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Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly alone, or dapagliflozin alone added to metformin monotherapy in subgroups of patients with type 2 diabetes in the DURATION-8 randomized controlled trial.
Frías, JP, Hardy, E, Ahmed, A, Öhman, P, Jabbour, S, Wang, H, Guja, C
Diabetes, obesity & metabolism. 2018;(6):1520-1525
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Abstract
This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1 mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55 kg for body weight. Potential treatment-by-subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m2 (least-squares mean reductions of -23.6 vs -19.0 mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0 mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9 mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range -2.56 to -3.98 kg vs -0.56 to -2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.
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Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study.
Fadini, GP, Zatti, G, Baldi, I, Bottigliengo, D, Consoli, A, Giaccari, A, Sesti, G, Avogaro, A, ,
Diabetes, obesity & metabolism. 2018;(7):1781-1786
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Abstract
In randomized controlled trials (RCTs), sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to confer glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase-4 inhibitors, gliclazide, or glucagon-like peptide-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose-lowering medications (GLMs), 6751 of whom had a follow-up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real-world study shows an initial channelling of dapagliflozin to difficult-to-treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.
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Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for the Treatment of Type 2 Diabetes.
Coppenrath, VA, Hydery, T
The Annals of pharmacotherapy. 2018;(1):78-85
Abstract
OBJECTIVE To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of the fixed-dose combination (FDC) product, QTERN (dapagliflozin/saxagliptin) tablets. DATA SOURCES Searches of MEDLINE (1946 to July 1, 2017) were conducted using the keywords QTERN, saxagliptin, and dapagliflozin. Additional data were obtained from the prescribing information, the product dossier, and Clinicaltrials.gov . STUDY SELECTION AND DATA EXTRACTION All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed. DATA SYNTHESIS The pharmacokinetics of saxagliptin and dapagliflozin were not affected significantly when administered as an FDC product. Saxagliptin may suppress the increased secretion of glucagon associated with dapagliflozin. The combination dapagliflozin/saxagliptin has been studied as add-on therapy to metformin in patients with uncontrolled type 2 diabetes mellitus (T2DM). The difference in hemoglobin A1C (A1C) between saxagliptin + dapagliflozin + metformin (triple therapy) and saxagliptin + metformin was -0.59 (95% CI = -0.81 to -0.37, P < 0.0001), and the difference between triple therapy and dapagliflozin + metformin was -0.27 (95% CI = -0.48 to -0.05, P = 0.0166). The combination was well tolerated when added to metformin. CONCLUSION QTERN (dapagliflozin/saxagliptin) tablets are a reasonable option for patients with T2DM not controlled on metformin, but cost, insurance coverage, and a lackluster reduction in A1C will likely limit its use until more data regarding its effects on complications of diabetes and cardiovascular outcomes become available.
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Sodium-glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline.
Tobe, K, Suganami, H, Kaku, K
Journal of diabetes investigation. 2018;(4):862-869
Abstract
AIMS/INTRODUCTION Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes mellitus that improve control of plasma glucose and bodyweight, giving great hope for the clinical utility of these agents. However, it is unclear for which patients SGLT2 inhibitors will be useful. MATERIALS AND METHODS We analyzed data from long-term tofogliflozin monotherapy in an open-label, randomized controlled trial in Japanese patients with type 2 diabetes mellitus. Patients were divided into tertiles by baseline insulin level: group low (L): insulin ≤5.6 μU/mL, group medium (M): 5.6< insulin ≤10 μU/mL and group high (H): insulin >10 μU/mL. RESULTS Glycated hemoglobin and fasting plasma glucose levels, along with bodyweight, were significantly reduced from the baseline in all groups. The changes in levels of plasma glucose area under the curve for 2 h, C-peptide index area under the curve for 2 h during the meal tolerance tests and the insulin secretion index were the largest in the H group. The incidence of drug-related adverse events was not different among the three groups. DISCUSSION Although tofogliflozin was effective regardless of baseline insulin level, it showed the highest efficacy in the H group.
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Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME® randomised trial.
Verma, S, Mazer, CD, Fitchett, D, Inzucchi, SE, Pfarr, E, George, JT, Zinman, B
Diabetologia. 2018;(8):1712-1723
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AIMS/HYPOTHESIS After coronary artery bypass graft (CABG) surgery in individuals with type 2 diabetes, there remains a considerable residual cardiovascular risk. In the EMPA-REG OUTCOME® trial in participants with type 2 diabetes and established cardiovascular disease, empagliflozin reduced the risk of cardiovascular death by 38%, all-cause mortality by 32%, hospitalisation for heart failure by 35% and incident or worsening nephropathy by 39% vs placebo when given in addition to standard of care. The aim of this post hoc analysis of the EMPA-REG OUTCOME® trial was to determine the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on cardiovascular events and mortality in participants with type 2 diabetes and a self-reported history of CABG surgery. METHODS The EMPA-REG OUTCOME® trial was a randomised, double-blind, placebo-controlled trial. Participants with type 2 diabetes and established cardiovascular disease were randomised 1:1:1 to receive placebo, empagliflozin 10 mg or empagliflozin 25 mg, once daily, in addition to standard of care. In subgroups by self-reported history of CABG (yes/no) at baseline, we assessed: cardiovascular death; all-cause mortality; hospitalisation for heart failure; and incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy or death due to renal disease). Differences in risk between empagliflozin and placebo were assessed using a Cox proportional hazards model. RESULTS At baseline, 25% (1175/4687) of participants who received empagliflozin and 24% (563/2333) of participants who received placebo had a history of CABG surgery. In participants with a history of CABG surgery, HRs (95% CI) with empagliflozin vs placebo were 0.52 (0.32, 0.84) for cardiovascular mortality, 0.57 (0.39, 0.83) for all-cause mortality, 0.50 (0.32, 0.77) for hospitalisation for heart failure and 0.65 (0.50, 0.84) for incident or worsening nephropathy. Results were consistent between participants with and without a history of CABG surgery (p > 0.05 for treatment by subgroup interactions). CONCLUSIONS/INTERPRETATION In participants with type 2 diabetes and a self-reported history of CABG surgery, treatment with empagliflozin was associated with profound reductions in cardiovascular and all-cause mortality, hospitalisation for heart failure, and incident or worsening nephropathy. These data have important implications for the secondary prevention of cardiovascular events after CABG in individuals with type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01131676.
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Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study.
Fioretto, P, Del Prato, S, Buse, JB, Goldenberg, R, Giorgino, F, Reyner, D, Langkilde, AM, Sjöström, CD, Sartipy, P, ,
Diabetes, obesity & metabolism. 2018;(11):2532-2540
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AIMS: Dapagliflozin is a selective inhibitor of sodium glucose co-transporter 2 (SGLT2). This study assessed the efficacy and safety of dapagliflozin 10 mg vs placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR], 45-59 mL/min/1.73 m2 ; chronic kidney disease [CKD] stage 3A). MATERIALS AND METHODS In this double-blind, parallel group, Phase 3 study (NCT02413398, clinicaltrials.gov) patients with inadequately controlled T2D (HbA1c 7.0%-11.0%) were randomized (1:1) to dapagliflozin 10 mg once daily (N = 160) or matching placebo (N = 161) for 24 weeks. Randomization was stratified by pre-enrolment glucose-lowering therapy. The primary endpoint was change from baseline in HbA1c at Week 24. RESULTS At Week 24, compared with placebo, dapagliflozin significantly decreased HbA1c (difference [95% CI], -0.34% [-0.53, -0.15]; P < 0.001), body weight (difference [95% CI], -1.25 kg [-1.90, -0.59]; P < 0.001), fasting plasma glucose (difference [95% CI], -0.9 mmol/L [-1.5, -0.4]; P = 0.001) and systolic blood pressure (difference [95% CI], -3.1 mm Hg [-6.3, 0.0]; P < 0.05). Decreases from baseline in eGFR were greater with dapagliflozin than placebo at Week 24 (-2.49 mL/min/1.73 m2 [-4.96, -0.02]), however, eGFR returned to baseline levels at Week 27 (3 weeks post-treatment) (0.61 mL/min/1.73 m2 [-1.59, 2.81]). No increase in adverse events (AEs; 41.9% vs 47.8%) or serious AEs (5.6% vs 8.7%) were reported with dapagliflozin versus placebo. No AEs of bone fractures, amputations or DKA were reported. CONCLUSIONS The findings of this study (NCT02413398, clinicaltrials.gov) support the positive benefit/risk profile of dapagliflozin for the treatment of patients with T2D and CKD 3A.
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Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials.
Jabbour, S, Seufert, J, Scheen, A, Bailey, CJ, Karup, C, Langkilde, AM
Diabetes, obesity & metabolism. 2018;(3):620-628
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AIM: To evaluate the safety and tolerability of dapagliflozin, a highly selective sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS Data were pooled from 13 placebo-controlled trials of up to 24 weeks' duration (dapagliflozin, n = 2360; placebo, n = 2295). Larger placebo-/comparator-controlled pools of 21 (≤208 weeks; dapagliflozin, n = 5936; control, n = 3403) and 30 trials (≥12 weeks; dapagliflozin, n = 9195; control, n = 4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower limb amputation, respectively. RESULTS Over 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively. Rates of hypoglycaemia, volume depletion AEs, urinary tract infections (UTIs) and fractures were balanced between the groups. Genital infections were more frequent with dapagliflozin (5.5%) vs placebo (0.6%) and renal function AEs occurred in 3.2% vs 1.8% of patients (the most common renal AE was decreased creatinine clearance: 1.1% vs 0.7%). In the 21-study pool, 1 SAE of DKA and 3 AEs of ketonuria/metabolic acidosis occurred with dapagliflozin vs none with control; estimated combined incidence for these events was 0.03% (95% confidence interval 0.010-0.089). In the 30-study pool, lower limb amputation occurred in 8 (0.1%) and 7 (0.2%) patients receiving dapagliflozin and control, respectively. CONCLUSION The overall incidence rates of AEs and SAEs were similar in the dapagliflozin and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.
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Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin.
Ouchi, M, Oba, K, Kaku, K, Suganami, H, Yoshida, A, Fukunaka, Y, Jutabha, P, Morita, A, Otani, N, Hayashi, K, et al
Diabetes, obesity & metabolism. 2018;(4):1061-1065
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An integrated analysis was performed with data from 4 phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10 -transformed urinary N-acetyl-β-D-glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 and 24 weeks in multivariate analysis (respectively, P < .0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c > 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decreased in patients with moderate HbA1c levels.
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Sodium-Glucose Cotransporter-2 Inhibition in Type 2 Diabetes Mellitus: A Review of Large-Scale Cardiovascular Outcome Studies and Possible Mechanisms of Benefit.
Dalan, R
Cardiology in review. 2018;(6):312-320
Abstract
Cardiovascular (CV) disease remains the leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). However, conventional antihyperglycemic medications seem to have minimal effect on lowering CV risk despite achieving excellent reductions in glycated hemoglobin A1c and associated reductions in microvascular risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as noteworthy antihyperglycemic agents with concomitant CV and renal protection in T2DM patients. In this comprehensive review, we present the key CV findings from major large-scale outcome trials of SGLT2 inhibitors to date. We also review the mechanistic studies that might explain the CV benefits of SGLT2 inhibition in patients with T2DM.
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Effect of Lachancea thermotolerans on the Formation of Polymeric Pigments during Sequential Fermentation with Schizosaccharosmyces pombe and Saccharomyces cerevisiae.
Escott, C, Morata, A, Ricardo-da-Silva, JM, Callejo, MJ, González, MDC, Suarez-Lepe, JA
Molecules (Basel, Switzerland). 2018;(9)
Abstract
Anthocyanins in red grape musts may evolve during the winemaking process and wine aging for several different reasons; colour stability and evolution is a complex process that may depend on grape variety, winemaking technology, fermentative yeast selection, co-pigmentation phenomena and polymerization. The condensation of flavanols with anthocyanins may occur either with the flavylium ion or with the hemiacetal formation in order to produce oligomers and polymers. The kinetics of the reaction are enhanced by the presence of metabolic acetaldehyde, promoting the formation of pyranoanthocyanin-type dimers or flavanol-ethyl-anthocyanin structures. The experimental design carried out using white must corrected with the addition of malvidin-3-O-glucoside and flavanols, suggests that non-Saccharomyces yeasts are able to provide increased levels of colour intensity and larger polymeric pigment ratios and polymerization indexes. The selection of non-Saccharomyces genera, in particular Lachancea thermotolerans and Schizosaccharomyces pombe in sequential fermentation, have provided experimental wines with increased fruity esters, as well as producing wines with potential pigment compositions, even though there is an important reduction of total anthocyanins.