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Rationale and design of the effects of EMpagliflozin on left ventricular DIAstolic function in diabetes (EmDia) study.
Jünger, C, Prochaska, JH, Gori, T, Schulz, A, Binder, H, Daiber, A, Koeck, T, Rapp, S, Lackner, KJ, Münzel, T, et al
Journal of cardiovascular medicine (Hagerstown, Md.). 2022;(3):191-197
Abstract
BACKGROUND Data of the EMPA-REG OUTCOME study have demonstrated a beneficial effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on cardiovascular outcome in patients with type 2 diabetes. The reduction in cardiovascular mortality and hospitalization due to heart failure might be in part explained by the direct effects of empagliflozin on cardiac diastolic function. The EmDia trial investigates the short-term effects of empagliflozin compared to placebo on the left ventricular E/E' ratio as a surrogate of left ventricular diastolic function. METHODS EmDia is a single-center, randomized, double-blind, two-arm, placebo-controlled, parallel group study of phase IV. Individuals with diabetes mellitus type 2 (T2DM) are randomized 1:1 to receive empagliflozin 10 mg per day or a placebo for 12 weeks. The main inclusion criteria are diagnosed as T2DM with stable glucose-lowering and/or dietary treatment, elevated HbA1c level (6.5-10.0% if receiving glucose-lowering therapy, or 6.5-9.0% if drug-naïve), and diastolic cardiac dysfunction with left ventricular E/E'≥8. The primary end point is the difference of the change in the E/E' ratio by treatment groups after 12 weeks. Secondary end points include assessment of the effect of empagliflozin on left ventricular systolic function, measures of vascular structure and function, as well as humoral cardiovascular biomarkers (i.e. brain natriuretic peptide, troponin, C-reactive protein). In addition, the multidimensional biodatabase enables explorative analyses of molecular biomarkers to gain insights into possible mechanisms of the effects of empagliflozin on human health in a systems medicine-oriented, multiomics approach. CONCLUSION By evaluating the short-term effect of empagliflozin with a comprehensive biobanking program, the EmDia Study offers an opportunity to primarily assess the effects on diastolic function but also to examine effects on clinical and molecular cardiovascular traits. TRIAL REGISTRATION ClinicalTrials.gov; NCT02932436. Registration date, 2016/10/13.
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Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.
Butt, JH, Docherty, KF, Petrie, MC, Schou, M, Kosiborod, MN, O'Meara, E, Katova, T, Ljungman, CEA, Diez, M, Ogunniyi, MO, et al
JAMA cardiology. 2021;(6):678-689
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Abstract
IMPORTANCE Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men. OBJECTIVE To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). DESIGN, SETTING, AND PARTICIPANTS Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021. INTERVENTIONS Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MAIN OUTCOMES AND MEASURES The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. RESULTS A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of ≥5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of ≥5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women. CONCLUSIONS AND RELEVANCE Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03036124.
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Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.
Kosiborod, MN, Esterline, R, Furtado, RHM, Oscarsson, J, Gasparyan, SB, Koch, GG, Martinez, F, Mukhtar, O, Verma, S, Chopra, V, et al
The lancet. Diabetes & endocrinology. 2021;(9):586-594
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BACKGROUND COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness. METHODS DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593. FINDINGS Between April 22, 2020 and Jan 1, 2021, 1250 patients were randomly assigned with 625 in each group. The primary composite outcome of prevention showed organ dysfunction or death occurred in 70 patients (11·2%) in the dapagliflozin group, and 86 (13·8%) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·58-1·10; p=0·17). For the primary outcome of recovery, 547 patients (87·5%) in the dapagliflozin group and 532 (85·1%) in the placebo group showed clinical status improvement, although this was not statistically significant (win ratio 1·09, 95% CI 0·97-1·22; p=0·14). There were 41 deaths (6·6%) in the dapagliflozin group, and 54 (8·6%) in the placebo group (HR 0·77, 95% CI 0·52-1·16). Serious adverse events were reported in 65 (10·6%) of 613 patients treated with dapagliflozin and in 82 (13·3%) of 616 patients given the placebo. INTERPRETATION In patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. FUNDING AstraZeneca.
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Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis of a Phase 3 Randomized Clinical Trial.
Docherty, KF, Jhund, PS, Claggett, B, Ferreira, JP, Bengtsson, O, Inzucchi, SE, Køber, L, Kosiborod, MN, Langkilde, AM, Martinez, FA, et al
JAMA cardiology. 2021;(11):1298-1305
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IMPORTANCE Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. OBJECTIVE To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient's lifetime. DESIGN, SETTING, AND PARTICIPANTS Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. INTERVENTIONS Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. MAIN OUTCOMES AND MEASURES The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient's lifetime for the primary outcome and the secondary outcome of death from any cause. RESULTS A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. CONCLUSIONS AND RELEVANCE These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03036124.
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Model-Informed Pediatric Dose Selection for Dapagliflozin by Incorporating Developmental Changes.
Jo, H, Pilla Reddy, V, Parkinson, J, Boulton, DW, Tang, W
CPT: pharmacometrics & systems pharmacology. 2021;(2):108-118
Abstract
This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.
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Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1β.
Hepprich, M, Wiedemann, SJ, Schelker, BL, Trinh, B, Stärkle, A, Geigges, M, Löliger, J, Böni-Schnetzler, M, Rudofsky, G, Donath, MY
Cell metabolism. 2020;(4):699-709.e5
Abstract
Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.
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Basal insulin secretion capacity predicts the initial response and maximum levels of beta-hydroxybutyrate during therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin, in relation to weight loss.
Sato, Y, Nunoi, K, Kaku, K, Yoshida, A, Suganami, H
Diabetes, obesity & metabolism. 2020;(2):222-230
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AIMS: To investigate predictors of the initial response of beta-hydroxybutyrate (BHB) and maximum BHB (max-BHB) values during long-term therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin (TOFO), and to explore the association of the initial elevation of BHB with subsequent clinical effects in people with type 2 diabetes mellitus. METHODS We analysed 774 people receiving TOFO in phase 3 trials in two groups based on measurable BHB change at week 4 (initial response): the top quartile [n = 194] and the three lower quartiles [n = 579]. Multivariate analysis was used to determine baseline predictors of inclusion in the top quartile and the max-BHB values. To investigate the association of the initial response with subsequent clinical effects, adjusted changes in variables in the two groups were compared using an analysis of covariance model. RESULTS Of the participants, 66% were men, and the mean age, glycated haemoglobin, body mass index and estimated glomerular filtration rate were 58.5 years, 8.1%, 25.6 kg/m2 and 83.9 mL/min/1.73 m2 , respectively. Median changes in BHB at week 4 in the top quartile and lower three quartiles were +246.4* and +30.8* μmol/L, respectively (*P < .001 vs baseline). Lower baseline insulin secretion capacity predicted the inclusion in the top quartile and greater max-BHB levels. The top quartile was associated with greater weight loss following greater increases in free fatty acids and greater reductions in fasting C-peptide levels compared with the lower three quartiles. CONCLUSIONS Lower basal insulin secretion capacity might predict greater initial BHB elevations and max-BHB levels during long-term TOFO therapy. Greater weight loss through lipid use might be related to high initial BHB elevations.
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Choice of endpoint in kidney outcome trials: considerations from the EMPA-REG OUTCOME® trial.
Perkovic, V, Koitka-Weber, A, Cooper, ME, Schernthaner, G, Pfarr, E, Woerle, HJ, von Eynatten, M, Wanner, C
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(12):2103-2111
Abstract
BACKGROUND Doubling of serum creatinine [equivalent to 57% reduction in estimated glomerular filtration rate (eGFR)] is an established surrogate for end-stage kidney disease (ESKD); however, this endpoint necessitates lengthy follow-up and large sample sizes in clinical trials. We explored whether alternative eGFR decline thresholds provide more feasible surrogate kidney endpoints. METHODS The study involved post hoc analysis of the EMPA-REG OUTCOME® trial. Adults with type 2 diabetes, high cardiovascular risk and eGFR ≥30 mL/min/1.73 m2 were assigned empagliflozin 10 mg or 25 mg (n = 4687) or placebo (n = 2333), on top of standard of care. We assessed composite endpoints incorporating different eGFR decline thresholds (≥30, ≥40, ≥50 or ≥57%) combined with initiation of renal replacement therapy (RRT) or renal death. This trial is registered with ClinicalTrials.gov (NCT01131676). RESULTS Empagliflozin versus placebo significantly lowered the risk of decline in eGFR for each threshold listed above, combined with initiation of RRT or renal death, ranging from a hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.72-0.91] for endpoints based on 30% eGFR decline to an HR of 0.37 (0.23-0.61) for endpoints based on 57% eGFR decline. Lower thresholds (e.g. 30%) were associated with higher event rates but weaker treatment effects. The time to the 95% CI of the HR falling to <1.0 decreased with increasing eGFR threshold. CONCLUSIONS The composite of 40% decline in eGFR, ESKD or renal death appears to provide reliable results similar to the traditional 57% decline in eGFR.
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Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer.
Fabian, CJ, Khan, SA, Garber, JE, Dooley, WC, Yee, LD, Klemp, JR, Nydegger, JL, Powers, KR, Kreutzjans, AL, Zalles, CM, et al
Cancer prevention research (Philadelphia, Pa.). 2020;(7):623-634
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We conducted a multiinstitutional, placebo-controlled phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was -1.8% in the SDG arm (P = 0.001) and -1.2% for placebo (P = 0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median = -2.2%; P = 0.002) but not placebo (median = -1.0%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (<0.5 or >2.0) with 7 of 10 increases in placebo and 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.
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Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.
Anker, SD, Butler, J, Filippatos, G, Shahzeb Khan, M, Ferreira, JP, Bocchi, E, Böhm, M, Brunner-La Rocca, HP, Choi, DJ, Chopra, V, et al
European journal of heart failure. 2020;(12):2383-2392
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AIMS: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials. METHODS AND RESULTS EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT-proBNP [974 (499-1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists. CONCLUSION When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021.