Linagliptin as add-on to empagliflozin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a two-part, randomized, placebo-controlled trial.

AIMS: This two-part, double-blind, double-dummy, randomized, placebo-controlled trial (83 sites) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg and linagliptin (Lina) 5 mg fixed-dose combinations (FDCs) in Japanese patients with type 2 diabetes mellitus (T2DM) who were poorly controlled with Empa. MATERIALS AND METHODS: Patients (previously drug-naive or using one oral antidiabetic drug for ≥ 12 weeks) entered an open-label stabilization period (16 weeks, Empa 10 mg [Part A] or Empa 25 mg [Part B]). Subsequently, they received Empa 10 mg plus placebo (Plc) for Empa/Lina10/5 (Empa/Plc 10/5; Part A) or Empa 25 mg plus Plc for Empa/Lina 25/5 (Empa/Plc 25/5; Part B) for 2 weeks. Patients with HbA1c 7.5-10.0% were randomized (1:1) to a 24-week regimen of once-daily Empa/Lina 10/5 (n = 107) or Empa/Plc 10/5 (n = 108) in Part A, or to Empa/Lina 25/5 (n = 116) or Empa/Plc 25/5 (n = 116) in Part B, with a 28-week extension period in Part B. RESULTS: Change from baseline in HbA1c at Week 24 was greater (P < 0.0001) with Empa/Lina than with Empa/Plc (primary outcome, Empa/Lina 10/5: -0.94 vs -0.12%; adjusted mean difference, -0.82%; Empa/Lina 25/5: -0.91 vs -0.33%; adjusted mean difference, -0.59%). Over 24- and 52-week periods, higher proportions of patients achieved HbA1c < 7.0% and greater decreases in fasting plasma glucose were observed with Empa/Lina compared with Empa/Plc. Empa/Lina was well tolerated, with no unexpected adverse events or diabetic ketoacidosis. One case of confirmed hypoglycaemia with Empa/Plc 25/5 was reported. CONCLUSIONS: These results support Empa/Lina FDC as a potential option for Japanese patients with T2DM who require combination therapy. ClinicalTrials.gov NCT02489968.

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial.

AIMS: This phase 2, double-blind, randomized, placebo-controlled trial (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 METHODS: Participants 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. RESULTS: PD: 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. CONCLUSIONS: Based 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.

Empagliflozin Induces Transient Diuresis Without Changing Long-Term Overall Fluid Balance in Japanese Patients With Type 2 Diabetes.

INTRODUCTION: Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, ameliorates hyperglycemia in patients with type 2 diabetes (T2D) by inducing sustained glucosuria. Empagliflozin treatment was previously associated with a transient increase in 24-h urine volume in Caucasian patients with T2D, however comparable evidence in Japanese T2D individuals is scarce. We therefore assessed acute and chronic changes in 24-h urine volume and fluid intake with empagliflozin in Japanese patients with T2D. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, multiple-dose, 4-week trial, 100 Japanese patients with T2D were randomized to receive either 1, 5, 10, or 25 mg empagliflozin or placebo once-daily. Changes from baseline in 24-h urine volume and fluid intake were assessed at days 1, 27, and 28 after the initiation of empagliflozin. RESULTS: The 24-h urine volume and fluid intake were comparable across all treatment groups at baseline. Patients treated with either 10 or 25 mg empagliflozin (i.e., the licensed doses in Japan) showed a significant increase in 24-h urine volume compared to placebo at day 1 (mean change from baseline: + 0.83, + 1.08, and + 0.29 L/day in the empagliflozin 10 and 25 mg groups and the placebo group, respectively; both p < 0.001 vs. placebo). However, 24-h urine volume levels in the empagliflozin groups were comparable to placebo at day 27 and 28 (differences vs placebo < 0.1 L/day; p > 0.05). The 24-h fluid intake was comparable across all study groups throughout the entire study period. No events consistent with dehydration were reported during empagliflozin treatment. CONCLUSION: Treatment initiation with empagliflozin in Japanese patients with T2D was associated with transient diuresis; however, overall urine volume returned towards baseline levels within 4 weeks of treatment. These findings are consistent with a physiological, adaptive mechanism of the kidney to maintain overall body fluid balance in response to treatment initiation with a SGLT2 inhibitor. TRIAL REGISTRATION NUMBER: NCT00885118. FUNDING: Nippon Boehringer Ingelheim Co., Ltd.

Effect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study.

The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ⩾20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5.