The Value of Glycemic Control Prior to Cancer Diagnosis on All-Cause Mortality among Patients with Type 2 Diabetes in Dutch Primary Care.

BACKGROUND: Poor glycemic control prior to cancer diagnosis for patients with preexisting type 2 diabetes (T2DM) may predict a worse cancer diagnosis. We investigated the association between pre-diagnosis glycemic control and all-cause mortality in patients with T2DM who develop cancer. METHODS: This prospective cohort study linked data from three sources covering 1989 to 2019: a T2DM benchmarking database, the Netherlands Cancer Registry, and the Personal Records Database. We included patients with T2DM and incident primary breast, colorectal, or prostate cancer (stage 0-III), with target glycemic control defined according to Dutch guidelines. Analysis involved estimating the association between glycemic control and all-cause mortality with Cox proportional hazard models, accounting for individual expected survival relative to the general population and relevant disease (e.g., diabetes duration and medications) and individual (e.g., age and gender) characteristics. RESULTS: Of the 71,648 linked cases, 620 had breast cancer, 774 had colorectal cancer, and 438 had prostate cancer, with follow-up data available for 6.4 (4.2-8.4), 5.6 (2.7-7.6), and 6.3 (4.5-8.2) years, respectively. Compared with patients with pre-diagnosis glycemic control at target, the HRs and 95% confidence intervals for mortality among those with pre-diagnosis glycemic control not at target were 1.40 (1.00-1.96) for breast cancer, 1.45 (1.12-1.88) for colorectal cancer, and 1.39 (0.98-1.98) for prostate cancer. CONCLUSIONS: Among patients with T2DM in Dutch primary care, poor glycemic control before diagnosis with breast and colorectal cancer can increase mortality compared with good control. IMPACT: Glycemic control prior to cancer diagnosis is of prognostic value.

The Risk of Cutaneous Squamous Cell Carcinoma Among Patients with Type 2 Diabetes Receiving Hydrochlorothiazide: A Cohort Study.

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.

Glycemic Control for Colorectal Cancer Survivors Compared to Those without Cancer in the Dutch Primary Care for Type 2 Diabetes: A Prospective Cohort Study.

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.

Effects of the Proactive Interdisciplinary Self-Management (PRISMA) Program on Online Care Platform Usage in Patients with Type 2 Diabetes in Primary Care: A Randomized Controlled Trial.

Online care platforms can support patients with type 2 diabetes (T2DM) in managing their health. However, in the use of eHealth, a low participation rate is common. The Proactive Interdisciplinary Self-Management (PRISMA) program, aimed at improving patients' self-management skills, was expected to encourage patients to manage their disease through the use of an online platform. Therefore, the objective of the current study was to investigate whether a group education program can improve the use of an online care platform in patients with T2DM treated by primary care providers in the Netherlands. In a randomized controlled trial, patients with T2DM received either PRISMA with usual care or usual care only. During a six-month follow-up period in 2014-2015, usage (number of log-ons and time spent per session) of an online care platform (e-Vita) aimed at improving T2DM self-management was assessed. A training about the functionalities of e-Vita was offered. The sample consisted of 203 patients. No differences were found between the intervention and control groups in the number of patients who attended the platform training (interested patients) (X 2(1) = 0.58; p = 0.45), and the number of patients who logged on at least once (platform users) (X 2(1) = 0.46; p = 0.50). In addition, no differences were found between the groups in the type of users-patients who logged on twice or more (active users) or patients who logged on once (nonactive users) (X 2(1) = 0.56; p = 0.45). The PRISMA program did not change platform usage in patients with T2DM. In addition, only a small proportion of the patients logged on twice or more. Patients probably need other encouragements to manage their condition using an online platform.

Effects of a Proactive Interdisciplinary Self-Management Program on Patient Self-Efficacy and Participation During Practice Nurse Consultations: A Randomized Controlled Trial in Type 2 Diabetes.

BACKGROUND: Nowadays, patients with chronic conditions such as type 2 diabetes mellitus (T2DM) need and want to be more active participants in their health care. This study aimed to investigate the effects of the Proactive Interdisciplinary Self-Management (PRISMA) training program on participation during consultations with practice nurses and self-efficacy of patients with T2DM in general practice. METHODS: Within a randomized controlled trial, patients were followed for 6 months. They received either PRISMA in addition to usual care or usual care only. Self-efficacy was assessed using the 5-item Perceived Efficacy in Patient-Physician Interactions (PEPPI-5) scale. Consultations were video-recorded and analyzed using the Roter interaction analysis system. Multilevel analysis was carried out. RESULTS: No differences in the PEPPI-5 were found between the intervention (n = 101) and control groups (n = 102) (U = 1,737.5, z = -0.2, P = 0.8). In addition, the groups did not differ in patient participation. However, patients who attended the PRISMA program expressed more counselling utterances (B = 0.22; standard error (SE) = 0.09). CONCLUSIONS: PRISMA did not result in higher self-efficacy or patient participation during the consultation with practice nurses at 6 months. Possibly, two training sessions are insufficient and a more powerful intervention might be needed. However, the study showed indications that patients counselled themselves more frequently during the consultation. Practice nurses could stimulate patients who are already engaged in self-counselling by further specifying their goals of behavior change.

Effects of the Proactive interdisciplinary self-management (PRISMA) program on self-reported and clinical outcomes in type 2 diabetes: a pragmatic randomized controlled trial.

BACKGROUND: Diabetes self-management education can be helpful for patients with type 2 diabetes in managing their condition. We aimed to study the effects of the group-based PRoactive Interdisciplinary Self-MAnagement (PRISMA) training program on self-reported and clinical outcomes in patients with type 2 diabetes treated in general practice. METHODS: Persons aged 18 years or older diagnosed with type 2 diabetes and treated in primary care were included. In a randomized controlled trial design (1:1), patients were followed for 6 months with an extension phase of 6 months. Block randomization was used. The patients with type 2 diabetes received either PRISMA in addition to usual care or usual care only. All patients completed a range of validated questionnaires (including knowledge, skills, and confidence for self-management [PAM], diabetes self-care behavior [SDSCA], health-related quality of life [EQ-5D], and emotional well-being [WHO-5]). In addition, clinical outcomes (HbA1c, body mass index, systolic blood pressure, and cholesterol levels) were collected during the routine diabetes checkups. RESULTS: Of the total sample (n = 193), 60.1% were men. The mean age was 69.9 years (SD = 9.1). No significant differences were found on self-reported outcomes between the groups at 0, 6, and 12 months. The clinical outcomes were not reported due to a large number of missing values. CONCLUSION: PRISMA did not improve self-reported outcomes in patients with type 2 diabetes treated in primary care. It was not possible to make a statement about the clinical effects. TRIAL REGISTRATION: date: 16/07/2014, number: NL4550 (https://www.trialregister.nl/trial/4550).

Different routes of insulin administration do not influence serum free thiols in type 1 diabetes mellitus.

AIMS: Intraperitoneal (IP) insulin administration is a last-resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As the IP route of insulin administration mimics the physiology more closely than the subcutaneous (SC) route, we hypothesized that IP insulin would result in less oxidative stress (expressed as systemic level of free sulphydryl (R-SH) content) compared to SC insulin in subjects with T1DM. MATERIALS AND METHODS: Prospective, observational case-control study. Serum thiol measurements were performed at baseline and at 26 weeks in age- and gender-matched patients with T1DM. Serum-free thiols, compounds with a R-SH group that are readily oxidized by reactive oxygen species, are considered to be a marker of systemic redox status. RESULTS: A total of 176 patients, 39 of which used IP and 141 SC insulin therapy were analysed. Mean baseline R-SH concentration was 248 (31) µmol/L. In multivariable analysis, the route of insulin therapy had no impact on baseline R-SH levels. The estimated geometric mean concentrations of R-SH did not differ significantly between both groups: 264 (95% CI 257, 270) for the IP group and 258 (95% CI 254, 261) for the SC group with a difference of 6 (95% CI -2, 14) µmol/L. CONCLUSIONS: Based on R-SH as a marker of systemic oxidative stress, these findings demonstrate that the route of insulin administration, IP or SC, does not influence systemic redox status in patients with T1DM.

Route of Insulin Does Not Influence 25-Hydroxyvitamin D Concentrations in Type 1 Diabetes: A Brief Report.

The increased prevalence of vitamin D [25(OH)D] deficiency in type 1 diabetes mellitus (T1DM) may be related to low insulin levels in the hepatic portal venous system. In this prospective matched-control study, we demonstrate that long-term intraperitoneal insulin does not influence 25(OH)D concentrations in patients with T1DM as compared with subcutaneous insulin administration.

Sulfonylurea derivatives and cancer, friend or foe?

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.

Effects of a Proactive Interdisciplinary Self-Management (PRISMA) program on medication adherence in patients with type 2 diabetes in primary care: a randomized controlled trial.

PURPOSE: The present study aims to investigate the effect of the group-based Proactive Interdisciplinary Self-Management (PRISMA) training program on medication adherence in patients with type 2 diabetes (T2DM) treated in primary care. PATIENTS AND METHODS: The current study is a two-arm, parallel group, randomized, open label trial (1:1) of 6-month duration with a 6-month extension period in which both groups received the intervention (wait-list control). People 18 years old or older who were diagnosed with T2DM were included. The intervention consisted of two group meetings about T2DM guided by care providers. The control group received usual care only (visits at the general practice). The primary outcome was adherence based on pharmacy refill data and was measured using medication possession ratio (MPR). The secondary outcomes were the number of drug holidays and self-reported adherence, measured by the 5-item Medication Adherence Rating Scale (MARS-5). RESULTS: Of the total sample (n=108), 66.6% were male. The mean age was 69.3 years (SD=9.1). In the 6-month period, patients were more adherent in the intervention group (n=56) (median MPR =100.0 [51.1-100.0]) than in the control group (n=52) (median MPR =97.7 [54.1-100.0]) (U=1,042, z=-2.783, P=0.005). The intervention group had less drug holidays than the control group (relative risk 0.55, 95% CI, 0.37-0.80). The sum scores of the MARS did not differ between the intervention group (median =23.98, SD=0.91) and the control group (median =24.00, SD=1.54). CONCLUSION: The PRISMA program resulted in a small improvement in MPR and fewer drug holidays, while no improvement has been found in self-reported adherence. However, health care providers and policy makers could take into account that adherence might be influenced by PRISMA.

Correction to: Mealtime insulin bolus adherence and glycemic control in adolescents on insulin pump therapy.

The Abstract section and the in the Results sections of the original version of this article, unfortunately, contained errors. The correct data are now shown in this article.

Mealtime insulin bolus adherence and glycemic control in adolescents on insulin pump therapy.

Poor self-management contributes to insufficient glycemic control in adolescents with type 1 diabetes (T1DM). We assessed the effects on glycemic control of adherence to self-measurement of blood glucose (SMBG) and insulin boluses in 90 adolescents with T1DM on insulin pump therapy over a 2-month period. We compared the number of insulin boluses and SMBGs around main meals to the "gold standard" of optimal diabetes management (SMBGs and a bolus before each main meal and SMBG before bedtime). The mean (95% CI) HbA1c levels were 2.9(1.7 to 4.0) mmol/mol lower for every additional insulin bolus and 3.1(1.6 to 4.5) mmol/mol lower for every additional SMBG. Patients performing SMBG and bolusing around each main meal had considerably lower HbA1c levels than those unable to do (95% CI for difference 4.3 to 10.4 mmol/mol and 11.5 to 20.1 mmol/mol respectively). For each additional mealtime bolus/day, the odds ratio of achieving target HbA1c levels of <58 mmol/mol was 6.73 (95% CI 2.94-15.38), after adjustment for gender, age, diabetes duration, and affective responses to SMBG in a multiple logistic regression model.Conclusion: Glycemic control in adolescents with T1DM on insulin pump therapy is strongly dependent on adherence to insulin boluses around mealtimes. What is Known: • In mixed groups of children and adolescents, insulin bolus frequency and self-monitoring of blood glucose (SMBG) frequency were determinants of HbA1c levels. • Adherence to insulin boluses and SMBG is particularly challenging in adolescents. What is New: • In adolescents on insulin pump therapy, each additional insulin bolus, particularly around mealtime, was significantly associated with approximately 3 mmol/mol lower HbA1c levels. • This beneficial effect of mealtime bolusing was strongest for the evening meal.

Is guideline-adherent prescribing associated with quality of life in patients with type 2 diabetes?

BACKGROUND: Guideline-adherent prescribing for treatment of multiple risk factors in type 2 diabetes (T2D) patients is expected to improve clinical outcomes. However, the relationship to Health-Related Quality of Life (HRQoL) is not straightforward since guideline-adherent prescribing can increase medication burden. OBJECTIVES: To test whether guideline-adherent prescribing and disease-specific medication burden are associated with HRQoL in patients with T2D. METHODS: Cross-sectional study including 1,044 T2D patients from the e-VitaDM/ZODIAC study in 2012 in the Netherlands. Data from the diabetes visit, such as laboratory and physical examinations and prescribed medication, and from two HRQoL questionnaires, the EuroQol 5 Dimensions 3 Levels (EQ5D-3L) and the World Health Organization Well-Being Index (WHO-5) were collected. Twenty indicators assessing prescribing of recommended glucose lowering drugs, statins, antihypertensives and renin-angiotensin-aldosterone system (RAAS)-inhibitors and potentially inappropriate drugs from a validated diabetes indicator set were included. Disease-specific medication burden was assessed using a modified version of the Medication Regimen Complexity Index (MRCI). Associations were tested with regression models, adjusting for age, gender, diabetes duration, comorbidity, body mass index and smoking. RESULTS: The mean MRCI was 7.1, the median EQ5D-3L-score was 0.86 and the mean WHO-5 score was 72. Seven indicators included too few patients and were excluded from the analysis. The remaining thirteen indicators focusing on recommended start, intensification, current and preferred use of glucose lowering drugs, statins, antihypertensives, RAAS inhibitors, and on inappropriate prescribing of glibenclamide and dual RAAS blockade were not significantly associated with HRQoL. Finally, also the MRCI was not associated with HRQoL. CONCLUSIONS: We found no evidence for associations between guideline-adherent prescribing or disease-specific medication burden and HRQoL in T2D patients. This gives no rise to refrain from prescribing intensive treatment in T2D patients as recommended, but the interpretation of these results is limited by the cross-sectional study design and the selection of patients included in some indicators.

Diagnosing orthostatic hypotension with continuous and interval blood pressure measurement devices.

Orthostatic hypotension (OH) is defined as a drop in systolic blood pressure (SBP) of ≥20 mm Hg and/or a drop in diastolic blood pressure (DBP) of ≥10 mm Hg within 3 min of standing. The international guidelines recommend ideally diagnosing OH with a continuous blood pressure (BP) measurement device, although in daily practice interval BP measurement devices are used more often. We aimed to investigate the difference in observed prevalence of OH between an interval and a continuous BP measurement device. A total of 104 patients with a mean age of 69 years were included. The prevalence of OH was 35.6% (95% CI: 26.4-44.8) with the interval BP measurement and 45.2% (95% CI: 35.6-54.8) with the continuous BP measurement device (P = .121). Lin's coefficient of concordance ranged from 0.47 to 0.59 for the drop in systolic blood pressure and from 0.33 to 0.42 for the drop in diastolic blood pressure. The positive proportion of agreement in diagnosis of OH between the interval and continuous measure was 59.5% and the negative proportion of agreement was 72.5%. Although the prevalence of OH was not significantly different between the continuous and the interval BP measurement devices using a similar amount of measurement, the concordance between interval and continuous measure is low resulting in low positive and negative proportions of agreement in the diagnosis of OH. We conclude that continuous BP measurement cannot be substituted by an interval BP measurement to diagnose OH.

Gender differences in the evaluation of care for patients with type 2 diabetes: a cross-sectional study (ZODIAC-52).

BACKGROUND: Little is known about the association between patient-related factors and patients' evaluation of care. Aim was to investigate which patient-related factors are associated with patients' evaluation of care in men and women with type 2 diabetes (T2D) in primary care. METHODS: This cross-sectional study included 1102 patients with T2D from 52 general practices. We measured patients' evaluation with the EUROPEP questionnaire and collected demographic, clinical and psychological data from questionnaires and health records. Stepwise linear regression analyses were used. RESULTS: The location where the questionnaire was completed (at home or at the general practice) was associated with all outcomes in men and women. Next to this, in men, explanatory factors for the care provider EUROPEP subscale were use of insulin, having some problems with T2D self-care and coffee consumption (R2 8.4%); coffee consumption was associated with the general practice subscale (R2 4.0%). In women, well-being, quality of life, following a general diet, and use of oral glucose-lowering drugs were associated with the care provider subscale (R2 16.8%). For the general practice subscale, well-being and age were explanatory factors (R2 9.4%). CONCLUSIONS: Only a few factors were found to be associated with patients' evaluation of care for men and women with T2D. Taken together, these factors explained only a small part of the variance of the EUROPEP scores. This explained variance was largely attributable to the location where the questionnaire was completed. We therefore advise to be aware of the possible consequences of filing-out questionnaires about patients' evaluation of care at the general practice. TRIAL REGISTRATION: NCT01570140 (Clinicaltrials.gov). Registered 29 March 2012.

Effects of three frequencies of self-monitored blood glucose on HbA1c and quality of life in patients with type 2 diabetes with once daily insulin and stable control: a randomized trial.

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.

Sex differences in obesity related cancer incidence in relation to type 2 diabetes diagnosis (ZODIAC-49).

BACKGROUND: Diabetes 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. METHODS: This 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. RESULTS: Women 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). CONCLUSIONS: Women 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.