[Diabetes mellitus at the interface between pediatric and adult medicine]. / Diabetes mellitus an der Schnittstelle von Pädiatrie und Erwachsenenmedizin.

Patients with chronic diseases manifesting in childhood, such as type 1 diabetes, need to make an optimal transition from pediatric to adult medical care. This or transitionis a challenge for patients and their treatment teams, since metabolic control is often unstable at this time of life. Additional factors like the social environment, as well as concomitant diseases, also need to be taken into account and often represent hurdles to optimal therapy. Transition is an important process to guarantee good self-management of diabetes therapy and good outcomes in the long term. This review provides an overview and recommendations on the topic of transition in diabetes.

Regardless of the degree of glycaemic control, linagliptin has lower hypoglycaemia risk than all doses of glimepiride, at all time points, over the course of a 2-year trial.

AIM: To evaluate the risk of documented hypoglycaemia with glimepiride versus linagliptin. METHODS: This was an exploratory analysis of data from a 2-year, randomized, double-blind study of the dipeptidyl peptidase-4 inhibitor linagliptin 5 mg once daily (n = 764) versus the sulphonylurea glimepiride 1-4 mg once daily (n = 755) in patients with type 2 diabetes uncontrolled by metformin. Patients randomized to glimepiride started on 1 mg and after 4 weeks were allowed to be individually uptitrated stepwise to glimepiride 4 mg if a fasting plasma glucose concentration ≤6.1 mmol/l was not achieved. Investigator-reported hypoglycaemia was evaluated by dose, over time, and by the degree of glycated haemoglobin (HbA1c) reduction. RESULTS: The percentages of patients with at least one hypoglycaemic event at the individual maximum glimepiride dose were: 1 mg, 45.0%; 2 mg, 50.8%; 3 mg, 36.1%; and 4 mg, 27.7%. The incidence of hypoglycaemia was higher with glimepiride than with linagliptin (36.1 vs. 7.5%; p < 0.0001); after performing sensitivity analyses by excluding events during dose escalation (weeks 0-16), this difference remained significant (weeks 16-104: 25.8 vs. 5.9%; p < 0.0001). Notably, the incidence of hypoglycaemia was higher with glimepiride than with linagliptin in each quartile of HbA1c change from baseline (all p < 0.0001); the incidence of hypoglycaemic episodes was not increased with greater reductions in HbA1c in either group. In all 4-week intervals across the 2-year study, the incidence of hypoglycaemia was lower with linagliptin than with glimepiride. CONCLUSION: Linagliptin was associated with a lower risk of hypoglycaemia than glimepiride at all dose levels and time intervals, and regardless of change in HbA1c level.

Treatment escalation options for patients with type 2 diabetes after failure of exenatide twice daily or glimepiride added to metformin: results from the prospective European Exenatide (EUREXA) study.

AIMS: To evaluate third-line thiazolidinedione (TZD) or glimepiride therapy in patients inadequately controlled on metformin + exenatide twice daily, and third-line exenatide twice daily in patients inadequately controlled on metformin + glimepiride. METHODS: In this randomized, open-label, multicentre trial, 144 patients with type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) >9% (75 mmol/mol) after 3 months' treatment or >7% (53 mmol/mol) at two consecutive visits 3 months apart, after 6 months' treatment] on metformin + exenatide twice daily were re-randomized to add-on TZD or glimepiride, and 166 patients inadequately controlled on metformin + glimepiride received add-on exenatide twice daily. Changes in HbA1c, body mass index (BMI), lipids, hypoglycaemia and vital signs were evaluated. RESULTS: The median duration of triple therapy was ∼2 years. In patients inadequately controlled on metformin + exenatide twice daily, add-on TZD decreased HbA1c levels significantly better than add-on glimepiride: 130-week difference 0.48% [95% confidence interval (CI) 0.19-0.77] or 5.2 mmol/mol (95% CI 2.1-8.4; p = 0.001), but with significantly increased BMI and systolic blood pressure. The ratio of documented symptomatic (blood glucose ≤70 mg/dl [3.9 mmol/l]) hypoglycaemia rates for add-on glimepiride to add-on TZD was 8.48 (p < 0.0001). Add-on exenatide twice daily after metformin + glimepiride significantly reduced HbA1c levels: mean [standard deviation (s.d.)] change from baseline -0.35 (0.89)% [-3.8 (9.7) mmol/mol] and BMI: mean (s.d.) change from baseline -0.82 (1.9) kg/m(2) at 130 weeks, with a slightly increased rate of documented symptomatic hypoglycaemia from metformin + glimepiride (ratio 1.49). CONCLUSIONS: TZD, but not glimepiride, was an effective and well tolerated third-line therapy in patients without glycaemic control after long-term therapy with metformin + exenatide twice daily. Exenatide twice daily was an effective and well tolerated third-line therapy in patients inadequately controlled on metformin + glimepiride.

Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial.

AIMS: To evaluate glucose-lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted. METHODS: A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5-12.0%, were randomized 1:1 to double-blind, free-combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245). RESULTS: The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by -2.8 ± 0.1% with linagliptin/metformin and -2.0 ± 0.1% with linagliptin; a treatment difference of -0.8% (95% confidence interval -1.1 to -0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean ± s.e. changes in HbA1c of -2.7 ± 0.1% and -1.8 ± 0.1%, respectively; treatment difference of -0.9% (95% CI -1.3 to -0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (-1.3 kg between-group difference; p =0.0033). CONCLUSIONS: Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy.

The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems.

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta-cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP-1 receptors are also expressed in extra-pancreatic tissues and trial data suggest that GLP-1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP-1 or GLP-1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP-1RAs in both people with type 2 diabetes and obese people without diabetes. GLP-1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP-1RA-induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP-1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra-pancreatic effects of GLP-1RAs could provide multi-factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP-1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP-1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.

Type II diabetes and its therapy in clinical practice - results from the standardised non-interventional registry SIRTA.

BACKGROUND AND METHODS: Modern antidiabetic therapies should achieve low HbA1c values and avoid hypoglycaemic complications. The registry SIRTA included 1522 patients with type II diabetes mellitus (T2DM) from 306 German medical practices. Patients had an HbA1c > 6.5% under the maximum tolerated metformin dose. If required, they received combination therapy with other antidiabetics according to the guideline of the German Diabetes Society [Deutsche Diabetes Gesellschaft (DDG)] or usual medical practice. Patients were followed up for 6 months. The target criteria included the achievement of HbA1c target values and the emergence of severe hypoglycaemic episodes. RESULTS: Most patients (64.0%) were planned to achieve an HbA1c target < 6.5%, the standard target recommended by the 2009 DDG guideline valid throughout the registry. Primarily to reduce the individual risk for hypoglycaemia, 32.4% of patients had a less strict HbA1c-target of 6.5-7.0%. These targets were achieved by 31.3% and 44.3% of patients, respectively. Combination therapies increased from 45% to 56% over the 6 months registry. Four patients had severe hypoglycaemias (0.26%). CONCLUSIONS: The registry confirms results from other epidemiologic studies on the therapy of T2DM in everyday practice. The treatment strategies applied effectively reduced blood glucose and avoided severe hypoglycaemias. An early therapy of insufficiently controlled patients with T2DM is important, as lower baseline values facilitated achieving HbA1c targets.

Improved glycaemic control with vildagliptin added to insulin, with or without metformin, in patients with type 2 diabetes mellitus.

AIM: The aim of this study is to assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in type 2 diabetes mellitus (T2DM). METHODS: This is a multicentre, double-blind, placebo-controlled, parallel group, clinical trial in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. Patients received treatment with vildagliptin 50 mg bid or placebo for 24 weeks. RESULTS: In all, 449 patients were randomized to vildagliptin (n = 228) or placebo (n = 221). After 24 weeks, the difference in adjusted mean change in haemoglobin A1c (HbA1c) between vildagliptin and placebo was -0.7 ± 0.1% (p < 0.001) in the overall study population, -0.6 ± 0.1% (p < 0.001) in the subgroup also receiving metformin and -0.8 ± 0.2% (p < 0.001) in the subgroup without metformin. Vildagliptin therapy was well tolerated and had a similarly low incidence of hypoglycaemia compared with placebo (8.4 vs. 7.2%, p = 0.66) in spite of improved glycaemic control, and was not associated with weight gain. (+0.1 vs. -0.4 kg). CONCLUSIONS: Vildagliptin 50 mg bid added to insulin significantly reduced HbA1c in patients with T2DM inadequately controlled by insulin, with or without metformin. Vildagliptin was well tolerated, with a safety profile similar to placebo. These results were achieved without weight gain or an increase in hypoglycaemia incidence or severity in spite of improved glycaemic control.

Linagliptin is more effective than glimepiride at achieving a composite outcome of target HbA1c < 7% with no hypoglycaemia and no weight gain over 2 years.

Linagliptin treatment for 104 weeks was recently reported to achieve non-inferior glucose-lowering effects compared with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Additional analyses from this randomised, active-controlled, double-blind trial have been performed in individuals completing the study on study drug without requiring rescue therapy. In this population, significantly more patients receiving linagliptin achieved HbA1c < 7% without hypoglycaemia and without body weight gain after 2 years compared with those receiving glimepiride (54% and 23%, respectively; odds ratio of 3.9, 95% confidence interval 2.6-5.7, p < 0.0001).

[Insulin degludec--a new basal insulin for the treatment of type 1 and type 2 diabetes]. / Insulin degludec--ein neues Basalinsulin zur Behandlung von Typ-1- und Typ-2-Diabetes.

After subcutaneous injection, IDeg self-associates to form multihexamer chains that slowly dissociate into monomers. This results in a duration of action of more than 42 hours as well as a smooth level action profile with low intra-individual variability. Pharmacokinetic studies foun IDeg to have a half-life of approximately 25 hours which is considerably longer than that from other current insulin formulations. Based on these properties, IDeg demonstrated low risk for nocturnal hypoglycaemic events in the clinical study program. Concurrently, phase 3 studies have provided evidence for a non-inferior glucose lowering effect when compared to other currently available basal insulin formulations. Moreover, the long duration of action suggests a flexible handling which could be better adapted to patients' needs in daily routine. This article gives an overview of the mechanism of action of IDeg and the latest results from phase 2 and phase 3 studies.

Association of somatostatin receptor 2 immunohistochemical expression with [111In]-DTPA octreotide scintigraphy and [68Ga]-DOTATOC PET/CT in neuroendocrine tumors.

In the absence of preoperative somatostatin receptor ( SST) scans, knowledge of immunohistochemical SST2 tumor expression may help predicting the success of somatostatin analogue-based follow-up studies and treatment of neuroendocrine tumors (NET). We studied the association between SST immunostaining and tracer uptake in [(111)In]-DTPA octreotide (DTPAOC) scintigraphy and [(68)Ga]-DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC) positron emission tomography (PET)/computed tomography (CT). Retrospective analy-sis of 36 NET patients was carried out. In 40 tumors, immunohistochemical SST2, SST3, and SST5 expressions were analyzed using a pathological scoring, applying monoclonal ( SST2) or polyclonal antibodies (SST3, SST5). In 14 lesions, [(111)In]-DTPAOC uptake was assessed by a semiquantitative score. In 26 tumors, [(68)Ga]-DOTATOC PET/CT was quantified using an uptake score and maximal standard uptake value (SUV(max)). Combined and separate qualitative analysis of SST scans revealed significant associations between increased tracer uptake and immunohistochemical SST2 detection (combined: rho=0.56, p=0.0002, [(111)In]-DTPAOC: rho=0.63, p=0.0152, and [(68)Ga]-DOTATOC: rho=0.52, p=0.0065, respectively). In contrast, SST3 and SST5 immunostaining was not associated with tracer uptake (all p>0.14). The semiquantitative immunohistochemical score for SST2 was associated with the [(68)Ga]-DOTATOC uptake score and SUV (max) values (rho=0.67, p=0.0002 and rho=0.63, p=0.0010, respectively), but not with the [(111)In]-DTPAOC uptake score (rho=0.24, p=0.4). In patients without preoperative SST scans, knowledge of immunohistochemical SST2 expression may help estimating the value of SST imaging in the clinical follow-up, in particular in those lesions with positive SST2 immunostaining. Negativity for SST2, however, does not rule out tracer uptake in some patients, with heterogeneous SST2 expression within the tumor as a potential explanation.

Future perspectives for insulinotropic agents in the treatment of type 2 diabetes-DPP-4 inhibitors and sulphonylureas.

The introduction of dipeptidyl-peptidase IV inhibitors (DPP-4 inhibitors) brought a novel class of insulinotropic agents into the treatment options for type 2 diabetes. This paper compares the actions, clinical efficacy and safety of sulphonylureas with those of the DPP-4 inhibitors. First, the mode of action of both classes of antidiabetic agents is described. Then clinical studies for both substances in monotherapy and combination therapies are compared concerning their effects on glycaemic parameters and long-term duration of action. Hypoglycaemia incidence and other adverse effects are compared and data on cardiovascular parameters and endpoints are summarized. The effects of sulphonylureas and DPP-4 inhibitors on beta-cell function and beta-cell mass are highlighted. The present and future indications for both sulphonylureas and DPP-4 inhibitors are discussed.

Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time.

AIM: To investigate the onset of treatment effects over time observed for liraglutide in combination with oral antidiabetic drugs (OADs). METHODS: This analysis included patients from three phase 3, 26-week, randomised, double-blind, parallel-group trials. Prior to randomisation, patients underwent a run-in and titration period with metformin (Liraglutide Effect and Action in Diabetes-2, LEAD-2), glimepiride (LEAD-1) or metformin plus rosiglitazone (LEAD-4). Patients were then randomised to receive liraglutide (0.6, 1.2 or 1.8 mg once-daily), active comparator and/or placebo. For this analysis, only the 1.2 mg and 1.8 mg liraglutide doses were included. Outcome measures included change in HbA(1c), fasting plasma glucose (FPG), weight and systolic blood pressure (SBP). The safety profile was also investigated. RESULTS: Significant reductions in HbA(1c) were observed within 8 weeks of treatment with liraglutide plus OADs (p < 0.0001) and maintained until week 26. Furthermore, liraglutide plus OADs led to significant reductions in FPG within 2 weeks (p < 0.0001) and sustained over 26 weeks. Adding liraglutide to metformin or metformin plus rosiglitazone also led to early reductions and maintained reductions in body weight (within 8 weeks, p < 0.0001); however, liraglutide treatment plus glimepiride was weight neutral. Rapid reductions in SBP were observed for liraglutide plus OADs (within 2 weeks, p < 0.05-0.001) and maintained for 26 weeks. Some patients experienced nausea, which for the majority it diminished within 2 weeks. CONCLUSION: Liraglutide treatment combined with OADs led to rapid improvements in FPG and SBP. Early reductions in HbA(1c) and body weight were also observed. Adding liraglutide to OADs early on may therefore be a good treatment option for patients with type 2 diabetes.

Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial.

AIM: To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone. METHODS AND PATIENTS: A total of 858 patients [age ≥ 18 years; glycated haemoglobin (HbA(1c) ) > 6.5 - 10.0%; on stable metformin doses ≥ 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA(1c) achieved with saxagliptin plus metformin was non-inferior to glipizide plus metformin. RESULTS: The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA(1c) were -0.74% vs. -0.80%, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p < 0.0001) and a divergent impact on body weight (adjusted mean change from baseline -1.1 kg with saxagliptin vs. 1.1 kg with glipizide; p < 0.0001). There was a significantly smaller rise in HbA(1c) (%/week) from week 24 to 52 with saxagliptin vs. glipizide (0.001% vs. 0.004%; p = 0.04) indicating a sustained glycaemic effect beyond week 24. Excluding hypoglycaemic events, the proportion of patients experiencing adverse events (AEs) was similar (60.0% saxagliptin vs. 56.7% glipizide); treatment-related AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%), attributable to the higher frequency of hypoglycaemia in glipizide patients. Discontinuation rates resulting from AEs were similar (∼4%). CONCLUSION: Saxagliptin plus metformin was well tolerated, provided a sustained HbA(1c) reduction over 52 weeks, and was non-inferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycaemia.

A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion.

AIMS/HYPOTHESIS: WFS1 type 2 diabetes risk variants appear to be associated with impaired beta cell function, although it is unclear whether insulin secretion is affected directly or secondarily via alteration of insulin sensitivity. We aimed to investigate the effect of a common WFS1 single-nucleotide polymorphism on several aspects of insulin secretion. METHODS: A total of 1,578 non-diabetic individuals (534 men and 1,044 women, aged 40 +/- 13 years, BMI 28.9 +/- 8.2 kg/m(2) [mean +/- SD]) at increased risk of type 2 diabetes were genotyped for rs10010131 within the WFS1 gene. All participants underwent an OGTT (and a subset additionally an IVGTT [n = 319]) and a hyperglycaemic clamp combined with glucagon-like peptide-1 (GLP-1) and arginine stimuli (n = 102). RESULTS: rs10010131 was associated with reduced OGTT-derived insulin secretion (p = 0.03). In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 infusion combined with a hyperglycaemic clamp showed a significant reduction of the insulin secretion rate during the first and second phases of GLP-1-induced insulin secretion in carriers of the risk allele (reduction of 36% and 26%, respectively; p = 0.007 and p = 0.04, respectively). CONCLUSIONS/INTERPRETATION: A common genetic variant in WFS1 specifically impairs GLP-1-induced insulin secretion independently of insulin sensitivity. This defect might explain the impaired insulin secretion in carriers of the risk allele and confer the increased risk of type 2 diabetes.

The risk allele load accelerates the age-dependent decline in beta cell function.

AIMS/HYPOTHESIS: Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function. In the present study we examined the effect of these genes' risk alleles on the age-dependent decline in insulin secretion. METHODS: The SNPs rs7903146 (TCF7L2), rs7754840(CDKAL1), rs7923837 (HHEX) and rs13266634 (SLC30A8) were genotyped in 1,412 non-diabetic patients, who were subsequently grouped according to their number of risk alleles. All participants underwent an OGTT. Insulin secretion was assessed by validated indices and proinsulin conversion by calculating AUC(proinsulin)/AUC(insulin). RESULTS: The number of risk alleles revealed a Gaussian distribution, with most participants carrying four risk alleles. Stratification into groups with low (LAL, up to three alleles), median (MAL, four alleles) and high (HAL, five to eight alleles) allele load resulted in MAL and HAL participants displaying significantly lower insulin secretion and proinsulin conversion than LAL participants (p

Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial.

AIMS: Insulin analogues are widely used but few data exist comparing different analogue regimens. We compared two such regimens in type 2 diabetes mellitus (T2DM) uncontrolled by oral antidiabetic agents (OADs) with or without basal insulin. METHODS: In a 26-week multinational, multicentre, randomized treat-to-target trial, OADs were discontinued and subjects randomized to analogue basal-bolus therapy (insulin detemir once daily and insulin aspart mealtimes) or biphasic insulin aspart 30 (30% rapid-acting insulin aspart), twice daily. Insulin was titrated to targets for fasting, predinner and postprandial plasma glucose (PG), as appropriate. RESULTS: Of 719 subjects, 92% completed the study; 58% achieved haemoglobin fraction A(1c) (HbA(1c)) < or =7.0%, with reductions of 1.56% (to 6.96%) with basal-bolus therapy and 1.23% (to 7.17%) with biphasic insulin aspart. Reduction with basal-bolus therapy was superior in the overall population by 0.23% (p = 0.0052), with no difference between regimens in insulin-naive patients. Major hypoglycaemia occurred in five basal-bolus patients (0.9%) and in no patients with biphasic insulin aspart. Incidence of minor hypoglycaemia was similar in both groups. All insulin doses increased during titration, with increase in lunchtime insulin aspart dose and equal distribution of breakfast and dinner biphasic insulin aspart doses. Insulin detemir remained once daily in 87% of patients. CONCLUSIONS: Modern insulin analogue regimens, adjusted to PG targets, enable a majority of people with T2DM to reach HbA(1c)< or =7.0% after failure of OADs and OAD-basal insulin therapy. Insulin-treated patients may benefit more from transfer to analogue basal-bolus therapy, while insulin-naive individuals benefit equally well from the more convenient biphasic analogue regimen.

The European Exenatide study of long-term exenatide vs. glimepiride for type 2 diabetes: rationale and patient characteristics.

AIM: To describe the rationale for the European Exenatide (EUREXA) clinical study and describe the characteristics of the patient cohort. METHODS: EUREXA is a multinational study of long-term effects of add-on exenatide vs. glimepiride in patients with type 2 diabetes and failure of diet/lifestyle plus metformin monotherapy. Metformin failure was defined as hemoglobin A1c (HbA1c) > or = 6.5% and patients were overweight/obese (BMI > or = 25 to < 40 kg/m(2)). The primary end point is time to failure of combination treatment, defined from HbA1c concentration according to current criteria. At baseline, an oral glucose tolerance test (OGTT) was performed, fasting blood was taken for lipid profile and patients were randomized to add-on exenatide (5 microg b.i.d. for 4 weeks then 10 microg b.i.d.) or glimepiride (1 mg/day titrated to maximum dose). RESULTS: A total of 1039 patients were entered in the study, with mean (+/- s.d.) age 57.2 +/- 9.6 years, body mass index (BMI) 32.4 +/- 4.1 kg/m(2), duration of diabetes 5.6 +/- 4.5 years and HbA1c 7.4 +/- 0.7%. A history of cardiovascular disease (CVD) was present for 64.8% of patients overall and duration of diabetes was statistically significantly longer for patients with CVD than without (p = 0.010). Lipid abnormalities were reported for 48.9% of patients and 40.9% were taking at least one lipid-lowering medication. CONCLUSION: Patients included in the EUREXA study had early failure of glucose control with metformin and presented typical features of type 2 diabetes: overweight/obesity and high prevalence of lipid abnormalities and CVD. In this population, the effects of exenatide vs. glimepiride will be evaluated over at least 2.5 years.

Excess glycaemic excursions after an oral glucose tolerance test compared with a mixed meal challenge and self-measured home glucose profiles: is the OGTT a valid predictor of postprandial hyperglycaemia and vice versa?

INTRODUCTION: Postprandial hyperglycaemia is often assumed in individuals with high glucose excursions during an oral glucose tolerance test (OGTT), but the relationship between glucose levels during the OGTT and after a mixed meal is yet unclear. We addressed whether (i) glucose concentrations after an oral glucose load are similar to those after a test meal or under daily life conditions and (ii) impaired glucose tolerance (IGT) predicts postprandial hyperglycaemia. PATIENTS AND METHODS: A total of 60 subjects with normal (NGT), IGT or diabetic (DM) glucose tolerance were examined with an OGTT, a mixed meal challenge (3433 kJ) and a self-determined 10-point home glucose profile. RESULTS: There was a significant correlation between the 120-min OGTT glucose levels and the glycaemic excursions after the test meal and during everyday conditions. However, glucose excursions during the OGTT exceeded those after the test meal and during everyday conditions by approximately 20 and approximately 30% respectively. Likewise, insulin and C-peptide levels rose to higher levels after oral glucose compared with mixed meal ingestion. The mean self-determined diurnal glucose levels were already 10% higher in subjects with IGT compared with NGT subjects (p < 0.0001). CONCLUSIONS: Glucose levels reached after an oral glucose challenge and during real life are correlated to some extent, but the absolute levels of glycaemia greatly differ between both conditions. Therefore, 'postchallenge' glucose levels measured during an OGTT might be used as a predictor of 'postprandial hyperglycaemia', but caution should be taken when both terms are used synonymously. Furthermore, subjects with IGT during an OGTT already exhibit increased postprandial glucose levels under real-life conditions. This suggests that IGT should already be considered an overt disease condition rather than merely a high-risk situation.

Lymph node gastrinoma in multiple endocrine neoplasia type 1 - a diagnostic challenge.

BACKGROUND: Gastrinomas are the most frequent hormonally-active neuroendocrine tu-mours in patients with multiple endocrine neoplasia type 1 (MEN1). CASE REPORT: We report on the diagnostic difficulties in a 62-year-old female patient with MEN1 and lymph node gastrinoma. At six and twelve months after resection of a lymph node gastrinoma, no signs of recurrence were observed. Basal and peak gastrin levels during secretin stimulation test were normalized. Extensive explorations, including gastrointesinal endoscopy, endoscopic ultrasonography, and Ga-68-DOTATOC-PET/CT, did not reveal a primary duodenal or pancreatic tumour. CONCLUSION: Localization of gastrinomas in patients with MEN1 is challenging due to their small size, frequent duodenal location, and multiplicity. Therefore, while some studies support the existence of primary lymph node gastrinoma in patients with sporadic disease, this diagnosis should not be made in MEN1 patients. In both cases, however, extensive follow-ups are required.