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

Functional characterisation and translational applications of kisspeptin-10.

Background: Kisspeptins, recently discovered hypothalamic neuropeptides encoded by the KISS1 gene, are essential for normal pubertal development and are modulated by diverse endocrine, metabolic and environmental signals. Exogenous kisspeptin administration potently stimulates LH secretion - by direct action on GnRH neurons while kisspeptin antagonists inhibit pulsatile LH secretion. Human studies of kisspeptin had hitherto used kisspeptin-54 that is cleaved further and the smallest bioactive form is a decapeptide (kisspeptin-10) with a shorter half-life. Kisspeptin-10 is thus putatively more attractive in studies assessing LH pulsatility and is also the basis for the development of antagonists. Unmet clinical needs: Decreased LH pulse frequency is the central pathology in pubertal delay, late-onset male hypogonadism and hypothalamic amenorrhoea. Manipulation of LH pulse frequency also has therapeutic potential in contraception, PCOS and sex-steroid dependant diseases such as endometriosis and prostatic hyperplasia. Hypothesis: That exogenous kisspeptin-10 enhances pulsatile LH secretion in healthy men and in patients with reproductive disorders associated with decreased pulse frequency. Research strategy: A first-in-human dose escalation study of kisspeptin-10 was performed in men and subsequently replicated in women. An intravenous infusion regime was optimised in healthy men and subsequently applied to hypogonadal patients. Specific questions were addressed sequentially as summarised below with key results. Dose escalation study: Question: Does kisspeptin-10 stimulate LH secretion in men? Findings: Six iv bolus doses (0.01 to 3 μg/kg) of GMP kisspeptin-10 and vehicle were administered at least a week apart to six healthy men. Rapid increase in LH, with peak concentrations was seen by 45 min post injection in all volunteers. There was a clear dose-dependent increase in LH concentrations in response to kisspeptin- 10 (P <0.0001). Area-Under-Curve analysis over 60 min following kisspeptin-10 administration showed 0.3 and 1μg/kg doses to be maximally stimulatory (P <0.01) with a reduced response at 3 μg/kg. Assessing the effect of steroid milieu: Question: Steroid feedback is central to the regulation of LH secretion: what effect does the steroid milieu have on LH responses to kisspeptin-10? Findings: The response to iv kisspeptin-10 (0.3μg/kg,) in the normal follicular phase (n=10) was compared with that in the presence of low endogenous sex steroids/high LH secretion (6 postmenopausal women) and in women taking combined contraceptive therapy (n=8) with suppressed LH secretion. Despite widely varying baseline secretion, LH increased significantly following kisspeptin-10 administration in the follicular phase (6.3±1.2 to 9.4±1.3 IU/L P=0.006), postmenopausal (35.3±2.8 to 44.7±3.4 IU/L P=0.005), etonogestrel (4.6±0.2 to 7.5±0.9 IU/L, P=0.02), and COCP groups (2.2±0.9 to 3.7±1.4 IU/L P<0.001). Pulse frequency study: Question: GnRH and LH secretion are pulsatile: can kisspeptin-10 enhance LH pulsatility? Findings: Four healthy men attended our clinical research facility for two visits five days apart for 10-min blood sampling. At the first visit, baseline LH pulsatility was assessed over a 9-hour period. During the second visit, an infusion of kisspeptin-10 was administered for 9 hours at 1.5μg/kg/hr after an hour of baseline sampling. LH pulse frequency increased in all subjects, with a mean increase from 0.7±0.1 to 1.0±0.2 pulses/hr (P = 0.01), with resultant increase in mean LH from 5.2±0.8 IU/L at baseline to 14.1±1.7 IU/L (P <0.01). High dose, longer duration infusion study: Question: Can kisspeptin-10 enhance testosterone secretion? Findings: Four healthy men attended our clinical research facility for a 34-hour supervised stay. Blood samples were collected at 10 min intervals for two 12 hour periods on consecutive days and hourly overnight. After 10.5 hours of baseline sampling a continuous intravenous infusion of kisspeptin-10 (4μg/kg/hr) was maintained for 22.5 hrs. Mean LH increased from 5.5±0.8 at baseline to 20.9±4.9 IU/L (P <0.05) and serum testosterone increased from 16.6±2.4 to 24.0±2.5 nmol/L (P <0.001). Translational studies in hypogonadal men with type 2 diabetes Question: Can kisspeptin-10 normalise testosterone secretion in hypogonadal men? Findings: Five hypogonadal men with T2DM (age 33.6±3 yrs, BMI 40.6±6.3, testosterone 8.5±1.0 nmol/L, LH 4.7±0.7 IU/L, HbA1c <8 %, duration of diabetes <5 yrs) and seven age matched healthy men were studied. Kisspeptin-10 was administered intravenous (0.3 μg/kg) with frequent (10-min) blood sampling. Mean LH increased in controls (5.5±0.8 to 13.9±1.7 IU/L P <0.001) and in T2DM (4.7±0.7 to 10.7±1.2 IU/L P=0.02) with comparable ΔLH (P=0.18). Baseline serum sampling for LH at 10-min intervals and hourly testosterone measurements were performed subsequently in four T2DM men for 12 hours. An intravenous infusion of kisspeptin-10 (4 μg/kg/hr) was administered 5 days later for 11 hours, with increases in serum LH (3.9±0.1 IU/L to 20.7±1.1 IU/L (P=0.03,) and testosterone (8.5±1.0 to 11.4±0.9 nmol/L, P=0.002). LH pulse frequency at baseline was lower in hypogonadal men with diabetes (0.6±0.1 vs. 0.8±0.1 pulses/hr, P=0.03) and increased to 0.9±0 pulses/hr (P=0.05). Translational studies in pubertal delay: Question: Defective Neurokinin B activity is associated with pubertal delay and the hierarchical interactions between kisspeptins and Neurokinin B remain to be elucidated: can kisspeptin-10 stimulate LH secretion with impaired Neurokinin B signalling? Findings: Four patients with TAC3 or TACR3 inactivating mutations presenting with delayed puberty were admitted for two 12 hr blocks of blood sampling every 10 min with vehicle (saline) or kisspeptin-10 (1.5 μg/kg/hour) infused intravenously. Mean LH and LH pulses frequency increased with kisspeptin-10 (P<0.05). However, four patients with Kallmann syndrome (with defective GnRH neuron migration), studied in parallel, did not respond, suggesting a potential diagnostic application for kisspeptin-10 in pubertal dysfunction. Conclusions In first-in-man studies of kisspeptin-10, it was demonstrated that endogenous LH pulse frequency can be enhanced in healthy men. The therapeutic potential of this finding in common reproductive endocrine disorders associated with decreased LH pulse frequency, i.e., late-onset male hypogonadism and pubertal dysfunction, was suggested in subsequent studies. Furthermore, kisspeptin signalling occurs upstream of GnRH neurons and is independent of Neurokinin B signalling in the central regulation of the hypothalamic-pituitary-gonadal axis

Micro-core decompression combined with intralesional zoledronic acid as a treatment of osteonecrosis of femoral head: a novel technique

Background: Avascular necrosis (AVN)/osteonecrosis of the femoral head is a debilitating condition affecting the hip joint and is one of the most common causes of total hip replacement. The available treatments include pharmacological and surgical options with total hip arthroplasty (THA) being the mainstay of treatment. This present study is a novel technique of combining micro core decompression with intra-lesional bisphosphonate as a treatment for osteonecrosis of the hip.Methods: A prospective study of 19 hips was done. There were 11 males and 4 females ranging 42-63 years. Four hips were stage I, ten hips were stage IIA, three hips were stage IIb and two hips were stage III.  16 hips (40%) had stage IIb and 24 hips (60%) had stage III ONFH. The minimum period of follow up was 24 months. All patients were assessed according to the Harris hip score. The operative procedure includes decompressing the avascular area with drilling then injecting the zoledronic acid locally.Results: The mean preoperative modified Harris hip score in stage I (n=4), stage IIa (n=10), stage IIb (n=3) and stage III (n=2) were 81.9, 72.7, 68.8 and 59.2 respectively. The mean postoperative modified Harris hip score at two years in stage I, stage IIa, stage IIb and stage III were 97.3, 91.1, 88.4 and 82.5 respectively.Conclusions: We found that the use of micro core-decompression with intra-lesional bisphosphonate will provide higher chances towards hip preservation especially in late cases or cases with larger lesions where core decompression may not be successful.

Hemophilic patient for emergency spinal decompression

Hemophilia is mostly an inherited genetic disorder, caused by mutations in the clotting factor gene. With the available treatment options, life expectancy of a hemophilic patient is usually of that of the general population. Hence, it is not uncommon that they present for surgical procedures. However, hemophilic patients for the major surgical procedure are always a real challenge for the perioperative physician. We have recently encountered one such patient who was hospitalized with acute paraplegia due to a mass lesion of spine and successfully managed with the recovery of motor power. His pre-operative Factor VIII level was 0. Desmopressin nasal spray has a limited role in severe hemophilic. Our main concern was effective replacement therapy and maintenance of desired Factor VIII levels not only during surgery but also in the immediate post-operative period

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