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International audience; 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.

International audience; Background: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known.Objectives: The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).Methods: Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin's effects and significance on SBP.Results: Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at 130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP

Baseline body mass index (BMI) and weight loss promoted by sodium-glucose cotransporter 2 inhibitors may impact outcomes in patients with heart failure with reduced ejection fraction (HFrEF). We assessed in the EMPEROR-Reduced population treated with empagliflozin versus placebo the relationship between baseline BMI, weight loss and effects on the primary (time to first hospitalization for heart failure [HHF] or cardiovascular death) and key secondary outcomes.We categorized patients according to their baseline BMI:20 kg/mThe benefits of empagliflozin versus placebo were consistently present across all BMI categories in HFrEF patients. Weight loss was associated with higher risk of all-cause mortality, regardless of treatment group.

Objectives Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified d...

Background: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated. Methods: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes. Results: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; P interaction =0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m 2 in patients without diabetes; P interaction =0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome ( P interaction =0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo. Conclusions: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057951.

Stroke and coronary artery disease (CAD) share several cardiovascular (CV) risk factors (RFs) , including type 2 diabetes (T2D.) RF control is vital for secondary prevention of both conditions, but systems for care of patients (pts) after stroke or CAD events differ, and distinctions in care for these pts have not been examined. We compared RF control in pts with CAD vs. stroke at baseline in 3 recent large CV outcome trials (OTs) involving 11,622 T2D pts at high CV risk.We analyzed baseline data from (1) EMPA-REG OUTCOME (2) CAROLINA and (3) CARMELINA. RFs assessed included dyslipidemia, hypertension, smoking, and use of anti-platelet/-coagulant drugs. RF control was defined as (a) LDL-C Disclosure P.Balasubramanian: None. W.Kernan: None. K.N.Sheth: Research Support; American Heart Association, Becton, Dickinson and Company, Biogen, National Institutes of Health. A.Ofstad: Employee; Boehringer Ingelheim International GmbH. M.Mattheus: Employee; Boehringer Ingelheim Pharma GmbH & Co.KG. N.Marx: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Genfit, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk, Research Support; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Speaker's Bureau; Abbott, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. S.E.Inzucchi: Advisory Panel; Abbott Diagnostics, ESPERION Therapeutics, Inc., vTv Therapeutics, Consultant; Merck & Co., Inc., Pfizer Inc., Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk.

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.

BackgroundPatients 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.MethodsA 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.ResultsMetS 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.ConclusionsA 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 registrationClinical Trial Registration: URL:https://www.clinicaltrials.gov. Unique identifier: NCT 01131676

Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials.We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model.Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race.The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF.Boehringer Ingelheim.

Context Control of multiple cardiovascular (CV) risk factors reduces CV events in individuals with type 2 diabetes. Objective To investigate this association in a contemporary clinical trial population, including how CV risk factor control affects the CV benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor. Design Post hoc analysis. Setting Randomized CV outcome trial (EMPA-REG OUTCOME). Participants Type 2 diabetes patients with established CV disease. Intervention Empagliflozin or placebo. Main Outcome Measures Risk of CV outcomes—including the treatment effect of empagliflozin—by achieving 7 goals for CV risk factor control at baseline: (1) glycated hemoglobin Results In the placebo group, the hazard ratio (HR) for CV death was 4.00 (95% CI, 2.26–7.11) and 2.48 (95% CI, 1.52–4.06) for patients achieving only 0–3 or 4–5 risk factor goals at baseline, respectively, compared with those achieving 6–7 goals. Participants achieving 0–3 or 4–5 goals also had increased risk for the composite outcome of hospitalization for heart failure or CV death (excluding fatal stroke) (HR 2.89 [1.82–4.57] and 1.90 [1.31–2.78], respectively) and 3-point major adverse CV events (HR 2.21 [1.53–3.19] and 1.42 [1.06–1.89]). Empagliflozin significantly reduced these outcomes across all risk factor control categories (P > 0.05 for treatment-by-subgroup interactions). Conclusions Cardiovascular risk in EMPA-REG OUTCOME was inversely associated with baseline CV risk factor control. Empagliflozin’s cardioprotective effect was consistent regardless of multiple baseline risk factor control.

Aims: \ud Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial.\ud \ud Materials and methods: \ud EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression.\ud \ud Results: \ud At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups.\ud \ud Conclusions: \ud Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk.

Aims Atrial fibrillation (AF) is common in patients with diabetes and heart failure (HF) and increases the future risk of adverse cardiovascular (CV) outcomes. This analysis from the EMPA-REG OUTCOME trial explores CV and renal outcomes in patients with vs. without AF at baseline and assesses the benefits of empagliflozin. Methods and results Analyses were conducted on patients distinguished by the presence (n = 389) or absence (n = 6631) of AF at baseline. Outcome events were more frequent in patients with AF than those without AF. Empagliflozin compared to placebo reduced CV death or HF hospitalisation consistently in patients with AF [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.36-0.92] and without AF (HR 0.67, 95% CI 0.55-0.82, Pinteraction = 0.56). Similar results were observed for the components of this endpoint, all-cause mortality, new or worsening nephropathy, first introduction of loop diuretics, or occurrence of oedema. The absolute number of prevented events was higher in patients with AF, resulting in larger absolute treatment effects of empagliflozin. New loop diuretics or oedema were associated with increased rates of subsequent events, and rates appeared lower in those randomised to empagliflozin. Conclusions In patients with type 2 diabetes mellitus and established CV disease, those with AF at baseline had higher rates of adverse HF outcomes than those without AF. Irrespective of the presence of AF, empagliflozin reduced HF-related and renal events. The absolute number of prevented events is higher in patients with AF than without AF. Patients with diabetes, CV disease and AF may especially benefit from use of empagliflozin.

Context Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that in patients with type 2 diabetes (T2D), SGLT2 inhibitor use was associated with a 49% lower risk of nephrolithiasis compared with GLP-1 receptor agonists. Objective We examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials. Methods We pooled data from 15 081 T2D patients randomized to empagliflozin (n = 10 177) or placebo (n = 4904) from 20 phase I-IV trials, including the large cardiovascular outcome trial, EMPA-REG OUTCOME. Incident urinary tract stone events were captured using a predefined collection of MedRA terms. A sensitivity analysis using a narrower definition was also performed. Incidence rate ratios (IRR) and 95% CIs were calculated using the relative risk estimate, stratified by study. Results The median exposures to study drug were 543 days (placebo) and 549 days (empagliflozin); 183 patients experienced an incident urolithiasis during follow-up (placebo, 79; empagliflozin, 104), yielding annual incidence rates of 1.01 vs 0.63 events/100 patient-years in the 2 respective groups. The IRR was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin. In the sensitivity analysis, the results were similar (IRR, 0.62 [95% CI, 0.45-0.85]). Conclusion Compared with placebo, empagliflozin therapy was associated with an approximate 40% reduced risk of urinary tract stone events in T2D patients. The underlying mechanisms are unknown but may involve altered lithogenic profile of the urine. Dedicated randomized prospective clinical trials are warranted to confirm these initial observations in patients with and without T2D.

Background There is uncertainty on how empagliflozin (EMPA) reduces blood pressure (BP), and in particular the potential role for changes in weight and haematocrit in mediating these effects. Purpose To assess the contributions of changes in weight and haematocrit on EMPA induced changes in BP in patients with type 2 diabetes mellitus (T2DM) in the EMPA-BP and EMPA-REG OUTCOME trials. Methods Patients received placebo (PBO), EMPA 10 mg or EMPA 25 mg. In EMPA-BP (12-week study), 823 patients with T2DM and hypertension (mean [SD] age 60.2 [9.0] years, HbA1c 7.90 [0.74] %, BMI 32.6 [5.1] kg/m2) were studied. In EMPA-REG OUTCOME, of the 7,020 treated patients with T2DM and cardiovascular disease (mean [SD] age 63.1 [8.6] years, HbA1c 8.07 [0.85] %, BMI 30.6 [5.3] kg/m2), 95.0% were on anti-hypertensive treatment at baseline. ANCOVA/MMRM models were applied to assess changes in systolic BP (SBP) at week 12 associated with, and independent of, changes in weight and haematocrit (Hct). SBP measurements are based on mean 24-h measurements from an ambulatory blood pressure monitoring (ABPM) device in EMPA-BP and seated office measurements in EMPA-REG OUTCOME. Results Mean (SD) baseline SBP was 131.7 (11.8), 131.3 (13.0) and 131.2 (12.1) mmHg in the PBO, EMPA 10 mg and EMPA 25 mg groups, respectively in EMPA-BP (mean 24-h SBP) and 135.8 (17.2), 134.9 (16.8) and 135.6 (17.0) mmHg (office SBP), respectively in EMPA-REG OUTCOME. In these relatively young patients with T2DM and mildly elevated mean SBP, EMPA reduced mean SBP by 3.4–4.2 mmHg compared with PBO (table) at week 12. Mean (SE) weight was reduced with EMPA (10 and 25mg) vs PBO treatment by −1.5 (0.2) kg and −2.0 (0.2) kg in EMPA-BP and by −1.2 (0.1) kg and −1.5 (0.1) kg in EMPA-REG OUTCOME at week 12. Mean (SE) haematocrit was increased by 2.1 (0.2) % and 1.8 (0.2) % versus placebo in EMPA-BP and by 2.2 (0.1) % and 2.5 (0.1) % in EMPA-REG OUTCOME with EMPA 10 mg and EMPA 25 mg, respectively. Weight loss accounted for 21–24% of the SBP reduction with EMPA treatment in EMPA-BP and 9–11% in EMPA-REG OUTCOME. Changes in Hct accounted for negligible (between −10% to 1%) SBP reduction with EMPA. Conclusion The reduction in SBP is modestly mediated through a reduction in weight. There was no meaningful effect of EMPA induced changes in Hct on SBP. Results were consistent using ABPM or office SBP. These findings suggest that EMPA's effects on SBP are likely mediated through other mechanisms such as natriuresis or reduction in arterial stiffness. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim and Eli Lilly and Company. Table 1

Background The validity of heart failure (HF) diagnoses made in hospitals has been debated and low positive predictive values (PPV) may represent a bias in epidemiological research. Purpose To validate primary and secondary HF diagnoses at discharge or during ambulatory evaluation in general hospitals aiming to obtain confirmed HF diagnoses to develop a HF-prediction risk score. Methods We extracted data on all patients with a HF diagnosis by ICD-10 codes (I50 HF, I42 cardiomyopathy and I11 hypertension with HF) in any position from the hospitals' electronic medical records from Oct. 2006 to Dec. 2018. One experienced cardiologist scrutinized all journals for events being either a valid HF event, unlikely, or uncertain due to lacking information, according to the 2016 ESC HF guidelines. In cases where first event was unlikely or uncertain subsequent events were judged for valid HF. Results A total of 3411 patients with at least one HF diagnosis were assessed (mean age 79.7±10.6 yrs, 49.1% men); 3089 after in-hospital stays and 322 after ambulatory consultations. Overall, 2174 were deemed as valid HF diagnosis with a PPV of 63.7%; PPV was higher when HF diagnosis was based on in-hospital diagnoses and when HF was the primary diagnosis (Table). Conclusions Only 64% of all HF diagnoses were likely HF according to present guidelines, with higher precision for in-hospital diagnoses and HF in the primary position. This underscores the importance to use validated HF-diagnoses for HF prediction risk score development. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Boehringer Ingelheim Norway KS

Aims Nephrolithiasis is a common disease, estimated to affect 10% of the US population. In addition to pain, often severe, it can lead to urinary tract infections and acute kidney injury, while contributing to health care costs from emergency room visits and follow-up interventions necessary to relieve stone burden. Type 2 diabetes (T2D) is a well-known risk factor for nephrolithiasis. Recently in an observational study of patients with T2D, use of sodium-glucose transport protein 2 (SGLT2) inhibitors as glucose lowering agents was associated with a 49% lower risk of nephrolithiasis when compared with use of glucagon like peptide 1 (GLP-1) receptor agonists. We examined, prospectively, the association between renal stone disease and the use of the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials. Methods Pooled data from 15,081 patients with T2D treated with empagliflozin (10,177) or placebo (4,904) from 20 phase I-IV randomized, placebo-controlled trials including the large cardiovascular outcome trial, EMPA-REG OUTCOME, were included in this analysis. Incident urinary tract stone events were captured using a pre-defined collection of MedDRA terms: nephrolithiasis, renal colic, ureterolithiasis, calculus bladder, calculus urinary, calculus urethral, and nephrocalcinosis (MedDRA version 22.1). A sensitivity analysis used a narrower definition by excluding the terms renal colic and nephrocalcinosis. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated using the relative risk estimate stratified by study. Results The median exposure to study drug was 543 (placebo) and 549 (empagliflozin 10 or 25 mg) days We found that a total of 183 patients experienced an incident urolithiasis during follow-up (79 in placebo, 104 in pooled empagliflozin) yielding annual incidence rates of 1.01 versus 0.63 events per 100 patient years in placebo and empagliflozin, respectively. All but one event occurred in patients with no prior history of urinary tract stones. The IRR was 0.64 (95% CI 0.48, 0.86), in favor of empagliflozin. In the sensitivity analysis, now restricted to nephrolithiasis, ureterolithiasis, calculus bladder, calculus urinary, and calculus urethral, the results were similar (IRR, empagliflozin vs. placebo, 0.62 [95% CI 0.45, 0.85]). Conclusion As compared to placebo, use of empagliflozin was associated with an approximate 40% reduction in the risk of urolithiasis in patients with T2D. Alterations in lithogenic profile of the urine (including dilutional effects) of potential stone formers after SGLT2 inhibition may explain this finding. Based on these initial observations, mechanistic studies to elucidate the mediator(s) of this seemingly protective effect and dedicated randomized prospective clinical trials appear warranted in patients with renal stone disease. As with follow-up SGLT2 inhibitor investigations conducted in patients with heart failure and chronic kidney disease, such trials should include individuals who do not have T2D. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.

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-naive 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

Treatment with empagliflozin (EMPA) improves cardiorenal outcomes, but also reduces liver fat content in individuals with both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Thus, we evaluated the effects of EMPA vs. placebo (PLAC) on NAFLD-related steatosis and fibrosis risks and the relation of fibrosis risk to cardiorenal outcomes in individuals with T2D in the randomized controlled trial EMPA-REG OUTCOME. The trial enrolled 7020 people with T2D and cardiovascular disease for treatment with 10 or 25 mg daily EMPA or PLAC. Post-hoc, we derived the Dallas Steatosis Index (DSI) and NAFLD fibrosis score (NFS) to assess the risks of steatosis and fibrosis from baseline to week 164 of treatment, respectively. Changes from baseline in DSI and NFS were examined by mixed model repeated measures analysis, and effects on cardiovascular and all-cause death, hospitalization for heart failure and nephropathy by Cox regression across fibrosis risk categories. At baseline, 72% of participants had high risk of steatosis (DSI probability of >50%; mean, 0.74±0.00 and 23% had high risk of advanced fibrosis (NFS >0.675; mean, 1.26±0.01. Overall DSI (logit) decreased with EMPA compared to PLAC at all timepoints (p In conclusion, EMPA may attenuate NAFLD-related steatosis as well as fibrosis progression specifically in individuals at risk of advanced fibrosis, and improves cardiorenal outcomes as well as all-cause mortality independent of fibrosis risk category. Disclosure S. Kahl: None. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. Wanner: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; Eli Lilly and Company. E. Schueler: None. S. E. Inzucchi: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Esperion, Merck & Co., Inc., Novo Nordisk. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.

Aims The prevalence of asymptomatic coronary artery disease (CAD) in type 2 diabetes (T2D) is unclear. We investigated the extent and prevalence of asymptomatic CAD in T2D patients by utilizing invasive coronary angiography (ICA) and intravascular ultrasound (IVUS), and whether CAD progression, evaluated by ICA, could be modulated with a multi-intervention to reduce cardiovascular (CV) risk. Methods Fifty-six T2D patients with ≥ 1 additional CV risk factor participated in a 2 year randomized controlled study comparing hospital-based multi-intervention (multi, n = 30) versus standard care (stand, n = 26), with a pre-planned follow-up at year seven. They underwent ICA at baseline and both ICA and IVUS at year seven. ICA was described by conventional CAD severity and extent scores. IVUS was described by maximal intimal thickness (MIT), percent and total atheroma volume and compared with individuals without T2D and CAD (heart transplant donors who had IVUS performed 7–11 weeks post-transplant, n = 147). Results Despite CV risk reduction in multi after 2 years intervention, there was no between-group difference in the progression of CAD at year seven. Overall, the prevalence of CAD defined by MIT ≥ 0.5 mm in the T2DM subjects was 84%, and as compared to the non-T2DM controls there was a significantly higher atheroma burden (mean MIT, PAV and TAV in the T2D population were 0.75 ± 0.27 mm, 33.8 ± 9.8% and 277.0 ± 137.3 mm3 as compared to 0.41 ± 0.19 mm, 17.8 ± 7.3% and 134.9 ± 100.6 mm3 in the reference population). Conclusion We demonstrated that a 2 year multi-intervention, despite improvement in CV risk factors, did not influence angiographic progression of CAD. Further, IVUS revealed that the prevalence of asymptomatic CAD in T2D patients is high, suggesting a need for a broader residual CV risk management using alternative approaches. Trial registration Clinical trials.gov id: NCT00133718 (https://clinicaltrials.gov/ct2/show/NCT00133718)

Background and aims Measures of HDL function are emerging tools for assessing cardiovascular disease (CVD) event risk. HDL-apoA-I exchange (HAE) reflects HDL capacity for reverse cholesterol transport. Methods HAE was measured in 93 participants with type 2 diabetes (T2D) and at least one additional CVD risk factor in the Asker and Baerum Cardiovascular Diabetes study. At baseline and after seven years, the atherosclerotic burden was assessed by invasive coronary angiography. Major CVD events were registered throughout the study. Results Linear regression analysis demonstrated a significant inverse association between HAE and atherosclerotic burden. Cox proportional hazard regression analysis showed a significant association between HAE and a composite of major CVD events when controlling for waist-hip ratio, HR = 0.89, 95% CI = 0.80–1.00 and p=0.040. Conclusions Despite the relatively small size of the study population and the limited number of CVD events, these findings suggest that HAE provides valuable information in determining CVD risk.

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.

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.

International audience; Background: In the EMPA-REG OUTCOME trial, ejection fraction (EF) data were not collected. In the subpopulation with heart failure (HF), we applied a new predictive model for EF to determine the effects of empagliflozin in HF with predicted reduced (HFrEF) vs preserved (HFpEF) EF vs no HF.Methods and results: We applied a validated EF predictive model based on patient baseline characteristics and treatments to categorize patients with HF as being likely to have HF with mid-range EF (HFmrEF)/HFrEF (EF

Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes.Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets).In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p0.30).Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676).

Type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) often co-exist, yielding increased risk of cardiovascular (CV) complications including heart failure (HF). We assessed risk of cardiorenal outcomes, mortality and safety in patients with versus without COPD in the EMPA-REG OUTCOME trial.Patients (n = 7,020) with T2DM and CV disease (CVD) were treated with empagliflozin (10 mg or 25 mg) or placebo. Cox regression was used to assess COPD subgroup (placebo only) associations with, and treatment effects of empagliflozin versus placebo on first hospitalization for HF (HHF), CV death, all-cause mortality, incident/worsening nephropathy, and all-cause hospitalization.At baseline, patients with COPD (n = 707) had more HF and used insulin more frequently than those without COPD. During follow-up in the placebo group, those with baseline COPD had increased risk of HHF (HR 2.15 [95% CI 1.32, 3.49]), HHF/CV death (1.60 [1.10, 2.33]), incident/worsening nephropathy (1.68 [1.26, 2.24]), all-cause hospitalization (1.44 [1.19, 1.74]) and all-cause death (1.60 [1.09, 2.35]) compared to those without COPD. Empagliflozin consistently reduced all clinical outcomes, irrespective of COPD status (interaction p-values 0.14 to 0.96), with a confirmed safety profile.In patients with T2DM and CVD, COPD increased the risk of mortality and cardiorenal outcomes, including HF. Empagliflozin consistently reduced these outcomes versus placebo regardless of COPD, suggesting that empagliflozin's benefits in patients with T2DM and CVD are not mitigated by the presence of COPD.

Introduction: In the REDUCE-IT trial, icosapent ethyl (IPE) was shown to reduce major adverse cardiac events (MACE) including cardiovascular (CV) death in patients with elevated triglycerides (TG) and atherosclerotic CV disease (ASCVD) and/or diabetes. There are limited data evaluating the external applicability of REDUCE-IT inclusion criteria in contemporary diabetes trials. In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced the risk of CV death and hospitalization for HF (HHF). We sought to evaluate the benefit of EMPA on CV outcomes across IPE eligibility in the EMPA-REG OUTCOME trial. Methods: In total, 7020 patients with type 2 diabetes and ASCVD were treated with EMPA 10mg, 25 mg, or placebo (PBO). We examined the proportion of patients that had baseline (BL) TG 135 to 499 mg/dl, LDL-C 41 to 100 mg/dl and using a statin (“REDUCE-IT-like patients”). We evaluated the effect of pooled EMPA vs. PBO on CV death, HHF, HHF or CV death (excluding fatal stroke), all-cause death, and 3-point-MACE across the subgroups of patients fulfilling vs not fulfilling the REDUCE-IT criteria at BL using Cox regression. Results: A total of 6935 patients had TG and 6932 had LDL-C available. 1810 patients (25.8%) were REDUCE-IT like with TG 206±69 vs. 158±140 mg/dl, and LDL-C 71±15 vs. 91±39 mg/dl in those who did not meet the criteria. At BL, the former had more often coronary artery disease (84 vs. 73%) and higher BMI (31.7±5.1 kg/m 2 vs. 30.3±5.3) vs. the latter group. CV event rates in PBO were similar in patients who met/did not meet the criteria. Treatment effects of EMPA vs. PBO were consistent in patients who met/did not meet the REDUCE-IT criteria (Fig). Conclusions: In patients with T2D and established ASCVD treated in EMPA-REG OUTCOME, about one-quarter of patients would qualify for IPE according to the REDUCE-IT inclusion criteria. Empagliflozin consistently reduced CV outcomes and mortality in this sub-group, suggesting that IPE and SGLT2 inhibition may be complementary.

Background: Many patients with type 2 diabetes (T2D) will, over time, require insulin therapy for glycemic control. Treatment-attendant adverse effects of insulin such as weight gain and hypoglycemia may be especially problematic in those with CVD. Delaying the need for insulin initiation may therefore be an important therapeutic goal, especially in those with CVD. Methods: This actuarial analysis evaluated the 3,633 (52%) of 7,020 EMPA-REG OUTCOME participants who were not using insulin at baseline. Patients were randomized to the SGLT2 inhibitor empagliflozin (EMPA) 10mg, 25mg, or placebo (PBO). After the first 12 weeks, changes in background antihyperglycemic therapy were allowed. We estimated survival time free from insulin initiation (sustained over ≥2 consecutive study visits) over patients’ lifetimes by using baseline age as the time horizon. Age-based Kaplan-Meier survival curves were constructed for each year of age between 45 and 80 years. Differences in area under the survival curve between treatment arms represented treatment effects on time spent alive and free from insulin initiation. Results: During median follow-up of 3.2 years, insulin was required in 172 patients (7.1%) with EMPA and 196 (16.4%) with PBO. Lifetime benefits on insulin-free survival were inversely related to baseline age, ranging from 1.4 to 11.3 years. For a 45-year-old, estimated insulin-free survival was 20.1 years with EMPA and 10.0 years with PBO (difference: 10.1 years; 95% CI 5.7-14.5 years; P Conclusions: Assuming stable lifetime effects, we estimate that initiation of EMPA prolongs time alive free from need for insulin by 1.4 to over 11 years among adults with T2D and CVD. While benefits were most pronounced among younger patients, EMPA reduced the need for insulin across a broad age range.

Introduction: Type 2 diabetes (T2D) and chronic obstructive pulmonary disease (COPD) often co-exist yielding increased risk of cardiovascular (CV) complications, including heart failure (HF). In the EMPA-REG OUTCOME trial, empagliflozin (EMPA) reduced the risk of CV death and hospitalization for HF (HHF) in patients with T2D and CV disease (CVD). We hypothesized that patients with COPD had a higher risk of CV outcomes than those without COPD, but similar treatment benefits on CV outcomes from EMPA as the overall population. Methods: In total, 7020 patients were treated with EMPA 10mg, 25mg, or placebo (PBO) with median follow-up of 3.1 years. We defined COPD at baseline (BL) by investigator reported presence of COPD or emphysema, or the use of medications for obstructive airways disease. We explored the effect of pooled EMPA groups vs. PBO within the subgroups of patients with vs. without COPD on CV death, HHF, HHF or CV death (excluding fatal stroke), all-cause death and 3-point-MACE by Cox regression adjusted for baseline risk factors. Results: The 707 (10.1%) patients with COPD at BL were slightly older (65±8 vs. 63±9 yrs), had more often HF at BL (17 vs. 9%) and coronary artery disease (84 vs. 75%), used insulin (56 vs. 47%) and diuretics (57 vs. 42%,) more frequently, but had similar beta-blocker use (64 vs. 65%) as compared to those without COPD. During follow-up, those with COPD in the placebo group had increased risk of HHF (HR 2.15 [95%CI 1.32-3.49], p=0.002), HHF or CV death (HR 1.60 [1.10-2.33], p Conclusions: In EMPA-REG OUTCOME, 10% of patients had concomitant COPD. COPD patients were at increased risk of HHF, HHF or CV death, as well as all-cause death. EMPA consistently reduced these outcomes vs PBO among patients with and without COPD. These data suggest that EMPA’s benefits in patients with T2D and CVD are not attenuated by presence of COPD.

Background Individuals with polyvascular disease and impaired renal function are at high risk of cardiovascular (CV) events, but this relationship is not well investigated in people with type 2 diabetes (T2D). Furthermore, the impact of polyvascular disease plus renal dysfunction on the risk for hospitalisation for heart failure (HHF) remains unclear. Purpose We investigated this in a post hoc analysis of the EMPA-REG OUTCOME trial in which empagliflozin reduced risk of CV death and HHF versus placebo in people with T2D and vascular disease. In addition, we explored the treatment effect of empagliflozin on CV, HF and mortality outcomes across the spectrum of baseline polyvascular disease and impaired renal function. Methods Patients with T2D, CV disease and estimated glomerular filtration rate (eGFR) of ≥30 ml/min/1.73 m2 received empagliflozin 10 mg, 25 mg, or placebo. Vascular beds (VBs) were defined as coronary artery disease, peripheral artery disease, and cerebrovascular disease (Fig). By use of Cox regression, we explored the association between baseline eGFR < or ≥60 ml/min/1.73 m2, with or without polyvascular disease (1 vs ≥2 VBs involved), and CV death, HHF, CV death (excl. fatal stroke)/HHF, and all-cause mortality (ACM), as well as the treatment effect of empagliflozin versus placebo on these outcomes. Results Patients with ≥2 VBs involved and eGFR 10 years more often (73.4% vs. 63.2% or 54.9%), and a higher HF prevalence at baseline (19.4% vs. 11.1% or 9.2%) versus those with ≥2 VBs involved and eGFR ≥60 ml/min/1.73 m2 [n=866], or those with only 1 VB involved regardless of eGFR [n=5630], respectively. However, characteristics were generally balanced between treatment groups. Notably, co-existing polyvascular disease and eGFR Conclusions Co-existing polyvascular disease and eGFR Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

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

Background: Glucose variability has been associated with cardiovascular (CV) outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and CV death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of CV death by 38%. We explore post-hoc the association between HbA1c variability and CV death, and the potential mediating effects of HbA1c variability on empagliflozin’s CV death reductions.Methods: In total, 7,020 patients with type 2 diabetes and established CV 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 CV 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 CV death in both treatment arms with no interaction with treatment.Conclusions: HbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of CV death. Empagliflozin’s reduction in CV death did not appear to be mediated by reductions in HbA1c variability.ClinicalTrials.gov number, NCT01131676. Registered May 27 2010. https://clinicaltrials.gov/ct2/show/NCT01131676

BACKGROUND The sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin reduced cardiovascular death or heart failure hospitalizations in type 2 diabetes (T2D) in addition to a reduction of SBP. As heart failure patients often present with low SBP, which can challenge treatment initiation, we explored if empagliflozin's effect on SBP was independent of baseline SBP and heart failure status, and if the effect on cardiovascular and heart failure outcomes was influenced by updated mean SBP or by an early change in SBP after drug initiation. METHODS AND RESULTS A total of 7020 patients were treated with empagliflozin 10 mg, 25 mg or placebo and followed for a median of 3.1 years. All of them had BP measurement at baseline. We evaluated changes in SBP in the context of heart failure status at baseline and according to baseline SBP categories (