Sodium-glucose cotransporter-2 (SGLT2) inhibitors are filtered and secreted to their primary site of action in the proximal tubule of the kidney. At this site, SGLT2 inhibitors also reduce renal elimination of ketone bodies, a finding implicated in their propensity to cause ketoacidosis. Many commonly used medications have potential to diminish renal elimination of SGLT2 inhibitors and to compound the effects of SGLT2 inhibitors on renal elimination of ketone bodies by inhibiting tubular secretion of the SGLT2 inhibitor itself and/or ketone bodies. We present a case of severe diabetic ketoacidosis (DKA) in a patient with type 2 diabetes occurring several days after co-prescription of empagliflozin and probenecid. Other than the recent introduction of empagliflozin, no cause for the DKA episode was apparent. A pharmacokinetic interaction between probenecid and empagliflozin, involving organic anion transporter 3 (OAT3), reduces proximal tubular secretion of empagliflozin and increases patient exposure to the drug. Whether or not this phenomenon is sufficient to cause severe DKA is discussed. An alternative explanation as to the DKA aetiology is proposed, wherein probenecid may compound effects of empagliflozin on renal elimination of ketone bodies. We suggest that clinicians exercise caution when prescribing SGLT2 inhibitors alongside pharmacologic inhibitors of, or competitors for, proximal tubular organic anion transporters in patients with diabetes mellitus due to the risk of severe DKA.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are filtered and secreted to their primary site of action in the proximal tubule of the kidney. At this site, SGLT2 inhibitors also reduce renal elimination of ketone bodies, a finding implicated in their propensity to cause ketoacidosis. Many commonly used medications have potential to diminish renal elimination of SGLT2 inhibitors and to compound the effects of SGLT2 inhibitors on renal elimination of ketone bodies by inhibiting tubular secretion of the SGLT2 inhibitor itself and/or ketone bodies. We present a case of severe diabetic ketoacidosis (DKA) in a patient with type 2 diabetes occurring several days after co-prescription of empagliflozin and probenecid. Other than the recent introduction of empagliflozin, no cause for the DKA episode was apparent. A pharmacokinetic interaction between probenecid and empagliflozin, involving organic anion transporter 3 (OAT3), reduces proximal tubular secretion of empagliflozin and increases patient exposure to the drug. Whether or not this phenomenon is sufficient to cause severe DKA is discussed. An alternative explanation as to the DKA aetiology is proposed, wherein probenecid may compound effects of empagliflozin on renal elimination of ketone bodies. We suggest that clinicians exercise caution when prescribing SGLT2 inhibitors alongside pharmacologic inhibitors of, or competitors for, proximal tubular organic anion transporters in patients with diabetes mellitus due to the risk of severe DKA.

Background: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes mellitus (T2DM), has been reported to improve psoriasis. Objective: We compared the effects of sitagliptin treatment, a DPP-4 inhibitor, in combination with narrow-band ultraviolet-B (NB-UVB) phototherapy compared to NB-UVB alone on psoriasis severity, quality of life, cardiovascular disease risk factors and immune parameters in people with moderate psoriasis without T2DM. Methods: In this 39-week, single-centre, randomised controlled trial, people were allocated randomly to receive sitagliptin for 24 weeks with NB-UVB or NB-UVB alone. The primary endpoint was the change in Psoriasis Area and Severity Index (PASI) from baseline to 24 weeks. We estimated that 120 participants would be needed to have 80% power to find a significant difference between the groups. Results: A total of 118 patients were randomised. The median (IQR) baseline PASI was 8.8 (7.5–11.6). At 24 weeks, the mean difference from baseline in PASI (–1.0 [95% CI –2.0 to 0.0]) was significantly larger in the sitagliptin/NB-UVB arm than in the NB-UVB-alone arm (p = 0.044). There were significant differences in the change in Hospital Anxiety and Depression Scale (–2.5 [95% CI –4.0 to –1.0]; p = 0.002) and EuroQol 5-item questionnaire (0.1 [95% CI 0.0–0.1]; p = 0.036) values from baseline to 24 weeks between the sitagliptin/NB-UVB and the NB-UVB-alone arm. There were no treatment-related serious adverse events. Conclusion: Sitagliptin therapy combined with NB-UVB phototherapy significantly improved psoriasis severity, albeit modestly, compared to NB-UVB phototherapy alone in patients with moderate psoriasis without T2DM.

Aim: Report the outcomes of pregnant women with type 1 and type 2 diabetes and to identify modifiable and non-modifiable factors associated with poor outcomes. Methods: Retrospective analysis of pregnancy preparedness, pregnancy care and outcomes in the Republic of Ireland from 2015 to 2020 and subsequent multivariate analysis. Results: In total 1104 pregnancies were included. Less than one third attended pre-pregnancy care (PPC), mean first trimester haemoglobin A1c was 7.2 +/- 3.6% (55.5 +/- 15.7 mmol/mol) and 52% received pre-conceptual folic acid. Poor preparation translated into poorer pregnancy outcomes. Livebirth rates (80%) were comparable to the background population however stillbirth rates were 8.7/1000 (four times the national rate). Congenital anomalies occurred in 42.5/1000 births (1.5 times the background rate). More than half of infants were large for gestational age and 47% were admitted to critical care. Multivariate analyses showed strong associations between non-attendance at PPC, poor glycaemic control and critical care admission (adjusted odds ratio of 1.68 (1.48-1.96) and 1.61 (1.43-1.86), p < 0.05 respectively) for women with type 1 diabetes. Smoking and teratogenic medications were also associated with critical care admission and hypertensive disorders of pregnancy. Conclusion: Pregnancy outcomes in women with diabetes are suboptimal. Significant effort is needed to optimize the modifiable factors identified in this study.

Aims: Pre-gestational diabetes mellitus (PGDM) is associated with adverse outcomes. We aimed to examine pregnancies affected by PGDM; report on these pregnancy outcomes and compare outcomes for patients with type 1 versus type 2 diabetes mellitus; compare our findings to published Irish and United Kingdom (UK) data and identify potential areas for improvement. Methods: Between 2016 and 2018 information on 679 pregnancies from 415 women with type 1 Diabetes Mellitus and 244 women with type 2 diabetes was analysed. Data was collected on maternal characteristics; pregnancy preparation; glycaemic control; pregnancy related complications; foetal and maternal outcomes; unscheduled hospitalisations; congenital anomalies and perinatal deaths. Results: Only 15.9% of women were adequately prepared for pregnancy. Significant deficits were identified in availability and attendance at pre-pregnancy clinic, use of folic acid, attaining appropriate glycaemic targets and appropriate retinal screening. The majority of pregnancies (n = 567, 83.5%) resulted in a live birth but the large number of infants born large for gestational age (LGA) (n = 280, 49.4%), born prematurely <37 weeks and requiring neonatal intensive care unit (NICU) admission continue to be significant issues. Conclusions: This retrospective cohort study identifies multiple targets for improvements in the provision of care to women with pre-gestational DM which are likely to translate into better pregnancy outcomes. (C) 2021 Elsevier B.V. All rights reserved.

Aims The purpose of this study was to identify the number of pregnancies affected by pre-gestational diabetes in the Republic of Ireland; to report on pregnancy outcomes and to identify areas for improvement in care delivery and clinical outcomes. Methods Healthcare professionals caring for women with pre-gestational diabetes during pregnancy were invited to participate in this retrospective study. Data pertaining to 185 pregnancies in women attending 15 antenatal centres nationally were collected and analysed. Included pregnancies had an estimated date of delivery between 1 January and 31 December 2015. Results The cohort consisted of 122 (65.9%) women with Type 1 diabetes and 56 (30.3%) women with Type 2 diabetes. The remaining 7 (3.8%) pregnancies were to women with maturity-onset diabetes of the young (MODY) (n = 6) and post-transplant diabetes (n = 1). Overall women were poorly prepared for pregnancy and lapses in specific areas of service delivery including pre-pregnancy care and retinal screening were identified. The majority of pregnancies 156 (84.3%) resulted in a live birth. A total of 103 (65.5%) women had a caesarean delivery and 58 (36.9%) infants were large for gestational age. Conclusions This audit identifies clear areas for improvement in delivery of care for women with diabetes in the Republic of Ireland before and during pregnancy.

Subjects with severe obesity (BMI > 40 kg/m2) have worse physical function and sleep less than lean people (BMI 18.5–25 kg/m2). In 554 subjects with severe obesity, we compared physical function in those with normal sleep duration (NSD, 6–9 h/night), short sleep duration (SSD, ≤ 6 h/night) and long sleep duration (LSD, ≥ 9 h/night). The mean (±SD) age and BMI were 43.1 (± 11.1) years and 50.9 ± 8.6 kg/m2 respectively. One hundred ninety-six (35.4%) were male. More subjects in the NSD group (n = 256) were able to ascend and descend a step 50 times than in the SSD group (n = 247) or the LSD group (n = 51, 75.5% vs 62.8% vs 56.9%, p = 0.002). A similar observation was made for step speed (0.45 ± 0.11 vs 0.43 ± 0.10 vs 0.40 ± 0.11 steps/s respectively, p = 0.001). NSD participants were less likely to have fallen in the preceding year compared to LSD participants (21.1% vs 39.2%, p = 0.007) and also reported less low back pain compared to SSD participants (60.8% vs 75.9%, p = 0.004). In conclusion, abnormal sleep duration is associated with reduced physical function in non-elderly severely obese subjects. The effects of sleep hygiene interventions in this cohort warrant further assessment and may be beneficial to their physical function.

Context Multiple factors contribute to sexual dysfunction in men with obesity. Sex hormone levels are commonly abnormal in men with obesity and this abnormality is often the focus of management in clinical practice. The role of small fibre neuropathy in obesity-related sexual dysfunction is not well established. Objective We aimed to investigate the relationship between sexual function, sex hormone levels and small nerve fibre morphology in men with severe obesity. Materials and methods A prospective study of 29 men with severe obesity was undertaken. Sexual function was assessed using the European Male Ageing Study Sexual Function Questionnaire. Small nerve fibre morphology was quantified using corneal confocal microscopy. Sex hormone levels were measured by mass spectrophotometry. Results Erectile dysfunction was present in 72% of the cohort with a higher prevalence of diabetes among the symptomatic group (88% vs 38%, p = 0.006). Corneal nerve fibre length (CNFL) and corneal nerve fibre density (CNFD) were both significantly lower in participants with erectile dysfunction compared to those without (p = 0.039 and p = 0.048 respectively). The erectile function score correlated with CNFL (r = -0.418, p = 0.034) and CNFD (r = -0.411, p = 0.037). Total testosterone and calculated free testosterone levels did not differ significantly between men with or without erectile dysfunction (median 8.8 nmol/L vs 9.0 nmol/L, p = 0.914; and median 176 pmol/L vs 179 pmol/L, p = 0.351 respectively), infrequent sexual thoughts (median 8.1 nmol/L vs 9.2 nmol/L, p = 0.650; and median 184 pmol/L, vs 176 pmol/L, p = 0.619 respectively) and decreased morning erections (median 9.0 nmol/L vs 8.8 nmol/L, p = 0.655; and median 170 pmol/L vs 193 pmol/L, p = 0.278 respectively). Conclusion Sexual dysfunction is highly prevalent in men with severe obesity. We found an association between small fibre neuropathy with erectile dysfunction with presence of diabetes a likely a significant contributing factor. We found no associations between testosterone levels with sexual symptoms (including frequency of sexual thoughts). The influence of small nerve fibre neuropathy on response to therapeutic interventions and whether interventions that improve small fibre neuropathy can improve erectile function in this population merits further study.

Abstract Background Hip fractures in the older person are associated with high mortality rates (NICE, 2011). Up to 40% of patients never regain their pre-fracture mobility, 10-20% never return to live at home. The Irish Hip Fracture Database (IHFD) National Report 2017 recommends appointment of an orthogeriatric consultant in this hospital to achieve IHFD standards 4 to 6. Methods We analysed a subset of HIPE data collected for the IHFD in patients over 60 years over a three month period from September – November 2017 and compare it to September – November 2018 after introduction of an orthogeriatric service. We looked at geriatrician review, bone health assessment, falls assessment, discharge destination, 30-day re-admission rate and mortality during admission. Results There were 45 hip fracture patients in each group. In the 2017 group, mean age was 79, female 64%; compared to mean age of 80, female 62.2% in 2018. In 2018, after the appointment of an orthogeriatrician, 95.6% of patients were seen by a geriatrician compared to 4.4% in 2017. In 2018, 97.7% received bone health assessment compared to 26.8% in 2017. In 2018 95.3% received specialist falls assessment, compared to 2.4% in 2017. Mean length of stay was 18 days in 2018 versus 13 days in 2017. 2.2% of patients were discharged to convalescence in 2018, 26.7% in 2017. 57.8% of patients were discharged to off-site rehabilitation in 2018 compared to 40% in 2017. 2.2% patients died during admission in 2018, 8.9% in 2017. In 2018, 6.7% of patients were readmitted within 30 days, 8.8% in 2017. Conclusion Provision of rapid Comprehensive Geriatric Assessment to all hip fracture patients, reduces falls and fracture risk. There is evidence of improvement in IHFD standards 4-6, mortality rate and 30-day readmission rate. Moreover, the orthogeriatric service has led to increased referral to rehabilitation services ensuring optimal functional recovery.

treat principle.Missing data were replaced using the last observation carried forward method.Between April 25, 2014, and April 22, 2015, 9 participants were randomized to the sitagliptin arm and 11 to the gliclazide arm.Recruitment was halted after 20 participants had been enrolled.The recruitment period and funding had finished at that time.The baseline PASI was similar in the sitagliptin (median 9.5, IQR, 7.8-9.6)and gliclazide (median 9.4, IQR, 7.6-12) arms (Table 1).There was no significant difference between treatment arms in the change in PASI from baseline to 16 weeks (Fig. 1).The sitagliptin arm had a median reduction in PASI of 0.9 (IQR, 0.4-2.1)compared to a median reduction of 0.8 (IQR, -0.2 to 2.1) for participants treated with gliclazide (U = 43.5, p = 0.648).From baseline to week 32, participants in the gliclazide arm (16 weeks of gliclazide and 16 weeks of sitagliptin) had a median reduction in PASI of 1.8 (IQR, 0.3-3), and those in the sitagliptin arm had a median reduction of 3 (IQR, 2-5.6, U = 29.5, p = 0.128).At 16 weeks, 50% reduction in PASI from baseline (PASI-50) was achieved by one participant per treatment arm (9.1% of the gliclazide arm, 11.1% of the sitagliptin arm).No participants achieved PASI-75 or PASI-90 after 16 weeks of treatment.At 32 weeks, 4 participants (44.4%) in the sitagliptin arm achieved PASI-50 compared to 2 (18.2%) in the gliclazide arm (p = 0.336).One participant (11.1%) in the sitagliptin arm achieved PASI-75 after 32 weeks, compared to 0 (0%) in the gliclazide arm (p = 0.45).No participant achieved PASI-90 or PASI-100 after 32 weeks of treatment.The only statistically significant difference between treatment arms in the QOL endpoints was a small negative median change in the EuroQol 5-item questionnaire (EQ-5D) score in the gliclazide arm after 16 weeks compared to the sitagliptin arm, whose median EQ-5D value did not change (U = 25.0,p = 0.047).After 32 weeks, there was no difference in median change of EQ-5D scores between the two arms.At 16 weeks, the change in high-sensitivity C-reactive protein (hs-CRP) concentration was lower in the sitagliptin arm than in the gliclazide arm: hs-CRP concentration did not change with sitagliptin therapy and increased with gliclazide therapy (U = 21.0,p = 0.030).At week 32, this difference was no longer significant.No other between-group differences were noted in CVD risk factors.At week 16, the increase in active glucagon-like peptide-1 (GLP-1) and decrease in total gastric inhibitory polypeptide (GIP) after sitagliptin treatment was not significant compared to the gliclazide arm, which is interesting as sulphonylurea therapy has not demonstrated effects on GLP-1 and GIP in patients with T2DM [6].The median insulin decreased significantly in the sitagliptin arm (median -3.91, IQR, -17.52 to 2.61) compared to the gliclazide arm (median 3.24, IQR, 1.36-7.54)at week 16 (U = 9.0, p = 0.02).

Abstract Background The Irish Hip Fracture Database (IHFD) National Report 2017 demonstrated poor performance across all six IHFD standards in our hospital. For the purpose of this study we focused on standards 1 and 2. IHFD standard 1: All patients with hip fracture should be admitted to an acute orthopaedic ward within 4 hours of ED presentation/ brought directly to theatre from ED within 4 hours, and IHFD standard 2: All patients with hip fracture who are medically fit should have surgery within 48 hours of admission and during normal working hours. Methods We examined IHFD standards 1 and 2 from August 2017-January 2018 and August 2018-January 2019 after the appointment of an orthogeriatrician and use of the first Hip Fracture Pathway in August 2018. We also analysed data collected from February-April 2019 after amendment of the hip fracture pathway for patients presenting to the ED. Results IHFD Standard 1: From August to January 2017, 2.5% of patients were admitted to an orthopaedic ward within 4 hours versus 18.1% in 2018. IHFD Standard 2: in 2017, 64.8% underwent surgery within 48 hours during working hours, versus 65.3% in 2018. From February to April 2019, 32.1% of patients were admitted to an orthopaedic ward within 4 hours (IFHD 1) and 56.6% of patients underwent surgery within 48 hours and during working hours (IFHD 2). Conclusion Close collaboration between Emergency Medicine, Orthopaedic Surgery, Radiology, Nursing colleagues, Allied Health Professionals and Orthogeriatrics and amendment of the Hip Fracture Pathway have led to improvements in Standards 1 and 2. The addition of an orthogeriatric service in the hospital has resulted in an improvement in adherence to all IFHD standards. However, there are ongoing challenges to achieving Standard 2 including limited theatre access and increasing numbers of older patients on novel oral anticoagulants.

OBJECTIVE:Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone-binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH).DESIGN:Prospective observational study with a median follow-up of 4.3 years.PATIENTS:Three thousand three hundred sixty-nine community-dwelling men aged 40-79 years from eight European centres.MEASUREMENTS:Subjects were categorized according to baseline and follow-up biochemical status into persistent eugonadal (referent group; n = 1880), incident LNSH (eugonadism to LNSH; n = 101) and incident LLSH (eugonadism to LLSH; n = 38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed.RESULTS:The cumulative incidence of LNSH and LLSH over 4.3 years was 4.9% and 1.9%, respectively. Baseline obesity predicted both LNSH and LLSH, but the former occurred more frequently in younger men. LLSH, but not LNSH, was associated with new/worsened sexual symptoms, including low desire [OR = 2.67 (1.27-5.60)], erectile dysfunction [OR = 4.53 (2.05-10.01)] and infrequent morning erections [OR = 3.40 (1.48-7.84)].CONCLUSIONS:These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT.

Background: Obesity hypoventilation syndrome diagnosis requires a body mass index (BMI) of >30kg/m2, and a raised daytime PaCO2 without another cause for hypoventilation. It has been argued that the definition of OHS should be broadened to include a raised daytime serum HCO3- >27mEq/L1. While cardiorespiratory fitness is preserved in mild-moderate obesity, little is known about the exercise physiology of the super-obese (BMI>50kg/m2). We hypothesize that daytime serum HCO3- levels could have utility as a screening tool in characterizing cardiorespiratory fitness in super-obese patients. Methods: This was a prospective study of patients attending an ambulatory weight management programme. Assessment was via the physiotherapy department. Data collection included demographics, anthropometrics, fitness including 6-minute walk test (6MWT), timed up and go (TUAG) and 90 second step test (90ST), and measurement of transcutaneous CO2 (TOSCA) and venous blood gas (VBG) sampling. Results: 111 patients were recruited. 41 were male, mean age and BMI were 44.2 and 52.1kg/m2 respectively. 9% had an elevated CO2 and 11% had an elevated HCO3-. Participants with elevated CO2 or HCO3-, respectively, scored worse on physical function on TUAG (11.7+/-3.7 or 12+/-4.7s, vs 8.6+/-4.8s), 90ST (0.4+/-0.1steps vs 0.5+/-0.1steps), 6MWT distance (201.5+/-132.7m or 219.8+/-152.8m vs 349.7+/-127.3m). Conclusion: This suggests that serum HCO3- may aid in identifying super-obese patients with impaired cardiorespiratory fitness and those at risk of OHS, and may identify increased cardiovascular mortality. References 1. Hart N, et al. Obesity hypoventilation syndrome: does the current definition need revisiting? Thorax 2014