Mortality of type 2 diabetes in Germany: additional insights from Gompertz models.

AIMS: The Gompertz law of mortality proclaims that human mortality rates in middle to old ages grow log-linearly with age and this law has been confirmed at multiple instances. We investigated if diabetes mortality in Germany also obeys to the Gompertz law and how this information helps to communicate diabetes mortality more intuitively. METHODS: We analyzed all statutory health-insured persons in Germany in 2013 that were aged 30 years or older. Deaths in 2014 were recorded and given in 5-year age groups. We fitted weighted linear regression models (separately for females and males and for people with and without diabetes) and additionally computed the probability that a person with diabetes dies before a person of the same age and sex without diabetes, and the "diabetes age", that is, the additional years of mortality risk added to an individual's chronological age due to diabetes-related excess mortality. RESULTS: We included N = 47,365,120 individuals, 6,541,181 of them with diabetes. In 2014, 763,228 deaths were recorded, among them 288,515 with diabetes. Diabetes mortality followed nearly perfectly Gompertz distributions. The probability that a person with diabetes dies before a person without diabetes was 61.9% for females and 63.3% for males. CONCLUSIONS: Diabetes mortality for females and males aged 30 years or older in Germany in 2014 followed the Gompertz law of mortality. The survival information of the population with diabetes during a large part of the lifespan can thus be reduced to the two parameters of the Gompertz distribution.

Assessing the potential for precision medicine in body weight reduction with regard to type 2 diabetes mellitus therapies: A meta-regression analysis of 120 randomized controlled trials.

AIMS: To assess the potential for precision medicine in type 2 diabetes by quantifying the variability of body weight as response to pharmacological treatment and to identify predictors which could explain this variability. METHODS: We used randomized clinical trials (RCTs) comparing glucose-lowering drugs (including but not limited to sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and thiazolidinediones) to placebo from four recent systematic reviews. RCTs reporting on body weight after treatment to allow for calculation of its logarithmic standard deviation (log[SD], i.e., treatment response heterogeneity) in verum (i.e., treatment) and placebo groups were included. Meta-regression analyses were performed with respect to variability of body weight after treatment and potential predictors. RESULTS: A total of 120 RCTs with a total of 43 663 participants were analysed. A slightly larger treatment response heterogeneity was shown in the verum groups, with a median log(SD) of 2.83 compared to 2.79 from placebo. After full adjustment in the meta-regression model, the difference in body weight log(SD) was -0.026 (95% confidence interval -0.044; 0.008), with greater variability in the placebo groups. Scatterplots did not show any slope divergence (i.e., interaction) between clinical predictors and the respective treatment (verum or placebo). CONCLUSIONS: We found no major treatment response heterogeneity in RCTs of glucose-lowering drugs for body weight reduction in type 2 diabetes. The precision medicine approach may thus be of limited value in this setting.

A parametric additive hazard model for time-to-event analysis.

BACKGROUND: In recent years, the use of non- and semi-parametric models which estimate hazard ratios for analysing time-to-event outcomes is continuously criticized in terms of interpretation, technical implementation, and flexibility. Hazard ratios in particular are critically discussed for their misleading interpretation as relative risks and their non-collapsibility. Additive hazard models do not have these drawbacks but are rarely used because they assume a non- or semi-parametric additive hazard which renders computation and interpretation complicated. METHODS: As a remedy, we propose a new parametric additive hazard model that allows results to be reported on the original time rather than on the hazard scale. Being an essentially parametric model, survival, hazard and probability density functions are directly available. Parameter estimation is straightforward by maximizing the log-likelihood function. RESULTS: Applying the model to different parametric distributions in a simulation study and in an exemplary application using data from a study investigating medical care to lung cancer patients, we show that the approach works well in practice. CONCLUSIONS: Our proposed parametric additive hazard model can serve as a powerful tool to analyze time-to-event outcomes due to its simple interpretation, flexibility and facilitated parameter estimation.

Absolute treatment effects of novel antidiabetic drugs on a composite renal outcome: meta-analysis of digitalized individual patient data.

BACKGROUND: Absolute treatment benefits-expressed as numbers needed to treat-of the glucose lowering and cardiovascular drugs, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose transporter 2 (SGLT2) inhibitors on renal outcomes remain uncertain. With the present meta-analysis of digitalized individual patient data, we aimed to display and compare numbers needed to treat of both drugs on a composite renal outcome. METHODS: From Kaplan-Meier plots of major cardiovascular outcome trials of GLP-1 receptor agonists and SGLT2 inhibitors vs. placebo, we digitalized individual patient time-to-event information on composite renal outcomes with WebPlotDigitizer 4.2; numbers needed to treat from individual cardiovascular outcome trials were estimated using parametric Weibull regression models and compared to original data. Random-effects meta-analysis generated meta-numbers needed to treat with 95% confidence intervals (CI). RESULTS: Twelve cardiovascular outcome trials (three for GLP-1 receptor agonists, nine for SGLT2 inhibitors) comprising 90,865 participants were included. Eight trials were conducted in primary type 2 diabetes populations, two in a primary heart failure and two in a primary chronic kidney disease population. Mean estimated glomerular filtration rate at baseline ranged between 37.3 and 85.3 ml/min/1.73 m2. Meta-analyses estimated meta-numbers needed to treat of 85 (95% CI 60; 145) for GLP-1 receptor agonists and 104 (95% CI 81; 147) for SGLT2 inhibitors for the composite renal outcome at the overall median follow-up time of 36 months. CONCLUSION: The present meta-analysis of digitalized individual patient data revealed moderate and similar absolute treatment benefits of GLP-1 receptor agonists and SGLT2 inhibitors compared to placebo for a composite renal outcome.

Synergism between coexisting eye diseases and sex in increasing the prevalence of the dry eye syndrome.

The aim was to investigate prevalence of dry eye syndrome (DES) in a population-based sample in Germany. The association between coexisting eye diseases and DES was also of interest. We recontacted participants of the Heinz Nixdorf Recall study between 2018 and 2021 by postal questionnaire that included the Women's Health Study questionnaire on DES. We estimated prevalence of DES and examined DES-associated factors among 2095 participants aged 62-91 years. We performed interaction analyses between sex and coexisting eye diseases in relation to the DES prevalence and performed bias analyses to examine the robustness of the results. The DES prevalence was 31.5% (34-36% after correction for potential non-response bias, 24.1% after correction for outcome misclassification) and it was almost 2.1-times higher in women than in men (women 42.3%, men 20.4%). Among DES subjects, 70.3% had received treatment in the previous 12 months. There was synergism between female sex and coexisting eye diseases (cataract, glaucoma, macular degeneration) in terms of DES prevalence. The extrapolated numbers of patients aged 62-91 years with DES in Germany are 1.1-1.3 million men and 6.1-6.8 million women. The observed synergism may be explained by differences in ocular physiology, subjective perception and response behavior. Women with eye diseases (cataract, glaucoma, macula degeneration) appear to have a markedly higher susceptibility to suffer from DES than men, so that a diagnostic workup of DES symptoms is particularly justified in women with these eye diseases.

Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort.

BACKGROUND: Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes. METHODS: For this cohort analysis, 927 participants aged 18-69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by 1 H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort. FINDINGS: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (pdim1<0·0001, pdim2=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, pdim1<0·0001, pdim2=0·037), pro-inflammatory biomarkers (IL-6: n=348, pdim1<0·0001, pdim2=0·013; IL-18: n=350, pdim1<0·0001, pdim2=0·38), and elevated cardiovascular risk (nevents=143, pdim1=0·14, pdim2<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (nevents=184, pdim1=0·012, pdim2=0·044) and cardiac autonomic neuropathy (nevents=118, pdim1=0·0094, pdim2=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (nevents=488, pdim1=0·12, pdim2=0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction. INTERPRETATION: These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis. FUNDING: German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung.

Efficacy of automated insulin delivery (AID) systems in type 1 diabetes: protocol of a systematic review and network meta-analysis of outpatient randomised controlled trials.

INTRODUCTION: Automated insulin delivery (AID), also known as artificial pancreas system or 'closed-loop system', represents a novel option for current treatments for type 1 diabetes (T1D). The objective of this systematic review and meta-analysis is to assess the efficacy of AID systems in comparison with current intensified insulin therapy for glycaemic control and patient-reported outcomes in individuals with T1D. METHODS AND ANALYSIS: Studies will be eligible if they are randomised controlled trials (RCTs) in people with T1D of all ages, and if they compare an AID system for self-administration during the day and night period with any other type of insulin therapy for at least 3 weeks. The primary outcome will be time in the glucose target range of 70-180 mg/dL. A systematic review will be conducted in the MEDLINE, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov registries from their inception dates. Two authors will independently screen all references based on titles and abstracts against the eligibility criteria. For data extraction, standard forms will be developed and tested before extraction. All information will be assessed independently by at least two reviewers. The risk of bias of the included studies will be assessed using the Cochrane Risk of Bias 2 tool. The data synthesis will include a random-effects pairwise and network meta-analysis (NMA) in a frequentist framework. Where applicable and if sufficient RCTs are available, sensitivity analyses will be performed, and heterogeneity and publication bias will be assessed. The certainty of evidence from the NMA will be evaluated following the Grading of Recommendations Assessment, Development, and Evaluation working group guidance. ETHICS AND DISSEMINATION: No ethical approval is needed. The results will be reported to the funder, presented in a peer-reviewed scientific journal and at conferences, and disseminated via press release, social media and public events. PROSPERO REGISTRATION NUMBER: CRD42023395492.

The mediating role of obesity on the prospective association between urinary sucrose and diabetes incidence in a sub-cohort of the EPIC-Norfolk.

BACKGROUND/OBJECTIVES: Findings from epidemiological studies showed controversial findings between dietary sugar intake and the development of diabetes. Most of these studies assessed dietary sugar intake by self-reports which might be prone to bias. Urinary sucrose, an objective biomarker of sucrose intake, might provide better insights into this association. Thus, the aim of this study was to investigate the associations between sucrose intake, measured via self-reports and urinary sucrose, with incident diabetes and to detect the impact of obesity on this association. SUBJECTS/METHODS: Data of a sub-group (n = 2996) from the prospective EPIC-Norfolk cohort were investigated. Sucrose intake was assessed by self-reports (validated food frequency questionnaire (FFQ) and 7-day diet diaries (7DD)) and as an objective urinary sucrose biomarker. Cox proportional hazard models were conducted to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for the associations between urinary and dietary sucrose intake and incident diabetes. Mediation analysis was performed to investigate the mediated percentage of body mass index (BMI) and waist circumference (WC) on this association. RESULTS: The mean age of the participants was 60.6 ± 9.5 years and 53% were women. After a mean follow-up of 11.2 ± 2.9 years, 97 participants developed diabetes. Findings suggested inverse associations regarding incident diabetes for self-reported sucrose intake per 50 g/d via 7DD [HR: 0.63 (95% CI: 0.43, 0.91)], and a tendency via FFQ [HR: 0.81 (95% CI: 0.46, 1.42)]. Urinary sucrose indicated a positive association with incident diabetes for each increase of 100 µM [HR: 1.14 (95% CI: 0.95, 1.36)]. The proportion mediated of BMI and WC for this association was 16 and 22%. CONCLUSIONS: These findings indicate that sucrose measured as objective urinary biomarker points to a positive association with incident diabetes. BMI might partly mediate this association. However, to obtain more precise results, more studies are warranted that consider this objective biomarker.

An Empirical Approach to Derive Water T1 from Multiparametric MR Images Using an Automated Pipeline and Comparison With Liver Stiffness.

BACKGROUND: Water T1 of the liver has been shown to be promising in discriminating the progressive forms of fatty liver diseases, inflammation, and fibrosis, yet proper correction for iron and lipid is required. PURPOSE: To examine the feasibility of an empirical approach for iron and lipid correction when measuring imaging-based T1 and to validate this approach by spectroscopy on in vivo data. STUDY TYPE: Retrospective. POPULATION: Next to mixed lipid-iron phantoms, individuals with different hepatic lipid content were investigated, including people with type 1 diabetes (N = 15, %female = 15.6, age = 43.5 ± 14.0), or type 2 diabetes mellitus (N = 21, %female = 28.9, age = 59.8 ± 9.7) and healthy volunteers (N = 9, %female = 11.1, age = 58.0 ± 8.1). FIELD STRENGTH/SEQUENCES: 3 T, balanced steady-state free precession MOdified Look-Locker Inversion recovery (MOLLI), multi- and dual-echo gradient echo Dixon, gradient echo magnetic resonance elastography (MRE). ASSESSMENT: T1 values were measured in phantoms to determine the respective correction factors. The correction was tested in vivo and validated by proton magnetic resonance spectroscopy (1 H-MRS). The quantification of liver T1 based on automatic segmentation was compared to the T1 values based on manual segmentation. The association of T1 with MRE-derived liver stiffness was evaluated. STATISTICAL TESTS: Bland-Altman plots and intraclass correlation coefficients (ICCs) were used for MOLLI vs. 1 H-MRS agreement and to compare liver T1 values from automatic vs. manual segmentation. Pearson's r correlation coefficients for T1 with hepatic lipids and liver stiffness were determined. A P-value of 0.05 was considered statistically significant. RESULTS: MOLLI T1 values after correction were found in better agreement with the 1 H-MRS-derived water T1 (ICC = 0.60 [0.37; 0.76]) in comparison with the uncorrected T1 values (ICC = 0.18 [-0.09; 0.44]). Automatic quantification yielded similar liver T1 values (ICC = 0.9995 [0.9991; 0.9997]) as with manual segmentation. A significant correlation of T1 with liver stiffness (r = 0.43 [0.11; 0.67]) was found. A marked and significant reduction in the correlation strength of T1 with liver stiffness (r = 0.05 [-0.28; 0.38], P = 0.77) was found after correction for hepatic lipid content. DATA CONCLUSION: Imaging-based correction factors enable accurate estimation of water T1 in vivo. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Mediation Analysis in Medical Research.

BACKGROUND: Mediation analysis addresses the question of the mechanisms by which an exposure causes an outcome. This article is intended to convey basic knowledge of statistical mediation analysis. METHODS: Selected articles and examples are used to explain the principle of mediation analysis. RESULTS: The goal of mediation analysis is to express an overall exposure effect as a combination of an indirect and a direct effect. For example, it might be of interest whether the increased risk of diabetes (outcome) due to obesity (exposure) is mediated by insulin resistance (indirect effect), and, if so, how much of a direct effect remains. In this example, insulin resistance is a potential mediator of the effect of obesity on the risk of diabetes. In general, for a mediation analysis to be valid, more confounders must be taken into account than in the estimation of the overall effect size. A regression-based approach can be used to ensure the consideration of all relevant confounders in a mediation analysis. CONCLUSION: By decomposing the overall exposure effect into indirect and direct components, a mediation analysis can reveal not just whether an exposure causes an outcome, but also how. For a mediation analysis to be valid, however, multiple assumptions must be satisfied that cannot easily be checked, potentially compromising such analyses as compared to the estimation of an overall effect.

How hazardous are hazard ratios? An empirical investigation of individual patient data from 27 large randomized clinical trials.

The use of hazard ratios as the standard treatment effect estimators for randomized trials with time-to-event outcomes has been the subject of repeated criticisms in recent years, e.g., for its non-collapsibility or with respect to (causal) interpretation. Another important issue is the built-in selection bias, which arises when the treatment is effective and when there are unobserved or not included prognostic factors that influence time-to-event. In these cases, the hazard ratio has even been termed "hazardous" because it is estimated from groups that increasingly differ in their (unobserved or omitted) baseline characteristics, yielding biased treatment estimates. We therefore adapt the Landmarking approach to assess the effect of ignoring a gradually increasing proportion of early events on the estimated hazard ratio. We propose an extension called "Dynamic Landmarking". This approach is based on successive deletion of observations, refitting Cox models and balance checking of omitted but observed prognostic factors, to obtain a visualization that can indicate built-in selection bias. In a small proof-of-concept simulation, we show that our approach is valid under the given assumptions. We further use "Dynamic Landmarking" to assess the suspected selection bias in the individual patient data sets of 27 large randomized clinical trials (RCTs). Surprisingly, we find no empirical evidence of selection bias in these RCTs and thus conclude that the supposed bias of the hazard ratio is of little practical relevance in most cases. This is mainly due to treatment effects in RCTs being small and the patient populations being homogeneous, e.g., due to inclusion and exclusion criteria.

Diabetes incidence before and after COVID-19 vaccination - Results from the German Disease Analyzer database.

Objective: We investigated whether COVID-19 vaccination had an impact on diabetes risk. Methods: We used data of 6,198 patients (mean age 64.3 years) from the nationwide Disease Analyzer database, a representative panel of physicians' practices in Germany. Patients received their first COVID-19 vaccination between 1 April 2021 and 31 March 2022, and all were newly diagnosed with diabetes within 183 days before or after this vaccination. Incident rates of diabetes after vaccination were compared to incident rates before vaccination. Results: The incidence rate of diabetes was lower after vaccination than before vaccination (incidence rate ratio = 0.79, 95% confidence interval: 0.75-0.83). The number of incident cases of diabetes was not greater in 2021 than in 2019. Conclusion: Our study did not confirm an increased risk of diabetes after COVID-19 vaccination. Further studies are needed to show whether the vaccination may be associated with a reduced diabetes risk.

Association of a lifestyle score with cardiometabolic markers among individuals with diabetes: a cross-sectional study.

INTRODUCTION: To investigate the associations of a lifestyle score with various cardiovascular risk markers, indicators for fatty liver disease as well as MRI-determined total, subcutaneous and visceral adipose tissue mass in adults with new-onset diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional analysis included 196 individuals with type 1 (median age: 35 years; median body mass index (BMI): 24 kg/m²) and 272 with type 2 diabetes (median age: 53 years; median BMI: 31 kg/m²) from the German Diabetes Study. A healthy lifestyle score was generated based on healthy diet, moderate alcohol consumption, recreational activity, non-smoking and non-obese BMI. These factors were summed to form a score ranging from 0 to 5. Multivariable linear and non-linear regression models were used. RESULTS: In total, 8.1% of the individuals adhered to none or one, 17.7% to two, 29.7% to three, 26.7% to four, and 17.7% to all five favorable lifestyle factors. High compared with low adherence to the lifestyle score was associated with more favorable outcome measures, including triglycerides (ß (95% CI) -49.1 mg/dL (-76.7; -21.4)), low-density lipoprotein (-16.7 mg/dL (-31.3; -2.0)), and high-density lipoprotein cholesterol (13.5 mg/dL (7.6; 19.4)), glycated hemoglobin (-0.5% (-0.8%; -0.1%)), high-sensitivity C reactive protein (-0.4 mg/dL (-0.6; -0.2)), as well as lower hepatic fat content (-8.3% (-11.9%; -4.7%)), and visceral adipose tissue mass (-1.8 dm³ (-2.9; -0.7)). The dose-response analyses showed that adherence to every additional healthy lifestyle factor was associated with more beneficial risk profiles. CONCLUSIONS: Adherence to each additional healthy lifestyle factor was beneficially associated with cardiovascular risk markers, indicators of fatty liver disease and adipose tissue mass. Strongest associations were observed for adherence to all healthy lifestyle factors in combination. TRIAL REGISTRATION NUMBER: NCT01055093.

How amenable is type 2 diabetes treatment for precision diabetology? A meta-regression of glycaemic control data from 174 randomised trials.

AIMS/HYPOTHESIS: There are two prerequisites for the precision medicine approach to be beneficial for treated individuals. First, there must be treatment heterogeneity; second, in the case of treatment heterogeneity, we need to detect clinical predictors to identify people who would benefit from one treatment more than from others. There is an established meta-regression approach to assess these two prerequisites that relies on measuring the variability of a clinical outcome after treatment in placebo-controlled randomised trials. Our aim was to apply this approach to the treatment of type 2 diabetes. METHODS: We performed a meta-regression analysis using information from 174 placebo-controlled randomised trials with 178 placebo and 272 verum (i.e. active treatment) arms including 86,940 participants with respect to the variability of glycaemic control as assessed by HbA1c after treatment and its potential predictors. RESULTS: The adjusted difference in log(SD) values between the verum and placebo arms was 0.037 (95% CI: 0.004, 0.069). That is, we found a small increase in the variability of HbA1c values after treatment in the verum arms. In addition, one potentially relevant predictor for explaining this increase, drug class, was observed, and GLP-1 receptor agonists yielded the largest differences in log(SD) values. CONCLUSIONS/INTERPRETATION: The potential of the precision medicine approach in the treatment of type 2 diabetes is modest at best, at least with regard to an improvement in glycaemic control. Our finding of a larger variability after treatment with GLP-1 receptor agonists in individuals with poor glycaemic control should be replicated and/or validated with other clinical outcomes and with different study designs. FUNDING: The research reported here received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. DATA AVAILABILITY: Two datasets (one for the log[SD] and one for the baseline-corrected log[SD]) to reproduce the analyses from this paper are available on https://zenodo.org/record/7956635 .

Risk phenotypes of diabetes and association with COVID-19 severity and death: an update of a living systematic review and meta-analysis.

AIMS/HYPOTHESIS: To provide a systematic overview of the current body of evidence on high-risk phenotypes of diabetes associated with COVID-19 severity and death. METHODS: This is the first update of our recently published living systematic review and meta-analysis. Observational studies investigating phenotypes in individuals with diabetes and confirmed SARS-CoV-2 infection with regard to COVID-19-related death and severity were included. The literature search was conducted from inception up to 14 February 2022 in PubMed, Epistemonikos, Web of Science and the COVID-19 Research Database and updated using PubMed alert to 1 December 2022. A random-effects meta-analysis was used to calculate summary relative risks (SRRs) with 95% CIs. The risk of bias was evaluated using the Quality in Prognosis Studies (QUIPS) tool and the certainty of evidence using the GRADE approach. RESULTS: A total of 169 articles (147 new studies) based on approximately 900,000 individuals were included. We conducted 177 meta-analyses (83 on COVID-19-related death and 94 on COVID-19 severity). Certainty of evidence was strengthened for associations between male sex, older age, blood glucose level at admission, chronic insulin use, chronic metformin use (inversely) and pre-existing comorbidities (CVD, chronic kidney disease, chronic obstructive pulmonary disease) and COVID-19-related death. New evidence with moderate to high certainty emerged for the association between obesity (SRR [95% CI] 1.18 [1.04, 1.34], n=21 studies), HbA1c (53-75 mmol/mol [7-9%]: 1.18 [1.06, 1.32], n=8), chronic glucagon-like peptide-1 receptor agonist use (0.83 [0.71, 0.97], n=9), pre-existing heart failure (1.33 [1.21, 1.47], n=14), pre-existing liver disease (1.40 [1.17, 1.67], n=6), the Charlson index (per 1 unit increase: 1.33 [1.13, 1.57], n=2), high levels of C-reactive protein (per 5 mg/l increase: 1.07 [1.02, 1.12], n=10), aspartate aminotransferase level (per 5 U/l increase: 1.28 [1.06, 1.54], n=5), eGFR (per 10 ml/min per 1.73 m2 increase: 0.80 [0.71, 0.90], n=6), lactate dehydrogenase level (per 10 U/l increase: 1.03 [1.01, 1.04], n=7) and lymphocyte count (per 1×109/l increase: 0.59 [0.40, 0.86], n=6) and COVID-19-related death. Similar associations were observed between risk phenotypes of diabetes and severity of COVID-19, with some new evidence on existing COVID-19  vaccination status (0.32 [0.26, 0.38], n=3), pre-existing hypertension (1.23 [1.14, 1.33], n=49), neuropathy and cancer, and high IL-6 levels. A limitation of this study is that the included studies are observational in nature and residual or unmeasured confounding cannot be ruled out. CONCLUSIONS/INTERPRETATION: Individuals with a more severe course of diabetes and pre-existing comorbidities had a poorer prognosis of COVID-19 than individuals with a milder course of the disease. REGISTRATION: PROSPERO registration no. CRD42020193692. PREVIOUS VERSION: This is a living systematic review and meta-analysis. The previous version can be found at https://link.springer.com/article/10.1007/s00125-021-05458-8 FUNDING: The German Diabetes Center (DDZ) is funded by the German Federal Ministry of Health and the Ministry of Culture and Science of the State North Rhine-Westphalia. This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD).

HbA1c trajectories over 3 years in people with type 2 diabetes starting second-line glucose-lowering therapy: The prospective global DISCOVER study.

AIM: To identify distinct HbA1c trajectories in people with type 2 diabetes (T2D) starting second-line glucose-lowering therapy. MATERIALS AND METHODS: DISCOVER was a 3-year observational study of individuals with T2D beginning second-line glucose-lowering therapy. Data were collected at initiation of second-line treatment (baseline) and at 6, 12, 24 and 36 months. Latent class growth modelling was used to identify groups with distinct HbA1c trajectories. RESULTS: After exclusions, 9295 participants were assessed. Four distinct HbA1c trajectories were identified. Mean HbA1c levels decreased between baseline and 6 months in all groups; 72.4% of participants showed stable good levels of glycaemic control over the remainder of follow-up, 18.0% showed stable moderate levels of glycaemic control and 2.9% showed stable poor levels of glycaemic control. Only 6.7% of participants showed highly improved glycaemic control at month 6 and stable control over the rest of follow-up. For all groups, dual oral therapy use decreased over time, compensated for by the increasing use of other treatment regimens. Use of injectable agents increased over time in groups with moderate and poor glycaemic control. Logistic regression models suggested that participants from high-income countries were more probable to be in the stable good trajectory group. CONCLUSIONS: Most people receiving second-line glucose-lowering treatment in this global cohort achieved stable good or highly improved long-term glycaemic control. One-fifth of participants showed moderate or poor glycaemic control during follow-up. Further large-scale studies are required to characterize possible factors associated with patterns of glycaemic control to inform personalized diabetes treatment.

Spatio-Temporal Trends in the Incidence of Type 2 Diabetes in Germany.

BACKGROUND: There are no data on recent trends in the incidence rate of type 2 diabetes (T2D) in Germany. The aim of this study was to determine the sex-, age-, and region-specific trends in the T2D incidence rate between 2014 and 2019. METHODS: Based on nationwide data from statutorily insured persons in Germany, negative binomial regression models were used to analyze age- and sex-specific trends in the T2D incidence rate. Age- and sex-adjusted trends were calculated for 401 administrative districts using a Bayesian spatio-temporal regression model. RESULTS: During the period concerned, approximately 450 000 new cases of T2D were observed each year among some 63 million persons. Taking all age groups together, the incidence rate decreased in both women and men, from 6.9 (95% confidence interval [6.7; 7.0]) and 8.4 [8.2; 8.6] respectively per 1000 persons in 2014 to 6.1 [5.9; 6.3] and 7.7 [7.5; 8.0] per 1000 persons in 2019. This corresponds to an annual reduction of 2.4% [1.5; 3.2] for women and 1.7% [0.8; 2.5] for men. The incidence rate increased in the age group 20-39 years. The age- and sex-adjusted incidence rate decreased in almost all districts, although regional differences persisted. CONCLUSION: The T2D incidence rate should be closely monitored to see whether the decreasing trend continues. One must not forget that the prevalence can rise despite decreasing incidence. For this reason, the findings do not necessarily mean a decrease in the disease burden of T2D and the associated demand on healthcare resources.

Impact of Left Atrial Appendage Amputation on Left Atrial Morphology and Rhythm after Off-Pump CABG.

OBJECTIVES: Left atrial appendage (LAA) amputation concomitant to coronary artery bypass grafting (CABG) has become an increasingly performed technique in patients with atrial fibrillation (AF) or with sinus rhythm and a CHA2DS2-VASc score ≥2. However, LAA amputation has come under suspicion to cause postoperative atrial fibrillation (POAF) due to left atrial (LA) dilation. This study aims to assess this assumption in patients undergoing CABG in off-pump technique with and without amputation of the LAA. METHODS: Patients who underwent isolated CABG in off-pump technique without history of AF were retrospectively examined. Cohorts were divided according to the concomitant execution of LAA amputation. LA volume was measured by transthoracic echocardiography and rhythm was analyzed by electrocardiography, medication protocol, and visit documentation. Propensity score (PS) matching was performed based on 20 preoperative risk variables to correct for selection bias. RESULTS: A total of 1,522 patients were enrolled, with 1,267 in the control group and 255 in the LAA amputation group. Occurrence of POAF was compared in 243 PS-matched patient pairs. Neither the unmatched cohort (odds ratio [OR] 0.82; 95% confidence interval or CI [0.61; 1.11], p = 0.19) nor the PS-matched cohort (OR 0.94; 95% CI [0.62; 1.41], p = 0.75) showed significant differences in POAF occurrence. Subgroup analysis of sex, use of ß-blockers, pulmonary disease, ejection fraction, and CHA2DS2-VASc-Score also showed no tendencies. LA volume did not change significantly (p = 0.18, 95% CI [-0.29; 1.51]). CONCLUSION: Surgical amputation of the LAA concomitant to CABG did not lead to LA dilation and has no significant impact on the occurrence of POAF.

Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis.

Impaired proinsulin-to-insulin processing in pancreatic ß-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. 1,2), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. 3-8); nonetheless, the role of specific SL species in ß-cell function and demise is unclear. Here we define the lipid signature of T2D-associated ß-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. ß-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL-protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum-Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in ß-cell function and T2D-associated ß-cell failure.