Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME® trial

Aims/hypothesis: In addition to beneficial effects on glycaemia and cardiovascular death, empagliflozin improves adiposity indices. We investigated the effect of empagliflozin on aminotransferases (correlates of liver fat) in individuals with type 2 diabetes. Methods: Changes from baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in the EMPA-REG OUTCOME® trial (n = 7020), pooled data from four 24-week placebo-controlled trials (n = 2477) and a trial of empagliflozin vs glimepiride over 104 weeks (n = 1545). Analyses were performed using data from all participants and by tertiles of baseline aminotransferases. Results: In the EMPA-REG OUTCOME® trial, mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo, respectively (adjusted mean difference: −2.22 [95% CI −2.83, −1.62]; p < 0.0001). Reductions in ALT were greatest in the highest ALT tertile (placebo-adjusted mean difference at week 28: −4.36 U/l [95% CI −5.51, −3.21]; p < 0.0001). The adjusted mean difference in change in ALT was −3.15 U/l (95% CI −4.11, −2.18) with empagliflozin vs placebo at week 24 in pooled 24-week data, and −4.88 U/l (95% CI −6.68, −3.09) with empagliflozin vs glimepiride at week 28. ALT reductions were largely independent of changes in weight or HbA1c. AST changes showed similar patterns to ALT, but the reductions were considerably lower. Conclusions/interpretation: These highly consistent results suggest that empagliflozin reduces aminotransferases in individuals with type 2 diabetes, in a pattern (reductions in ALT>AST) that is potentially consistent with a reduction in liver fat, especially when ALT levels are high

Differences in level of confidence in diabetes care between different groups of trainees: the TOPDOC diabetes study

Background There is an increasing prevalence of diabetes. Doctors in training, irrespective of specialty, will have patients with diabetes under their care. The aim of this further evaluation of the TOPDOC Diabetes Study data was to identify if there was any variation in confidence in managing diabetes depending on the geographical location of trainees and career aspirations. Methods An online national survey using a pre-validated questionnaire was administered to trainee doctors. A 4-point confidence rating scale was used to rate confidence in managing aspects of diabetes care and a 6-point scale used to quantify how often trainees would contribute to the management of patients with diabetes. Responses were grouped depending on which UK country trainees were based and their intended career choice. Results Trainees in Northern Ireland reported being less confident in IGT diagnosis, use of IV insulin and peri-operative management and were less likely to adjust oral treatment, contact specialist, educate lifestyle, and optimise treatment. Trainees in Scotland were less likely to contact a specialist, but more likely to educate on lifestyle, change insulin, and offer follow-up advice. In Northern Ireland, Undergraduate (UG) and Postgraduate (PG) training in diagnosis was felt less adequate, PG training in emergencies less adequate, and reporting of need for further training higher. Trainees in Wales felt UG training to be inadequate. In Scotland more trainees felt UG training in diagnosis and optimising treatment was inadequate. Physicians were more likely to report confidence in managing patients with diabetes and to engage in different aspects of diabetes care. Aspiring physicians were less likely to feel the need for more training in diabetes care; however a clear majority still felt they needed more training in all aspects of care. Conclusions Doctors in training have poor confidence levels dealing with diabetes related care issues. Although there is variability between different groups of trainees according to geographical location and career aspirations, this is a UK wide issue. There should be a UK wide standardised approach to improving training for junior doctors in diabetes care with local training guided by specific needs.</p

Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men

OBJECTIVE : Patients with mutations of neurokinin B (NKB) and its receptor show hypogonadotrophic hypogonadism, but there is little evidence for the importance of this pathway in reproductive function in normal men, or its functional hierarchy with kisspeptin. DESIGN : An open label study wherein men (n = 6) were administered the NK3R antagonist MLE4901 40 mg orally twice a day for 7 days. Kisspeptin-10 (0.3 μg/kg iv bolus) was given before and on day 7 of NK3R antagonist treatment. PATIENTS : Subjects were healthy men. MEASUREMENTS : Reproductive hormones were measured before and during the NK3R antagonist administration, including frequent sampling on two occasions for analysis of pulsatile LH secretion. RESULTS : LH, FSH and testosterone secretion were decreased during NK3R antagonist administration. LH showed a biphasic response, being reduced after 24 hours of treatment (4.5 ± 0.6 IU/L pretreatment to 1.7 ± 0.2 IU/L, P < .05), with partial recovery thereafter, but it was again decreased on day 7 (2.5 ± 0.6 IU/L, P < .05 vs pretreatment). FSH secretion was also suppressed, with a similar temporal pattern to that of LH. Testosterone secretion was decreased from 24 hours (18.4 ± 1.6 pretreatment vs 5.6 ± 1.5 nmol/L, P < .01) and remained suppressed throughout the treatment period. Analysis of LH pulsatility showed that both basal and pulsatile LH secretion were markedly suppressed but there was no detected change in LH pulse frequency. Kisspeptin-10 stimulated LH secretion, with similar responses before and during NK3R antagonist administration. CONCLUSIONS : These data demonstrate a central role for NKB/NK3R in the physiological regulation of reproductive function in men, and that this is functionally upstream of kisspeptin-mediated GnRH secretion.The Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative STMTI and MRC grant G0701682 to RAA and RPMhttp://wileyonlinelibrary.com/journal/cenam2017Mammal Research Institut

Non-European Union doctors in the National Health Service: why, when and how do they come to the United Kingdom of Great Britain and Northern Ireland?

BACKGROUND: As many as 30% of doctors working for the National Health System (NHS) of the United Kingdom of Great Britain and Northern Ireland (UK) have obtained their primary qualifications from a country outside the European Union. However, factors driving this migration of doctors to the UK merit continuing exploration. Our objective was to obtain training and employment profile of UK doctors who obtained their primary medical qualification outside the European Union (non-European doctors) and to assess self-reported reasons for their migration. METHODS: We conducted an online survey of non-European doctors using a pre-validated questionnaire. RESULTS: One thousand six hundred and nineteen doctors of 26 different nationalities completed the survey. Of the respondents, 90.1% were from India and over three-quarters migrated to the UK mainly for 'training'. Other reasons cited were 'better pay' (7.2%), 'better work environment' (7.1%) and 'having family and friends in the UK' (2.8%). Many of the respondents have been in the UK for more than a year (88.8%), with 31.3% having spent more than 3 years gaining experience of working in the NHS. Most respondents believe they will be affected by recent changes to UK immigration policy (86.6%), few report that they would be unaffected (3.7%) and the rest are unsure (9.8%). CONCLUSION: The primary reason for many non-European doctors to migrate to the UK is for training within the NHS. Secondary reasons like better pay, better work environment and having friends and family in the UK also play a role in attracting these doctors, predominantly from the Indian subcontinent and other British Commonwealth countries