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

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

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 (T-50 test). A shorter T-50 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 T-50 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 T-50 was 356 (45) minutes. The geometric mean T-50 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 T-50 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

Comparison of Methods for Renal Risk Prediction in Patients with Type 2 Diabetes (ZODIAC-36)

BACKGROUND: Patients with diabetes are at high risk of death prior to reaching end-stage renal disease, but most models predicting the risk of kidney disease do not take this competing risk into account. We aimed to compare the performance of Cox regression and competing risk models for prediction of early- and late-stage renal complications in type 2 diabetes. METHODS: Patients with type 2 diabetes participating in the observational ZODIAC study were included. Prediction models for (micro)albuminuria and 50% increase in serum creatinine (SCr) were developed using Cox regression and competing risk analyses. Model performance was assessed by discrimination and calibration. RESULTS: During a total follow-up period of 10 years, 183 out of 640 patients (28.6%) with normoalbuminuria developed (micro)albuminuria, and 22 patients (3.4%) died without developing (micro)albuminuria (i.e. experienced the competing event). Seventy-nine out of 1,143 patients (6.9%) reached the renal end point of 50% increase in SCr, while 219 (19.2%) died without developing the renal end point. Performance of the Cox and competing risk models predicting (micro)albuminuria was similar and differences in predicted risks were small. However, the Cox model increasingly overestimated the risk of increase in SCr in presence of a substantial number of competing events, while the performance of the competing risk model was quite good. CONCLUSIONS: In this study, we demonstrated that, in case of substantial numbers of competing events, it is important to account for the competing risk of death in renal risk prediction in patients with type 2 diabetes

Gender differences in adverse drug reactions: knowledge synthesis and exploration

This project was a knowledge synthesis with the aim to identify gaps in evidence and improve the understanding of gender differences in adverse drug reactions (ADRs). The following studies were conducted

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

Gender differences in adverse drug reactions: knowledge synthesis and exploration

This project was a knowledge synthesis with the aim to identify gaps in evidence and improve the understanding of gender differences in adverse drug reactions (ADRs). The following studies were conducted:* In the first study we assessed and characterized gender differences in ADRs reported to the national pharmacovigilance centre in the Netherlands while adjusting for gender differences in drug use.* In the second study we assessed whether gender differences were consistent for drug-ADR associations reported by patients/caretakers and healthcare providers (HCPs).* In the third study we assessed whether gender differences in reported ADRs for drugs commonly prescribed among patients with type 2 diabetes were consistent at different time periods of drug exposure after treatment initiation. We also explored the association between gender differences in reported ADRs and gender differences in the dose of the prescribed drug over time.* In the fourth study we assessed whether there are gender differences in drug treatment (i.e. stage of drug treatment, type of drug treatment, and drug dosing), among patients with type 2 diabetes. We also assessed whether the observed gender differences for a sample of spontaneously reported drug-ADR combinations of the first study were also reflected in ADR-like symptoms as documented in medical dossiers.* In the final study we assessed 1) whether the observed gender differences in spontaneously reported ADRs for a sample of drugs of the first study had already been described in other data sources, and 2) whether gender differences in pharmacokinetics (PK) and pharmacodynamics (PD) had been described that could explain the observed gender differences in ADRs. More details can be found in the attached file. Data was used from the following sources:* Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) database: https://www.giantt.nl/nl/* Lareb Intensive Monitoring (LIM): https://www.lareb.nl/nl/image-widget/lareb-intensive-monitoring/* Lareb database of spontaneously reported adverse drug reactions: http://databank.lareb.nl/* Summary of Product Characteristics (SmPCs) and European Public Assessment Reports (EPARs): https://www.geneesmiddeleninformatiebank.nl/nl/ and https://www.ema.europa.eu/* Data from the Drug Information System of the National Health Care Institute (GIP): https://www.gipdatabank.nl

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