OBJECTIVEWe investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODSPatients inadequately controlled on MDI insulin 6 metformin (mean HbA 1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m 2 ; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25 mg (n = 189), or placebo (n = 188) for 52 weeks. Insulin dose was to remain stable in weeks 1-18, adjusted to meet glucose targets in weeks 19-40, then stable in weeks 41-52. The primary end point was change from baseline in HbA 1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA 1c at week 52. RESULTSAdjusted mean 6 SE changes from baseline in HbA 1c were 20.50 6 0.05% (25.5 6 0.5 mmol/mol) for placebo versus 20.94 6 0.05% (210.3 6 0.5 mmol/mol) and 21.02 6 0.05% (211.1 6 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P < 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA 1c of 20.81 6 0.08% (28.9 6 0.9 mmol/mol), 21.18 6 0.08% (212.9 6 0.9 mmol/mol), and 21.27 6 0.08% (213.9 6 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA 1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA 1c <7% (<53 mmol/mol) with empagliflozin (31-42%) versus placebo (21%; both P < 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (29 to 211 international units/day) and weight (22.4 to 22.5 kg) versus placebo (all P < 0.01) at week 52. CONCLUSIONSIn obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.
Purpose: The current study aimed to compare 2 topical diclofenac products (diclofenac diethylamine [DEA] 1.16% emulsion and diclofenac sodium [Na] 5% gel). The quantitative evaluation of skin permeability and the qualitative evaluation of their physical characteristics were performed. Methods: The skin permeability of diclofenac DEA 1.16% emulsion and diclofenac Na 5% gel was compared in vitro using Franz diffusion cells following a single, fixed, 10 mg/cm 2 dose of product applied to a 0.64 cm 2 area of the stratum corneum surface of ex vivo human skin samples. The physical characteristics of the 2 formulations were assessed by rheological measurement and microscopy observation. Results: Diclofenac DEA 1.16% emulsion exhibited a statistically significant higher permeation through human skin at 24 hrs than diclofenac Na 5% gel (554 vs 361 ng/cm 2 , respectively; ratio of adjusted geometric means, 1.54 [95% CI, 1.14–2.07]). When expressed as a percentage of the applied dose of diclofenac that permeated through human skin, a 7-fold difference was observed between the diclofenac DEA 1.16% emulsion (0.54%) and the diclofenac Na 5% gel (0.077%). Qualitative composition and physical characterization showed differences between the formulations that may explain some of the permeation data observed. Based on rheological assessments, diclofenac Na 5% gel had a higher viscosity (24.82 Pa.s) than diclofenac DEA 1.16% emulsion (10.29 Pa.s). Conclusion: A topical diclofenac product with a higher concentration of the active ingredient does not necessarily lead to greater absorption relative to a product with lower concentration of the active ingredient but different characteristics. These observations highlight the importance of considering parameters beyond drug concentration, such as composition, which may influence the solubility of the drug and permeation of topical nonsteroidal anti-inflammatory drugs.
Background: Topical diclofenac, a nonsteroidal anti-inflammatory drug, has proven efficacy and safety in the management of osteoarthritis pain. We investigated penetration of topical diclofenac into knee synovial tissue and fluid (primary objective) and evaluated relative exposure in the knee versus plasma (secondary objective). Methods: In this phase I, double-blind, multicenter study, patients scheduled for arthroplasty for end-stage knee osteoarthritis were randomly assigned 2:1 to 4 g diclofenac diethylamine 2.32% w/w gel (92.8 mg diclofenac diethylamine, equivalent to 74.4 mg diclofenac, per application) or placebo gel, applied to the affected knee by a trained nurse/designee every 12 h for 7 days before surgery. Diclofenac concentrations were measured in synovial tissue, synovial fluid and plasma from samples obtained during surgery ⩾12 h after last application. Treatment-emergent adverse events (TEAEs) were evaluated. Results: Evaluable synovial tissue or fluid samples were obtained from 45 (diclofenac n = 29; placebo n = 16) of 47 patients. All diclofenac-treated participants had measurable diclofenac concentrations in synovial tissue [geometric mean 1.57 (95% confidence interval (CI) 1.12, 2.20) ng/g] and fluid [geometric mean 2.27 (95% CI 1.87, 2.76) ng/ml] ⩾12 h after the last dose. Geometric mean (95% CI) ratio of diclofenac in synovial tissue:plasma was 0.32 (0.23, 0.45) and in synovial fluid:plasma was 0.46 (0.40, 0.54). TEAE rates were similar for diclofenac (55.2%) and placebo (58.8%); none were treatment related. Conclusions: Topical diclofenac diethylamine 2.32% w/w gel penetrated into the osteoarthritic knee after repeated application and remained detectable in synovial tissue and fluid at the end of the final 12 h dosing cycle.
Background and Objective: Maintaining adequate glycaemic control reduces the long-term risk of some type 2 diabetes (T2D) complications. Despite this, many individuals with T2D do not have their treatment intensified and remain on suboptimal HbA1c targets. It is therefore important to consider which treatment will enable patients to maintain glycaemic control over time. To date, continuous patient-level data for duration of time spent with HbA1c < 7.0% (53 mmol/mol) and the likelihood of maintaining HbA1c < 7.0% in the PIONEER efficacy trials have not been reported. The PIONEER phase 3a clinical trial programme evaluated the efficacy and safety of oral semaglutide vs active comparators (empagliflozin, sitagliptin and subcutaneous [s.c.] liraglutide) and placebo in patients with T2D. – PIONEER 2–4 and 7 consistently demonstrated that greater proportions of patients achieved HbA1c < 7.0% at week 26 (or week 52 for PIONEER 7) with oral semaglutide compared with active comparators or placebo. Objective: This post hoc analysis of the PIONEER 2–4 and 7 trials aimed to determine the duration of time patients spent with HbA1c. Methods: Mean duration of time spent with HbA1c <7.0%. Proportion of patients achieving HbA1 <7.0% for different time intervals. Estimated odds ratio of achieving HbA1c <7.0% at week 26 (week 24 for PIONEER 7, as week 26 data were unavailable) and week 52 (and week 78 for PIONEER 3). Data are for all randomised patients from PIONEER 2–4 and 7 assigned to receive oral semaglutide or active comparator (empagliflozin, sitagliptin, s.c. liraglutide). Oral semaglutide dose was escalated, starting at 3 mg once daily and increasing to 7 mg after 4 weeks and then to 14 mg after 8 weeks in all trials except PIONEER 7, which used a flexible dose adjustment approach based on HbA1c and gastrointestinal tolerability. Empagliflozin was initiated at 10 mg and escalated to 25 mg after 8 weeks. Sitagliptin was initiated at 100 mg and not escalated. S.c. liraglutide was initiated at 0.6 mg and escalated to 1.2 mg and then 1.8 mg after 1 and 2 weeks, respectively. For each patient, duration of time spent with HbA1c <7.0% was calculated based on the HbA1c–time curve derived using all visits with HbA1c measurements and linear interpolation between two consecutive visits. Study visits were scheduled for every 4–8 weeks. Outcomes were evaluated for oral semaglutide vs active comparators using the on-treatment without rescue medication observation period. Patients who discontinued treatment early or who used rescue medication were considered not in glycaemic control after the event in question. Results: Mean baseline HbA1c ranged from 8.0 to 8.3% (64–67 mmol/mol). Across PIONEER 2, 3 and 7, mean duration of time spent with HbA1c <7.0% was greater with oral semaglutide 14 mg, or flexibly dosed, than with oral competitors empagliflozin 25 mg and sitagliptin 100 mg (Figure 2). – Similar mean duration was observed between oral semaglutide and s.c. liraglutide 1.8 mg in PIONEER 4. There was a significantly greater likelihood of maintaining HbA1c <7.0% for >75% of the trial duration compared with empagliflozin 25 mg and sitagliptin 100 mg (Figure 3). – Similar proportions were observed between oral semaglutide 14 mg and s.c. liraglutide 1.8 mg Summary: Oral semaglutide 14 mg, or flexibly dosed, resulted in a greater duration of time spent with HbA1c <7.0% vs empagliflozin and sitagliptin. Oral semaglutide 14 mg resulted in a similar duration of time spent with HbA1c < 7.0% to s.c. liraglutide, despite a longer dose escalation with oral semaglutide. The odds of maintaining HbA1c <7.0% at weeks 24/26 and 52 (and 78 for PIONEER 3) were significantly greater with oral semaglutide vs empagliflozin, sitagliptin and s.c. liraglutide. Conclusion: In patients with T2D, oral semaglutide may lead to longer sustained glycaemic control vs oral comparators, on an individual level
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