Sitagliptin and Narrow-Band Ultraviolet-B for Moderate Psoriasis (DINUP): A Randomised Controlled Clinical Trial.

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.

Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism: Prospective results from the EMAS.

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.

Elevated luteinizing hormone despite normal testosterone levels in older men-natural history, risk factors and clinical features.

OBJECTIVE: Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). DESIGN, PATIENTS AND MEASUREMENTS: We conducted a 4.3-year prospective observational study of 3369 community-dwelling European men aged 40-79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. RESULTS: Age >70 years (OR = 4.12 [2.07-8.20]), diabetes (OR = 2.86 [1.42-5.77]), chronic pain (OR = 2.53 [1.34-4.77]), predegree education (OR = 1.79 [1.01-3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24-4.50]) predicted development of HLH. Younger age (40-49 years, OR = 8.14 [1.35-49.13]) and nonsmoking (OR = 5.39 [1.48-19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85-43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. CONCLUSIONS: Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism.

Glycemia but not the Metabolic Syndrome is Associated with Cognitive Decline: Findings from the European Male Ageing Study.

OBJECTIVE: Previous research has indicated that components of the metabolic syndrome (MetS), such as hyperglycemia and hypertension, are negatively associated with cognition. However, evidence that MetS itself is related to cognitive performance has been inconsistent. This longitudinal study investigates whether MetS or its components affect cognitive decline in aging men and whether any interaction with inflammation exists. METHODS: Over a mean of 4.4 years (SD ± 0.3), men aged 40-79 years from the multicenter European Male Ageing Study were recruited. Cognitive functioning was assessed using the Rey-Osterrieth Complex Figure (ROCF), the Camden Topographical Recognition Memory (CTRM) task, and the Digit Symbol Substitution Test (DSST). High-sensitivity C-reactive protein (hs-CRP) levels were measured using a chemiluminescent immunometric assay. RESULTS: Overall, 1,913 participants contributed data to the ROCF analyses and 1,965 subjects contributed to the CTRM and DSST analyses. In multiple regression models the presence of baseline MetS was not associated with cognitive decline over time (p > 0.05). However, logistic ordinal regressions indicated that high glucose levels were related to a greater risk of decline on the ROCF Copy (ß = -0.42, p < 0.05) and the DSST (ß = -0.39, p < 0.001). There was neither a main effect of hs-CRP levels nor an interaction effect of hs-CRP and MetS at baseline on cognitive decline. CONCLUSION: No evidence was found for a relationship between MetS or inflammation and cognitive decline in this sample of aging men. However, glycemia was negatively associated with visuoconstructional abilities and processing speed.

Evaluation of cognitive subdomains, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D in the European Male Ageing Study.

PURPOSE: Although lower levels of vitamin D have been related to poor cognitive functioning and dementia in older adults, evidence from longitudinal investigations is inconsistent. The objective of this study was to determine whether 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels are associated with specified measures of cognitive decline in ageing men. METHODS: The European Male Ageing Study (EMAS) followed 3369 men aged 40-79 over 4.4 years. 25(OH)D levels at baseline were measured by radioimmunoassay, and 1,25(OH)2D levels were obtained with liquid chromatography-tandem mass spectrometry. Visuoconstructional abilities, visual memory, and processing speed at baseline and follow-up were assessed using the Rey-Osterrieth Complex Figure Test (ROCF), Camden Topographical Recognition Memory (CTRM), and the Digit Symbol Substitution Test (DSST). RESULTS: Following attritions, a total of 2430 men with a mean (SD) age of 59.0 (10.6) were included in the analyses. At baseline, the mean 25(OH)D concentration was 64.6 (31.5) nmol/l, and mean 1,25(OH)2D level was 59.6 (16.6) pmol/l. In age-adjusted linear regression models, high 25(OH)D concentrations were associated with a smaller decline in the DSST (ß = 0.007, p = 0.020). Men with low 25(OH)D levels (<50 nmol/l) showed a greater decline in the CTRM compared to men with higher (≥75 nmol/l) levels (ß = -0.41, p = 0.035). However, these associations disappeared after adjusting for confounders such as depressive symptoms, BMI, and comorbidities. There was no indication of a relationship between 1,25(OH)2D and decline in cognitive subdomains. CONCLUSION: We found no evidence for an independent association between 25(OH)D or 1,25(OH)2D levels and visuoconstructional abilities, visual memory, or processing speed over on average 4.4 years in this sample of middle-aged and elderly European men.

Natural history, risk factors and clinical features of primary hypogonadism in ageing men: Longitudinal Data from the European Male Ageing Study.

OBJECTIVE: In ageing men, the incidence and clinical significance of testosterone (T) decline accompanied by elevated luteinizing hormone (LH) are unclear. We describe the natural history, risk factors and clinical features associated with the development of biochemical primary hypogonadism (PHG, T < 10·5 nmol/l and LH>9·4U/l) in ageing men. DESIGN, PATIENTS AND MEASUREMENTS: A prospective observational cohort survey of 3,369 community-dwelling men aged 40-79 years, followed up for 4·3 years. Men were classified as incident (i) PHG (eugonadal [EUG, T ≥ 10·5 nmol/l] at baseline, PHG at follow-up), persistent (p) PHG (PHG at baseline and follow-up), pEUG (EUG at baseline and follow-up) and reversed (r) PHG (PHG at baseline, EUG at follow-up). Predictors and changes in clinical features associated with the development of PHG were analysed by regression models. RESULTS: Of 1,991 men comprising the analytical sample, 97·5% had pEUG, 1·1% iPHG, 1·1% pPHG and 0·3% rPHG. The incidence of PHG was 0·2%/year. Higher age (>70 years) [OR 12·48 (1·27-122·13), P = 0·030] and chronic illnesses [OR 4·24 (1·08-16·56); P = 0·038] predicted iPHG. Upon transition from EUG to PHG, erectile function, physical vigour and haemoglobin worsened significantly. Men with pPHG had decreased morning erections, sexual thoughts and haemoglobin with increased insulin resistance. CONCLUSIONS: Primary testicular failure in men is uncommon and predicted by old age and chronic illness. Some clinical features attributable to androgen deficiency, but not others, accompanied the T decline in men who developed biochemical PHG. Whether androgen replacement can improve sexual and/or physical function in elderly men with PHG merits further study.

New horizons in testosterone and the ageing male.

The fall in testosterone levels with age appears to be a real phenomenon. Declining testicular function and hypothalamic dysregulation appear to be the mechanisms explaining the fall in testosterone levels with age. The increased prevalence of obesity and chronic illness in ageing men both cause a large drop in testosterone levels independent of ageing. Age-related hypogonadism appears to be different to other 'classical' causes of hypogonadism. Testosterone levels are not unequivocally low and associated symptoms are non-specific. In frail older men with low testosterone levels, testosterone therapy appears to improve QOL and physical function. In less frail men, however, effects of testosterone therapy in the ageing male are small and/or inconsistent. There remains an urgent need for randomised clinical trials with sufficient size, duration and power to determine specific benefits and risks of testosterone therapy in older men.

Case Report: Diabetic ketoacidosis after co-administration of empagliflozin and probenecid.

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.

Generalist vs specialist acute medical admissions - What is the impact of moving towards acute medical subspecialty admissions on efficacy of care provision?

INTRODUCTION: The discussion surrounding generalist versus specialist acute medical admissions continues to stimulate debate and patients with certain conditions benefit from specialist care. AIM: To determine whether a specialty medical admission program would reduce inpatient length of stay (LOS), mortality and readmission rates. DESIGN/METHODS: A prospective cohort study of inpatients admitted under a general internal medicine (GIM) service before and after introduction of a specialty-directing programme. We hypothesized that early transfer of patient care to a specialty suited to their presenting complaint would reduce LOS and a specialty-directing early redistribution of care programme was introduced. Seven of the ten clinical teams participating in the GIM roster adopted the programme. On the morning following a specialty-directing team being on call for all new GIM admissions during a 24-hour period, specialty-directing teams were allocated one patient appropriate to their specialty. RESULTS: 5,144 patient-care episodes were analysed over the two-year study period. LOS increased by greater than 15%, one year after introducing the specialty-directing programme (8.5±8.4 vs 7.3±7.5 days, p < 0.001). LOS did not differ between teams that participated and those who did not (8.4±8.1 vs 8.1±7.9 days, p = 0.298). No differences were found in the proportion of patients who were discharged home, died while an inpatient or re-admitted within 30 days of discharge. The proportion of patients aged greater than 80 years increased significantly also - from 24.7% in 2017 to 27.9% in 2019(p == 0.009). CONCLUSION: Widespread adoption of specialist care may not be beneficial for all medical inpatients and physicians should continue to undergo dual specialist and GIM training.

Retrospective national cohort study of pregnancy outcomes for women with type 1 and type 2 diabetes mellitus in Republic of Ireland.

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.

BMI > or = 50 kg/m2 is associated with a younger age of onset of overweight and a high prevalence of adverse metabolic profiles.

OBJECTIVE: To study the demographic and clinical parameters of three different categories of obesity, with particular focus on a cohort of individuals with BMI > or = 50 kg/m2, the fastest growing category of obesity. DESIGN: Over 700 obese individuals were studied (186 with BMI = 30-39 kg/m2, 316 with BMI = 40-49 kg/m2 and 290 with BMI > or = 50 kg/m2). RESULTS: Median BMI was 51 kg/m2 for patients who reported onset of overweight before 15 years of age, 47 kg/m2 for patients who reported onset between 15 and 30 years, and 42 kg/m2 for patients who became overweight after 30 years of age. The BMI > or = 50 kg/m2 group was notably younger than the group with BMI = 30-39 kg/m2 (44 (SD 11) years v. 50 (SD 15) years; P < 0.0001). Eighteen per cent of obese patients studied were considered metabolically healthy according to standard cut-off points for blood pressure, fasting glucose and lipid profiles. However, the proportion of metabolically healthy individuals was significantly higher in the BMI = 30-39 kg/m2 group than in the BMI = 40-49 kg/m2 and BMI > or = 50 kg/m2 groups (31% v. 17% and 12% respectively; P < 0.05 and P < 0.005). When compared with people of similar age in the general population, individuals with BMI > or = 50 kg/m2 had lower rates of marriage (51% v. 72%) and a higher prevalence of unemployment (14% v. 5%). CONCLUSIONS: The current study suggests that the increasing prevalence of childhood obesity worldwide will lead to many more individuals achieving a higher BMI at a younger age. Furthermore, an earlier onset of overweight does not appear to prevent the adverse metabolic health outcomes associated with extreme obesity.

Sleep duration and physical function in people with severe obesity: a prospective cross-sectional study.

BACKGROUND: Subjects with severe obesity (BMI > 40 kg/m2) have worse physical function and sleep less than lean people (BMI 18.5-25 kg/m2). METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Male sexual dysfunction in obesity: The role of sex hormones and small fibre neuropathy.

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.

Adipokines, psoriasis, systemic inflammation, and endothelial dysfunction.

Adipokines are secreted by white adipose tissue, an active endocrine organ, and play a role in the regulation of metabolic functions such as lipid metabolism, inflammation, and vascular homeostasis. Adipokines are secreted in excess in obesity and contribute to the development of associated comorbidities such as metabolic syndrome and atherosclerosis. Psoriasis, a chronic immune-mediated skin disease, is associated with obesity and increased cardiovascular risk. Understanding the role of adipokines in psoriasis may in part explain the association between psoriasis and cardiovascular disease. This review summarizes the data regarding key adipokines in patients with psoriasis and the change in adipokine profiles with psoriasis therapy. Adipokines may be mediators of cutaneous inflammation suggesting a role in the pathophysiology of psoriasis and the development of comorbidities.

Nonandrogenic Anabolic Hormones Predict Risk of Frailty: European Male Ageing Study Prospective Data.

Context: Low levels of nonandrogenic anabolic hormones have been linked with frailty, but evidence is conflicting and prospective data are largely lacking. Objective: To determine associations between nonandrogenic anabolic hormones and prospective changes in frailty status. Design/Setting: A 4.3-year prospective observational study of community-dwelling men participating in the European Male Ageing Study. Participants: Men (n = 3369) aged 40 to 79 years from eight European centers. Main Outcome Measures: Frailty status was determined using frailty phenotype (FP; n = 2114) and frailty index (FI; n = 2444). Analysis: Regression models assessed relationships between baseline levels of insulinlike growth factor 1 (IGF-1), its binding protein 3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEA-S), 25-hydroxyvitamin D (25OHD), and parathyroid hormone (PTH), with changes in frailty status (worsening or improving frailty). Results: The risk of worsening FP and FI decreased with 1 standard deviation higher IGF-1, IGFBP-3, and 25OHD in models adjusted for age, body mass index, center, and baseline frailty [IGF-1: odds ratio (OR) for worsening FP, 0.82 (0.73, 0.93), percentage change in FI, -3.7% (-6.0, -1.5); IGFBP-3: 0.84 (0.75, 0.95), -4.2% (-6.4, -2.0); 25OHD: 0.84 (0.75, 0.95); -4.4%, (-6.7, -2.0)]. Relationships between IGF-1 and FI were attenuated after adjusting for IGFBP-3. Higher DHEA-S was associated with a lower risk of worsening FP only in men >70 years old [OR, 0.57 (0.35, 0.92)]. PTH was unrelated to change in frailty status. Conclusions: These longitudinal data confirm the associations between nonandrogenic anabolic hormones and the changes in frailty status. Interventional studies are needed to establish causality and determine therapeutic implications.

Dipeptidyl peptidase-4 inhibition and narrow-band ultraviolet-B light in psoriasis (DINUP): study protocol for a randomised controlled trial.

BACKGROUND: Moderate to severe psoriasis is a systemic inflammatory disease associated with insulin resistance, obesity and type 2 diabetes (T2DM). Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that improves glycaemia and has a marketing authorisation for the treatment of T2DM. Non-immunosuppressive therapies that are effective for psoriasis and its associated comorbidities would be a significant advance in the treatment of this chronic disease. METHODS/DESIGN: This is a single centre, 39-week, prospective, randomised, open label, clinical trial of oral sitagliptin (Januvia(®)) in psoriasis patients who are due to undergo a course of narrow-band ultraviolet-B (NB-UVB) phototherapy. We plan to enrol 120 participants and allocate participants on a random and 1:1 basis to receive sitagliptin 100 mg daily for 24 weeks combined with NB-UVB or NB-UVB monotherapy. Participants will be followed up for 12 weeks after sitagliptin therapy is discontinued. The primary endpoint is the change in Psoriasis Area and Severity Index (PASI) 24 weeks after treatment initiation. Secondary endpoints include cumulative NB-UVB dose, number of NB-UVB treatments required to clear psoriasis, proportions of participants who achieve PASI-50 (50 % reduction in PASI from baseline), PASI-75, PASI-90 and the proportion of participants who relapse in each group. We will also analyse changes in cardiovascular disease risk factors, serum cytokine and hormone levels and peripheral blood mononuclear expression of immune proteins at 24 and 36 weeks. A subgroup of participants will have skin biopsies taken and analysed for skin levels and expression of immune cells, receptors, hormones and immune proteins. The genetic or epigenetic profile that predicts best response to DPP-4 inhibitor therapy will be analysed. The safety endpoints include the rate and severity of adverse events. DISCUSSION: This is the first randomised clinical trial assessing dipeptidyl peptidase-4 inhibition therapy in psoriasis. We hypothesise that sitagliptin therapy in combination with NB-UVB improves psoriasis severity compared to NB-UVB monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02347501 (Date of registration: 27 January 2015).

The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men.

CONTEXT: The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive. OBJECTIVE: To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men. DESIGN: Multinational European observational prospective cohort study. PARTICIPANTS: A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic-pituitary-testicular (HPT) axis. MAIN OUTCOME MEASURES: Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6-20; 21-23; 24-39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels. RESULTS: The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels. CONCLUSION: Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.

Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone.

CONTEXT: During aging, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free T (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT. OBJECTIVE: Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints. METHODS: A total of 3334 community-dwelling men, aged 40-79 years, were included in this study. Differences in clinical variables between the referent group of men with both normal TT (≥10.5 nmol/liter) and normal cFT (≥220 pmol/liter) with those who had normal TT/low cFT, low TT/normal cFT, and low TT/low cFT were assessed by regression models adjusted for age, center, body mass index, and comorbidities. RESULTS: A total of 2641 men had normal TT (18.4 ± 5.5 [mean ± SD] nmol/liter)/normal cFT (326 ± 74 pmol/liter), 277 men had normal TT (14.2 ± 3.7)/low cFT (194 ± 23), 96 men had low TT (9.6 ± 0.7)/normal cFT (247 ± 20), and 320 men had low TT (7.8 ± 2.5)/low cFT (160 ± 55). Men with normal TT/low cFT were older and in poorer health. They had higher SHBG and LH and reported more sexual and physical symptoms, whereas hemoglobin and bone ultrasound parameters were lower compared to the referent group. Men with low TT/normal cFT were younger and more obese. They had lower SHBG, but LH was normal, whereas features of androgen deficiency were lacking. CONCLUSIONS: Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms; therefore, cFT levels should be assessed in men with suspected hypogonadal symptoms.

Development of and Recovery from Secondary Hypogonadism in Aging Men: Prospective Results from the EMAS.

CONTEXT: Secondary hypogonadism is common in aging men; its natural history and predisposing factors are unclear. OBJECTIVES: The objectives were 1) to identify factors that predispose eugonadal men (T ≥ 10.5 nmol/L) to develop biochemical secondary hypogonadism (T < 10.5 nmol/L; LH ≤ 9.4 U/L) and secondary hypogonadal men to recover to eugonadism; and 2) to characterize clinical features associated with these transitions. DESIGN: The study was designed as a prospective observational general population cohort survey. SETTING: The setting was clinical research centers. PARTICIPANTS: The participants were 3369 community-dwelling men aged 40-79 years in eight European centers. INTERVENTION: Interventions included observational follow-up of 4.3 years. MAIN OUTCOME MEASURE: Subjects were categorized according to change/no change in biochemical gonadal status during follow-up as follows: persistent eugonadal (n = 1909), incident secondary hypogonadal (n = 140), persistent secondary hypogonadal (n = 123), and recovered from secondary hypogonadism to eugonadism (n = 96). Baseline predictors and changes in clinical features associated with incident secondary hypogonadism and recovery from secondary hypogonadism were analyzed by regression models. RESULTS: The incidence of secondary hypogonadism was 155.9/10 000/year, whereas 42.9% of men with secondary hypogonadism recovered to eugonadism. Incident secondary hypogonadism was predicted by obesity (body mass index ≥ 30 kg/m(2); odds ratio [OR] = 2.86 [95% confidence interval, 1.67; 4.90]; P < .0001), weight gain (OR = 1.79 [1.15; 2.80]; P = .011), and increased waist circumference (OR = 1.73 [1.07; 2.81], P = .026; and OR = 2.64 [1.66; 4.21], P < .0001, for waist circumference 94-102 and ≥102 cm, respectively). Incident secondary hypogonadal men experienced new/worsening sexual symptoms (low libido, erectile dysfunction, and infrequent spontaneous erections). Recovery from secondary hypogonadism was predicted by nonobesity (OR = 2.28 [1.21; 4.31]; P = .011), weight loss (OR = 2.24 [1.04; 4.85]; P = .042), normal waist circumference (OR = 1.93 [1.01; 3.70]; P = .048), younger age (< 60 y; OR = 2.32 [1.12; 4.82]; P = .024), and higher education (OR = 2.11 [1.05; 4.26]; P = .037), but symptoms did not show significant concurrent improvement. CONCLUSION: Obesity-related metabolic and lifestyle factors predispose older men to the development of secondary hypogonadism, which is frequently reversible with weight loss.