Diabetes as a risk factor for tuberculosis disease.

BACKGROUND: Tuberculosis (TB) is amongst the leading causes of death from an infectious disease, with an estimated 1.3 million deaths from TB in 2022. Approximately 25% of the global population is estimated to be infected with the TB bacterium, giving rise to 10.6 million episodes of TB disease in 2022. The prevalence of diabetes influences TB incidence and TB mortality. It is associated not only with an increased risk of TB disease but also death during TB treatment, TB relapse after treatment completion and multidrug-resistant TB. Since 2011, the World Health Organization (WHO) has recommended collaborative TB and diabetes activities as outlined in the Collaborative Framework for Care and Control of TB and Diabetes. OBJECTIVES: To determine the prognostic value of diabetes mellitus (DM) in the general population of adults, adolescents and children for predicting tuberculosis disease. SEARCH METHODS: We searched the literature databases MEDLINE (via PubMed) and WHO Global Index Medicus, and the WHO International Clinical Trials Registry Platform (ICTRP) on 3 May 2023 (date of last search for all databases); we placed no restrictions on the language of publication. SELECTION CRITERIA: We included retrospective and prospective cohort studies, irrespective of publication status or language. The target population comprised adults, adolescents and children from diverse settings, encompassing outpatient and inpatient cohorts, with varying comorbidities and risk of exposure to tuberculosis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and the Quality In Prognosis Studies (QUIPS) tool. Prognostic factors assessed at enrolment/baseline included diabetes, as defined by the individual studies, encompassing patient-reported status, abstracted from medical records or claims data, or diagnosed by plasma glucose/glycosylated haemoglobin. The primary outcome was the incidence of tuberculosis disease. The secondary outcome was recurrent TB disease. We performed a random-effects meta-analysis for the adjusted hazard ratios, risk ratios, or odds ratios, employing the restricted maximum likelihood estimation. We rated the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 48 cohort studies with over 61 million participants from the six WHO regions. However, the representation was variable as eight population-based studies were from South Korea and 19 from China, with overlapping study periods, and only one from the African region (Ethiopia). All studies included adults, and nine studies also included children and adolescents. Most studies diagnosed DM based on clinical records, including fasting blood glucose levels or glucose-lowering treatments. The studies did not distinguish between type 1 and type 2 DM; only one study focused on type 1 DM. Diagnosis and exclusion of TB were performed using culture or molecular WHO-recommended rapid diagnostic tests (mWRD) in only 12 studies, which could have biassed the effect estimate. The median follow-up time was five years (interquartile range 1.5 to 10, range 1 to 16.9), and the studies primarily reported an adjusted hazard ratio from a multivariable Cox-proportional hazard model. Hazard Ratios (HR) The HR estimates represent the highest certainty of the evidence, explored through sensitivity analyses and excluding studies at high risk of bias. We present 95% confidence intervals (CI) and prediction intervals, which show between-study heterogeneity represented in measuring the variability of effect sizes (i.e. the interval within which the effect size of a new study would fall considering the same population of studies included in the meta-analysis). DM may increase the risk of tuberculosis disease (HR 1.90, 95% CI 1.51 to 2.40; prediction interval 0.83 to 4.39; 10 studies; 11,713,023 participants). The certainty of the evidence is low, due to a moderate risk of bias across studies and inconsistency. Considering a risk without diabetes of 129 cases per 100,000 population, this represents 102 more (59 to 153 more) cases per 100,000. When stratified by follow-up time, the results are more consistent across < 10 years follow-up (HR 1.52, 95% CI 1.47 to 1.57; prediction interval 1.45 to 1.59; 7 studies; 10,380,872 participants). This results in a moderate certainty of the evidence due to a moderate risk of bias across studies. However, at 10 or more years of follow-up, the estimates yield a wider CI and a higher HR (HR 2.44, 95% CI 1.22 to 4.88; prediction interval 0.09 to 69.12; 3 studies; 1,332,151 participants). The certainty of the evidence is low due to the moderate risk of bias and inconsistency. Odds Ratio (OR) DM may increase the odds of tuberculosis disease (OR 1.61, 95% CI 1.27 to 2.04; prediction interval 0.96 to 2.70; 4 studies; 167,564 participants). Stratification by follow-up time was not possible as all studies had a follow-up < 10 years. The certainty of the evidence is low due to a moderate risk of bias and inconsistency. Risk Ratio (RR) The RR estimates represent the highest certainty of the evidence, explored through sensitivity analyses and excluding studies at high risk of bias. DM probably increases the risk of tuberculosis disease (RR 1.60, 95% CI 1.42 to 1.80; prediction interval 1.38 to 1.85; 6 studies; 44,058,675 participants). Stratification by follow-up time was not possible as all studies had a follow-up < 10 years. The certainty of the evidence is moderate due to a moderate risk of bias. AUTHORS' CONCLUSIONS: Diabetes probably increases the risk of developing TB disease in the short term (< 10 years) and may also increase the risk in the long term (≥ 10 years). As glycaemic control and access to care may be potential effect modifiers of the association between diabetes and the risk of TB disease, the overall estimates should be interpreted with caution when applied locally. Policies targeted at reducing the burden of diabetes are needed to contribute to the aims of ending TB. Large population-based cohorts, including those derived from high-quality national registries of exposures (diabetes) and outcomes (TB disease), are needed to provide estimates with a high certainty of evidence of this risk across different settings and populations, including low- and middle-income countries from different WHO regions. Moreover, studies including children and adolescents and currently recommended methods for diagnosing TB would provide more up-to-date information relevant to practice and policy. FUNDING: World Health Organization (203256442) REGISTRATION: PROSPERO registration: CRD42023408807.

Undernutrition as a risk factor for tuberculosis disease.

BACKGROUND: Tuberculosis (TB) is a leading cause of mortality due to an infectious disease, with an estimated 1.6 million deaths due to TB in 2022. Approximately 25% of the global population has TB infection, giving rise to 10.6 million episodes of TB disease in 2022. Undernutrition is a key risk factor for TB and was linked to an estimated 2.2 million TB episodes in 2022, as outlined in the World Health Organization (WHO) Global Tuberculosis Report. OBJECTIVES: To determine the prognostic value of undernutrition in the general population of adults, adolescents, and children for predicting tuberculosis disease over any time period. SEARCH METHODS: We searched the literature databases MEDLINE (via PubMed) and WHO Global Index Medicus, as well as the WHO International Clinical Trials Registry Platform (ICTRP) on 3 May 2023 (date of last search for all databases). We placed no restrictions on the language of publication. SELECTION CRITERIA: We included retrospective and prospective cohort studies, irrespective of publication status or language. The target population comprised adults, adolescents, and children from diverse settings, encompassing outpatient and inpatient cohorts, with varying comorbidities and risk of exposure to tuberculosis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and the Quality In Prognosis Studies (QUIPS) tool to assess the risk of bias of the studies. Prognostic factors included undernutrition, defined as wasting, stunting, and underweight, with specific measures such as body mass index (BMI) less than two standard deviations below the median for children and adolescents and low BMI scores (< 18.5) for adults and adolescents. Prognostication occurred at enrolment/baseline. The primary outcome was the incidence of TB disease. The secondary outcome was recurrent TB disease. We performed a random-effects meta-analysis for the adjusted hazard ratios (HR), risk ratios (RR), or odds ratios (OR), employing the restricted maximum likelihood estimation. We rated the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 51 cohort studies with over 27 million participants from the six WHO regions. Sixteen large population-based studies were conducted in China, Singapore, South Korea, and the USA, and 25 studies focused on people living with HIV, which were mainly conducted in the African region. Most studies were in adults, four in children, and three in children and adults. Undernutrition as an exposure was usually defined according to standard criteria; however, the diagnosis of TB did not include a confirmatory culture or molecular diagnosis using a WHO-approved rapid diagnostic test in eight studies. The median follow-up time was 3.5 years, and the studies primarily reported an adjusted hazard ratio from a multivariable Cox-proportional hazard model. Hazard ratios (HR) The HR estimates represent the highest certainty of the evidence, explored through sensitivity analyses and excluding studies at high risk of bias. We present 95% confidence intervals (CI) and prediction intervals, which present between-study heterogeneity represented in a measurement of the variability of effect sizes (i.e. the interval within which the effect size of a new study would fall considering the same population of studies included in the meta-analysis). Undernutrition may increase the risk of TB disease (HR 2.23, 95% CI 1.83 to 2.72; prediction interval 0.98 to 5.05; 23 studies; 2,883,266 participants). The certainty of the evidence is low due to a moderate risk of bias across studies and inconsistency. When stratified by follow-up time, the results are more consistent across < 10 years follow-up (HR 2.02, 95% CI 1.74 to 2.34; prediction interval 1.20 to 3.39; 22 studies; 2,869,077 participants). This results in a moderate certainty of evidence due to a moderate risk of bias across studies. However, at 10 or more years of follow-up, we found only one study with a wider CI and higher HR (HR 12.43, 95% CI 5.74 to 26.91; 14,189 participants). The certainty of the evidence is low due to the moderate risk of bias and indirectness. Odds ratio (OR) Undernutrition may increase the odds of TB disease, but the results are uncertain (OR 1.56, 95% CI 1.13 to 2.17; prediction interval 0.61 to 3.99; 8 studies; 173,497 participants). Stratification by follow-up was not possible as all studies had a follow-up of < 10 years. The certainty of the evidence is very low due to the high risk of bias and inconsistency. Contour-enhanced funnel plots were not reported due to the few studies included. Risk ratio (RR) Undernutrition may increase the risk of TB disease (RR 1.95, 95% CI 1.72 to 2.20; prediction interval 1.49 to 2.55; 4 studies; 1,475,867 participants). Stratification by follow-up was not possible as all studies had a follow-up of < 10 years. The certainty of the evidence is low due to the high risk of bias. Contour-enhanced funnel plots were not reported due to the few studies included. AUTHORS' CONCLUSIONS: Undernutrition probably increases the risk of TB two-fold in the short term (< 10 years) and may also increase the risk in the long term (> 10 years). Policies targeted towards the reduction of the burden of undernutrition are not only needed to alleviate human suffering due to undernutrition and its many adverse consequences, but are also an important part of the critical measures for ending the TB epidemic by 2030. Large population-based cohorts, including those derived from high-quality national registries of exposures (undernutrition) and outcomes (TB disease), are needed to provide high-certainty estimates of this risk across different settings and populations, including low and middle-income countries from different WHO regions. Moreover, studies including children and adolescents and state-of-the-art methods for diagnosing TB would provide more up-to-date information relevant to practice and policy. FUNDING: World Health Organization (203256442). REGISTRATION: PROSPERO registration: CRD42023408807 Protocol: https://doi.org/10.1002/14651858.CD015890.

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.

Thermal stability and storage of human insulin.

BACKGROUND: Health authorities stress the temperature sensitivity of human insulin, advising protection from heat and freezing, with manufacturers suggesting low-temperature storage for intact vials, and once opened, storage at room temperature for four to six weeks, though usage time and maximum temperature recommendations vary. For human insulin, the recommendations of current shelf life in use may range from 10 to 45 days, and the maximum temperature in use varies between 25 °C and 37 °C. Optimal cold-chain management of human insulin from manufacturing until the point of delivery to people with diabetes should always be maintained, and people with diabetes and access to reliable refrigeration should follow manufacturers' recommendations. However, a growing segment of the diabetes-affected global population resides in challenging environments, confronting prolonged exposure to extreme heat due to the climate crisis, all while grappling with limited access to refrigeration. OBJECTIVES: To analyse the effects of storing human insulin above or below the manufacturers' recommended insulin temperature storage range or advised usage time, or both, after dispensing human insulin to people with diabetes. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 12 July 2023. SELECTION CRITERIA: We included clinical and laboratory studies investigating the storage of human insulin above or below manufacturers' recommended temperature storage range, advised usage time, or both. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for the clinical study. Most information emerged from in vitro studies, mainly from pharmaceutical companies. There is no validated risk of bias and certainty of evidence rating for in vitro studies. We thus presented a narrative summary of the results. MAIN RESULTS: We included 17 eligible studies (22 articles) and additional information from pharmaceutical companies. Pilot clinical study One pilot clinical study investigated temperature conditions for insulin stored for six weeks in an unglazed clay pot with temperatures ranging between 25 °C and 27 °C. The mean fall in plasma glucose in eight healthy volunteers after clay pot-stored insulin injection was comparable to refrigerator-stored insulin injection (very low-certainty evidence). In-vitro studies Nine, three and four laboratory studies investigated storage conditions for insulin vials, insulin cartridges/pens and prefilled plastic syringes, respectively. The included studies reported numerous methods, laboratory measurements and storage conditions. Three studies on prefilled syringes investigating insulin potency at 4 °C up to 23 °C for up to 28 days showed no clinically relevant loss of insulin activity. Nine studies examined unopened vials and cartridges. In studies with no clinically relevant loss of insulin activity for human short-acting insulin (SAI), intermediate-acting insulin (IAI) and mixed insulin (MI) temperatures ranged between 28.9 °C and 37 °C for up to four months. Two studies reported up to 18% loss of insulin activity after one week to 28 days at 37 °C. Four studies examined opened vials and cartridges at up to 37 °C for up to 12 weeks, indicating no clinically relevant reduction in insulin activity. Two studies analysed storage conditions for oscillating temperatures ranging between 25 °C and 37 °C for up to 12 weeks and observed no loss of insulin activity for SAI, IAI and MI. Four studies, two on vials (including one on opened vials), and two on prefilled syringes, investigated sterility and reported no microbial contamination. Data from pharmaceutical companies Four manufacturers (BIOTON, Eli Lilly and Company, Novo Nordisk and Sanofi) provided previously unreleased human insulin thermostability data mostly referring to unopened containers (vials, cartridges). We could not include the data from Sanofi because the company announced the permanent discontinuation of the production of human insulins Insuman Rapid, Basal and Comb 25. BIOTON provided data on SAI after one, three and six months at 25 °C: all investigated parameters were within reference values, and, compared to baseline, loss of insulin activity was 1.1%, 1.0% and 1.7%, respectively. Eli Lilly and Company provided summary data: at below 25 °C or 30 °C SAI/IAI/MI could be stored for up to 25 days or 12 days, respectively. Thereafter, patient in-use was possible for up to 28 days. Novo Nordisk provided extensive data: compared to baseline, after three and six months at 25 °C, loss of SAI activity was 1.8% and 3.2% to 3.5%, respectively. Loss of IAI activity was 1.2% to 1.9% after three months and 2.0% to 2.3% after six months. Compared to baseline, after one, two and three months at 37 °C, loss of SAI activity was 2.2% to 2.8%, 5.7% and 8.3% to 8.6%, respectively. Loss IAI activity was 1.4% to 1.8%, 3.0% to 3.8% and 4.7% to 5.3%, respectively. There was no relevant increase in insulin degradation products observed. Up to six months at 25 °C and up to two months at 37 °C high molecular weight proteins were within specifications. Appearance, visible particles or macroscopy, particulate matter, zinc, pH, metacresol and phenol complied with specifications. There were no data for cold environmental conditions and insulin pumps. AUTHORS' CONCLUSIONS: Under difficult living conditions, pharmaceutical companies' data indicate that it is possible to store unopened SAI and IAI vials and cartridges at up to 25 °C for a maximum of six months and at up to 37 °C for a maximum of two months without a clinically relevant loss of insulin potency. Also, oscillating temperatures between 25 °C and 37 °C for up to three months result in no loss of insulin activity for SAI, IAI and MI. In addition, ambient temperature can be lowered by use of simple cooling devices such as clay pots for insulin storage. Clinical studies on opened and unopened insulin containers should be performed to measure insulin potency and stability after varying storage conditions. Furthermore, more data are needed on MI, insulin pumps, sterility and cold climate conditions.

Parathyroidectomy for adults with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT), a disorder in which the parathyroid glands produce excessive amounts of parathyroid hormone, is most common in older adults and postmenopausal women. While most people with PHPT are asymptomatic at diagnosis, symptomatic disease can lead to hypercalcaemia, osteoporosis, renal stones, cardiovascular abnormalities and reduced quality of life. Surgical removal of abnormal parathyroid tissue (parathyroidectomy) is the only established treatment for adults with symptomatic PHPT to prevent exacerbation of symptoms and to be cured of PHPT. However, the benefits and risks of parathyroidectomy compared to simple observation or medical therapy for asymptomatic and mild PHPT are not well established. OBJECTIVES: To evaluate the benefits and harms of parathyroidectomy in adults with PHPT compared to simple observation or medical therapy. SEARCH METHODS: We searched CENTRAL, MEDLINE, LILACS, ClinicalTrials.gov and WHO ICTRP from their date of inception until 26 November 2021. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing parathyroidectomy with simple observation or medical therapy for the treatment of adults with PHPT. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. cure of PHPT, 2. morbidity related to PHPT and 3. serious adverse events. Our secondary outcomes were 1. all-cause mortality, 2. health-related quality of life and 3. hospitalisation for hypercalcaemia, acute renal impairment or pancreatitis. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We identified eight eligible RCTs that included 447 adults with (mostly asymptomatic) PHPT; 223 participants were randomised to parathyroidectomy. Follow-up duration varied from six months to 24 months. Of the 223 participants (37 men) randomised to surgery, 164 were included in the analyses, of whom 163 were cured at six to 24 months (overall cure rate 99%). Parathyroidectomy compared to observation probably results in a large increase in cure rate at six to 24 months follow-up: 163/164 participants (99.4%) in the parathyroidectomy group and 0/169 participants in the observation or medical therapy group were cured of their PHPT (8 studies, 333 participants; moderate certainty).  No studies explicitly reported intervention effects on morbidities related to PHPT, such as osteoporosis, osteopenia, kidney dysfunction, urolithiasis, cognitive dysfunction or cardiovascular disease, although some studies reported surrogate outcomes for osteoporosis and cardiovascular disease. A post-hoc analysis revealed that parathyroidectomy, compared to observation or medical therapy, may have little or no effect after one to two years on bone mineral density (BMD) at the lumbar spine (mean difference (MD) 0.03 g/cm2,95% CI -0.05 to 0.12; 5 studies, 287 participants; very low certainty). Similarly, compared to observation, parathyroidectomy may have little or no effect on femoral neck BMD after one to two years (MD -0.01 g/cm2, 95% CI -0.13 to 0.11; 3 studies, 216 participants; very low certainty). However, the evidence is very uncertain for both BMD outcomes. Furthermore, the evidence is very uncertain about the effect of parathyroidectomy on improving left ventricular ejection fraction (MD -2.38%, 95% CI -4.77 to 0.01; 3 studies, 121 participants; very low certainty). Four studies reported serious adverse events. Three of these reported zero events in both the intervention and control groups; consequently, we were unable to include data from these three studies in the pooled analysis. The evidence suggests that parathyroidectomy compared to observation may have little or no effect on serious adverse events (RR 3.35, 95% CI 0.14 to 78.60; 4 studies, 168 participants; low certainty).  Only two studies reported all-cause mortality. One study could not be included in the pooled analysis as zero events were observed in both the intervention and control groups. Parathyroidectomy compared to observation may have little or no effect on all-cause mortality, but the evidence is very uncertain (RR 2.11, 95% CI 0.20 to 22.60; 2 studies, 133 participants; very low certainty). Three studies measured health-related quality of life using the 36-Item Short Form Health Survey (SF-36) and reported inconsistent differences in scores for different domains of the questionnaire between parathyroidectomy and observation. Six studies reported hospitalisations for the correction of hypercalcaemia. Two studies reported zero events in both the intervention and control groups and could not be included in the pooled analysis. Parathyroidectomy, compared to observation, may have little or no effect on hospitalisation for hypercalcaemia (RR 0.91, 95% CI 0.20 to 4.25; 6 studies, 287 participants; low certainty). There were no reported hospitalisations for renal impairment or pancreatitis. AUTHORS' CONCLUSIONS: In accordance with the literature, our review findings suggest that parathyroidectomy, compared to simple observation or medical (etidronate) therapy, probably results in a large increase in cure rates of PHPT (with normalisation of serum calcium and parathyroid hormone levels to laboratory reference values). Parathyroidectomy, compared with observation, may have little or no effect on serious adverse events or hospitalisation for hypercalcaemia, and the evidence is very uncertain about the effect of parathyroidectomy on other short-term outcomes, such as BMD, all-cause mortality and quality of life. The high uncertainty of evidence limits the applicability of our findings to clinical practice; indeed, this systematic review provides no new insights with regard to treatment decisions for people with (asymptomatic) PHPT. In addition, the methodological limitations of the included studies, and the characteristics of the study populations (mainly comprising white women with asymptomatic PHPT), warrant caution when extrapolating the results to other populations with PHPT. Large-scale multi-national, multi-ethnic and long-term RCTs are needed to explore the potential short- and long-term benefits of parathyroidectomy compared to non-surgical treatment options with regard to osteoporosis or osteopenia, urolithiasis, hospitalisation for acute kidney injury, cardiovascular disease and quality of life.

[Linkage of claims data with data from epidemiological cancer registries: possibilities and limitations in the German federal states]. / Verknüpfung von Abrechnungsdaten gesetzlicher Krankenkassen mit Daten epidemiologischer Krebsregister: länderspezifische Möglichkeiten und Limitationen.

BACKGROUND: In recent years, there has been an increasing demand for the reuse of research data in accordance with the so-called FAIR principles. This would allow researchers to conduct projects on a broader data basis and to investigate new research questions by linking different data sources. OBJECTIVES: We explored if nationwide linking of claims data from statutory health insurances (SHI) with data from population-based cancer registries can be used to obtain additional information on cancer that is missing in claims data and to assess the validity of SHI tumour diagnoses. This paper focuses on describing the specific requirements of German federal states for such data linkage. MATERIALS AND METHODS: The Pharmacoepidemiological Research Database GePaRD at the Leibniz Institute for Prevention Research and Epidemiology - BIPS and six cancer registries were used as data sources. The logistically complex direct linkage was compared with a less complex indirect linkage. For this purpose, permission had to be obtained for GePaRD and for each cancer registry from the respective responsible authority. RESULTS: Regarding the linkage of cancer registry data with GePaRD, the cancer registries showed profound differences in the modalities for data provision, ranging from a complete rejection to an uncomplicated implementation of linkage procedures. DISCUSSION: In Germany, a consistent legal framework is needed to adequately enable the reuse and record linkage of personal health data for research purposes according to the FAIR principles. The new law on the consolidation of cancer registry data could provide a remedy regarding the linkage of cancer registry data with other data sources.

Pharmacogenetics of novel glucose-lowering drugs.

The aim of this work was to review studies in which genetic variants were assessed with respect to metabolic response to treatment with novel glucose-lowering drugs: dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). In total, 22 studies were retrieved from the literature (MEDLINE). Variants of the GLP-1 receptor gene (GLP1R) were associated with a smaller reduction in HbA1c in response to DPP-4i. Variants of a number of other genes (KCNQ1, KCNJ11, CTRB1/2, PRKD1, CDKAL1, IL6 promoter region, TCF7L2, DPP4, PNPLA3) have also been related to DPP-4i response, although replication studies are lacking. The GLP1R gene was also reported to play a role in the response to GLP-1 RA, with larger weight reductions being reported in carriers of GLP1R variant alleles. There were variants of a few other genes (CNR1, TCF7L2, SORCS1) described to be related to GLP-1 RA. For SGLT2i, studies have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2) but no relationship between SLC5A2 variants and response to empagliflozin has been found. The relevance of the included studies is limited due to small genetic effects, low sample sizes, limited statistical power, inadequate statistics (lack of gene-drug interactions), inadequate accounting for confounders and effects modifiers, and a lack of replication studies. Most studies have been based on candidate genes. Genome-wide association studies, in that respect, may be a more promising approach to providing novel insights. However, the identification of distinct subgroups of type 2 diabetes might also be necessary before pharmacogenetic studies can be successfully used for a stratified prescription of novel glucose-lowering drugs.

A variant of the glucose transporter gene SLC2A2 modifies the glycaemic response to metformin therapy in recently diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to investigate the modifying effect of the glucose transporter (GLUT2) gene SLC2A2 (rs8192675) variant on the glycaemic response to metformin in individuals recently diagnosed with type 2 diabetes. METHODS: Individuals with type 2 diabetes (n = 508) from the prospective German Diabetes Study (age [mean ± SD] 53 ± 10 years; 65% male; BMI 32 ± 6 kg/m2, metformin use 57%) underwent detailed metabolic characterisation (hyperinsulinaemic-euglycaemic clamp, IVGTT) during the first year after diagnosis. Participants provided self-reported data from the time of diagnosis. The change in fasting glucose was assessed in relation to SLC2A2 genotype and glucose-lowering treatment using two-way ANCOVA with gene×treatment interactions adjusted for age, sex, BMI and diabetes duration. RESULTS: The C variant allele of rs8192675 was associated with a higher prevalence of diabetes symptoms at diabetes diagnosis. In the metformin monotherapy group only, patients with a C allele showed a larger adjusted blood glucose reduction during the first year after diabetes diagnosis than patients with the TT genotype (6.3 mmol/l vs 3.9 mmol/l; genotype difference 2.4 mmol/l, p = 0.02; p value for genotype interaction [metformin monotherapy vs non-pharmacological therapy] <0.01). The greater decline in fasting glucose (CC/CT vs TT) in metformin monotherapy persisted after further adjusting for glucose values at diagnosis (genotype difference 1.0 mmol/l, p = 0.01; genotype×treatment interaction p = 0.06). CONCLUSIONS/INTERPRETATION: The variant rs8192675 in the SLC2A2 gene (C allele) is associated with an improved glucose response to metformin monotherapy during the first year after diagnosis in type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01055093.

Circulating Levels of Interleukin 1-Receptor Antagonist and Risk of Cardiovascular Disease: Meta-Analysis of Six Population-Based Cohorts.

OBJECTIVE: Interleukin (IL)-1ß represents a key cytokine in the development of cardiovascular disease (CVD). IL-1ß is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg). APPROACH AND RESULTS: We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case-cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06-1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (P<0.0001). There was no heterogeneity in effect sizes (I2=0%; P=0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1. CONCLUSIONS: Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.

Neuropathic pain is not adequately treated in the older general population: Results from the KORA F4 survey.

PURPOSE: We evaluated the pharmacological treatment of distal sensorimotor polyneuropathy (DSPN) among older subjects from the general population. METHODS: The study included subjects aged 61 to 82 years from the KORA F4 survey (2006-2008). DSPN was defined as the presence of bilaterally impaired foot-vibration perception and/or bilaterally impaired foot-pressure sensation. Pain intensity was assessed with the painDETECT questionnaire. RESULTS: From the included 1076 older persons, 172 (16%) persons reported pain in the lower extremities and DSPN was present in 150 (14%) subjects. Forty-eight people with pain in the lower extremities reported DSPN. Only 38% of the subjects with DSPN reporting an average pain level of ≥4 during the past 4 weeks received medical treatment, predominantly nonsteroidal anti-inflammatory drugs (NSAIDs 20% and opioids 12%). The medication of choice for neuropathic pain, antidepressants, anticonvulsants, and opioids was relatively being underused. However, opioids and neuropathy preparations were prescribed preferably for subjects with painful DSPN. CONCLUSIONS: In the older general population, only a small proportion of subjects with painful DSPN receive analgesic pharmacotherapy. Although not recommended by guidelines for the treatment of neuropathic pain, NSAIDs were the most frequently used class of analgesic drugs.

Basic characteristics and representativeness of the German Disease Analyzer database
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PURPOSE: The aim of this study was to evaluate the representativeness of diagnoses in the Disease Analyzer (DA) database for major chronic diseases (cancer, dementia, diabetes). MATERIALS AND METHODS: DA contains anonymized longitudinal data on drug prescriptions, diagnoses as well as medical and demographic data directly obtained from the computer system of a representative sample of practices throughout Germany. DA contains data from 2,498 practices with 7.8 million patients (2017). The distribution and sex-specific incidence of various cancer subsites among new cancer cases, the age- and sex-specific prevalence of dementia, and the prevalence of diabetes were assessed. National reference data were obtained from official sources. RESULTS: Mean age (43 years) and sex distribution (47% men) of primary care patients in DA were similar to the German population. Among incident cancer cases, there was good agreement between DA data and national data with respect to the various cancer subsites (e.g., breast cancer: DA 17%; reference: 15%). Furthermore, sex distribution was largely similar. The age distribution of prevalent dementia was similar to national reference data, both in men (80 - 84 years: DA: 26.8%; reference: 27.0%) and in women (80 - 84 years: DA: 24.6%; reference: 24.1%). Diabetes prevalence in the DA (10.7%) was higher than in claims data from physicians (9.8%) or patients from statutory health insurances (9.9%). CONCLUSION: There was a good agreement of the incidence or prevalence of major chronic diseases in the outpatient DA with German reference data. The higher diabetes prevalence in the DA is due to the increased number of outpatient visits of diabetes patients.
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Impact of insulin sensitivity, beta-cell function and glycaemic control on initiation of second-line glucose-lowering treatment in newly diagnosed type 2 diabetes.

AIMS: The aim of this study was to investigate whether insulin sensitivity, beta-cell function or glycaemic control at diagnosis predict initiation of second-line treatment in newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: Type 2 diabetes patients (n = 138) undergoing initial metformin monotherapy (age [mean ± SD], 52 ± 10 years; 67% males; BMI, 32 ± 6 kg/m2 ) from the prospective German Diabetes Study cohort (n = 398) were included. Patients remained under care of their general practitioners, yet underwent detailed metabolic characterization after diabetes diagnosis for study purposes (hyperinsulinemic-euglycemic clamp, M value; i.v. glucose tolerance test, incremental C-peptide area under the curve0-60 minutes, CP iAUC). The associations of baseline M value, CP iAUC, fasting glucose and HbA1c with time to second-line therapy were assessed using parametric survival analysis, accounting for interval-censoring. RESULTS: Second-line treatment was initiated in 26% of newly diagnosed type 2 diabetes patients within the first 3.3 years after diagnosis, using mostly DPP-4 inhibitors or GLP-1 receptor agonists (64%). In age-, sex- and BMI-adjusted survival models, higher baseline HbA1c and fasting glucose values were associated with earlier treatment intensification. Lower baseline M value and C-peptide secretion (CP iAUC) were also related to an earlier initiation of second-line treatment. In the best multivariable model, baseline HbA1c ≥ 7% (hazard ratio, HR; 95% CI: 3.18; 1.35-7.50) and fasting glucose ≥140 mg/dL (HR, 2.45; 95% CI, 1.04-5.78) were associated with shorter time to second-line therapy, adjusting for age, sex and BMI. CONCLUSIONS: Baseline hyperglycaemia is a strong predictor of requirement of early intensification of glucose-lowering therapy in newly diagnosed type 2 diabetes.

High-sensitive troponin T assay for the diagnosis of acute myocardial infarction: an economic evaluation.

BACKGROUND: Delayed diagnosis and treatment of Acute Myocardial Infarction (AMI) has a major adverse impact on prognosis in terms of both morbidity and mortality. Since conventional cardiac Troponin assays have a low sensitivity for diagnosing AMI in the first hours after myocardial necrosis, high-sensitive assays have been developed. The aim of this study was to assess the cost effectiveness of a high-sensitive Troponin T assay (hsTnT), alone or combined with the heart-type fatty acid-binding protein (H-FABP) assay in comparison with the conventional cardiac Troponin (cTnT) assay for the diagnosis of AMI in patients presenting to the hospital with chest pain. METHODS: We performed a cost-utility analysis (quality adjusted life years-QALYs) and a cost effectiveness analysis (life years gained-LYGs) based on a decision analytic model, using a health care perspective in the Dutch context and a life time time-horizon. The robustness of model predictions was explored using one-way and probabilistic sensitivity analyses. RESULTS: For a life time incremental cost of 30.70 Euros, use of hsTnT over conventional cTnT results in gain of 0.006 Life Years and 0.004 QALY. It should be noted here that hsTnT is a diagnostic intervention which costs only 4.39 Euros/test more than the cTnT test. The ICER generated with the use of hsTnT based diagnostic strategy comparing with the use of a cTnT-based strategy, is 4945 Euros per LYG and 7370 Euros per QALY. The hsTnT strategy has the highest probability of being cost effective at thresholds between 8000 and 20000 Euros per QALY. The combination of hsTnT and h-FABP strategy's probability of being cost effective remains lower than hsTnT at all willingness to pay thresholds. CONCLUSION: Our analysis suggests that hsTnT assay is a very cost effective diagnostic tool relative to conventional TnT assay. Combination of hsTnT and H-FABP does not offer any additional economic and health benefit over hsTnT test alone.

Dispensation Patterns of Glucose-Lowering Drugs in Newly Diagnosed Type 2 Diabetes: Routine Data Analysis of Insurance Claims in Germany.

AIMS: To describe dispensation patterns of glucose-lowering drugs in newly diagnosed type 2 diabetes in Germany. MATERIALS AND METHODS: Based on claims data from four statutory health insurances (German Pharmacoepidemiological Research Database,>25 million insurants), all individuals with newly diagnosed type 2 diabetes were identified. Eligible patients had a first diagnosis for type 2 diabetes between January 2012 and December 2016. We analyzed the dispensation patterns of first-line glucose-lowering therapies initiated in the year after diabetes diagnosis and patterns of second-line therapies dispensed one year after first-line treatment. RESULTS: A total of 356,647 individuals with newly diagnosed type 2 diabetes were included (average age [SD]: 63.5 [13.4] years; 49.3% males). Of the 31.6% of individuals who were pharmacologically treated in the year after diagnosis, metformin monotherapy was most frequently dispensed (73.1%), followed by dual therapy of metformin and dipeptidyl peptidase-4 inhibitors (DPP-4is) (6.4%), and monotherapy with DPP-4is (2.9%). From 2012 through 2016, sulfonylurea dispensations were reduced by more than 50%. Dispensations for combination therapies with DPP-4is increased up to 10.6%. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors contributed to 2% of all treatments. After a median of 5 months, 20.0% of individuals on pharmacological therapy initiated second-line glucose-lowering treatment. CONCLUSIONS: Data from German statutory health insurances (2012 to 2016) showed that most individuals with newly diagnosed type 2 diabetes were dispensed metformin monotherapy in line with diabetes care guidelines. A substantial decrease in the use of sulfonylureas was observed after the introduction of DPP-4i and GLP-1 receptor agonists.

Avoiding Time-Related Biases: A Feasibility Study on Antidiabetic Drugs and Pancreatic Cancer Applying the Parametric g-Formula to a Large German Healthcare Database.

PURPOSE: Investigating intended or unintended effects of sustained drug use is of high clinical relevance but remains methodologically challenging. This feasibility study aims to evaluate the usefulness of the parametric g-formula within a target trial for application to an extensive healthcare database in order to address various sources of time-related biases and time-dependent confounding. PATIENTS AND METHODS: Based on the German Pharmacoepidemiological Research Database (GePaRD), we estimated the pancreatic cancer incidence comparing two hypothetical treatment strategies for type 2 diabetes mellitus (T2DM), i.e., (A) sustained metformin monotherapy vs (B) combination therapy with DPP-4 inhibitors after one year metformin monotherapy. We included 77,330 persons with T2DM who started metformin therapy at baseline between 2005 and 2011. Key aspects for avoiding time-related biases and time-dependent confounding were the emulation of a target trial over a 7-year follow-up period and application of the parametric g-formula. RESULTS: Over the 7-year follow-up period, 652 out of the 77,330 study subjects had a diagnosis of pancreatic cancer. Assuming no unobserved confounding, we found evidence that the metformin/DPP-4i combination therapy increased the risk of pancreatic cancer compared to a sustained metformin monotherapy (risk ratio: 1.47; 95% bootstrap CI: 1.07-1.94). The risk ratio decreased in sensitivity analyses addressing protopathic bias. CONCLUSION: While protopathic bias could not fully be ruled out, and computational challenges necessitated compromises in the analysis, the g-formula and target trial emulation proved useful: Self-inflicted biases were avoided, observed time-varying confounding was adjusted for, and the estimated risks have a clear causal interpretation.

Association of persistent organic pollutants with sensorimotor neuropathy in participants with and without diabetes or prediabetes: Results from the population-based KORA FF4 study.

BACKGROUND: Concentrations of persistent organic pollutants (POPs) have been associated with an increased type 2 diabetes (T2D) risk. It remains unclear whether POPs are also associated with the risk of diabetes complications including neuropathy and evidence on this topic is scarce. We aimed to investigate the hypothesis that low-dose background concentrations of POPs were positively associated with distal sensorimotor polyneuropathy (DSPN). METHODS: This cross-sectional study was based on data from the second follow-up (FF4, 2013-2014, N = 2279) of the population-based KORA S4 study (Augsburg, Germany). The study sample consisted of 200 participants, including four groups of 50 persons each with known T2D, prediabetes, newly diagnosed diabetes, and normal glucose tolerance (NGT) based on an oral glucose tolerance test. We analyzed the association of six most abundant serum concentrations of POPs, including polychlorinated biphenyls (PCBs) as well as organochlorine (OC) pesticides, with DSPN by multivariable logistic regression adjusted for age, sex, glycaemic status, body mass index, physical activity, smoking and alcohol consumption. We assessed effect modification by age, sex, glycaemic status and obesity and conducted two-pollutant models to check the robustness of the estimates. RESULTS: For all pollutants, the main models indicated no significant association of having DSPN but pointed to rather decreased odds for DSPN. Two-pollutant models supported these findings, though only the association between the combination of PCB-138 and beta-hexachlorocyclohexane (ß-HCH) (OR: 0.59; 95% CI: 0.35-0.99) with DSPN became significant. No effect modification was found by age, sex, glycaemic status and obesity. CONCLUSION: Low-dose concentrations of POPs were not associated with increased odds of having DSPN in T2D, prediabetes and NGT.

Inappropriate intensification of glucose-lowering treatment in older patients with type 2 diabetes: the global DISCOVER study.

INTRODUCTION: Although individualized target glycated hemoglobin (HbA1c) levels are recommended in older people with type 2 diabetes, studies report high levels of potential overtreatment. We aimed to investigate the proportion of older patients (aged ≥65 years) who potentially received an inappropriately intensive treatment (HbA1c level <7.0% (53.0 mmol/mol)) in a global study. Factors associated with intensive glycemic management and using glucose-lowering medications associated with a high risk of hypoglycemia (high-risk medications (insulin, sulfonylureas, and meglitinides)) were also assessed. RESEARCH DESIGN AND METHODS: DISCOVER is a 3-year observational study program of 15 992 people with type 2 diabetes initiating second-line glucose-lowering therapy in 38 countries. Data were collected at baseline (initiation of second-line therapy) and at 6, 12, and 24 months. Factors associated with an inappropriately intensive treatment or using high-risk medications were assessed using a hierarchical regression model. RESULTS: Of the 3344 older patients with baseline HbA1c data in our analytic cohort, 23.5% received inappropriate treatment intensification. Among those who had follow-up HbA1c data, 55.2%, 54.2%, and 53.5% were inappropriately tightly controlled at 6, 12, and 24 months, respectively, with higher proportions in high-income than in middle-income countries. The proportion of patients receiving high-risk medications was higher in middle-income countries than in high-income countries. Gross national income (per US$5000 increment) was associated with increased odds of inappropriately intensive treatment but with decreased odds of receiving high-risk medications. CONCLUSIONS: A large proportion of older DISCOVER patients received an inappropriately intensive glucose-lowering treatment across the 2 years of follow-up, with substantial regional variation. The use of high-risk medications in these patients is particularly concerning.

Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes.

A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven cluster analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after (model 2) adjustment for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (21%), severe insulin-deficient diabetes (SIDD) (3%), severe insulin-resistant diabetes (SIRD) (9%), mild obesity-related diabetes (32%), and mild age-related diabetes (35%). In model 1, 23 biomarkers showed one or more pairwise differences between subgroups (Bonferroni-corrected P < 0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with one or more of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g., lower CASP8, EN-RAGE, and IL-6 in SIDD vs. all other subgroups, all P < 0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD.

Biomarkers of Inflammation and Glomerular Filtration Rate in Individuals with Recent-Onset Type 1 and Type 2 Diabetes.

CONTEXT: While inflammation has been associated with kidney function in long-standing diabetes, its possible association in newly diagnosed diabetes is unknown. OBJECTIVE: To investigate cross-sectional and prospective associations between biomarkers of inflammation and kidney function in recent-onset diabetes. METHODS: The study included individuals with type 1 and type 2 diabetes with known diabetes duration of <1 year from the German Diabetes Study. Baseline serum concentrations of 74 biomarkers were measured using proximity extension assay technology and their associations with estimated glomerular filtration rate (eGFR) and kidney function decline over 5 years were tested using multiple linear and logistic regression analysis. RESULTS: The cross-sectional analysis included 165 individuals with type 1 diabetes and 291 with type 2 diabetes. Baseline eGFR was higher in type 1 compared with type 2 diabetes (102 ±â€…15 vs 90 ±â€…16 mL/min/1.73 m2; P < 0.0001). After full adjustment for covariates and multiple testing, 7 biomarkers were associated with lower baseline eGFR in type 1 diabetes and 24 were associated with lower baseline eGFR in type 2 diabetes. Among these biomarkers, 6 biomarkers (CD5, CCL23, CST5, IL-10RB, PD-L1, TNFRSF9) were inversely associated with eGFR in both diabetes types. The prospective analysis did not detect associations between inflammatory biomarkers and kidney function decline. No evidence of an interaction between diabetes type and inflammatory biomarkers was found. CONCLUSION: Several biomarkers of inflammation associate with lower baseline eGFR in recent-onset type 1 and type 2 diabetes, but do not associate with kidney function loss during the first 5 years after the diagnosis of diabetes.

Persistent organic pollutants and the incidence of type 2 diabetes in the CARLA and KORA cohort studies.

BACKGROUND: Associations between several persistent organic pollutants (POPs) and type 2 diabetes have been found in humans, but the relationship has rarely been investigated in the general population. The current nested case-control study examined internal exposure to polychlorinated biphenyls (PCB) and pesticides and the incidence of type 2 diabetes among participants of two population-based German cohort studies. METHODS: We retrospectively selected 132 incident cases of type 2 diabetes and 264 age- and sex-matched controls from the CARdiovascular Living and Aging in Halle (CARLA) study (2002-2006, East Germany) and the Cooperative Health Research in the Region of Augsburg (KORA) study (1999-2001, South Germany) based on diabetes status at follow-up examinations in 2007-2010 and 2006-08, respectively (60% male, mean age 63 and 54 years). We assessed the association between baseline POP concentrations and incident diabetes by conditional logistic regression adjusted for cohort, BMI, cholesterol, alcohol, smoking, physical activity, and parental diabetes. Additionally, we examined effect modification by sex, obesity, parental diabetes and cohort. RESULTS: In both cohorts, diabetes cases showed a higher BMI, a higher frequency of parental diabetes, and higher levels of POPs. We observed an increased chance for incident diabetes for PCB-138 and PCB-153 with an odds ratio (OR) of 1.50 (95%CI: 1.07-2.11) and 1.53 (1.15-2.04) per interquartile range increase in the respective POP. In addition, explorative results suggested higher OR for women and non-obese participants. CONCLUSIONS: Our results add to the evidence on diabetogenic effects of POPs in the general population, and warrant both policies to prevent human exposure to POPs and additional research on the adverse effects of more complex chemical mixtures.