The use of composite endpoints in cardiovascular outcome trials for diabetes: A review of 22 randomized clinical trials published since 2008.

AIM: To describe the use of composite endpoints (CEs) in cardiovascular outcome trials (CVOTs) of type 2 diabetes and to evaluate the significance of the individual outcomes included within these CEs from the perspectives of both patients and clinicians. Secondary objectives were to estimate the gradient of treatment effects and events across outcomes. MATERIALS AND METHODS: Eligible studies were randomized controlled trials assessing CV outcomes for patients with diabetes from 2008 and onwards. Trials were identified by searching the reports from the CVOT Summit of the Diabetes & CV Disease EASD (European Association for the Study of Diabetes) Study Group. The individual outcomes comprising the CE were compared for differences in importance for patients and clinicians, proportion of events, and effect size. RESULTS: We included 22 trials randomizing a mean of 8098 patients to an active intervention or a comparator group for an average of 33 months (standard deviation 16). All primary outcomes were CEs, and from a patient perspective there was no gradient of importance across outcomes in 22 of 22 (100%) CEs, while the gradient was small in 22 of 22 (100%) from a clinician perspective. The gradient of effect was moderate to large in 9 of 18 (50%) reporting studies, while assessment of events was available in 15 of 22 studies (68%), finding that three of 15 (20%) had a gradient of effect of more than 5% points between included outcomes. In 10 of 22 (45%) trial reports, the results were not clearly presented as based on a CE. CONCLUSIONS: To avoid misinterpretation, clinicians and regulatory authorities should be careful when interpreting the results of trials, of which the main outcomes are CEs.

Summary of clinical investigation plan for The DIATEC trial: in-hospital diabetes management by a diabetes team and continuous glucose monitoring or point of care glucose testing - a randomised controlled trial.

BACKGROUND: Worldwide, up to 20 % of hospitalised patients have diabetes mellitus. In-hospital dysglycaemia increases patient mortality, morbidity, and length of hospital stay. Improved in-hospital diabetes management strategies are needed. The DIATEC trial investigates the effects of an in-hospital diabetes team and operational insulin titration algorithms based on either continuous glucose monitoring (CGM) data or standard point-of-care (POC) glucose testing. METHODS: This is a two-armed, two-site, prospective randomised open-label blinded endpoint (PROBE) trial. We recruit non-critically ill hospitalised general medical and orthopaedic patients with type 2 diabetes treated with basal, prandial, and correctional insulin (N = 166). In both arms, patients are monitored by POC glucose testing and diabetes management is done by ward nurses guided by in-hospital diabetes teams. In one of the arms, patients are monitored in addition to POC glucose testing by telemetric CGM viewed by the in-hospital diabetes teams only. The in-hospital diabetes teams have operational algorithms to titrate insulin in both arms. Outcomes are in-hospital glycaemic and clinical outcomes. DISCUSSION: The DIATEC trial will show the glycaemic and clinical effects of in-hospital CGM handled by in-hospital diabetes teams with access to operational insulin titration algorithms in non-critically ill patients with type 2 diabetes. The DIATEC trial seeks to identify which hospitalised patients will benefit from CGM and in-hospital diabetes teams compared to POC glucose testing. This is essential information to optimise the use of healthcare resources before broadly implementing in-hospital CGM and diabetes teams. TRIAL REGISTRATION: Prospectively registered at ClinicalTrials.gov with identification number NCT05803473 on March 27th 2023.

Effect of insulin degludec versus insulin glargine U100 on nocturnal glycaemia assessed by plasma glucose profiles in people with type 1 diabetes prone to nocturnal severe hypoglycaemia.

AIM: To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia. MATERIALS AND METHODS: The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia. RESULTS: There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of -4.3% (95% confidence interval [CI] -8.1 to -0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]). CONCLUSION: Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

Flexible inclusion of dialogue about psychosocial aspects of life with type 1 diabetes in routine consultations: A study of a questionnaire-based dialogue tool to promote person-centred support.

AIMS: To explore (1) experiences among people with type 1 diabetes and diabetologists of using a questionnaire-based dialogue tool in routine consultations to identify and address psychosocial challenges and (2) experiences of person-centredness in this group compared with a group who did not use the tool. METHODS: In all, 42 people with type 1 diabetes (mean age 54 years, mean diabetes duration 31 years and 60% women) were interviewed and completed an evaluation questionnaire following a routine consultation with the use of a dialogue tool including PAID-5, WHO-5 and open-ended questions. A comparison group of 42 people with type 1 diabetes attending routine consultations without the use of dialogue tools completed evaluation questionnaires. All consultations were audio recorded. Diabetologists were interviewed after completing all test consultations. Interviews were analysed using thematic text condensation. Evaluation questionnaires were analysed using descriptive statistics, chi square tests and Student's two-sided t-tests. RESULTS: Most participants found questions in the dialogue tool relevant to discuss with the diabetologist, and two-thirds were satisfied with the time spent on that. Experiences of people with type 1 diabetes and diabetologists were related to three pathways: (1) the tool supported valuable conversations with the diabetologist, (2) conversations with the diabetologist were unchanged and (3) the tool derailed conversations. All participants reported high levels of person centredness; however, significantly more in the comparison group reported that the diabetologist made them feel at ease (80 vs. 55%) and discussed and planned specific changes with them (93 vs. 67%). CONCLUSION: A questionnaire-based dialogue tool in consultations can support the discussion of psychosocial issues of people with type 1 diabetes. However, flexible and tailored use of the dialogue tool is crucial as consultations may otherwise be derailed.

Glycemic variability assessed by continuous glucose monitoring in hospitalized patients with community-acquired pneumonia.

BACKGROUND: Glycemic variability (GV) has only been sparsely studied in patients with community-acquired pneumonia (CAP). This study aimed to quantify in-hospital GV in CAP patients, including determining the impact of type 2 diabetes mellitus (T2DM) and glucocorticoid (GC) treatment on GV. METHODS: This is a prospective cohort study of CAP patients (N = 40) with or without T2DM and treated or not with GCs. The primary endpoint was GV measured as glucose standard deviation (SD), coefficient of variation (CV), and postprandial glucose excursions (PPGE) based on continuous glucose monitoring (CGM). Analysis of glucose data was split into daytime and nighttime when possible. RESULTS: Patients included had a mean age of 74 (range 55 to 91) years. SD (95%CI) increased by a factor of 1.93 (1.40 to 2.66) and 2.29 (1.38 to 3.81) in patients with T2DM and not treated with GCs during the daytime and the nighttime, respectively (both P < 0.01), and by a factor of 1.42 (1.04 to 1.97) in patients treated with GCs but without T2DM during the daytime (P = 0.031) compared to patients without T2DM and not treated with GCs. CV (95%CI) increased by 5.1 (0.0 to 10.1) and 8.1 (1.0 to 15.2) percentage points during the daytime and the nighttime, respectively, in patients with T2DM and not treated with GCs compared to patients without T2DM and not treated with GCs (P = 0.046 and P = 0.026, respectively). PPGE (95% CI) increased during lunch by 2.5 (0.7 to 4.3) mmol/L (45 (13 to 77) mg/dL) in patients with T2DM and treated with GCs compared to patients without T2DM and not treated with GCs (P = 0.018). CONCLUSIONS: CAP patients receiving GCs, especially those with T2DM, are at great risk of developing high GV and therefore require clinical attention to mitigate GV. This applies particularly during the daytime. Results support the 1 to 2-h post-lunch screening procedure for glucocorticoid-induced hyperglycemia in patients without diabetes. SD was positively correlated with hospital length of stay.

Factors Influencing Physical Activity Level in Adults With Type 1 Diabetes: A Cross-sectional Study.

OBJECTIVES: Exercise is a recommended component of type 1 diabetes (T1D) treatment because high physical activity levels improve health outcomes. However, many people with T1D do not meet physical activity recommendations. Our aim in this study was to identify factors influencing physical activity levels in people with T1D. METHODS: This questionnaire-based study included adults with T1D from 1 outpatient clinic in the United Kingdom and 2 clinics in Denmark. Exercise characteristics, motivators, and barriers were assessed. Physical activity level was measured using the Saltin-Grimby Physical Activity Level Scale. Respondents were categorized into 3 activity groups: inactive, light active, and moderate-to-vigourous active. RESULTS: Of the 332 respondents, 8.4% rated themselves as inactive, 48% as light active, and 43% as moderate-to-vigourous active. Seventy-eight percent of inactive and light active repondents expressed a desire to become more physically active. Fifty-three percent of respondents had received guidance concerning exercise/physical activity from their diabetes team. Being male and having received guidance were associated with a higher physical activity level. The major motivators for exercising/being physically active were improved mental and physical health and glycemic control, whereas the most frequent barriers were busyness with work/private life and lack of motivation. Worries about glucose excursions, costs, lack of knowledge, and health-related reasons were more prevalent barriers in the least active groups. CONCLUSIONS: This study demonstrated that 78% of inactive and light active respondents reported wishing to become more physically active. Receiving guidance about exercise/physical activity was associated with a higher physical activity level, but only 53% of respondents had received support from their diabetes team.

Risk factors at admission of in-hospital dysglycemia, mortality, and readmissions in patients with type 2 diabetes and pneumonia.

AIMS: In-hospital dysglycemia is associated with adverse outcomes. Identifying patients at risk of in-hospital dysglycemia early on admission may improve patient outcomes. METHODS: We analysed 117 inpatients admitted with pneumonia and type 2 diabetes monitored by continuous glucose monitoring. We assessed potential risk factors for in-hospital dysglycemia and adverse clinical outcomes. RESULTS: Time in range (3.9-10.0 mmol/l) decreased by 2.9 %-points [95 % CI 0.7-5.0] per 5 mmol/mol [2.6 %] increase in admission haemoglobin A1c, 16.2 %-points if admission diabetes therapy included insulin therapy [95 % CI 2.9-29.5], and 2.4 %-points [95 % CI 0.3-4.6] per increase in the Charlson Comorbidity Index (CCI) (integer, as a measure of severity and amount of comorbidities). Thirty-day readmission rate increased with an IRR of 1.24 [95 % CI 1.06-1.45] per increase in CCI. In-hospital mortality risk increased with an OR of 1.41 [95 % CI 1.07-1.87] per increase in Early Warning Score (EWS) (integer, as a measure of acute illness) at admission. CONCLUSIONS: Dysglycemia among hospitalised patients with pneumonia and type 2 diabetes was associated with high haemoglobin A1c, insulin treatment before admission, and the amount and severity of comorbidities (i.e., CCI). Thirty-day readmission rate increased with high CCI. The risk of in-hospital mortality increased with the degree of acute illness (i.e., high EWS) at admission. Clinical outcomes were independent of chronic glycemic status, i.e. HbA1c, and in-hospital glycemic status.

Statistical Packages and Algorithms for the Analysis of Continuous Glucose Monitoring Data: A Systematic Review.

BACKGROUND: Continuous glucose monitoring (CGM) measures glucose levels every 1 to 15 minutes and is widely used in clinical and research contexts. Statistical packages and algorithms reduce the time-consuming and error-prone process of manually calculating CGM metrics and contribute to standardizing CGM metrics defined by international consensus. The aim of this systematic review is to summarize existing data on (1) statistical packages for retrospective CGM data analysis and (2) statistical algorithms for retrospective CGM analysis not available in these statistical packages. METHODS: A systematic literature search in PubMed and EMBASE was conducted on September 19, 2023. We also searched Google Scholar and Google Search until October 12, 2023 as sources of gray literature and performed reference checks of the included literature. Articles in English and Danish were included. This systematic review is registered with PROSPERO (CRD42022378163). RESULTS: A total of 8731 references were screened and 46 references were included. We identified 23 statistical packages for the analysis of CGM data. The statistical packages could calculate many metrics of the 2022 CGM consensus and non-consensus CGM metrics, and 22/23 (96%) statistical packages were freely available. Also, 23 statistical algorithms were identified. The statistical algorithms could be divided into three groups based on content: (1) CGM data reduction (eg, clustering of CGM data), (2) composite CGM outcomes, and (3) other CGM metrics. CONCLUSION: This systematic review provides detailed tabular and textual up-to-date descriptions of the contents of statistical packages and statistical algorithms for retrospective analysis of CGM data.

A Cross-sectional Study on the Impact of Educational Status on Physical Activity Level in Danish and English Adults With Type 1 Diabetes.

OBJECTIVES: Physical activity is associated with improved health in people with type 1 diabetes. However, physical activity level may be associated with socioeconomic status. The primary aim of this study was to investigate the association between education level and physical activity level among people with type 1 diabetes. METHODS: In this cross-sectional study, data on physical activity level (high or low) was measured using the Saltin-Grimby Physical Activity Level Scale, and education level (low, medium, or high) was self-reported. RESULTS: Respondents were recruited from outpatient clinics (Steno Diabetes Centre Aarhus, Denmark; Nordsjællands Hospital, Denmark; or Sheffield Diabetes and Endocrine Centre, United Kingdom), by health-care personnel from September 2019 to July 2021. A total of 324 people with type 1 diabetes were included (54% male, median age 50 years [interquartile range 30-60 years]). Education level was low in 10%, medium in 33%, and high in 57%. A logistic regression analysis, adjusted for age, sex, cohabitation status and nationality, found that a medium vs. high education level was associated with lower odds of a high physical activity level (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.32-0.94, p=0.029), while no association was found for low vs. high education level with high physical activity level (OR 0.56, 95% CI 0.25-1.29, p=0.173). CONCLUSIONS: Medium education level compared with a high education level was associated with a lower level of physical activity in people with type 1 diabetes. Health-care professionals are advised to be attentive of physical activity levels among people with type 1 diabetes.

Corrigendum: Adiponectin as a predictor of mortality and readmission in patients with community-acquired pneumonia: a prospective cohort study.

[This corrects the article DOI: 10.3389/fmed.2024.1329417.].

Adiponectin as a predictor of mortality and readmission in patients with community-acquired pneumonia: a prospective cohort study.

Background: Adiponectin is secreted by adipocytes and is inversely associated with obesity. Given the association between low body mass index (BMI) and higher mortality risk after community-acquired pneumonia (CAP), we hypothesized that high adiponectin levels are associated with a higher risk of adverse clinical outcomes in patients with CAP. Methods: In a prospective cohort study of 502 patients hospitalized with CAP, adiponectin was measured in serum at admission. The associations between adiponectin and clinical outcomes were estimated with logistic regression analyses adjusted for age, sex, and measures of obesity (BMI, waist circumference or body fat percentage). Results: Adiponectin was associated with higher 90-day mortality for each 1 µg/mL increase [OR 1.02, 95% CI (1.00, 1.04), p = 0.048] independent of age and sex. Likewise, adiponectin was associated with a higher risk of 90-day readmission for each 1 µg/mL increase [OR 1.02, 95% CI (1.01, 1.04), p = 0.007] independent of age and sex. The association between adiponectin and 90-day mortality disappeared, while the association with 90-day readmission remained after adjusting for adiposity. Conclusion: Adiponectin was positively associated with mortality and readmission. The association with mortality depended on low body fat, whereas the association with readmission risk was independent of obesity.

Inflammatory and endothelial host responses in community-acquired pneumonia: exploring the relationships with HbA1c, admission plasma glucose, and glycaemic gap-a cross-sectional study.

Introduction: Diabetes is associated with dysregulated immune function and impaired cytokine release, while transient acute hyperglycaemia has been shown to enhance inflammatory cytokine release in preclinical studies. Although diabetes and acute hyperglycaemia are common among patients with community-acquired pneumonia (CAP), the impact of chronic, acute, and acute-on-chronic hyperglycaemia on the host response within this population remains poorly understood. This study investigated whether chronic, acute, and acute-on- chronic hyperglycaemia are associated with distinct mediators of inflammatory, endothelial, and angiogenic host response pathways in patients with CAP. Methods: In a cross-sectional study of 555 patients with CAP, HbA1c, admission plasma (p)-glucose, and the glycaemic gap (admission p-glucose minus HbA1c- derived average p-glucose) were employed as measures of chronic, acute, and acute-on-chronic hyperglycaemia, respectively. Linear regression was used to model the associations between the hyperglycaemia measures and 47 proteins involved in inflammation, endothelial activation, and angiogenesis measured at admission. The models were adjusted for age, sex, CAP severity, pathogen, immunosuppression, comorbidity, and body mass index. Adjustments for multiple testing were performed with a false discovery rate threshold of less than 0.05. Results: The analyses showed that HbA1c levels were positively associated with IL-8, IL-15, IL-17A/F, IL-1RA, sFlt-1, and VEGF-C. Admission plasma glucose was also positively associated with these proteins and GM-CSF. The glycaemic gap was positively associated with IL-8, IL-15, IL-17A/F, IL-2, and VEGF-C. Conclusion: In conclusion, chronic, acute, and acute-on-chronic hyperglycaemia were positively associated with similar host response mediators. Furthermore, acute and acute-on-chronic hyperglycaemia had unique associations with the inflammatory pathways involving GM-CSF and IL-2, respectively.

Management of diabetes and hyperglycaemia in non-intensive care units.

Diabetes and hyperglycaemia are frequent diagnoses in the hospital, and in-hospital hyperglycaemia is associated with adverse clinical outcomes. Insulin is the preferred treatment for in-hospital hyperglycaemia. This review summarises the management of hyperglycaemia in Danish hospitals. In Denmark, sliding-scale insulin is often applied with the addition of basal insulin after 1-2 days with hyperglycaemia which differs from international guidelines recommending a basal-bolus regimen. The optimal non-intensive care unit glucose targets, the safety and efficacy level of non-insulin antidiabetic agents, and continuous glucose monitoring are subjects of further research.

Thyrotoxic periodic paralysis in a Caucasian man without identifiable genetic predisposition: a case report.

BACKGROUND: Thyrotoxic periodic paralysis (TPP) is a rare condition characterized by muscle paralysis, thyrotoxicosis, and hypokalemia. It presents with paralysis of both proximal and distal musculature in upper and lower limbs and may affect respiratory musculature and the cardiac conduction system. Early diagnosis is essential, as the condition is potentially reversible by oral or intravenous potassium treatment, leading to rapid resolution without lasting weakness. Overlooking the diagnosis may result in respiratory failure and cardiac arrhythmias including QT prolongation, Torsades de points, and ventricular arrhythmias. CASE PRESENTATION: A 19-year-old Caucasian man was admitted acutely with paralysis in upper and lower limbs and tachycardia. Over several months, he had experienced anxiousness, sweating more than usual, had daily palpitations, shortness of breath on exertion, and loose stools, and had lost 21 kg over the last year. Initial blood gas showed very low potassium of 1.4 mM, and blood tests showed decreased Thyroid-stimulating hormone (TSH) < 0.01 × 10- 3 IU/L, elevated free thyroxine (fT4) of 63.5 pM (reference interval (RI): 12.0-22.0 pM), and elevated total triiodothyronine (T3) of 8.2 nM (RI: 1.0-2.6 nM). He was diagnosed with TPP and treated with liquid oral potassium chloride (30 mmol every 30 minutes) and propylthiouracil (initial dose of 400 mg followed by 200 mg three times daily). TSH-receptor antibodies (TRAB) and thyroid-peroxidase antibodies (TPO-ab) were highly elevated. Thyroid ultrasound showed a normal-sized gland and color Doppler sonography showed increased vascularity throughout the gland, compatible with Graves' disease. He was discharged on day 4 with a normal potassium level and followed in the outpatient clinic where he received standard care for Graves' disease. Genetic testing using whole-genome sequencing found no genetic variants in genes previously associated with TPP. CONCLUSION: TPP is very rare in Caucasians but more often affects young men in East Asian populations. The case presents a Caucasian man with TPP where genetic testing of CACNA1S, KCNJ18, SCN4A, KCNJ2, KCNE3, and ABCC8 shows no pathogenic variants in genes previously associated with TPP.

The effect of insulin analogs in people with type 1 diabetes at increased risk of severe hypoglycemia.

Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins.

Association of COVID-19 and Development of Type 1 Diabetes: A Danish Nationwide Register Study.

OBJECTIVE: To compare the incidence of type 1 diabetes (T1D) before and during the coronavirus disease 2019 (COVID-19) pandemic and determine whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with T1D development. RESEARCH DESIGN AND METHODS: All Danish residents aged <30 years free of diabetes from 2015 to 2021 were included. Individuals were followed from 1 January 2015 or birth until the development of T1D, the age of 30, the end of the study (31 December 2021), emigration, development of type 2 diabetes, onset of any cancer, initiation of immunomodulating therapy, or development of any autoimmune disease. We compared the incidence rate ratio (IRR) of T1D using Poisson regression models. We matched each person with a SARS-CoV-2 infection with three control individuals and used a cause-specific Cox regression model to estimate the hazard ratio (HR). RESULTS: Among 2,381,348 individuals, 3,579 cases of T1D occurred. The adjusted IRRs for T1D in each quarter of 2020 and 2021 compared with 2015-2019 were as follows: January-March 2020, 1.03 (95% CI 0.86; 1.23); January-March 2021, 1.01 (0.84; 1.22), April-June 2020, 0.98 (0.80; 1.20); April-June 2021, 1.34 (1.12; 1.61); July-September 2020, 1.13 (0.94; 1.35); July-September 2021, 1.21 (1.01; 1.45); October-December 2020, 1.09 (0.91; 1.31); and October-December 2021, 1.18 (0.99; 1.41). We identified 338,670 individuals with a positive SARS-CoV-2 test result and matched them with 1,004,688 control individuals. A SARS-2-CoV infection was not significantly associated with the risk of T1D development (HR 0.90 [95% CI 0.60; 1.35]). CONCLUSIONS: There was an increase in T1D incidence during April-June 2021 compared with April-June 2015-2019, but this could not be attributed to SARS-CoV-2 infection.

Diabetes Status, c-Reactive Protein, and Insulin Resistance in Community-Acquired Pneumonia-A Prospective Cohort Study.

C-reactive protein (CRP) is commonly used to guide community-acquired pneumonia (CAP) treatment. A positive association between admission glucose and CRP levels has been observed in patients with CAP. The associations between prediabetes, unknown diabetes, acute-on-chronic hyperglycaemia, and CRP levels, and between admission CRP levels and insulin resistance (IR) in CAP, remain unexplored. This study investigated the associations firstly between chronic, acute, and acute-on-chronic hyperglycaemia and CRP levels, and secondly between admission CRP levels and IR in CAP. In a prospective cohort study of adults with CAP, the associations between chronic, acute, and acute-on-chronic hyperglycaemia (admission glucose minus HbA1c-derived average glucose) and CRP levels until admission day 3 were modelled with repeated-measures linear mixed models. IR was estimated with the homeostasis model assessment of IR (HOMA-IR). The association between admission CRP levels and HOMA-IR was modelled with linear regression. In 540 patients, no association between chronic, acute, or acute-on-chronic hyperglycaemia and CRP levels was found. In 266 patients, every 50 mg/L increase in admission CRP was associated with a 7% (95% CI 1-14%) higher HOMA-IR. In conclusion, our findings imply that hyperglycaemia does not influence CRP levels in patients with CAP, although admission CRP levels were positively associated with IR.

A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design.

BACKGROUND: Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. METHODS/DESIGN: The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. DISCUSSION: In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996.