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Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis.
de Jong, MA, Petrykiv, SI, Laverman, GD, van Herwaarden, AE, de Zeeuw, D, Bakker, SJL, Heerspink, HJL, de Borst, MH
Clinical journal of the American Society of Nephrology : CJASN. 2019;(1):66-73
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Abstract
BACKGROUND AND OBJECTIVES The sodium glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin is a novel drug for the treatment of diabetes mellitus. Recent studies suggest that SGLT-2 inhibitors affect phosphate homeostasis, but their effects on phosphate-regulating hormones in patients with diabetic kidney disease are still unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a post-hoc analysis of a double-blind, randomized, crossover trial in patients with type 2 diabetes with early-stage diabetic kidney disease on stable renin-angiotensin-aldosterone system blockade, with an albumin-to-creatinine ratio between 100 and 3500 mg/g, eGFR≥45 ml/min per 1.73 m2, and glycosylated hemoglobin≥7.2% and <11.4%. Patients were randomized to dapagliflozin 10 mg/d or placebo during consecutive 6-week study periods, separated by a 6-week wash-out. We investigated effects on circulating phosphate, calcium, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) levels. RESULTS Thirty-one patients (age 62 years; 23% female) were analyzed. Compared with placebo, dapagliflozin increased serum phosphate by 9% (95% confidence interval, 4% to 15%; P=0.002), PTH increased by 16% (3% to 30%; P=0.01), FGF23 increased by 19% (0.3% to 42%; P=0.05), and serum 1,25(OH)2D decreased by -12% (-25% to 4%; P=0.12). Calcium and 25(OH)D were unaffected. We found no correlation between changes in markers of phosphate homeostasis and changes in eGFR or 24-hour albumin excretion during dapagliflozin treatment. CONCLUSIONS Dapagliflozin increases serum phosphate, plasma PTH, and FGF23. This effect was independent of concomitant changes in eGFR or 24-hour albumin excretion.
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Urinary glucose excretion after dapagliflozin treatment: An exposure-response modelling comparison between Japanese and non-Japanese patients diagnosed with type 1 diabetes mellitus.
Sokolov, V, Yakovleva, T, Ueda, S, Parkinson, J, Boulton, DW, Penland, RC, Tang, W
Diabetes, obesity & metabolism. 2019;(4):829-836
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Abstract
AIMS: To assess the dapagliflozin exposure-response relationship in Japanese and non-Japanese patients with type 1 diabetes mellitus (T1DM) and investigate if a dose adjustment is required in Japanese patients. MATERIALS AND METHODS Data from two clinical studies were used to develop a non-linear mixed effects model describing the relationship between dapagliflozin exposure (area under the concentration curve) and response (24-hour urinary glucose excretion [UGE]) in Japanese and non-Japanese patients with T1DM. The effects of patient-level characteristics (covariates; identified using a stepwise procedure) on response was also assessed. Simulations were performed using median-normalized covariate values. RESULTS Data from 84 patients were included. Average self-monitored blood glucose (SMBG) at day 7, change from baseline in total insulin dose at day 7, and baseline estimated glomerular filtration rate (eGFR) all had a significant effect on 24-hours UGE, with SMBG being the most influential. Dapagliflozin systemic exposure for matching doses and baseline eGFR was similar between Japanese and non-Japanese patients; however, higher SMBG and a greater reduction in total insulin dose was observed in the Japanese population. When the significant covariates were included, the model fit the data well for both populations, and accurately predicted exposure-response in the Japanese and non-Japanese populations, in agreement with the observed data. CONCLUSIONS There was no difference in dapagliflozin exposure-response in Japanese and non-Japanese patients with T1DM once differences in renal function, glycaemic control and insulin dose reductions between studies were considered. Therefore, no dose adjustment is recommended in Japanese patients with T1DM.
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Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: Pooled analysis of phase I-III clinical trials.
Yabe, D, Yasui, A, Ji, L, Lee, MK, Ma, RCW, Chang, TJ, Okamura, T, Zeller, C, Kaspers, S, Lee, J, et al
Journal of diabetes investigation. 2019;(2):418-428
Abstract
AIMS/INTRODUCTION We investigated the safety and tolerability of empagliflozin (EMPA) in East Asian patients with type 2 diabetes. MATERIALS AND METHODS Data were pooled from participants with type 2 diabetes evenly randomized to a placebo, EMPA 10 mg or EMPA 25 mg in 15 phase I-III trials. Adverse events (AEs) were analyzed in the subgroup of trial participants from East Asian countries/regions. RESULTS In total, 709, 724 and 708 East Asian trial participants with type 2 diabetes received a placebo, EMPA 10 mg and EMPA 25 mg, respectively; total exposure was 953, 1,072, and 1,033 patient-years in these groups, respectively. The EMPA and placebo groups had similar incidences of severe AEs, serious AEs and AEs leading to discontinuation. Incidences of hypoglycemia differed according to anti-diabetes medication used at baseline. Higher rates of events consistent with genital infection were observed with EMPA (EMPA 1.5-1.7/100, placebo 0.2/100 patient-years). Rates of AEs consistent with volume depletion were comparable among treatment groups (0.8-1.4/100 patient-years), but in trial participants aged ≥65 years, the rate was greater with EMPA 25 mg (EMPA 25 mg 3.5/100, placebo 2.0/100 patient-years). Incidences of events consistent with urinary tract infection, thromboembolic events, renal events, hepatic AEs, diabetic ketoacidosis, fractures and lower limb amputation were similar between EMPA and the placebo. CONCLUSIONS In the present pooled analysis, EMPA was well tolerated in East Asian type 2 diabetes patients based on >2,100 patient-years' exposure, consistent with results from the overall analysis population.
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Empagliflozin reduces the risk of a broad spectrum of heart failure outcomes regardless of heart failure status at baseline.
Januzzi, J, Ferreira, JP, Böhm, M, Kaul, S, Wanner, C, Brueckmann, M, Petrie, MC, Ofstad, AP, Zeller, C, George, J, et al
European journal of heart failure. 2019;(3):386-388
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Occurrence of Bisphenol A and its analogues in some foodstuff marketed in Europe.
Russo, G, Barbato, F, Mita, DG, Grumetto, L
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2019;:110575
Abstract
Bisphenol A and its analogues belong to the class of endocrine disrupting chemicals, massively employed by industries to produce polycarbonate and epoxy resins, designed to be in direct contact with foodstuffs. Their leaching from the canned packaging into its content results in food contamination. This review aims at offering a country-specific overview of the occurrence of bisphenols in six main categories of foodstuff marketed in the EU, based on monitoring studies performed in the 27 EU countries for which data are available and prevalently published in the last five years. The general overview of the literature data shows that concentration values of BPs detected into foodstuff is lower in Northern Europe than Southern Europe. A probable daily intake was hypothesized for some countries to provide an EU population exposure assessment. The consumption of canned meat and vegetables is responsible of PDI values higher than those of other food categories. These data emphasize that food and beverage monitoring should deserve greater attention especially by European countries for which no studies are available and especially with regards to bisphenols other than BPA whose limits are not set by the European regulations and whose toxicity has not been fully established.
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Empagliflozin Targeting the Real-World Heart Failure Population.
Rocha, BML, Gomes, RV, Cunha, GJL, Mendes, G, Morais, R, Campos, L, Araújo, I, Fonseca, C
Journal of cardiac failure. 2019;(3):218-219
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Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPA-REG OUTCOME® trial.
Kadowaki, T, Nangaku, M, Hantel, S, Okamura, T, von Eynatten, M, Wanner, C, Koitka-Weber, A
Journal of diabetes investigation. 2019;(3):760-770
Abstract
AIMS/INTRODUCTION In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients. MATERIALS AND METHODS Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety. RESULTS Of 7,020 treated patients, 1,517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95% confidence interval 0.49-0.83), progression to macroalbuminuria (hazard ratio 0.64, 95% confidence interval 0.49-0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95% confidence interval 0.25-0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population. CONCLUSIONS In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings.
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The effect of dapagliflozin on glycaemic control and other cardiovascular disease risk factors in type 2 diabetes mellitus: a real-world observational study.
McGurnaghan, SJ, Brierley, L, Caparrotta, TM, McKeigue, PM, Blackbourn, LAK, Wild, SH, Leese, GP, McCrimmon, RJ, McKnight, JA, Pearson, ER, et al
Diabetologia. 2019;(4):621-632
Abstract
AIMS/HYPOTHESIS Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is indicated for improving glycaemic control in type 2 diabetes mellitus. Whether its effects on HbA1c and other variables, including safety outcomes, in clinical trials are obtained in real-world practice needs to be established. METHODS We used data from the comprehensive national diabetes register, the Scottish Care Information-Diabetes (SCI-Diabetes) collaboration database, available from 2004 to mid-2016. Data within this database were linked to mortality data from the General Registrar, available from the Information Services Division (ISD) of the National Health Service in Scotland. We calculated crude within-person differences between pre- and post-drug-initiation values of HbA1c, BMI, body weight, systolic blood pressure (SBP) and eGFR. We used mixed-effects regression models to adjust for within-person time trajectories in these measures. For completeness, we evaluated safety outcomes, cardiovascular disease events, lower-limb amputation and diabetic ketoacidosis, focusing on cumulative exposure effects, using Cox proportional hazard models, though power to detect such effects was limited. RESULTS Among 8566 people exposed to dapagliflozin over a median of 210 days the crude within-person change in HbA1c was -10.41 mmol/mol (-0.95%) after 3 months' exposure. The crude change after 12 months was -12.99 mmol/mol (-1.19%) but considering the expected rise over time in HbA1c gave a dapagliflozin-exposure-effect estimate of -15.14 mmol/mol (95% CI -15.87, -14.41) (-1.39% [95% CI -1.45, -1.32]) at 12 months that was maintained thereafter. A drop in SBP of -4.32 mmHg (95% CI -4.84, -3.79) on exposure within the first 3 months was also maintained thereafter. Reductions in BMI and body weight stabilised by 6 months at -0.82 kg/m2 (95% CI -0.87, -0.77) and -2.20 kg (95% CI -2.34, -2.06) and were maintained thereafter. eGFR declined initially by -1.81 ml min-1 [1.73 m]-2 (95% CI -2.10, -1.52) at 3 months but varied thereafter. There were no significant effects of cumulative drug exposure on safety outcomes. CONCLUSIONS/INTERPRETATION Dapagliflozin exposure was associated with reductions in HbA1c, SBP, body weight and BMI that were at least as large as in clinical trials. Dapagliflozin also prevented the expected rise in HbA1c and SBP over the period of study.
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Efficacy of intermittent empagliflozin supplementation on dietary self-management and glycaemic control in patients with poorly controlled type 2 diabetes: A 24-week randomized controlled trial.
Yoshikawa, F, Kumashiro, N, Shigiyama, F, Uchino, H, Ando, Y, Yoshino, H, Miyagi, M, Ikehara, K, Hirose, T
Diabetes, obesity & metabolism. 2019;(2):303-311
Abstract
AIMS: To explore the effects of intermittent use of empagliflozin, a sodium-glucose co-transporter-2 inhibitor, on dietary self-management and glycaemic control in patients with inadequately controlled type 2 diabetes. MATERIALS AND METHODS We conducted a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial of 50 patients with type 2 diabetes, treated with no more than three oral antidiabetic drugs (glycated haemoglobin [HbA1c] ≥52 mmol/mol but <86 mmol/mol). The participants were randomized to take 10 mg/d empagliflozin either every day (regular group, n = 25) or on the day on which they considered they had overeaten (intermittent group, n = 25) for 24 weeks. We limited empagliflozin prescription to half of the required period in the intermittent group. The primary endpoint was change in HbA1c at the end of the 24-week treatment period relative to baseline. The secondary outcomes included changes in body weight, daily energy intake and diabetes treatment-related quality of life (QoL). Energy intake was assessed using a diet-specific validated questionnaire rather than actual assessments of food intake. RESULTS The intake rate of empagliflozin was 96.7 ± 7.2% for the regular group and 45.7 ± 7.0% for the intermittent group. Interestingly, ΔHbA1c was identical in the two groups (-0.64 ± 0.19% and - 0.65 ± 0.17%, respectively). Body weight decreased (-2.72 ± 0.52 and - 1.50 ± 0.45 kg, respectively) and diabetes treatment-related QoL increased significantly from baseline in both groups. Energy intake, however, decreased significantly only in the intermittent group (-221.0 ± 108.3 kcal/d). CONCLUSIONS Intermittent empagliflozin supplementation is a useful therapeutic option that empowers dietary self-management, improves glycaemic control and is accompanied by body weight loss and an increase in diabetes treatment-related QoL in patients with inadequately controlled type 2 diabetes.
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Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study.
Javed, Z, Papageorgiou, M, Deshmukh, H, Rigby, AS, Qamar, U, Abbas, J, Khan, AY, Kilpatrick, ES, Atkin, SL, Sathyapalan, T
Clinical endocrinology. 2019;(6):805-813
Abstract
BACKGROUND Empagliflozin is a sodium-glucose-cotransporter-2 inhibitor that improves cardiovascular risk and promotes weight loss in patients with type-2 diabetes. Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular risk; therefore, empagliflozin may be of benefit for these women. The aim of this study was to compare the effects of empagliflozin vs metformin on anthropometric and body composition, hormonal and metabolic parameters in women with PCOS. MATERIALS AND METHODS A randomized open-label study was conducted in women with PCOS who were randomized to either empagliflozin 25 mg (n = 19) or metformin 1500 mg (n = 20) daily for 12 weeks. The main outcomes assessed were changes in anthropometric and body composition, hormonal and metabolic parameters. RESULTS Univariate analysis showed significant differences in weight (empagliflozin: -1.4 ± 3.2% vs metformin: 1.2 ± 2.3%; P = 0.006), body mass index (empagliflozin: -1.4 ± 3.2% vs metformin: 1.1 ± 2.2%; P = 0.006), waist circumference (empagliflozin: -1.6 ± 2.8% vs metformin: 0.2 ± 2.1%; P = 0.029) and hip circumference (empagliflozin: -2.0 ± 3.0% vs metformin: 1.1 ± 1.9%; P = 0.001), basal metabolic rate (empagliflozin: -1.8 ± 2.9% vs metformin: 0.1 ± 1.9%, P = 0.024) and fat mass (empagliflozin: -0.7 ± 4.9% vs metformin, 3.2 ± 5.0%; P = 0.023) between the empagliflozin and the metformin groups. These differences were confirmed in linear regression analysis after adjustment for relevant covariates. There were no significant changes in hormonal or metabolic parameters between both groups. CONCLUSION There was a significant improvement in anthropometric parameters and body composition, in overweight and obese women with PCOS after 12 weeks of treatment with empagliflozin compared to metformin, although no changes were seen in hormonal or metabolic parameters.