Peter R. van Dijk

Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials.

Objective and Design Gliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156) Data Sources Medline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database. Selection Included were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used. Results Nineteen trials were included; 3,083 patients treated with gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin, gliclazide was slightly more effective (−0.13% (95%CI: −0.25, −0.02, I2 55%)). One out of 2,387 gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I2 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes. Conclusions The methodological quality of randomized trials comparing gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.

Device-Guided Breathing as Treatment for Hypertension in Type 2 Diabetes Mellitus A Randomized, Double-blind, Sham-Controlled Trial

IMPORTANCE Biofeedback with device-guided lowering of breathing frequency could be an alternate nonpharmacologic treatment option for hypertension. Evidence from trials with high methodologic quality is lacking. OBJECTIVE To evaluate the effects of device-guided lowering of breathing frequency on blood pressure in patients with type 2 diabetes mellitus and hypertension. DESIGN Single-center, double-blind, sham-controlled trial. SETTING A large nonacademic teaching hospital in the Netherlands. PARTICIPANTS Patients with type 2 diabetes mellitus and hypertension. INTERVENTION Fifteen-minute sessions with either the device that guides breathing through musical tones to a lower breathing frequency (aiming at <10 breaths/min) or a sham device (music without aiming at lowering of breathing frequency) for an 8-week study period. MAIN OUTCOMES AND MEASURES Systolic and diastolic blood pressure measured in the physicians office. RESULTS Forty-eight patients were randomized; 21 patients (88%) in the intervention group and 24 patients (100%) in the control group completed the study. There were no significant changes in systolic and diastolic blood pressure, with a difference in systolic blood pressure of 2.35 mm Hg (95% CI, -6.50 to 11.20) in favor of the control group and a difference in diastolic blood pressure of 2.25 mm Hg (95% CI, -2.16 to 6.67) in favor of the intervention group. Three patients in the intervention group experienced adverse events. CONCLUSIONS AND RELEVANCE This high methodologic quality study shows no significant effect of device-guided lowering of breathing frequency on office-measured blood pressure in patients with type 2 diabetes. On the basis of this study, together with results from all but one previous trial, device-guided lowering of breathing frequency does not appear to be a viable nonpharmacologic option for hypertension treatment.

The Effects of a Mobile Phone Application on Quality of Life in Patients With Type 1 Diabetes Mellitus A Randomized Controlled Trial

Background: The combination of an increasing prevalence of diabetes mellitus and more people having access to smartphones creates opportunities for patient care. This study aims to investigate whether the use of the Diabetes Under Control (DBEES) mobile phone application, a digital diabetes diary, results in a change in quality of life for patients with type 1 diabetes mellitus (T1DM) compared with the standard paper diary. Methods: In this randomized controlled open-label trial, 63 patients with T1DM having access to a smartphone were assigned to the intervention group using the DBEES application (n = 31) or the control group using the standard paper diary (n = 32). Primary outcome was the change in quality of life, as measured by the RAND-36 questionnaire, between both groups. Secondary outcomes included diabetes-related distress (PAID), HbA1c, frequency of self-monitoring blood glucose, and the usability of the diabetes application (SUS). Results: Patients had a median age (IQR) of 33 (21) years, diabetes duration of 17 (16) years, and an HbA1c of 62 ± 16 mmol/mol. No significant differences in the QOL, using the RAND-36, within and between both groups were observed after 3 months. Glycemic control, diabetes-related emotional distress, and frequency of self-monitoring of blood glucose remained within and between groups. Users reviewed the usability of DBEES with a 72 ± 20, on a range of 0-100. Conclusions: The use of the DBEES application in the management of patients with T1DM for 3 months yields no alterations in quality of life compared to the standard paper diary.

Midregional Fragment of Proadrenomedullin, New-Onset Albuminuria, and Cardiovascular and All-Cause Mortality in Patients With Type 2 Diabetes (ZODIAC-30)

OBJECTIVE The midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patients with type 2 diabetes treated in primary care. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes participating in the observational Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study were included. Cox regression analyses were used to assess the relation of baseline MR-proADM with new-onset albuminuria and CV and all-cause mortality. Risk prediction capabilities of MR-proADM for new-onset albuminuria and CV and all-cause mortality were assessed with Harrell’s C and the integrated discrimination improvement. RESULTS In 1,243 patients (mean age 67 [±12] years), the median follow-up was 5.6 years (interquartile range 3.1–10.1); 388 (31%) patients died, with 168 (12%) CV deaths. Log2 MR-proADM was associated with CV (hazard ratio 1.96 [95% CI 1.27–3.01]) and all-cause mortality (1.78 [1.34–2.36]) after adjusting for age, sex, BMI, smoking, systolic blood pressure, cholesterol-to-HDL ratio, duration of diabetes, HbA1c, ACE inhibitor/angiotensin receptor blocker, history of CV diseases, log serum creatinine, and log albumin-to-creatinine ratio. MR-proADM slightly improved mortality risk prediction. The age- and sex-adjusted, but not multivariate-adjusted, MR-proADM levels were associated with new-onset albuminuria. CONCLUSIONS MR-proADM was associated with CV and all-cause mortality in patients with type 2 diabetes after a median follow-up of 5.6 years. There was no independent relationship with new-onset albuminuria. In the availability of an extensive set of risk factors, there was little added effect of MR-proADM in risk prediction of CV and all-cause mortality.

Incidence of renal replacement therapy for diabetic nephropathy in the Netherlands: Dutch diabetes estimates (DUDE)-3.

Objectives Describe the incidence, prevalence and survival of patients needing renal replacement therapy (RRT) for end-stage renal disease (ESRD) due to diabetes mellitus (DM)-related glomerulosclerosis or nephropathy (diabetic nephropathy, DN) in the Netherlands. Design Using the national registry for RRT (RENINE-registry), data of all Dutch individuals initiating RRT for ESRD and having DN as primary diagnosis in the period 2000–2012 were obtained. Setting Observational study in the Netherlands. Patients Patients with ESRD needing RRT for DN. Outcome measurements Age and gender adjusted incidence and prevalence of RRT for DN in the period 2000–2012. In addition, trends in time and patients survival were examined. Results The prevalence of DM in the general population increased from approximately 466 000 in 2000 to 815 000 in 2011. The number of individuals who started RRT with DN as primary diagnosis was 17.4 per million population (pmp) in 2000 and 19.1 pmp in 2012, with an annual percentage change (APC) of 0.8% (95% CI −0.4 to 2.0). For RRT due to type 1 DN, the incidence decreased from 7.3 to 3.5 pmp (APC −4.8%, 95% CI −6.5 to −3.1) while it increased for type 2 DN from 10.1 to 15.6 pmp (APC 3.1%, 95% CI 1.3 to 4.8). After 2009, the prevalence of RRT for DN remained stable (APC 1.0%, 95% CI −0.4 to 2.5). Compared to the period 2000–2004, patients initiating RRT and dialysis in 2005–2009 had better survival, HRs 0.8 (95% CI 0.7 to 0.8) and 0.8 (95% CI 0.7 to 0.9), respectively, while survival after kidney transplantation remained stable, HR 0.8, 95% CI 0.5 to 1.1). Conclusions Over the last decade, the incidence of RRT for DN was stable, with a decrease in RRT due to type 1 DN and an increase due to type 2 DN, while survival increased.

Fifteen-year follow-up of quality of life in type 1 diabetes mellitus.

AIM To evaluate metabolic control and health-related quality of life (HRQOL) in a type 1 diabetes mellitus (T1DM) population. METHODS As part of a prospective cohort study, 283 T1DM patients treated with various insulin treatment modalities including multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) were examined annually. HRQOL was measured using the SF-36 and EuroQol questionnaires. Data regarding HRQOL, glycaemic and metabolic control from baseline and follow-up measures in 2002 and 2010 were analysed. Linear mixed models were used to calculate estimated values and differences between the three moments in time and the three treatment modalities. RESULTS Significant changes [mean Δ (95%CI)] in body mass index [2.4 kg/m(2) (1.0, 3.8)], systolic blood pressure [-6.4 mmHg (-11.4, -1.3)] and EuroQol-VAS [-7.3 (-11.4, -3.3)] were observed over time. In 2010, 168 patients were lost to follow-up. Regarding mode of therapy, 52 patients remained on MDI, 28 remained on CSII, and 33 patients switched from MDI to CSII during follow-up. Among patients on MDI, HRQOL decreased significantly over time: mental component summary [-9.8 (-16.3, -3.2)], physical component summary [-8.6 (-15.3, -1.8)] and EuroQol-VAS [-8.1 (-14.0, -2.3)], P < 0.05 for all. For patients using CSII, the EuroQol-VAS decreased [-9.6 (-17.5, -1.7)]. None of the changes over time in HRQOL differed significantly with the changes over time within the other treatment groups. CONCLUSION No differences with respect to metabolic and HRQOL parameters between the various insulin treatment modalities were observed after 15 years of follow-up in T1DM patients.

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

BackgroundPrevious 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.MethodsRetrospective, 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.ResultsA 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.ConclusionAlthough type 2 diabetes was more frequently diagnosed among patients with carpal tunnel syndrome, it could not be identified as an independent risk factor.

Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes

CONTEXT In type 1 diabetes mellitus, low levels of insulin-like growth factor -1 (IGF-1) and IGF binding protein-3 (IGFBP-3) and high levels of GH and IGFBP-1 are present, probably due to portal vein insulinopenia. OBJECTIVE To test the hypothesis that continuous ip insulin infusion (CIPII) has a more pronounced effect than sc insulin therapy on regulation of the GH-IGF-1 axis. DESIGN This was a prospective, observational case-control study. Measurements were performed twice at a 26-week interval. SETTING Two secondary care hospitals in the Netherlands participated in the study. PATIENTS There were a total of 184 patients, age- and gender-matched, of which 39 used CIPII and 145 sc insulin therapy for the past 4 years. OUTCOMES Primary endpoint included differences in IGF-1. Secondary outcomes were differences in GH, IGFBP-1, and IGFBP-3. RESULTS IGF-1 was higher with CIPII as compared to SC insulin therapy: 124 μg/liter (95% confidence interval [CI], 111-138) vs 108 μg/liter (95% CI 102-115) (P = .035). Additionally, IGFBP-3 concentrations were higher and IGFBP-1 and GH concentrations were lower with CIPII as compared to SC insulin therapy: 3.78 mg/liter (95% CI, 3.49-4.10) vs 3.31 mg/liter (95% CI, 3.17-3.47) for IGFBP-3, 50.9 μg/liter (95% CI, 37.9-68.2) vs 102.6 μg/liter (95% CI, 87.8-119.8) for IGFBP-1 and 0.68 μg/liter (95% CI, 0.44-1.06) vs 1.21 μg/liter (95% CI, 0.95-1.54) for GH, respectively. In multivariate analysis, IGF-1 had no significant association with HbA1c. CONCLUSIONS The GH-IGF-1 axis may be affected by the route of insulin administration with CIPII counteracting dysregulation of the GH-IGF1 axis present during sc insulin therapy.

Seasonality of diagnosis of type 1 diabetes mellitus in the Netherlands (Young Dudes-2)

Abstract Background: The aim of this study was to investigate seasonality in the initial presentation of type 1 diabetes mellitus (T1DM) among Dutch children. Methods: Observational, nationwide study in the Netherlands. Using the national registry for both healthcare reimbursement and pharmaceutical care, data of all Dutch children (aged 0–14 years) with a diagnosis of T1DM in the period 2009–2011 were obtained. Results: During the study period (2009–2011) an average annual number of 2.909.537 children aged 0–14 lived in the Netherlands and 676 children were diagnosed with T1DM per year, translating into an annual incidence rate (IR) of T1DM of 23.2 per hundred thousand children (ptc). The annual IR differed significantly (p=0.03) between seasons: 6.4 ptc in winter, 4.9 ptc in spring, 5.4 ptc in summer and 6.6 ptc in autumn. This pattern was present within both boys and girls Conclusions: Among Dutch children aged 0–14 years, there is seasonality in the of T1DM with a peak incidence in autumn and winter.

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.