Dapagliflozin Group Research Articles

Effects of Dapagliflozin on Epicardial Fat Thickness in Patients with Type 2 Diabetes and Obesity.

Epicardial adipose tissue (EAT) thickness is a marker of visceral fat and an emerging therapeutic target. Dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, improves glucose control and induces moderate weight loss in patients with type 2 diabetes mellitus. Dapagliflozin has recently been shown to reduce cardiovascular risk. Nevertheless, whether dapagliflozin could reduce EAT thickness is unknown. This hypothesis was tested in a 24-week, randomized, double-blind, placebo-controlled clinical trial in 100 patients with type 2 diabetes mellitus with BMI ≥ 27 kg/m2 and a hemoglobin A1c level ≤ 8% on metformin monotherapy. Individuals were randomly assigned to 2 groups to receive additional dapagliflozin up to 10 mg once daily or to remain on metformin up to 1,000 mg twice daily. Ultrasound-measured EAT thickness was measured at baseline, 12 weeks, and 24 weeks. In the dapagliflozin group, EAT decreased by 20% from baseline to 24 weeks, by 15% after 12 weeks, and by 7% between 12 and 24 weeks, respectively (P < 0.01 for all), whereas in the metformin group, there was a significant but smaller EAT reduction. There was no statistically significant correlation between EAT and body weight changes. Dapagliflozin causes a rapid and significant EAT reduction that could be independent of weight loss.

Carotid Doppler ultrasonographic findings of dapagliflozin use in type 2 diabetic patients

Aim Sodium-glucose cotransporter 2 inhibitors have been shown to reduce the risk of cardiovascular disease in type 2 diabetes (T2DM) patients. The purpose of this study was to evaluate cardiovascular disease risk indirectly through Doppler ultrasonography (USG) of carotid artery vascular markers in T2DM patients using dapagliflozin. Methods One hundred forty-five patients presenting to our clinic between March 2016 and June 2018 and diagnosed with T2DM were included in the study. These were divided into two groups – a dapagliflozin group of 85 patients and a 60-member non-dapagliflozin control group. Common carotid artery end-diastolic velocity (EDV), peak systolic velocity (PSV), and resistive index (RI) parameters were evaluated using Doppler USG in both groups. Results The mean duration of follow-up was 2.2 ± 0.4 years. Mean ages were 45 ± 14 years in the dapagliflozin group and 42 ± 15 in the control group. Mean HbA1c was 7.4 ± 1.6 in the dapagliflozin group and 7.3 ± 2.1 in the control group. Common carotid artery, PSV, and EDV parameters were higher (p = .012/p = .036), while RI was lower (p ˂ .001), in the dapagliflozin group than in the control group. Conclusion Vascular resistance was lower in the group using dapagliflozin for diabetes management.

Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes

Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%. Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. ClinicalTrials.gov Identifier: NCT03036124.

The Effect of Dapagliflozin Treatment on Epicardial Adipose Tissue Volume and P-Wave Indices: An Ad-hoc Analysis of The Previous Randomized Clinical Trial.

Aim: Epicardial adipose tissue (EAT) may be associated with arrhythmogenesis. P-wave indices such as P-wave dispersion and P-wave variation indicated a slowed conduction velocity within the atria. This study investigated the effect of dapagliflozin on EAT volume and P-wave indices.Methods: In the present ad hoc analysis, 35 patients with type 2 diabetes mellitus and coronary artery disease were classified into dapagliflozin group (n = 18) and conventional treatment group (n = 17). At baseline, EAT volume, HbA1c and plasma level of tumor necrotic factor-α (TNF-α) levels, echocardiography, and 12-lead electrocardiogram (ECG) were performed. EAT volume was measured using computed tomography. Using 12-lead ECG, P-wave indices were measured.Results: At baseline, EAT volumes in the dapagliflozin and conventional treatment groups were 113 ± 20 and 110 ± 27 cm3, respectively. Not only HbA1c and plasma level of TNF-α but also echocardiography findings including left atrial dimension and P-wave indices were comparable between the two groups. After 6 months, plasma level of TNF-α as well as EAT volume significantly decreased in the dapagliflozin group only. P-wave dispersion and P-wave variation significantly decreased in the dapagliflozin group only (−9.2 ± 8.7 vs. 5.9 ± 19.9 ms, p = 0.01; −3.5 ± 3.5 vs. 1.7 ± 5.9 ms, p = 0.01). The change in P-wave dispersion correlated with changes in EAT volume and plasma level of TNF-α. In multivariate analysis, the change in EAT volume was an independent determinant of the change in P-wave dispersion.Conclusion: Dapagliflozin reduced plasma level of TNF-α, EAT volume, and P-wave indices, such as P-wave dispersion. The changes in P-wave indices were especially associated with changes in EAT volume.The number and date of registration: UMIN000035660, 24/Jan/2019

Effects of Dapagliflozin and Sitagliptin on Insulin Resistant and Body Fat Distribution in Newly Diagnosed Type 2 Diabetic Patients.

BackgroundThe current study aimed to compare the effects of dapagliflozin and sitagliptin on insulin resistant and body fat distribution in newly diagnosed type 2 diabetic patients.Material/MethodsThis study was an open-label, parallel controlled study. Patients were included if they were newly diagnosed with type 2 diabetes (<6 months) and had been receiving dapagliflozin or sitagliptin for 12 weeks in combination with a stable dose of metformin in the last month. At baseline and 12 weeks, insulin resistant (homeostatic model assessment of insulin resistance [HOMA-IR]), body fat distribution (waist/hip ratio), fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), lipid profiles, and C-reactive protein (CRP) level were compared.ResultsThere were 59 patients receiving dapagliflozin and 67 patients receiving sitagliptin. There was no significant between-group difference in baseline characteristics. After 12 weeks of treatment, compared to the sitagliptin group, the FBG (6.4±0.5 versus 6.7±0.7 mmol/L), HbA1c (7.0±0.4 versus 7.2±0.5%), HOMA-IR (1.6±0.5 versus 1.8±0.6), triglyceride (1.6±0.4 versus 1.8±0.3 mmol/L), and CRP (3.1±0.7 versus 3.3±0.5 mg/L) were slightly lower in the dapagliflozin group. Within each group, compared to baseline, FBG (dapagliflozin [6.4±0.5 versus 7.8±0.7 mmol/L]; sitagliptin [6.7±0.7 versus 7.7±0.6 mmol/L]), HbA1c (dapagliflozin [7.0±0.4 versus 8.0±0.5%]; sitagliptin [7.2±0.5 versus 8.1%±0.6%]), HOMA-IR (dapagliflozin [1.6±0.5 versus 2.4±0.4]; sitagliptin [1.8±0.6 versus 2.5±0.4]), triglyceride (dapagliflozin [1.6±0.4 versus 2.2±0.5 mmol/L]; sitagliptin [1.8±0.3 versus 2.1±0.5 mmol/L]), and CRP (dapagliflozin [3.1±0.7 versus 6.2±1.1 mg/L]; sitagliptin [3.3±0.5 versus 6.1±1.0 mg/L]) were significantly decreased.ConclusionsDapagliflozin and sitagliptin had comparable effects on improving insulin resistant and blood glucose control, and these benefits may be associated with improvement of systemic inflammation.

Efficacy of dapagliflozin versus sitagliptin on cardiometabolic risk factors in Japanese patients with type 2 diabetes: a prospective, randomized study (DIVERSITY-CVR)

BackgroundFew prospective studies have compared the cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. We aimed to clarify the efficacy of dapagliflozin versus sitagliptin for modulating cardiometabolic risk factors including high glycated hemoglobin (HbA1c) levels, hypoglycemia, and body weight.MethodsThis prospective, randomized, open-label, blinded-endpoint, parallel-group trial enrolled 340 Japanese patients with early-stage type 2 diabetes receiving metformin alone or no glucose-lowering agents, who were randomized to receive dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was the proportion of patients who achieved the composite endpoint of HbA1c level maintenance < 7.0% (53 mmol/mol), avoidance of hypoglycemia (maintenance of sensor glucose ≥ 3.0 mmol/L or ≥ 54 mg/dL), and ≥ 3.0% body weight loss from baseline. Secondary endpoints included components of the primary endpoint, other metabolic indices, and glucose variability indices measured using flash glucose monitoring.ResultsClinical characteristics of patients were age, 58.1 ± 12.2 years; known duration of diabetes, 5.8 ± 6.1 years; body weight, 74.7 ± 14.2 kg; body mass index, 27.9 ± 4.1 kg/m2; and HbA1c level, 7.8 ± 0.8% at baseline. The achievement ratio of primary endpoint was significantly higher in the dapagliflozin group than in the sitagliptin group (24.4% vs. 13.8%, P < 0.05). While the rates of HbA1c level maintenance < 7.0% (53 mmol/mol) and avoidance of hypoglycemia were comparable between the groups (49.4 vs. 50.0% and 88.7 vs. 92.3% for dapagliflozin vs. sitagliptin, respectively), body weight loss of ≥ 3.0% was significantly achieved in the dapagliflozin group (54.4 vs. 19.6%, P < 0.001). Moreover, dapagliflozin was superior to sitagliptin regarding several secondary endpoints that modulate cardiometabolic risk, namely reducing fasting plasma glucose, insulin, uric acid, increasing high-density lipoprotein cholesterol, and suppressing the increase in serum creatinine and the decrease in estimated glomerular filtration rate. On the other hand, sitagliptin was superior to dapagliflozin in suppressing glucose variability.ConclusionsCompared to sitagliptin, dapagliflozin was significantly more effective at improving cardiometabolic risk factors, suggesting that SGLT2 inhibitors might be more suitable than DPP-4 inhibitors for preventing cardiovascular events in patients with early-stage but inadequately controlled type 2 diabetes.Trial registration Trial number, UMIN000028014; registered on June 30, 2017

Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.

Effects of dapagliflozin on the serum levels of fibroblast growth factor21 and myokines and muscle mass in Japanese patients with type2 diabetes: A randomized, controlled trial.

Aims/IntroductionOur 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 MethodsA 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.ResultsBodyweight 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.ConclusionsDapagliflozin add‐on therapy in patients with type 2 diabetes reduced myostatin levels significantly and maintained SMM, without significant changes in FGF21 levels.

Improved glycaemic variability and time in range with dapagliflozin versus gliclazide modified release among adults with type 2 diabetes, evaluated by continuous glucose monitoring: A 12-week randomized controlled trial.

To evaluate whether there is a difference between the effects of dapagliflozin and gliclazide modified release (MR) on glycaemic variability (GV) and glycaemic control, as assessed by continuous glucose monitoring (CGM), in individuals with uncontrolled type 2 diabetes. This randomized, open-label, active-controlled study was conducted in individuals with uncontrolled type 2 diabetes who were drug-naïve or on steady-dose metformin monotherapy. Participants were treated once daily with 10 mg dapagliflozin or 120 mg gliclazide MR. CGM and GV index calculations were performed at baseline and after 12 weeks. In total, 97 participants (age 57.9 ± 8.7 years, 50.5% men, baseline glycated haemoglobin 63 ± 9.8 mmol/mol [7.9 ± 0.9%]) were randomized, and 94 completed the 12-week protocol. Intention-to-treat (ITT) and per-protocol (PP) analyses showed that the reduction in GV, as measured by the mean amplitude of glycaemic excursions, was superior in the dapagliflozin group versus the gliclazide MR group (-0.9 mmol/L [95% CI -1.5, -0.4] vs -0.2 mmol/L [95% CI -0.6, 0.3]; P = 0.030 [ITT]). The reductions in GV estimated by the coefficient of variation and SD were greater in the dapagliflozin group. Moreover, dapagliflozin increased the glucose time in range (TIR; 3.9-10 mmol/L) by 24.9% (95% CI 18.6, 31.2) vs. 17.4% (95% CI 11.6, 23.3) in the gliclazide MR group (P = 0.089 [ITT]; P = 0.041 [PP]). Dapagliflozin improved GV and increased TIR more efficiently than gliclazide MR in individuals with type 2 diabetes over 12 weeks, as demonstrated by CGM.

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

BackgroundIn patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.MethodsIn this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.ResultsOver a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.ConclusionsAmong patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.)

Effects of Dapagliflozin on Endothelial Dysfunction in Type 2 Diabetes With Established Ischemic Heart Disease (EDIFIED).

ObjectivesTo evaluate the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2-I) dapagliflozin on endothelial function in patients with high-risk type 2 diabetes mellitus (T2DM).MethodsThis was a prospective, double-blind, randomized, placebo-controlled, clinical trial of patients with T2DM with underlying ischemic heart disease who were receiving metformin and insulin therapy (n = 81). After 12-weeks of additional therapy with either dapagliflozin (n = 40) or placebo (n = 41), systemic endothelial function was evaluated by change in flow-mediated dilation (ΔFMD), change in nitroglycerin-mediated dilation (ΔNMD) and surrogate markers including intercellular adhesion molecule 1 (ICAM-1), endothelial nitric oxide synthase (eNOS), high-sensitivity C-reactive protein (hs-CRP), and lipoprotein(a) (Lp[a]). Glycemic and lipid profiles were also measured.ResultsThe dapagliflozin group demonstrated significant reductions of hemoglobin A1c (HbA1c) and fasting blood glucose (FBG) compared to the placebo group (ΔHbA1c –0.83 ± 1.47% vs –0.16 ± 1.25%, P = 0.042 and ΔFBG vs –0.73 ± 4.55 mmol/L vs –1.90 ± 4.40 mmol/L, P = 0.015, respectively). The placebo group showed worsening of ΔFMD while the dapagliflozin group maintained similar measurements pre- and posttherapy (P = not significant). There was a reduction in ICAM-1 levels in the dapagliflozin group (–83.9 ± 205.9 ng/mL, P < 0.02), which remained unchanged in the placebo group (–11.0 ± 169.1 ng/mL, P = 0.699). Univariate correlation analysis revealed a significant negative correlation between HbA1c and ΔFMD within the active group.ConclusionA 12-week therapy with dapagliflozin, in addition to insulin and metformin therapies, in high-risk patients resulted in significant reductions in HbA1c, FBG, and surrogate markers of the endothelial function. Although the dapagliflozin group demonstrated a significant association between reduction in HbA1c and improvement in FMD, there was no significant difference in FMD between the 2 groups.

Effect of dapagliflozin on obstructive sleep apnea in patients with type 2 diabetes: a preliminary study

ObjectiveThe aim of this case-control study was to assess the efficacy of dapagliflozin combined with metformin for type-2 diabetes mellitus (T2DM) with obstructive sleep apnea hypopnea syndrome (OSAHS).MethodsA total of 36 patients with newly-diagnosed T2DM and OSAHS were randomized divided into two groups. Eighteen OSAHS patients with T2DM, who were treated with dapagliflozin and metformin, were assigned as the dapagliflozin group. These patients were given dapagliflozin and metformin for 24 weeks between February 2017 and February 2018. Another 18 OSAHS patients with T2DM, who were treated with glimepiride and metformin for 24 weeks, were assigned as the control group. Fasting plasma glucose (FPG) level, postprandial blood glucose (PPG), hemoglobin A1C (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), blood lipids, body mass index (BMI), blood pressure, apnea-hypopnea index (AHI), minimum oxygen saturation (LSpO2), and Epworth Somnolence Scale (ESS) score were measured before and at 24 weeks after the initiation of treatment.ResultsIn the dapagliflozin group, triglyceride (TG), systolic pressure (SBP) and diastolic pressure (DBP) significantly decreased following treatment, while high-density lipoprotein cholesterol (HDL-C) significantly increased (P < 0.05). Furthermore, a reduction in AHI, an increase in LSpO2 and a decrease in ESS score were observed in the dapagliflozin group (P < 0.05), but not in the control group. Moreover, blood glucose, HbA1c, HOMA-IR, and BMI significantly decreased in these two groups, and the decrease was more significant in the dapagliflozin group.ConclusionThese present results indicate that dapagliflozin can significantly reduce glucose, BMI, blood pressure and AHI, and improve hypoxemia during sleep and excessive daytime sleepiness, which thereby has potential as an effective treatment approach for OSAHS.

Comparison of Canagliflozin, Dapagliflozin and Empagliflozin Added to Heart Failure Treatment in Decompensated Heart Failure Patients With Type 2 Diabetes Mellitus.

Background: Three sodium-glucose cotransporter-2 inhibitors (SGLT2i), canagliflozin, dapagliflozin and empagliflozin, successfully reduced hospitalization for heart failure (HF) in patients with type 2 diabetes mellitus (T2DM). It remains unclear, however, whether the efficacy of the 3 SGLT2i for HF in T2DM patients is similar.Methods and Results: Eighty-one T2DM patients hospitalized due to decompensated HF were enrolled. After treatment for HF, one of the 3 SGLT2i was non-randomly used, and clinical parameters for HF and T2DM were followed for 7 days. The attending physician was allowed to adjust the dose of furosemide. No differences were observed between the 3 groups in the increase of glycosuria, or in the decreases of body weight and blood pressure 7 days after SGLT2i (interaction P>0.05). Urine volume was similarly increased on day 1, and returned to the baseline on day 7 in each group. Decrease in B-type natriuretic peptide and increase in plasma renin activity were significant in each group. Plasma aldosterone concentration, however, was significantly increased in the empagliflozin and canagliflozin groups (P<0.01, respectively), but not in the dapagliflozin group. Additionally, plasma noradrenaline was significantly increased in the empagliflozin group (P<0.01), but not in the canagliflozin and dapagliflozin groups.Conclusions: The neurohumoral responses to the 3 SGLT2i are different under similar volume correction in HF patients with T2DM.

Differential pharmacology and clinical utility of dapagliflozin in type 2 diabetes.

Dapagliflozin belongs in the family of sodium-glucose cotransporter 2 (SGLT2) inhibitors and acts by reducing glucose reabsorption in the proximal tubule. The aim of this review is to present the differential pharmacology and clinical utility of dapagliflozin. Dapagliflozin is orally administered, has a long half-life of 12.9 hours and (similar to empagliflozin) is a much weaker SGLT1 inhibitor compared with canagliflozin. Dapagliflozin significantly decreases glycated hemoglobin and fasting glucose levels in patients with type 2 diabetes mellitus (T2DM). The drug improves body weight, blood pressure, uric acid, triglycerides and high-density lipoprotein cholesterol. In the DECLARE-TIMI 58 trial, a large trial of 17,160 T2DM patients with established cardiovascular disease (CVD) or without established CVD but with multiple risk factors, dapagliflozin compared with placebo resulted in a significantly lower rate of the composite outcome of CVD death or hospitalization for heart failure (HHF); this effect was mainly due to a lower rate of HHF in the dapagliflozin group (HR: 0.73; 95%CI: 0.61–0.88), whereas no difference was observed in the rate of CVD death (HR: 0.98; 95%CI: 0.82–1.17). Moreover, dapagliflozin was noninferior to placebo with respect to major adverse CVD events. Dapagliflozin exerts beneficial effects on albuminuria. Additionally, in the DECLARE-TIMI 58 trial it significantly reduced the composite renal endpoint (40% decrease in glomerular filtration rate, end stage renal disease, or renal death) in both patients with established CVD and patients with multiple risk factors (overall HR: 0.53; 95%CI: 0.43–0.66). However dapagliflozin, like the other SGLT2 inhibitors, is associated with an increased risk of genital and urinary tract infections (usually mild mycotic infections) and acute kidney injury in cases of reduced extracellular volume. Dapagliflozin is a useful antidiabetic treatment which also exerts beneficial effects in the management of heart failure and diabetic kidney disease.

Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 randomised trial

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function. In DECLARE-TIMI 58, patients with type 2 diabetes, HbA1c 6·5-12·0% (47·5-113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate [eGFR] to less than 60 mL/min per 1·73m2, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min per 1·73 m2), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, subgroup analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, number NCT01730534. The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m2, 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m2, and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m2 at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio [HR] 0·76, 95% CI 0·67-0.87; p<0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p<0·0001). We identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73 m2 (120 [1·4% vs 221 [2·6%]; HR 0·54 [95% CI 0·43-0·67]; p<0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11 [0·1%] vs 27 [0·3%]; HR 0·41 [95% CI 0·20-0·82]; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus placebo across various prespecified subgroups, including those defined by baseline eGFR (cardiorenal outcome pinteraction=0·97; renal-specific outcome pinteraction=0·87) and the presence or absence of established atherosclerotic cardiovascular disease (cardiorenal outcome pinteraction=0·67; renal-specific outcome pinteraction=0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the placebo group. The mean change equalised by 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with placebo. Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function. AstraZeneca.

132-OR: Effects of Dapagliflozin, an SGLT2 Inhibitor, on Hepatic Steatosis and Fibrosis Evaluated by Transient Elastography in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Objective: To investigate the effects of dapagliflozin on liver steatosis and fibrosis evaluated in patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Research Design and Methods: In a randomized, active-controlled, open-label trial, 57 patients with type 2 diabetes and NAFLD were randomized to a dapagliflozin (5 mg/day) group (n=33) or to the control group (n=24) and were treated for 24 weeks. Hepatic steatosis and fibrosis were assessed by using a transient elastography (FibroScan) to measure the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. Results: At baseline, LSM was positively correlated with several markers and scoring systems for liver fibrosis in a total of 57 patients with T2D and NAFLD. In week 24, CAP showed a significant decrease from 314±61 to 290±73 dB/m (P=0.0424) in the dapagliflozin group, while there was no significant change in the control group. In addition, LSM tended to decrease from 9.49±6.05 kPa to 8.01±5.78 kPa in the dapagliflozin group. In 14 patients from this group with LS values ≥8.0 kPa, indicating significant liver fibrosis, LSM decreased significantly from 14.7±5.7 to 11.0±7.3 kPa (P=0.0158). Furthermore, serum alanine aminotransferase and γ-glutamyltranspeptidase levels decreased in the dapagliflozin group, but not in the control group, and visceral fat mass was significantly reduced in the dapagliflozin group. Conclusions: Based on these findings, the SGLT2 inhibitor dapagliflozin improves liver steatosis in parallel with a decrease of liver enzymes in patients with type 2 diabetes and NAFLD, and attenuates liver fibrosis in only patients with significant liver fibrosis. (UMIN000022155) Disclosure Y. Aso: Research Support; Self; Ono Pharmaceutical Co., Ltd. T. Jojima: None. T. Iijima: None. I. Usui: None.

164-LB: A Randomized Controlled Trial to Compare the Glycemic Effects of Dapagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, and Gliclazide Modified Release, a Sulfonylurea, Assessed by Continuous Glucose Monitoring among People with Type 2 Diabetes

Aims: This study aims to evaluate whether there is a difference between the effects of dapagliflozin and gliclazide MR (modified release) on glycemic variability (GV) and control, as assessed by continuous glucose monitoring (CGM), in individuals with uncontrolled type 2 diabetes (T2DM). Methods: An open-label, randomized study was conducted in uncontrolled T2DM individuals drug naïve or on steady-dose metformin monotherapy which were treated with 10 mg dapagliflozin once daily or 60 to 120 mg of gliclazide MR once daily. CGM and GV indices calculation were performed at baseline and after 12 weeks. Results: In total, 97 patients (age: 57.9 ± 8.7 years, male sex: 50.5%, baseline glycated hemoglobin (HbA1c): 7.9 ± 0.9) were randomized and 94 completed the 12-week protocol. Per protocol analysis demonstrated that the reduction of GV, as measured by the mean amplitude of glycemic excursions (MAGE), was superior in the dapagliflozin versus gliclazide MR group (-17.8 ± 33.3 vs. -3.3 ± 42.9 mg/dL, mean ± SD, p= 0.037). The improvement of GV, as measured by the coefficient of variation (CV) and the standard deviation (SD) was also superior in the dapagliflozin group (p=0.021 and 0.024, respectively). Moreover, dapagliflozin increased the time in range (TIR, between 70-180 mg/dL) by 28.6 ± 24.4% vs.19.8 ± 33.1 % (p=0.041). The intention-to-treat (ITT) analysis was also performed and did not alter the significance of the results. Conclusions: Dapagliflozin reduced glycemic variability and increased the TIR more efficiently than gliclazide MR in individuals with T2DM after 12 weeks of treatment as demonstrated by continuous glucose monitoring evaluation. Disclosure A.G.D. Vianna: Board Member; Self; Abbott, Novo Nordisk Inc. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Lilly Diabetes. C.S. de Lacerda: None. L.M. Pechmann: None. M.G. Polesel: None. J.C. Detsch: None. K.R. Marques: None. C.P. Rocha: None. Funding AstraZeneca

1229-P: Dapagliflozin Improves Liver Dysfunction in Parallel with a Decrease in Serum Soluble DPP-4/CD26 Level in Type 2 Diabetic Patients with Nonalcoholic Fatty Liver Disease

Objective: Serum levels of soluble DPP-4/CD26 are elevated in patients with type 2 diabetes and nonalcoholic fatty disease (NAFLD). Hepatocyte-secreted sDPP-4 induce directly adipose inflammation and insulin resistance in the liver. SGLT2 inhibitors reduce hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated effects of dapagliflozin, an SGLT2 inhibitor, on liver dysfunction, hepatic steatosis, and serum levels of sDPP-4 in patients with type 2 diabetes and NAFLD. Methods: Fifty-seven patients with type 2 diabetes and NAFLD were randomized into a dapagliflozin (5 mg/day) treatment group (n=33) or an active placebo group (n=24) for 24 weeks. Visceral adipose tissue (VAT) volumes were measured using a dual bioelectrical impedance analysis. Hepatic steatosis was evaluated by controlled attenuated parameter (CAP) using a transient elastography. Results: At baseline, serum sDPP-4 showed positive correlations with AST, ALT, GGT, and HOMA-IR in a total of 57 patients. VAT significantly decreased in the dapagliflozin group, but not in the placebo group. AST, ALT, and GGT showed a significant decrease at 24 weeks in the dapagliflozin group, while they were unchanged in the control group. CAP also significantly decreased in the dapagliflozin group. Although both groups showed a significant reduction in serum sDPP-4 at 24 weeks after treatment, the magnitude of sDPP-4 reduction was greater in the dapagliflozin group. Changes in liver enzymes after dapagliflozin treatment correlated positively with those in serum sDPP-4 levels, but not those in VAT or HbA1c. Conclusions: An improvement of liver dysfunction was associated with a decrease in serum sDPP-4, but not that in VAT or HbA1c, after treatment with dapagliflozin in these patients, suggesting that reducing serum sDPP-4 by SGLT2 inhibitors may be a therapeutic strategy for treatment of NAFLD/NASH in people with type 2 diabetes. Disclosure K. Kato: None. Y. Aso: Research Support; Self; Ono Pharmaceutical Co., Ltd. T. Jojima: None. T. Iijima: None. I. Usui: None.

1195-P: Effect of Dapagliflozin on Obstructive Sleep Apnea in Patients with Type 2 Diabetes: A Randomized Controlled Trial

Background: Obstructive sleep apnea hypopnea syndrome (OSAHS) is closely correlated to obesity and T2DM. Lose weight is helpful for OSAHS patients. Dapagliflozin, a new hypoglycemic drug, was found to reduce weight of T2DM patients, just like metformin. Therefore, they might have potential therapeutic effects on OSAHS patients with T2DM. Aim: A randomized controlled trial was designed to observe the effects of dapagliflozin combined with metformin on body mass index (BMI), and the ventilation and sleep quality of patients with OSAHS combined with T2DM, as well as some metabolic indicators. Methods: 36 enrolled OSAHS patients with newly-diagnosed T2DM were randomly assigned to two groups (dapagliflozin group and control group). These patients in dapagliflozin group were given dapagliflozin and metformin for 24 weeks, while controls were given glimepiride and metformin for 24 weeks. apnea-hypopnea index (AHI), minimum oxygen saturation (LSpO2), Epworth somnolence scale (ESS) score and some metabolic indicators were measured before and at 24 weeks after the initiation of treatment. Results and Conclusion: Our study indicate that dapagliflozin can significantly reduce glucose, BMI, blood pressure and AHI, and improve hypoxemia during sleep and excessive daytime sleepiness (Table 1), which thereby has potential as an effective treatment approach for OSAHS. Disclosure Q. Sun: None. Y. Tang: None. M. Zhang: None.

7-OR: Effect of Dapagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, on Vascular Function in Patients with Type 2 Diabetes Compared with Gliclazide

Objective: Recent studies showed that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of cardiovascular events and mortality in patients with type 2 diabetes (T2D). However, the mechanisms underlying this effect remain unclear. We compared the effects of dapagliflozin, a SGLT2 inhibitor, with those of gliclazide on vascular function in patients with T2D. Research Design and Methods: This was a prospective, randomized, blinded-endpoint, comparative clinical trial. In 2016−2017, T2D patients treated with ≥750 mg of metformin (HbA1c, 7.5%−10.0%; n = 32) were enrolled and randomized to receive either gliclazide (30 mg/day) with uptitration, or dapagliflozin (10 mg/day) for 24 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the study. The secondary outcomes included changes in pulse wave velocity (PWV), microvascular reactivity, ankle-brachial index (ABI), and carotid intima-medial thickness (IMT). Biochemical parameters related to glucose homeostasis, atherogenic dyslipidemia, oxidative stress, and adverse events, were evaluated. Results: Glycated hemoglobin and fasting glucose levels decreased significantly in both groups. The FMD, PWV, microvascular reactivity, and ABI improved significantly in the dapagliflozin group, but not in the gliclazide group. Lipoprotein(a), oxidized LDL, and thiobarbituric acid reactive substance levels decreased, whereas LDL particle sizes increased, in the dapagliflozin group exclusively. Hypoglycemia was more common in the gliclazide group. Conclusions: Dapagliflozin therapy for 24 weeks improved vascular function, alleviated atherogenic dyslipidemia, and decreased oxidative stress in patients with T2D. Glucose independent changes in cardiometabolic risk factors may contribute to the cardiovascular benefits observed in clinical trials with SGLT2 inhibitors. Disclosure S. Lim: None. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi.