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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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Abstract
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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Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial.
Ludvik, B, Giorgino, F, Jódar, E, Frias, JP, Fernández Landó, L, Brown, K, Bray, R, Rodríguez, Á
Lancet (London, England). 2021;(10300):583-598
Abstract
BACKGROUND Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors. METHODS In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA1c) of 7·0-10·5%, body-mass index of at least 25 kg/m2, stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete. FINDINGS Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting (6-10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment. INTERPRETATION In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists. FUNDING Eli Lilly and Company.
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Combined effects of ARNI and SGLT2 inhibitors in diabetic patients with heart failure with reduced ejection fraction.
Kim, HM, Hwang, IC, Choi, W, Yoon, YE, Cho, GY
Scientific reports. 2021;(1):22342
Abstract
Angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose co-transporter-2 inhibitor (SGLT2i) have shown benefits in diabetic patients with heart failure with reduced ejection fraction (HFrEF). However, their combined effect has not been revealed. We retrospectively identified diabetic patients with HFrEF who were prescribed an ARNI and/or SGLT2i. The patients were divided into groups treated with both ARNI and SGLT2i (group 1), ARNI but not SGLT2i (group 2), SGLT2i but not ARNI (group 3), and neither ARNI nor SGLT2i (group 4). After propensity score-matching, the occurrence of hospitalization for heart failure (HHF), cardiovascular mortality, and changes in echocardiographic parameters were analyzed. Of the 206 matched patients, 92 (44.7%) had to undergo HHF and 43 (20.9%) died of cardiovascular causes during a median 27.6 months of follow-up. Patients in group 1 exhibited a lower risk of HHF and cardiovascular mortality compared to those in the other groups. Improvements in the left ventricular ejection fraction and E/e' were more pronounced in group 1 than in groups 2, 3 and 4. These echocardiographic improvements were more prominent after the initiation of ARNI, compare to the initiation of SGLT2i. In diabetic patients with HFrEF, combination of ARNI and SGT2i showed significant improvement in cardiac function and prognosis. ARNI-SGLT2i combination therapy may improve the clinical course of HFrEF in diabetic patients.
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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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Efficacy of DPP-4 inhibitors and SGLT2 inhibitors compared to sulphonylureas in adult patients with diabetes with low c-peptide levels with or without anti-GAD65 antibody positivity.
Sudan, A, Kalra, A, Mirza, AA, Kant, R
Diabetes & metabolic syndrome. 2021;(4):102197
Abstract
BACKGROUND AND AIMS Latent Autoimmune Diabetes of Adulthood (LADA) is different from type 2 diabetes. Present treatment protocols do not reflect that. DPP-4 and SGLT2 inhibitors have changed therapy. DPP-4 inhibitor use has shown delayed decline in beta-cell reserve in LADA. We studied patients with low c-peptide to assess relationship between c-peptide and anti-GAD65 antibody levels and compare DPP-4 inhibitors with SGLT2 inhibitors and sulphonylureas. METHODS The study was an open-label trial conducted in 156 participants with low c-peptide (<0.8 ng/mL), age > 25 years, recently diagnosed diabetes with HBA1c ≥ 6.5%. Participants were enrolled into three arms: Group A received sulphonylureas + metformin, Group B received DPP-4 inhibitors + metformin, and Group C received SGLT-2 inhibitors + metformin. Serum anti-GAD-65 antibodies were assessed using sandwich ELISA. Participants were assessed on enrolment and after three months of dual pharmacotherapy. RESULTS The three arms were comparable on enrolment. 52% of participants with low c-peptide had high anti-GAD65 antibody titers. Significant differences were observed after three months - DPP-4 inhibitors reduced HbA1c by 1.1 ± 0.3%, compared to SGLT2 inhibitors (0.8 ± 0.13%) and sulphonylureas (0.7 ± 0.3%) CONCLUSION DPP-4 inhibitors appear to provide better glycemic control than alternate therapeutic options in patients with low serum c-peptide.
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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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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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Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus.
Liu, J, Tarasenko, L, Pong, A, Huyck, S, Wu, L, Patel, S, Hickman, A, Mancuso, JP, Gantz, I, Terra, SG
Current medical research and opinion. 2020;(8):1277-1284
Abstract
Objective: To assess the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor ertugliflozin across racial groups in patients with type 2 diabetes mellitus (T2DM).Methods: Pooled analysis of data from randomized, double-blind studies in the ertugliflozin phase III development program. Seven placebo- and comparator-controlled studies were used to assess safety (N = 4859) and three placebo-controlled studies were used to assess efficacy (N = 1544). Least-squares (LS) mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).Results: At Week 26, ertugliflozin provided a greater reduction in HbA1c, body weight and SBP versus placebo in all racial subgroups. The placebo-adjusted LS mean change (95% confidence interval) from baseline in HbA1c was -0.8% (-1.0, -0.7) and -1.0% (-1.1, -0.8) with ertugliflozin 5 mg and 15 mg, respectively, in the White subgroup, -0.7% (-1.2, -0.2) and -0.8% (-1.3, -0.3) in the Black subgroup, and -0.8% (-1.1, -0.5) and -1.0% (-1.3, -0.8) in the Asian subgroup. The incidences of overall AEs, serious AEs and AEs leading to discontinuation from study medication were similar between the ertugliflozin 5 mg, 15 mg and non-ertugliflozin groups within each racial subgroup. The incidence of female genital mycotic infection (GMI) was higher with ertugliflozin than non-ertugliflozin across all racial subgroups. The incidence of male GMI was higher with ertugliflozin than non-ertugliflozin in the White sub-group; however, there were few male GMI events in the non-White subgroups.Conclusions: In patients with T2DM, treatment with ertugliflozin improved HbA1c, body weight and SBP across all racial subgroups. Ertugliflozin had a generally similar safety profile across racial subgroups and was generally well tolerated. Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.
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Canagliflozin Increases Calorie Intake in Type 2 Diabetes Without Changing the Energy Ratio of the Three Macronutrients: CANA-K Study.
Matsuba, I, Kanamori, A, Takihata, M, Takai, M, Maeda, H, Kubota, A, Iemitsu, K, Umezawa, S, Obana, M, Kaneshiro, M, et al
Diabetes technology & therapeutics. 2020;(3):228-234
Abstract
Background: Sodium/glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control and reduce body weight by increasing glycosuria. Although a compensatory increase of food intake has been reported, the long-term effect of SGLT2 inhibitors on food intake remains unclear. This study investigated the influence of canagliflozin on calorie and nutrient intake over 1 year. Materials and Methods: Patients with type 2 diabetes (n = 107) were enrolled and followed prospectively while receiving canagliflozin at 100 mg/day for 12 months. Intake of nutrients was investigated by using the food frequency questionnaire. Hemoglobin A1c, body weight, and satisfaction with diabetes treatment (assessed by the Diabetes Treatment Satisfaction Questionnaire: DTSQ) were also investigated. Results: The baseline total energy intake was 1723 ± 525 kcal/day and it showed a persistent increase during treatment with canagliflozin, being 132 kcal higher at 6 months (P = 0.0058) and 113 kcal higher at 12 months (P = 0.0516). Intake of all three macronutrients (carbohydrate, protein, and fat) was significantly increased after 6 months of canagliflozin treatment (P = 0.0129, P = 0.0160, and P = 0.0314, respectively), but their ratio was unchanged. The DTSQ score improved significantly and both hemoglobin A1c and body weight showed a significant decrease throughout treatment (all P < 0.0001). Conclusions: After patients with type 2 diabetes commenced canagliflozin, their calorie intake increased without changing the ratio of the three macronutrients. Despite elevation of the calorie intake, glycemic control improved and weight loss was achieved. Satisfaction with treatment of diabetes also increased.