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Background: Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial. Methods: A total of 7020 patients with T2D and atherosclerotic cardiovascular disease were treated with empagliflozin (10 mg or 25 mg) or placebo for a median of 3.1 years. The World Health Organization MetS criteria could be determined for 6985 (99.5%) patients. We assessed the association between baseline MetS and multiple cardio-renal endpoints using Cox regression models, and we studied the change in the individual component over time of the MetS using mixed effect models. Results: MetS at baseline was present in 5740 (82%) patients; these were more often white and had more often albuminuria and heart failure, had lower eGFR and HDL-cholesterol, and higher blood pressure, body mass index, waist circumference, and triglycerides. In the placebo group, patients with MetS had a higher risk of all outcomes including cardiovascular death: HR = 1.73 (95% CI 1.01–2.98), heart failure hospitalization: HR = 2.64 (95% CI 1.22, 5.72), and new or worsening nephropathy: HR = 3.11 (95% CI 2.17–4.46). The beneficial effect of empagliflozin was consistent on all cardio-renal outcomes regardless of presence of MetS. Conclusions: A large proportion of the EMPA-REG OUTCOME population fulfills the criteria for MetS. Those with MetS had increased risk of adverse cardio-renal outcomes. Compared with placebo, empagliflozin improved cardio-renal outcomes in patients with and without MetS. Trial registration Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT 01131676 [ABSTRACT FROM AUTHOR]

Severe HYPO is associated with higher CV and mortality risk. The CAROLINA® trial evaluated the CV safety of linagliptin (LINA) and glimepiride (GLIM) in 6033 subjects with relatively early type 2 diabetes (T2D) and elevated CV risk (mean age 64.0 years, HbA1c 7.2%, median T2D duration 6.3 years) and demonstrated non-inferiority for 3P-MACE and no difference for CV and mortality outcomes. However, a significant lower risk of HYPO was observed with LINA vs. GLIM regardless of severity classification. We assessed, in 6014 participants, the associations between severe HYPO and/or documented HYPO (BG <54 mg/dl), which occurred in 109/3014 (3.6%) and 537/3000 (17.9%) in the LINA and GLIM groups, respectively (HR 0.19 [95% CI 0.15, 0.23]), and CV and mortality outcomes using Cox regression models. HYPO events preceded CV outcomes in 0.0-3.6% of all events with LINA and in 8.0-26.2% events with GLIM. Of note, even when multivariably adjusted, occurrence of HYPO was associated only with higher risk for all-cause mortality (HR 1.49 [1.16, 1.92]), and non-CV mortality (HR 2.16 [1.57, 2.97]) (Fig A). The relative effect of LINA vs. GLIM on any CV or mortality outcome (Fig B) was not influenced by antecedent HYPO. In conclusion, preceding HYPO was associated with higher risk for all-cause and non-CV mortality, but not with any other outcomes in a relatively early T2D population at elevated CV risk. Disclosure: J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Mattheus: None. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. Funding: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance [ABSTRACT FROM AUTHOR]

Aims: In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced hospitalization for heart failure risk and cardiovascular (CV) mortality in patients (pts) with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD). We assessed the effect of EMPA on total (first and recurrent) events of ACH and all-cause mortality (ACM). Methods: Pts were randomized to EMPA 10 mg, EMPA 25 mg, or placebo (PBO). We assessed the effect of EMPA pooled vs. PBO on total events of a composite of ACH or ACM using a negative binomial model. Results: Among 7,020 pts (mean [SD] age 63 [9] years), there were 5,399 total events of ACH and ACM. The most frequent hospitalizations were cardiac disorders (1,339), infections and infestations (841), and nervous system disorders (511); ACM: n=463. EMPA reduced the risk of total events of ACH or ACM by 19% vs. PBO (event rate ratio (95% CI): 0.81 (0.74, 0.89), p<0.0001) (Figure); ACH alone 0.83 (0.76, 0.91), ACM alone 0.69 (0.57, 0.83). Across most hospitalization categories, a numerically smaller proportion of pts experienced events with EMPA vs. PBO. The estimated number of total ACH or ACM events prevented with EMPA was 793.3; number of pts needed to treat (NNT) over 3 years to prevent one event was 5.4 (3.8, 9.3). Conclusion: EMPA reduced risk of the total burden of ACH and mortality in pts with T2D and ASCVD, with a clinically relevant number of events prevented and a low NNT. Disclosure: S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. S. Anker: Research Support; Self; Abbott Laboratories, Vifor Pharma Group. Other Relationship; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Cardiac Dimension, Impulse Dynamics, Novartis AG, Respicardia, St. Jude Medical, Vifor Pharma Group. S. Pocock: Consultant; Self; Boehringer Ingelheim International GmbH. S. Kaspers: Employee; Self; Boehringer Ingelheim International GmbH. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. W. Jamal: Employee; Self; Boehringer Ingelheim International GmbH. S. Hantel: Employee; Self; Boehringer Ingelheim Pharma GmbH & Co. KG. S.S. Lund: Employee; Self; Boehringer Ingelheim International GmbH. Stock/Shareholder; Self; Novo Nordisk A/S. Other Relationship; Self; Investment funds. Funding: Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance [ABSTRACT FROM AUTHOR]

More than 400 million people have T2D but an intuitive staging system like TNM used in oncology that predicts survival based on stage is lacking. DSS is designed to fill this void, facilitate communication and management and predict survival. DSS uses discrete CV events (none to ≥3: stage 1 to 4), end-stage renal disease (stage 5) and microvascular complications (none to ≥3: A to D) to stage T2D patients. It is hypothesized that higher DSS stage is associated with higher mortality. We used three large CVOTs (CAROLINA, n=6014, pooled linagliptin and glimepiride; CARMELINA, n=3792, pooled linagliptin and placebo; and the placebo group of EMPA-REG OUTCOME, n= 2300, with information available) that included patients with T2D with or without CVD and chronic kidney disease. By use of investigator reported baseline conditions, we categorized patients into DSS stages and calculated incidence rates (IR) for all-cause death. We observed a pattern of increasing IR for death with more advanced DSS stage, although with overlapping confidence intervals, with some variations between trials (Figure). A pattern of eGFR<60 ml/min/1.73m2 impacting in more advanced stages were observed across trials, whereas the pattern for HbA1c was less clear. Higher DSS stage appeared to be associated with increased mortality across all three CVOT trials but needs validation in the general T2D populations. Disclosure: M. Dar: None. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. M. Mattheus: None. S. Kaspers: Employee; Self; Boehringer Ingelheim International GmbH. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. S.A. Beg: None. [ABSTRACT FROM AUTHOR]

Treatment guideline recommendations for individuals with cardiovascular (CV) disease and type 2 diabetes (T2D) focus on medications with proven CV benefits. However, considerations relating to avoidance of hypoglycemia (HYPO) remain important. We report in the CARdiovascular Outcome Study of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) the effects of treatment on a range of HYPO outcomes. CAROLINA recruited adults with relatively early T2D, HbA1c 6.5-8.5%, and elevated CV risk who were randomized to linagliptin 5 mg (LINA) or glimepiride 1-4 mg (GLIM) once daily added to usual care. Time to first or sum of first plus recurrent HYPO was assessed across categories: any, symptomatic with BG ≤70 mg/dL or severe, BG <54 mg/dL or severe, severe, or, leading to hospitalization, using Cox proportional hazards models or negative binomial regression. 6033 participants (mean age 64.0 years, HbA1c 7.2%, median T2D duration 6.3 years, 42% with CV disease) were followed for median 6.3 years. HbA1c over time did not differ between groups, but a significantly lower frequency of HYPO events was observed with LINA (Fig), regardless of definition, a difference further accentuated when including recurrent HYPO. In conclusion, these data demonstrate that LINA, compared with GLIM, has a significantly lower HYPO burden. Given the potentially harmful clinical impact of HYPO, these data may help inform therapy selection. Disclosure: B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. M. Hoeiberg: Employee; Self; Boehringer Ingelheim International GmbH. E. Pfarr: None. M. Mattheus: None. T. Meinicke: None. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. Funding: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance [ABSTRACT FROM AUTHOR]

In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced risk of cardiovascular (CV) death by 38% and hospitalization for heart failure (HHF) by 35% in patients with type 2 diabetes (T2D) and CV disease. We aimed to identify phenotypes of patients with different risk of outcomes and to explore treatment effects across these groups. Overall, 7020 patients were treated with EMPA 25, 10 mg or placebo (PBO). For this post-hoc analysis, patients were randomly separated into training (2/3) and validation sets (1/3 of patients). Latent class analysis identified 3 clusters using 6639 patients with complete data. The association of clusters to CV death and CV death/HHF, and treatment effect of EMPA vs. PBO across clusters was explored by Cox regression. Cluster 1 included younger patients with shorter T2D duration. Cluster 2 included more women with non-coronary atherosclerotic disease (CAD), and Cluster 3 older patients with advanced CAD. In the training set, risk of CV death varied across clusters (Cluster 2 vs. 1 HR 1.83 [95% CI 1.23, 2.71], Cluster 3 vs. 1 HR 1.86 [1.30, 2.67]) with similar pattern for CV death/HHF. Treatment effect of EMPA was consistent across clusters (Figure). Results were replicated in the validation set. We identified 3 phenotypes of patients with varying risk of outcomes. The consistent treatment effect across clusters reaffirms the robustness of CV death/HHF reduction with EMPA. Disclosure: A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. T. Ahmad: None. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. I. Zwiener: Employee; Self; Boehringer Ingelheim International GmbH. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. S. Hantel: Employee; Self; Boehringer Ingelheim Pharma GmbH & Co. KG. N. Desai: None. R.J. Mentz: Consultant; Self; Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Sanofi. Research Support; Self; GlaxoSmithKline plc. Funding: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance [ABSTRACT FROM AUTHOR]

In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes (T2D) with established atherosclerotic cardiovascular disease (ASCVD), empagliflozin reduced the risk of hospitalization for HF (HHF) by 35% (HR [95%CI] 0.65 [0.50-0.85]), CV death/HHF by 34% (0.66 [0.55-0.79]), and CV death by 38% (0.62 [0.49-0.77]) with an early separation of the cumulative incidence curves. We aimed to explore at what time point after randomization the benefits became apparent. Overall, 7020 patients were treated with empagliflozin 10, 25 mg or placebo. We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF and CV death based on Hazard Ratios (HRs) (95% CI), and calculated the HR on the day the effect reached significance using Cox proportional hazards models. The reduction in risk with empagliflozin vs. placebo reached significance at day 17 for HHF [0.10 [0.01, 0.87), p=0.0372], and day 27 for CV death/HHF [HR 0.28 (0.08, 0.97), p=0.0445], and sustained significant throughout follow-up (Figure). The benefit on CV death reached significance for the first time at day 59 [HR 0.28 (0.08, 0.96)]. HRs stabilized as the number of patients with events increased over time. The benefit of empagliflozin in reducing the risk of HHF, CV death/HHF and CV death emerged within weeks after treatment initiation in EMPA-REG OUTCOME. The earliest effect appears to be on HHF. Disclosure: S. Verma: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Other Relationship; Self; AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Eli Lilly and Company, EOCI Pharmacomm, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi, Sanofi, Sun Pharmaceuticals, Toronto Knowledge Translation Working Group. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker's Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. M. Mattheus: None. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker's Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics. Funding: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance [ABSTRACT FROM AUTHOR]

ADA/EASD guidelines emphasize the importance of patient engagement in therapy decisions. Beyond glycemic effects of type 2 diabetes (T2D) therapies, only SGLT2i and GLP-1RA have cardiovascular (CV) benefits. Key attributes of such therapies may influence their use/adoption. We evaluated patient preferences towards three oral T2D therapies using conjoint analysis. This analysis used an online survey, completed by 553 respondents with T2D in the U.S. (mean age ±SD was 64±9; 55% had CV risk; 27% had CV disease), to present 7 hypothetical, blinded pair-wise drug profile comparison choices composed of different benefit-risk attributes and effect ranges (levels). Attributes/levels were derived from combinations of phase 3 trial data for empagliflozin 25mg (SGLT2i), oral semaglutide 14mg (GLP-1RA) and sitagliptin 100mg (DPP-4i). The predicted therapy preference outcomes and the relative importance of one attribute relative to another were calculated (in %). The preference outcome was highest for the profile matching empagliflozin, ranked first by 56% (z-test, p<0.05), versus 38% for sitagliptin and 6% for oral semaglutide. Results were overall consistent in subgroup analyses. Genital infection risk was the most important perceived attribute with a relative score of 19% (z-test, p<0.05). Second and similarly important were fasting requirements (15%), weight reduction (15%), risk of vomiting (14%) and CV benefit (12%). Next was risk of nausea (11%). Last were HbA1c reduction (8%) and ability to take medication with other drugs (6%). While blinded to drug name/dose, respondents were also asked to choose explicitly between drug profiles similar to empagliflozin (chosen by 41%), sitagliptin (31%), oral semaglutide (11%), and 'none of the options' (17%). The drug profile comparable to empagliflozin was the preferred agent; however, CV benefit was not the top patient priority. A shared physician-patient decision model and increased patient education are needed to ensure optimal use of guideline directed therapies in T2D. Disclosure: G. Savarese: Advisory Panel; Self; AstraZeneca. Consultant; Self; Genesis, Societ Prodotti Antibiotici. Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Vifor Pharma Group. Speaker's Bureau; Self; Roche Pharma, Servier, Vifor Pharma Group. A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation. C. Pang: None. R. Wood: Consultant; Self; Abbott, ADOCIA, American Diabetes Association, Ascensia Diabetes Care, Boehringer Ingelheim Pharmaceuticals, Inc., CeQur Corporation, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation. Employee; Self; dQ&A Market Research Inc. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Self; Boehringer Ingelheim (Canada) Ltd. Funding: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance [ABSTRACT FROM AUTHOR]

CAROLINA® (CARdiovascular Outcome Study of LINAgliptin Versus Glimepiride in Type 2 Diabetes) was a randomized controlled clinical trial designed to compare the effects of linagliptin (LINA) with glimepiride (GLIM) on CV events and other outcomes in patients with relatively early type 2 diabetes (T2D) with elevated CV risk. To characterize the effects on net CV disease and hospitalization burden of this population, we assessed effects of LINA vs. GLIM on all first plus recurrent CV events and any-cause hospitalizations using a negative binomial model. A total of 6033 participants were enrolled (mean age 64.0 years, HbA1c 7.2%, BMI 30.1 kg/m2, eGFR 77 ml/min/1.73m2, median T2D duration 6.3 years, UACR 9 mg/g, 42% with CV disease, 4.5% with heart failure [HF]). Adding recurrent events increased the number of events for analysis from first event by 10 to 77% across CV/HF outcomes and by 119% for hospitalizations with corresponding increase in rates per 100-patient years in both treatment groups (e.g., 3P-MACE from 2.1 to 2.8 [LINA] and 2.1 to 2.9 [GLIM]), over median 6.3 years. Analyses of first-event and first plus recurrent events are presented (Fig). In conclusion, no significant differences were observed between LINA or GLIM for either first or recurrent CV or hospitalization events. These data underscore the significant CV disease burden experienced even in relatively early T2D and reinforce the safety of LINA. Disclosure: N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. E. Pfarr: None. M. Mattheus: None. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. Funding: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: In EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) empagliflozin significantly reduced the risk of cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus and established cardiovascular disease. Post hoc, we evaluated empagliflozin on kidney outcomes in patients with or without heart failure (HF). Methods and Results: Individuals were randomized to empagliflozin 10 mg, 25 mg, or placebo. Prespecified analyses by baseline HF status included risk of incident or worsening nephropathy and estimated glomerular filtration rate slope analyses. Cox proportional hazards models assessed consistency of treatment effect across subgroups. Safety evaluations included kidney-related adverse events. At baseline, 244 (10.5%) and 462 (9.9%) patients had HF in the placebo and empagliflozin groups, respectively. Overall, the incidence of kidney outcome events was numerically higher in patients with than without HF. In the HF group, empagliflozin reduced risk of incident or worsening nephropathy or cardiovascular death by 43% (hazard ratio, 0.57 [95% CI, 0.42–0.77]) and progression to macroalbuminuria by 50% (hazard ratio, 0.50 [0.33–0.75]). After an initial transient decrease, estimated glomerular filtration rate stabilized over time with empagliflozin but gradually declined with placebo. Kidney effects in patients with HF were consistent with those in the overall study population (all P values for interaction >0.05). Across groups, the incidence rate of kidney-related adverse events/100 patient-years was higher in patients with than without HF; however, overall rates were comparable between groups. Conclusions: These findings from EMPA-REG OUTCOME support the hypothesis that empagliflozin could reduce the risk of clinically relevant kidney events and may slow progression of chronic kidney disease in individuals with type 2 diabetes mellitus regardless of HF status. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676. [ABSTRACT FROM AUTHOR]

In EMPA-REG OUTCOME, EMPA in 7020 patients with type 2 diabetes mellitus and CV disease significantly reduced 3P-MACE (14%), CV death (38%), all-cause death (32%) and heart failure hospitalization (HHF) (35%.) In addition, HbA1c was reduced but not associated with increased hypo. We investigated the relationship between on-trial hypo with a range of CV outcomes, using adjusted Cox regression models with time-varying covariate for hypo. We employed two hypo definitions: HYPObroad: time to first symptomatic hypo adverse event (AE) with plasma glucose [PG] ≤ 70mg/dL, any hypo AE with PG < 54mg/dL, or severe hypo AE. HYPOstrict: hypo AE with PG < 54mg/dL, or severe hypo AE. HYPObroad occurred in 28% of participants in each group, whereasHYPOstrict in 19%.In the placebo group, hypo was associated with an increased risk of HHF using both HYPObroad (HR 1.91, [95% CI: 1.25, 2.93], Fig A) or HYPOstrict (1.72 [1.06, 2.78]) and for myocardial infarction (MI) using only HYPObroad (1.56 [1.06, 2.29], Fig A.) EMPA reduced 3P-MACE, CV and all-cause death, and HHF, regardless of occurrence (Fig B) or severity of hypo (p-for interactions > 0.05). In conclusion, in this post hoc analysis, hypo was associated with an increased risk of MI and HHF but no other investigated CV outcomes. Hypoglycemia did not influence the cardio-protective effect of EMPA. Disclosure: B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. D.H. Fitchett: Speaker's Bureau; Self; Boehringer Ingelheim International GmbH, Lilly Diabetes. Other Relationship; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M. Mattheus: Employee; Self; Boehringer Ingelheim Pharma GmbH&Co.KG. C. Wanner: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. Board Member; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Mitsubishi Tanabe Pharma Corporation. J.T. George: None. O. Vedin: Employee; Self; Boehringer Ingelheim International GmbH. S.E. Inzucchi: Consultant; Self; vTv Therapeutics, Zafgen, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. Funding: Boehringer Ingelheim; Eli Lilly and Company [ABSTRACT FROM AUTHOR]

Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. Methods: CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5–10.0% (48–86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. Results: Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. Conclusions: CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier—NCT01897532; registered July 9, 2013 [ABSTRACT FROM AUTHOR]

Objective: Surgical drainage of the parotid abscess is the current standard of treatment which is carried out under general anaesthesia and carries the risk of iatrogenic facial nerve injury. Ultrasound-guided needle aspiration can be an alternative to surgical drainage. Methods: All parotid abscess patients who are treated surgically (n = 18) vs ultrasoundguided needle aspiration (n = 12) at Department of Surgery, MKCG MCH, were included in this monocentric retrospective analysis. Results: There was no statistically significant difference (p = 0.142) regarding the mean in both groups. There was a change in the duration of hospital stay(5.416 vs. 7.77 days) after ultrasound-guided needle aspiration. This trend did not reach statistical significance (p = 0.031). Facial nerve injury did not occur in any of the patients. Postoperative bleeding didn’t occur after needle aspirations but same is seen in 2% of the patients after surgical abscess revision. Conclusion: Ultrasound-guided needle aspiration is safe and effective in the treatment of parotid abscesses. [ABSTRACT FROM AUTHOR]

BACKGROUND Diabetic foot ulcer is a serious complication that often arises in patients with diabetes mellitus, particularly among the elderly population. Studies suggest that around 15% of diabetic patients will experience this condition during their lifetime. AIM This study aimed to compare the efficacy of autologous platelet-rich plasma (PRP) dressing versus moist saline/povidone iodine dressing in diabetic patients with foot ulcers. MATERIAL AND METHOD A total of 72 patients were enrolled in an open-label prospective randomised study. The primary objective was to compare the mean reduction in ulcer area at the end of 4 weeks. The study included two groups of patients: Group 1 (Study Group) received PRP clot dressing, while Group 2 (Control Group) received conventional saline dressing. The dressings were left in place for 1 week, and a total of 4 PRP treatments at weekly intervals were given for 4 weeks. RESULTS The results showed that there was no significant difference between the demographic parameters among the two study groups. However, the mean ulcer size (in cm2) in group 2 was significantly smaller compared to group 1 at the end of week 4 CONCLUSION The study concluded that PRP dressing may be more effective than conventional dressings for diabetic foot ulcers. This study may contribute to improved management strategies for diabetic foot ulcers, which is a serious complication that often arises in patients with diabetes mellitus, particularly among the elderly population. Ongoing research in this field has explored the potential of PRP, which is derived from a patient's own blood and contains growth factors that can stimulate wound healing. Using an autologous preparation reduces the risk of allergic reactions and may be more effective than conventional dressings. [ABSTRACT FROM AUTHOR]

Background: Burst abdomen is post-operative separation of the Musculo-aponeurotic layers, including the peritoneum, with exposure of the intestines. Type of incision, vertical or transverse, nature of surgery, elective or emergency, and postoperative complications affect the outcome of Laparotomy. Objective: The study aims to find the etiological factors of burst abdomen and to find and evaluate effective management of abdominal wound dehiscence in elective and emergency Laparotomy and how to prevent and overcome its complications. This post-operative complication encountered by the surgeon is always a challenge. The main concern is because of the risk of evisceration and the need to intervene; there is always a possibility of recurrence of dehiscence. Material and Methods: Our study was conducted on 280 patients who had undergone exploratory laparotomy at MKCG MCH, BERHAMPUR, ODISHA. Of 280 patients, 136 underwent emergency laparotomy, and 144 were elective cases. They were managed either by midline vertical incision or transverse incision, and results were analysed for wound dehiscence. Result: Most significant variation associated with wound dehiscence was hypoproteinaemia, anaemia, chronic cough and emergency procedures. Pre-operative and post-operative etiological factors such as chronic cough, anaemia, hypoproteinaemia, diabetes, obesity, use of Steroids. Results concluded that male patients have higher incidence of laparotomy wound dehiscence and in fourth and fifth decade. Patients presented with peritonitis secondary to gastro-duodenal or ileal perforation are more prone to burst abdomen. Conclusion: Burst abdomen is a serious sequela of impaired wound healing. Incidence of burst abdomen is less in transverse incision in comparation to midline vertical incision. [ABSTRACT FROM AUTHOR]

Adiposity is associated with reduced fertility in men. The aetiology is multifactorial, with obese men at greater risk of suffering from impaired spermatogenesis, reduced circulating testosterone levels, erectile dysfunction and poor libido. The diagnosis and treatment of reduced fertility observed in obese men therefore requires insight into the underlying pathology, which has hormonal, mechanical and psychosocial aspects. This article summarises the current epidemiological, experimental and clinical trial evidence from the perspective of a practicing clinician. The following conclusions and recommendations can be drawn: Obesity is associated with low serum testosterone concentrations, but treatment with exogenous testosterone is likely to adversely impact on fertility. It is important to discuss this with men prior to initiation of testosterone therapy. Obesity adversely affects sperm concentration and may affect sperm quality. However, whether or not weight loss will correct these factors remain to be established. Oestrogen receptor modulators (and aromatase inhibitors) are unlicensed in the treatment for male hypogonadism and/or infertility. These treatments should hence be considered experimental approach until ongoing clinical trials report their outcomes. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial. Materials and Methods: In EMPA‐REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow‐up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin‐naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin‐treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%. Results: In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32‐0.49]; P <.0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36‐0.49]; P <.0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39‐2.51]; P <.0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered. Conclusions: In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether the cardiorenal benefits of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians. Methods: In this exploratory analysis of the EMPA‐REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all‐cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category. Results: Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all‐cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were.6772,.3087 and.6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m2 or higher. Conclusion: Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI. [ABSTRACT FROM AUTHOR]

Aims: Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial.Methods and Results: The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes).Conclusion: Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated. [ABSTRACT FROM AUTHOR]

Aim: To determine the relationship between polyvascular disease and risk of hospitalization for heart failure (HHF) and cardiovascular (CV) death in the EMPA‐REG OUTCOME population, and the relationship of kidney dysfunction co‐existent with polyvascular disease on CV/heart failure (HF) outcomes. Materials and Methods: Patients with type 2 diabetes and atherosclerotic CV (ASCVD) received empagliflozin 10, 25 mg or placebo. Post hoc, subgroups were analyzed by one versus two or more vascular beds, and the estimated glomerular filtration rate ([eGFR] < vs. ≥60 mL/min/1.73 m2) at baseline. The empagliflozin arms were pooled. Time to CV death, HHF, CV death (excluding fatal stroke) or HHF, all‐cause mortality (ACM) and 3‐point major adverse CV events (3P‐MACE) were assessed using multivariable Cox regression models. Results: Baseline characteristics (N = 6959) within subgroups were balanced between treatment groups. In the placebo group, two or more versus one vascular bed increased HHF risk (1.59 [95% confidence interval 1.02, 2.49]), CV death (2.17 [1.52, 3.09]), CV death/HHF (1.79 [1.32, 2.43]), ACM (1.95 [1.44, 2.64]) and 3P‐MACE (1.76 [1.36, 2.27]). Hazard ratios for those with polyvascular disease/kidney dysfunction (vs. 1 vascular bed/eGFR ≥60 mL/min/1.73 m2) were HHF 2.80 (1.46, 5.36), CV death 3.10 (1.87, 5.13), CV death/HHF 2.71 (1.74, 4.23), ACM 2.59 (1.67, 4.02) and 3P‐MACE 2.62 (1.82, 3.77). Empagliflozin reduced the risk of all outcomes across subgroups. Conclusions: Polyvascular disease with/without kidney dysfunction markedly increases the risk of HF/CV events. Empagliflozin consistently reduces risk, regardless of vascular bed and kidney function status. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association of different categories of baseline cardio‐metabolic risk factors on the treatment effects of empagliflozin 10 and 25 mg when added as second‐line therapy to metformin in patients with type 2 diabetes (T2D). Materials and Methods: Patients aged 18 years or older with HbA1c 7.0%‐10.0% were included. Analysis of covariance compared change from baseline to weeks 24 and 76 in HbA1c, body weight (BW) and systolic blood pressure (SBP) by respective baseline categories (HbA1c <8.5/≥8.5%; BW <80/80‐90/>90 kg, SBP <130/130‐140/>140 mmHg). Analyses were also conducted with a model using continuous covariates of cardio‐metabolic factors. Results: In total, 637 patients (56.7% males; mean [SD] age 55.7 [9.9] years, HbA1c 7.9% [0.9%], BW 81.2 [18.8] kg, SBP 129.4 [14.6] mmHg) received one or more dose of either empagliflozin 10 mg (n = 217) or 25 mg (n = 213), or placebo (n = 207). At both time points, empagliflozin 10/25 mg versus placebo significantly (P <.0001) reduced HbA1c and BW, with greater reductions in HbA1c at higher baseline HbA1c (P interaction week 24/76 categorical and continuous models:.0290/.1431 and.0004/.0042, respectively) and in BW (P interaction.1340/.0012 and.0202/<.0001, respectively). Both empagliflozin doses also significantly lowered SBP versus placebo at both time points, with similar efficacy by subgroups of baseline SBP. Adverse events were consistent with the established empagliflozin safety profile across treatment groups. Conclusions: Empagliflozin, as add‐on to metformin, decreases HbA1c and BW, particularly in patients with higher HbA1c and BW baseline values, and effectively lowers SBP. [ABSTRACT FROM AUTHOR]

Background: Glucose variability has been associated with cardiovascular outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and cardiovascular death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 38%. We explore post-hoc the association between HbA1c variability and cardiovascular death, and the potential mediating effects of HbA1c variability on empagliflozin's cardiovascular death reductions. Methods: In total, 7,020 patients with type 2 diabetes and established cardiovascular disease received placebo, empagliflozin 10 mg or 25 mg. We defined within-patient HbA1c variability as standard deviation, coefficient of variation and range of HbA1c measurements (%) post-baseline. First, we compared HbA1c variability until week 28 and 52 by Wilcoxon tests. We explored the association between cardiovascular death and HbA1c variability in placebo and pooled empagliflozin arms separately with landmark analyses at week 28 and 52, and additionally with HbA1c variability as a time-dependent co-variate. We used Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12, and the interaction term HbA1c variability* treatment. Results: HbA1c variability was lower with empagliflozin compared to placebo. In all Cox analyses, high HbA1c variability increased the risk for cardiovascular death in both treatment arms with no interaction with treatment: e.g. an increase in HbA1c variability of one unit for the standard deviation at week 28 was associated with a subsequent increased risk of CV death with HRs of 1.97 (95% CI 1.36, 2.84) and 1.53 (1.01, 2.31) in the placebo and empagliflozin groups, separately, interaction p-value 0.3615. Conclusions: HbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of cardiovascular death. Empagliflozin's reduction in cardiovascular death did not appear to be mediated by reductions in HbA1c variability. ClinicalTrials.gov number, NCT01131676 [ABSTRACT FROM AUTHOR]

Aims: In the EMPA‐REG OUTCOME® trial, the sodium‐glucose cotransporter 2 inhibitor empagliflozin when given in addition to standard care improved cardiovascular (CV) and renal outcomes, and reduced mortality. Trial participants were on a variety of glucose‐lowering therapies at baseline, some of which could potentially affect CV risk. This analysis investigated whether the use of background diabetes therapy affected the risk of CV death, hospitalizations for heart failure, and progression of chronic kidney disease, among patients treated with empagliflozin. Materials and methods: Patients meeting inclusion and exclusion criteria were randomized to placebo, empagliflozin 10 mg or empagliflozin 25 mg; glucose‐lowering therapy was to remain unchanged for 12 weeks and then adjusted to achieve glycaemic control according to local guidelines. Differences in risk of cardio‐renal outcomes between empagliflozin and placebo by baseline use of metformin, sulphonylurea (SU) and insulin were assessed using a Cox proportional hazards model. Results: Of 7020 eligible patients, 74% were receiving metformin, 43% SU and 48% insulin at baseline (each alone or in combination); the most common regimens were metformin plus SU (20%) and metformin plus insulin (20%). Empagliflozin reduced the risk of CV death irrespective of the use of: metformin [with: hazard ratio (HR) 0.71 (95% confidence interval, CI, 0.54–0.94); without: 0.46 (0.32–0.68); Pinteraction= 0.07]; SU [with: HR 0.64 (0.44–0.92); without: 0.61 (0.46–0.81); Pinteraction = 0.85]; or insulin [with: HR 0.63 (0.46–0.85); without: 0.61 (0.44–0.85); Pinteraction = 0.92]. Reductions in three‐point major adverse CV events, hospitalizations for heart failure, and all‐cause mortality were consistent across subgroups of baseline therapies. Empagliflozin reduced the risks of incident or worsening nephropathy versus placebo irrespective of the use of SU or insulin at baseline (Pinteraction > 0.05), but there was a greater reduction in this risk for patients not using metformin [HR 0.47 (95% CI 0.37–0.59)] versus those using metformin [HR 0.68 (95% CI 0.58–0.79)] at baseline (Pinteraction = 0.01). Conclusions: The addition of empagliflozin to antihyperglycaemic regimens of patients with type 2 diabetes and CV disease consistently reduced their risks of adverse CV outcomes and mortality irrespective of baseline use of metformin, SU or insulin. For chronic kidney disease progression, there may be a larger benefit from empagliflozin in those patients who are not using metformin. [ABSTRACT FROM AUTHOR]

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice. [ABSTRACT FROM AUTHOR]

Background: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium-glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF.Study Design: The EMPEROR-Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities.Study Aims: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options. [ABSTRACT FROM AUTHOR]

Drugs that inhibit the sodium-glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin-angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction. [ABSTRACT FROM AUTHOR]

Hyperglycemia is an undisputed epidemiological risk factor for microvascular complications in both type 1 and type 2 diabetes, integral in their causal pathways. Importantly, interventions that reduce the hyperglycemic burden in patients with either type of diabetes reduce the risk of microvascular complications (e.g., retinopathy, nephropathy, neuropathy). Hence, for microvascular risk, hyperglycemia is a proven risk factor and a proven treatment target, as reflected by treatment recommendations and guidelines across most scientific societies world-wide. However, although reducing the hyperglycemic burden to reduce microvascular risk remains a cornerstone of care for patients with type 2 diabetes, this therapeutic imperative does not apply to cardiovascular risk mitigation. This latter aspect is important in the context of interpreting therapeutic impact of treating hyperglycemia on risk for macrovascular complications in patients with type 2 diabetes. This letter, in response to a previous paper, discuss how modest differential glucose control contribute little if anything to the results observed of contemporary cardiovascular outcome trials in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. 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. [ABSTRACT FROM AUTHOR]

Background: In the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure. We investigated whether these effects varied across the spectrum of baseline cardiovascular risk.Methods: Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention.Results: Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline ( P>0.05 for randomized group-by-subgroup interactions).Conclusions: Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events. Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk.Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676. [ABSTRACT FROM AUTHOR]

The article presents a study which examines cardiovascular outcome with empagliflozin in patients with type 2 diabetes mellitus (T2DM). Empagliflozin Cardiovascular Outcome Event Trial in T2DM Patients and analysis of the risk of cardiovascular disease were conducted in the study which involved 7020 patient with T2DM and cardiovascular disease (CVD). Results highlight the benefit of empagliflozin on the risks of cardiovascular death but demonstrate minor impact of glycemic control.

Background: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and established cardiovascular disease in the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.Methods: Patients with type 2 diabetes mellitus, established cardiovascular disease, and estimated glomerular filtration rate (eGFR) ≥30 mL·min-1·1.73 m-2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization, and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL·min-1·1.73 m-2 and/or urine albumin-creatinine ratio >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45-<60, 60-<90, ≥90 mL·min-1·1.73 m-2) and baseline urine albumin-creatinine ratio (>300, 30-≤300, <30 mg/g).Results: Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes mellitus for >10 years, 58% were receiving insulin, and 84% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98), the risk of all-cause mortality by 24% (HR, 0.76; 95% CI, 0.59-0.99), the risk of hospitalization for heart failure by 39% (HR, 0.61; 95% CI, 0.42-0.87), and the risk of all-cause hospitalization by 19% (HR, 0.81; 95% CI, 0.72-0.92). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and urine albumin-creatinine ratio at baseline and across the 2 doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL·min-1·1.73 m-2 was consistent with the overall trial population.Conclusions: Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676. [ABSTRACT FROM AUTHOR]

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication: "32%" in the previous sentence was corrected to "38%"]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate. [ABSTRACT FROM AUTHOR]

Cardiovascular (CV) events after index heart failure (HF) hospitalization in the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Our analysis showed lower rates of HF readmission and the composite outcomes of HF readmission and cardiovascular or all-cause death in patients treated with empagliflozin after an index HF hospitalization. [Extracted from the article]

The article presents the EMPA-REG OUTCOME trial on Type 2 diabetes mellitus patients with and established cardiovascular disease to examine the impact of long-term use of empaglifloxin on their life expectancy. It found that the risk of cardiovascular death was reduced by 38% and all-cause mortality by 32% due to the sodium-glucose cotransporter 2 inhibitor empagliflozi.

Peripheral artery disease (PAD) is one of the most common cardiovascular complications in patients with type 2 diabetes mellitus (T2DM)1 and is a predictor of cardiovascular death.2 Interventions that reduce cardiovascular complications in this patient population are urgently required. In the EMPA-REG OUTCOME trial, the sodium glucose cotransporter 2 inhibitor empagliflozin reduced the risk of cardiovascular death by 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI] 0.49-0.77]) and hospitalization for heart failure (HHF) by 35% (HR, 0.65; 95% CI, 0.50-0.85) versus placebo when given in addition to standard of care.3 We report analyses of the effects of empagliflozin on cardiovascular outcomes, mortality, and renal outcomes in patients with and without PAD at baseline in the EMPA-REG OUTCOME trial. [ABSTRACT FROM AUTHOR]

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., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR)., Methods and Results: The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by 31 Phosphorus-MRS., Conclusions: EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved)., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes and established atherosclerotic cardiovascular (CV) disease, empagliflozin vs. placebo reduced the risk of hospitalization for heart failure (HHF) by 35%, CV death/HHF by 34%, and CV death by 38%, with an early separation of the cumulative incidence curves. We explored at what time point after randomization these benefits became apparent., Methods and Results: We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF, and CV death based on hazard ratios (95% confidence interval) and calculated the hazard ratio on the day the effect reached significance using Cox proportional hazards models. Overall, 7020 patients aged ≥18 years were treated with empagliflozin 10 mg (N = 2345), empagliflozin 25 mg (N = 2342), or placebo (N = 2333) once daily in addition to standard of care. Mean age (years ± SD) was 63.1 ± 8.6, and 72% were male. The benefit of empagliflozin on CV death first reached statistical significance on Day 59 (HR [95% confidence interval]) (0.28 [0.08, 0.96], P = 0.0424) and was generally sustained throughout the trial (overall 0.62 [0.49, 0.77], P < 0.0001). Risk reduction with empagliflozin on HHF reached statistical significance on Day 17 (0.10 [0.01, 0.87], P = 0.0372) and was sustained throughout the study (overall 0.65 [0.50, 0.85], P = 0.0017). For the composite outcome of CV death or HHF, risk reduction with empagliflozin reached statistical significance on Day 27 (0.28 [0.08, 0.97], P = 0.0445) and was sustained throughout follow-up (overall 0.66 [0.55, 0.79], P < 0.0001)., Conclusions: In EMPA-REG OUTCOME, the benefit of empagliflozin in reducing the risk of HHF, CV death/HHF, and CV death emerged within weeks after treatment initiation. The earliest benefit appears to be on HHF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.

Background: Type 2 diabetes (T2D) and resistant hypertension often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676)., Methods: Overall, 7,020 patients received empagliflozin 10, 25 mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ≥3 classes of antihypertensive drugs including a diuretic and uncontrolled blood pressure (BP; systolic blood pressure (SBP) ≥140 and/or diastolic blood pressure ≥90 mm Hg) or ≥4 classes of antihypertensive, including a diuretic, and controlled BP. We explored the effect of empagliflozin on cardiovascular (CV) death, heart failure (HF) hospitalization, 3-point major adverse cardiac events, all-cause death, and incident/worsening nephropathy by Cox regression and BP over time by a mixed-repeated-measures-model analysis., Results: 1,579 (22.5%) patients had prHT. The mean difference in change in SBP from baseline to week 12 vs. placebo was -4.5 (95% confidence interval, -5.9 to -3.1) mm Hg (P < 0.001) in prHT and -3.7 (-4.5, -2.9) mm Hg (P < 0.001) in patients without prHT. SBP was more frequently controlled (<130/80 mm Hg) with empagliflozin than with placebo. Patients with prHT had 1.5- to 2-fold greater risk of HF hospitalization, incident/worsening nephropathy, and CV death compared with those without prHT. Empagliflozin improved all outcomes in patients with and without prHT (interaction P > 0.1 for all outcomes)., Conclusions: Empagliflozin induced a clinically relevant reduction in SBP and consistently improved all outcomes regardless of prHT status. Due to these dual effects, empagliflozin should be considered for patients with hypertension and T2D., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Aims: The EMPA-REG OUTCOME trial demonstrated reductions in cardiovascular (CV) death and heart failure (HF) outcomes with empagliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes and established CV disease over a study period of 3 years. We aimed to investigate the early benefit-risk profile of empagliflozin in patients enrolled in the EMPA-REG OUTCOME trial according to HF status at baseline., Methods and Results: The effects of treatments on glycated haemoglobin, systolic blood pressure and body weight, and on the HF endpoints of hospitalization for HF (HHF), HHF or CV death, and HHF or all-cause mortality were evaluated at 12 weeks, 6 months, and 1 year after randomization. Occurrence of adverse events (AEs) during these time points was also evaluated. Compared with placebo, empagliflozin lowered glycated haemoglobin, systolic blood pressure, and body weight and rates of all the HF endpoints, as early as at 12 weeks, regardless of HF status at baseline. Favourable clinical and metabolic effects were maintained over time. AEs were generally higher in those with HF than without HF; however, compared with placebo, empagliflozin did not increase risk of developing AEs over the first year of treatment., Conclusions: In the EMPA-REG OUTCOME trial, the use of empagliflozin led to early and beneficial effects on clinical, metabolic, and HF outcomes in patients with type 2 diabetes with or without HF at baseline, which were already apparent within 12 weeks from initiation of treatment. Over the first year of treatment, no safety concern was detected with the use of empagliflozin., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Heart failure (HF) and type 2 diabetes (T2D), common co-morbidities, translate into worse patient prognoses and higher direct costs than for either condition alone. Empagliflozin has been shown to markedly reduce cardiovascular (CV) deaths and HF hospitalizations (HHF) in HF patients with T2D. This study evaluated the lifetime cost-effectiveness of supplementing standard of care (SoC) with empagliflozin, relative to SoC alone, in HF patients with T2D from the UK payer perspective., Methods and Results: An existing discrete-event simulation model was adapted for the economic evaluation. Risk equations developed from time-dependent parametric survival analyses using patient-level HF subpopulation data from the EMPA-REG OUTCOME trial were employed to predict CV and renal events. Non-CV death, utility weights, and costs were drawn from UK sources. Quality-adjusted life years (QALYs) and costs were discounted at 3.5% per annum. Relative to SoC, empagliflozin with SoC yielded fewer first HHF, recurrent HHF, CV death, and non-fatal myocardial infarction but more non-fatal stroke events. Empagliflozin with SoC vs. SoC alone was associated with increased average life expectancy (10.80 vs. 9.59 LYs) and quality of life (6.27 vs. 5.62 QALYs), though at higher lifetime cost (£18 197 vs. £16 829) per person, resulting in an incremental cost-effectiveness ratio of £2093 per QALY. The probability of empagliflozin being cost-effective in the HF subpopulation at a £20 000 per QALY willingness-to-pay threshold was 91%., Conclusions: This analysis suggests that adding empagliflozin to SoC in HF patients with T2D constitutes a cost-effective use of UK healthcare resources and may provide long-term health benefits to patients., (© 2020 Boehringer Ingelheim. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)