Oral Administration of Apple Pectin Solution Improves Atopic Dermatitis in a Mouse Model.

The development of atopic dermatitis (AD) involves multiple factors. Three such factors are particularly important in AD onset: immune abnormalities, skin barrier dysfunction, and itching. Many studies report that an imbalance between helper T (Th)1 and Th2 cells causes AD. Apple pectin, a prebiotic, has preventative effects in other allergic diseases (e.g., bronchial asthma and AD), but its potential benefits in AD are unclear. In this study, we investigated the effect of oral apple pectin administration on skin inflammation in an AD mouse model and examined changes in T cells involved in AD. To induce AD, a picryl chloride solution was applied to the shaved back skin of male NC/Nga mice. AD mice then received an oral apple pectin solution (0.4% or 4%) for 35 d. Compared with untreated AD mice, mice in both apple pectin-treated groups showed improvement in AD-induced inflammation and skin symptoms. Histological evaluation showed that apple pectin treatment attenuated epidermal thickening and decreased the number of mast cells and CD4+ cells in AD-induced mice. Apple pectin treatment also reduced serum IgE concentration, as well as expression of the inflammation indicator cyclooxygenase-2 and the Th2-related factors thymic stromal lymphopoietin, interleukin-4, and GATA3. Additionally, increased mRNA expression of the genes that encode interferon-γ and T-bet, which are Th1-related factors, and forkhead box protein P3, were observed in the apple pectin-treated groups. Our findings suggest that apple pectin treatment ameliorates AD by increasing regulatory T cells and improving the Th1/Th2 balance in the skin of AD model mice.

Efficacy and safety of the sodium-glucose co-transporter-2 inhibitor empagliflozin in elderly Japanese adults (≥65 years) with type 2 diabetes: A randomized, double-blind, placebo-controlled, 52-week clinical trial (EMPA-ELDERLY).

AIM: Use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) for glycaemic control is increasing in individuals with type 2 diabetes (T2D) for their additional benefits on heart failure and chronic kidney disease. However, SGLT2is generally reduce body weight, which might promote sarcopenia in older individuals. We evaluated the effects of the SGLT2i empagliflozin on muscle mass and strength in addition to glucose control in elderly adults with T2D. MATERIALS AND METHODS: Individuals with T2D aged ≥65 years with body mass index ≥22 kg/m2 and glycated haemoglobin (HbA1c) 7.0%-10.0% were randomized 1:1 to once-daily empagliflozin 10 mg or placebo for 52 weeks. The primary endpoint was change from baseline in HbA1c at week 52. Secondary endpoints included changes from baseline in muscle mass and strength. RESULTS: Of the 129 individuals randomized, 72.4% were men, mean age 74.1 years, body mass index 25.6 kg/m2 and HbA1c 7.6%. The placebo-adjusted mean change from baseline in HbA1c at week 52 with empagliflozin was -0.57% [95% confidence interval (CI) -0.78, -0.36]. Change in body weight was -3.26 kg and -0.90 kg with empagliflozin and placebo, respectively (placebo-adjusted difference: -2.37 kg; 95% CI -3.07, -1.68). Placebo-adjusted change in muscle mass was -0.61 kg (95% CI -1.61, 0.39), fat mass -1.84 kg (95% CI -2.65, -1.04) and grip strength -0.3 kg (95% CI -1.1, 0.5). CONCLUSIONS: Empagliflozin improved glucose control and reduced body weight without compromising muscle mass or strength in elderly adults with T2D in this trial.

Rationale and design of the EMPA-ELDERLY trial: a randomised, double-blind, placebo-controlled, 52-week clinical trial of the efficacy and safety of the sodium-glucose cotransporter-2 inhibitor empagliflozin in elderly Japanese patients with type 2 diabetes.

INTRODUCTION: Elderly 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 ANALYSIS: EMPA-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 DISSEMINATION: We will submit the trial results to conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04531462.

Efficacy and safety of empagliflozin as add-on to insulin in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial.

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.

Safety and Efficacy of Empagliflozin as Add-On Therapy to GLP-1 Receptor Agonist (Liraglutide) in Japanese Patients with Type 2 Diabetes Mellitus: A Randomised, Double-Blind, Parallel-Group Phase 4 Study.

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.

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 as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial.

AIMS: This double-blind, randomized, placebo-controlled trial (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. METHODS: The 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. RESULTS: Change 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. CONCLUSIONS: These results support the notion that empagliflozin-linagliptin in fixed-dose combination is a therapeutic option for Japanese patients with type 2 diabetes.

The efficacy and long-term safety of a triple combination of 80 mg telmisartan, 5 mg amlodipine and 12.5 mg hydrochlorothiazide in Japanese patients with essential hypertension: a randomized, double-blind study with open-label extension.

The aim of this study was to compare 80 mg telmisartan/5 mg amlodipine/12.5 mg hydrochlorothiazide (T80/A5/H12.5) with 80 mg telmisartan/12.5 mg hydrochlorothiazide (T80/H12.5) to determine their relative blood pressure (BP) lowering effects in essential hypertensive patients with inadequate control and to evaluate the long-term safety of T80/A5/H12.5 in a 52-week extension period. Patients (n=132) were randomly assigned to receive double-blind treatment with T80/A5/H12.5 or T80/H12.5 for 8 weeks after a 6-week run-in-period of T80/H12.5. All 126 patients who completed the double-blind period entered the 52-week open-label extension and received T80/A5/H12.5. The adjusted mean changes from the reference baseline of the trough-seated systolic and diastolic BP (SBP/DBP) at week 8 were significantly larger in the T80/A5/H12.5 group (-10.6/-8.8 mm Hg) than in the T80/H12.5 group (-2.3/-1.3 mm Hg) (P<0.0001). The BP-lowering effect of T80/A5/H12.5 was maintained over the 52-week extension period. The adverse events (AEs) during both treatment periods were generally mild. Drug-related AEs were reported in one patient in each group in the double-blind period and in five patients exposed to T80/A5/H12.5 in the double-blind and/or open-label extension period. T80/A5/H12.5 therapy was clinically and statistically superior to T80/H12.5 therapy for the reduction of BP in patients with essential hypertension uncontrolled with T80/H12.5, and its BP-lowering effect was maintained in the long term. T80/A5/H12.5 was generally well-tolerated.

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.