Safety Of Dapagliflozin In Patients Research Articles

Efficacy and Safety of Dapagliflozin in Patients with CKD Stages 4-5

Efficacy and Safety of Dapagliflozin in Patients with CKD Stages 4-5

Dapagliflozin and quality of life measured using the EuroQol 5-dimension questionnaire in patients with heart failure with reduced and mildly reduced/preserved ejection fraction.

Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure

BackgroundThe primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. ObjectivesThe authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. MethodsIn a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. ResultsFor diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. ConclusionsEarly dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229)

Influence of background therapy on efficacy of dapagliflozin in patients with heart failure and improved ejection fraction

Abstract Introduction Heart failure with improved ejection fraction (HFimpEF), defined as prior reduced left ventricular EF (LVEF) ≤40% with a subsequent measurement LVEF >40%, is growing in prevalence, in part because of effective guideline directed medical therapy (GDMT) initiated when LVEF was ≤40%. These patients have been largely excluded from major HF clinical trials. The DELIVER trial demonstrated dapagliflozin to be beneficial in patients with symptomatic HFimpEF; whether this benefit differs by background medical therapy is unclear. Purpose We investigated the efficacy and safety of dapagliflozin in patients with HFimpEF by background HF GDMT (beta-blocker [BB], mineralocorticoid receptor antagonist [MRA], and ACEi/ARB/ARNI at baseline). Methods The DELIVER trial randomized patients with symptomatic heart failure and LVEF>40% to dapagliflozin or placebo. Treatment effects on the primary endpoint, worsening heart failure or cardiovascular (CV) death, and its components were assessed by a GDMT composite score. We assigned 1 point each for baseline use of ACEi/ARB, evidence-based BB, or MRA, and 2 points for sacubitril/valsartan. The composite GDMT score could range from 0 (no GDMT) to 4 (triple therapy inclusive of sacubitril/valsartan). Results Among the 6,263 patients randomized, 1,151 (18%) had HFimpEF. Of those, 2% of patients were on no GDMT, 14% were on 1 GDMT, 47% were on 2 GDMT therapies, and 37% were on triple therapy at baseline (Figure 1). Patients treated with triple therapy, compared to those on less than 3 therapies, were younger, more likely male, have a history of myocardial infarction, less likely to have diabetes, had a lower baseline LVEF and systolic blood pressure, and higher eGFR. During 2.2 years of median follow-up, the incidence rate was 9.8 per 100 person-years among those on 1 or no medications at baseline compared with 8.6 per 100 person-years among those on 2 or 3 therapies. Relative benefits of dapagliflozin on the primary outcome were not significantly modified by baseline GDMT score (Pinteraction = 0.11), but absolute benefits appeared more pronounced in those receiving 1 or no medications at baseline (Figure 2). Serious adverse events were well-balanced between treatment arms in the HFimpEF cohort, including among those already treated with triple therapy. Conclusions In patients with HFimpEF, the benefits of dapagliflozin are similar irrespective of background GDMT. Dapagliflozin was safe and did not lead to higher risk of adverse events among those with HFimpEF, including those already treated with triple therapy.Figure 1Figure 2

Abstract 18437: Efficacy and Safety of Dapagliflozin in Patients With Heart Failure and Previous Myocardial Infarction

Introduction: Patients with HF and history of myocardial infarction (MI) may represent a distinct subpopulation with unique pathways of disease progression and elevated risk of clinical events. Whether SGLT2 inhibitors may modify disease trajectory in such individuals is uncertain. Methods: The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with LVEF ≤40% and >40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular (CV) death or worsening HF. Results: Of the total of 11,007 patients, 3,731 (34%) had a prior MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (HR 1.12 [95% CI 1.02-1.24]; Left Panel ). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83 [95% CI 0.72-0.96]) and without prior MI (HR 0.76 [95% CI 0.68-0.85]; P i nteraction =0.36), with consistent benefits on key secondary outcomes as well ( Right Panel ). Serious adverse events did not occur more frequently with dapagliflozin, irrespective of prior MI. Conclusions: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the spectrum of ejection fraction. Dapagliflozin consistently and safely reduces the risk of adverse cardiovascular outcomes, regardless of previous MI. Ongoing trials are actively examining SGLT2 inhibitors when introduced early after acute MI.

Influence of background medical therapy on efficacy and safety of dapagliflozin in patients with heart failure with improved ejection fraction in the DELIVER trial.

The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium-glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy. Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, evidence-based beta-blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0-1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow-up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person-years for patients on 0-1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0-1 therapies at baseline (pinteraction = 0.09), driven mostly by a significant interaction for HF hospitalization (pinteraction = 0.023) with no evidence of effect modification for cardiovascular death (pinteraction = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (pinteraction = 0.39). The use of dapagliflozin was not associated with changes in use or doses of background HF therapies, and among patients on three HF medications at baseline, the addition of dapagliflozin did not lead to higher adverse events. In patients with HFimpEF, the safety and efficacy of dapagliflozin were largely similar by background use and dosing of HF medical therapies. The benefit of dapagliflozin in reducing HF events tended to be greater in those patients on 0-1 medications at baseline. Among patients already on three HF medical therapies, the addition of dapagliflozin was safe without requiring de-escalation of other therapies.

Efficacy of Dapagliflozin According to Geographic Location of Patients With Heart Failure

BackgroundBecause clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. ObjectivesThe goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. MethodsWe conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. ResultsAmong 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region. ConclusionsThe efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.

DELIVER: Extending the benefits of SGLT-2 inhibitors.

The DELIVER trial investigated the efficacy and safety of dapagliflozin in patients with heart failure and preserved or mildly reduced ejection fraction. The trial demonstrated that dapagliflozin significantly reduced the risk of worsening heart failure or cardiovascular death compared to placebo. The benefit was mainly driven by a decrease in heart failure hospitalizations, with no significant impact on mortality. Patients with different ejection fractions and diabetes status showed similar treatment effects. Dapagliflozin also improved functional capacity and quality of life. These findings support the use of SGLT-2 inhibitors in HFpEF and HFmrEF, potentially influencing clinical practice and future guidelines.

A multicentre, prospective, non-interventional study evaluating the safety of dapagliflozin in patients with type 2 diabetes in routine clinical practice in China (DONATE)

BackgroundThere are few large-scale studies evaluating the safety of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, in Chinese patients with type 2 diabetes. DONATE, a multicentre, single-arm, prospective, non-interventional study, is the first real-world study evaluating the safety of dapagliflozin in Chinese patients with type 2 diabetes in routine clinical practice.MethodsBetween August 2017 and July 2020, patients with type 2 diabetes who had initiated dapagliflozin therapy and received ≥1 dose were prospectively recruited from 88 hospitals in China. Patients were subsequently followed up for 24 weeks; if patients discontinued dapagliflozin they were followed up for an additional 7 days after treatment discontinuation. The primary outcome was the proportion of patients with adverse events and serious adverse events, particularly key adverse events of special interest (AESI) including urinary tract infection, genital tract infection (typical symptoms with or without microbiological diagnosis) and hypoglycaemia (typical symptoms with or without blood glucose ≤3.9 mmol/L, or blood glucose ≤3.9 mmol/L without symptoms). Exploratory outcomes included the absolute change in metabolic parameters and the proportion of patients with other AESI including volume depletion, abnormal blood electrolytes, polyuria, renal impairment, diabetic ketoacidosis, hepatic impairment and haematuria.ResultsA total of 3000 patients were enrolled, of whom 2990 (99.7%) were included in the safety analysis set. Mean (SD) age was 52.6 (12.0) years, and 65.8% of patients were male. Mean (SD) duration of type 2 diabetes at enrolment was 8.4 (7.1) years. Mean (SD) treatment duration of dapagliflozin was 209.1 (157.6) days. Adverse events were reported in 35.4% (n = 1059) of patients during the 24-week follow-up period. Overall, 9.0% (n = 268) were related to treatment and 6.2% (n = 186) were serious. Urinary tract infection, genital tract infection and hypoglycaemia were reported in 2.3% (n = 70), 1.3% (n = 39) and 1.1% (n = 32) of patients, respectively. The proportion of patients with other AESI was also low: polyuria (0.7%; n = 21), volume depletion (0.3%; n = 9), renal impairment (0.3%; n = 8), hepatic impairment (0.2%; n = 7), haematuria (0.2%; n = 6) and diabetic ketoacidosis (0.1%; n = 2).ConclusionsThis study demonstrated that once-daily dapagliflozin was well tolerated in Chinese patients with type 2 diabetes and the overall safety profile of dapagliflozin in clinical practice in China was consistent with that reported in clinical trials.Trial registrationClinicalTrials.gov, NCT03156985. Registered on 16 May, 2017.

Pharmacokinetic Properties of Dapagliflozin in Hemodialysis and Peritoneal Dialysis Patients.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors attenuate incident cardiovascular outcomes, irrespective of baseline GFR, in conservatively managed CKD. As this condition inexorably progresses to demanding KRT, drug withdrawal is supported by the current lack of evidence of safety of SGLT2 inhibitors in dialysis. This study was a prospective, single-center, open-label trial ( ClinicalTrials.gov identifier: NCT05343078 ) aimed at assessing the pharmacokinetic properties and safety of dapagliflozin in patients with kidney failure on regular dialysis regimens compared with those with type 2 diabetes and age- and sex-matched controls with normal kidney function. Peripheral blood samples were collected from both groups every 30 minutes for 4 hours and again after 48 hours after ingestion of dapagliflozin 10 mg, which occurred immediately before dialysis session initiation in the kidney failure group. This protocol occurred in drug-naïve patients and again after six daily doses of dapagliflozin to assess whether the drug had accumulated. The plasma and dialysate levels of dapagliflozin at each time point were determined by liquid chromatography and used to calculate pharmacokinetics parameters (peak concentration [C max ] and area under the plasma concentration-versus-time curve) for each participant. Dapagliflozin C max was 117 and 97.6 ng/ml in the kidney failure and control groups, respectively, whereas the corresponding accumulation ratios were 26.7% and 9.5%. No serious adverse events were reported for either group. Dapagliflozin recovered from dialysate corresponded to 0.10% of the administered dose. In patients with kidney failure on dialysis, dapagliflozin was well tolerated, was slightly dialyzable, and had nonaccumulating pharmacokinetic properties. Pharmacokinetics and Dialyzability of Dapagliflozin in Dialysis Patients (DARE-ESKD 1), NCT05343078.

Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.

Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

Efficacy and safety of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction by baseline glycaemic status (DELIVER): a subgroup analysis from an international, multicentre, double-blind, randomised, placebo-controlled trial

Type 2 diabetes and prediabetes are risk factors for heart failure and adverse heart failure outcomes. The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial showed that dapagliflozin was associated with a reduction in the primary outcome of worsening heart failure or cardiovascular mortality in patients with heart failure with mildly reduced or preserved ejection fraction. We aimed to assess the efficacy and safety of oral dapagliflozin in these patients by their baseline glycaemia categories. DELIVER was an international, multicentre, double-blind, randomised, placebo-controlled trial done in 350 health-care centres and hospitals across 20 countries. Patients aged 40 years or older with New York Heart Association class II-IV, left ventricular ejection fraction of more than 40%, elevated natriuretic peptides (N-terminal pro B-type natriuretic peptide ≥300 pg/mL or ≥600 pg/mL for patients in atrial fibrillation or flutter), and evidence of structural heart disease were randomly assigned (1:1) to 10 mg dapagliflozin or placebo, administered orally, and followed up for a median of 2·3 years (IQR 1·7-2·8). The primary outcome, a composite of time from randomisation to first worsening heart failure events (defined as an unplanned hospitalisation or urgent heart failure visit requiring intravenous therapy) or cardiovascular death, in participants with type 2 diabetes (history of or identified by HbA1c ≥6·5% [48 mmol/mol] at baseline) or prediabetes (HbA1c 5·7 to <6·5% [39 mmol/mol to <48 mmol/mol] at baseline) was compared with those with normoglycaemia (HbA1c <5·7% [39 mmol/mol]). Efficacy of dapagliflozin versus placebo was assessed according to glycaemic status and based on HbA1c as a continuous measure. The full-analysis set comprised all patients who were randomly assigned to study treatment, with patients analysed according to their randomised treatment assignment, irrespective of the treatment received (ie, intention to treat). The safety analysis set comprised patients who were randomly assigned to study treatment and who took at least one dose of investigational product, with patients analysed according to the treatment actually received. This trial is registered with ClinicalTrials.gov, NCT03619213. Between Sept 1, 2018, and Jan 18, 2021, 6263 patients were randomly assigned to oral dapagliflozin (n=3131) or placebo (n=3132). Of these patients, 1175 had normoglycaemia, 1934 had prediabetes, and 3150 had type 2 diabetes and were included in the glycaemia subgroup analysis (3515 [56·2%] of 6263 patients were men and 4435 [70·9%] were White). The incidence rate of the primary outcome was 6·9 per 100 patient-years in the normoglycaemia subgroup (reference), increasing to 7·6 per 100 patient-years in the prediabetes subgroup (hazard ratio 1·09 [95% CI 0·90-1·31]) and 10·1 per 100 patient-years in the type 2 diabetes subgroup (1·46 [1·24-1·73]; p<0·0001 for trend). Dapagliflozin reduced the risk of the primary outcome versus placebo in each subgroup (hazard ratio 0·77 [95% CI 0·57-1·04], log-rank p=0·088, for patients with normoglycaemia, 0·87 [0·69-1·08], log-rank p=0·21, for patients with prediabetes, and 0·81 [0·69-0·95], log-rank p=0·0077, for patients with type 2 diabetes; pinteraction=0·82) and across the continuous HbA1c range (pinteraction=0·85). Volume-related or renal serious adverse events or adverse events leading to discontinuation of the study drug, hypoglycaemia, and amputations were not differentially affected by treatment in any of the glycaemia categories. In patients with heart failure with mildly reduced or preserved ejection fraction, oral dapagliflozin improved heart failure outcomes to a similar extent in three glycaemia subgroups: normoglycaemia, prediabetes, and type 2 diabetes. Moreover, the heart failure benefits of dapagliflozin seem to be consistent across a continuous glycaemic range. AstraZeneca.

877-P: Safety of Dapagliflozin in Patients with Type 2 Diabetes Mellitus in China: Results from the DONATE Study

Background: Dapagliflozin significantly improves glycemic control, body weight and blood pressure in Asian patients with type 2 diabetes mellitus (T2DM) , but safety data from studies with a large population are lacking. The DONATE study investigated the real-world safety of dapagliflozin in Chinese patients with T2DM. Methods: This observational study enrolled patients with T2DM from 88 hospitals in China, who had received ≥1 dose of dapagliflozin between August 2017 and July 2020. Patients were followed for 6 months, or 7 days after discontinuing study drug. Primary outcome was the incidence of adverse events (AEs) and serious adverse events (SAEs) , particularly urinary tract infections (UTIs) , genital tract infections (GTIs) and hypoglycemia. Exploratory outcomes included the incidence of AEs of specific interest (AESI) and absolute changes in metabolic factors. Results: Of 3000 patients enrolled, 2990 patients were included in the safety analysis set; 1059 (35.4%) reported ≥1 AE, including 186 (6.2%) with ≥1 SAE. Adverse drug reaction was reported in 268 (9.0%) patients. In total, there were 70 (2.3%) , 39 (1.3%) and 32 (1.1%) patients with UTI, GTI and hypoglycemia, respectively. The occurrence of other AESIs was also low: polyuria (0.7%) , volume depletion (0.3%) , renal impairment (0.3%) , hepatic impairment (0.2%) , haematuria (0.2%) and diabetic ketoacidosis (0.1%) . There were no abnormal electrolytes events reported. At Week 24 (metabolic analysis set) , mean change from baseline in HbA1c was −1.318%; 161/417 (38.6%) achieved HbA1c &amp;lt;7.0%; Mean change from baseline in FPG, 2h-PPG, weight and waist circumference was −1.826 mmol/L, −5.466 mmol/L, −1.89 kg and -2cm, respectively. Conclusion: Dapagliflozin showed a good safety profile in real-world clinical practice in China, with a low incidence of AEs, especially AESI. Meanwhile, a trend of improvement was found in blood glucose control as well as other metabolic factors.

The clinical efficacy and safety of dapagliflozin in patients with diabetic nephropathy

ObjectiveTo investigate the clinical efficacy and safety of dapagliflozin in the treatment of diabetic nephropathy (DN).MethodsA total of 120 DN patients admitted to our hospital from June 2017 to March 2020 were divided into control and experimental groups, with 60 cases in each group. The control group received valsartan, and the experimental group received dapagliflozin for 3 months. Body mass index (BMI), hemoglobin A1c (HbA1c), serum creatinine (sCr), uric acid (UA), urine microalbumin (uMA), urine creatinine (uCr), and bilateral kidney function were compared before and after treatment, and adverse reactions in both groups were observed. Serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were also evaluated.ResultsAfter treatment, except for BMI in the control group, all indexes in both groups were significantly improved. The BMI, HbA1c, sCr, UA, and uMA/uCr ratios of the experimental group were lower than those of the control group. Serum albumin (sAlb) levels were increased in both groups, and the experimental group showed a significant difference compared with the control group. Estimated glomerular filtration rate (eGFR) levels were increased in both groups, and the experimental group was higher than the control group, with no significant differences. Serum IL-6 and TNF-α levels in both groups were lower, and the experimental group was significantly lower than the control group. No serious adverse reactions were observed in either group.ConclusionThe efficacy of dapagliflozin was demonstrated by its ability to improve diabetes, prevent nephropathy exacerbation, and reduce symptomatic reactions. The low rate of adverse reactions makes dapagliflozin a very safe medication.

Efficacy and Safety of Dapagliflozin in Patients With CKD Across Major Geographic Regions

IntroductionThis study aimed to examine the efficacy and safety of dapagliflozin in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (NCT03036150) by geographic region.MethodsAdults with chronic kidney disease (CKD) with or without type 2 diabetes, with estimated glomerular filtration rate (eGFR) 25 to 75 ml/min per 1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 200 to 5000 mg/g were randomized to dapagliflozin (10 mg once daily) or placebo. The primary end point was a composite of a sustained decline in eGFR of ≥50%, end-stage kidney disease or death from kidney or cardiovascular causes. We categorized recruiting countries into 4 broad global regions: Asia, Europe, Latin America, and North America. Of 4304 randomized patients, 1346 (31.3%) were from Asia, 1233 (28.6%) from Europe, 912 (21.2%) from Latin America, and 813 (18.9%) from North America.ResultsThe relative risk of the primary composite end point was lower in patients randomized to dapagliflozin (relative to placebo) in all regions, with hazard ratios (95% CI) of 0.70 (0.48–1.00), 0.60 (0.43–0.85), 0.61 (0.43–0.86), and 0.51 (0.34–0.76) among patients from Asia, Europe, Latin America, and North America, respectively. There was no effect modification by region (interaction P = 0.77). Occurrence of serious adverse events (SAEs) was lower among patients randomized to dapagliflozin versus placebo (21.9% vs. 26.8%, 34.1% vs. 38.6%, 29.8% vs. 31.5%, and 34.9% vs. 41.0% in Asia, Europe, Latin America, and North America, respectively).ConclusionDapagliflozin reduced kidney and cardiovascular events and prolonged survival in patients with CKD, with and without type 2 diabetes, with no apparent effect modification by geographic region.

Dapagliflozin and atrial fibrillation in heart failure with reduced ejection fraction: insights from DAPA-HF.

Among patients with heart failure (HF) and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on new-onset AF. The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had 'any AF' (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62-0.92 and 0.74, 95% CI 0.62-0.88, respectively; p for interaction=0.88]. Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new-onset AF compared with placebo (HR 0.86, 95% CI 0.60-1.22). However, patients with new-onset AF had a 5 to 6-fold higher risk of adverse outcomes when compared to those without incident AF. Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all-cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new-onset AF.

Influence of cardiovascular drugs on the efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial

Abstract Background In DECLARE-TIMI 58, the sodium glucose co-transporter 2 inhibitor (SGLT2i) dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in a broad range of patients with type 2 diabetes mellitus (T2DM). SGLT2i are known to have diuretic and anti-hypertensive effects. However, whether concomitant CV drugs influence the efficacy and safety of dapagliflozin in these populations is less well known. Purpose We examined whether dapagliflozin consistently reduced the risk of CV outcomes and whether the safety of dapagliflozin was similar with or without the concurrent use of various CV drugs. Methods DECLARE–TIMI 58 was a randomized trial of dapagliflozin versus placebo in patients with T2DM and either atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for CV disease followed for a median of 4.2 years. We stratified patients by the use of CV drugs at baseline commonly used for heart failure: angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers (ACEi/ARB), beta-blockers, diuretics, and mineralocorticoid receptor antagonists (MRA). Efficacy outcomes of interest were the composite of CV death/HHF and HHF alone. We used the Cox proportional-hazard model for these analyses. Results Of 17,160 patients, 13,950 (81%) used ACEi/ARB, 9,030 (53%) used beta-blockers, 6,967 (41%) used diuretics, and 762 (4%) used MRA at baseline. All were balanced by randomized treatment groups. Patients using CV drugs at baseline had a greater prevalence of atherosclerotic risk factors and established CV disease than those without. Dapagliflozin consistently reduced the risk of CV death/HHF regardless of the use of CV medications (Figure). For HHF alone, similar results were seen with no significant interactions for any of the classes. There were no significant treatment interactions by the concomitant use of any of CV drugs for adverse events including symptoms of volume depletion or acute kidney injury. Conclusions In this analysis from the DECLARE–TIMI 58 trial, dapagliflozin consistently reduced the risk of CV death/HHF and HHF alone irrespective of the concurrent use of various CV drugs without any treatment interaction for key safety events. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The DECLARE–TIMI 58 trial was supported by AstraZeneca.

Safety of Dapagliflozin in Patients with Type 2 Diabetes Mellitus in Saudi Arabia: A Post Authorization Safety Study

IntroductionSodium-glucose co-transporter-2 (SGLT2) inhibitors moderately reduce glucose levels in type-2 diabetes mellitus (T2DM). Some cases of diabetic ketoacidosis (DKA) were reported with SGLT2 inhibitors. However, data on the long-term safety of dapagliflozin in Saudi Arabia are lacking. The present study aimed to monitor the safety of dapagliflozin in patients with T2DM and evaluate the change in HbA1c during the observation period compared to baseline.MethodsThis was a local, prospective, single-arm, non-interventional, regulatory post-marketing study. The study was conducted in Saudi Arabia from May 2017 to September 2019. Patients received either 5 or 10 mg dapagliflozin in conjunction with diet and exercise modifications to treat T2DM. The occurrence of adverse events was observed over the treatment duration and for 3 days after administering the last dose of dapagliflozin.ResultsA total of 527 patients were recruited in the study, 524 of which were eligible for the statistical analysis. About 62% were males. The median (IQR) age was 52.3 (14.8) years, while the median (IQR) body mass index was 31.6 (7.7) kg/m2. The median (IQR) duration since the patients were first diagnosed with T2DM was 8.78 (6.73) years. The most common comorbidities were hyperlipidemia (51.1%) and hypertension (41.1%). Almost three-quarters of the study population (73.7%) received other antidiabetic medications in addition to dapagliflozin. Over a period of 12 months, a total of 106 adverse events were experienced by 65 (12.33%) patients. Vulvovaginal pruritus (3.1%), dysuria (2.7%), polyuria (1.3%), urinary tract infections (1%), fatigue (0.8%), and hypoglycemia (0.8%) were among the reported adverse events. One case of DKA (0.2%) was reported. The mean (SD) HbA1c% level significantly decreased from 8.6 (1.6) % at baseline to reach 7.2 (1.2) % after 12 months of treatment (p < 0.0001).ConclusionDapagliflozin was found to be a well tolerated and effective treatment option for T2DM patients in Saudi Arabia. Vulvovaginal pruritus and dysuria were the most common adverse events.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01092-0.

Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists: An Analysis of DAPA-HF

ObjectivesThe purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial. BackgroundMRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination. MethodsA total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10 mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes. ResultsA total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m2), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction = 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo. ConclusionsDapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial

ObjectivesThis study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial. BackgroundBoth the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown. MethodsDAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group. ResultsA total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan. ConclusionsDapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124)