Air pollution, air temperature and the influence on cause-specific mortality and morbidity

Epidemiological studies have shown that short-term changes in air pollution and air temperature have an impact on cardiovascular and respiratory health. However, only a few studies have investigated the association between ultrafine particles (UFP) with a diameter <100 nm (0.1 µm) and cardio-respiratory health so far and especially results from Eastern Europe are rare. Moreover, finding the underlying biological mechanisms, which explain the relationships between environmental changes and cardiovascular health, remains a major challenge. Investigating specific characteristics such as endothelial function in association with environmental stimuli might help to clarify potential biological pathways. The main objectives of this thesis were to investigate short-term associations between air pollution and daily cause-specific mortality as well as hospital admissions in five Central and Eastern European cities (Augsburg, Chernivtsi, Dresden, Ljubljana and Prague) within the EU-project UFIREG. To investigate potential biological mechanisms explaining the associations between air pollution or air temperature and cardiovascular diseases we also examined the influence of short-term changes in air temperature and ozone on markers of endothelial function in individuals with type-2 diabetes (T2D) within the DEPS panel study in Chapel Hill in North Carolina, USA. Our results of the UFIREG study indicated delayed and prolonged effects of UFP exposure on respiratory mortality and hospital admissions in Central and Eastern Europe. Although our results on UFP and respiratory health outcomes were not statistically significant, we consider these findings as potentially important. Further, we assume that the short study period might be one explanation for the non-significant associations. PM2.5 exposure was associated with delayed and prolonged effects on cardiovascular and respiratory mortality and morbidity. We observed a stronger association between PM2.5 and respiratory hospital admissions compared to results from other European regions and the U.S. Our findings of the DEPS panel study suggested a linear association between temperature decreases as well as ozone increases and markers of endothelial function in individuals with T2D. We observed immediate and delayed decreases in flow-mediated dilatation of the brachial artery, a marker of endothelial function, in association with a decrease in temperature as well as with an increase in ozone. This thesis adds to the existing knowledge in the field of short-term effects of air pollution since it reports results on the association between UFP and cause-specific mortality and morbidity from Central and Eastern European cities. Results of the UFIREG project indicated that it is important to integrate UFP into routine measurement networks to provide data for future short- and long-term epidemiological studies. Further studies are needed investigating the association between UFP and (cause-specific) mortality and morbidity at multiple locations using harmonized UFP measurements. This thesis also discusses short-term changes in endothelial function in response to temperature decreases and ozone increases. We conclude that endothelial dysfunction might be one of the possible biological pathways explaining the association between environmental changes and cardiovascular events that have been observed worldwide.Epidemiologische Studien haben gezeigt, dass sich Tag-zu-Tag-Veränderungen in Luftschadstoffkonzentrationen sowie der Lufttemperatur auf die menschliche Gesundheit auswirken. Bisher haben jedoch nur wenige Studien den Zusammenhang zwischen ultrafeinen Partikeln (UFP) mit einem Durchmesser <100 nm (0.1 µm) und kardio-respiratorischen Gesundheitsparametern untersucht. Des Weiteren gibt es bisher wenige Ergebnisse aus osteuropäischen Ländern. Die Untersuchung spezifischer Merkmale wie zum Beispiel die Endothelfunktion, geben einen Einblick in mögliche biologische Mechanismen, die Herzkreislauferkrankungen, die im Zusammenhang mit Umweltveränderungen auftreten, erklären können. Die Hauptziele dieser Dissertation waren, die Kurzzeitauswirkungen von ultrafeinen und feinen Partikeln auf die tägliche ursachenspezifische Mortalitäts- und Krankheitsrate in fünf zentral- und osteuropäischen Städten (Augsburg, Czernowitz, Dresden, Ljubljana und Prag) im Rahmen des EU-Projekts UFIREG zu untersuchen. Darüber hinaus untersuchten wir Veränderungen der Endothelfunktion bei Patienten mit Typ-2 Diabetes (T2D) in Zusammenhang mit einem kurzzeitigen Temperaturanstieg sowie einem Anstieg der Ozonkonzentration. Dieser Zusammenhang wurde innerhalb der DEPS Panel Studie in Chapel Hill, North Carolina, USA analysiert und könnte einen Aufschluss über mögliche biologische Mechanismen geben, wie Umweltveränderungen zu Herzkreislauferkrankungen führen können. Ergebnisse des UFIREG Projekts zeigten einen Anstieg der Todesfälle und Krankenhauseinweisungen auf Grund von respiratorischen Erkrankungen in Zusammenhang mit einer kumulativen UFP Exposition. Die Einflüsse von UFP auf respiratorische Erkrankungen und Todesursachen waren zwar nicht statistisch signifikant, dennoch bewerten wir die Ergebnisse als wichtig. Die kurze Studienperiode könnte eine mögliche Erklärung für die nicht signifikanten Ergebnisse sein. Darüber hinaus zeigte ein Anstieg der PM2.5-Konzentration einen Zusammenhang mit kardiovaskulärer sowie respiratorischer Mortalität und Morbidität. Unsere Ergebnisse des UFIREG Projekts zeigen einen stärkeren Zusammenhang zwischen PM2.5 und respiratorischer Krankenhauseinweisungen als Studien, die in anderen europäischen Regionen und den USA durchgeführt wurden. Die Ergebnisse der DEPS Panel Studie weisen auf eine lineare Assoziation zwischen einem Temperaturabfall sowie Ozonanstieg und Veränderungen in der Endothelfunktion bei T2D hin. Die flussvermittelte Dilatation der Arteria brachialis, ein Marker für die Endothelfunktion, nahm unmittelbar und mit einer Verzögerung von einem Tag ab wenn die Lufttemperatur sank bzw. wenn die Ozonkonzentration anstieg. Diese Dissertation zeigt Ergebnisse zu den Kurzzeitauswirkungen von UFP auf die tägliche ursachenspezifische Mortalitäts- und Morbiditätsrate in zentral- und osteuropäischen Städten und leistet daher einen wichtigen Beitrag zum aktuellen Wissensstand. Des Weiteren zeigen die Ergebnisse des UFIREG Projekts, dass es wichtig ist, UFP in Routinemessnetzwerke zu integrieren, um Daten für zukünftige Studien zu den Kurz- und Langzeiteffekten von UFP zu liefern. Weitere multizentrische Studien mit harmonisierten UFP Messungen sind notwendig, um den Zusammenhang zwischen UFP und (ursachenspezifischen) Todesursachen und Krankenhauseinweisungen in verschiedenen Regionen zu untersuchen. Diese Arbeit diskutiert darüber hinaus Veränderungen in der Endothelfunktion bei Temperaturabfall und Ozonkonzentrationsanstieg. Die Ergebnisse deuten darauf hin, dass eine Endotheldysfunktion einen möglichen Mechanismus für die weltweit beobachteten Herzkreislauferkrankungen im Zusammenhang mit Umweltveränderungen darstellt

Spatiotemporal association between COVID-19 incidence and type 1 diabetes incidence among children and adolescents: a register-based ecological study in Germany

ObjectiveStudies have shown an increased incidence of pediatric type 1 diabetes during the COVID-19 pandemic, but the detailed role of SARS-CoV-2 infection in the incidence increase in type 1 diabetes remains unclear. We investigated the spatiotemporal association of pediatric type 1 diabetes and COVID-19 incidence at the district level in Germany.MethodsFor the period from March 2020 to June 2022, nationwide data on incident type 1 diabetes among children and adolescents aged &lt;20 years and daily documented COVID-19 infections in the total population were obtained from the German Diabetes Prospective Follow-up Registry and the Robert Koch Institute, respectively. Data were aggregated at district level and seven time periods related to COVID-19 pandemic waves. Spatiotemporal associations between indirectly standardized incidence rates of type 1 diabetes and COVID-19 were analyzed by Spearman correlation and Bayesian spatiotemporal conditional autoregressive Poisson models.ResultsStandardized incidence ratios of type 1 diabetes and COVID-19 in the pandemic period were not significantly correlated across districts and time periods. A doubling of the COVID-19 incidence rate was not associated with a significant increase in the incidence rate of type 1 diabetes (relative risk 1.006, 95% CI 0.987; 1.019).ConclusionOur findings based on data from the pandemic period indirectly indicate that a causal relationship between SARS-COV-2 infection and type 1 diabetes among children and adolescents is unlikely

Empagliflozin cardiovascular and renal effectiveness and safety compared to dipeptidyl peptidase-4 inhibitors across 11 countries in Europe and Asia : Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study

Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies. Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014 -2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary end-points included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined.Findings: Among 83,946 matched patient pairs, (0.7 years overall mean follow-up time), initiation of empagli-flozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0.70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0.55; 0.48 to 0.63), stroke (0. 82; 0.71 to 0.96), and end-stage renal disease (0.43; 0.30 to 0.63) were lower and risk for myocardial infarc-tion, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1.97; 1.28 to 3.03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions.Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors.(c) 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Peer reviewe

Comparing diabetes due to diseases of the exocrine pancreas to type 1 and type 2 diabetes using propensity score matching

Objective: To estimate the prevalence of diabetes due to diseases of the exocrine pancreas (DEP) using data of the multicentre diabetes patient follow-up registry. Moreover, we aimed at comparing individuals with diabetes due to DEP to individuals with type 1 and type 2 diabetes. Methods: Individuals with DEP, type 1 or type 2 diabetes ≥18 years of age were studied. We aggregated the most recent treatment year per patient and used propensity scores to match diabetes due to DEP to type 1 and type 2 diabetes. Matching was conducted one-to-one with sex, age, diabetes duration, migration background and the German index of socioeconomic deprivation as covariates. Results: We identified 7,093 (1.6%) individuals with diabetes due to DEP. In the matched cohort DEP-type 1 diabetes we observed a similar daily insulin dose (0.62 IU/kg (95% confidence interval:0.60-0.63), 0.60 IU/kg (0.58-0.62)) and significant differences regarding microvascular (41.0% (39.7-42.2), 45.3% (44.0-46.6)), and macrovascular disease (16.6% (15.7-17.6), 14.7% (13.8-15.6)). HbA1c (8.2% (8.1-8.3), 7.9% (7.8-8.0)), daily insulin dose (0.60 IU/kg (0.58-0.62), 0.56 IU/kg (0.54-0.58)) and event rates of severe hypoglycemia (23.9 events/100 PY (21.4-26.8), (9.5 events/100 PY (8.0-11.2)) were significantly higher in individuals with diabetes due to DEP compared to type 2 diabetes. Conclusions: Using registry data, rare diabetes types such as diabetes due to DEP can be studied with a significant sample size. Our study identified differences and similarities between adult individuals with DEP related diabetes and type 1 or type 2 diabetes

Sex differences over time for glycemic control, pump use and insulin dose in patients aged 10-40 years with type 1 diabetes: a diabetes registry study.

INTRODUCTION To evaluate sex differences in people with type 1 diabetes concerning changes in glycemic control and trends in insulin pump use and insulin dose over two decades in adolescents and one-and-a-half decades in adults. RESEARCH DESIGN AND METHODS People aged 10-20 years (data years 1999-2018) and 21-40 years (data years 2004-2018) with type 1 diabetes were identified in the Diabetes Prospective Follow-up Registry (DPV). All available patients' data sets of the respective period were used for linear regression analyses to investigate trends in HbA1c, pump use, insulin doses and body mass index SD scores (BMI-SDS) in females and males. In addition, stratification by migrant background was made for the adolescent group. RESULTS In the youth group (n=68 662), both boys and girls showed an HbA1c decrease over the period examined. After stratification for migrant background, an HbA1c convergence between boys and girls was seen in those without migrant background as of 2016. Usage of insulin pumps increased continuously from 3% (boys and girls) to 47% (boys) and 54% (girls), respectively. The daily insulin dose in units per kilogram body weight and day increased continuously from 1999 to 2018. An insulin dose leveling between boys and girls occurred. BMI-SDS consistently increased in girls whereas only slight variations were observed in boys.The adult group (n=15 380) showed constant HbA1c sex differences from 2004 to 2018 with lower HbA1c level in females. The use of insulin pump therapy rose from 18% to 35% (males) and 30% to 50% (females). CONCLUSIONS The gap in metabolic control between boys and girls with type 1 diabetes seems to close, but predominantly in adolescents without a migrant background. Improved HbA1c was associated with increased insulin pump use, especially in girls.In adult patients, sex differences in metabolic control and insulin pump use persist: women show constantly lower HbA1c values and higher insulin pump use

An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria

Abstract Background The FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany. Methods German patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared. Results Overall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT’s albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible. Conclusions Certain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted

Lean diabetes in middle-aged adults: A joint analysis of the German DIVE and DPV registries.

To assess differences in demographics, treatment and outcome of lean (LD) compared to overweight and obese people with diabetes clinically classified as type 2 diabetes mellitus (T2DM).We combined data from the German DIVE (Diabetes Versorgungs-Evaluation) and DPV (Diabetes-Patienten-Verlaufsdokumentation) databases to produce a large cohort of people with T2DM. The characteristics of people with Body Mass Index (BMI) <25 kg/m2, ≥25-30 kg/m2 and ≥30 kg/m2 aged 30 to 50 years were compared, including demographics, cardiovascular (CV) risk factors, comorbidities and outcomes.A total of 37,870 people were included in the analysis, 3,191 of these (8.4%) had a BMI < 25 kg/m2. LD reported more nicotine (41.6% of 2,070 vs. 38.1% of 6,070 and 33.4% of 16,823; P<0.001)and alcohol consumption (12.0% of 1,282, 10.3% of 3,594 and 6.6% of 9,418; P<0.001)compared to overweight and obese people. More LD were treated with insulin in comparison to the other subgroups (short acting insulin 33.1% of 3,191 vs. 28.4% of 9,234 and 28.0% of 25,445; P <0.001; long acting insulin 31.3% of 3,191 vs. 28.9% of 9,234 and 29.3% of 25,445; P = 0.043). Regression models adjusted for age, gender and diabetes duration showed a 2.50 times higher odds ratio (OR) for hypoglycemia and a 2.52 higher OR for mortality in LD compared to the BMI subgroup ≥30 kg/m2.LD is associated with an increased risk of hypoglycaemia and death. Patients are characterized by male gender, lifestyle habits as smoking and alcohol consumption while cardiovascular comorbidities are less important. In comparison to patients of the other weight groups they are treated with insulin more often and considerably less with metformin

Longitudinal relationship of particulate matter and metabolic control and severe hypoglycaemia in children and adolescents with type 1 diabetes

Background: Evidence for the metabolic impact of long-term exposure to air pollution on diabetes is lacking. We investigated the association of particulate matter <10 mu m (PM10) and <2.5 mu m (PM2.5) with yearly averages of HbA1c, daily insulin dose (IU/kg) and rates of severe hypoglycaemia in type 1 diabetes (T1D). Methods: We studied data of 44,383 individuals with T1D < 21 years which were documented in 377 German centres within the diabetes prospective follow-up registry (DPV) between 2009 and 2018. Outcomes were aggregated by year and by patient. PM10- and PM2.5-yearly averages prior to the respective treatment year were linked to individuals via the five-digit postcode areas of residency. Repeated measures linear and negative binomial regression were used to study the association between PM-quartiles (Q1 lowest, Q4 highest concen-tration) and yearly averages of HbA1c, daily insulin dose and rates of severe hypoglycaemia (confounders: sex, time-dependent age, age at diabetes onset, time-dependent type of treatment, migratory background, degree of urbanisation and socioeconomic index of deprivation). Results: Adjusted mean HbA1c increased with PM10 (Q1: 7.96% [95%-CI: 7.95-7.98], Q4: 8.03% [8.02-8.05], p-value<0.001) and with PM2.5 (Q1: 7.97% [7.95-7.99], Q4: 8.02% [8.01-8.04], p < 0.001). Changes in daily insulin dose were inversely related to PM (PM10 and PM2.5: Q1 0.85 IU/kg [0.84-0.85], Q4: 0.83 IU/kg [0.82-0.83], p < 0.001). Adjusted rates of severe hypoglycaemia increased with PM-quartile groups (PM10 Q1:11.2 events/100 PY [10.9-11.5], PM10 Q4: 15.3 [14.9-15.7], p < 0.001; PM2.5 Q1: 9.9 events/100 PY [9.6-10.2], PM2.5 Q4: 14.2 [13.9-14.6], p < 0.001). Discussion: Air pollution was associated with higher HbA1c levels and increased risk of severe hypoglycaemia in people with T1D, consequently indicating a higher risk of diabetes complications. Further studies are needed to explore causal pathways of the observed associations