Serum T50 predicts cardiovascular mortality in individuals with type 2 diabetes: A prospective cohort study.

BACKGROUND AND AIMS: Individuals with type 2 diabetes (T2D) have a higher risk of cardiovascular disease, compared with those without T2D. The serum T50 test captures the transformation time of calciprotein particles in serum. We aimed to assess whether serum T50 predicts cardiovascular mortality in T2D patients, independent of traditional risk factors. METHODS: We analyzed 621 individuals with T2D in this prospective cohort study. Cox regression models were performed to test the association between serum T50 and cardiovascular and all-cause mortality. Causes of death were categorized according to ICD-10 codes. Risk prediction improvement was assessed by comparing Harrell's C for models without and with T50. RESULTS: The mean age was 64.2 ± 9.8 years, and 61% were male. The average serum T50 time was 323 ± 63 min. Higher age, alcohol use, high-sensitive C-reactive protein, and plasma phosphate were associated with lower serum T50 levels. Higher plasma triglycerides, venous bicarbonate, sodium, magnesium, and alanine aminotransferase were associated with higher serum T50 levels. After a follow-up of 7.5[5.4-10.7] years, each 60 min decrease in serum T50 was associated with an increased risk of cardiovascular (fully adjusted HR 1.32, 95% CI 1.08-1.50, and p = 0.01) and all-cause mortality (HR 1.15, 95%CI 1.00-1.38, and p = 0.04). Results were consistent in sensitivity analyses after exclusion of individuals with estimated glomerular filtration rate <45 or <60 mL/min/1.73 m2 and higher plasma phosphate levels. CONCLUSIONS: Serum T50 improves prediction of cardiovascular and all-cause mortality risk in individuals with T2D. Serum T50 may be useful for risk stratification and to guide therapeutic strategies aiming to reduce cardiovascular mortality in T2D.

Effect of high in comparison to low dairy intake intervention on markers of bone and cartilage remodeling and phosphate metabolism in healthy adults with overweight.

BACKGROUND: In the ageing population, issues with bone and joint health are highly prevalent. Both beneficial and potential risks of dairy products on bone and joint health are reported in epidemiological studies. Furthermore, the phosphorus (P) load from dairy could potentially lead to unfavorable changes in P metabolism. OBJECTIVE: To investigate the effect of dairy intake on markers of bone and joint metabolism and P metabolism in an intervention study with high and low dairy intake. METHODS: In a post hoc analysis of a randomized cross-over trial with overweight adults, the effect of a standardized high dairy intake [HDI (5-6 dairy portions per day) versus low dairy intake (LDI, ≤ 1 dairy portion/day)] for 6 weeks on markers of bone and joint health was assessed using enzyme-linked immunosorbent assays and electrochemiluminescence immunoassays. Markers indicative for cartilage breakdown, including urinary CTX-II, serum COMP and 4-hydroxyproline, and markers indicative for bone remodeling, such as serum CTX-I, PTH, 25(OH)D, osteocalcin, P1NP and FGF23, were investigated using linear mixed models. Furthermore, changes in P metabolism, including the main phosphate-regulating hormone FGF23 were explored. RESULTS: This study was completed by 46 adults (57% female, age 59 ± 4 years, BMI 28 ± 2 kg/m2). Following HDI, markers such as urinary CTX-II excretion, COMP, 25(OH)D, PTH and CTX-I were significantly lower after HDI, as compared to LDI. For example, CTX-II excretion was 1688 ng/24 h at HDI, while it was 2050 ng/24 h at LDI (p < 0.001). Concurrently, P intake was higher at HDI than at LDI (2090 vs 1313 mg/day, p < 0.001). While plasma P levels did not differ (1.03 vs 1.04 mmol/L in LDI, p = 0.36), urinary P excretion was higher at HDI than at LDI (31 vs 28 mmol/L, p = 0.04). FGF23 levels tended to be higher at HDI than at LDI (76.3 vs. 72.9 RU/mL, p = 0.07). CONCLUSIONS: HDI, as compared to LDI, reduced markers that are indicative for joint and bone resorption and bone turnover. No changes in P metabolism were observed. CLINICAL TRIAL REGISTRY: This trial was registered at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR4899 as NTR4899.

Both LDL and HDL particle concentrations associate positively with an increased risk of developing microvascular complications in patients with type 2 diabetes: lost protection by HDL (Zodiac-63).

BACKGROUND: Triglyceride-rich lipoproteins (TRL) and low-density lipoproteins (LDL) are associated positively whereas high-density lipoproteins (HDL) are associated inversely with the development of new-onset type 2 diabetes (T2D). Here we studied potential associations between these lipoprotein particle concentrations and the risk of developing microvascular complications in patients with established T2D. METHODS: Lipoprotein particle concentrations (TRLP, LDLP, and HDLP) were determined in 278 patients with T2D participating in a primary care-based longitudinal cohort study (Zwolle Outpatient Diabetes project Integrating Available Care [ZODIAC] study) leveraging the Vantera nuclear magnetic resonance (NMR) platform using the LP4 algorithm. Associations between lipoprotein particles and incident microvascular complications (nephropathy, neuropathy, and retinopathy) were assessed using Cox proportional hazards regression models. RESULTS: In total, 136 patients had microvascular complications at baseline. During a median follow-up of 3.2 years, 49 (34.5%) of 142 patients without microvascular complications at baseline developed new-onset microvascular complications. In multivariable Cox proportional hazards regression analyses, both total LDLP and HDLP concentrations, but not total TRLP concentrations, were positively associated with an increased risk of developing any microvascular complications after adjustment for potential confounding factors, including age, sex, disease duration, HbA1c levels, history of macrovascular complications, and statin use (adjusted hazard ratio [HR] per 1 SD increment: 1.70 [95% CI 1.24-2.34], P < 0.001 and 1.63 [95% CI 1.19-2.23], P = 0.002, respectively). When analyzing each microvascular complication individually, total LDLP concentrations were positively associated with retinopathy (adjusted HR 3.35, 95% CI 1.35-8.30, P = 0.009) and nephropathy (adjusted HR 2.13, 95% CI 1.27-3.35, P = 0.004), and total HDLP concentrations with neuropathy (adjusted HR 1.77, 95% CI 1.15-2.70, P = 0.009). No significant associations were observed for lipoprotein particle subfractions. CONCLUSIONS: Total lipoprotein particle concentrations of both LDL and HDL associate positively with an increased risk of developing microvascular complications in T2D. We propose that the protective role of HDL on the development of microvascular complications may be lost in established T2D.

Lower Extremity Amputation Rates in People With Diabetes Mellitus: A Retrospective Population Based Cohort Study in Zwolle Region, The Netherlands.

OBJECTIVE: Lower extremity amputations are a major complication of diabetes mellitus (DM). In a previous Dutch study, the incident rate of major amputations was 89.2 per 100 000 person years. The primary aim of this study was to describe the lower extremity amputation rates in people with DM in the Zwolle region, where preventive and curative footcare is organised according to the guidelines of the International Working Group of the Diabetic Foot (IWGDF). The secondary aim was to evaluate outcomes and underlying characteristics of these people. METHODS: This was a retrospective regional population based cohort study. Data from all people with DM treated in primary and secondary care, living in the region Zwolle were collected. All amputations in the period 2017 to 2019 were analysed. Comparisons were made between those with and without an amputation. RESULTS: In the analysis 5 915 people with DM were included, with a mean age of 67.8 (IQR 57.9, 75.9) years. Of those people, 47% were women and the median HbA1c was 53 (IQR 47, 62) mmol/mol. Over the three year study period 68 amputations were performed in 59 people: 46 minor, 22 major. This translated into an average annual crude amputation incidence rate of non-traumatic major and minor amputations of 41.5 and 86.9 per 100 000 person years among people with diabetes. Compared with those not undergoing amputations, those who underwent an amputation were more often men, older, mainly had T2DM, were treated in secondary care, had higher diastolic blood pressure, worse diabetic footcare profile, longer DM duration and higher HbA1c. At the end of the follow up, 111 people died: 96 (1.6%) without and 15 (25.4%) with amputations (p < .001). CONCLUSIONS: This retrospective study provides detailed insight into the rate of amputations in Dutch people with diabetes in the region Zwolle. Compared with previous Dutch estimates, these data suggest a considerable decrease in the major amputation incidence rate.

Plasma phosphate and all-cause mortality in individuals with and without type 2 diabetes: the Dutch population-based lifelines cohort study.

INTRODUCTION: Individuals with type 2 diabetes have a substantially elevated cardiovascular risk. A higher plasma phosphate level promotes vascular calcification, which may adversely affect outcomes in individuals with type 2 diabetes. We hypothesized that the association between plasma phosphate and all-cause mortality is stronger in individuals with type 2 diabetes, compared to those without diabetes. METHODS: We analysed the association between plasma phosphate and all-cause mortality in the Dutch population-based Lifelines cohort and in subgroups with and without type 2 diabetes, using multivariable Cox regression adjusted for potential confounders. Effect modification was tested using multiplicative interaction terms. RESULTS: We included 57,170 individuals with 9.4 [8.8-10.4] years follow-up. Individuals within the highest phosphate tertile (range 1.00-1.83 mmol/L) were at higher risk of all-cause mortality (fully adjusted HR 1.18 [95% CI 1.02-1.36], p = 0.02), compared with the intermediate tertile (range 0.85-0.99 mmol/L). We found significant effect modification by baseline type 2 diabetes status (p-interaction = 0.003). Within the type 2 diabetes subgroup (N = 1790), individuals within the highest plasma phosphate tertile had an increased mortality risk (HR 1.73 [95% CI 1.10-2.72], p = 0.02 vs intermediate tertile). In individuals without diabetes at baseline (N = 55,380), phosphate was not associated with mortality (HR 1.12 [95% CI 0.96-1.31], p = 0.14). Results were similar after excluding individuals with eGFR < 60 mL/min/1.73 m2. DISCUSSION: High-normal plasma phosphate levels were associated with all-cause mortality in individuals with type 2 diabetes. The association was weaker and non-significant in those without diabetes. Measurement of phosphate levels should be considered in type 2 diabetes; whether lowering phosphate levels can improve health outcomes in diabetes requires further study.

Phosphate and fibroblast growth factor 23 in diabetes.

Diabetes is associated with a strongly elevated risk of cardiovascular disease, which is even more pronounced in patients with diabetic nephropathy. Currently available guideline-based efforts to correct traditional risk factors are only partly able to attenuate this risk, underlining the urge to identify novel treatment targets. Emerging data point towards a role for disturbances in phosphate metabolism in diabetes. In this review, we discuss the role of phosphate and the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) in diabetes. We address deregulations of phosphate metabolism in patients with diabetes, including diabetic ketoacidosis. Moreover, we discuss potential adverse consequences of these deregulations, including the role of deregulated phosphate and glucose as drivers of vascular calcification propensity. Finally, we highlight potential treatment options to correct abnormalities in phosphate and FGF23. While further studies are needed to more precisely assess their clinical impact, deregulations in phosphate and FGF23 are promising potential target in diabetes and diabetic nephropathy.

Circulating trimethylamine-N-oxide is associated with all-cause mortality in subjects with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Trimethylamine-N-oxide (TMAO), a gut microbiota-liver metabolite, has been associated with cardiometabolic disease. However, whether TMAO is associated with nonalcoholic fatty liver disease (NAFLD) and NAFLD-related health outcomes remains unclear. We aimed to investigate the association of TMAO with NAFLD and to assess the extent to which the association of TMAO with all-cause mortality is dependent on the presence of NAFLD in the general population. METHODS: We included 5292 participants enrolled in the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort study. Cox proportional-hazards regression analyses were performed to study the association of TMAO with all-cause mortality in subjects with and without a fatty liver index (FLI) ≥60, which was used as a proxy of NAFLD. RESULTS: During a median follow-up of 8.2 years, 307 subjects died, of whom 133 were classified with NAFLD. TMAO was positively and independently associated with baseline FLI (Std ß 0.08, 95% CI 0.05, 0.11, P < .001). Higher TMAO was associated with increased risk of all-cause mortality in subjects with NAFLD, in crude analysis (hazard ratio [HR] per 1 SD, 2.55, 95% CI 1.60, 4.05, P < .001) and after full adjustment (adj HR 1.90, 95% CI 1.18, 3.04, P = .008). Such an association was not present in subjects without NAFLD (crude HR 1.14, 95% CI 0.81, 1.71, P = .39; adj HR 0.95, 95% CI 0.65, 1.39, P = .78). CONCLUSION: This prospective study revealed that plasma concentrations of TMAO were associated with all-cause mortality in subjects with NAFLD, independently of traditional risk factors.

Serum Calcification Propensity and the Risk of Cardiovascular and All-Cause Mortality in the General Population: The PREVEND Study.

OBJECTIVE: Vascular calcification contributes to the cause of cardiovascular disease. The calciprotein particle maturation time (T50) in serum, a measure of calcification propensity, has been linked with adverse outcomes in patients with chronic kidney disease, but its role in the general population is unclear. We investigated whether serum T50 is associated with cardiovascular mortality in a large general population-based cohort. Approach and Results: The relationship between serum T50 and cardiovascular mortality was studied in 6231 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort. All-cause mortality was the secondary outcome. Mean (±SD) age was 53±12 years, 50% were male, and mean serum T50 was 329±58 minutes. A shorter serum T50 is indicative of a higher calcification propensity. Serum T50 was inversely associated with circulating phosphate, age, estimated glomerular filtration rate, and alcohol consumption, whereas plasma magnesium was positively associated with serum T50 (P<0.001, total multivariable model R2=0.281). During median (interquartile range) follow-up for 8.3 (7.8-8.9) years, 364 patients died (5.8%), of whom 95 (26.1%) died from a cardiovascular cause. In multivariable Cox proportional hazard models, each 60 minutes decrease in serum T50 was independently associated with a higher risk of cardiovascular mortality (fully adjusted hazard ratio [95% CI], 1.22 [1.04-1.36], P=0.021). This association was modified by diabetes mellitus; stratified analysis indicated a more pronounced association in individuals with diabetes mellitus. CONCLUSIONS: Serum T50 is independently associated with an increased risk of cardiovascular mortality in the general population and thus may be an early and potentially modifiable risk marker for cardiovascular mortality.

High-sensitive troponin T is associated with all-cause and cardiovascular mortality in stable outpatients with type 2 diabetes (ZODIAC-37).

BACKGROUND: We aimed to investigate whether high-sensitive cardiac troponin T (hs-cTnT) is associated with all-cause and cardiovascular mortality in stable type 2 diabetes (T2D) outpatients treated in primary care. METHODS: Cardiac troponin T was measured with a high-sensitive assay at baseline in patients with T2D participating in the observational ZODIAC study. Cox proportional hazards models were used to investigate the relationship between hs-cTnT and mortality with adjustment for selected confounders. Risk prediction capabilities of hs-cTnT were assessed with Harrell C statistics. RESULTS: Complete baseline data were available for 1,133 patients. During median follow-up of 11 (7-14) years, 513 (45%) patients died, of which 218 (42%) died of cardiovascular causes. Of the patients with undetectable hs-cTnT levels (<3 ng/L), only 23% died, compared with 58% with low detectable levels (3-14 ng/L) and 84% with raised levels (≥14 ng/L). Natural log hs-cTnT was significantly associated with all-cause mortality (hazard ratio 1.30, 95% CI 1.19-1.42) and cardiovascular mortality (hazard ratio 1.33, 95% CI 1.15-1.53), independent of potential confounders. The Harrell C statistic for the crude model of hs-cTnT was 0.72 (95% CI 0.70-0.75) for all-cause mortality and 0.74 (95% CI 0.71-0.77) for cardiovascular mortality. CONCLUSIONS: Higher levels of hs-cTnT are associated with mortality in stable outpatients with T2D. The high crude Harrell C values and the excellent prognosis of patients with undetectable levels illustrate the strength of hs-cTnT as a potential marker for mortality.

The relationship between N-terminal prosomatostatin, all-cause and cardiovascular mortality in patients with type 2 diabetes mellitus (ZODIAC-35).

BACKGROUND: The hormone somatostatin inhibits growth hormone release from the pituitary gland and is theoretically linked to diabetes and diabetes related complications. This study aimed to investigate the relationship between levels of the stable somatostatin precursor, N-terminal prosomatostatin (NT-proSST), with mortality in type 2 diabetes (T2DM) patients. METHODS: In 1,326 T2DM outpatients, participating in this ZODIAC prospective cohort study, Cox proportional hazards models were used to investigate the independent relationship between plasma NT-proSST concentrations with all-cause and cardiovascular mortality. RESULTS: Median concentration of NT-proSST was 592 [IQR 450-783] pmol/L. During follow-up for 6 [3-10] years, 413 (31%) patients died, of which 176 deaths (43%) were attributable to cardiovascular causes. The age and sex adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.48 (95%CI 1.14 - 1.93) and 2.21 (95%CI 1.49 - 3.28). However, after further adjustment for cardiovascular risk factors there was no independent association of log NT-proSST with mortality, which was almost entirely attributable to adjustment for serum creatinine. There were no significant differences in Harrell's C statistics to predict mortality for the models with and without NT-proSST: both 0.79 (95%CI 0.77 - 0.82) and 0.81 (95%CI 0.77 - 0.84). CONCLUSIONS: NT-proSST is unsuitable as a biomarker for cardiovascular and all-cause mortality in stable outpatients with T2DM.

Validation of the howRu and howRwe questionnaires at the individual patient level.

BACKGROUND: The howRu and howRwe are new short questionnaires which are meant to measure health-related quality of life and patient experience. However, validation at the individual patient level has not yet taken place. We aimed to investigate the validity of both questionnaires at the individual patient level. METHODS: In this prospective validation study, patients were asked to complete both questionnaires and comment on their answers in a semi-structured in-depth interview. Based on the transcribed interviews, a panel of 45 general practitioners and 45 patients filled out the questionnaires as they thought the patients had completed them. The questionnaires were considered valid instruments when a reliable and acceptable level of agreement was reached between the patient's score and the score of a review panel, defined as a concordance correlation coefficient (CCC) of ≥0.70. Bland-Altman plots were also made. RESULTS: Ninety patients were included. The CCC of the howRu total score of the review panel and patients was 0.80 (95 % CI 0.73 to 0.86). Bland-Altman plots showed a mean difference of -0.96 and the limits of agreement ranged from -2.87 to 0.95. The CCC of the howRwe total score was 0.57 (95 % CI 0.42 to 0.69). The mean difference on the Bland-Altman plots was -0.54 and the limits of agreement ranged from -3.59 to 2.52. CONCLUSIONS: The howRu seems to be a valid questionnaire for measuring health-related quality of life at the individual patient level. We do not advice to use the tested version of the howRwe questionnaire for assessing patient experience at the individual patient level. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov NCT01830803 . Registration date: 5 April 2013.

Long-term outcomes in idiopathic membranous nephropathy using a restrictive treatment strategy.

Recently published Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend limiting the use of immunosuppressive drugs in idiopathic membranous nephropathy to patients at the highest risk of kidney failure. However, recommendations are based on natural history rather than direct assessment of a restrictive treatment strategy. Here, we describe the long-term outcomes of treating a large cohort of patients with idiopathic membranous nephropathy according to a restrictive treatment policy. We analyzed data for 254 patients who visited our outpatient clinic between 1995 and 2009. All patients were treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Immunosuppressive therapy was recommended in cases of deteriorating renal function or untreatable nephrotic syndrome. Primary outcomes for the present study were renal replacement therapy and death. Secondary outcomes included adverse events during follow-up and remission of proteinuria. In total, 124 patients (49%) received immunosuppressive therapy, which predominantly consisted of cyclophosphamide combined with steroids. Ten-year cumulative incidence rates were 3% for renal replacement therapy and 10% for death. Partial remission rates were 39%, 70%, and 83% after 1, 3, and 5 years, respectively; complete remission rates were 5%, 24%, and 38% at 1, 3, and 5 years, respectively. A serious adverse event occurred in 23% of all patients. The most notable complications were infections (17%), leukopenia (18%), cardiovascular events (13%), and malignancies (8%). In conclusion, the use of a restrictive treatment strategy in this cohort of patients with idiopathic membranous nephropathy yielded favorable outcomes while limiting the number of patients exposed to toxic drugs. These results support current KDIGO guidelines.

Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up.

BACKGROUND: Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a treatment option for patients with type 1 diabetes mellitus (T1DM). Aim of the present study was to describe the long-term course of glycaemic control, complications, health related quality of life (HRQOL) and treatment satisfaction among T1DM patients treated with CIPII. METHODS: Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) therapy in 2006 were followed until 2012. Laboratory, continuous glucose monitoring, HRQOL and treatment satisfaction measurements were performed at the start of the study, the end of the SC-, the end of the CIPII treatment phase in 2006 and during CIPII therapy in 2012. Linear mixed models were used to calculate estimated values and to test differences between the moments in time. RESULTS: In 2012, more time was spent in hyperglycaemia than after the CIPII treatment phase in 2006: 37% (95% CI 29, 44) vs. 55% (95% CI 48, 63), mean difference 19.8% (95% CI 3.0, 36.6). HbA1c was 65 mmol/mol (95% CI 60, 71) at the end of the SC treatment phase in 2006, 58 mmol/mol (95% CI 53, 64) at the end of the CIPII treatment phase and 65 mmol/mol (95% CI 60, 71) in 2012, respectively (p > 0.05). In 2012, the median number of grade 2 hypoglycaemic events per week (1 (95% CI 0, 2)) was still significantly lower than during prior SC therapy (3 (95% CI 2, 4)): mean change -1.8 (95% CI -3.4, -0.4). Treatment satisfaction with CIPII was better than with SC insulin therapy and HRQOL remained stable. Pump or catheter dysfunction of the necessitated re-operation in 7 patients. No mortality was reported. CONCLUSIONS: After 6 years of CIPII treatment, glycaemic regulation is stable and the number of hypoglycaemic events decreased compared to SC insulin therapy. Treatment satisfaction with CIPII is superior to SC insulin therapy, HRQOL is stable and complications are scarce. CIPII is a safe and effective treatment option for selected patients with T1DM, also on longer term.

Type 2 diabetes seems not to be a risk factor for the carpal tunnel syndrome: a case control study.

BACKGROUND: Previous studies have shown that the carpal tunnel syndrome seems to occur more frequently in patients with diabetes mellitus and might be associated with the duration of diabetes mellitus, microvascular complications and degree of glycaemic control. Primary aim was to determine if type 2 diabetes can be identified as a risk factor for carpal tunnel syndrome after adjusting for possible confounders. Furthermore, the influence of duration of diabetes mellitus, microvascular complications and glycaemic control on the development of carpal tunnel syndrome was investigated. METHODS: Retrospective, case-control study using data from electronic patient charts from the Isala (Zwolle, the Netherlands). All patients diagnosed with carpal tunnel syndrome in the period from January 2011 to July 2012 were included and compared with a control group of herniated nucleus pulposus patients. RESULTS: A total of 997 patients with carpal tunnel syndrome and 594 controls were included. Prevalence of type 2 diabetes was 11.5% in the carpal tunnel syndrome group versus 7.2% in the control group (Odds Ratio 1.67 (95% confidence interval 1.16-2.41)). In multivariate analyses adjusting for gender, age and body mass index, type 2 diabetes was not associated with carpal tunnel syndrome (OR 0.99 (95% CI 0.66-1.47)). No differences in duration of diabetes mellitus, microvascular complications or glycaemic control between groups were detected. CONCLUSION: Although type 2 diabetes was more frequently diagnosed among patients with carpal tunnel syndrome, it could not be identified as an independent risk factor.

Balancing Risks and Benefits: Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a new class of drugs that have been proven beneficial in the management of diabetes, chronic kidney disease, and heart failure and in the mitigation of cardiovascular risk. The benefits of SGLT2i therapy have led to the rapid adoption of these drugs in clinical guidelines. Since the introduction of these drugs, concerns have arisen, as diabetic ketoacidosis (DKA) unexpectedly occurred in patients treated with SGLT2i. DKA is an infrequent but serious complication of SGLT2i therapy, and is potentially preventable. The risk factors for the development of SGLT2i-associated DKA are inappropriate dose reductions of insulin, the dietary restriction of carbohydrates, and factors that may increase insulin demand such as excessive alcohol intake and major surgery. Moreover, the risk of SGLT2i-associated DKA is higher in persons with type 1 diabetes. It is crucial that both patients and healthcare providers are aware of the risks of SGLT2i-associated DKA. In an effort to encourage safe prescribing of this effective class of drugs, we present two cases that illustrate the risks of SGLT2i therapy with regard to the development of DKA.

Evaluating the Cost-Utility of Continuous Glucose Monitoring in Individuals with Type 1 Diabetes: A Systematic Review of the Methods and Quality of Studies Using Decision Models or Empirical Data.

INTRODUCTION: This review presents a critical appraisal of differences in the methodologies and quality of model-based and empirical data-based cost-utility studies on continuous glucose monitoring (CGM) in type 1 diabetes (T1D) populations. It identifies key limitations and challenges in health economic evaluations on CGM and opportunities for their improvement. METHODS: The review and its documentation adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews. Searches for articles published between January 2000 and January 2023 were conducted using the MEDLINE, Embase, Web of Science, Cochrane Library, and Econlit databases. Published studies using models and empirical data to evaluate the cost utility of all CGM devices used by T1D patients were included in the search. Two authors independently extracted data on interventions, populations, model settings (e.g., perspectives and time horizons), model types and structures, clinical outcomes used to populate the model, validation, and uncertainty analyses. They subsequently met to confirm consensus. Quality was assessed using the Philips checklist for model-based studies and the Consensus Health Economic Criteria (CHEC) checklist for empirical studies. Model validation was assessed using the Assessment of the Validation Status of Health-Economic decision models (AdViSHE) checklist. The extracted data were used to generate summary tables and figures. The study protocol is registered with PROSPERO (CRD42023391284). RESULTS: In total, 34 studies satisfied the selection criteria, two of which only used empirical data. The remaining 32 studies applied 10 different models, with a substantial majority adopting the CORE Diabetes Model. Model-based studies often lacked transparency, as their assumptions regarding the extrapolation of treatment effects beyond available evidence from clinical studies and the selection and processing of the input data were not explicitly stated. Initial scores for disagreements concerning checklists were relatively high, especially for the Philips checklist. Following their resolution, overall quality scores were moderate at 56%, whereas model validation scores were mixed. Strikingly, costing approaches differed widely across studies, resulting in little consistency in the elements included in intervention costs. DISCUSSION AND CONCLUSION: The overall quality of studies evaluating CGM was moderate. Potential areas of improvement include developing systematic approaches for data selection, improving uncertainty analyses, clearer reporting, and explaining choices for particular modeling approaches. Few studies provided the assurance that all relevant and feasible options had been compared, which is required by decision makers, especially for rapidly evolving technologies such as CGM and insulin administration. High scores for disagreements indicated that several checklists contained questions that were difficult to interpret consistently for quality assessment. Therefore, simpler but comprehensive quality checklists may be needed for model-based health economic evaluation studies.

Serum carnosinase 1, an early indicator for incident microalbuminuria in type 1 diabetes.

Aims: Carnosinase (CN1) polymorphisms have been linked to diabetic kidney disease (DKD), as CN1 degrades dipeptides which scavenge oxidative metabolites and prevent the formation of advanced glycation end-products. In this work, we studied the association between serum CN1, the systemic redox status and long-term renal outcome in type 1 diabetes. Methods: Serum CN1 was measured in a prospective type 1 diabetes cohort (n = 218) with a 16-year follow-up. A total of 218 patients treated at the Diabetes Outpatient Clinic of the Weezenlanden Hospital (nowadays Isala Hospital, Zwolle, The Netherlands) were included in this analysis. We assessed whether serum CN1 was associated with renal function and development of DKD as well as other diabetic complications. Results: At baseline, age, systemic redox status and N-terminal pro brain-natriuretic peptide (NT-proBNP) were associated with serum CN1 concentration (p < 0.05). During follow-up, CN1 concentration in the middle tertile was associated with less incident microalbuminuria (odds ratio = 0.194, 95% C.I.: 0.049-0.772, p = 0.02) after adjustment for age, systemic redox status, NT-proBNP and sex. Discussion: Serum CN1 could predict incident microalbuminuria and may be used as a novel parameter to identify patients at risk for DKD.