Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis

Intensive versus standard multifactorial cardiovascular risk factor control in screen-detected type 2 diabetes: 5-year and longer-term modelled outcomes of the ADDITION-Leicester study.

AIMS: Diabetes treatment algorithms recommend intensive intervention in those with a shorter duration of disease. Screening provides opportunities for earlier multifactorial cardiovascular risk factor control. Using data from the ADDITION-Leicester study (NCT00318032), we estimated the effects of this approach on modelled risk of diabetes-related complications in screen-detected patients. METHODS: A total of 345 (41% South Asian) people with screen-detected type 2 diabetes were cluster randomised to receive 5 years of (1) intensive multifactorial risk factor intervention or (2) standard treatment according to national guidance. Estimated 10 to 20-year risk of ischaemic heart disease, stroke, congestive cardiac failure, and death was calculated using UK-PDS risk equations. RESULTS: Compared with standard care, mean treatment differences for intensive management at 5 years were -11.7(95%CI: -15.0, -8.4) and -6.6(-8.8, -4.4) mmHg for systolic and diastolic blood pressure, respectively; -0.27 (-0.66, -0.26) % for HbA1c; and -0.46(-0.66; -0.26), -0.34 (-0.51; -0.18), and -0.19 (-0.28; -0.10) mmol/L for total cholesterol, LDL-cholesterol, and triglycerides, respectively. There was no significant weight gain in the intensive group despite additional medication use. Modelled risks were consistently lower for intensively managed patients. Absolute risk reduction associated with intensive treatment at 10 and 20 years were 3.5% and 6.2% for ischaemic heart disease and 6.3% and 8.8% for stroke. Risk reduction for congestive heart failure plateaued after 15 years at 5.3%. No differences were observed for blindness and all-cause death. CONCLUSION: Intensive multifactorial intervention in a multi-ethnic population with screen-detected type 2 diabetes results in sustained improvements in modelled ischaemic heart disease, stroke, and congestive cardiac failure.We acknowledge the support from the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care – East Midlands (NIHR CLAHRC – EM), the Leicester Clinical Trials Unit, and the NIHR Leicester BRC (Biomedical Research Centre). This report is independent research funded by the National Institute for Health Research

The safety and effectiveness of non-insulin glucose lowering agents in the treatment of people with Type 2 Diabetes who observe Ramadan: A systematic review and meta-analysis

Aims: To determine which non-insulin glucose lowering treatment regimens are most appropriate in people with type 2 diabetes who choose to fast during Ramadan. Materials and methods: Electronic databases were searched for randomised controlled trials (RCT) and observational studies comparing non-insulin glucose lowering agents in people with type 2 diabetes fasting during Ramadan reporting hypoglycaemia, weight and HbA1c change were included. Data were pooled using random effects models. Results: Sixteen studies included; nine RCTs and seven observational studies. There was evidence that DPP-4 inhibitors led to less hypoglycaemic events compared to sulphonylureas. Sitagliptin significantly reduced the number of patients ≥1 hypoglycaemic episodes during Ramadan (RR 0.48, 95%CI 0.36, 0.64, p>0.0001), this was not replicated in the RCTs of vildagliptin but a significant reduction was found in the observational studies (RR 0.28, 95%CI 0.10, 0.75, p=0.01) with high heterogeneity (I2=86.7%). Significant reductions in HbA1c and weight were seen in the observational studies of vildagliptin vs. sulfonylureas. The use of liraglutide led to significant weight loss (-1.81kg, 95%CI -2.91, -0.71, p=0.001) compared to sulfonylureas. Pioglitazone significantly increased weight compared to placebo (3.48kg, 95%CI 2.82, 4.14, p<0.0001). Conclusions: The analysis supports the use of DPP-4 inhibitors during Ramadan over sulfonylureas for reduction in hypoglycaemic episodes without a cost to diabetes control and weight. The GLP-1 agonist liraglutide provides clinical benefits, but more studies are required. RCTs of DPP-4 inhibitors against GLP-1 agonists and novel therapies including the SGLT-2 and alpha-glucosidase inhibitors are needed to inform evidence based guidelines