Empagliflozin after Acute Myocardial Infarction.

BACKGROUND: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown. METHODS: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. RESULTS: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups. CONCLUSIONS: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.).

Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial.

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown. METHODS: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes. RESULTS: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P=0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P=0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P<0.05). CONCLUSIONS: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.

Empagliflozin in patients post myocardial infarction rationale and design of the EMPACT-MI trial.

BACKGROUND: Patients with acute myocardial infarction (MI) are at risk for developing heart failure (HF) and subsequently are at an increased risk of mortality. Sodium-glucose cotransporter-2 inhibitors have been proven to improve outcomes in patients with HF with reduced ejection fraction, and, in the case of empagliflozin, in HF with preserved ejection fraction even without diabetes, but their efficacy and safety in the post-MI population has not yet been evaluated. METHODS: The EMPACT-MI trial will evaluate the safety and efficacy of empagliflozin compared with placebo in patients hospitalized for MI with or at high risk of new onset HF, in addition to standard care. EMPACT-MI is a streamlined, multinational, randomized, double-blind, placebo-controlled trial randomizing 5,000 participants at approximately 480 centers in 22 countries. Eligible patients presenting with spontaneous MI must have new signs or symptoms of pulmonary congestion requiring treatment or new left ventricular dysfunction (LVEF<45%), and at least 1 additional risk factor for development of future HF. Eligible and consenting patients are randomized to empagliflozin 10mg or placebo daily in addition to standard of care within 14 days of hospital admission for MI. The primary composite end point is time to first hospitalization for HF or all-cause mortality. CONCLUSIONS: EMPACT-MI will inform clinical practice regarding the role of empagliflozin in patients after an MI with high-risk for the development of future HF and mortality.

Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial.

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 <50%) or HFpEF (EF ≥50%). Cox regression was used to assess the effect of empagliflozin vs placebo on cardiovascular death/HF hospitalization (HHF), cardiovascular and all-cause mortality, and HHF in patients with predicted HFpEF, HFmrEF/HFrEF and no HF. Of 7001 EMPA-REG OUTCOME patients with data available for this analysis, 6314 (90%) had no history of HF. Of the 687 with history of HF, 479 (69.7%) were predicted to have HFmrEF/HFrEF and 208 (30.3%) to have HFpEF. Empagliflozin's treatment effect was consistent in predicted HFpEF, HFmrEF/HFrEF and no-HF for each outcome (HR [95% CI] for the primary outcome 0.60 [0.31-1.17], 0.79 [0.51-1.23], and 0.63 [0.50-0.78], respectively; P interaction = 0.62). CONCLUSIONS: In EMPA-REG OUTCOME, one-third of the patients with HF had predicted HFpEF. The benefits of empagliflozin on HF and mortality outcomes were consistent in nonHF, predicted HFpEF and HFmrEF/HFrEF.

Empagliflozin treatment effects across categories of baseline HbA1c, body weight and blood pressure as an add-on to metformin in patients with type 2 diabetes.

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.

Impact of polyvascular disease with and without co-existent kidney dysfunction on cardiovascular outcomes in diabetes: A post hoc analysis of EMPA-REG OUTCOME.

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.

Effect of empagliflozin on cardiorenal outcomes and mortality according to body mass index: A subgroup analysis of the EMPA-REG OUTCOME trial with a focus on Asia.

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.

Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial.

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.

Metabolic syndrome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a post hoc analyses of the EMPA-REG OUTCOME trial.

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: NCT01131676.

Empagliflozin reduces the risk of mortality and hospitalization for heart failure across Thrombolysis In Myocardial Infarction Risk Score for Heart Failure in Diabetes categories: Post hoc analysis of the EMPA-REG OUTCOME trial.

AIM: To investigate the association of the Thrombolysis In Myocardial Infarction (TIMI) Risk Score for Heart Failure in Diabetes (TRS-HFDM ) with mortality using data from the EMPA-REG OUTCOME trial. MATERIALS AND METHODS: In EMPA-REG OUTCOME, patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease (N = 7020) received the sodium-glucose co-transporter-2 inhibitor, empagliflozin, 10 or 25 mg or placebo. Post hoc, patients were stratified into risk categories (low-intermediate, high, very-high risk scores) using baseline TRS-HFDM . Cox regression analyses evaluated the association of TRS-HFDM categories with all-cause mortality (ACM), CV death, hospitalization for heart failure (HHF) and CV death (excluding fatal stroke) or HHF, and whether empagliflozin reduced the risk of CV outcomes across these risk categories. RESULTS: In placebo patients, increasing risk category was associated with a higher risk of ACM, CV death, and HHF. Empagliflozin reduced the risk of ACM (low-intermediate HR 0.68 [95% CI 0.48, 0.97] and very-high 0.69 [0.52, 0.91]), CV death (0.75 [0.48, 1.18] and 0.56 [0.41, 0.78]), HHF (0.53 [0.28, 1.01] and 0.67 [0.48, 0.96]), and CV death or HHF (0.69 [0.46, 1.03]) and (0.64 [0.49, 0.82]) across all risk categories versus placebo. Higher absolute risk reductions (ARRs) were observed for CV death in the very-high versus low-intermediate category (P = 0.01). CONCLUSIONS: Applied to EMPA-REG OUTCOME, higher TRS-HFDM was associated with increased HHF and mortality risk. Empagliflozin reduced CV outcomes across TRS-HFDM categories. Higher ARRs were associated with higher risk scores.

Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: A subanalysis of EMPA-REG OUTCOME.

In the EMPA-REG OUTCOME trial, we explored the association between pre-randomization uric acid level tertile (<309.30 µmol/L; 309.30 to <387.21 µmol/L; ≥387.21 µmol/L) and cardiovascular (CV) death, hospitalization for heart failure (HHF), HHF or CV death, all-cause mortality, three-point major adverse CV events (MACE), and incident or worsening nephropathy. Patients with type 2 diabetes and CV disease received empagliflozin or placebo. The median baseline plasma uric acid level was 344.98 µmol/L, and patients' baseline characteristics were mainly balanced across tertiles. Baseline uric acid levels were associated with cardio-renal outcomes: in the placebo group, for the highest versus lowest tertile, the multivariable hazard ratios for three-point MACE, HHF or CV death, and incident or worsening nephropathy were 1.22 (95% confidence interval [CI] 0.89-1.67; P = 0.2088), 1.51 (95% CI 1.02-2.23; P = 0.0396) and 1.77 (95% CI 1.33-2.34; P < 0.0001), respectively. When tested as a continuous variable, baseline uric acid was associated with all outcomes in the placebo group. Empagliflozin improved all cardio-renal outcomes across tertiles, with all interaction P values >0.05. Further investigation of these relationships is required.

Development of a mobbing short scale in the Gutenberg Health Study.

PURPOSE: Despite its highly detrimental potential, most standard questionnaires assessing psychosocial stress at work do not include mobbing as a risk factor. In the German standard version of COPSOQ, mobbing is assessed with a single item. In the Gutenberg Health Study, this version was used together with a newly developed short scale based on the Leymann Inventory of Psychological Terror. The purpose of the present study was to evaluate the psychometric properties of these two measures, to compare them and to test their differential impact on relevant outcome parameters. METHODS: This analysis is based on a population-based sample of 1441 employees participating in the Gutenberg Health Study. Exploratory and confirmatory factor analyses and reliability analyses were used to assess the mobbing scale. To determine their predictive validities, multiple linear regression analyses with six outcome parameters and log-binomial regression models for two of the outcome aspects were run. RESULTS: Factor analyses of the five-item scale confirmed a one-factor solution, reliability was α = 0.65. Both the single-item and the five-item scales were associated with all six outcome scales. Effect sizes were similar for both mobbing measures. CONCLUSION: Mobbing is an important risk factor for health-related outcomes. For the purpose of psychosocial risk assessment in the workplace, both the single-item and the five-item constructs were psychometrically appropriate. Associations with outcomes were about equivalent. However, the single item has the advantage of parsimony, whereas the five-item construct depicts several distinct forms of mobbing.

Myopia and level of education: results from the Gutenberg Health Study.

PURPOSE: To analyze the association between myopia and educational level in an adult European cohort. DESIGN: Population-based cross-sectional study. PARTICIPANTS: A cohort of the Gutenberg Health Study, including 4658 eligible enrollees between 35 and 74 years of age. METHODS: We applied a standardized protocol entailing a comprehensive questionnaire; thorough ophthalmic, general, cardiovascular, and psychological examinations; and laboratory tests, including genetic analyses. We documented achievement levels in school education and post-school professional education. The spherical equivalent (SE) was determined by noncycloplegic autorefractometry. We fitted mixed linear models including age, gender, and 45 myopia-associated single nucleotide polymorphisms (SNP) as covariates. MAIN OUTCOME MEASURES: Prevalence and magnitude of myopia in association with years spent in school and level of post-school professional education. RESULTS: Individuals who graduated from school after 13 years were more myopic (median, -0.5 diopters [D]; first quartile [Q1]/third quartile [Q3], -2.1/0.3 D) than those who graduated after 10 years (median, -0.2 D; Q1/Q3, -1.3/0.8 D), than those who graduated after 9 years (median, 0.3 D; Q1/Q3, -0.6/1.4 D), and than those who never finished secondary school (median, 0.2 D; Q1/Q3, -0.5/1.8 D; P<0.001, respectively). The same holds true for persons with a university degree (median, -0.6 D; Q1/Q3, -2.3/0.3 D) versus those who finished secondary vocational school (median, 0 D; Q1/Q3, -1.1/0.8 D) or primary vocational school (median, 0 D; Q1/Q3, -0.9/1.1 D) versus persons without any post-school professional qualification (median, 0.6 D; Q1/Q3, -0.4/1.7 D; P<0.001, respectively). Of persons who graduated from school after 13 years, 50.9% were myopic (SE, ≤-0.5 D) versus 41.6%, 27.1%, and 26.9% after 10 years, in those who graduated after 9 years, and in those who never graduated from secondary school, respectively (P<0.001). In university graduates, the proportion of myopic persons was higher (53%) than that of those who graduated from secondary (34.8%) or primary (34.7%) vocational schools and than in those without any professional training (23.9%; P<0.001, respectively). In multivariate analyses: higher school and professional levels of education were associated with a more myopic SE independent of gender. There was a small effect of age and SNPs. CONCLUSIONS: Higher levels of school and post-school professional education are associated with a more myopic refraction. Participants with higher educational achievements more often were myopic than individuals with less education.

Prevalence of age-related macular degeneration in a large European cohort: results from the population-based Gutenberg Health Study.

BACKGROUND: The aim of this study was to describe the sex- and age-specific prevalence of age-related macular degeneration (AMD) and its correlation with urban or rural residence in a large and relatively young European cohort. METHODS: We evaluated fundus photographs from participants in the Gutenberg Health Study (GHS), a population-based, prospective, observational, single-centre study in the Rhineland-Palatine region in midwestern Germany. The participants were 35-74 years of age at enrolment. The fundus images were classified as described in the Rotterdam Study and were graded independently by two experienced ophthalmologists (CK and UBK) based on the presence of hard and soft drusen, retinal pigmentary abnormalities, and signs of atrophic or neovascular age-related macular generation (AMD). RESULTS: Photographs from 4,340 participants were available for grading. Small, hard drusen (<63 µm, stages 0b and 0c) were present in 37.4% of participants (95% confidence interval [CI], stage 0b, 31.6% [30.3-33.7]; stage 0c, 5.8% [5.1-6.5]). Early AMD (soft drusen, pigmentary abnormalities, stages 1-3) was present in 3.8% of individuals in the youngest age group (35-44 years) (95% CI, stage 1a, 0.4% [0.3-0.5%]; stage 1b, 3.2% [2.9-3.5%]; stage 2a, 0.1% [0.1-0.2%]; stage 2b, 0% [0-0.0%]; stage 3, 0.1% [0.1-0.2%]), whereas late AMD (stages 4a and 4b) did not appear in the youngest age group. In all age groups, signs of early AMD were detected in 11.9% of individuals (stage 1a, 2.1% [1.7-2.6]; stage 1b, 8.0% [7.2-8.8]; stage 2a, 1.0% [0.7-1.3]; stage 2b, 0.5% [0.3-0.7]; stage 3, 0.3% [0.2-0.6]). Late AMD (geographic atrophy or neovascular AMD) was found in 0.2% of individuals (stage 4a, 0.1 % [0.0-0.2]; stage 4b, 0.1% [0.0-0.2]). AMD increased significantly with age (odds ratio [OR], 1.09; 95% CI, 1.08-1.10). Sex, iris colour, and residence (rural vs. urban) were not associated with different rates of AMD. CONCLUSIONS: In this study, the prevalence of AMD increased dramatically with age; however, although AMD is usually thought to occur after age 50, signs of early AMD were found in 3.8% of individuals in the youngest age group (younger than 45 years). This population-based sample is the first to provide substantial epidemiologic data from a large German cohort, including data on macular degeneration in younger age groups and incidence data after recall.

Effect of Qualifying Atherosclerotic Cardiovascular Disease Diagnosis Proximity on Cardiovascular Risk and Benefit of Empagliflozin in the EMPA-REG OUTCOME Trial.

Background: In patients with type 2 diabetes mellitus (T2DM), a history of an ischemic event is associated with increased risk for cardiovascular (CV) disease. Whether patients with T2DM and a recent atherothrombotic diagnosis benefit from early intervention with a sodium-glucose co-transporter 2 inhibitor is unknown. Methods: This study is a secondary analysis of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), which compared empagliflozin to placebo in adults with T2DM and atherosclerotic CV disease (ASCVD). Participants were categorized based on the time since their last qualifying ASCVD diagnosis (≤ 1 year vs > 1 year). Qualifying ASCVD diagnoses included ischemic or hemorrhagic stroke, myocardial infarction, coronary artery disease, and peripheral artery disease. The primary outcome was a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Results: A total of 6796 participants (n = 4547 empagliflozin, n = 2249 placebo) were included. Median time since the last qualifying ASCVD diagnosis was 3.8 years (quartile 1-quartile 3: 1.5-7.6), and most qualifying diagnoses occurred > 1 year before randomization (≤ 1 year, n = 1214; > 1 year, n = 5582). Empagliflozin reduced the incidence of the primary outcome irrespective of the time since the last qualifying ASCVD diagnosis (≤ 1 year: hazard ratio 0.82, 95% confidence interval: 0.57-1.16; vs > 1 year: hazard ratio 0.85, 95% confidence interval: 0.72-1.00; P for interaction = 0.84). Results were similar for the composite of CV death or hospitalization for heart failure. Conclusions: Empagliflozin improved CV outcomes in participants with T2DM, irrespective of the time since the last qualifying ASCVD diagnosis at randomization. Prospective trials are necessary to investigate the use of sodium-glucose co-transporter 2 inhibitors at the time of an acute ASCVD event. Trial Registration: EMPA-REG OUTCOME (Clinicaltrials.gov identifier: NCT01131676).

Contexte: Chez les patients atteints de diabète de type 2 (DT2), des antécédents d'accidents ischémiques sont associés à un risque accru de maladie cardiovasculaire (CV). On ignore si une intervention précoce par un inhibiteur du cotransporteur sodium-glucose de type 2 pourrait être bénéfique pour les patients atteints de DT2 ayant récemment reçu un diagnostic d'athérothrombose. Méthodologie: Cette étude est une analyse secondaire de l'essai EMPA-REG OUTCOME ( Empa gliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients­ R emoving E xcess G lucose), qui visait à comparer l'empagliflozine à un placebo chez des adultes atteints de DT2 et d'une maladie CV athéroscléreuse. Les participants ont été répartis selon le temps écoulé depuis leur plus récent diagnostic de maladie CV athéroscléreuse admissible (≤ 1 an vs > 1 an). Les diagnostics de maladies CV athéroscléreuses admissibles comprenaient un accident vasculaire cérébral ischémique ou hémorragique, un infarctus du myocarde, une coronaropathie et une artériopathie périphérique. Le critère d'évaluation principal était composé des décès d'origine CV, des infarctus du myocarde non mortels et des accident vasculaire cérébral non mortels. Résultats: Au total, 6796 participants (n = 4547 pour l'empagliflozine, n = 2249 pour le placebo) ont été inclus. Le temps écoulé médian depuis le diagnostic le plus récent de maladie CV athéroscléreuse admissible était de 3,8 ans (quartile 1-quartile 3 : 1,5-7,6). La plupart des diagnostics admissibles avaient été posés plus de 1 an avant la répartition aléatoire (≤ 1 an, n = 1214; > 1 an, n = 5582). L'empagliflozine a réduit la fréquence des événements constituant le critère d'évaluation principal, sans égard au temps écoulé depuis le plus récent diagnostic de maladie CV athéroscléreuse admissible (≤ 1 an : rapport des risques instantanés 0,82, intervalle de confiance à 95 % : 0,57-1,16; vs > 1 an : rapport des risques instantanés 0,85, intervalle de confiance à 95 % : 0,72-1,00; p pour l'interaction = 0,84). Les résultats étaient comparables à ceux observés pour le critère composé des décès d'origine CV et des hospitalisations pour insuffisance cardiaque. Conclusions: L'empagliflozine a amélioré les issues CV chez les patients atteints de DT2 sans égard au temps écoulé depuis le plus récent diagnostic de maladie CV admissible au moment de la répartition aléatoire. Des essais prospectifs sont nécessaires pour étudier l'utilisation des inhibiteurs du cotransporteur sodium-glucose de type 2 lorsqu'une manifestation de maladie CV athéroscléreuse aiguë survient. Inscription de l'essai: EMPA-REG OUTCOME (numéro d'identification dans clinicaltrials.gov : NCT01131676).

Sample size planning for survival prediction with focus on high-dimensional data.

Sample size planning should reflect the primary objective of a trial. If the primary objective is prediction, the sample size determination should focus on prediction accuracy instead of power. We present formulas for the determination of training set sample size for survival prediction. Sample size is chosen to control the difference between optimal and expected prediction error. Prediction is carried out by Cox proportional hazards models. The general approach considers censoring as well as low-dimensional and high-dimensional explanatory variables. For dimension reduction in the high-dimensional setting, a variable selection step is inserted. If not all informative variables are included in the final model, the effect estimates are biased towards zero. The bias affects the prediction error, and its magnitude is influenced by the sample size. For variable selection, we consider two approaches: least absolute shrinkage and selection operator (LASCO) and univariable selection. For univariable selection, we can calculate input parameters for the sample size formula. For the LASCO, supportive simulations are necessary to appropriately choose the input parameters. We investigate the performance of the proposed formulas with the use of simulations. Simulation results support the validity of the sample size formulas. An application of a real data example illustrates the practical implementation of the method.

Midregional pro-atrial natriuretic peptide in the general population/Insights from the Gutenberg Health Study.

BACKGROUND: The use of biomarkers is firmly established for the assessment of cardiovascular disease. Emerging biomarkers such as midregional pro-atrial natriuretic peptide (MR-proANP) challenge established markers regarding risk prediction and stratification ability. The aim of the present study was to describe the distribution of a contemporary MR-proANP assay in a large population-representative sample and to evaluate the association with prevalent cardiac diseases and cardiovascular risk factors. METHODS: MR-proANP was determined by the use of a contemporary commercially available assay (BRAHMS GmbH, Hennigsdorf, Germany) in a representative sample of 5000 participants from the large population-based Gutenberg Health Study. N-terminal pro B-type natriuretic peptide (NT-proBNP) was used as a comparator. RESULTS: Mean age was 55.5 ± 10.9 years. Coronary artery disease (CAD) was documented in 4.6%, heart failure (HF) in 1.5% of the study participants. We observed a moderate to strong correlation of the biomarkers with age, diabetes, hypertension, smoking, renal function, prevalence of CAD and HF. Males showed lower MR-proANP concentrations than females. MR-proANP showed no relevant correlation with BMI (ρ=-0.030) and CRP (ρ=0.039). Reference limits for MR-proANP representing the 95th/97.5th/99th percentile were determined for healthy individuals with 116/132/169 pmol/mL. CONCLUSIONS: The current analysis in a large population-based sample elucidates the correlations and distribution of MR-proANP. Its concentration in healthy individuals depends on prevalent cardiovascular diseases and classical risk factors. The reported population-based reference values might be useful for distinguishing between healthy and diseased individuals, thus improving risk stratification and triaging in various clinical settings.

Associations between depression and different measures of obesity (BMI, WC, WHtR, WHR).

BACKGROUND: Growing evidence suggests that abdominal obesity is a more important risk factor for the prognosis of cardiovascular and metabolic diseases than BMI. Somatic-affective symptoms of depression have also been linked to cardiovascular risk. The relationship between obesity and depression, however, has remained contradictory. Our aim was therefore to relate body mass index (BMI) and different measures for abdominal obesity (waist circumference, WC, waist-to-hip ratio, WHR, waist-to-height ratio, WHtR) to somatic vs. cognitive-affective symptoms of depression. METHODS: In a cross-sectional population based study, data on the first N = 5000 participants enrolled in the Gutenberg Health Study (GHS) are reported. To analyze the relationship between depression and obesity, we computed linear regression models with the anthropometric measure (BMI, WC, WHR, WHtR) as the dependent variable and life style factors, cardiovascular risk factors and psychotropic medications as potential confounders of obesity/depression. RESULTS: We found that only the somatic, but not the cognitive-affective symptoms of depression are consistently positively associated with anthropometric measures of obesity. CONCLUSIONS: We could demonstrate that the somatic-affective symptoms of depression rather than the cognitive-affective symptoms are strongly related to anthropometric measures. This is also true for younger obese starting at the age of 35 years. Our results are in line with previous studies indicating that visceral adipose tissue plays a key role in the relationship between obesity, depression and cardiovascular disease.

Risk factors of a reduced response to ranibizumab treatment for neovascular age-related macular degeneration--evaluation in a clinical setting.

BACKGROUND: To identify risk factors for being a "reduced responder" to ranibizumab treatment in a clinical setting in patients with neovascular age-related macular degeneration. METHODS: This retrospective study included 165 eyes of 165 consecutive patients with choroidal neovascularisation secondary to neovascular, age-related macular degeneration. Eyes were treated with three intravitreal injections of ranibizumab, followed by PRN (pro re nata) dosing thereafter. All patients were reevaluated every four weeks and then followed for six months. Reduced responders were defined as patients with a loss in visual acuity of at least 1 visual acuity line at the last follow-up and/or persistent intraretinal or subretinal fluid or detectable choroidal neovascularisation at the last follow-up, compared to baseline. RESULTS: Overall, 58 out of 165 eyes (35.2%) were considered to be reduced responders to treatment at the end of follow-up. The initial CNV size at baseline was correlated with the risk of being a reduced responder at the end of follow-up (p = 0.017). CONCLUSION: We identified the initial lesion size as a predictor for a reduced response to treatment in this study. Patients with a large initial lesion size should be thoroughly informed about the possible poorer response to the intravitreal treatment.

The Gutenberg Health Study: measuring psychosocial factors at work and predicting health and work-related outcomes with the ERI and the COPSOQ questionnaire.

BACKGROUND: Several instruments have been developed to assess psychosocial workload. We compared two of these instruments, the Effort-Reward Imbalance (ERI) model and the Copenhagen Psychosocial Questionnaire (COPSOQ) with regard to congruent validity and internal validity. METHODS: This analysis is based on a population-based sample of the baseline examination of 2,783 employees from the Gutenberg Health Study (GHS). About half of the participants completed the ERI questionnaire (n = 1,342), the other half completed the COPSOQ (n = 1,441). First, the two samples were compared and descriptive analyses were carried out calculating mean values for both instruments in general, then separately for age, gender and main occupational groups. Second, we analyzed the relationship between ERI and COPSOQ scales on the workplace situation and on the workplace outcomes: job satisfaction, general health, burnout, satisfaction with life, by applying stepwise logistic regression analysis. RESULTS AND DISCUSSION: For the majority of occupations, high effort as reflected by the ERI corresponded with high demands as reflected by the COPSOQ. Comparably, high reward (according to ERI) yielded a good agreement with high "influence and development" (according to COPSOQ). However, we could also find differences between ERI and COPSOQ concerning the intensity of psychosocial workload in some occupations (e.g., physicians/pharmacists or warehouse managers/warehousemen/transport workers). These differences point to differing theoretical concepts of ERI and COPSOQ. When the ability of ERI and COPSOQ was examined to determine the associations with health and work outcomes, burnout could be better predicted by the COPSOQ; this might be due to the fact that COPSOQ comprises the constructs "work-privacy conflict" and "emotional demand", which are closely related to burnout. However, methodological differences between these instruments limit their direct comparability. CONCLUSIONS: The ERI and COPSOQ instrument yielded similar results for most occupational groups. The slightly stronger association between psychosocial workload as assessed by COPSOQ and burnout might be explained by its broader approach. The ability of the ERI and COPSOQ instrument to reflect relevant risk factors for clinically manifest disorders (e.g., coronary heart disease) will be derived from subsequent prospective analyses of the GHS with the follow-up data.