Safety Of Dapagliflozin Research Articles

Efficacy and safety of dapagliflozin in non-diabetic patients with primary anterior ST-elevation myocardial infarction initiated in early hospital period

Abstract Background The effectiveness of SGLT2 inhibitors has been proven in all types of chronic heart failure (HFpEF, HFmrEF, and HFrEF), regardless of the presence of diabetes mellitus. There are still no clear recommendations regarding the timing of SGLT2 inhibitor administration after myocardial infarction (MI) and its influence on prognosis. It can be assumed that it is appropriate to consider the possibility that, if started quickly after the presentation of acute MI, SGLT inhibition might enhance outcomes in patients. Objective This study aims to investigate the efficacy and safety of the SGLT2 inhibitor Dapagliflozin in primary anterior ST-segment elevation myocardial infarction (STEMI) initiated in early hospital period, irrespective of heart failure manifestation. Methods The study includes 124 non-diabetic patients with primary anterior STEMI who underwent primary PCI and had left ventricular ejection fraction (LV EF) ≤45% and NT-proBNP > 900 pg/ml at symptom onset within 24 hours, regardless of heart failure symptom manifestation. Patients with cardiogenic shock were excluded. 62 patients received standard medical treatment including beta-blockers, ACE inhibitors (Control group), while the other 62 patients were administered the SGLT2 inhibitor Dapagliflozin 10 mg once a day during the first 48 hours of inpatient treatment, in addition to standard therapy (Dapa group). All patients were followed up for one year. Echocardiography was performed during the first 24 hours. Echocardiography and NT-proBNP were repeated at the end of the year. The primary endpoint was the one-year heart failure hospitalizations and secondary endpoints included one year cardiovascular mortality and changes in NT-proBNP, plasma creatinine and glycosylated hemoglobin levels. Results The study shows a significant difference in heart failure hospitalization between the groups. In the Control group, it was 25.8%, and in the Dapa group, it was 8.1% (p = 0.008). Initially, there were no significant changes in NT-proBNP levels; 1152.2 ± 222.4 pg/ml in the Control group and 1197.3 ± 279.8 pg/ml in the Dapa group (p= 0.33). At the end of a year, NT-proBNP increased in the Control group (1827.4 ± 317.8 pg/ml), whereas in the Dapa group, it significantly decreased (613.5 ± 215.6 pg/ml) (p < 0.01). One-year cardiovascular mortality in the Control and Dapa groups was 9.7% and 4.8%, respectively(p=0.491). Other blood markers did not differ, and side effects were comparable during the in-hospital period as well as at the end of the year. Conclusion Early administration of Dapagliflozin among non-diabetic patients with primary anterior STEMI is associated with a significant decreasing of heart failure hospitalization rate and NT-proBNP level. Additionally, early administration of dapagliflozin does not impact on safety indicators.

Effects of dapagliflozin in heart failure according to duration of type 2 diabetes: a patient-level meta-analysis of DAPA-HF and DELIVER

Abstract Introduction Type 2 diabetes (T2D) is a common comorbidity in heart failure (HF), and long-standing T2D is associated with worse outcomes. Purpose To investigate the efficacy and safety of dapagliflozin, compared with placebo, according to duration of T2D in patients with HF and established T2D. Methods We conducted a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the effects of dapagliflozin, compared with placebo, in patients with HF with reduced ejection fraction and HF with mildly reduced/preserved ejection fraction, respectively. T2D duration was categorized as <5 years, 6-10 years, and >11 years. The primary outcome was a composite of worsening HF or cardiovascular death. Results Of the 4,784 patients with a history of T2D, 1,879 (39.3%) had a T2D duration of <5 years, 1,074 (22.4%) 5-10 years, and 1,831 (38.3%) >11 years. Patients with longer-duration T2D were older, more often female, and White, and had a higher HbA1c, body mass index, and left ventricular ejection fraction. They were more likely to have ischaemic heart disease, peripheral artery disease, hypertension, and chronic kidney disease, but were less likely to have atrial fibrillation/flutter. Although patients with longer-duration T2D had longer duration of HF, they were not more likely to have a prior HF hospitalization or worse New York Heart Association functional class. Despite similar N-terminal pro-B-type natriuretic peptide levels, patients with longer-duration T2D had a higher risk of the primary outcome, even after adjustment for potential confounders (<5 years, reference; 6-10 years, HR 1.25 [95% CI, 1.06-1.46]; >11 years, HR 1.33 [1.15-1.54]). The benefit of dapagliflozin on the primary outcome was consistent across T2D duration category: <5 years, HR 0.85 (95% CI, 0.69-1.04); 5-10 years, HR 0.65 (0.51-0.83); >11 years, HR 0.84 (0.70-1.01) (Pinteraction=0.18). Dapagliflozin reduced the risk of secondary clinical outcomes and increased (improved) mean KCCQ scores from baseline to 8 months, regardless of T2D duration (Table). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of T2D duration. Conclusions Dapagliflozin reduced the risk of worsening HF or cardiovascular death, and improved symptoms, in patients with HF and T2D, irrespective of T2D duration.

Safety of dapagliflozin and empagliflozin in cases with diabetes mellitus or/and heart failure: a retrospective pharmacovigilance study conducted on the eudravigilance database.

Dapagliflozin and empagliflozin are sodium-glucose cotransporter-2 (SGLT2) inhibitors initially approved for the treatment of type 2 diabetes mellitus (DM), and later for heart failure (HF). Considering this differential therapeutic use, we decided to evaluate cases related to these agents by comparing those with DM, HF, or both (DM and HF). A retrospective, pharmacovigilance study was conducted by using data contained in the EudraVigilance from January 1st, 2021, to December 31st, 2023. Cases were classified into those with DM, HF, or both diseases. The Reporting Odds Ratio (ROR), and its 95% confidence interval (95%CI) were computed to compare the reporting probability of the four most reported adverse events. The following comparisons were performed: DM vs. HF; both DM and HF vs. HF; both DM and HF vs. DM. Analyses were adjusted for age, sex, and time between the approval date of the SGLT2 inhibitor and the reporting date. A total of 14,594 (50.5%) cases were classifiable for DM (N = 11,962; 82.0%), HF (N = 2,100; 14.4%), or both DM and HF (N = 532; 3.64%). The empagliflozin was the most reported SGLT2 inhibitor (60.1%), and only 15 cases (0.1%) reported both empagliflozin and dapagliflozin. Cases with DM and both DM and HF were associated with a higher reporting probability of ketoacidosis (ROR: 5.95, 95%CI: 4.87-7.26; ROR: 3.05, 95%CI: 2.27-4.09) and Fournier's gangrene (ROR: 2.30, 95%CI: 1.65-3.20; ROR: 2.30, 95%CI: 1.38-3.82) than HF. These results were also confirmed by adjusted analyses. We found that ketoacidosis and Fournier's gangrene had a higher reporting in cases with DM. Further studies are warranted.

Efficacy and safety of Dapagliflozin and Glimepiride in combination with Metformin: Randomized clinical trial

Objective: To identify the effective treatment option between dapagliflozin-metformin and glimepiride-metformin combination in patients with type 2 diabetes who were inadequately controlled with metformin monotherapy. Study design and setting: The present study is randomized, conducted for 12 weeks at the National Medical center, Karachi, Pakistan. Methodology: The patients were divided into 2 treatment groups; group A was given dapagliflozin-metformin combination, while group B was given glimepiride-metformin combination. The efficacy endpoint of groups was estimated by hemoglobin A1c and fasting blood glucose levels at 0-, 6- and 12-week. While, safety endpoints were identified by analyzing liver function tests, lipid profile tests, renal function test, and urine analysis. The significant difference of data was analyzed by using statistical package of social sciences (SPSS) version 25. The parametric t-test and paired t-test were performed and considered p-value = 0.05 as statistical significant. Results: Baseline demographics, clinical features of diabetes, levels of liver enzymes, liver function test, renal function test, lipid profile, and urinalysis of randomized patients were similar in both treatment groups by showing p = 0.05. Followed by the initiation of the respective treatment, the baseline change of mean FBG and hemoglobin A1c levels with dapagliflozinmetformin combination was shown significantly reduce more compared to glimepiride-metformin combination (p = 0.05). Conclusion: Dapagliflozin-metformin combination therapy was superior and well-tolerated to regulate glycemic control as compare to glimepiride-metformin combination

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

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

Efficacy and safety of dapagliflozin in children with kidney disease: real-world data

BackgroundDapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown results in slowing estimated glomerular filtration rate (eGFR) decline and reducing proteinuria in adult patients with chronic kidney disease. This retrospective study examines dapagliflozin’s effects in 22 children with kidney disease and proteinuria.MethodsChildren with a median age of 15.6 years were treated with dapagliflozin for > 3 months between July 2022 and December 2023. All children had been treated with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 1 month before starting dapagliflozin.ResultsThe most common kidney disease diagnoses in this study included Alport syndrome (n = 7) and medication-resistant nephrotic syndrome or focal segmental glomerulosclerosis (n = 7). After 6.1 months of treatment, dapagliflozin treatment did not result in significant changes in eGFR or proteinuria. However, at the latest follow-up, a statistically significant decrease in eGFR was noted (65.5 compared to the baseline 71.1 mL/min/1.73 m2, P = 0.003). Proteinuria remained stable between baseline and the last follow-up (final spot urine protein/creatinine ratio (uPCR) 0.7 vs. baseline uPCR 0.6 mg/mg, P = 0.489). In the subgroup analysis of children treated for > 8 months, the eGFR decline post-treatment changed from − 0.5 to − 0.2 ml/min/1.73 m2 per month (P = 0.634). Only two children discontinued dapagliflozin due to suspected adverse events.ConclusionsDapagliflozin has not been associated with serious side effects. Further prospective clinical trials are needed to confirm the efficacy and safety of dapagliflozin in children with kidney disease.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Efficacy and safety of dapagliflozin in non-diabetic patients with anterior wall ST-segment elevation acute myocardial infarction (STEMI) in early-hospital period

Efficacy and safety of dapagliflozin in non-diabetic patients with anterior wall ST-segment elevation acute myocardial infarction (STEMI) in early-hospital period

#2817 Preliminary results of dapagliflozin in inactive lupus nephritis cross-over randomized trial

Abstract Background and Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD). Lupus nephritis (LN) patients in remission may continue with residual proteinuria due to scars and hyperfiltration. However, LN patients were excluded from the main trials with SGLT2 inhibitors. This trial aims to assess the effect and safety of dapagliflozin in inactive LN patients with residual proteinuria. Method For this cross-over randomized trial, we include adult patients with LN class III, IV (±V) without active nephritis but with proteinuria >500 mg/24 h or UPC > 200 mg/g and eGFR ≥ 20 ml/min, in the maintenance treatment with a RAAS and mycophenolate mofetil (<2g/day) in stable a dose for at least four weeks before the randomization. We excluded patients with other etiologies of CKD, those with active LN lesions on the recent biopsy (AI>2), use of induction therapy in the last 12 months (cyclophosphamide, mycophenolate mofetil >2g/day and calcineurin inhibitors) and prednisone dose ≥ 20 mg/day. Due to safety issues, we excluded patients with recurrent urinary infections (>3 times/year). Those included were randomized to receive dapagliflozin 10 mg on top of standard of care therapy (SoC) or not. After 24 weeks the groups were switched and those without dapagliflozin received it for the next 24 weeks. Primary endpoint is reduction of proteinuria compared to baseline at 6 and 12 months. Secondary endpoints are sustained reduction of eGFR>30%; occurrence of hypotension symptoms; and number of infections on dapagliflozin treatment versus exclusive SoC therapy. The sample size was calculated for 28 patients enrolled providing 80% power to detect a 25% relative risk reduction in proteinuria (α level of 0.05). Results From 97 screened class III, IV (± V) LN patients under maintenance therapy, we excluded 67 due to active nephritis, low proteinuria or low eGFR. We included 30 patients that were randomized 14 to start the treatment with dapagliflozin on top of SoC and 16 to remain with the usual therapy for 24 weeks. Six patients were excluded from the analysis due to new LN flare or lost to follow-up. We analyzed the data of 12 patients in the initial Dapa + SoC and 12 patients in the initial SoC group after 3 (n = 21), 6 (n = 18), 9 (n = 14) and 12 (n = 12) months. Patients in initial Dapa group had a significant decrease in proteinuria after 6 months (1159 to 882 mg/day; p = 0.017) but increased to 1105 mg/day 6 months after the drug withdrawal (Fig. 1A). This preliminary analysis shows a significant reduction in the proteinuria of –35.8% in patients after 6 mo of dapagliflozin as opposed to an increase in 7.2% for those in the SoC therapy at the end of a 6 mo period, p = 0.02 (Fig. 1C). The drug was well tolerated, but 4 (33.3%) of the patients reported hypotension symptoms during the first days of dapagliflozin. There was one case of urinary infection in each group, but in the same patient. Conclusion Preliminary results show a significant reduction in residual proteinuria in patients with inactive LN with dapagliflozin without an increase in infections.

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)

Evaluating the Safety and Efficacy of Sodium-Glucose Co-transporter2 Inhibitors in Subjects with Prediabetes: A Protocol for a Randomized Controlled Trial.

Prediabetes is a state of subclinical glycemic impairment, bridging normal glucose tolerance and diabetes. Globally, over 30% of individuals exhibit prediabetic conditions, with a significant proportion progressing to diabetes. Prediabetes augments risks of various diseases including cardiovascular and kidney disease. While interventions like lifestyle changes have shown promise in diabetes prevention, their long-term sustainability is challenging. Alternative pharmacological treatments, such as acarbose and metformin, have demonstrated efficacy in certain populations. Sodium-glucose co-transporter2 inhibitors, a novel class of glucose-lowering agents, have shown potential benefits for heart and kidney health in patients with diabetes. This research aims to evaluate the effectiveness and safety of dapagliflozin in individuals with prediabetes, elucidating its potential role in diabetes prevention strategies. This prospective trial is being conducted at Peking University Third Hospital. A total of 240 participants with prediabetes will be enrolled and randomly divided into two groups: one receiving dapagliflozin (10mg/day) with lifestyle education, and the other with lifestyle education alone over a 12-week duration (with male/female = 1:1 in each group). Anthropometric, clinical and laboratory tests, including body mass index, waist circumference, fasting blood glucose, oral glucose tolerance test, insulin, lipid profile, liver and kidney function, sperm quality, will be conducted at the onset and conclusion of the trial. For adherence monitoring, participants will receive phone follow-ups at week4 and week8. The primary outcome is the change in 2-h plasma glucose during an oral glucose tolerance test over the study duration. Secondary outcomes encompass changes in various health metrics, including body mass index, lipid profiles, and liver function. The proposed study is set to refine diabetes prevention strategies on the basis of its potential benefits observed in patients with diabetes. This will be the first randomized controlled trial to evaluate the safety and effectiveness of sodium-glucose co-transporter2 inhibitors compared with lifestyle education for individuals with prediabetes. ClinicalTrials.gov identifier NCT05914857 (registered 24 July 2023).

Effects of Dapagliflozin in Chronic Kidney Disease Across the Spectrum of Age and by Sex

BackgroundThe sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown.ObjectiveWe performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex.DesignProspective randomized placebo-controlled trial.ParticipantsA total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200–5000 mg/g) with and without type 2 diabetes.InterventionDapagliflozin 10 mg versus placebo once daily.Main MeasuresPrimary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality.Key ResultsMedian follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope.ConclusionsDapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit.Trial Registryclinicaltrials.govNIH Trial Registry NumberNCT03036150

Efficacy of dapagliflozin according to geographic regions in patients with heart failure: a patient-level pooled analysis of DAPA-HF and DELIVER

Abstract Background Clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF). Some previous reports suggested the efficacy of certain treatments for HF may be modified by region. However, most analyses based on regions in individual trials are hampered by modest subgroup sizes and small numbers of events and can give unreliable results. Purpose To evaluate the difference in outcomes between regions, and to examine whether the efficacy and safety of dapagliflozin in HF were consistent across regions, using the patient-level pooled data of DAPA-HF and DELIVER. Methods The DAPA-HF (n = 4744) and DELIVER (n = 6263) trials enrolled patients with HF, functional limitation, and elevated natriuretic peptide. The main difference between the trials was that patients with a left ventricular ejection fraction (LVEF) ≤40% were randomized in DAPA-HF and those with a LVEF &amp;gt;40% in DELIVER. In both trials, patients were randomized to dapagliflozin 10 mg daily, or placebo, in addition to standard care. The primary outcome of both trials was the composite of worsening HF or cardiovascular death. Results Of the total 11,007 patients, 5159 patients (46.9%) were enrolled in Europe; 1528 (13.9%) in North America; 1998 (18.2%) in South America; and 2322 (21.1%) in Asia. Patients were younger in Asia and South America and were more often female in South America and Europe. The mean baseline LVEF and median natriuretic peptide level did not vary significantly across regions. Mineralocorticoid receptor antagonists were prescribed less frequently in patients with HF and reduced ejection fraction in North America (46.4%) compared to other regions (70-80%). 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: 10.8 (10.1-11.5) in Europe, 10.0 (9.0-11.1) in South America, and 10.5 (9.5-11.5) in Asia. The rate of the primary outcome increased with decreasing LVEF similarly across all regions studied (Figure 1). The benefit of dapagliflozin on the primary outcome was not modified by region: hazard ratio for dapagliflozin versus placebo 0.85 (95%CI 0.75-0.96) in Europe, 0.75 (0.61-0.93) in North America, 0.72 (0.58-0.89) in South America, and 0.74 (0.61-0.91) in Asia (p-interaction = 0.40). This was the same when evaluated separately for patients with LVEF ≤40% (p-interaction = 0.39) and for those with LVEF &amp;gt;40% (p-interaction = 0.84). In each region, the effect of dapagliflozin was consistent regardless of LVEF (Figure 2). Patients in North America discontinued randomized treatment more frequently than anywhere else (in the placebo group, 21.8% in North America versus 6.4% in South America), but the discontinuation rates did not differ between placebo and dapagliflozin by region. Conclusions The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.Incidence rate according to regionDapagliflozin effect according to region

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 &amp;gt;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&amp;gt;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 13026: Effects of Dapagliflozin in Heart Failure, Type 2 Diabetes, and Neuropathy - A Patient-Level Meta-Analysis of DAPA-HF and DELIVER

Introduction: Type 2 diabetes (T2D) is a common comorbidity in heart failure (HF), and neuropathy is a serious complication in patients with T2D that is associated with worse outcomes. Purpose: To investigate the efficacy and safety of dapagliflozin, compared with placebo, according to neuropathy status in patients with HF and T2D. Methods: We conducted a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the effects of dapagliflozin, compared with placebo, in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome was a composite of worsening HF or cardiovascular death. Results: Of the 5,274 patients with T2D at baseline, 756 (14.3%) had a history of neuropathy. Compared to patients without neuropathy, those with neuropathy more often had a history of hypertension and PAD and were female. They also had a higher BMI, HbA1c, and LVEF, but a lower eGFR and NT-proBNP. Patients with neuropathy had a longer duration of both T2D and HF, worse NYHA functional class and KCCQ scores and a higher incidence of all outcomes. The benefit of dapagliflozin on the primary outcome was consistent irrespective of neuropathy status: no neuropathy, HR: 0.81 (95% CI: 0.72-0.92); neuropathy, HR: 0.63 (0.46-0.84) (P interaction =0.11). Dapagliflozin reduced the risk of secondary clinical outcomes and increased (improved) mean KCCQ scores from baseline to 8 months in both patients with and without neuropathy. The effects on secondary outcomes appeared larger in those with neuropathy (Table) . Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of neuropathy status. Conclusions: Dapagliflozin reduced the risk of worsening HF or cardiovascular death and improved symptoms in patients with HF and T2D, with and without neuropathy, possibly with larger effects in individuals with neuropathy. In addition, dapagliflozin was safe and well-tolerated, irrespective of neuropathy status.

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 &gt;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.

Abstract 14120: Characteristics, Outcomes and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in People With HF and a History of CABG Surgery: A Pooled Analysis From DAPA-HF and DELIVER

Introduction: There is a paucity of data on contemporary outcomes of patients with a history of CABG who have heart failure (HF) with either reduced or preserved left ventricular ejection fraction (LVEF). We aimed to compare the baseline characteristics and outcomes by history of CABG, as well the efficacy and safety of the SGLT2 inhibitor, dapagliflozin, across the full range of LVEF in patients with heart failure. Methods: We conducted a patient-level pooled analysis of two trials testing dapagliflozin in 11,007 participants with HF and LVEF ≤40% (DAPA-HF trial) and &gt;40% (DELIVER trial). The primary outcome was the composite of a worsening HF event or death from CV causes; other outcomes examined included total hospital admissions for HF, MACE, all-cause mortality and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Outcomes were compared by history of CABG. Results: Among 11,007 patients, 1576 had a prior history of CABG (~14%). Patients with CABG were characterised by a higher proportion of men, lower eGFR and LVEF, and higher rates of prior MI, PCTA, type 2 diabetes, antiplatelet and statin therapy. CABG patients were more likely to experience primary outcome (adjusted hazard ratio [aHR] 1.21, 95% CI 1.08-1.36), CV death (aHR 1.22, 95% CI 1.04-1.42), all-cause death (aHR 1.22, 95% CI 1.07-1.38), HF hospitalization (aHR 1.31, 95% CI 1.14-1.51), total HF events (adjusted rate ratio 1.38, 95% CI 1.20-1.59), and MACE (aHR 1.34 (1.17-1.52). Dapagliflozin consistently reduced the primary and key secondary endpoints in both people with and without a history of CABG across the entire spectrum of LVEF (P-interaction for all &gt; 0.48) (Table). Adverse events and tolerability were similar between groups. Conclusions: In patients with HF, a prior history of CABG is associated with higher rates of CV outcomes and mortality compared to those without a history of CABG. The efficacy and safety of dapagliflozin was similar in patients with and without a history of CABG.

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.