inhibitors were randomised (1:1) to receive linagliptin 5 mg qd or placebo. The primary end point was the change in glycated haemoglobin (HbA1c) after 24 weeks of treatment, with additional analyses at 52 weeks.

Results: Mean age and HbA1c of the study population were 71 years and 8.1%, respectively. Approximately two-thirds of participants were aged ≥ 70 years, two-thirds had macrovascular complications, approximately half had a baseline estimated glomerular filtration rate < 60 ml/min/1.73 m2, and two-thirds had a time since diagnosis of diabetes > 10 years. Significant HbA1c reductions with linagliptin vs. placebo were observed at 24 weeks, - 0.71% (95% CI - 0.96, - 0.45, p < 0.0001), and maintained at 52 weeks, - 0.58% (95% CI - 0.82, - 0.34, p < 0.0001). Linagliptin improved the chances of achieving a categorical HbA1c target (< 8.0% and < 7.0%) at 24 and 52 weeks in patients who were not at their respective target at the beginning of the study. Addition of linagliptin to insulin was associated with a numerical increase in the risk of any hypoglycaemia, but not in the risk of clinically significant hypoglycaemia, severe hypoglycaemia or recurring hypoglycaemia.

Conclusion: Linagliptin was effective in improving glucose control in Japanese patients aged ≥ 60 years with T2DM on stable glucose-lowering therapy with basal insulin. Linagliptin was well tolerated and no new safety concerns were raised. The results presented here are highly consistent with the results from the global study, which was conducted over a 24-week period.

Trial registration: ClinicalTrials.gov identifier, NCT02240680.

Funding: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.

Keywords: Basal insulin; DPP-4 inhibitors; Elderly patients; Japanese; Linagliptin; Type 2 diabetes.

Figures

Fig. 1

Change in HbA1c from baseline at weeks 24 and 52 (a); change over time in HbA1c (b) and FPG (c). aMMRM analysis, FAS (OC), model includes baseline HbA1c, baseline daily basal insulin, baseline HbA1c by week interaction as linear covariates, treatment, week, treatment by week interaction as fixed effects and patient as random effect. bMMRM analysis, FAS (OC), model includes treatment, week and treatment by week interaction as fixed categorical effects and baseline FPG, baseline HbA1c and baseline daily basal insulin dose as fixed linear covariates as well as baseline FPG by week interaction. CI confidence interval, FAS full analysis set—all patients who were treated with ≥ 1 dose of study medication and had a baseline and ≥ 1 on-treatment HbA1c measurement. HbA1c glycated haemoglobin, MMRM mixed model repeating measurements, OC observed cases

Fig. 2

Proportion of patients with HbA1c a) and < 7.0% (b) and no hypoglycaemia accompanied by a prespecified glucose valuea after 24 and 52 weeks, FAS (NCF). aAny hypoglycaemia with BG < 54 mg/dl (3.0 mmol/l) as measured by the central laboratory (FPG) or SMBG device, any symptomatic event ≤ 70 mg/dl (3.9 mmol/l) or severe hypoglycaemia (requiring third-party assistance to administer carbohydrate or glucagon). bLogistic regression model includes continuous baseline HbA1c and baseline daily basal insulin as linear covariates and treatment as a fixed effect. c Only participants who were not at the HbA1c target of < 8.0% and < 7.0% at the beginning of the trial (HbA1c ≥ 8.0% and ≥ 7.0%, respectively) were included in the analysis. CI confidence interval, FAS full analysis set—all patients who were treated with ≥ 1 dose of study medication and had a baseline and ≥ 1 on-treatment HbA1c measurement. FPG fasting plasma glucose, HbA1c glycated haemoglobin, NCF non-completers considered failures, SMBG self-monitoring blood glucose

Fig. 3

Hypoglycaemia accompanied by a prespecified glucose valuea over 24 and 52 weeks, FAS (OC): proportion of patients with ≥ 1 episode (a) and recurring hypoglycaemia (b). aAny hypoglycaemia with BG < 54 mg/dl (3.0 mmol/l) as measured by the central laboratory (FPG) or SMBG device, or any symptomatic hypoglycaemic event with BG ≤ 70 mg/dl (3.9 mmol/l) or any severe hypoglycaemic event (defined as requiring third-party assistance to administer carbohydrate or glucagon). bLogistic regression model includes continuous baseline HbA1c, baseline daily basal insulin as linear covariates and treatment as a fixed effect. cNegative binomial model includes terms for treatment, baseline HbA1c, baseline daily basal insulin dose and adjusted for log (days of follow-up). BG blood glucose, CI confidence interval, FAS full analysis set—all patients who were treated with ≥ 1 dose of study medication and had a baseline and ≥ 1 on-treatment HbA1c measurement. FPG fasting plasma glucose, OC observed cases, SMBG self-monitoring blood glucose