Fasting and meal-stimulated serum C-peptide in long-standing type 1 diabetes mellitus.

AIMS: This study aims to evaluate the stability of C-peptide over time and to compare fasting C-peptide and C-peptide response after mixed-meal tolerance test (MMTT) at T90 or T120 with C-peptide area under the curve (AUC) in long-standing type 1 diabetes. METHODS: We included 607 type 1 diabetes individuals with diabetes duration >5 years. C-peptide concentrations (ultrasensitive assay) were collected in the fasting state, and in a subpopulation after MMTT (T0, just prior to, T30-T60-T90-T120, 30-120 min after ingestion of mixed-meal) (n = 168). Fasting C-peptide concentrations (in n = 535) at Year 0 and Year 1 were compared. The clinical determinants associated with residual C-peptide secretion and the correspondence of C-peptide at MMTT T90 / T120 and total AUC were assessed. RESULTS: A total of 153 participants (25%) had detectable fasting serum C-peptide (i.e ≥ 3.8 pmol/L). Fasting C-peptide was significantly lower at Year 1 (p < 0.001, effect size = -0.16). Participants with higher fasting C-peptide had a higher age at diagnosis and shorter disease duration and were less frequently insulin pump users. Overall, 109 of 168 (65%) participants had both non-detectable fasting and post-meal serum C-peptide concentrations. The T90 and T120 C-peptide values at MMTT were concordant with total AUC. In 17 (10%) individuals, C-peptide was only detectable at MMTT and not in the fasting state. CONCLUSIONS: Stimulated C-peptide was detectable in an additional 10% of individuals compared with fasting in individuals with >5 years of diabetes duration. T90 and T120 MMTT measurements showed good concordance with the MMTT total AUC. Overall, there was a decrease of C-peptide at 1-year follow-up.

Residual C-peptide secretion and hypoglycemia awareness in people with type 1 diabetes.

INTRODUCTION: This study aimed to assess the association between fasting serum C-peptide levels and the presence of impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed a cross-sectional study among 509 individuals with type 1 diabetes (diabetes duration 5-65 years). Extensive clinical data and fasting serum C-peptide concentrations were collected and related to the presence or absence of IAH, which was evaluated using the validated Dutch version of the Clarke questionnaire. A multivariable logistic regression model was constructed to investigate the association of C-peptide and other clinical variables with IAH. RESULTS: In 129 (25%) individuals, residual C-peptide secretion was detected, while 75 (15%) individuals reported IAH. The median (IQR) C-peptide concentration among all participants was 0.0 (0.0-3.9) pmol/L. The prevalence of severe hypoglycemia was lower in people with demonstrable C-peptide versus those with absent C-peptide (30% vs 41%, p=0.025). Individuals with IAH were older, had longer diabetes duration, more frequently had macrovascular and microvascular complications, and more often used antihypertensive drugs, antiplatelet agents and cholesterol-lowering medication. There was a strong association between IAH and having a severe hypoglycemia in the preceding year. In multivariable regression analysis, residual C-peptide, either continuously or dichotomous, was associated with lower prevalence of IAH (p=0.040-0.042), while age at diabetes onset (p=0.001), presence of microvascular complications (p=0.003) and body mass index (BMI) (p=0.003) were also independently associated with the presence of IAH. CONCLUSIONS: Higher BMI, the presence of microvascular complications and higher age at diabetes onset were independent risk factors for IAH in people with type 1 diabetes, while residual C-peptide secretion was associated with lower risk of this complication.

Type 2 diabetes in South Asians compared to Europeans: Higher risk and earlier development of major cardiovascular events irrespective of the presence and degree of retinopathy. Results from The HinDu The Hague Diabetes Study.

INTRODUCTION: South Asians with diabetes have more severe diabetic retinopathy (DR) and cardiovascular complications than white Caucasians. However, how big this gap is and the relation with the severity of DR has not been studied. Here, we quantify the difference in time from diabetes diagnosis until a first non-fatal Major Adverse Cardiovascular Event (TUF MACE) in different DR groups in South Asians and Europeans. METHODS: 3831 adults with type 2 diabetes, 1358 South Asians and 2473 Europeans, treated in our diabetes clinic between 2006 and 2017 were included. Data on risk factors, diabetes duration, age of diagnosis and diabetes complications were collected from the diabetes-specific database and analysed using descriptive statistics and Cox regression. DR was graded in 3 categories, and non-fatal MACE was pre-specified. RESULTS: Prevalence of non-fatal MACE was the same when DR was absent, increased with increasing severity of DR in both ethnic groups, but was more frequent in South Asians with DR (mild: 50 vs. 42% and severe 62 vs. 46%. Classic risk factors only differed in relation to smoking habits, which were significantly lower in South Asians.After correction for classic risk factors and age at diabetes diagnosis TUF MACE was significantly shorter in South Asians, an effect also seen in the no-DR group (4.1 yrs. HR 1.5, 95% CI 1.3-1.8 and 7.4 yrs. earlier, HR 2.0, 95% CI 1.6-2.6 for no-DR and severe DR, respectively). CONCLUSIONS: When adjusted for age at diabetes diagnosis, we show that time until first non-fatal MACE in South Asians is significantly shorter compared to Europeans and increases from no- to severe DR.

DPARD: rationale, design and initial results from the Dutch national diabetes registry.

BACKGROUND: Treatment of diabetes mellitus has majorly improved over the past century, however, the disease burden is high and its prevalence still expanding. Further insight in the diabetes population is imperative to improve the quality of diabetes care by enhancement of knowledge-based diabetes management strategies. To this end, in 2017 a Dutch nationwide consortium of diabetologists, paediatric endocrinologists, and diabetes patients has founded a national outpatient diabetes care registry named Dutch Pediatric and Adult Registry of Diabetes (DPARD). We aim to describe the implementation of DPARD and to provide an overview of the characteristics of patients included during the first 2 years. METHODS: For the DPARD cohort with long-term follow-up of observational nature, hospital data are gathered directly from electronic health records and securely transferred and stored. DPARD provides weekly updated clinical information on the diabetes population care on a hospital-level benchmarked against the national average. RESULTS: Between November 2017 and January 2020, 20,857 patients were included from 8 (11%) Dutch hospitals with a level of care distribution representative of all diabetic outpatients in the Netherlands. Among patients with known diabetes type, 41% had type 1 diabetes, 51% type 2 diabetes, and 8% had diabetes due to other causes. Characteristics of the total patient population were similar to patients with unknown diabetes classification. HbA1c levels decreased over the years, while BMI levels showed an increase over time. CONCLUSIONS: The national DPARD registry aims to facilitate investigation of prevalence and long-term outcomes of Dutch outpatients with diabetes mellitus and their treatment, thus allowing for quality improvement of diabetes care as well as allowing for comparison of diabetes care on an international level.

Efficacy of liraglutide on glycemic endpoints in people of Western European and South Asian descent with T2DM using multiple daily insulin injections: results of the MAGNA VICTORIA studies.

AIMS: Data on the effect of liraglutide on glycemic endpoints in people with T2DM using multiple daily insulin injections (MDI) are scarce, especially in the context of ethnicity. METHODS: This is a secondary analysis of the placebo-controlled randomized clinical "MAGNA VICTORIA" trials in Western European (WE) and South Asian (SA) people with T2DM. Participants had inadequate glycemic control despite using metformin and/or sulfonylurea derivatives and/or insulin. Participants were assigned to liraglutide (1.8 mg) or placebo for 6 months, in addition to standard care. The primary endpoint number of participants reaching target HbA1c was compared for liraglutide versus placebo in the complete dataset and MDI-treated participants using Chi-square test. Liraglutide's efficacy in WE and SA was compared using a generalized linear model. RESULTS: Forty-five subjects were randomized to liraglutide and 51 to placebo. In each group, one participant did not complete the study. Liraglutide-treated patients reached target HbA1c more frequently: 23/45 (51%) vs 11/51 (22%), relative probability 2.4 (1.3-4.3), p = 0.002. Subgroup analysis in 43 MDI participants showed that the proportion reaching target HbA1c using liraglutide was significantly higher than in placebo: 9/22 (41%) vs 1/21 (5%), p = 0.005. There was no difference between WE and SA in terms of liraglutide efficacy (p = 0.18). CONCLUSIONS: Liraglutide treatment resulted in increased chance of reaching target HbA1c as compared to placebo. Liraglutide efficacy was sustained in participants using MDI regimens and those of SA descent. Liraglutide should be considered for T2DM people with inadequate glycemic control despite MDI.

Effect of Liraglutide on Cardiovascular Function and Myocardial Tissue Characteristics in Type 2 Diabetes Patients of South Asian Descent Living in the Netherlands: A Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide may be beneficial in the regression of diabetic cardiomyopathy. South Asian ethnic groups in particular are at risk of developing type 2 diabetes. PURPOSE: To assess the effects of liraglutide on left ventricular (LV) diastolic and systolic function in South Asian type 2 diabetes patients. STUDY TYPE: Prospective, double-blind, randomized, placebo-controlled trial. POPULATION: Forty-seven type 2 diabetes patients of South Asian ancestry living in the Netherlands, with or without ischemic heart disease, who were randomly assigned to 26-week treatment with liraglutide (1.8 mg/day) or placebo. FIELD STRENGTH/SEQUENCE: 3T (balanced steady-state free precession cine MRI, 2D and 4D velocity-encoded MRI, 1 H-MRS, T1 mapping). ASSESSMENT: Primary endpoints were changes in LV diastolic function (early deceleration peak [Edec], ratio of early and late peak filling rate [E/A], estimated LV filling pressure [E/Ea]) and LV systolic function (ejection fraction). Secondary endpoints were changes in aortic stiffness (aortic pulse wave velocity [PWV]), myocardial steatosis (myocardial triglyceride content), and diffuse fibrosis (extracellular volume [ECV]). STATISTICAL TESTS: Data were analyzed according to intention-to-treat. Between-group differences were reported as mean (95% confidence interval [CI]) and were assessed using analysis of covariance (ANCOVA). RESULTS: Liraglutide (n = 22) compared with placebo (n = 25) did not change Edec (+0.2 mL/s2 × 10-3 (-0.3;0.6)), E/A (-0.09 (-0.23;0.05)), E/Ea (+0.1 (-1.2;1.3)) and ejection fraction (0% (-3;2)), but decreased stroke volume (-9 mL (-14;-5)) and increased heart rate (+10 bpm (4;15)). Aortic PWV (+0.5 m/s (-0.6;1.6)), myocardial triglyceride content (+0.21% (-0.09;0.51)), and ECV (-0.2% (-1.4;1.0)) were unaltered. DATA CONCLUSION: Liraglutide did not affect LV diastolic and systolic function, aortic stiffness, myocardial triglyceride content, or extracellular volume in Dutch South Asian type 2 diabetes patients with or without coronary artery disease. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1679-1688.

A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

BACKGROUND: South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes. METHODS: In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy. RESULTS: In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (- 3.9 ± 3.6 kg vs - 0.6 ± 2.2 kg; mean change from baseline (liraglutide vs placebo): - 3.5 kg; 95% CI [- 5.3, - 1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (- 23 ± 27 cm2 vs - 2 ± 17 cm2; mean change from baseline (liraglutide vs placebo): - 17 cm2; 95% CI [- 32, - 3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (- 1.0 ± 0.8% (- 10.5 ± 9.1 mmol/mol)) vs (- 0.6 ± 0.8% (- 6.1 ± 8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): - 0.6% (- 6.5 mmol/mol); 95% CI [- 1.1, - 0.1 (- 11.5, - 1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (ß: 0.165 mmol/mol (0.015%) per 1 cm2 decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]). CONCLUSIONS: While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016.

A cost of illness study of hypoglycaemic events in insulin-treated diabetes in the Netherlands.

OBJECTIVES: Patients with diabetes mellitus are at a risk for hypoglycaemia. Besides the burden of hypoglycaemia for patients, hypoglycaemia poses an economic burden to society. The aim of this study was to calculate the per patient societal costs of hypoglycaemia among patients with type1 diabetes (T1DM) and type 2 diabetes (T2DM) on insulin therapy in the Netherlands. METHODS: To calculate the costs of hypoglycaemia, data from the Global Hypoglycaemia Assessment Tool (HAT) study were used. Dutch patients were selected from the HAT study database and data regarding healthcare resource use, informal care use and productivity losses were combined with Dutch unit costs to calculate the per patient 4-week costs of patients experiencing hypoglycaemia. Besides these 4-week costs, costs per hypoglycaemic event were calculated by dividing the study population total 4-week costs by the total number of events in this period. RESULTS: Mean 4-week total costs of hypoglycaemia amounted to €163 (SD, €870) in T1DM and €134 (SD, €364) in T2DM. While productivity costs were the most important cost driver of hypoglycaemia in patients with T1DM (accounting for 72% of the total costs), costs of hypoglycaemia in patients with T2DM were almost entirely driven by costs within the healthcare sector (accounting for 98% of the total costs). Mean costs of a severe hypoglycaemic event were €828 and €508 in T1DM and T2DM, respectively, whereas mean costs of a non-severe event were almost zero. CONCLUSIONS: This study showed that the economic burden of severe hypoglycaemia is substantial. The prevention of hypoglycaemia could therefore not only reduce the burden for patients, but also the economic burden to society.

Continuous Glucose Monitoring in Patients with Type 1 Diabetes and Impaired Awareness of Hypoglycemia: Also Effective in Patients with Psychological Distress?

The aim of this study was to evaluate whether psychological distress modifies the effect of continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D) and impaired awareness of hypoglycemia. Fifty-two patients with T1D and impaired awareness of hypoglycemia participated in an earlier reported randomized crossover trial with two 16-week intervention periods comparing CGM with self-monitoring of blood glucose (SMBG). During the CGM phase, time spent in euglycemia (4-10 mmol/L), the primary outcome, was 9.6% higher compared with the SMBG phase (P < 0.0001). Psychological distress was operationalized as low emotional well-being (World Health Organization Well-being Index 5 [WHO-5] < 50), high diabetes-related distress (Problem Areas in Diabetes 5 [PAID-5] ≥ 8), and/or high fear of hypoglycemia (Hypoglycemia Fear Survey [HFS] Worry > mean HFS Worry score +1 standard deviation). Modifying effects were assessed by analyzing psychological distress score × intervention-interaction effects. Results showed that both the low emotional well-being group and normal emotional well-being group had equal glycemic outcomes during the CGM phase. High diabetes distress and elevated fear of hypoglycemia did not result in significant interaction effects for glycemic outcomes. This study demonstrated that CGM is equally effective in terms of glycemic improvements in high versus low distressed patients with T1D and impaired awareness of hypoglycemia.

Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial.

BACKGROUND: Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population. METHODS: We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903. FINDINGS: Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p<0·0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose ≤3·9 mmol/L [6·8% vs 11·4%, mean difference 4·7%, 3·4-5·9; p<0·0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; p<0·0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0·033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention. INTERPRETATION: CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population. FUNDING: Eli Lilly and Sanofi.

Design and rationale of the IN CONTROL trial: the effects of real-time continuous glucose monitoring on glycemia and quality of life in patients with type 1 diabetes mellitus and impaired awareness of hypoglycemia.

BACKGROUND: Hypoglycemia is the main side effect of intensified insulin therapy in type 1 diabetes and recognized as a limitation in achieving glycemic targets. Patients with impaired awareness of hypoglycemia have a threefold to sixfold increased risk of severe hypoglycemia. Real-time continuous glucose monitoring may help patients with type 1 diabetes to achieve better glycemic control with less hypoglycemic episodes. Accordingly, one may hypothesize that particularly type 1 diabetes mellitus patients with impaired awareness of hypoglycemia will profit most from this technology with improvements in their quality of life. However, this has not yet been established. This trial aims to study the effect of real-time continuous glucose monitoring on glycemia and quality of life specifically in type 1 diabetes mellitus patients with established impaired awareness of hypoglycemia. METHODS/DESIGN: This is a two-center, randomized, cross-over trial with a 12-week wash-out period in between intervention periods. A total of 52 type 1 diabetes mellitus patients with impaired awareness of hypoglycemia according to Gold et al. criteria will be randomized to receive real-time continuous glucose monitoring or blinded continuous glucose monitoring for 16 weeks. After a wash-out period, patients will cross over to the other intervention. The primary outcome measure is time spent in euglycemia. Secondary outcomes include (diabetes-specific) markers of quality of life and other glycemic variables. DISCUSSION: It remains unclear whether patients with type 1 diabetes and impaired awareness of hypoglycemia benefit from real-time continuous glucose monitoring in real-life. This study will provide insight into the potential benefits of real-time continuous glucose monitoring in this patient population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01787903.

Similar adverse pregnancy outcome in native and nonnative dutch women with pregestational type 2 diabetes: a multicentre retrospective study.

Objective. To assess the incidence of adverse pregnancy outcome in native and nonnative Dutch women with pregestational type 2 diabetes (T2D) in a multicenter study in The Netherlands. Methods. Maternal characteristics and pregnancy outcome were retrospectively reviewed and the influence of ethnicity on outcome was evaluated using independent t-test, Mann-Whitney U-test, and chi-square test. Results. 272 pregnant women (80 native and 192 non-native Dutch) with pregestational T2D were included. Overall outcome was unfavourable, with a perinatal mortality of 4.8%, major congenital malformations of 6.3%, preeclampsia of 11%, preterm birth of 19%, birth weight >90th percentile of 32%, and a Caesarean section rate of 42%. In nonnative Dutch women, the glycemic control was slightly poorer and the gestational age at booking somewhat later as compared to native Dutch women. However, there were no differences in incidence of preeclampsia/HELLP, preterm birth, perinatal mortality, macrosomia, and congenital malformations between those two groups. Conclusions. A high incidence of adverse pregnancy outcomes was found in women with pregestational T2D, although the outcome was comparable between native and non-native Dutch women. This suggests that easy access to and adequate participation in the local health care systems contribute to these comparable outcomes, offsetting potential disadvantages in the non-native group.

Effects of patient-reported non-severe hypoglycemia on healthcare resource use, work-time loss, and wellbeing in insulin-treated patients with diabetes in seven European countries.

PURPOSE: Hypoglycemia is a frequent side effect induced by insulin treatment of type 1 (T1DM) and type 2 diabetes (T2DM). Limited data exist on the associated healthcare resource use and patient impact of hypoglycemia, particularly at a country-specific level. This study investigated the effects of self-reported non-severe hypoglycemic events (NSHE) on use of healthcare resources and patient wellbeing. METHODS: Patients with T1DM or insulin-treated T2DM diabetes from seven European countries were invited to complete four weekly questionnaires. Data were collected on patient demographics, NSHE occurrence in the last 7 days, hypoglycemia-related resource use, and patient impact. NSHE were defined as events with hypoglycemia symptoms, with or without blood glucose measurement, or low blood glucose measurement without symptoms, which the patient could manage without third-party assistance. RESULTS: Three thousand, nine hundred and fifty-nine respondents completed at least one wave of the survey, with 57% completing all four questionnaires; 3827 respondents were used for data analyses. Overall, 2.3% and 8.9% of NSHE in patients with T1DM and T2DM, respectively, resulted in healthcare professional contact. Across countries, there was a mean increase in blood glucose test use of 3.0 tests in the week following a NSHE. Among respondents who were employed (48%), loss of work-time after the last hypoglycemic event was reported for 9.7% of NSHE. Overall, 10.2% (daytime) and 8.0% (nocturnal) NSHE led to work-time loss, with a mean loss of 84.3 (daytime) and 169.6 (nocturnal) minutes among patients reporting work-time loss. Additionally, patients reported feeling tired, irritable, and having negative feelings following hypoglycemia. LIMITATIONS: Direct comparisons between studies must be interpreted with caution because of different definitions of hypoglycemia severity, duration of the studies, and methods of data collection. CONCLUSIONS: NSHE were associated with use of extra healthcare resources and work-time loss in all countries studied, suggesting that NSHE have considerable impact on patients/society.

Prescribing of rosiglitazone and pioglitazone following safety signals: analysis of trends in dispensing patterns in the Netherlands from 1998 to 2008.

BACKGROUND: Relevant safety signals in the EU are regularly communicated in so-called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases. OBJECTIVE: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands. METHODS: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists. RESULTS: For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings. CONCLUSIONS: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications.

Family communication as strategy in diabetes prevention: an observational study in families with Dutch and Surinamese South-Asian ancestry.

OBJECTIVE: To explore the possibility of utilizing family communication as a diabetes prevention strategy, specifically targeting high-risk families with South-Asian ancestry in The Netherlands. METHODS: In a cross-sectional study, type 2 diabetes patients from Dutch (n=311) and Surinamese South-Asian (n=157) origin filled in a questionnaire assessing socio-demographic characteristics, beliefs and concerns about familial diabetes risk, primary prevention, and diabetes-related family communication. RESULTS: Discussing diabetes is regarded acceptable in most families. Especially Surinamese South-Asian patients (68%) seemed motivated to convey risk messages to their relatives; they reported a higher risk perception and expressed more concern than Dutch patients. While 40% in both groups thought relatives are able to prevent developing diabetes, 46% in Dutch and 33% in Surinamese South-Asian patients were unsure. CONCLUSION: Promoting family communication appears a feasible strategy in diabetes prevention in high-risk (Surinamese South-Asian) families. Health care providers should address patients' concern and emphasize opportunities for prevention. PRACTICE IMPLICATIONS: Findings favor training of clinicians in utilizing a family approach as prevention strategy. Patients (particularly Surinamese South-Asians) are in need of professional help in the process of family risk disclosure. (Online) Educational tools should be made available at which patients can refer their relatives.

Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study.

OBJECTIVE: Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives. RESEARCH DESIGN AND METHODS: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. RESULTS: Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88-0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives. CONCLUSIONS: In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.

Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension.

The efficacy and safety of oral pamidronate was examined in a double-blind, placebo-controlled trial in women and men with established osteoporosis. Seventy-eight postmenopausal women and 23 men with at least one prevalent vertebral fracture were randomized separately to 150 mg/day of pamidronate or placebo for 3 years followed by 150 mg/day of pamidronate for an additional 2 years. In addition, all patients received 400 U/day of cholecalciferol and 500 mg/day of elemental calcium. Pamidronate increased significantly bone mineral density of the lumbar spine (LS-BMD) and of the femoral neck (FN-BMD). The total increase in BMD of the spine after 5 years of treatment was 14.3%. Lateral spine radiographs were obtained at baseline and after 3 years of treatment. Fractures of previously normal vertebrae occurred in 15 of 45 patients treated with placebo (33.3%) and in 5 of 46 patients treated with pamidronate (11%). The relative risk was 0.33 (95% CI, 0.14-0.77). Treatment was well tolerated and there was no difference in gastrointestinal toxicity between pamidronate and placebo-treated patients. One hundred fifty milligrams daily of pamidronate is an effective and safe treatment of women and men with established osteoporosis.