Effectiveness of insulin therapy in people with Type 2 diabetes in the Hoorn Diabetes Care System.

AIMS: To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy. METHODS: The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System (n = 9849). Inclusion criteria were: age ≥ 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels ≤ 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up ≥ 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c . Subjects considered to be 'off target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during less than one-third of the follow-up time. RESULTS: Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment. CONCLUSIONS: Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control.

Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.

AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic ß-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans. METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*104) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*104) but again not in men (P = 0.34). CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.

Applying a cost-based pricing model for innovative cancer treatments subject to indication expansion: A case study for pembrolizumab and daratumumab.

BACKGROUND: Expanding the indication of already approved immuno-oncology drugs presents treatment opportunities for patients but also strains healthcare systems. Cost-based pricing models are discussed as a possibility for cost containment. This study focuses on two drugs, pembrolizumab (Keytruda) and daratumumab (Darzalex), to explore the potential effect of indication broadening on the estimated price when using the cost-based pricing (CBP) model proposed by Uyl-de Groot and Löwenberg (2018). METHODS: The model was used to calculate cumulative yearly prices, cumulative prices per indication, and non-cumulative indication-based prices using inputs such as research and development (R&D) costs, manufacturing costs, eligible patient population, and a profit margin. A deterministic stepwise analysis and scenario analysis were conducted to examine how sensitive the estimated price is to the different input assumptions. RESULTS: The yearly cumulative cost-based prices (CBPs) ranged from €52 to €885 for pembrolizumab per vial and €823 to €31,941 for daratumumab per vial. Prices were higher in initial years or indications due to smaller patient populations, decreased over time or after additional indications. Sensitivity analysis showed that the number of eligible patients had the most significant impact on the estimated price. In the scenario analysis the profit margin contributed most to a higher CBPs for both drugs. Lower estimates resulted from assumed lower R&D costs. DISCUSSION: The estimated CBPs are consistently lower than Dutch list prices for pembrolizumab (€2,861), mainly resulting from larger patient populations in registered indications. However, daratumumab's list prices fall within the range of modeled CBPs depending on the year or indication (€4,766). Both CBPs decrease over time or with additional indications. The number of eligible patients and initial R&D costs have the most significant influence on the CBPs. These findings contribute to the ongoing discussions on pharmaceutical pricing, especially concerning cancer drugs with expanding indications.

Limited effect of screening for depression with written feedback in outpatients with diabetes mellitus: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to test the effectiveness of a screening procedure for depression (SCR) vs care as usual (CAU) in outpatients with diabetes. The primary outcome measured was depression score and the secondary outcomes were mental healthcare consumption, diabetes-distress and HbA(1c). MATERIALS AND METHODS: In a multicentre parallel randomised controlled trial, 223 outpatients with diabetes, who had an elevated depression score, were randomly assigned to SCR (n = 116) or CAU (n = 107), using computer generated numbers. SCR-patients were invited for a Composite International Diagnostic Interview (CIDI) to diagnose depression and/or anxiety (interviewers were not blinded for group assignment). As part of the intervention, patients and their physicians were informed of the outcome of the CIDI in a letter and provided with treatment advice. At baseline and 6 month follow-up, depression and diabetes-distress were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Problem Areas in Diabetes survey (PAID). HbA(1c) levels were obtained from medical charts. RESULTS: Mean CES-D depression scores decreased from baseline to 6 months in both groups (24 ± 8 to 21 ± 8 [CAU] and 26 ± 7 to 22 ± 10 [SCR] respectively [p < 0.001]), with no significant differences between groups. Neither diabetes-distress nor HbA(1c) changed significantly within and between groups. The percentage of patients receiving mental healthcare increased in the SCR group from 20% to 28%, compared with 15% to 18% in the CAU group. CONCLUSIONS/INTERPRETATION: Depression screening with written feedback to patient and physician does not improve depression scores and has a limited impact on mental healthcare utilisation, compared with CAU. It appears that more intensive depression management is required to improve depression outcomes in patients with diabetes.

HbA1(c) and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes: the A1C-Derived Average Glucose (ADAG) study.

AIMS: Increased glucose excursions and postprandial hyperglycaemia have been suggested as unique risk factors for cardiovascular disease (CVD) and mortality in patients with diabetes mellitus. Much of the evidence is based on a single 2 h glucose value after oral glucose tolerance testing in epidemiological studies. We examined the association between various indices of glycaemia measured during everyday activities and metabolic CVD risk factors in the A1C-Derived Average Glucose (ADAG) study. METHODS: Participants (268 with type 1 diabetes, 159 with type 2 diabetes) completed 16 weeks of intensive continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). From these data, common indices of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA1(c) were derived. The associations between glycaemic indices and known CVD risk factors (lipids, high-sensitivity C-reactive protein and blood pressure) were explored in linear regression models. RESULTS: For both diabetes types, the overall strongest associations with CVD risk factors were seen for the measures of average glycaemia (mean blood glucose and HbA1(c)). Associations between self-monitored postprandial and fasting glucose and CVD risk factors were weaker, but significant. Measurements of blood glucose variability showed non-significant associations. Overall, calculations based on CGM were not more informative than those based on frequent SMBG. CONCLUSIONS/INTERPRETATION: Mean glycaemia and HbA1(c) show consistent and stronger associations with CVD risk factors than fasting glucose or postprandial glucose levels or measures of glucose variability in patients with diabetes.

Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial.

AIMS/HYPOTHESIS: Traditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2 years). Whether this effect persists after cessation of treatment remains unknown. Here, we assessed the insulin secretory capacity in drug-naive patients with type 2 diabetes after a 52 week treatment period with vildagliptin or placebo, and again after a 12 week washout period. METHODS: This study was conducted at a single university medical centre, and was a double-blind, randomised clinical trial in 59 drug-naive patients with type 2 diabetes and mild hyperglycaemia to either vildagliptin 100 mg (n = 29) or placebo (n = 30). Randomisation was performed by a validated 1:1 system. Neither patient, nor caregiver, was informed about the assigned treatment. Inclusion criteria were drug-naive patients ≥30 years, with HbA(1c) ≤7.5% and BMI of 22-45 kg/m(2). The mildly hyperglycaemic patient population was chosen to minimise glucose toxicity as a confounding variable. Beta-cell function was measured during an arginine-stimulated hyperglycaemic clamp at week 0, week 52 and after a 12 week washout period. All patients with at least one post-randomisation measure were analysed (intent-to-treat). RESULTS: Fifty-two week vildagliptin 100 mg (n = 26) treatment increased the primary efficacy variable, combined hyperglycaemia and arginine-stimulated C-peptide secretion (AIR(arg)), by 5.0 ± 1.8 nmol/l × min, while it decreased by 0.8 ± 1.8 nmol/l × min with placebo (n = 25) (between-group difference p = 0.030). No significant between-group difference in AIR(arg) was seen after the 12 week washout period. The between-group difference adjusted mean 52 week changes from baseline was -0.19 ± 0.11, p = 0.098 and -0.22 ± 0.23%, p = 0.343 for HbA(1c) and fasting plasma glucose, respectively. There were no suspected drug treatment-related serious adverse events. CONCLUSIONS/INTERPRETATION: One year treatment with vildagliptin significantly increased beta cell secretory capacity. This effect was not maintained after the washout, indicating that this increased capacity was not a disease modifying effect on beta cell mass and/or function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00260156.

The heritability of beta cell function parameters in a mixed meal test design.

AIMS/HYPOTHESIS: We estimated the heritability of individual differences in beta cell function after a mixed meal test designed to assess a wide range of classical and model-derived beta cell function parameters. METHODS: A total of 183 healthy participants (77 men), recruited from the Netherlands Twin Register, took part in a 4 h protocol, which included a mixed meal test. Participants were Dutch twin pairs and their siblings, aged 20 to 49 years. All members within a family were of the same sex. Insulin sensitivity, insulinogenic index, insulin response and postprandial glycaemia were assessed, as well as model-derived parameters of beta cell function, in particular beta cell glucose sensitivity and insulin secretion rates. Genetic modelling provided the heritability of all traits. Multivariate genetic analyses were performed to test for overlap in the genetic factors influencing beta cell function, waist circumference and insulin sensitivity. RESULTS: Significant heritabilities were found for insulinogenic index (63%), beta cell glucose sensitivity (50%), insulin secretion during the first 2 h postprandial (42-47%) and postprandial glycaemia (43-52%). Genetic factors influencing beta cell glucose sensitivity and insulin secretion during the first 30 postprandial min showed only negligible overlap with the genetic factors that influence waist circumference and insulin sensitivity. CONCLUSIONS/INTERPRETATION: The highest heritability for postprandial beta cell function was found for the insulinogenic index, but the most specific indices of heritability of beta cell function appeared to be beta cell glucose sensitivity and the insulin secretion rate during the first 30 min after a mixed meal.

Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes.

Preclinical studies suggest that incretin-based therapies may be beneficial for the bone; however, clinical data are largely lacking. We assessed whether the differential effects of these therapies on body weight differed with respect to their effect on bone mineral density (BMD) and markers of calcium homeostasis in patients with type 2 diabetes (T2D). Sixty-nine metformin-treated patients with T2D were randomized to exenatide twice daily (n = 36) or insulin glargine once daily (n = 33). Total body BMD, measured by dual-energy X-ray absorptiometry, and serum markers of calcium homeostasis were assessed before and after 44-week treatment. Exenatide or insulin glargine treatment decreased body weight by 6%. Endpoint BMD was similar in both groups after 44-week therapy (LSmean ± s.e.m. between-group difference -0.002 ± 0.007 g/cm(2) ; p = 0.782). Fasting serum alkaline phosphatase, calcium and phosphate remained unaffected. Forty-four-week treatment with exenatide or insulin glargine had no adverse effects on bone density in patients with T2D, despite differential effects on body weight.

Real-life glycaemic profiles in non-diabetic individuals with low fasting glucose and normal HbA1c: the A1C-Derived Average Glucose (ADAG) study.

AIMS/HYPOTHESIS: Real-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes. METHODS: In the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA(1c). RESULTS: We found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA(1c), fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring. CONCLUSIONS/INTERPRETATION: Even though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be 'prediabetic' or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements.

Diabetes, prediabetes and cancer mortality.

AIMS/HYPOTHESIS: We aimed to investigate the risk of cancer mortality in relation to the glucose tolerance status classified according to the 2 h OGTT. METHODS: Data from 17 European population-based or occupational cohorts involved in the DECODE study comprising 26,460 men and 18,195 women aged 25-90 years were collaboratively analysed. The cohorts were recruited between 1966 and 2004 and followed for 5.9 to 36.8 years. Cox proportional hazards analysis with adjustment for cohort, age, BMI, total cholesterol, blood pressure and smoking status was used to estimate HRs for cancer mortality. RESULTS: Compared with people in the normal glucose category, multivariable adjusted HRs (95% CI) for cancer mortality were 1.13 (1.00, 1.28), 1.27 (1.02, 1.57) and 1.71 (1.35, 2.17) in men with prediabetes, previously undiagnosed diabetes and known diabetes, respectively; in women they were 1.11 (0.94, 1.30), 1.31 (1.00, 1.70) and 1.43 (1.01, 2.02), respectively. Significant increases in deaths from cancer of the stomach, colon-rectum and liver in men with prediabetes and diabetes, and deaths from cancers of the liver and pancreas in women with diabetes were also observed. In individuals without known diabetes, the HR (95% CI) for cancer mortality corresponding to a one standard deviation increase in fasting plasma glucose was 1.06 (1.02, 1.09) and in 2 h plasma glucose was 1.07 (1.03, 1.11). CONCLUSIONS/INTERPRETATION: Diabetes and prediabetes were associated with an increased risk of cancer death, particularly death from liver cancer. Mortality from all cancers rose linearly with increasing glucose concentrations.

The relationship between self-monitored blood glucose values and glycated haemoglobin in insulin-treated patients with Type 2 diabetes.

AIMS: Self-monitoring of blood glucose (SMBG) is an important self-management tool for insulin-treated patients with Type 2 diabetes mellitus (T2DM). Its value in estimating glycaemic control in insulin-treated T2DM patients remains unclear. The relationship between glycated haemoglobin (HbA(1c)) and SMBG measures in T2DM patients treated with premixed insulin lispro mixtures or basal insulin glargine was examined. METHODS: HbA(1c) and plasma equivalent glucose (PGe) data derived from SMBG profiles were pooled from five randomized clinical trials of patients with T2DM on one or more oral glucose-lowering medication +/- 0-2 insulin injections per day switching to insulin lispro mixtures (N = 317) or glargine (N = 306). Patients generated seven-point SMBG profiles three times in a 2-week period prior to each HbA(1c) measurement. Pearson's correlation coefficients (r) were calculated for PGe values and HbA(1c). Receiver-operating characteristic (ROC) curves determined the ability of sets of PGe to estimate HbA(1c) (< or > 7.0%). RESULTS: Mean +/- standard deviation age was 57.5 +/- 9.5 years, body mass index 31.3 +/- 5.6 kg/m(2), 52.5% were male and HbA(1c) overall was 7.4 +/- 1.0% at end-point. Among individual SMBG measures, r for HbA(1c) ranged from 0.34 to 0.49. For means of two or more PGe measures, r for HbA(1c) ranged from 0.51 to 0.59. Correlations were similar for either regimen. ROC curves were consistent with the correlation data. CONCLUSIONS: These data provide patients and clinicians information on the relationship between HbA(1c) and SMBG measurements in patients with T2DM, and support the value of frequent blood glucose measurements for assessing overall glycaemic control.

Diabetes-specific emotional distress mediates the association between depressive symptoms and glycaemic control in Type 1 and Type 2 diabetes.

OBJECTIVES: To investigate whether diabetes-specific emotional distress mediates the relationship between depression and glycaemic control in patients with Type 1 and Type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were derived from the baseline assessment of a depression in diabetes screening study carried out in three tertiary diabetes clinics in the Netherlands. Most recent glycated haemoglobin (HbA(1c)) measurement was obtained from medical records. The Centre for Epidemiologic Studies Depression Scale (CES-D) and Problem Areas in Diabetes scale (PAID) were used to measure depression and diabetes-specific emotional distress respectively. Linear regression was performed to examine the mediating effect of diabetes-distress. RESULTS: Complete data were available for 627 outpatients with Type 1 (n = 280) and Type 2 (n = 347) diabetes. Analyses showed that diabetes-distress mediated the relation between depression and glycaemic control and not differently for both disease types. Post-hoc analyses revealed that patients depressed and distressed by their diabetes were in significantly poorer glycaemic control relative to those not depressed nor distressed (HbA(1c) 8.7 +/- 1.7 vs. 7.6 +/- 1.2% in those without depressive symptoms, 7.6 +/- 1.1% in depressed only and 7.7 +/- 1.1% in the distressed only, P < 0.001). Depressed patients without elevated diabetes-distress did not show a significantly increased risk of elevated HbA(1c). CONCLUSIONS: In explaining the association between depression and glycaemic control, diabetes-specific emotional distress appears to be an important mediator. Addressing diabetes-specific emotional problems as part of depression treatment in diabetes patients may help improve glycaemic outcomes.

Prevalence of comorbid depression is high in out-patients with Type 1 or Type 2 diabetes mellitus. Results from three out-patient clinics in the Netherlands.

AIMS: Depression is common in diabetes, but the scope of the problem and associated correlates are not well established in specialist diabetes care. We aimed to determine the prevalence of depression among adult outpatients with Type 1 (T1DM) or Type 2 diabetes (T2DM) using both self-report measures and a diagnostic interview, and to establish demographic and clinical characteristics associated with depressive affect. METHODS: A random sample of 2055 diabetes out-patients from three diabetes clinics was invited to participate. Depressive affect was assessed using the World Health Organization-5 Well Being Index (WHO-5), the Centre for Epidemiologic Studies-Depression scale (CESD) using predefined cut-off scores, and depressive disorder with the Composite International Diagnostic Interview (CIDI). Associations between depression and patient characteristics were explored using regression analyses. RESULTS: Seven hundred and seventy-two patients completed the depression questionnaires. About one-third of T1DM patients and 37-43% of T2DM patients reported depressive affect (WHO-5). The prevalence of depressive affect (CESD) was 25% and 30% for men and women with T1DM, and 35% and 38% for men and women with T2DM, respectively. Based on the CIDI, 8% of T1DM patients (no gender difference) and 2% of men and 21% of women with T2DM suffered from a depressive disorder. Depressive affect was associated with poor glycaemic control and proliferative retinopathy in T1DM, while non-Dutch descent, obesity and neuropathy were correlates in T2DM. CONCLUSIONS: Depressive symptoms and major depressive disorder constitute a common comorbid problem among Dutch out-patients with T1DM or T2DM and appear particularly common in migrants and women with T2DM.

Genetic influences on the insulin response of the beta cell to different secretagogues.

AIMS/HYPOTHESIS: The aim of the present study was to estimate the heritability of the beta cell insulin response to glucose and to glucose combined with glucagon-like peptide-1 (GLP-1) or with GLP-1 plus arginine. METHODS: This was a twin-family study that included 54 families from the Netherlands Twin Register. The participants were healthy twin pairs and their siblings of the same sex, aged 20 to 50 years. Insulin response of the beta cell was assessed by a modified hyperglycaemic clamp with additional GLP-1 and arginine. Insulin sensitivity index (ISI) was assessed by the euglycaemic-hyperinsulinaemic clamp. Multivariate structural equation modelling was used to obtain heritabilities and the genetic factors underlying individual differences in BMI, ISI and secretory responses of the beta cell. RESULTS: The heritability of insulin levels in response to glucose was 52% and 77% for the first and second phase, respectively, 53% in response to glucose + GLP-1 and 80% in response to an additional arginine bolus. Insulin responses to the administration of glucose, glucose + GLP-1 and glucose + GLP-1 + arginine were highly correlated (0.62< r <0.79). Heritability of BMI and ISI was 74% and 60% respectively. The genetic factors that influenced BMI and ISI explained about half of the heritability of insulin levels in response to the three secretagogues. The other half was due to genetic factors specific to the beta cell. CONCLUSIONS/INTERPRETATION: In healthy adults, genetic factors explain most of the individual differences in the secretory capacity of the beta cell. These genetic influences are partly independent from the genes that influence BMI and ISI.

Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not known precisely. A study was undertaken to investigate the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand, and cardiovascular disease (CVD) on the other. METHODS: The prevalence of CVD (coronary, cerebral and peripheral arterial disease) was determined in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged 50-75 years; the CARRE study) and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). Patients with RA with normal fasting glucose levels from the CARRE study (RA, n = 294) were compared with individuals from the Hoorn study with normal glucose metabolism (non-diabetic, n = 258) and individuals with DM2 (DM2, n = 194). RESULTS: The prevalence of CVD was 5.0% (95% CI 2.3% to 7.7%) in the non-diabetic group, 12.4% (95% CI 7.5% to 17.3%) in the DM2 group and 12.9% (95% CI 8.8% to 17.0%) in those with RA. With non-diabetic individuals as the reference category, the age- and gender-adjusted prevalence odds ratio (OR) for CVD was 2.3 (95% CI 1.1 to 4.7) for individuals with DM2 and 3.1 (95% CI 1.6 to 6.1) for those with RA. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (OR 2.0 (95% CI 0.9 to 4.5) and 2.7 (95% CI 1.2 to 5.9), respectively). CONCLUSIONS: The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.

Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: A post-hoc analysis of a 52-week randomised trial.

AIMS: To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. METHODS: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean  ±â€¯SD age 60 ±â€¯8 years, HbA1c 7.5 ±â€¯0.9%, eGFR 86 ±â€¯16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. RESULTS: HbA1c-reductions were similar with exenatide (mean ±â€¯SEM -0.80 ±â€¯0.10%) and iGlar (-0.79 ±â€¯0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ±â€¯2.1 mL/min/1.73 m2; P = 0.069) and iGlar (-2.7 ±â€¯1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. CONCLUSIONS: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00097500.

Absence of an acute insulin response predicts onset of type 2 diabetes in a Caucasian population with impaired glucose tolerance.

CONTEXT: In persons with impaired glucose tolerance (IGT), both impaired insulin secretion and insulin resistance contribute to the conversion to type 2 diabetes mellitus (T2DM). However, few studies have used criterion standard measures to asses the predictive value of impaired insulin secretion and insulin resistance for the conversion to T2DM in a Caucasian IGT population. OBJECTIVES: The objective of the study was to determine the predictive value of measures of insulin secretion and insulin resistance derived from a hyperglycemic clamp, including the disposition index, for the development of T2DM in a Caucasian IGT population. DESIGN, SETTING, AND PARTICIPANTS: The population-based Hoorn IGT study consisted of 101 Dutch IGT subjects (aged < 75 yr), with mean 2-h plasma glucose values, of two separate oral glucose tolerance tests, between 8.6 and 11.1 mmol/liter. A hyperglycemic clamp at baseline was performed to assess first-phase and second-phase insulin secretion and insulin sensitivity. During follow-up, conversion to T2DM was assessed by means of 6-monthly fasting glucose levels and yearly oral glucose tolerance tests. RESULTS: The cumulative incidence of T2DM was 34.7%. Hazard ratio for T2DM development adjusted for age, sex, and body mass index was 5.74 [95% confidence interval (CI) 2.60-12.67] for absence of first insulin peak, 1.58 (95% CI 0.60-4.17) for lowest vs. highest tertile of insulin sensitivity, and 1.78 (95% CI 0.65-4.88) for lowest vs. highest tertile of the disposition index. CONCLUSIONS: In these Caucasian persons with IGT, the absence of the first insulin peak was the strongest predictor of T2DM.

Evaluation of the one-minute exercise test to detect peripheral arterial disease.

BACKGROUND: Asymptomatic peripheral arterial disease (PAD) is common amongst the elderly and is a risk factor for cardiovascular morbidity and mortality. PAD can be assessed by non-invasive tests such as the ankle/brachial pressure index (ABPI) at rest and Doppler flow velocity (DFV) scanning, but these tests may underestimate the prevalence of PAD. The aim of this study was to estimate the added value, for the detection of PAD, of the one-minute exercise test, defined as positive if the drop of the ankle systolic pressure was more than 30 mmHg. We also investigated whether the combination of the ABPI at rest and the one-minute exercise test could replace DFV scanning. MATERIALS AND METHODS: We studied this in a random sample (n = 631) of a 50- to 75-year-old population. RESULTS: Of these subjects 11% (66/631) had an abnormal ABPI (< 0.9) and 16% (102/631) had an abnormal DFV curve. Of this sample 72% of the subjects performed a one-minute exercise test. Of all subjects 6% (27/451) had an abnormal ABPI (< 0.9) and 12% (54/451) had an abnormal DFV curve. The one-minute exercise test revealed seven cases of PAD (beyond the 67 already identified) which were not detected by an abnormal ABPI at rest and/or DFV scanning. As a result the prevalence of PAD increased by 2%. All patients with an aortoiliac or femoropopliteal obstruction had an ABPI at rest < 0.9. The sensitivity of the combination of the ABPI at rest and the one-minute exercise test to detect abnormal DFV curves was low for crural obstructions. CONCLUSION: The one-minute exercise test slightly improves the detection of peripheral arterial disease in the general population.

The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitus.

Latent autoimmune diabetes in the adult (LADA) is a slowly progressive form of autoimmune diabetes, characterized by diabetes-associated autoantibody positivity. A recent hypothesis proposes that LADA consists of a heterogeneous population, wherein several subgroups can be identified based on their autoimmune status. A systematic review of the literature was carried out to appraise whether the clinical characteristics of LADA patients correlate with the titre and numbers of diabetes-associated autoantibodies. We found that the simultaneous presence of multiple autoantibodies and/or a high-titre anti-glutamic acid decarboxylase (GAD)--compared with single and low-titre autoantibody--is associated with an early age of onset, low fasting C-peptide values as a marker of reduced pancreatic B-cell function, a high predictive value for future insulin requirement, the presence of other autoimmune disorders, a low prevalence of markers of the metabolic syndrome including high body mass index, hypertension and dyslipidaemia, and a high prevalence of the genotype known to increase the risk of Type 1 diabetes. We propose a more continuous classification of diabetes mellitus, based on the finding that the clinical characteristics gradually change from classic Type 1 diabetes to LADA and finally to Type 2 diabetes. Future studies should focus on determining optimal cut-off points of anti-GAD for differentiating clinically relevant diabetes mellitus subgroups.

Cognitive behavioural therapy (CBT) compared with blood glucose awareness training (BGAT) in poorly controlled Type 1 diabetic patients: long-term effects on HbA moderated by depression. A randomized controlled trial.

OBJECTIVE: To test the effectiveness at 6 and 12 months' follow-up of group cognitive behavioural therapy (CBT) compared with blood glucose awareness training (BGAT) in poorly controlled Type 1 diabetic patients and to explore the moderating effect of baseline depression. RESEARCH DESIGN AND METHODS: Adults with Type 1 diabetes (n = 86) with glycated haemoglobin (HbA(1c)) >or= 8% were randomized to CBT or BGAT. Primary outcome was HbA(1c) control. Secondary outcomes were: self-care, diabetes-related distress (Problem Areas in Diabetes scale; PAID), diabetes self-efficacy (Confidence in Diabetes Self-care scale; CIDS) and depressive symptoms (Centre for Epidemiological Studies--Depression scale; CES-D). Measurements were scheduled before CBT and BGAT, and at 3, 6 and 12 months after. Differential effects were analysed for the subgroup of patients reporting low vs. high baseline levels of depression. RESULTS: Neither CBT nor BGAT had a significant impact on HbA(1c) at 6 and 12 months' follow-up. Both interventions resulted in lower depressive symptoms (CES-D 15.7-13.3, P = 0.01) up to 12 months, but only CBT was effective in lowering HbA(1c) in patients with high baseline depression scores (HbA(1c) 9.5-8.8%) up to 1 year of follow-up (P = 0.03). CONCLUSIONS: Our findings suggest that group CBT can effectively help Type 1 diabetic patients with co-morbid depression achieve and maintain better glycaemic outcomes.