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1.
Prognosis of patients eligible for dapagliflozin in acute heart failure.
Carballo, S, Stirnemann, J, Garin, N, Darbellay Farhoumand, P, Serratrice, J, Carballo, D
European journal of clinical investigation. 2020;(6):e13245
Abstract
BACKGROUND Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, was shown in the DAPA-HF study to reduce the risk of worsening heart failure or death in symptomatic patients with left ejection fraction <40%, irrespective of diabetes. The aim of this study was to evaluate eligibility status for dapagliflozin in non-selected patients hospitalized for acute decompensated heart failure (ADHF), as well as prognostic implications of this status. MATERIALS AND METHODS Analysis of 815 patients recruited in a prospective cohort of acute heart failure at the University Hospitals of Geneva, consisting of consecutive patients admitted with ADHF. Eligibility for dapagliflozin was determined using criteria described DAPA-HF. RESULTS Of 815 patients, 220 (27%) were eligible for dapagliflozin treatment. In survival analysis, patients who were eligible for dapagliflozin had better clinical outcomes with respect to all-cause mortality and rehospitalization as compared to those who were not eligible. In multivariate analysis, the hazard ratio for all-cause mortality or readmission in patients eligible for dapagliflozin was 0.82 (95% CI 0.68-0.999, P = .049) as compared to the non-eligible. CONCLUSIONS Using DAPA-HF criteria, only 27% of non-selected patients admitted for ADHF are theoretically eligible for dapagliflozin. This eligibility for dapagliflozin is associated with better outcomes. Further evaluation of the benefits of dapagliflozin in selected HF patients may be of interest. This may have implications for selection criteria in future randomized effectiveness studies.
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2.
Fournier's gangrene and SGLT2 inhibitors: A case study.
García-García, A, Galeano-Valle, F, Nuevo-González, JA, Demelo-Rodríguez, P
Endocrinologia, diabetes y nutricion. 2020;(6):423-425
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3.
Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: A randomized, controlled trial.
Yamakage, H, Tanaka, M, Inoue, T, Odori, S, Kusakabe, T, Satoh-Asahara, N
Journal of diabetes investigation. 2020;(3):653-661
Abstract
AIMS/INTRODUCTION Our aims were to examine the add-on effects of a sodium-glucose cotransporter 2 inhibitor, dapagliflozin, compared with existing antidiabetes treatments, on anthropometric/metabolic parameters, the levels of an endocrine regulator, fibroblast growth factor 21 (FGF21); a skeletal muscle mass (SMM) negative regulator, myostatin; and a metabolic regulator, irisin, in patients with type 2 diabetes. MATERIALS AND METHODS A total of 54 patients with type 2 diabetes were randomly divided into dapagliflozin and control groups. The dapagliflozin group received dapagliflozin 5 mg/day in addition to conventional therapy for 24 weeks. The primary outcome was the change in the level of serum FGF21 from baseline. The secondary outcomes included changes from baseline in anthropometric/metabolic parameters and serum levels of myostatin and irisin. RESULTS Bodyweight decreased in the dapagliflozin group compared with the control group (P < 0.001), but the changes in SMM were not significant between the groups (P = 0.611), thereby elevating the ratio of SMM-to-bodyweight in the dapagliflozin group (P = 0.028). Myostatin levels were significantly decreased (P = 0.010), and irisin levels showed a nearly significant reduction (P = 0.052) in the dapagliflozin group compared with the control group, whereas FGF21 levels did not change significantly from baseline to the end of the intervention in both the dapagliflozin (P = 0.673) and the control (P = 0.823) groups. CONCLUSIONS Dapagliflozin add-on therapy in patients with type 2 diabetes reduced myostatin levels significantly and maintained SMM, without significant changes in FGF21 levels.
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4.
Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction.
Omar, M, Jensen, J, Frederiksen, PH, Kistorp, C, Videbæk, L, Poulsen, MK, Möller, S, Ali, M, Gustafsson, F, Køber, L, et al
Journal of the American College of Cardiology. 2020;(23):2740-2751
Abstract
BACKGROUND Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear. OBJECTIVES This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF. METHODS This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up. RESULTS Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (-0.13 mm Hg/l/min/m2; 95% confidence interval: -1.60 to 1.34 mm Hg/l/min/m2; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (-2.40 mm Hg; 95% confidence interval: -3.96 to -0.84 mm Hg; p = 0.003), but not CI (-0.09 l/min/m2; 95% confidence interval: -0.14 to 0.32 l/min/m2; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes. CONCLUSIONS Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.
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5.
Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58.
Bonaca, MP, Wiviott, SD, Zelniker, TA, Mosenzon, O, Bhatt, DL, Leiter, LA, McGuire, DK, Goodrich, EL, De Mendonca Furtado, RH, Wilding, JPH, et al
Circulation. 2020;(8):734-747
Abstract
BACKGROUND Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. METHODS A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. RESULTS Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively). CONCLUSIONS Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.
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Effects of liraglutide and empagliflozin added to insulin therapy in patients with type 2 diabetes: A randomized controlled study.
Nakaguchi, H, Kondo, Y, Kyohara, M, Konishi, H, Oiwa, K, Terauchi, Y
Journal of diabetes investigation. 2020;(6):1542-1550
Abstract
AIMS/INTRODUCTION Liraglutide and empagliflozin suppress cardiovascular events. However, reports on their long-term combined use with insulin therapy or direct comparisons of these drugs are limited. MATERIALS AND METHODS This open-label, parallel-group, randomized controlled trial compared the effects of liraglutide and empagliflozin combined with insulin therapy in type 2 diabetes patients. Adult type 2 diabetes outpatients undergoing stable insulin therapy with glycated hemoglobin levels of 7.0-9.5% were enrolled. Participants received 0.9 mg/day liraglutide or 10 mg/day empagliflozin for 24 weeks. The primary end-point was the change in glycated hemoglobin levels from week 0 to 24. Body composition was assessed by dual-energy X-ray absorptiometry. RESULTS A total of 64 insulin-treated patients were randomized to receive liraglutide or empagliflozin. We analyzed 61 patients (30 liraglutide and 31 empagliflozin) who could be followed up. Liraglutide induced greater changes in glycated hemoglobin and glycated albumin than empagliflozin (glycated hemoglobin -1.24 ± 0.15% vs -0.35 ± 0.11%, P < 0.0001; glycated albumin -4.4 ± 0.6% vs -2.4 ± 0.5%, P < 0.01). Bodyweight (-1.3 ± 0.4 kg vs -1.5 ± 0.3 kg, P = 0.69) or body fat mass/lean tissue mass; urinary albumin excretion (median -5.3 mg/g-creatinine [interquartile range -60.6, 9.9 mg/g-creatinine] vs -12.9 mg/g-creatinine [interquartile range -70.8, -2.0 mg/g-creatinine], P = 0.23); and frequency of hypoglycemia did not differ significantly between the groups over a period of 24 weeks. There were no cases of study discontinuation owing to adverse effects. CONCLUSIONS Liraglutide addition to ongoing insulin therapy more effectively reduced glycated hemoglobin and glycated albumin levels than empagliflozin in patients with inadequately controlled type 2 diabetes.
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7.
Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE-TIMI 58 Study.
Cahn, A, Mosenzon, O, Wiviott, SD, Rozenberg, A, Yanuv, I, Goodrich, EL, Murphy, SA, Bhatt, DL, Leiter, LA, McGuire, DK, et al
Diabetes care. 2020;(2):468-475
Abstract
OBJECTIVE Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. RESEARCH DESIGN AND METHODS The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. RESULTS Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively). CONCLUSIONS The overall efficacy and safety of dapagliflozin are consistent regardless of age.
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Dapagliflozin effects on haematocrit, red blood cell count and reticulocytes in insulin-treated patients with type 2 diabetes.
Aberle, J, Menzen, M, Schmid, SM, Terkamp, C, Jaeckel, E, Rohwedder, K, Scheerer, MF, Xu, J, Tang, W, Birkenfeld, AL
Scientific reports. 2020;(1):22396
Abstract
Recent studies have shown that high-risk patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose cotransporter 2 (SGLT2) inhibitors have improved cardiovascular (CV) outcomes. In an exploratory analysis of data from the EMPA-REG study, elevations in haematocrit were shown to be strongly associated with beneficial CV effects. As insulin treatment has been shown to be antinatriuretic, with an associated increase in extracellular fluid volume, it is important to confirm whether haematocrit increase is maintained with concomitant insulin therapy. Here, we investigate the effect of the SGLT2 inhibitor dapagliflozin on haematocrit, red blood cell (RBC) counts and reticulocyte levels in high-risk patients with T2DM receiving insulin. A 24-week, double-blinded, randomised, placebo-controlled trial (ClinicalTrials.gov: NCT00673231) was reported previously with extension periods of 24 and 56 weeks (total of 104 weeks). Patients receiving insulin were randomised 1:1:1:1 to placebo or dapagliflozin at 2.5, 5 or 10 mg. Haematocrit, RBC and reticulocyte measurements were conducted during this study, and a longitudinal repeated-measures analysis was performed here to examine change from baseline during treatment. Dapagliflozin treatment in combination with insulin resulted in a dose-dependent increase in haematocrit levels and RBCs over a 104 week period. There was a short-term increase in reticulocyte levels at the start of treatment, which dropped to below baseline after 8 weeks. SGLT2 inhibition with dapagliflozin leads to a sustained increase in haematocrit in patients receiving chronic insulin treatment.
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Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer.
Fabian, CJ, Khan, SA, Garber, JE, Dooley, WC, Yee, LD, Klemp, JR, Nydegger, JL, Powers, KR, Kreutzjans, AL, Zalles, CM, et al
Cancer prevention research (Philadelphia, Pa.). 2020;(7):623-634
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Abstract
We conducted a multiinstitutional, placebo-controlled phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was -1.8% in the SDG arm (P = 0.001) and -1.2% for placebo (P = 0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median = -2.2%; P = 0.002) but not placebo (median = -1.0%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (<0.5 or >2.0) with 7 of 10 increases in placebo and 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.
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Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review.
Sampani, E, Sarafidis, P, Dimitriadis, C, Kasimatis, E, Daikidou, D, Bantis, K, Papanikolaou, A, Papagianni, A
BMC nephrology. 2020;(1):276
Abstract
BACKGROUND Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 DM with a generally acceptable safety profile. However, these agents have been associated with rare events of a serious and potentially life-threatening complication named euglycemic diabetic ketoacidosis (euDKA). euDKA is not identical with the typical diabetic ketoacidosis, as it often presents with serious metabolic acidosis but only mild to moderate glucose and anion gap elevation. CASE PRESENTATION We report a case of a 51-year old female with Type 2 DM treated with an SGLT-2 inhibitor, developing severe metabolic acidosis with only mild blood glucose elevation after a routine surgery. A careful evaluation of involved factors led to the diagnosis of euDKA, followed by cautious application of simple therapeutic measures that resulted in complete restoration of acidosis and glycemic control in less than 48-h. CONCLUSIONS Euglycemic ketoacidosis is a rare but rather serious complication of SGLT-2 inhibitors use, often with a multifactorial etiology. Its atypical presentation requires a high level of awareness by physicians as early recognition of this complication can quickly and safely restore acid-base balance.