Is Gliclazide Associated with a Lower Obesity-Related Cancer Risk Compared to Other Sulfonylureas? A Long-term Prospective Cohort Study.

BACKGROUND: Gliclazide has been suspected to be associated with a lower obesity-related cancer risk; however, current evidence is limited by important methodologic shortcomings. This study aimed to evaluate whether gliclazide is preferred over other sulfonylureas regarding obesity-related cancer risk. METHODS: In this prospective cohort study, an annual benchmarking database in Dutch primary care (Zwolle Outpatient Diabetes project Integrating Available CareZODIAC, 1998-2014) was linked to the Netherlands Cancer Registry and the Dutch Personal Record Database. Of the 71,648 patients with type 2 diabetes, we included 26,207 who used sulfonylureas and had no history of cancer or insulin use at baseline. Obesity-related cancer was defined using the latest definition of the World Cancer Research Fund. Cox regression analyses were used to estimate HRs, with both baseline sulfonylurea and cumulative exposure modeled and corrected for baseline covariates. RESULTS: During follow-up for 167,692 person-years, there were 1,111 obesity-related cancer events. For males, the adjusted HRs [95% confidence interval (CI)] for baseline sulfonylurea compared with gliclazide were as follows: glibenclamide, 1.10 (0.92-2.69); glimepiride, 1.13 (0.68-1.84); and tolbutamide, 0.93 (0.59-1.48). For females, these were as follows: glibenclamide, 1.49 (0.72-3.13); glimepiride, 0.96 (0.59-1.54); and tolbutamide, 0.84 (0.54-1.28). The adjusted HRs (95% CI) for one more year of cumulative exposure compared with gliclazide were as follows: glibenclamide, 0.90 (0.71-1.14); glimepiride, 0.96 (0.87-1.06); and tolbutamide, 1.00 (0.92-1.09). For females, these were as follows: glibenclamide, 0.93 (0.77-1.13); glimepiride, 0.99 (0.90-1.10); and tolbutamide, 1.04 (0.96-1.13). CONCLUSIONS: Obesity-related cancer risk was comparable between gliclazide and other sulfonylureas. IMPACT: Gliclazide is not preferred over other sulfonylureas regarding obesity-related cancer risk.

Favourable serum calcification propensity with intraperitoneal as compared with subcutaneous insulin administration in type 1 diabetes.

BACKGROUND: Serum calcification propensity can be monitored using the maturation time of calciprotein particles in serum (T50 test). A shorter T50 indicates greater propensity to calcify; this is an independent determinant of cardiovascular disease. As the intraperitoneal (IP) route of insulin administration mimics the physiology more than the subcutaneous (SC) route in persons with type 1 diabetes (T1DM), we hypothesized that IP insulin influences determinants of calcium propensity and therefore result in a longer T50 than SC insulin administration. METHODS: Prospective, observational case-control study. Measurements were performed at baseline and at 26 weeks in age and gender matched persons with T1DM. RESULTS: A total of 181 persons, 39 (21.5%) of which used IP and 142 (78.5%) SC insulin were analysed. Baseline T50 was 356 (45) minutes. The geometric mean T50 significantly differed between both treatment groups: 367 [95% confidence interval (CI) 357, 376] for the IP group and 352 (95% CI 347, 357) for the SC group with a difference of -15 (95% CI -25, -4) minutes, in favour of IP treatment. In multivariable analyses, the IP route of insulin administration had a positive relation on T50 concentrations while higher age, triglycerides and phosphate concentrations had an inverse relation. CONCLUSION: Among persons with T1DM, IP insulin administration results in a more favourable calcification propensity time then SC insulin. It has yet to be shown if this observation translates into improved cardiovascular outcomes.

Adherence to insulin pump treatment declines with increasing age in adolescents with type 1 diabetes mellitus.

AIM: This study assessed the impact of illness perceptions, emotional responses to the disease and its management, and patient characteristics on the adherence to optimal insulin pump management in adolescents with type 1 diabetes mellitus. METHODS: From May to December 2013 and May 2015 to September 2016, we investigated 90 adolescents (50% boys), 12-18 years with type 1 diabetes. We analysed the association of optimal adherence to insulin pump therapy to age, gender, diabetes duration, results of questionnaires relating to fear and problems of self-testing, illness perceptions, emotional distress and family conflicts. Optimal adherence was defined as bolusing insulin on average ≥2.5/3 main meals/d. RESULTS: Adolescents with suboptimal adherence were on average 1.8 years older (95% Confidence Interval 1.09-2.50 years, P < .001) than those with optimal adherence. After adjustment for age, no other patient or parent factors were related to optimal adherence. CONCLUSION: Adherence to insulin pump self-management in adolescents with type 1 diabetes declined with increasing age, illustrating the challenges of transition of self-management from parents to the adolescent patient themselves.

Development and validation of prescribing quality indicators for patients with type 2 diabetes.

AIM: Quality indicators are used to measure whether healthcare professionals act according to guidelines, but few indicators focus on the quality of pharmacotherapy for diabetes. The aim of this study was to develop and validate a set of prescribing quality indicators (PQIs) for type 2 diabetes in primary care, and to apply this set in practice. To take into account the stepwise treatment of chronic disease, clinical action indicators were specifically considered. METHODS: Potential PQIs were derived from clinical practice guidelines and evaluated using the RAND/UCLA Appropriateness Method, a modified Delphi panel. Thereafter, the feasibility of calculating the PQIs was tested in two large Dutch primary care databases including >80 000 diabetes patients in 2012. RESULTS: 32 PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on vaccination, medication safety and adherence were assessed by ten experts. After the Delphi panel, the final list of twenty PQIs was tested for feasibility. All PQIs definitions were feasible for measuring the quality of medication treatment using these databases. Indicator scores ranged from 18.8% to 90.8% for PQIs focusing on current medication use, clinical action and medication choice, and from 2.1% to 37.2% for PQIs focusing on medication safety. DISCUSSION AND CONCLUSIONS: Twenty PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on medication safety in type 2 diabetes were developed, considered valid and operationally feasible. Results showed room for improvement, especially in initiation and intensification of treatment as measured with clinical action indicators.

Continuous intraperitoneal insulin infusion versus subcutaneous insulin therapy in the treatment of type 1 diabetes: effects on glycemic variability.

INTRODUCTION: As continuous intraperitoneal insulin infusion (CIPII) results in a more physiologic action of insulin than subcutaneous (SC) insulin administration, we hypothesized that CIPII would result in less glycemic variability (GV) than SC insulin therapy among type 1 diabetes mellitus (T1DM) patients. MATERIALS AND METHODS: Data from 5-day blind continuous glucose monitoring (CGM) measurements performed during a 26-week, prospective, observational case-control study were analyzed. The coefficient of variation (CV) was the primary measure of GV. In addition, the SD of the mean glucose level, mean of daily differences, and mean amplitude of glycemic excursions were calculated. RESULTS: In total, 176 patients (36% male; mean age, 49 [SD 13] years; median diabetes duration, 24 [interquartile range, 17, 35] years; glycated hemoglobin level, 63 [10] mmol/mmol), of which 37 used CIPII and 139 SC insulin therapy, were analyzed. CGM data were available for 169 patients at baseline (CIPII, n=35; SC, n=134) and for 164 patients at 26 weeks (CIPII, n=35; SC, n=129). After adjustment for baseline differences, the CV was 4.9% (95% confidence interval, 1.0, 8.8) lower with CIPII- compared with SC-treated patients, irrespective of the use of multiple daily injections or continuous SC insulin infusion. There were no differences in other indices of GV between groups. CONCLUSIONS: Despite higher blood glucose, the CV was slightly lower with CIPII compared with SC insulin therapy in T1DM patients, and other measures of GV were identical. Future studies are needed to confirm these findings and investigate whether this results in prevention of hypoglycemia and even perhaps (less) microvascular complications.

Complications of continuous intraperitoneal insulin infusion with an implantable pump.

AIM: To monitor the course of continuous intraperitoneal insulin infusion (CIPII) and to gain more insight into possible complications. METHODS: A retrospective, longitudinal observational cohort study in patients with type 1 diabetes mellitus (T1DM) was performed. Only patients with "brittle" T1DM who started CIPII between January 1, 2000 and June 1, 2011, and were treated in the only centre in The Netherlands providing CIPII treatment (Isala clinics, Zwolle) were eligible for inclusion. Outcomes were defined as operation-free period (OFP), rate and type of complications. Subanalyses were made between patients starting CIPII from 2000 to 2007 and from 2007 onwards in order to study possible changes over time in complications and/or OFP. The OFP was calculated as the time from initial implantation to the date of first documented re-operation. If patients had not experienced an operation, their data were recorded at the date of last follow up or death. Kaplan-Meier curves were constructed to visualize the OFP. A (two-sided) P value of less than 0.05 was considered statistically significant. RESULTS: Fifty-seven patients were treated with CIPII, although one patient was excluded from analyses because of self-induced complications. In the remaining 56 patients, 70 complications occurred during 283 patient years. Catheter occlusion (32.9%), pump dysfunction (17.1%), pain at the pump site (15.7%) and infections (10.0%) were the most frequent complications. This resulted in a median OFP of 4.5 years (95% confidence interval 4.1-4.8 years) without any difference between the time periods. Fifty re-operations were performed because of complications, one per 5.6 patient years, with a decrease in pump dysfunction (P = 0.04) and pump explantations (P = 0.02) after 2007. In total, 9 episodes of ketoacidosis occurred during follow up and there were 69 hospital re-admissions, with a median duration of 6 d. CIPII was ceased in five patients due to recurrent infections (n = 2), pain (n = 1), inadequate glycaemic control (n = 1) or by own choice (n = 1). No CIPII related mortality was reported. CONCLUSION: The OFP has been stable over the last decade. No CIPII related mortality was reported. A significant decrease in pump dysfunction and explantation was seen after 2007 compared to the period 2000-2007. CIPII remains a safe treatment modality for specific patient groups.

Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials.

Objective. We performed a systematic review of the literature to evaluate the effects of alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes mellitus. Research design and methods. The databases MEDLINE and EMBASE were searched using the key words "lipoic acid", "thioctic acid", "diabet∗", and the MeSH-terms "thioctic acid" and "diabetes mellitus". Randomised controlled trials using the TSS score as the outcome measure were selected and assessed for their methodological quality. Study selection and quality assessment were performed independently by three observers. Results. Overall, the pooled standardized mean difference estimated from all trials revealed a reduction in TSS scores of -2.26 (CI: -3.12 to -1.41; P = 0.00001) in favour of alpha lipoic acid administration. Subgroup analyses of oral administration (-1.78 CI: -2.45 to -1.10; P = 0.00001) and intravenous administration (-2.81 CI: -4.16 to -1.46; P = 0.0001) confirmed the robustness of the overall result. Conclusions. When given intravenously at a dosage of 600 mg/day over a period of 3 weeks, alpha lipoic acid leads to a significant and clinically relevant reduction in neuropathic pain (grade of recommendation A). It is unclear if the significant improvements seen after 3-5 weeks of oral administration at a dosage of >600 mg/day are clinically relevant.

Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts.

Screening for chronic kidney disease is recommended in people at high risk, but data on the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with all-cause and cardiovascular mortality are limited. To clarify this, we performed a collaborative meta-analysis of 10 cohorts with 266,975 patients selected because of increased risk for chronic kidney disease, defined as a history of hypertension, diabetes, or cardiovascular disease. Risk for all-cause mortality was not associated with eGFR between 60-105 ml/min per 1.73 m², but increased at lower levels. Hazard ratios at eGFRs of 60, 45, and 15 ml/min per 1.73 m² were 1.03, 1.38 and 3.11, respectively, compared to an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log risk for all-cause mortality without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 10, 30 and 300 mg/g were 1.08, 1.38, and 2.16, respectively compared to a ratio of five. Albuminuria and eGFR were multiplicatively associated with all-cause mortality, without evidence for interaction. Similar associations were observed for cardiovascular mortality. Findings in cohorts with dipstick data were generally comparable to those in cohorts measuring albumin-to-creatinine ratios. Thus, lower eGFR and higher albuminuria are risk factors for all-cause and cardiovascular mortality in high-risk populations, independent of each other and of cardiovascular risk factors.