Objective: To assess frequency, symptoms and outcome of pituitary apoplexy (PA) among pituitary adenoma patients, to gain better insight into risk factors for bleeding into pituitary adenoma and to estimate the sequelae of PA by means of a matched control group. Method: By reviewing charts of 574 patients with pituitary adenoma, we analysed incidence, symptoms and outcome of PA and potential risk factors for developing PA by means of a control group (patients with pituitary adenoma without PA). Results: In total, 42 suffered from PA, all had macroadenomas; 30/217 male (14%) and 12/179 female (7%) macroadenoma patients, 32/194 patients with clinically non-functioning (16.5%) and 10/202 with clinically active (5.0%) macroadenoma were affected. Antithrombotic therapy predisposed patients to PA (PZ0.026), diabetes mellitus and hypertension did not (PZ1.00). Patients with PA and pituitary adenoma patients without PA had similar frequencies of hypopituitarism (45 vs 48%, PO0.05) and visual field defects (38 vs 55%, PO0.05), but ophthalmoplegia was significantly more common (76 vs 5%, P!0.001) in patients with PA. Nearly all patients were treated by surgery; most recovered from ophthalmoplegia, whereas visual function improved only moderately. Endocrine outcome was worse in patients with PA than in patients without PA. Conclusions: Male sex and characteristics of the adenoma itself (especially tumour size and tumour type) rather than patient's cardiovascular risk factors such as diabetes and hypertension seem to predispose to PA; antithrombotic therapy may also be important.

ClinicalTrials.gov number NCT00655863.

Aims/hypothesisTraditional 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.MethodsThis 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 HbA1c ≤7.5% and BMI of 22–45 kg/m2. 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).ResultsFifty-two week vildagliptin 100 mg (n = 26) treatment increased the primary efficacy variable, combined hyperglycaemia and arginine-stimulated C-peptide secretion (AIRarg), 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 AIRarg 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 HbA1c and fasting plasma glucose, respectively. There were no suspected drug treatment-related serious adverse events.Conclusions/interpretationOne 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 NCT00260156Funding:This study was sponsored by the Novartis Pharmaceutical Cooperation.

Objective: Type 2 diabetes mellitus (T2DM) management requires continuous treatment intensification due to progressive decline in b-cell function in insulin resistant individuals. Initial combination therapy of a dipeptidyl peptidase (DPP)-4 inhibitor with a thiazolidinedione (TZD) may be rational. We assessed the effects of the DPP4 inhibitor alogliptin (ALO) combined with the TZD pioglitazone (PIO), vs ALO monotherapy or placebo (PBO), on b-cell function and glycemic control in T2DM. Material and methods: A 16-week, two-center, randomized, double-blind, PBO-controlled, parallel-arm intervention study in 71 patients with well-controlled T2DM (age 59.1G6.3 years; A1C 6.7G0.1%) treated with metformin, sulfonylurea, or glinide monotherapy was conducted. Patients were treated with combined ALO 25 mg and PIO 30 mg daily or ALO 25 mg daily monotherapy or PBO. Main outcome measures included change in A1C and fasting plasma glucose (FPG) from baseline to week 16. In addition, change in b-cell function parameters obtained from standardized meal tests at baseline and at week 16 was measured. Results: ALO/PIO and ALO decreased A1C from baseline by 0.9G0.1 and 0.4G0.2% respectively (both P!0.001 vs PBO). FPG was decreased to a greater extent by ALO/PIO compared with ALO monotherapy (P!0.01). ALO/PIO treatment improved b-cell glucose sensitivity (vs PBO; P!0.001) and fasting secretory tone (vs PBO; PZ0.001), while ALO monotherapy did not change b-cell function parameters. All treatments were well tolerated. Conclusion: Short-term treatment with ALO/PIO or ALO improved glycemic control in well-controlled T2DM patients, but only combined ALO/PIO improved b-cell function. These data support that initial combination therapy with a DPP4 inhibitor and TZD to address multiple core defects in T2DM may be a sensible approach.

Development of cardiovascular disease is one of the major complications of type 2 diabetes mellitus (T2DM). The chronic hyperglycaemic state is often accompanied by dyslipidaemia, hypertension, low-grade systemic inflammation and oxidative stress which collectively result in a high risk of micro- and macrovascular complications. Current glucose-lowering agents do not sufficiently address fore-mentioned macrovascular-risk factors. Recently, new therapeutic agents were introduced, based on the incretin hormone glucagon-like peptide-1 (GLP-1), that is, the GLP-1 receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 (DPP-4) inhibitors. Beside its effect on pancreatic insulin secretion, GLP-1 exerts several extra-pancreatic effects such as slowing down gastric emptying, promoting satiety and reducing food intake and weight loss. Also, GLP-1 and GLP-1RA were shown to improve cardiovascular-risk profiles, by reducing body fat content, blood pressure, circulating lipids and inflammatory markers in patients with T2DM. This review summarizes the presently known evidence with regard to extra-pancreatic effects of the incretin-based agents, focusing on the actions that improve the cardiovascular-risk profile. We present available data from clinical trials of at least 24 week duration, but also findings from small-sized clinical 'proof of principle' studies. We conclude that GLP-1 RA and to a lesser extent DPP-4 inhibitors are promising agents with regard to their effects on body weight, blood pressure and lipids, which collectively ameliorate the cardiovascular-risk profile and as such may have added value in the treatment of T2DM. However, large-sized long-term outcome studies are warranted to show the true added value of these agents in the treatment of patients with T2DM.