DailyMed – DAPAGLIFLOZIN tablet, film coated – Inergency

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DailyMed – DAPAGLIFLOZIN tablet, film coated – Inergency


14.1 Glycemic Control in Patients with Type 2 Diabetes Mellitus

Overview of Clinical Studies of dapagliflozin for Type 2 Diabetes Mellitus

Dapagliflozin has been studied as monotherapy, in combination with metformin, pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), metformin plus a sulfonylurea, or insulin (with or without other oral antidiabetic therapy), compared to a sulfonylurea (glipizide), and in combination with a GLP-1 receptor agonist (exenatide extended-release) added-on to metformin. Dapagliflozin has also been studied in patients with type 2 diabetes mellitus and moderate renal impairment.

Treatment with dapagliflozin as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).

Monotherapy

A total of 840 treatment-naive patients with inadequately controlled type 2 diabetes mellitus participated in 2 placebo-controlled studies to evaluate the safety and efficacy of monotherapy with dapagliflozin.

In 1 monotherapy study, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week study (NCT00528372). Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% and ≤10% were randomized to dapagliflozin 5 mg or dapagliflozin 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo.

At Week 24, treatment with dapagliflozin 10 mg QAM provided significant improvements in HbA1c and the fasting plasma glucose (FPG) compared with placebo (see Table 8).

Initial Combination Therapy with Metformin XR

A total of 1236 treatment-naive patients with inadequately controlled type 2 diabetes mellitus (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled studies of 24-week duration to evaluate initial therapy with dapagliflozin 5 mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release (XR) formulation.

In 1 study, 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in period received: dapagliflozin 10 mg plus metformin XR (up to 2000 mg per day), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.

The combination treatment of dapagliflozin 10 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 9 and Figure 2). Dapagliflozin 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was non-inferior to metformin XR monotherapy in lowering HbA1c.

Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XR

DailyMed – DAPAGLIFLOZIN tablet, film coated – Inergency

In a second study, 603 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: dapagliflozin 5 mg plus metformin XR (up to 2000 mg per day), dapagliflozin 5 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.

The combination treatment of dapagliflozin 5 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 10).

Add-On to Metformin

A total of 546 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin (NCT00528879). Patients on metformin at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dose of metformin.

As add-on treatment to metformin, dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 11 and Figure 3). Statistically significant (p <0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were -4.5 mmHg and -5.3 mmHg with dapagliflozin 5 mg and 10 mg plus metformin, respectively.

Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Placebo-Controlled Study of Dapagliflozin in Combination with Metformin

Figure_3

Active Glipizide-Controlled Study Add-On to Metformin

A total of 816 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, non-inferiority study to evaluate dapagliflozin as add-on therapy to metformin (NCT00660907). Patients on metformin at a dose of at least 1500 mg per day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.

At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating non-inferiority (see Table 12). Dapagliflozin treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was -5.0 mmHg with dapagliflozin plus metformin.

Add-On Combination Therapy with Other Antidiabetic Agents

Add-On Combination Therapy with a Sulfonylurea

A total of 597 patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled study to evaluate dapagliflozin in combination with glimepiride (a sulfonylurea) (NCT00680745).

Patients on at least half the maximum recommended dose of glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed.

In combination with glimepiride, dapagliflozin 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24 (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus glimepiride were -2.8 mmHg and -3.8 mmHg with dapagliflozin 5 mg and 10 mg plus glimepiride, respectively.

Add-on Combination Therapy with Metformin and a Sulfonylurea

A total of 218 patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin and a sulfonylurea (NCT01392677). Patients on a stable dose of metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose, which must be at least half the maximum dose, of a sulfonylurea for at least 8 weeks prior to enrollment were randomized after an 8-week placebo lead-in period to dapagliflozin 10 mg or placebo. Dose-titration of dapagliflozin or metformin was not permitted during the 24-week treatment period. Down-titration of the sulfonylurea was permitted to prevent hypoglycemia, but no up-titration was permitted. As add-on treatment to combined metformin and a sulfonylurea, treatment with dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG and statistically significant reduction in body weight compared with placebo at Week 24 (Table 13). A statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with metformin and a sulfonylurea was -3.8 mmHg with dapagliflozin 10 mg in combination with metformin and a sulfonylurea at Week 8.

Add-On Combination Therapy with a Thiazolidinedione

A total of 420 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate dapagliflozin in combination with pioglitazone (a thiazolidinedione [TZD]) alone (NCT00683878). Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 or 10 mg of dapagliflozin or placebo in addition to their current dose of pioglitazone. Dose titration of dapagliflozin or pioglitazone was not permitted during the study.

In combination with pioglitazone, treatment with dapagliflozin 10 mg provided statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and a statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (see Table 13) at Week 24. A statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with pioglitazone was -4.5 mmHg with dapagliflozin 10 mg in combination with pioglitazone.

Add-On Combination Therapy with a DPP4 Inhibitor

A total of 452 patients with type 2 diabetes mellitus who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study to evaluate dapagliflozin in combination with sitagliptin (a DPP4 inhibitor) with or without metformin (NCT00984867).

Eligible patients were stratified based on the presence or absence of background metformin (≥1500 mg per day), and within each stratum were randomized to either dapagliflozin 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for dapagliflozin 10 mg versus placebo for the total study group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of dapagliflozin, sitagliptin, or metformin was not permitted during the study.

In combination with sitagliptin (with or without metformin), dapagliflozin 10 mg provided statistically significant improvements in HbA1c, FPG, and a statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (see Table 13). These improvements were also seen in the stratum of patients who received dapagliflozin 10 mg plus sitagliptin alone (placebo-corrected mean change for HbA1c -0.56%; n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received dapagliflozin 10 mg plus sitagliptin and metformin (placebo-corrected mean change for HbA1c -0.40; n=113) compared with placebo plus sitagliptin with metformin (n=113).

Add-On Combination Therapy with Insulin

A total of 808 patients with type 2 diabetes mellitus who had inadequate glycemic control (HbA1c ≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled study to evaluate dapagliflozin as add-on therapy to insulin (NCT00673231). Patients on a stable insulin regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at least 8 weeks prior to enrollment and on a maximum of 2 oral antidiabetic medications (OADs), including metformin, were randomized after completing a 2-week enrollment period to receive either dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals. Dose modifications of blinded study medication or OAD(s) were not allowed during the treatment phase, with the exception of decreasing OAD(s) where there were concerns over hypoglycemia after cessation of insulin therapy.

In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were on 1 or 2 OADs in addition to insulin. At Week 24, dapagliflozin 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (see Table 13); the effect of dapagliflozin on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with insulin was -3.0 mmHg with dapagliflozin 10 mg in combination with insulin.

At Week 24, dapagliflozin 5 mg (-5.7 IU, difference from placebo) and 10 mg (-6.2 IU, difference from placebo) once daily resulted in a statistically significant reduction in mean daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with insulin, and a statistically significantly higher proportion of patients on dapagliflozin 10 mg (19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%).

Combination Therapy with Exenatide-Extended Release as Add-On to Metformin

A total of 694 adult patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥8.0 and ≤12.0%) on metformin, were evaluated in a 28-week double-blind, active-controlled study to compare dapagliflozin in combination with exenatide extended-release (a GLP-1 receptor agonist) to dapagliflozin alone and exenatide extended-release alone, as add-on to metformin (NCT02229396). Patients on metformin at a dose of at least 1,500 mg per day were randomized following a 1-week placebo lead-in period to receive either dapagliflozin 10 mg once daily (QD) in combination with exenatide extended-release 2 mg once weekly (QW), dapagliflozin 10 mg QD, or exenatide extended–release 2 mg QW.

At Week 28, dapagliflozin in combination with exenatide extended-release provided statistically significantly greater reductions in HbA1c (-1.77%) compared to dapagliflozin alone (-1.32%, p=0.001) and exenatide extended-release alone (-1.42%, p=0.012). Dapagliflozin in combination with exenatide extended-release provided statistically significantly greater reductions in FPG (-57.35 mg/dL) compared to dapagliflozin alone (-44.72 mg/dL, p=0.006) and exenatide extended-release alone (-40.53, p <0.001).

Use in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment

Dapagliflozin was assessed in two placebo-controlled studies of patients with type 2 diabetes mellitus and moderate renal impairment.

Patients with type 2 diabetes mellitus and an eGFR between 45 to less than 60 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in a 24-week, double-blind, placebo-controlled clinical study (NCT02413398). Patients were randomized to either Dapagliflozin 10 mg or placebo, administered orally once daily. At Week 24, dapaliflozin provided statistically significant reductions in HbA1c compared with placebo (Table 14).

14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) was an international, multicenter, randomized, double-blind, placebo-controlled, clinical study conducted to determine the effect of dapagliflozin relative to placebo on cardiovascular (CV) outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either established CV disease or two or more additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidemia, hypertension, or current tobacco use). Concomitant antidiabetic and atherosclerotic therapies can be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did not have established CV disease. A total of 8582 patients were randomized to dapagliflozin 10 mg, 8578 to placebo, and patients were followed for a median of 4.2 years.

Approximately 80% of the trial population was White, 4% Black or African American, and 13% Asian. The mean age was 64 years, and approximately 63% were male.

Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than 5 years. Mean eGFR was 85.2 mL/min/1.73 m2. At baseline, 23.5% of patients had microalbuminuria (UACR ≥30 to ≤300 mg/g) and 6.8% had macroalbuminuria (UACR >300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m2. At baseline, 10% of patients had a history of heart failure.

Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 receptor agonist.

Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics, and 10.5% with loop diuretics.

A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction (MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death, and 2) MACE.

The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per 100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with a 95% CI of (0.84, 1.03). The upper bound of this confidence interval, 1.03, excluded the pre-specified non-inferiority margin of 1.3.

Dapagliflozin was superior to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death (HR 0.83 [95% CI 0.73, 0.95]).

The treatment effect was due to a significant reduction in the risk of hospitalization for heart failure in subjects randomized to Dapagliflozin (HR 0.73 [95% CI 0.61, 0.88]), with no change in the risk of CV death (Table 15 and Figures 4 and 5).

Figure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the DECLARE Study

Figure_4

Figure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE Study

Figure_5

14.3 Chronic Kidney Disease

The Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD, NCT03036150) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with chronic kidney disease (CKD) (eGFR between 25 and 75 mL/min/1.73 m2) and albuminuria (urine albumin creatinine ratio [UACR] between 200 and 5000 mg/g) who were receiving standard of care background therapy, including a maximally tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The trial excluded patients with autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis and patients requiring cytotoxic, immunosuppressive, or immunomodulatory therapies in the preceding 6 months.

The primary objective was to determine whether dapagliflozin reduces the incidence of the composite endpoint of ≥50% sustained decline in eGFR, progression to end-stage kidney disease (ESKD) (defined as sustained eGFR <15 mL/min/1.73 m2, initiation of chronic dialysis treatment or renal transplant), CV or renal death.

A total of 4304 patients were randomized equally to dapagliflozin 10 mg or placebo and were followed for a median of 28.5 months.

The mean age of the study population was 62 years and 67% were male. The population was 53% White, 4% Black or African American, and 34% Asian; 25% were of Hispanic or Latino ethnicity.

At baseline, mean eGFR was 43 mL/min/1.73 m2, 44% of patients had an eGFR 30 mL/min/1.73 m2 to less than 45 mL/min/1.73 m2, and 15% of patients had an eGFR less than 30 mL/min/1.73 m2. Median UACR was 950 mg/g. A total of 68% of the patients had type 2 diabetes mellitus at randomization. The most common etiologies of CKD were diabetic nephropathy (58%), ischemic/hypertensive nephropathy (16%), and IgA nephropathy (6%).

At baseline, 97% of patients were treated with ACEi or ARB. Approximately 44% were taking antiplatelet agents, and 65% were on a statin.

Dapagliflozin reduced the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, progression to ESKD, CV or renal death (HR 0.61 [95% CI 0.51,0.72]; p<0.0001). The dapagliflozin and placebo event curves separate by Month 4 and continue to diverge over the study period. The treatment effect reflected a reduction in ≥50% sustained decline in eGFR, progression to ESKD, and CV death. There were few renal deaths during the trial (Table 16, Figure 6).

Dapagliflozin also reduced the incidence of the composite endpoint of CV death or hospitalization for heart failure (HR 0.71 [95% CI 0.55, 0.92], p=0.0089) and all-cause mortality (HR 0.69 [95% CI 0.53, 0.88], p=0.0035).

Figure 6: Time to First Occurrence of the Primary Composite Endpoint, ≥50% Sustained Decline in eGFR, ESKD, CV or Renal Death (DAPA-CKD Study)

Figure_6

Patients at risk is the number of subjects at risk at the beginning of the period. 1 month corresponds to 30 days. 2-sided p-value is displayed. HR, CI and p-value are from the Cox proportional hazard model.

HR=hazard ratio; CI=confidence interval; eGFR=estimated glomerular filtration rate; ESKD=end stage kidney disease; CV=cardiovascular; vs=versus.

The results of the primary composite endpoint were consistent across the subgroups examined, including CKD patients with and without type 2 diabetes mellitus, causes of CKD, age, biological sex, race, UACR, and eGFR.

DAPA-CKD enrolled a population with relatively advanced CKD at high risk of progression. Exploratory analyses of a randomized, double-blind, placebo-controlled trial conducted to determine the effect of dapagliflozin on CV outcomes (the DECLARE trial) support the conclusion that dapagliflozin is also likely to be effective in patients with less advanced CKD.

14.4 Heart Failure

The efficacy and safety of dapagliflozin 10 mg were assessed independently in two Phase 3 studies in patients with heart failure.

Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF, NCT03036124) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with heart failure (New York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] 40% or less) to determine whether dapagliflozin reduces the risk of cardiovascular death and hospitalization for heart failure. Of 4744 patients, 2373 were randomized to dapagliflozin 10 mg and 2371 to placebo and were followed for a median of 18 months.

Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure (DELIVER, NCT03619213) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients aged ≥40 years with heart failure (NYHA class II-IV) with LVEF >40% and evidence of structural heart disease to determine whether dapagliflozin reduces the risk of cardiovascular death, hospitalization for heart failure or urgent heart failure visits. Of 6263 patients, 3131 were randomized to dapagliflozin 10 mg and 3132 to placebo and were followed for a median of 28 months. The study included 654 (10%) heart failure patients who were randomized during hospitalization for heart failure or within 30 days of discharge.

In DAPA-HF, at baseline, 94% of patients were treated with ACEi, ARB or angiotensin receptor-neprilysin inhibitor (ARNI, including sacubitril/valsartan 11%), 96% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic, and 26% had an implantable device.

In DELIVER, at baseline, 77% of patients were treated with ACEi, ARB or ARNI, 83% with beta-blocker, 43% with MRA, 98% with diuretic.

In both studies, dapagliflozin reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit (see Table 17).

NOTE: Time to first event was analyzed in a Cox proportional hazards model. The number of first events for the single components are the actual number of first events for each component and does not add up to the number of events in the composite endpoint. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.

In both studies, all three components of the primary composite endpoint individually contributed to the treatment effect. In both studies, the dapagliflozin and placebo event curves separated early and continued to diverge over the study period (see Figures 7 and 9).

Figure 7: Time to the First Occurrence of the Composite of Cardiovascular Death*, Hospitalization for Heart Failure or Urgent Heart Failure Visit

A) DAPA-HF Study

Figure_7a

B) DELIVER Study

Figure-7b

NOTE: An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g., in an Emergency Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).

* In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.

† Patients at risk is the number of patients at risk at the beginning of the period.

HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.

Figure 8: Time to Cardiovascular Death*

A) DAPA-HF Study

Figure-8a

B) DELIVER Study

Figure_8b

* In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.

† Patients at risk is the number of patients at risk at the beginning of the period.

HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.

Figure 9: Time to the First Occurrence of Hospitalization for Heart Failure or Urgent Heart Failure Visit

A) DAPA-HF Study

Figure-9a

B) DELIVER Study

Figure-9b

* Patients at risk is the number of patients at risk at the beginning of the period.

HR=Hazard ratio, CI=Confidence interval.

In DAPA-HF, dapagliflozin reduced the total number of hospitalizations for heart failure (first and recurrent) events and CV death, with 567 and 742 total events in the dapagliflozin-treated vs placebo group (Rate Ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002).

In DELIVER, dapagliflozin reduced the total number of heart failure events (first and recurrent hospitalization for heart failure or urgent heart failure visit) and CV death, with 815 and 1057 total events in the dapagliflozin treated vs placebo group (Rate Ratio 0.77 [95% CI 0.67, 0.89]; p=0.0003).

In both studies, the results of the primary composite endpoint were consistent across the subgroups examined (see Figure 10).

Figure 10: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) Subgroup Analysis

A) DAPA-HF Study

Figure_10a

a Hazard ratio estimates are not presented for subgroups with less than 15 events in total, both arms combined.

n/N# Number of subjects with event/number of subjects in the subgroup.

NT-proBNP = N-terminal pro b-type natriuretic peptide, HF = Heart failure, MRA = mineralocorticoid receptor antagonist,

ECG = electrocardiogram, eGFR = estimated glomerular filtration rate.

Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

B) DELIVER Study

Figure_10b

a Subacute patient defined as randomized during hospitalization for heart failure or within 30 days of discharge.

b Defined as history of type 2 diabetes mellitus. This analysis does not include type 2 diabetes mellitus as a stratification factor.

n/N# Number of subjects with event/number of subjects in the subgroup.

NT-proBNP = N-terminal pro b-type natriuretic peptide, HF = Heart failure, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, BMI = body mass index, SBP = systolic blood pressure, T2DM = type 2 diabetes mellitus.

NOTE: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

The treatment effect of dapagliflozin on the composite endpoint of cardiovascular death, hospitalization for heart failure or urgent heart failure was consistent across the LVEF range as evaluated in DAPA-HF and DELIVER studies (Figure 11).

Figure 11: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) by LVEF (DAPA-HF and DELIVER Studies)

Figure_11

* 1 patient in DAPA-HF study had LVEF >40. 4 patients in DELIVER study had LVEF≤40.

In DAPA-HF study, the 5% and 95% percentiles of LVEF were 20 and 40 respectively. In DELIVER study, the 5% and 95% percentiles of LVEF were 42 and 70, respectively.


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Hosting a dedicated platform for the convergence of disaster risk reduction, the keynote line up for Disasters Expo USA 2024 will provide an insight into successful case studies and
programs to accurately prepare for disasters. Featuring sessions from the likes of The Federal Emergency Management Agency,
NASA, The National Aeronautics and Space Administration, NOAA, The National Oceanic and Atmospheric Administration, TSA and several more this event is certainly providing you with the knowledge
required to prepare, respond and recover to disasters.
With over 50 hours worth of unmissable content, exciting new features such as their Disaster
Resilience Roundtable, Emergency Response Live, an Immersive Hurricane Simulation and
much more over just two days, you are guaranteed to gain an all-encompassing insight into
the industry to tackle the challenges of disasters.
By uniting global disaster risk management experts, well experienced emergency
responders and the leading innovators from the world, the event is the hub of the solutions
that provide attendees with tools that they can use to protect the communities and mitigate
the damage from disasters.
Tickets for the event are $119, but we have been given the promo code: HUGI100 that will
enable you to attend the event for FREE!

So don’t miss out and register today: https://shorturl.at/aikrW

And in case you missed it, here is our ultimate road trip playlist is the perfect mix of podcasts, and hidden gems that will keep you energized for the entire journey

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