AimsThis phase 2, double‐blind, randomized, placebo‐controlled trial (http://clinicaltrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin.Materials and methodsParticipants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%‐10.0%, entered a 2‐week, open‐label, placebo run‐in period, followed by a 4‐week, double‐blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment.ResultsPD: Empagliflozin resulted in a dose‐dependent significant increase in 24‐hour UGE compared with placebo (UGE placebo‐corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose‐dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose‐dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported.ConclusionsBased on this short‐duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non‐Japanese participants.

AimsThis double‐blind, randomized, placebo‐controlled trial (http://clinicaltrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add‐on to linagliptin (Lina) 5 mg (fixed‐dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients.MethodsThe trial (40 sites; May 2015‐March 2017) involved screening 433 adults (≥20 years) who were treatment‐naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%‐10.0% after ≥16 weeks of using Lina (pre‐enrolment or during a 16‐week, open‐label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once‐daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up‐titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks.ResultsChange from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, −0.93% vs 0.21%; adjusted mean difference, −1.14%) and Week 52 (−1.16% vs 0.06%; adjusted mean difference, −1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin‐associated events (eg, increased urination, increased blood ketones). There were no adjudication‐confirmed diabetic ketoacidosis events or lower limb amputations.ConclusionsThese results support the notion that empagliflozin‐linagliptin in fixed‐dose combination is a therapeutic option for Japanese patients with type 2 diabetes.

Aim To assess the efficacy and safety of empagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes (T2D). Materials and methods This multicentre, double‐blind, parallel‐group study randomized Japanese patients with T2D insufficiently controlled with insulin (1:1:1) to empagliflozin 10 mg (n=89), empagliflozin 25 mg (n=90) or placebo (n=90) for 52 weeks. The primary endpoint was change from baseline in glycated haemoglobin (HbA1c) at 16 weeks. Results At 16 weeks, empagliflozin 10 mg and 25 mg significantly decreased HbA1c: adjusted mean difference −0.92% (95% confidence interval [CI] −1.11, −0.73) and −1.00% (95% CI −1.18, −0.82; both P<0.0001) compared with placebo. This difference was maintained up to 52 weeks: adjusted mean difference at 52 weeks −0.90% (95% CI −1.09, −0.70) and −0.96% (95% CI −1.15, −0.77; both P<0.0001). At 52 weeks, significant improvements in fasting plasma glucose (adjusted mean difference −27.62 mg/dL [95% CI −36.15, −19.08] and −31.99 mg/dL [95% CI −40.35, −23.62]) and in body weight (−1.78 kg [95% CI −2.46, −1.10] and −1.92 kg [95% CI −2.58, −1.25]) were also seen with empagliflozin 10 mg and 25 mg compared with placebo (all P<0.0001). At 52 weeks, the frequency of adverse events (AEs) and serious AEs was similar in the three treatment groups; confirmed hypoglycaemia was reported slightly more in participants in the empagliflozin 10 mg and 25 mg groups (23.3% and 22.2% vs 14.4%). All hypoglycaemic events were mild in severity; no episodes required assistance. Conclusions In Japanese patients with insufficiently controlled T2D, adding empagliflozin 10 mg or 25 mg to insulin treatment was associated with clinically meaningful reductions in HbA1c at 16 weeks and was generally well tolerated.

Introduction Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) by inducing urinary glucose excretion. Combination therapy with empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonists had not previously been assessed, so we investigated the safety, tolerability and efficacy of empagliflozin as an add-on therapy to liraglutide, a GLP-1 receptor agonist. Methods This was a randomised, double-blind, parallel-group phase 4 trial of empagliflozin (10 mg or 25 mg) for 52 weeks as an add-on therapy to liraglutide (0.9 mg/day) in Japanese patients with T2DM insufficiently controlled by liraglutide alone. Results 59.4% (19/32) and 66.7% (22/33) of patients in the empagliflozin 10 mg and 25 mg groups, respectively, reported at least one adverse event (AE). 9.4% (3/32) and 21.2% (7/33) of patients, respectively, reported drug-related AEs (primary endpoint). From baseline to week 52, adjusted mean changes with empagliflozin 10 mg and 25 mg, respectively, were: − 0.55 (standard error: 0.15) and − 0.77 (0.14)% for glycated haemoglobin; − 32.5 (4.6) and − 36.0 (4.5) mg/dL for fasting plasma glucose; − 2.6 (0.4) and −3.1 (0.3) kg for body weight; − 6.7 (2.2) and − 8.4 (2.1) mmHg for systolic blood pressure; and − 3.0 (1.2) and − 4.7 (1.1) mmHg for diastolic blood pressure. Conclusion Empagliflozin as an add-on to liraglutide for 52 weeks was well tolerated and led to clinically meaningful and sustained improvements in glycaemic control, body weight and blood pressure in Japanese patients with T2DM. Trial Registration ClinicalTrials.gov with the identifier NCT02589626. Funding Nippon Boehringer Ingelheim Co. Ltd. Electronic supplementary material The online version of this article (10.1007/s13300-019-0604-8) contains supplementary material, which is available to authorized users.

IntroductionElderly people (≥65 years) with type 2 diabetes mellitus (T2DM) are becoming increasingly prevalent, notably in Japan. As cardiovascular (CV) risk increases with age and sodium–glucose cotransporter-2 (SGLT2) inhibitors reduce CV risk, elderly patients with T2DM are increasingly likely to be prescribed these glucose-lowering drugs. There is controversy surrounding the effects of SGLT2 inhibitors on muscle mass, particularly in elderly patients for whom loss of muscle is especially undesirable; however, robust evidence on this important issue is lacking. Consequently, we have designed a clinical trial of the SGLT2 inhibitor empagliflozin in elderly Japanese patients with T2DM (Empagliflozin in Elderly T2DM Patients (EMPA-ELDERLY)) to assess its effects on body composition as well as glycaemic control. EMPA-ELDERLY will be the first randomised clinical trial of an SGLT2 inhibitor in elderly patients with T2DM to evaluate effects on skeletal muscle mass, muscle strength and physical performance concurrently.Methods and analysisEMPA-ELDERLY is a randomised, double-blind, placebo-controlled, parallel-group clinical trial to be conducted in Japan. Patients with T2DM aged ≥65 years are eligible if they are Japanese with a body mass index of ≥22 kg/m2 and glycated haemoglobin (HbA1c) levels from ≥7.0% to ≤10.0% from either diet and exercise alone or treatment with oral glucose-lowering drugs. Approximately 128 participants will be randomised 1:1 to once per day, oral, double-blind treatment with empagliflozin 10 mg or matching placebo for 52 weeks. The primary endpoint is the change in HbA1c level from baseline at week 52. Secondary endpoints include changes from baseline to 52 weeks in body composition, including muscle mass and body fat, measured by bioelectrical impedance analysis, as well as skeletal muscle index, grip strength and time in the five-time chair stand test. Other endpoints include changes in patient-reported outcomes (including quality of life), cognitive function and safety.Ethics and disseminationWe will submit the trial results to conferences and peer-reviewed journals.Trial registration numberNCT04531462.