Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).

AIMS: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. METHODS: TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. RESULTS: Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. CONCLUSION: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.

Late-onset hypogonadism and mortality in aging men.

CONTEXT: Late-onset hypogonadism (LOH) has recently been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of low T. The natural history of LOH, especially its relationship to mortality, is currently unknown. OBJECTIVE: The aim of this study was to clarify the associations between LOH, low T, and sexual symptoms with mortality in men. DESIGN, SETTING, AND PARTICIPANTS: Prospective data from the European Male Aging Study (EMAS) on 2599 community-dwelling men aged 40-79 years in eight European countries was used for this study. MAIN OUTCOME MEASURE(S): All-cause, cardiovascular, and cancer-related mortality was measured. RESULTS: One hundred forty-seven men died during a median follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After adjusting for age, center, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH had a 5-fold [hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.7, 11.4] higher risk of all-cause mortality. Compared with eugonadal men, the multivariable-adjusted risk of mortality was 2-fold higher in those with T less than 8 nmol/L (irrespective of symptoms; HR 2.3; 95% CI 1.2, 4.2) and 3-fold higher in those with three sexual symptoms (irrespective of serum T; compared with asymptomatic men; HR 3.2; 95% CI 1.8, 5.8). Similar risks were observed for cardiovascular mortality. CONCLUSIONS: Severe LOH is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of T and the presence of sexual symptoms contribute independently. Detecting low T in men presenting with sexual symptoms offers an opportunity to identify a small subgroup of aging men at particularly high risk of dying.

Functioning of the hypothalamic-pituitary-adrenal and growth hormone axes in frequently unexplained disorders: results of a population study.

BACKGROUND: The aim of the study was to test the hypothesis that associations with specific stress systems [hypothalamic-pituitary-adrenal (HPA) and growth hormone (GH) axes] would increase as the number of unexplained disorders increased while accounting for the possible confounding effects of psychosocial factors. METHODS: A cross-sectional study identified those reporting chronic widespread pain, irritable bowel syndrome, chronic orofacial pain and chronic fatigue. Of the 1315 subjects, disorder status was available for 1180 (89.7%), of whom 766 (64.9%) reported no disorders, 277 (23.5%) reported one and 137 (11.6%) reported two or more. Eighty subjects were sought from each group for assessment of HPA (morning 8:00 a.m. and evening 10:00 p.m. saliva, and post-dexamethasone serum cortisol levels) and GH [serum insulin-like growth factor 1 (IGF-1) level] axis function. Validated questionnaires informed current psychological state. RESULTS: Two hundred twenty-seven subjects participated [79 (35%) with no disorders, 78 (34%) with one disorder and 70 (31%) with two or more disorders]. There were no significant associations (p < 0.05) between individual disorders or an increasing disorder load with any of the neuroendocrine levels measured: saliva/serum cortisol, IGF-1 and dehydroepiandrosterone. Psychosocial factors were independently associated with disorders and with an increasing disorder load: health anxiety p < 0.01, anxiety p < 0.01, depression p < 0.01, life events p = 0.03. CONCLUSION: Although previous studies have shown that stress axis function acts to moderate the risk of onset of some of these disorders, the present study shows that the degree of dysfunction is not correlated with a corresponding increasing load of disorders. The uncertainty surrounding the role of these biomarkers in the aetiology of unexplained disorders needs further investigation.

Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study.

OBJECTIVE: Health and lifestyle factors are associated with variations in serum testosterone levels in ageing men. However, it remains unclear how age-related changes in testosterone may be attenuated by lifestyle modifications. The objective was to investigate the longitudinal relationships between changes in health and lifestyle factors with changes in hormones of the reproductive endocrine axis in ageing men. DESIGN: A longitudinal survey of 2736 community-dwelling men aged 40-79 years at baseline recruited from eight centres across Europe. Follow-up assessment occurred mean (±S.D.) 4.4±0.3 years later. RESULTS: Paired testosterone results were available for 2395 men. Mean (±S.D.) annualised hormone changes were as follows: testosterone -0.1±0.95  nmol/l; free testosterone (FT) -3.83±16.8  pmol/l; sex hormone-binding globulin (SHBG) 0.56±2.5  nmol/l and LH 0.08±0.57  U/l. Weight loss was associated with a proportional increase, and weight gain a proportional decrease, in testosterone and SHBG. FT showed a curvilinear relationship to weight change; only those who gained or lost ≥15% of weight showed a significant change (in the same direction as testosterone). Smoking cessation was associated with a greater decline in testosterone than being a non-smoker, which was unrelated to weight change. Changes in number of comorbid conditions or physical activity were not associated with significant alterations in hypothalamic-pituitary-testicular (HPT) axis function. CONCLUSIONS: Body weight and lifestyle factors influence HPT axis function in ageing. Weight loss was associated with a rise, and weight gain a fall, in testosterone, FT and SHBG. Weight management appears to be important in maintaining circulating testosterone in ageing men, and obesity-associated changes in HPT axis hormones are reversible following weight reduction.

Frailty Is Associated with Impaired Quality of Life and Falls in Middle-Aged and Older European Men.

OBJECTIVES: Adapt a measure of frailty for use in a cohort study of European men and explore relationships with age, health related quality of life and falls. DESIGN: Longitudinal cohort study. SETTING: 8 European centers. PARTICIPANTS: 3047 men aged 40-79 participating in the European Male Ageing Study (EMAS). MEASUREMENTS: Frailty was assessed using an adaptation of the Cardiovascular Health Study criteria. Health related quality of life was evaluated using the Rand Short Form-36 (SF-36) questionnaire which comprises both mental and physical component scores. Self reported falls in the preceding 12 months were recorded at 2-year follow-up. RESULTS: 78 men (2.6%) were classified as frail (≥3 criteria) and 821 (26.9%) as prefrail (1-2 criteria). The prevalence of frailty increased from 0.1% in men aged 40-49 up to 6.8% in men aged 70-79. Compared to robust men, both prefrail and frail men had lower health related quality of life. Frailty was more strongly associated with the physical than mental subscales of the SF-36. Frailty was associated with higher risk of falls OR (95% CI) 2.92 (1.52, 5.59). CONCLUSIONS: Frailty, assessed by the EMAS criteria, increased in prevalence with age and was related to poorer health related quality of life and higher risk of falls in middle-aged and older European men. These criteria may help to identify a vulnerable subset of older men.

Epidemiological evidence against a role for C-reactive protein causing leptin resistance.

OBJECTIVE: It has been suggested that elevated levels of C-reactive protein (CRP) might interfere with leptin signalling and contribute to leptin resistance. Our aim was to assess whether plasma levels of CRP influence leptin resistance in humans, and our hypothesis was that CRP levels would modify the cross-sectional relationships between leptin and measures of adiposity. DESIGN AND METHODS: W assessed four measures of adiposity: BMI, waist circumference, fat mass and body fat (%) in 2113 British Regional Heart Study (BRHS) men (mean (s.d.) age 69 (5) years), with replication in 760 (age 69 (6) years) European Male Ageing Study (EMAS) subjects. RESULTS: IN BRHS subjects, leptin correlated with CRP (SPEARMAN'S R=0.22, P0.0001). Leptin and crp correlated with all four measures of adiposity (R VALUE RANGE: 0.22-0.57, all P<0.0001). Age-adjusted mean levels for adiposity measures increased in relation to leptin levels, but CRP level did not consistently influence the ß-coefficients of the regression lines in a CRP-stratified analysis. In BRHS subjects, the BMI vs leptin relationship demonstrated a weak statistical interaction with CRP (P=0.04). We observed no similar interaction in EMAS subjects and no significant interactions with other measures of adiposity in BRHS or EMAS cohorts. CONCLUSION: We have shown that plasma CRP has little influence on the relationship between measures of adiposity and serum leptin levels in these middle-aged and elderly male European cohorts. This study provides epidemiological evidence against CRP having a significant role in causing leptin resistance.

Do androgens play any role in the physical frailty of ageing men?

The term frailty describes an age-related state of vulnerable health. The aetiology of this condition is not well understood. A number of mechanisms may contribute to frailty. Amongst these is the possible influence of age-related perturbations of sex hormones, particularly, the fall in testosterone in ageing men. This declining androgenic function has been thought to contribute to the loss of muscle mass (sarcopaenia) and strength that occurs with ageing and thereby underpin the development of frailty. Testosterone replacement has therefore been suggested as a possible intervention to treat frailty. This review summarizes evidence from observational and interventional studies on the effects of testosterone on frailty and its key components including body composition, muscle strength and physical function. Evidence from these studies is considered against study design, methodological issues and in the context of the current understanding of frailty. The role of androgens in the development of frailty and their utility in treating this condition are evaluated. Future research directions for the use of androgens in the treatment of frailty are suggested. The potential interaction between testosterone and other frailty mechanisms and the possibility that secondary components of the sex hormone system may be appropriate frailty biomarkers are also discussed.

Chronic widespread pain is associated with slower cognitive processing speed in middle-aged and older European men.

Evidence from clinic-based studies suggests that the fibromyalgia syndrome (FMS) is associated with impairment in cognitive function though the mechanism is unclear. The aim of this analysis was to determine whether there is a similar association between chronic widespread pain (CWP), a cardinal feature of FMS, and impaired cognition in a community setting. Men (n=3369, 40-79 years) were recruited from population registers in eight centres for participation in the European Male Ageing Study (EMAS). The subjects completed a pain questionnaire and pain manikin, with the presence of CWP defined using the American College of Rheumatology criteria. The cognitive functions measured were visuospatial-constructional ability and visual memory (Rey-Osterrieth Complex Figure [ROCF]); visual recognition (Camden Topographical Recognition Memory test [CTRM]); and psychomotor processing speed (Digit-Symbol Substitution test [DSST]). We restricted our analysis to those subjects reporting pain that satisfied the criteria for CWP and those who were pain free. Of these 1539 men [mean (SD) age 60 (11) years], 266 had CWP. All cognitive test scores declined cross-sectionally with age (P<0.05). In age-adjusted linear regressions men with CWP had a lower DSST score (ß=-2.4, P<0.001) compared to pain-free subjects. After adjustment for lifestyle and health factors the association between pain status and the DSST score was attenuated but remained significant (ß=-1.02, P=0.04). There was no association between CWP and the ROCF-copy, ROCF-recall or CTRM scores. CWP is associated with slower psychomotor processing speed among community-dwelling European men. Prospective studies are required to confirm this observation and explore possible mechanisms for the association.