Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial.

AIMS: Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated. METHODS AND RESULTS: A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL -1.97 (-2.86, -1.08), -1.74 (-2.73, -0.74); -1.53 (-2.75, -0.31) kg; for WL-adjusted: -2.31 (-3.77, -0.85), -2.79 (-5.03, -0.54), -3.18 (-6.08, -0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001). CONCLUSION: Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90.

Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.

BACKGROUND: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized). METHODS: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model. RESULTS: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P=0.03; 4.80 [95% CI, 0.00-9.61], P=0.05; 4.66 [95% CI, 0.32-9.01], P=0.04; 4.85 [95% CI, 0.77-8.92], P=0.02; and 4.40 points [95% CI, 0.33-8.48], P=0.03, respectively). CONCLUSIONS: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0415775.

Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial.

BACKGROUND: The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA. METHODS: The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA. RESULTS: Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28-2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35-2.91); all-cause mortality, HR 1.8 (95% CI 1.29-2.49), all P < 0.001] in multivariate adjusted analyses, as compared with the lowest tertile. SUA was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: -1.12 ± 0.04 mg/dL, P < 0.0001) and remained lower throughout follow-up, with a similar reduction in all prespecified subgroups. Empagliflozin reduced events of clinically relevant hyperuricaemia (acute gout, gouty arthritis or initiation of anti-gout therapy) by 32% [HR 0.68 (95% CI 0.52-0.89), P = 0.004]. The beneficial effect of empagliflozin on the primary endpoint was independent of baseline SUA [HR 0.76 (95% CI 0.65-0.88), P < 0.001) and of the change in SUA at 4 weeks [HR 0.81 (95% CI 0.69-0.95), P = 0.012]. As a hypothesis-generating finding, an interaction between SUA and treatment effect suggested a benefit of empagliflozin on mortality (cardiovascular and all-cause mortality) in patients in elevated SUA (P for interaction = 0.005 and = 0.011, respectively). CONCLUSION: Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA.

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

AIMS: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). METHODS AND RESULTS: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. CONCLUSION: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

Potential contribution of haemoconcentration to changes in lipid variables with empagliflozin in patients with type 2 diabetes: A post hoc analysis of pooled data from four phase 3 randomized clinical trials.

AIM: To examine the association between changes in lipids and markers of haemoconcentration (haematocrit and serum albumin) with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes (T2D) using pooled data from four phase 3 randomized trials. MATERIALS AND METHODS: Patients with T2D received placebo (n = 825), empagliflozin 10 mg (n = 830) or 25 mg (n = 822) for 24 weeks. In post hoc mediation analyses, we assessed total changes in LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein (Apo) B, and Apo A-I, and changes in these variables associated with, and independent of, changes in haematocrit and serum albumin at week 24 using ANCOVA models. RESULTS: Empagliflozin versus placebo increased serum LDL-cholesterol, HDL-cholesterol, and Apo A-I, decreased triglycerides (empagliflozin 10 mg only), and (non-significantly) increased Apo B. Empagliflozin modestly increased haematocrit and serum albumin. In mediation analyses, haematocrit changes (increases) with empagliflozin were associated with significant changes (increases) in all lipid variables, including Apo B. Except for triglycerides (non-significant), similar lipid variable associations were observed with serum albumin changes. Haematocrit- and serum albumin-independent changes in lipids with empagliflozin were significant for HDL-cholesterol (increases), mostly significant for triglycerides (decreases), and less so for other lipid fractions. CONCLUSION: Haematocrit and serum albumin increases were associated with increases in lipid fractions with empagliflozin. Empagliflozin-associated changes in serum lipids, particularly LDL-cholesterol increases, may be partly attributable to haemoconcentration resulting from increased urinary volume and subsequent volume contraction.

Antihyperglycemic and Blood Pressure Effects of Empagliflozin in Black Patients With Type 2 Diabetes Mellitus and Hypertension.

BACKGROUND: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor indicated for type 2 diabetes mellitus (T2DM), can lower blood pressure (BP) and reduce cardiovascular mortality in patients with T2DM and preexisting cardiovascular disease. Its effects in blacks have been understudied. METHODS: In this 24-week study, 150 blacks with T2DM and hypertension had glycohemoglobin (primary end point), office and 24-hour ambulatory BP, body weight, and safety assessments. After a 2-week, open-label, placebo run-in, patients were randomly assigned to once daily empagliflozin (10 mg for the first 4 weeks, then force-titrated to 25 mg until week 24) or placebo. A mixed-effects model for repeated measures was performed on the primary and 2 key secondary end points, and an analysis of covariance for nonrepeated measures with last observation carried forward was performed for 2 other key secondary end points. Hierarchical testing was applied for these end points. RESULTS: Overall, 52.7% of participants were men, mean (SD) age, 56.8 (9.3) years; mean duration of T2DM, 9.3 (7.1) years. The baseline values of key parameters (mean [SD]) were as follows: glycohemoglobin, 8.59 (1.02)%; ambulatory systolic BP, 146.3 (11.0) mm Hg; and ambulatory diastolic BP, 89.4 (8.1) mm Hg. By week 24, the mean (standard error) change in glycohemoglobin in the empagliflozin group was -0.77 (0.15%) in comparison with an increase of 0.07 (0.16%) in the placebo group; placebo-corrected difference, -0.78% (95% CI, -1.18 to -0.38; P=0.0002). Reductions in body weight by week 24 were -2.38 (0.38) empagliflozin and -0.80 (0.47) placebo; the placebo-corrected difference was -1.23 kg (95% CI, -2.39 to -0.07; P=0.0382). Empagliflozin significantly reduced 24-hour ambulatory systolic BP versus placebo by weeks 12 and 24 (placebo-corrected difference, -5.21 mm Hg [95% CI, -9.24 to -1.18; P=0.0117] and -8.39 mm Hg [95% CI, -13.74 to -3.04; P=0.0025], respectively). Diastolic BP was also reduced. CONCLUSIONS: In blacks with T2DM, empagliflozin reduced glycohemoglobin, body weight, and BP. The effect of empagliflozin on BP increased from 12 to 24 weeks, suggesting a full antihypertensive effect takes ≥6 months to be fully realized. At week 24, the placebo-subtracted BP effect was similar to standard antihypertensive monotherapies, suggesting that empagliflozin may be beneficial for this high-risk population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02182830.

Empagliflozin compared with glimepiride in metformin-treated patients with type 2 diabetes: 208-week data from a masked randomized controlled trial.

AIM: To report results at week 208, including a 104-week masked extension, of the EMPA-REG H2H-SU trial in patients with type 2 diabetes with inadequate glycaemic control on metformin, in which empagliflozin 25 mg given for 104 weeks provided a sustained reduction in glycated haemoglobin (HbA1c) with a small but statistically significant benefit vs glimepiride, sustained reductions in weight and blood pressure, and low risk of hypoglycaemia. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes and HbA1c 53-86 mmol/mol (7% to 10%) were randomized to empagliflozin 25 mg or glimepiride 1 to 4 mg for 104 weeks as add-on to metformin. Patients who completed the randomized treatment period could participate in a 104-week extension in which they continued the double-blind treatment allocated at randomization. RESULTS: Of 765 and 780 patients treated with empagliflozin and glimepiride, 576 and 549 patients, respectively, entered the extension period of the study. At week 208, the adjusted mean difference in change from baseline in HbA1c with empagliflozin vs glimepiride was -1.96 mmol/mol, 95% CI -3.57, -0.35 (-0.18%, 95% CI -0.33, -0.03); P = 0.0172. Rescue therapy was given to 23% of patients on empagliflozin and 34% on glimepiride (odds ratio 0.56 [95% CI 0.45, 0.71]; P < 0.0001). Confirmed hypoglycaemic adverse events (plasma glucose ≤3.9 mmol/L and/or requiring assistance) occurred in 3% of patients on empagliflozin and 28% on glimepiride (odds ratio 0.08 [95% CI 0.05, 0.13]; P < 0.0001). CONCLUSIONS: In patients with type 2 diabetes, empagliflozin 25 mg as add-on to metformin for 208 weeks reduced HbA1c with a significantly lower risk of hypoglycaemia and a significantly smaller proportion of patients receiving rescue therapy compared with glimepiride.

Influence of common polymorphisms in the SLC5A2 gene on metabolic traits in subjects at increased risk of diabetes and on response to empagliflozin treatment in patients with diabetes.

OBJECTIVE: Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. PATIENTS AND METHODS: Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies ≥5%) present in the SLC5A2 gene locus. RESULTS: In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA1c, plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P≥0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA1c, fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study. CONCLUSION: Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin.

Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial.

AIMS: We previously reported that in the EMPA-REG OUTCOME(®) trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure. METHODS AND RESULTS: Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin [265/4687 patients (5.7%)] than with placebo [198/2333 patients (8.5%)] [hazard ratio, HR: 0.66 (95% confidence interval: 0.55-0.79); P < 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure [2.8 vs. 4.5%; HR: 0.61 (0.47-0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization [36.8 vs. 39.6%; HR: 0.89 (0.82-0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo. CONCLUSION: In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure.

Efficacy and safety of empagliflozin in patients with type 2 diabetes from Asian countries: pooled data from four phase III trials.

We investigated the efficacy and safety of empagliflozin over 24 weeks in Asian patients with type 2 diabetes (T2DM) using pooled data from four phase III trials. In these trials, patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo as monotherapy or add-on to metformin, metformin plus sulphonylurea or pioglitazone ± metformin. In total, 1326 patients from Asia received ≥1 dose of study drug. At week 24, adjusted mean differences versus placebo in change from baseline in glycated haemoglobin (HbA1c) were -0.66% [95% confidence interval (CI) -0.76, -0.56] and -0.73% (95% CI -0.83, -0.64) and in weight were -1.6 kg (95% CI -1.9, -1.3) and -1.8 kg (95% CI -2.1, -1.5) with empagliflozin 10 and 25 mg, respectively (all p < 0.001). Empagliflozin significantly reduced systolic and diastolic blood pressure. The proportion of patients reporting ≥1 adverse event was similar across treatment groups, but events consistent with genital infection were more common in patients treated with empagliflozin 10 mg (3.4%) or 25 mg (2.3%) than placebo (0.9%). Thus in Asian patients with T2DM, empagliflozin reduced HbA1c, weight and blood pressure, and was well tolerated.

Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study.

BACKGROUND: This study evaluated the effect of empagliflozin on postprandial glucose (PPG) and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: Patients (N = 60; baseline mean [SD] HbA1c 7.91 [0.80]%; body mass index 24.3 [3.2] kg/m(2)) were randomized to receive empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19) or placebo (n = 21) once daily as monotherapy for 28 days. A meal tolerance test and continuous glucose monitoring (CGM) for 24 hours were performed at baseline and on days 1 and 28. The primary endpoint was change from baseline in area under the glucose concentration-time curve 3 hours after breakfast (AUC1-4h for PPG) at day 28. RESULTS: Adjusted mean (95%) differences versus placebo in changes from baseline in AUC1-4h for PPG at day 1 were -97.1 (-126.5, -67.8) mg · h/dl with empagliflozin 10 mg and -91.6 (-120.4, -62.8) mg · h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were -85.5 (-126.0, -45.0) mg · h/dl with empagliflozin 10 mg and -104.9 (-144.8, -65.0) mg · h/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Adjusted mean (95% CI) differences versus placebo in change from baseline in 24-hour mean glucose (CGM) at day 1 were -20.8 (-27.0, -14.7) mg/dl with empagliflozin 10 mg and -23.9 (-30.0, -17.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo) and at day 28 were -24.5 (-35.4, -13.6) mg/dl with empagliflozin 10 mg and -31.7 (-42.5,-20.9) mg/dl with empagliflozin 25 mg (both p < 0.001 versus placebo). Changes from baseline in mean amplitude of glucose excursions (MAGE; CGM) were not significantly different with either empagliflozin dose versus placebo at either timepoint. Curves of mean glucose (CGM) did not change between baseline and day 1 or 28 with placebo, but shifted downward with empagliflozin. Percentage of time with glucose ≥70 to <180 mg/dl increased from 52.0% at baseline to 77.0% at day 28 with empagliflozin 10 mg and from 55.0% to 81.1% with empagliflozin 25 mg, without increasing time spent with hypoglycemia. CONCLUSION: Empagliflozin for 28 days reduced PPG from the first day and improved daily blood glucose control in Japanese patients with T2DM. TRIAL REGISTRATION: Clinicaltrials.gov NCT01947855.

Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial.

BACKGROUND: To investigate the long-term efficacy and safety of empagliflozin monotherapy compared with placebo and sitagliptin in drug-naïve patients with type 2 diabetes mellitus. METHODS: Of 899 patients randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, placebo, or sitagliptin 100 mg once daily for 24 weeks, 615 continued in a double-blind extension trial for ≥52 weeks. Exploratory endpoints included changes from baseline in HbA1c, weight and blood pressure at week 76. RESULTS: Compared with placebo, adjusted mean changes from baseline in HbA1c at week 76 were -0.78 % (95 % CI -0.94, -0.63; p < 0.001) and -0.89 % (95 % CI -1.04, -0.73; p < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, adjusted mean changes from baseline in weight at week 76 were -1.8 kg (95 % CI -2.4, -1.3; p < 0.001) and -2.0 kg (95 % CI -2.6, -1.5; p < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Empagliflozin led to reductions in systolic blood pressure (SBP) compared with placebo in the primary analysis but not in sensitivity analyses. Compared with sitagliptin, empagliflozin 25 mg reduced HbA1c and both empagliflozin doses reduced weight and SBP. Adverse events (AEs) were reported in 76.8, 78.0, 76.4 and 72.2 % of patients on empagliflozin 10 mg, empagliflozin 25 mg, placebo and sitagliptin, respectively. Confirmed hypoglycaemic AEs (glucose ≤3.9 mmol/l and/or requiring assistance) were reported in two patients (0.9 %) per treatment group. CONCLUSIONS: Empagliflozin monotherapy for ≥76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov NCT01289990.

Effect of food on the pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and assessment of dose proportionality in healthy volunteers.

OBJECTIVES: Empagliflozin is an orally available, potent and highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2). This study was undertaken to investigate the effect of food on the pharmacokinetics of 25 mg empagliflozin and to assess dose proportionality between 10 mg and 25 mg empagliflozin under fasted conditions. MATERIALS AND METHODS: In this open-label, 3-way, cross-over study, 18 healthy volunteers received 3 single doses of empagliflozin in a randomized sequence (25 mg empagliflozin under fasted conditions, 25 mg empagliflozin after a high-fat, high-calorie breakfast and 10 mg empagliflozin under fasted conditions), each separated by a washout period of at least 7 days. Serial plasma samples were collected at selected time points over a period of 72 hours. RESULTS: Administration with food had no clinically relevant effect on the area under the plasma concentration-time curve (AUC0-∞) of empagliflozin (geometric mean ratio (GMR): 84.04, 90% confidence interval (CI): 80.86 - 87.34). The decrease observed in the maximum plasma concentrations (Cmax) of empagliflozin (GMR: 63.22, 90% CI: 56.74 - 70.44) when administered with food was not considered clinically meaningful. The increases in AUC0-∞ and Cmax for 10 mg vs. 25 mg empagliflozin administered under fasting conditions were roughly dose-proportional, as demonstrated by the slope ß of the regression lines being slightly less than 1 (slope ß for AUC0-∞: 0.94, 95% CI: 0.90 - 0.97; slope ß for Cmax: 0.91, 95% CI: 0.80 - 1.01). Empagliflozin was well tolerated under fed and fasting conditions. CONCLUSIONS: The results support administration of empagliflozin tablets independently of food. Increases in empagliflozin exposure under fasting conditions were roughly dose-proportional between 10 mg and 25 mg empagliflozin.

Impact of anaemia and the effect of empagliflozin in heart failure with reduced ejection fraction: findings from EMPEROR-Reduced.

AIMS: Anaemia is frequent among patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with poor outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) increase haematocrit and may correct anaemia. This study aims to investigate the impact of empagliflozin on haematocrit and anaemia, and whether anaemia influenced the effect of empagliflozin in EMPEROR-Reduced. METHODS AND RESULTS: Mixed-effects models and survival analysis. A total of 3726 patients (out of 3730) had baseline haematocrit values, 3013 (81%) had no anaemia and 713 (19%) had anaemia. Patients with anaemia were older (70.4 vs. 66.0 years), had lower body mass index (26.6 vs. 28.2 kg/m2 ), lower estimated glomerular filtration rate (54.2 vs. 63.9 ml/min/1.73 m2 ), and higher N-terminal pro-B-type natriuretic peptide (2362 vs. 1800 pg/ml). Compared to patients without anaemia, those with anaemia had 1.5 to 2.5-fold higher rates of cardiovascular and all-cause mortality, total HF hospitalizations, and kidney composite outcomes. The effect of empagliflozin to reduce the primary composite outcome of cardiovascular death or HF hospitalizations, total HF hospitalizations, and kidney composite outcome was not modified by baseline anaemia status (interaction p > 0.1 for all). Compared to placebo, empagliflozin rapidly (as early as week 4) increased haematocrit and haemoglobin and reduced the rates of new-onset anaemia throughout the follow-up (22.6% in placebo vs. 12.3% in empagliflozin; hazard ratio 0.49, 95% confidence interval 0.41-0.59; p < 0.001). CONCLUSIONS: Anaemia was associated with poor outcomes. Empagliflozin reduced new-onset anaemia throughout the follow-up and improved HF and kidney outcomes irrespective of anaemia status at baseline.

Minimally Clinically Important Difference in Health Status Scores in Patients With HFrEF vs HFpEF.

BACKGROUND: Differences in clinically important thresholds in patient-reported outcomes measures such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) remain less well-established in patients with heart failure with preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: The purpose of this study was to estimate meaningful thresholds for improvement or deterioration in the KCCQ-Total Symptom Score (TSS) in patients with HFrEF versus HFpEF. METHODS: This secondary analysis of EMPERIAL program used anchor- and distribution-based approaches to estimate thresholds for improvement or deterioration in the KCCQ-TSS using Patient Global Impression of Severity (PGIS) as the primary anchor. Mean change in KCCQ-TSS from baseline to week 12 was calculated for each PGIS. RESULTS: A total of 312 HFrEF and 315 HFpEF patients were enrolled. At week 12, mean changes in KCCQ-TSS corresponding to PGIS changes of "any improvement," "1-category improvement," and "1-category deterioration" were 13 ± 17, 12 ± 17, -3 ± 16 points in HFrEF, and 15 ± 18, 13 ± 17, -7 ± 18 points in HFpEF. Threshold for meaningful within-patient change in KCCQ-TSS was ≥9 points in HFrEF and ≥7 points in HFpEF patients. Sensitivity and specificity of ≥9 points/≥7 points change was 0.65 and 0.70 for HFrEF and 0.64 and 0.66 for HFpEF. Cumulative distribution function curves of KCCQ-TSS change from baseline to week 12 showed a shift to higher scores in both HFrEF and HFpEF patients. CONCLUSIONS: In the EMPERIAL program, a change in KCCQ-TSS of ≥9 points in HFrEF and ≥7 points in HFpEF represents the minimal clinically important difference for improvement, confirming the broad range of 5-10 points as meaningful thresholds.

Biomarker-driven prognostic models in chronic heart failure with preserved ejection fraction: the EMPEROR-Preserved trial.

AIMS: Biomarker-driven prognostic models incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in heart failure (HF) with preserved ejection fraction (HFpEF) are lacking. We aimed to generate a biomarker-driven prognostic tool for patients with chronic HFpEF enrolled in EMPEROR-Preserved. METHODS AND RESULTS: Multivariable Cox regression models were created for (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, (iii) cardiovascular death, and (iv) HF hospitalization. PARAGON-HF was used as a validation cohort. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last hospitalization, New York Heart Association (NYHA) class III or IV, history of chronic obstructive pulmonary disease (COPD), insulin-treated diabetes, low haemoglobin, and a longer time since HF diagnosis were key predictors (eight variables, all p < 0.001). The consequent primary outcome risk score discriminated well (c-statistic = 0.75) with patients in the top 10th of risk having an event rate >22× higher than those in the bottom 10th. A model for HF hospitalization alone had even better discrimination (c = 0.79). Empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients across all risk levels. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality followed by history of COPD, low albumin, older age, left ventricular ejection fraction ≥50%, NYHA class III or IV and insulin-treated diabetes (eight variables, all p < 0.001). The mortality risk model had similar discrimination for all-cause and cardiovascular mortality (c-statistic = 0.72 for both). External validation provided c-statistics of 0.71, 0.71, 0.72, and 0.72 for the primary outcome, HF hospitalization alone, all-cause death, and cardiovascular death, respectively. CONCLUSIONS: The combination of NT-proBNP and hs-cTnT along with a few readily available clinical variables provides effective risk discrimination both for morbidity and mortality in patients with HFpEF. A predictive tool-kit facilitates the ready implementation of these risk models in routine clinical practice.

Renal effects of empagliflozin in patients hospitalized for acute heart failure: from the EMPULSE trial.

AIM: The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved clinical outcomes in patients hospitalized for acute heart failure. In patients with chronic heart failure, SGLT2 inhibitors cause an early decline in estimated glomerular filtration rate (eGFR) followed by a slower eGFR decline over time than placebo. However, the effects of SGLT2 inhibitors on renal function during a hospital admission for acute heart failure remain largely unknown. METHODS AND RESULTS: Between 1 and 5 days after a hospitalization for acute heart failure, 530 patients with an eGFR >20 ml/min/1.73 m2 were randomized to 10 mg of empagliflozin or placebo and treated for 90 days. Renal function and electrolytes were measured at baseline, and after 15, 30 and 90 days. We evaluated the effect of empagliflozin on eGFR over time and the impact of baseline eGFR on the primary hierarchical outcome of death, worsening heart failure events and quality of life. Mean baseline eGFR was 52.4 ml/min/1.73 m2 in the empagliflozin group and 55.7 ml/min/1.73 m2 in the placebo group. Empagliflozin caused an initial decline in eGFR (-2 ml/min/1.73 m2 at day 15 compared to placebo). At day 90, eGFR was similar between empagliflozin and placebo. Investigator-reported acute renal failure occurred in 7.7% of empagliflozin versus 12.1% of placebo patients. The overall clinical benefit (hierarchical composite of all-cause death, heart failure events and quality of life) of empagliflozin was unaffected by baseline eGFR. CONCLUSION: In patients hospitalized for acute heart failure, empagliflozin caused an early modest decline in renal function which was no longer evident after 90 days. Acute renal events were similar in both groups. The clinical benefit of empagliflozin was consistent regardless of baseline renal function.

The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial.

AIMS: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death. METHODS AND RESULTS: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated. CONCLUSIONS: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.