Eliminating exogenous insulin therapy in patients with type 2 diabetes by duodenal ablation and GLP-1RA decreases risk scores for cardiovascular events.

INTRODUCTION: Duodenal Mucosal Resurfacing (DMR) is an endoscopic ablation technique aimed at improving glycaemia and metabolic health in patients with type 2 diabetes mellitus (T2DM). DMR has an insulin sensitizing effect in patients with T2DM. Reducing hyperinsulinemia can improve cardiovascular health. In the INSPIRE trial, we combined a single DMR with a glucagon-like-peptide-1 receptor agonist (GLP-1RA) and demonstrated elimination of insulin treatment in 69% of patients at 6 months and 53% of patients at 18 months while improving glycaemic control and metabolic health. We hypothesized that this treatment approach is associated with improved cardiovascular health, by reducing hyperinsulinemia. METHODS: Before and 6 months after starting the combination treatment to replace insulin, the following assessments were performed to evaluate cardiovascular health: magnetic resonance imaging (MRI) to measure abdominal visceral adipose tissue volume, ambulatory 24 h blood pressure (ABPM) analysis, postprandial insulin and triglycerides, fasting lipid panel and urine microalbumin. The Atherosclerotic Cardiovascular Disease (ASCVD) score was calculated to estimate 10-year risk of cardiovascular disease or stroke and the diabetes lifetime-perspective prediction (DIAL) score was calculated to estimate years free of cardiovascular disease. RESULTS: Six months after replacing exogenous insulin by DMR and GLP-1RA, visceral adipose tissue decreased significantly by 24%. Postprandial triglyceride and insulin concentrations decreased significantly (p < 0.001), as did total cholesterol (from median 3.64 (IQR 3.34-4.89) to 3.48 (3.18-3.97) mmol/l, p = 0.008), LDL (from median 1.92 (IQR 1.49-2.30) to 1.79 (1.49-2.08 mmol/l, p = 0.044), and urine microalbumin (from median 7 (IQR 3-27) to 4 (3-8) mg/l, p = 0.018). All daytime blood pressure values decreased significantly. The ASCVD 10-year risk score decreased (from median 13.6 (IQR 5.7-26.0) to 11.5 (4.2-22.5) %, p = 0.030)) and the DIAL score increased (from median 82 (IQR 81-83) to 83 (81-84) years, (p = 0.039)). DISCUSSION: The combination of DMR and GLP-1RA to replace insulin therapy in patients with T2DM is associated with a positive effect on multiple parameters of cardiovascular health. Taken together, they show a pattern of overall improvement in cardiovascular health, as evidenced by decreased risk scores for cardiovascular complications. However, it is not yet clear whether these improvements will translate into a true reduction in cardiovascular events.

Cocoon vaccination for influenza in patients with a solid tumor: a retrospective study.

PURPOSE: Oncological patients are susceptible to various severe viral infections, including influenza. Vaccinating oncological patients and their household contacts ("cocoon vaccination") may protect these patients from contracting influenza. To understand the potential of cocoon vaccination in oncological patients, this study assesses the influenza vaccination status of oncological patients and their household contacts and their considerations regarding the vaccination. METHODS: In this retrospective study, oncological patients with a solid tumor were asked to fill in a questionnaire about their own and their household contacts' influenza vaccination status in the influenza season of 2018-2019. RESULTS: Ninety-eight patients were included (response rate 88%). The influenza vaccination rates of oncological patients and their first household contacts were 43.9% and 44.9%, respectively. The majority of vaccinated patients and vaccinated first household contacts had been advised by their general practitioner to get the vaccination. A minority of the first household contacts reported getting vaccinated specifically because of the patient's vulnerability. Unvaccinated patients and unvaccinated household contacts mainly believed the vaccination was unnecessary or were afraid of side effects. None of the included patients had been hospitalized with influenza. CONCLUSION: The oncological patients' and first household contacts' vaccination rates in this study were lower than the vaccination rates of the general Dutch population of over 60 years old, possibly due to a lack of knowledge and misconceptions about the vaccination. Further research is required to establish whether cocoon vaccination can contribute to protecting oncological patients from contracting an influenza infection.

Individual and partner's level of occupation and the association with HbA1c levels in people with Type 2 diabetes mellitus: the Dutch Diabetes Pearl cohort.

AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

¹8F-FDG PET/CT in inflammation of unknown origin: a cost-effectiveness pilot-study.

PURPOSE: Patients with increased inflammatory parameters, nonspecific signs and symptoms without fever and without a diagnosis after a variety of diagnostic procedures are a diagnostic dilemma and are referred to as having inflammation of unknown origin (IUO). The objective of this pilot study was to compare the cost-effectiveness of a diagnostic work-up/strategy with and without (18)F-FDG PET/CT in patients with IUO using a published dataset as a reference. METHODS: IUO patients without (18)F-FDG PET/CT (group A, 46 patients) and IUO patients referred for (18)F-FDG PET/CT (group B, 46 patients) were selected. IUO was defined as the combination of nonspecific signs and symptoms and a prolonged erythrocyte sedimentation rate (ESR), defined as ≥age/2 in men and ≥(age + 10)/2 in women (ESR in millimetres per hour and age in years), and/or C-reactive protein (CRP) ≥15 mg/l. The costs of all tests and procedures and the number of hospitalization days in each patient to reach a diagnosis were calculated using current Dutch tariffs. RESULTS: In group A a diagnosis was reached in 14 of the 46 patients. The mean cost per patient of all the diagnostic procedures was 2,051, and including the cost of hospitalization was 12,614. In group B a diagnosis was reached in 32 of the 46 patients. The mean cost per patient of all the diagnostic procedures was 1,821, significantly lower than in group A (p < 0.0002), and including the cost of hospitalization was 5,298. CONCLUSION: In IUO (18)F-FDG PET/CT has the potential to become a cost-effective routine imaging technique indicating the direction for further diagnostic decisions thereby allowing unnecessary, invasive and expensive diagnostic investigations to be avoided and possibly the duration of hospitalization to be reduced. However, a prospective multicentre "bottom-up microcosting" cost-effectiveness study is warranted before these preliminary data can be extrapolated to clinical practice.

Factors that drive insulin-dosing decisions of diabetes care providers: a vignette-based study in the Netherlands.

AIM: To test how certain patient factors would influence the decision of Dutch care providers regarding insulin dose adjustments. We hypothesize that some of these decisions would diverge from recent evidence and consensus statements. METHODS: We developed narrative vignettes describing clinical scenarios of patients receiving basal insulin therapy. For each vignette, the respondents were asked to indicate whether they would advise a change in insulin dose. A total of 520 paper questionnaires were distributed among physicians and nurses in primary and secondary care in the Netherlands. Multivariate linear and logistic regression analyses were performed to identify factors associated with dosing decisions. RESULTS: A total of 190 (37%) questionnaires were returned. In cases of a severe rather than mild hypoglycaemic event, care providers were nearly five times more likely to decrease the dose (odds ratio 4.77, 95% CI 1.65-13.75). Care providers were six times more likely to increase the dose when the patient's current dose was low (30 units) rather than high (90 units) (odds ratio 6.38, 95% CI 3.04-13.37). The plasma glucose concentration during a hypoglycaemic event and a known history of cardiovascular disease did not influence the care providers' dosing decisions. CONCLUSION: Evidence regarding the optimum insulin titration is not always translated into clinical practice. When formulating guidelines, misconceptions should be identified and addressed.

Effects of sitagliptin on counter-regulatory and incretin hormones during acute hypoglycaemia in patients with type 1 diabetes: a randomized double-blind placebo-controlled crossover study.

AIMS: To assess whether the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin affects glucagon and other counter-regulatory hormone responses to hypoglycaemia in patients with type 1 diabetes. METHODS: We conducted a single-centre, randomized, double-blind, placebo-controlled, three-period crossover study. We studied 16 male patients with type 1 diabetes aged 18-52 years, with a diabetes duration of 5-20 years and intact hypoglycaemia awareness. Participants received sitagliptin (100 mg/day) or placebo for 6 weeks and attended the hospital for three acute hypoglycaemia studies (at baseline, after sitagliptin treatment and after placebo). The primary outcome was differences between the three hypoglycaemia study days with respect to plasma glucagon responses from the initialization phase of the hypoglycaemia intervention to 40 min after onset of the autonomic reaction. RESULTS: Sitagliptin treatment significantly increased active levels of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. No significant differences were observed for glucagon or adrenergic counter-regulatory responses during the three hypoglycaemia studies. Growth hormone concentration at 40 min after occurrence of autonomic reaction was significantly lower after sitagliptin treatment [median (IQR) 23 (0.2-211.0) mEq/l] compared with placebo [median (IQR) 90 (8.8-180) mEq/l; p = 0.008]. CONCLUSIONS: Sitagliptin does not affect glucagon or adrenergic counter-regulatory responses in patients with type 1 diabetes, but attenuates the growth hormone response during late hypoglycaemia.

The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis.

Patients with type 2 diabetes mellitus using sulfonylurea derivatives or insulin may experience hypoglycaemia. However, recent data regarding the incidence of hypoglycaemia are scarce. We conducted a systematic review and meta-analysis to determine the proportion of patients with type 2 diabetes mellitus that experience hypoglycaemia when treated with sulfonylurea or insulin. We searched MEDLINE and EMBASE for randomized controlled trials that compared incretin-based drugs to sulfonylureas or insulin and assessed hypoglycaemia incidence in the latter therapies. Subgroup and meta-regression analyses were performed to study possible associations with potential risk factors for hypoglycaemia. Data of 25 studies were extracted, 22 for sulfonylurea and 3 for insulin. Hypoglycaemia with glucose ≤3.1 mmol/L or ≤2.8 mmol/L was experienced by 10.1% [95% confidence interval (CI) 7.3-13.8%] and 5.9% (95% CI 2.5-13.4%) of patients with any sulfonylurea treatment. Severe hypoglycaemia was experienced by 0.8% (95% CI 0.5-1.3%) of patients. Hypoglycaemia with glucose ≤3.1 mmol/L and severe hypoglycaemia occurred least frequently with gliclazide: in 1.4% (95% CI 0.8-2.4%) and 0.1% (95% CI 0-0.7%) of patients, respectively. None of the risk factors were significant in a stepwise multivariate meta-regression analysis. Too few studies had insulin as comparator, so these data could not be meta-analysed. The majority of patients with type 2 diabetes mellitus on sulfonylurea therapy in clinical trials remain free of any relevant hypoglycaemia. Gliclazide was associated with the lowest risk of hypoglycaemia. Because participants in randomized controlled trials differ from the general population, care should be taken when translating these data into clinical practice.

Physical characteristics that predict final basal insulin dose in type 2 diabetes mellitus, with a special focus on BMI.

BACKGROUND AND AIMS: The possibility to predict final insulin dose based on patient's characteristics would allow for efficient titration for patients with higher dose needs. The primary aim of this post-hoc analysis of the L2T3 study was to determine predictors for final dose. Specifically, we focused on the relationship between BMI and dose. The secondary aims were to investigate (i) the predictive value of BMI and age on final dose and (ii) the possibility to tailor the starting dose of insulin based on BMI and age. METHODS AND RESULTS: We performed two stepwise regression analyses, one using all baseline characteristics, and one using physical characteristics and FPG which can be assessed "at the bedside" only. Furthermore, median [min, max] final doses of groups stratified according to BMI and age were calculated. BMI clearly correlated with final dose in IU (Pearson correlation 0.42 [0.37; 0.48], p < 0.001). Characteristics which can be assessed "at the bedside" that predict high final dose were allocation to detemir, absence or discontinuation of insulin secretagogues, high BMI, low age, male gender and high FPG. Final dose varied among strata (BMI ≥30 kg/m(2): 64 IU; BMI <30 kg/m(2): 38 IU, p < 0.001 and age <59 years: 52 IU; age ≥59 years: 44 IU, p < 0.001). All groups stratified for both BMI and age showed similarly low minimal final dose (5-17 IU). CONCLUSION: Our data showed a high predictive value of BMI on final dose. However, it does not seem possible to tailor starting dose based on BMI and age.

Cold-induced activity of brown adipose tissue in young lean men of South-Asian and European origin.

AIMS/HYPOTHESIS: South Asians have a disproportionately high risk of developing abdominal obesity, insulin resistance and type 2 diabetes. Brown adipose tissue (BAT) has been identified as a possible target to fight obesity and protect against metabolic disturbance. We explored whether lower BAT activity in South Asians compared with Europids may contribute to the high risk of metabolic disturbance. METHODS: We studied 20 healthy men (ten Europids/ten South Asians, BMI 19-25 kg/m(2), age 18-32 years). Following 2 h of cold exposure (16-18°C) after an overnight fast, (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomography-computed tomography (CT) and (123)I-metaiodobenzylguanidine ((123)I-MIBG) single-photon emission computed tomography-CT were performed to visualise metabolic BAT activity and sympathetic stimulation of BAT. Metabolic BAT activity was defined as maximal standardised uptake value (SUV(max)) of (18)F-FDG, and sympathetic stimulation of BAT as semiquantitative uptake value (SQUV) of (123)I-MIBG. We performed hyperinsulinaemic-euglycaemic clamps to assess insulin sensitivity. Spearman's correlations for SUV(max) of (18)F-FDG and both SQUV of (123)I-MIBG and insulin sensitivity were determined. RESULTS: The median (interquartile range) SUV(max) of (18)F-FDG in South Asians (7.5 [2.2-10.6] g/ml) was not different from the median SUV(max) obtained in Europids (4.5 [2.2-8.4] g/ml; p = 0.59). There was no correlation between BAT activity and insulin sensitivity. Correlations between SQUV of (123)I-MIBG and SUV(max) of (18)F-FDG were positive, both in the total population (ρ = 0.80, p < 0.001) and after stratification by ethnicity (Europids, ρ = 0.65, p = 0.04; South Asians, ρ = 0.83, p = 0.01). CONCLUSIONS/INTERPRETATION: This is the first study to prospectively investigate ethnic differences in metabolic BAT activity during cold exposure. We did not find differences in BAT activity between South Asians and Europids. Therefore, it seems unlikely that BAT plays an important role in the development of unfavourable metabolic profiles in South Asians.

The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus.

Obesity and type 2 diabetes mellitus (T2DM) are attributed to a combination of genetic susceptibility and lifestyle factors. Their increasing prevalence necessitates further studies on modifiable causative factors and novel treatment options. The gut microbiota has emerged as an important contributor to the obesity--and T2DM--epidemic proposed to act by increasing energy harvest from the diet. Although obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota, the pathophysiological processes remain only partly understood. In this review we will describe the development of the adult human microbiome and discuss how the composition of the gut microbiota changes in response to modulating factors. The influence of short-chain fatty acids, bile acids, prebiotics, probiotics, antibiotics and microbial transplantation is discussed from studies using animal and human models. Ultimately, we aim to translate these findings into therapeutic pathways for obesity and T2DM in humans.

The longitudinal association between glycaemic control and health-related quality of life following insulin therapy optimisation in type 2 diabetes patients. A prospective observational study in secondary care.

PURPOSE: To test whether improvement in glycosylated haemoglobin (HbA(1c)) as a marker of glycaemic control, following intensifying insulin therapy, is associated with improvements in HRQoL. METHODS: Dutch sub-optimally controlled (HbA(1c) > 7%) type 2 diabetes patients (N = 447, mean age 59 ± 11) initiated insulin glargine therapy. Data were collected at baseline, 3 and 6 months, and included HbA(1c) and measures of HRQoL: diabetes symptom distress (Diabetes Symptom Checklist-revised; DSC-r), fear of hypoglycaemia (Hypoglycaemia Fear Survey; HFS-w) and emotional well-being (WHO-5 wellbeing index). RESULTS: HbA(1c) decreased from 8.8 ± 1.4% to 8.0 ± 1.2% and 7.7 ± 1.3% at 3 and 6 months follow-up, respectively (P < 0.001), DSC-r score improved from 17.7 ± 14.7 to 14.3 ± 13.3 and 13.6 ± 13.3 (P < 0.001). HFS-w score did not significantly change. WHO-5 score increased from 56 ± 23 to 62 ± 23 and 65 ± 22 P < 0.001). A modest, significant association was found between HbA(1c) and WHO-5 score (B = -1.8, 95% CI: -2.7 to -0.8) and HbA1c and DSC-r score (B = 1.0, 95% CI: 0.4 to 1.6). No such association was found for HFS-w score. CONCLUSIONS: An association between improvement in HbA(1c) by means of optimising insulin therapy and improvement in HRQoL in type 2 diabetes patients has been observed. A weak, yet significant longitudinal association was found between improved HbA(1c) and emotional well-being and diabetes symptom distress.

Safety of a web-based insulin titration system for patients with type 2 diabetes mellitus - pilot study.

The treatment of type 2 diabetes patients with insulin requires active dose titration to obtain optimal glycemic control. We developed a web-based decision support system to guide patients in performing the titration task autonomously, at their homes. The system is based on a clinically validated algorithm. The aim of this study was to test the safety of the system in a pilot implementation in clinical practice. Patients were blinded from the advice given by the system and instead received insulin dosing advice given by caregivers. At the end of the pilot, advice of the system were evaluated on safety by an expert panel. In this pilot study six patients used the web-based system at their home. In total, 48 advice were logged in the system resulting in eighteen deviating systems dosing advice as compared to the advice of the caregiver. Evaluation of the eighteen deviating systems advice lead to the detection of one unsafe advice indicating a need to extend the algorithm with an additional safety decision rule.

Initiation of insulin glargine in patients with Type 2 diabetes in suboptimal glycaemic control positively impacts health-related quality of life. A prospective cohort study in primary care.

AIMS: To study prospectively the impact of initiating insulin glargine in suboptimally controlled insulin-naïve patients with Type 2 diabetes on health-related quality of life in relation to glycaemic control. METHODS: Insulin-naïve Dutch patients with Type 2 diabetes in suboptimal glycaemic control (HbA(1c) > 53 mmol/mol; 7%) on maximum dose of oral glucose-lowering medications were included from 363 primary care practices (n = 911). Patients started insulin glargine and were followed up for 6 months. At baseline (start insulin therapy), 3 and 6 months, HbA(1c) was measured and patients completed self-report health-related quality of life measures, including emotional well-being (World Health Organization-5 well-being index), fear of hypoglycaemia (Hypoglycaemia Fear Survey) and diabetes symptom distress (Diabetes Symptom Checklist-revised). Data were analysed using generalized estimating equations analysis. RESULTS: HbA(1c) (mmol/mol; %) decreased from 69 ± 16; 8.5 ± 1.7 to 60 ± 11; 7.6 ± 1.0 and 57 ± 11; 7.3 ± 1.0 at 3 and 6 months, respectively (P < 0.001). Pre-insulin BMI (kg/m(2) ) was 30 ± 5.7, which remained stable at 3 months (30 ± 5.8) and increased to 31 ± 5.9 at 6 months (P = 0.004); no significant changes in self-reported symptomatic and severe hypoglycaemia were observed, while nocturnal hypoglycaemia slightly decreased. The Hypoglycaemia Fear Survey score decreased from 14.6 ± 16.2 to 12.1 ± 15.2 and 10.8 ± 14.4 at 3 and 6 months, respectively (P < 0.001). The Diabetes Symptom Checklist-revised score decreased from 15 ± 14 to 10 ± 12 and 10 ± 13 (P < 0.001), with most pronounced reductions in hyperglycaemic symptoms and fatigue. The World Health Organization-5 score increased from 57 ± 25.3 to 65 ± 21.6 at 3-month follow-up and 67 ± 21.8 at 6-month follow-up (P < 0.001). CONCLUSIONS: Results of this observational study demonstrate combined glycaemic and health-related quality of life benefits of initiating insulin glargine in patients with Type 2 diabetes in routine primary care.

The association of physical inactivity with Type 2 diabetes among different ethnic groups.

AIMS: To study differences in the association between physical inactivity and Type 2 diabetes among subjects from different ethnic groups. METHODS: We analysed data on 508 Caucasian, 596 African-Surinamese and 339 Hindustani-Surinamese participants, aged 35-60 years, in the population-based, cross-sectional Surinamese in the Netherlands Study on Health and Ethnicity (SUNSET) study. Physical inactivity was defined as the lowest quartile of reported activity, measured with the validated Short Questionnaire to Assess Health-Enhancing Physical Activity. Type 2 diabetes was defined as fasting plasma glucose levels ≥7.0 mmol/l or self-reported diagnosis. RESULTS: Physical inactivity was associated with Type 2 diabetes (OR 1.63, 95% CI 1.12-2.38) in the total group after adjustment for sex, age, BMI, ethnicity, resting heart rate, hypertension, smoking, history of cardiovascular disease, having a first-degree relative with Type 2 diabetes and educational level. However, this association was only significant in Caucasians (OR 3.17, 95% CI 1.37-7.30). Moreover, it appeared stronger in Caucasians than in Hindustani-Surinamese (OR 1.43, 95% CI 0.78-2.63) and African-Surinamese (OR 1.13, 95% CI 0.58-2.19), although the P-value for interaction was not significant. CONCLUSIONS: Physical inactivity was associated with Type 2 diabetes in the total group after adjustment for multiple risk factors, but this association was only significant in Caucasians. Also, it appeared stronger in Caucasians than in Hindustani and African-Surinamese, but formal testing for interaction provided no further evidence. These findings confirm the importance of exercise, but suggest that potential health gain may differ between ethnic groups. However, it should be noted that, in general, promotion of physical activity in populations with an increased a priori risk of Type 2 diabetes, remains of the utmost importance.

Development of a web-based decision support system for insulin self-titration.

Insulin is the most potent agent for the treatment of diabetes mellitus. However insulin treatment requires frequent evaluation of blood glucose levels and adjustment of the insulin dose. This process is called titration. To guide patients with type 2 diabetes using once-daily long-acting insulin, we have developed a web-based decision support system for insulin self-titration. The purpose of this paper is to provide an overview of the phases of development and the final design of the system. We reviewed the literature, consulted an expert panel, and conducted interviews with patients to elicit system requirements. This revealed four important aspects: the insulin titration algorithm, the handling of hypoglycemic events, telemedicine functionalities, and visiting frequency monitoring. We used these requirements to develop a fully functional system.

The environment within: how gut microbiota may influence metabolism and body composition.

Obesity, diabetes and consequently atherosclerotic vascular disease have become major health and public health issues worldwide. The increasing and staggering prevalence of obesity might not only be explained by nutritional habits or the reduction of energy expenditure through decreased physical activity. In addition, recent studies have focused on intestinal microbiota as environmental factors that increase energy yield from diet, regulate peripheral metabolism and thereby increase body weight. Obesity is associated with substantial changes in composition and metabolic function of gut microbiota, but the pathophysiological processes driving this bidirectional relationship have not been fully elucidated. This review discusses the relationships between the following: composition of gut microbiota, energy extracted from diet, synthesis of gut hormones involved in energy homeostasis, production of butyrate and the regulation of fat storage.

Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties. METHODS: Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TER(alb)) and hyaluronan catabolism were assessed as measures of vascular permeability. RESULTS: Both sublingual dimensions (0.64 [0.57-0.75] µm vs 0.78 [0.71-0.85] µm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] µm vs 8.89 [4.74-11.84] µm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TER(alb) was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] µm and to 5.88 [5.33-6.26] µm, respectively, p < 0.05). In line, a trend towards TER(alb) normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group. CONCLUSION/INTERPRETATION: Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk. TRIAL REGISTRATION: www.trialregister.nl NTR780/ http://isrctn.org ISRCTN82695186 FUNDING: An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037).

Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes.

We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2 diabetes inadequately controlled on oral agents (including metformin) were randomized to insulin glargine or detemir. Secretagogues were stopped or maintained at the site-investigators' discretion. During the study, 57.6% of patients continued their secretagogue treatment. Compared with patients stopping secretagogues, those who continued experienced significantly more hypoglycaemia and weight gain. Insulin doses, however, were significantly lower: 0.6 ± 0.4 versus 0.8 ± 0.4 U/kg/day (p < 0.001). The difference between groups in mean HbA1c reduction was not statistically significant. In conclusion, in type 2 diabetic patients starting basal insulin analogue therapy, continuing both metformin and secretagogues results in more hypoglycaemia and weight gain and lower insulin doses than only maintaining metformin.

A healthcare failure mode and effect analysis to optimise the process of blood culture performance.

BACKGROUND: Blood cultures are essential diagnostic tools to identify pathogens in systemic infections. However, logistics of blood culture performance is often suboptimal. This study analyses the pre-analytic phase of blood culture processing through different types of risk assessments. METHODS: We performed direct observations to gain in-depth knowledge of the root causes of suboptimal blood culture performance. These findings were summarised in a Bow-Tie chart. We then utilised a healthcare failure mode and effect analysis to prioritise failures per step in the process and to organise improvement activities. Finally, improvement actions were planned. RESULTS: Not obtaining a second set of blood cultures in the logistics of blood culture performance had the highest priority for action. Several failure modes, including human and system factors, were identified. Improvement actions included training and clinical lessons for nurses in the emergency department, updating hospital search engines to ease identification of relevant protocols, and an evaluation of the workload at the emergency department. Failure modes caused by human factors appear easy to address, however changing human behaviour is challenging. CONCLUSIONS: The analysis provided useful insight into the different steps in the logistics of blood culture performance and facilitated the organisation of actions focused on addressing the most urgent root causes.

Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia.

AIMS/HYPOTHESIS: The aim of this analysis was to quantify the relationship between the frequency of hypoglycaemia and various glucose cut-off points for the definition of hypoglycaemia, within a range of HbA(1c) strata. METHODS: Data from two trials examining insulin glargine dose titration in 12,837 type 2 diabetic participants starting insulin therapy were combined. Curves for hypoglycaemia frequency plotted against endpoint HbA(1c) level were constructed, using a range of glucose cut-off points for hypoglycaemia. RESULTS: During the 12-week study period, 3,912 patients recorded 21,592 hypoglycaemic episodes, comprising 242 severe, 8,871 symptomatic and 12,479 asymptomatic events, corresponding to hypoglycaemia event rates of 0.10, 3.8 and 5.3 events per patient year. Increasing the hypoglycaemia cut-off point from, for instance, <3.1 to <3.9 mmol/l more than doubled the percentage of affected patients, e.g. from 17.7 to 43.3% at HbA(1c) 7.0-7.2%. At higher hypoglycaemia cut-off points the proportion of patients having only asymptomatic hypoglycaemia increased, e.g. from 30.7% at <3.1 mmol/l to 61.7% of patients at a cut-off point of <3.9 mmol/l. In sensitivity analysis, 121 of 1,756 patients with at least one self-monitored blood glucose value <3.1 mmol/l experienced severe hypoglycaemia, compared with 149 of 3,912 patients with a self-monitored blood glucose level of <3.9 mmol/l. Thus, to identify 28 more patients with severe hypoglycaemia, the number of patients experiencing only non-severe hypoglycaemia more than doubled. CONCLUSIONS/INTERPRETATION: The glucose cut-off point defining hypoglycaemia greatly affects the reported frequency of hypoglycaemia. When hypoglycaemia is to be defined by a predetermined glucose level, to have clinical relevance the cut-off should be set at a lower level than the threshold of 3.9 mmol/l proposed by the American Diabetes Association.