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Simple SummaryA growing number of colorectal cancer survivors live with type 2 diabetes, as a result of improved cancer diagnosis and treatment. These patients might have worse glycemic control after their cancer diagnosis, which may increase the risk of cardiovascular diseases. This prospective cohort study evaluated the quality of glycemic control for colorectal cancer survivors, as compared to those without cancer in Dutch primary care for diabetes. During a 10-year follow-up for 57,330 patients, there were 705 patients diagnosed with colorectal cancer. No clinically relevant difference on the probability of reaching the target HbA1c was observed between colorectal cancer survivors and patients with no history of cancer. These results showed a robust diabetes care system, implying that the glycemic control for colorectal cancer survivors can be delegated to the primary care professionals.Cancer survivors with diabetes tend to have worse glycemic control after their cancer diagnosis, which may increase the risk of cardiovascular diseases. We aimed to investigate whether glycemic control differs between colorectal cancer (CRC) survivors and those without cancer, among patients with type 2 diabetes being treated in the Dutch primary care. The Zwolle Outpatient Diabetes project Integrating Available Care database was linked with the Dutch Cancer Registry (n = 71,648, 1998-2014). The cases were those with stage 0-III CRC, and the controls were those without cancer history. The primary and secondary outcomes were the probability of reaching the glycated hemoglobin (HbA1c) target and the mean of HbA1c during follow-up, respectively. Mixed linear modeling was applied, where the status of CRC was a time-varying variable. Among the 57,330 patients included, 705 developed CRC during follow-up. The mean probability of reaching the HbA1c target during follow-up was 73% versus 74% (p = 0.157) for CRC survivors versus those without cancer, respectively. The mean HbA1c was 51.1 versus 50.8 mmol/mol (p = 0.045) among CRC survivors versus those without cancer, respectively. We observed a clinically comparable glycemic control among the CRC survivors without cancer, indicating that glycemic control for CRC survivors can be delegated to primary care professionals.

Background: Because of continuous hyperglycemia and hyperinsulinemia and the use of photosensitizing drug, hydrochlorothiazide (HCTZ), the risk of cutaneous squamous cell carcinoma (cSCC) might be increased among patients with diabetes. This study aimed to estimate the risk of cSCC among HCTZ users with type 2 diabetes, and to determine whether thiazide-like diuretics, another drug in the same class with HCTZ, would be safer. Methods: We linked the benchmarking database in Dutch primary care, the Netherlands Cancer Registry, and the Dutch Personal Records Database (1998–2019). All 71,648 patients were included, except for those who had a history of skin cancer prior to cohort entry. We used Cox modeling to estimate the HRs and 95% confidence intervals for cSCC. The model was adjusted by cumulative exposure to each antihypertensive, age, sex, smoking, body mass index, blood pressure, serum creatinine, other confounding drug use at cohort entry, and cohort entry year. Results: There were 1,409 cSCC events (23 among thiazide-like diuretics users), during a follow-up of 679,789 person-years. Compared with no HCTZ use, the adjusted HRs for HCTZ use were 1.18 (1.00–1.40) for ≤2 years, 1.57 (1.32–1.88) for 2 to 4 years, and 2.09 (1.73–2.52) for >4 years. The HR was 0.90 (0.79–1.03) for an additional year of thiazide-like diuretic use. Conclusions: In patients with diabetes, exposure to HCTZ for >2 years is associated with an increased risk of cSCC, whereas no increased risk associated with thiazide-like diuretics was observed. Impact: The potential increased risk of cSCC should be a consideration when prescribing HCTZ, with thiazide-like diuretics offering a safer alternative.

Objective The optimal frequency of self-monitoring of blood glucose (SMBG) in patients with type 2 diabetes (T2DM) with stable glycemic control is unknown. This study investigated effects of 3 frequencies of SMBG on glycemic control and quality of life after 9 months in patients using one long-acting insulin injection a day. In an open-label, multi-center, primary-care, parallel (1:1:1) randomized trial in the Netherlands including patients with T2DM, HbA1c ≤ 58 mmol/mol (≤ 7.5%), stable glycemic control, treated with one insulin injection daily, three frequencies of 4-point glucose measurements (before meals and bedtime) were weekly (n = 22), every 2 weeks (n = 16) and monthly (n = 20) were compared. Results A total of 58 patients with T2DM were included by 38 general practitioners, which was lower then anticipated. There were no significant between group differences in HbA1c (mmol/mol); group C compared to A and B; − 2.7 (95% CI − 6.4, 1.0) and − 1.0 (95% CI − 4.9, 3.0) and quality of life. Baring in mind the lower than anticipated inclusion rate, there were no significant differences in HbA1c and quality of life between three different frequencies of SMBG in patients with stable glycemic control using one long-acting insulin injection. Trial registration NCT01460459, registered 10-2011, recruitment between 05-2011 and 12-2011

Background orthostatic hypotension (OH) is one out of many risk factors believed to contribute to an increased fall risk in elderly subjects but it is unclear whether an independent association between OH and falling exists. Objectives to perform an individual patient data (IPD) meta-analysis of prospective observational studies investigating the relationship between OH and falling. Design MEDLINE, EMBASE, the Cochrane Library and the abstracts of annual meetings of selected hypertension societies were searched. Both one-stage (analysing all IPD from all studies simultaneously) and two-stage (analysing IPD per study, and then pooling the results) methods were used, and both logistic and cox regression analyses were performed. The study protocol was published on PROSPERO (2015:CRD42015019178). Results from 34 selected abstracts, 6 studies were included. IPD were provided in 1,022 patients from 3 cohorts and were included in the IPD meta-analysis. The one-stage meta-analysis showed a significant relationship between OH and time to first fall incident (hazard ratio (HR) 1.52 (95% Confidence Interval (CI) 1.23-1.88)). No significant relationship between OH and falling was found in the one-stage logistic regression analysis and the two-stage logistic and cox regression analyses. Conclusions this IPD meta-analysis of prospective observational studies showed a clear and significant relationship between OH and time to first fall incident. Although the ORs of falling was not significantly different for patients with and without OH, a the cox regression analyses reporting HRs and including time to incident provided more clinically relevant information in present meta-analysis.

Item does not contain fulltext BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0.83 (95% CI 0.74-0.94), decreasing to 0.78 (0.66-0.92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction

Background: Type 2 diabetes mellitus (T2DM) is a risk factor for the development of non-alcoholic fatty liver disease, which can lead to liver fibrosis and ultimately to cirrhosis. Transient elastography (TE), by using the FibroScan, and is a non-invasive ultrasonography method to measure liver elasticity. TE has been related with the degree of liver fibrosis. Objective: To investigate the applicability of TE in daily clinical practice among T2DM patients. Method: In a non-academic teaching hospital, T2DM patients without a history of liver disease the degree of liver stiffness was measured using TE. Successful measurements were defined as 10 validated measurements per patient and an interquartile range (IQR) to median ratio of ≤30%. Results: In 90 of 126 patients (71%) valid measurements were be obtained. Among the patients with invalid measurements, 33 had < 10 valid measurements and 3 had a IQR to median ratio of 2 and 39% in patients with a BMI ≥30 kg/m2. Among the 90 patients with valid liver stiffness measurements, the median liver stiffness was 6.7 [4.6-8.5] kPa with a IQR of measurements of 1.1 [0.6-1.8] kPa and IQR to median ratio of 17 (13-23)%. Conclusion: The success rate of TE measurements using the FibroScan in patients with T2DM was 71%, with a lower success rate in patients with a BMI ≥ 30 kg/m2. This diagnostic modality needs further investigation being introduced as a marker of fibrosis in daily diabetes practice.

Aim: To investigate changes in body weight trajectories after the addition of individual sulphonylureas (SUs) to metformin in patients with type 2 diabetes.Materials and methods: We conducted a retrospective observational cohort study, in a primary care setting in the Netherlands. Patients aged >= 18 years with type 2 diabetes who were included in the ZODIAC cohort between 1998 and 2012 and who received metformin monotherapy at inclusion (n = 29 195), and had used metformin as monotherapy for at least 1 year before receiving dual therapy through the addition of an SU for at least 1 year were eligible for inclusion. The primary outcome was within-drug yearly change in body weight after receiving add-on therapy with individual SUs during 5 years of follow-up. The secondary outcome was within-drug yearly change in glycated haemoglobin (HbA1c). Annual changes in weight and HbA1c were estimated with linear mixed models, adjusted for age, gender and diabetes duration.Results: A total of 2958 patients were included. No significant weight changes were observed within and between any of the individual SUs after treatment intensification (p = 0.24). In addition, no significant difference in weight between the add-on therapy combinations was observed (p = 0.26). The average HbA1c the year before intensification was 7.2% (55 mmol/mol) and dropped below 7.0% (53 mmol/mol) the year after.Conclusions: In patients with type 2 diabetes treated in primary care, strict glycaemic control can be maintained with SUs used as add-on therapy to metformin, without the offset of relevant weight changes.

Background: C-reactive protein (CRP), procalcitonin (PCT) and pro-adrenomedullin (MR-proADM) are inflammation markers associated with long-term mortality risk. We compared the associations and predictive capacities of CRP, PCT and MR-proADM with cardiovascular and all-cause mortality in patients with type 2 diabetes.Methods: This study included primary care treated patients with type 2 diabetes participating in the ZODIAC cohort study. A total of 1005 out of 1688 patients (60%) had complete baseline variables. Baseline CRP, PCT and MR-proADM were assessed in relation to cardiovascular and all-cause mortality with Cox proportional hazard analyses. Hazard Ratios (HR) were adjusted for age, gender, BMI, smoking, systolic blood pressure, cholesterol-HDL ratio, duration of diabetes, HbA(1c), history of cardiovascular diseases, albumin-creatinine ratio and creatinine. Risk prediction capabilities were assessed with Harrell's C statistics and proportion of explained variance (R-2).Results: After a median follow-up of 11 years, 472 (47%) of 1005 patients had died. The likelihood ratio test showed that CRP and MR-proADM significantly improved prediction in cardiovascular mortality [HRs 1.20 (95% CI 1.09-1.33) and 1.56 (95% CI 1.06-2.30)] and in all-cause mortality [HRs 1.10 (95% CI: 1.03-1.18) and 1.31 (95% CI 1.02-1.69)]. Harrell's C values and R-2 measures showed slightly improved discrimination for cardiovascular mortality in patients without macrovascular disease (C: 0.80 to 0.81; R-2: 0.50 to 0.52) and MR-proADM (C: 0.80 to 0.82; R-2: 0.50 to 0.52).Conclusions: CRP and MR-proADM, but not PCT, were independently associated with cardiovascular and all-cause mortality. In patients without macrovascular diseases, CRP and MR-proADM slightly improved discrimination, in absolute sense, of patients at risk for cardiovascular mortality. (C) 2016 Published by Elsevier Ireland Ltd.

BackgroundDiabetes and obesity seem to be partly overlapping risk factors for the development of obesity- related cancer (mainly breast, prostate and colorectal cancer) in patients with type 2 diabetes (T2DM). In the general population, women have a lower risk for obesity-related cancer compared to men. Previous studies involving cardiovascular disease have shown that T2DM eliminates a female advantage of lower CVD risk in the general population compared to men. It is unclear whether the same could be true for obesity-related cancer. This study aimed to this investigate obesity-related cancer incidence in women and men known with T2DM as compared to the Dutch general population.MethodsThis study included 69,583 patients with T2DM selected from a prospective primary care cohort, which was linked to the Dutch National Cancer Registry to obtain cancer specific data. Obesity-related cancers included liver, kidney, colorectal, gallbladder, pancreas, ovarian, endometrial, advanced prostate cancer, post-menopausal breast cancer and oesophageal adenocarcinoma. Primary outcome was sex-stratified, age and year of cancer diagnosis adjusted standardized incidence ratios (SIRs) for three time periods: 5 years before, the year after diagnosis and the next 4 years after T2DM diagnosis. The Dutch general population was used as reference group.ResultsWomen with T2DM were at an increased risk for obesity-related cancer compared to women in the general population already 5 years before diabetes diagnosis (SIR 1.77; 95% CI: 1.63 +/- 1.91). In both men and women, there was a peak in obesity-related cancer incidence following diabetes diagnosis (SIR: 1.38; 95% CI 1.11 +/- 1.64 and SIR: 2.21; 95% CI 1.94-2.30, respectively). From the second to the fifth year after diabetes diagnosis the obesity-related cancer incidence was higher in women compared to women in the general population (SIR: 2.12; 95% CI 1.94 +/- 2.30).ConclusionsWomen with T2DM seem to have a substantially higher obesity-related cancer risk. As opposed to men, in women this risk was already increased years before diabetes diagnosis. These results could imply that a relative advantage of women in the general population with regard to cancer risk is lost in women with T2DM.

ObjectiveTo investigate the relationship between body mass index (BMI) and obesity-related cancers in men and women with type 2 diabetes (T2D).DesignObservational cohort study.SettingPrimary care.ParticipantsA total of 52 044 patients with T2D who participated in the ZODIAC (Zwolle Outpatient Diabetes project Integrating Available Care) study between 1998 and 2012 was included (49% women). A dataset of these patients was linked to available information of the Netherlands Cancer Registry to obtain data on cancer incidents.Primary outcome measuresAnalyses were performed for the total group of obesity-related cancers and for non-sex-specific and sex-specific obesity-related cancers (in men: advanced prostate cancer, in women: ovarian, endometrial and postmenopausal breast cancer).ResultsThe median follow-up period in all analyses was 3.1 (1.7–5.0) years in men and 3.1 (1.7–5.1) in women. During follow-up, 689 men and 914 women were diagnosed with an obesity-related cancer. In men, BMI was associated with a higher risk of the total group of obesity-related cancers and non-sex-specific obesity-related cancers (HR (per 5 kg/m2increase) 1.12 (95% CI 1.02 to 1.23) and HR 1.18 (95% CI 1.06 to 1.31)). No association was found with prostate cancer. In women, an association between BMI and all obesity-related cancers combined and sex-specific obesity-related cancers was present (HR 1.15 (95% CI 1.08 to 1.22) and HR 1.22 (95% CI 1.14 to 1.32)). No association with non-sex-specific cancers was found in women.ConclusionsBMI is associated with obesity-related cancers in men with T2D, except with advanced prostate cancer. The results of this study provide reason to reconsider the classification of advanced prostate cancer as an obesity-related cancer, at least in T2D. In women, BMI is associated with the total group of obesity-related cancers and with sex-specific obesity-related cancers.

Introduction Combined data suggest a bimodal association of alanine aminotransferase (ALT) with mortality in the general population. Little is known about the association of ALT with mortality in patients with type 2 diabetes. We therefore investigated the association of ALT with all-cause, cardiovascular and noncardiovascular mortality in patients with type 2 diabetes.Design A prospective study was performed in patients with type 2 diabetes, treated in primary care, participating in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study. Cox regression analyses were performed to determine the associations of log(2)-transformed baseline ALT with all-cause, cardiovascular and noncardiovascular mortality.Results In 1187 patients with type 2 diabetes (6712years, 45% female), ALT levels were 11 (8-16)U/L. During median follow-up for 111 (61-140)years, 553 (47%) patients died, with 238 (20%) attributable to cardiovascular causes. Overall, ALT was inversely associated with all-cause mortality (hazard ratio [HR] 081; 95% confidence interval [CI] 072-092), independently of potential confounders. This was less attributable to cardiovascular mortality (HR 087; 95% CI 072-105), than to noncardiovascular mortality (HR 077; 95% CI 065-090). Despite the overall inverse association of ALT with mortality, it appeared that a bimodal association with all-cause mortality was present with increasing risk for levels of ALT above normal (P=0003).Discussion In patients with type 2 diabetes, low levels of ALT are associated with an increased risk of all-cause mortality, in particular noncardiovascular mortality, compared to normal levels of ALT, while risk again starts to increase when levels are above normal.

OBJECTIVE: There is limited evidence with respect to the between-group effects of various angiotensin receptor blockers (ARBs) on blood pressure and albuminuria in patients with type 2 diabetes mellitus. Therefore, we aimed to investigate the effects of differing ARBs on systolic blood pressure (SBP) and the albumin-creatinine ratio after 1 year in a large cohort of patients with type 2 diabetes mellitus.METHODS: In 2007, 24 940 primary care patients with type 2 diabetes mellitus participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study, a prospective observational cohort study. Patients were included in the current study if they were prescribed an ARB in 2007 and if 1-year follow-up data were available. The final study population comprised 3610 patients. Multivariate mixed-model analyses were performed to estimate effects of the various ARBs on SBP and albuminuria. Stratified subgroup analyses were performed according to baseline hypertension and albuminuria.RESULTS: SBP decreased in all groups, the largest decrease being observed in the group receiving telmisartan. No significant or relevant changes over time were observed among groups for SBP and albuminuria. In the subgroup (n=1225) of normotensive patients, telmisartan was associated with a larger decrease in SBP after 1 year compared to other ARBs, without different effects on the albumin-creatinine ratio.CONCLUSIONS: We observed no differences in effects on SBP and the albumin-creatinine ratio among differing ARBs in patients with type 2 diabetes mellitus.

Background: Recent decades have seen a constant upward projection in the prevalence of diabetes. Attempts to estimate diabetes prevalence rates based on relatively small population samples quite often result in underestimation. The aim of the present study was to investigate whether the Dutch diabetes prevalence estimate of 930 000 for 2013, based on a relatively small sample, still holds true when a larger population is studied using actual prevalence data. Methods: Data were collected from 92 primary care groups, including the total number of people with and without diabetes in 2013. Patients with diabetes were identified using the International Classification of Primary Care codes T90.02 (diabetes mellitus type 2; T2DM), T90.01 (diabetes mellitus type 1) and T90 (diabetes mellitus). Prevalence data were compared with previous estimates made in 2009. Diabetes prevalence was estimated using linear extrapolation. Results: Complete data were available from 67 (73%) care groups, which together provided care for 7 922 403 subjects; 431 396 patients were coded as having diabetes, of whom 406 183 were coded as having T2DM. Based on these results, the extrapolated Dutch diabetes prevalence was 914 387 (5.45%). Conclusions The results show that the previous estimate (reported in 2009), which was based on data collected in 2007, resulted in a

Background Patients with type 2 diabetes (T2D) are at increased risk for developing cancer. As approximately 8% of the world’s population is living with T2D, even a slight increase in cancer risk could result in an enormous impact on the number of persons developing cancer. In addition, several glucose lowering drug classes for treating patients with T2D have been associated with a difference in risk of cancer overall, and especially for obesity related cancers. In what way and to what degree cancer risk is modified by the use of different sulfonylureas (SU) is unclear. The primary aim of this study will be to evaluate within-class SU differences in obesity related cancer risk. Secondary aims will be to investigate within-class SU differences in risk for all cancers combined and site-specific cancers separately (i.e. breast, colorectal, prostate, bladder and lung cancer) and to account for duration-response relationships between individual SU use and cancer risk. Methods Patients will be selected from a Dutch primary care cohort of patients with T2D linked with the Dutch Cancer Registration (ZODIAC-NCR). Within this cohort study annually collected clinical data (e.g. blood pressure, weight, HbA1c) and nationwide data on cancer incidence are available. Time-dependent cox proportional hazard analyses will be performed to evaluate SU cancer risk, adjusted for potential confounders. Discussion This study will be the first prospective cohort study investigating within-class SU differences in cancer risk and could contribute to improved decision making regarding the individual drugs within the class of SUs, and possibly improve quality of life and result in an increased cost-effectiveness of healthcare in patients with T2D. Trial registration Nederlands Trialregister ( NTR6166 ), 6 Jan 2017.

Aims: To estimate the annual amputation rate in all secondary care treated patients with diabetes in the Netherlands and specifically in patients known with diabetic retinopathy.Methods: A nationwide population-based retrospective cohort study was performed including the years 2007-2011. Data of patients were retrieved from reimbursement registries for hospital care from a nationwide insurance database including codes for diabetes, retinopathy and amputation. Traumatic amputations were excluded.Results: The number of patients with secondary care treated diabetes increased from 132.499 to 137.049 over the years 2007-2011 in the Netherlands. The annual rate of non-traumatic lower-extremity amputations ranged from 4.32 to 5.28 amputations per 1.000 patients.For patients diagnosed with non-proliferative and (pre-) proliferative diabetic retinopathy, the mean amputation rates were 7.9 per 1.000 and 14.7 per 1.000, respectively.Conclusion: The Dutch annual incidence rates of non-traumatic lower extremity amputations in secondary care treated patients with diabetes is relatively low and remained stable over the years 2007 to 2011. The amputation rate in patients with retinopathy was substantially higher compared to patients without retinopathy. (C) 2017 Elsevier Inc. All rights reserved.

ObjectiveTo investigate sex differences in survival of primary care treated patients with type 2 diabetes (T2D) in the Netherlands.SettingPrimary care.ParticipantsA total of 1815 patients who participated in a prospective observational cohort study (Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC)) were included of which 56% was female. Inclusion took place in 1998, 1999 and 2001. Vital status was assessed in 2013.Main outcome measureRelative survival of men and women with T2D. The relative survival rate was expressed as the ratio of observed survival of patients divided by the survival of the general population in the Netherlands with comparable age.ResultsAfter 14 years, 888 (49%) patients had died. The relative survival rate was 0.88 (0.81–0.94) for men and 0.82 (0.76–0.87) for women with T2D after 14 years (p value for difference between sexes=0.169). In patients without a history of cardiovascular diseases (CVD), the relative survival was 0.99 (0.94–1.05) in men and 0.92 (0.87–0.97) in women (p value for difference between sexes=0.046).ConclusionsThe survival of men and women with T2D was 12% and 18% lower, respectively, after 14 years of follow-up compared with men and women in the general population. This corresponds to a decrease in median survival of 2.2 and 3.5 years in men and women, respectively. Only for patients with T2D without a history of CVD, a significantly lower relative survival in women compared with men with T2D was found.

IMPORTANCE: Device-guided breathing (DGB) is recommended by the American Heart Association for its blood pressure-lowering effects. Most previous studies that showed beneficial effects on blood pressure had low methodological quality and only investigated short-term blood pressure effects.OBJECTIVE: To assess the efficacy of DGB on blood pressure in a meta-analysis of individual patient data from blinded, randomized controlled trials with an active control group.DATA SOURCES: MEDLINE, EMBASE, clinicaltrials.gov, and the Cochrane Library.STUDY SELECTION: Included were randomized studies of at least 4 weeks' duration, with a single- or double-blind design and an active control group. Bias was assessed with the Cochrane risk of bias tool, and analyses were performed with linear mixed models.DATA EXTRACTION AND SYNTHESIS: Articles were searched in MEDLINE (using PubMed), EMBASE, and the Cochrane Library.MAIN OUTCOMES AND MEASURES: Office blood pressure.RESULTS: From the 15 selected abstracts, 5 studies were suitable for inclusion. Individual patient data from 2 of 5 studies were not provided. The effect of DGB on office systolic blood pressure compared with music therapy or a sham device was 2.2 mm Hg (95% CI, -2.7 to 7.0) in favor of the control group; DGB did not significantly lower office diastolic blood pressure (0.2 mm Hg [95% CI, -2.8 to 3.1] in favor of DGB).CONCLUSIONS AND RELEVANCE: All trials included in the analysis had a short follow-up period; therefore, no recommendations could be made regarding hypertension treatment. Treatment with DGB did not significantly lower office blood pressure compared with a sham procedure or music therapy.

Van Hateren KJJ, Houweling ST, De Bock GH, Van Dijk PR, Groenier KH, Gans ROB, et al. Veiligheid en effectiviteit van gliclazide. Huisarts Wet 2014;57(8):400-3. In deze meta-analyse hebben wij de veiligheid en effectiviteit van gliclazide onderzocht en vergeleken met die van andere orale bloedglucoseverlagende middelen. Op 17 april 2013 hebben we Medline (PubMed), EMBASE en de Cochrane-database doorzocht op geschikte gerandomiseerde onderzoeken met een minimale onderzoeksduur van twaalf weken bij volwassenen met diabetes mellitus type 2, waarbij een verandering in HbA1c werd gerapporteerd en gliclazide werd vergeleken met een ander oraal middel. De primaire uitkomstmaat wat betreft veiligheid was het aantal patienten met minimaal een ernstige hypoglykemie, en ten aanzien van effectiviteit de verandering in HbA1c. We hebben 19 onderzoeken geincludeerd, bijna alle van een slechte methodologische kwaliteit. Het HbA1c daalde 0,12% (95%-BI 0,01 tot 0,23%) meer in de gliclazidegroep dan in de actieve controlegroepen. We vonden 1 ernstige hypoglykemie bij 2387 gliclazidegebruikers en 1 bij de 2430 gebruikers van een actieve controle. De ernstige hypoglykemie in de gliclazidegroep trad op bij iemand die in de weken voorafgaand aan de hypoglykemie ook was gestart met NPH-insuline. Hypoglykemieen met gliclazide zijn zeldzaam en gliclazide is ten minste zo effectief als de andere orale bloedglucoseverlagende middelen. De methodologische kwaliteit van bijna alle onderzoeken was slecht.

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.

Background: The prevalence of type 2 diabetes mellitus (T2DM) is rising in the Netherlands, and health care’s workload will increase. e-Health applications may increase patients’ participation in their care and could help reducing workload. To explore potential users, differences in patients interested and uninterested in e-Health are characterized. Methods: A prospective cohort study was initiated in the Drenthe region of the Netherlands. This study included inviting T2DM patients to use e-Health (the e-Vita platform). Patients were offered access to clinical data, laboratory results, educational modules, and a self-management support program. Data were obtained from health record systems of general practices and questionnaires. Results: Out of 2674 patients, 1378 (51.5%) participated in the study. Of the 1378 patients, 974 (70.7%) were interested in e-Health. Of 974, 405 (41.6%) were registered for e-Health. Interested patients were more often male, were younger, had shorter T2DM duration, and were higher educated. Of 405, 110 (27.2%) used the e-Health. No differences were found between users and nonusers of e-Health. Discussion: Patients interested in e-Health were more often male, were younger, had shorter T2DM duration, and were more often higher educated. However, even in this interested group, the actual participation rate remained low. Together with characteristics and attitudes of caregivers and T2DM patients, the look and content of the e-Health platform strategies that increase interest and participation need to be developed.

We investigated the association between the current use of individual sulphonylureas and the risk of a first‐ever acute myocardial infarction (AMI) and all‐cause mortality, in a population‐based cohort study, using primary care data from the Clinical Practice Research Datalink database (2004‐2012). New users (N = 121 869), aged ≥18 years, with at least one prescription for a non‐insulin antidiabetic agent were included. The first prescription defined start of follow‐up. Time‐dependent Cox proportional hazard models were used to estimate the risk of a first‐ever AMI and all‐cause mortality associated with the use of individual sulphonylureas, and other non‐insulin glucose‐lowering drugs. No differences in risk of a first‐ever AMI (adjusted hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.70‐1.50) or all‐cause mortality (adjusted HR 0.97, 95% CI 0.80‐1.17) were observed when comparing gliclazide use with non‐gliclazide sulphonylurea use. Similar results were found for each individual sulphonylurea. As evidence is accumulating that gliclazide is no safer than other sulphonylureas, current guidelines suggesting superiority should be carefully evaluated.

Dear editor,Barros et al. reported the long-term effects of device-guided slow breathing (DGB) in hypertensive patients comparing DGB using a device called the REPeRATE® (InterCure Ltd, Tel-Aviv, I...

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.

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 MAIN OUTCOMES AND MEASURES Systolic and diastolic blood pressure measured in the physician's 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 2.35mmHg (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.

Ticagrelor and aspirin may differ in their effects on the risk of acute stroke or transient ischemic attack.

OBJECTIVE The aim of this study was to investigate the association between plasma COOH-terminal proendothelin-1 (CT-proET-1) and fatal cardiovascular events, all-cause mortality, and new-onset albuminuria in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 1,225 patients with type 2 diabetes participated in this prospective observational study of two combined cohorts. Three clinical end points were studied: fatal cardiovascular events, all-cause mortality, and new-onset albuminuria. After a median follow-up of 3 or 10 years, Cox proportional hazard modeling was used to investigate the association between CT-proET-1 and the end points. Harrell C statistic, the Groennesby and Borgan test, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI) were used to evaluate whether CT-proET-1 is of additional value compared with classic cardiovascular and renal risk factors. RESULTS During follow-up, 364 (30%) patients died, 150 (42%) of whom died of cardiovascular disease; 182 (26.7%) of 688 patients with normoalbuminuria at baseline developed albuminuria. CT-proET-1 was associated with fatal cardiovascular events, all-cause mortality, and new-onset albuminuria with hazard ratios of 1.59 (95% CI 1.15–2.20), 1.41 (95% CI 1.14–1.74), and 1.48 (95% CI 1.10–2.01), respectively. Addition of CT-proET-1 to a model containing traditional risk factors leads only to improved prediction of fatal cardiovascular events. The IDI appeared significant for fatal cardiovascular events (0.82 [0.1–1.54]) and all-cause mortality (0.4 [0.05–0.92]), but not for new-onset albuminuria. CONCLUSIONS CT-proET-1 has additional value for the prediction of fatal cardiovascular events and new-onset albuminuria in patients with type 2 diabetes, compared with conventional risk factors, but not for all-cause mortality.

Aims: To test whether the genetic variant CCR5 Delta 32 in the CC-chemokine receptor 5, which is known to lead to CCR5 deficiency, is associated with mortality in type 2 diabetes patients.Methods: We examined the effect of presence or absence of the CCR5 Delta 32 on overall and cardiovascular mortality risk in the Zwolle outpatient Diabetes project Integrating Available Care (ZODIAC) cohort, a type 2 diabetes patient cohort.Results: We studied 756 patients with a mean duration of follow-up of 5.4 (+/- 1.4) years. 194 patients died during follow up of which 83 were cardiovascular deaths. 144 subjects (19%) carried the CCR5 Delta 32 deletion. CCR5 Delta 32 carriers had an adjusted hazard ratio of 0.62 (95%CI: 0.40-0.96; p = 0.03) for all-cause mortality and 0.63 (95%CI: 0.33-1.19; p = 0.16) for cardiovascular mortality.Conclusions: The presence of CCR5 Delta 32 is associated with better survival in type 2 diabetes patients. These data suggest that it is worthwhile to explore the protective potential of pharmacological blockade of CCR5 in type 2 diabetic patients. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Background and aims: Hyponatremia has been associated with an increased mortality risk in the general population. Diabetes is a condition predisposing for elevated levels of arginine vasopressin (AVP) and heart failure, both common causes of hyponatremia. These factors, however, are also associated with an increased mortality risk. We aimed to investigate whether serum sodium is associated with cardiovascular and all-cause mortality in type 2 diabetes and whether these associations could be explained by copeptin, a surrogate for AVP, or NT-proBNP, a marker for heart failure.Methods: Patients with type 2 diabetes participating in the observational ZODIAC study were included. Cox regression analyses were used to investigate the association of serum sodium with mortality.Results: We included 1068 patients (age 67 +/- 12 years, 45% male, serum sodium 142 +/- 3 mmol/L). After 15 years of follow-up, 519 patients (49%) died, with 225 cardiovascular deaths (21%). In univariable analyses, serum sodium, copeptin, and NT-proBNP were all significantly associated with cardiovascular and all-cause mortality. These associations remained significant after combination of these markers in a multivariable model. Serum sodium and NT-proBNP remained significantly associated with mortality after further adjustment for potential confounders, whereas copeptin lost significance after adjustment for SCr and ACR.Conclusion: Low serum sodium was associated with an increased risk of cardiovascular and all-cause mortality in type 2 diabetes. Moreover, these associations were not explained by copeptin and NT-proBNP. Whether low serum sodium itself leads to poor outcome or is a marker for (unidentified) comorbidity severity or use of specific medications remains to be elucidated. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

BackgroundTwo previous studies concluded that proenkephalin A (PENK-A) had predictive capabilities for stroke severity, recurrent myocardial infarction, heart failure and mortality in patients with stroke and myocardial infarction.ObjectivesThis study aimed to investigate the value of PENK-A as a biomarker for predicting mortality in patients with type 2 diabetes mellitus.MethodsPatients with type 2 diabetes mellitus were included from the prospective observational ZODIAC (Zwolle Outpatient Diabetes project Integrating Available Care) study. The present analysis incorporated two ZODIAC cohorts (1998 and 2001). Since blood was drawn for 1204 out of 1688 patients (71%), and information on relevant confounders was missing in 47 patients, the final sample comprised 1157 patients. Cox proportional hazard models were used for evaluating the relationship between PENK-A and (cardiovascular) mortality. Risk prediction capabilities were assessed with Harrell's C statistics and the integrated discrimination improvement (IDI).ResultsAfter a follow-up period of 14 years, 525 (45%) out of 1157 patients had died, of which 224 (43%) were attributable to cardiovascular factors. Higher Log PENK-A levels were not independently associated with increased (cardiovascular) mortality. Patients with PENK-A values in the highest tertile had a 49% (95% CI 1%-121%) higher risk of cardiovascular mortality compared to patients in the reference category (lowest tertile). C-values were not different after removing PENK-A from the Cox models and there were no significant differences in IDI values.ConclusionsThe associations between PENK-A and mortality were strongly attenuated after accounting for all traditional risk factors. Furthermore, PENK-A did not seem to have additional value beyond conventional risk factors when predicting all-cause and cardiovascular mortality.

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 (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.

Recent decades have seen a constant upward projection in the prevalence of diabetes. Attempts to estimate diabetes prevalence rates based on relatively small population samples quite often result in underestimation. The aim of the present study was to investigate whether the Dutch diabetes prevalence estimate of 930 000 for 2013, based on a relatively small sample, still holds true when a larger population is studied using actual prevalence data.Data were collected from 92 primary care groups, including the total number of people with and without diabetes in 2013. Patients with diabetes were identified using the International Classification of Primary Care codes T90.02 (diabetes mellitus type 2; T2DM), T90.01 (diabetes mellitus type 1) and T90 (diabetes mellitus). Prevalence data were compared with previous estimates made in 2009. Diabetes prevalence was estimated using linear extrapolation.Complete data were available from 67 (73%) care groups, which together provided care for 7 922 403 subjects; 431 396 patients were coded as having diabetes, of whom 406 183 were coded as having T2DM. Based on these results, the extrapolated Dutch diabetes prevalence was 914 387 (5.45%).The results show that the previous estimate (reported in 2009), which was based on data collected in 2007, resulted in a2% (~16 000) overestimation in diabetes prevalence in 2013 compared with the analysis presented. These results indicate that no upward adjustment in Dutch diabetes prevalence estimates is necessary. Repeated large-scale monitoring can help develop more accurate prevalence estimates and improve future prevalence predictions.

Background: In a sham-controlled double-blind trial, we aim to establish the efficacy and safety of the local application of laser therapy in patients with diabetes, onychomycosis and risk factors for diabetes-related foot complications. Onychomycosis leads to thickened and distorted nails, which in turn lead to increased local pressure. The combination of onychomycosis and neuropathy or peripheral arterial disease (PAD) increases the risk of developing diabetes-related foot complications. Usual care for high-risk patients with diabetes and onychomycosis is completely symptomatic with frequent shaving and clipping of the nails. No effective curative local therapies exist, and systemic agents are often withheld due to concerns for side effects and interactions. Methods/Design: The primary aim is to evaluate the efficacy of four sessions of Nd:YAG 1064 nM laser application on the one-year clinical and microbiological cure rate in a randomized, double-blind, sham-controlled design with blinded outcome assessment. Mandatory inclusion criteria are diagnosis of diabetes, risk factors for developing foot ulcers defined as a modified Simm’s classification score 1 or 2 and either neuropathy or PAD. A total of 64 patients are randomized to intervention or sham treatment performed by a podiatrist. Discussion: This study will be the first double-blind study that investigates the effects of local laser therapy on onychomycosis, specifically performed in patients with diabetes with additional risk factors for foot complications. Trial registration: Clinical trials.gov as NCT01996995, first received 22 November 2013.

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.

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, I(2) 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.

Background: Oxidative stress plays an underlying pathophysiologic role in the development of diabetes complications. The aim of this study was to investigate peroxiredoxin 4 (Prx4), a proposed novel biomarker of oxidative stress, and its association with and capability as a biomarker in predicting (cardiovascular) mortality in type 2 diabetes mellitus.Methods: Prx4 was assessed in baseline serum samples of 1161 type 2 diabetes patients. Cox proportional hazard models were used to evaluate the relationschip between Prx4 and (cardiovascular) mortality. Risk prediction capabilities of Prx4 for (cardiovascular) mortality were assessed with Harrell's C statistic, the integrated discrimination improvement and net reclassification improvement.Results: Mean age was 67 and the median diabetes duration was 4.0 years. After a median follow-up period of 5.8 years, 327 patients died; 137 cardiovascular deaths. Prx4 was associated with (cardiovascular) mortality. The Cox proportional hazard models added the variables: Prx4 (model 1); age and gender (model 2), and BMI, creatinine, smoking, diabetes duration, systolic blood pressure, cholesterol-HDL ratio, history of macrovascular complications, and albuminuria (model 3). Hazard ratios (HR) (95% CI) for cardiovascular mortality were 1.93 (1.57 - 2.38), 1.75 (1.39 - 2.20), and 1.63 (1.28 - 2.09) for models 1, 2 and 3, respectively. HR for all-cause mortality were 1.73 (1.50 - 1.99), 1.50 (1.29 - 1.75), and 1.44 (1.23 - 1.67) for models 1, 2 and 3, respectively. Addition of Prx4 to the traditional risk factors slightly improved risk prediction of (cardiovascular) mortality.Conclusions: Prx4 is independently associated with (cardiovascular) mortality in type 2 diabetes patients. After addition of Prx4 to the traditional risk factors, there was a slightly improvement in risk prediction of (cardiovascular) mortality in this patient group.

In the statement of the American Heart Association on nonpharmacological options for blood pressure (BP) reduction, device-guided slow breathing exercises with the RESPeRATE (Intercure Lt) device are mentioned as a reasonable option to support lowering BP.1 The authors conclude that the RESPeRATE (costing ≈299 US Dollar) could harbor benefits for a wide range of populations (class IIA evidence, level of recommendation B).1 We respectfully disagree with this conclusion. The conclusions presented in the …

BackgroundPrevious studies have shown that many within-class differences exist between sulfonylureas (SUs), however, whether differences exist regarding the time it takes between initiating an SU and the need to intensify treatment with insulin is unclear. The aim of this study was investigate the relationships between the three frequently used sulphonylureas, prescribed as dual therapy next to metformin, and the time needed to treatment intensification with either insulin or oral triple therapy in patients with type 2 diabetes mellitus.MethodsZwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) is a prospective observational cohort study set in primary care in the Netherlands. Annually collected data on diabetes medication and clinical variables within ZODIAC are used to evaluate the primary outcome, time to insulin and secondary outcome, time to either insulin or triple oral therapy. For statistical analysis a time-dependent cox proportional hazard model was used.Results3507 patients were included in the analysis, with a mean age of 61 (SD 11.4) and a median HbA1c of 6.8% [IQR 6.4-7.4] (50.8 mmol/mol [IQR 46.4-57.4]). The hazard ratio (HR) for the primary endpoint was 1.10 (95% CI 0.78-1.54) for metformin/glimepiride and 0.93 (95% CI 0.67-1.30) for metformin/tolbutamide with metformin/gliclazide as reference group. The HR for the secondary outcome was 1.04 (95% CI 0.78-1.40) and 0.85 (95% CI 0.64-1.13), respectively.ConclusionIn this large Dutch primary care cohort, new users of neither gliclazide, glimepiride nor tolbutamide as dual therapy with metformin, resulted in differences in the time needed for further treatment intensification.

OBJECTIVE Evidence that midregional fragment of pro-A–type natriuretic peptide (MR-proANP) is a marker of mortality in patients with type 2 diabetes is limited. Therefore, we aimed to investigate the capabilities of MR-proANP in predicting mortality. We also investigated whether MR-proANP influences the relationship between blood pressure and mortality in old age. RESEARCH DESIGN AND METHODS In 1998, 1,143 primary care patients with type 2 diabetes participated in the ZODIAC study. Because blood was drawn for 867 patients (76%) and confounders were missing for 19 patients, the final study sample comprised 848 patients. After a follow-up time of 10 years, we used Cox proportional hazard models to evaluate the relationship between MR-proANP and (cardiovascular) mortality. Harrell C statistic was used to compare models with and without MR-proANP. The regression analyses were repeated without MR-proANP for patients aged older than 75 years. RESULTS Median MR-proANP in the total study sample was 75 pmol/L (interquartile range, 48–124 pmol/L). During follow-up, 354 (42%) out of 848 patients had died, of whom 152 (43%) deaths were attributable to cardiovascular factors. MR-proANP was independently associated with all-cause and cardiovascular mortality, irrespective of age. During old age, there was a significant inverse relationship between blood pressure and mortality. This relationship did not change after adjustment for MR-proANP. CONCLUSIONS MR-proANP is independently associated with mortality in patients with type 2 diabetes. MR-proANP did not influence the inverse relationship between blood pressure and mortality in elderly patients.

Two recent meta-analyses focused on the risk-benefit ratio of metformin in the treatment of type 2 diabetes mellitus. Both studies conclude that the risk-benefit ratio of metformin monotherapy or combined with insulin is uncertain. In our opinion, the interpretation of the known literature in these meta-analyses could be flawed. To ascertain the effects of metformin on cardiovascular end-points, a follow-up period of at least 8 years proved necessary. However, these meta-analyses included a number of studies with a limited follow-up period, thus impairing the possibility to make a proper comparison of the long-term effects of metformin. In addition, one meta-analysis based the weight of included studies on the number of events in all studies, including two safety studies, as opposed to the number of studied patients.

OBJECTIVE The aim of this study was to investigate the association between plasma COOH-terminal proendothelin-1 (CT-proET-1) and fatal cardiovascular events, all-cause mortality, and new-onset albuminuria in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 1,225 patients with type 2 diabetes participated in this prospective observational study of two combined cohorts. Three clinical end points were studied: fatal cardiovascular events, all-cause mortality, and new-onset albuminuria. After a median follow-up of 3 or 10 years, Cox proportional hazard modeling was used to investigate the association between CT-proET-1 and the end points. Harrell C statistic, the Groennesby and Borgan test, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI) were used to evaluate whether CT-proET-1 is of additional value compared with classic cardiovascular and renal risk factors. RESULTS During follow-up, 364 (30%) patients died, 150 (42%) of whom died of cardiovascular disease; 182 (26.7%) of 688 patients with normoalbuminuria at baseline developed albuminuria. CT-proET-1 was associated with fatal cardiovascular events, all-cause mortality, and new-onset albuminuria with hazard ratios of 1.59 (95% CI 1.15–2.20), 1.41 (95% CI 1.14–1.74), and 1.48 (95% CI 1.10–2.01), respectively. Addition of CT-proET-1 to a model containing traditional risk factors leads only to improved prediction of fatal cardiovascular events. The IDI appeared significant for fatal cardiovascular events (0.82 [0.1–1.54]) and all-cause mortality (0.4 [0.05–0.92]), but not for new-onset albuminuria. CONCLUSIONS CT-proET-1 has additional value for the prediction of fatal cardiovascular events and new-onset albuminuria in patients with type 2 diabetes, compared with conventional risk factors, but not for all-cause mortality.