Pharmacotherapy for older people with obesity.

Rates of obesity continue to rise, including in older adults. Use of medication for obesity in the elderly has been considered controversial, due to concerns around potential progression of age-related sarcopenia and a general lack of evidence for its use in this age group. Within this review, we describe the general considerations when prescribing obesity pharmacotherapy for older adults living with obesity. We evaluate in detail the anti-obesity medications currently licenced in Europe, with emphasis on the available efficacy, safety and cardiovascular outcome data gathered from study of older people. Finally, we discuss future directions and avenues of research.

UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors.

OBJECTIVE: Brown adipose tissue (BAT) is a therapeutic target for obesity. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is commonly used to quantify human BAT mass and activity. Detectable 18F-FDG uptake by BAT is associated with reduced prevalence of cardiometabolic disease. However, 18F-FDG uptake may not always be a reliable marker of BAT thermogenesis, for example insulin resistance may reduce glucose uptake. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT. Therefore, we hypothesized that UCP1 expression may be altered in individuals with cardiometabolic risk factors. METHODS: We quantified UCP1 expression as an alternative marker of thermogenic capacity in BAT and white adipose tissue (WAT) samples (n = 53) and in differentiated brown and white pre-adipocytes (n = 85). RESULTS: UCP1 expression in BAT, but not in WAT or brown/white differentiated pre-adipocytes, was reduced with increasing age, obesity and adverse cardiometabolic risk factors such as fasting glucose, insulin and blood pressure. However, UCP1 expression in BAT was preserved in obese subjects of <40 years of age. To determine if BAT activity was also preserved in vivo, we undertook a case-control study, performing 18F-FDG scanning during mild cold exposure in young (mean age ∼22y) normal weight and obese volunteers. 18F-FDG uptake by BAT and BAT volume were similar between groups, despite increased insulin resistance. CONCLUSION: 18F-FDG uptake by BAT and UCP1 expression are preserved in young obese adults. Older subjects retain precursor cells with the capacity to form new thermogenic adipocytes. These data highlight the therapeutic potential of BAT mass expansion and activation in obesity.

Effects of Obesity and Insulin on Tissue-Specific Recycling Between Cortisol and Cortisone in Men.

CONTEXT: 11ß-Hydroxysteroid dehydrogenase 1 (11ßHSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11ßHSD1 transcripts are more abundant in adipose, but the consequences for oxidation vs reduction remain unknown. OBJECTIVE: This work aimed to determine whether 11ßHSD1 equilibrium in metabolic tissues is regulated by insulin and obesity. METHODS: A 2-phase, randomized, crossover, single-blinded study in a clinical research facility was conducted of 10 lean and obese healthy men. 11ß-Reductase and 11ß-dehydrogenase activities were measured during infusion of 9,11,12,12-[2H]4-cortisol and 1,2-[2H]2-cortisone, respectively, on 2 occasions: once during saline infusion and once during a hyperinsulinemic-euglycemic clamp. Arterialized and venous samples were obtained across forearm skeletal muscle and abdominal subcutaneous adipose. Steroids were quantified by liquid chromatography-tandem mass spectrometry and adipose tissue transcripts by quantitative polymerase chain reaction. RESULTS: Neither whole-body nor tissue-specific rates of production of cortisol or cortisone differed between lean and obese men, however insulin attenuated the diurnal decrease. Whole-body 11ß-HSD1 reductase activity tended to be higher in obesity (~ 10%) and was further increased by insulin. Across adipose tissue, 11ß-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.99 ±â€…9.62 vs placebo 11.68 ±â€…3.63 pmol/100 g/minute; P < .05). Across skeletal muscle, 11ß-dehydrogenase activity was reduced by insulin in lean men only (2.55 ±â€…0.90 vs 4.50 ±â€…1.42 pmol/100 g/minute, P < .05). CONCLUSIONS: Regeneration of cortisol is upregulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11ß-reductase and 11ß-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences.

Validated criteria for the interpretation of a single measurement of serum cortisol in the investigation of suspected adrenal insufficiency.

OBJECTIVE: The diagnostic value of a single measurement of serum cortisol as a first step in the investigation of suspected adrenal insufficiency remains unclear. Previously proposed criteria have not been validated, and little is known regarding the performance of the test outwith morning samples in outpatients. We aimed to identify and validate criteria for morning and afternoon serum cortisol which could be used to determine which individuals require dynamic testing, in both outpatient and medical inpatient settings. METHODS: We performed a retrospective analysis of 2768 patients attending endocrinology clinics and patients admitted to general medical units in two hospitals in Edinburgh, UK. In baseline samples from the short synacthen test, thresholds which identified a subnormal-stimulated serum cortisol (<430 nmol/L using the Abbott Architect assay) with 95% sensitivity were identified. Criteria drawn from data in patients attending outpatient clinics in one hospital were tested in additional outpatient and inpatient validation cohorts. RESULTS: A morning (8 am-12 pm) serum cortisol of <275 nmol/L identified subnormal-stimulated cortisol with 96.2% sensitivity. For afternoon (12 pm-6 pm) samples, a cut-off of <250 nmol/L achieved 96.1% sensitivity. Sensitivity was maintained when the criteria were applied to outpatients in the validation cohort for both morning and afternoon samples. For inpatients, the test was sufficiently sensitive in morning samples only. CONCLUSIONS: A single measurement of serum cortisol carries the potential to significantly reduce the need for dynamic testing in the investigation of adrenal insufficiency, whether this is taken in morning or afternoon outpatient clinics, or in morning samples from medical inpatients.

Long-term exposure to ambient air pollution and renal function in African Americans: the Jackson Heart Study.

Renal dysfunction is prevalent in the US among African Americans. Air pollution is associated with renal dysfunction in mostly white American populations, but has not been studied among African Americans. We evaluated cross-sectional associations between 1-year and 3-year fine particulate matter (PM2.5) and ozone (O3) concentrations, and renal function among 5090 African American participants in the Jackson Heart Study. We used mixed-effect linear regression to estimate associations between 1-year and 3-year PM2.5 and O3 and estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio (UACR), serum creatinine, and serum cystatin C, adjusting for: sociodemographic factors, health behaviors, and medical history and accounting for clustering by census tract. At baseline, JHS participants had mean age 55.4 years, and 63.8% were female; mean 1-year and 3-year PM2.5 concentrations were 12.2 and 12.4 µg/m3, and mean 1-year and 3-year O3 concentrations were 40.2 and 40.7 ppb, respectively. Approximately 6.5% of participants had reduced eGFR (< 60 mL/min/1.73m2) and 12.7% had elevated UACR (> 30 mg/g), both indicating impaired renal function. Annual and 3-year O3 concentrations were inversely associated with eGFR and positively associated with serum creatinine; annual and 3-year PM2.5 concentrations were inversely associated with UACR. We observed impaired renal function associated with increased O3 but not PM2.5 exposure among African Americans.

Neutrophil elastase-cleaved corticosteroid-binding globulin is absent in human plasma.

Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid-binding activity. Measurements of CBG levels are typically based on steroid-binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circulation. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) expected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-cleaved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry confirmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that alter epitopes recognized by specific monoclonal antibodies.

A safety evaluation of canagliflozin : a first-in-class treatment for type 2 diabetes.

INTRODUCTION: Numerous treatments are available for type 2 diabetes mellitus (T2DM), which can improve insulin sensitivity or stimulate its secretion. These are usually unable to halt progression. Inhibition of glucose reabsorption from the renal filtrate was proposed as a novel therapeutic target. Sodium/glucose co-transporter 2 (SGLT2) inhibitors were developed accordingly, with canagliflozin the first to launch in the US in 2013. AREAS COVERED: The mechanism of action of canagliflozin, its pharmacokinetic data and its clinical applications and efficacy data from clinical studies of both subjects with T2DM controlled on diet and exercise, and those on glucose-lowering agents and insulin. The evaluation focuses primarily on the safety of canagliflozin in clinical trials conducted for initial registration due to limited post-marketing data, discusses safety in special populations, before comparing its safety with existing therapies. EXPERT OPINION: Canagliflozin offers a novel therapeutic approach to T2DM; advantages include weight loss and blood pressure lowering with a low intrinsic risk of hypoglycaemia. The main adverse effects likely to be seen are a very small increase in risk of urinary tract infections and a modest risk of developing genital fungal infections. Studies suggest no increased risk of cardiovascular (CV) disease, but longer duration outcome studies are essential.

Emerging sodium/glucose co-transporter 2 inhibitors for type 2 diabetes.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a public health challenge globally. Numerous treatments are available which can improve insulin sensitivity or stimulate its secretion including biguanides, sulphonylureas and glitazones, as well as insulin, GLP-1 agonists and DPP-IV inhibitors. These are usually unable to halt progression with high resulting morbidity and mortality. New therapies are, therefore, being developed; inhibition of glucose reabsorption from the renal filtrate has been proposed as a novel therapeutic target, and sodium/glucose co-transporter 2 (SGLT2) inhibitors have been developed accordingly. AREAS COVERED: This review summarises the challenge that T2DM poses and describes established therapies. The market for these therapies and likely changes are examined, as well as the scientific rationale behind the development of SGLT2 inhibitors. SGLT2 inhibitors in clinical trials worldwide are reviewed and issues affecting their development are discussed. EXPERT OPINION: SGLT2 inhibitors offer a novel therapeutic approach to the management of T2DM; advantages over other agents include weight loss and blood pressure lowering with a low intrinsic risk of hypoglycaemia. The main adverse effects likely to be seen in clinical practice are a very small increase in risk of urinary tract infections, and a modest risk of developing genital fungal infections - which appear more common in the first few months of treatment. Meta-analyses suggest no increased risk of cardiovascular disease, but longer duration outcome studies are essential to prove long-term safety and efficacy.

Ambient fine particulate matter alters cerebral hemodynamics in the elderly.

BACKGROUND AND PURPOSE: Short-term elevations in fine particulate matter air pollution (PM2.5) are associated with increased risk of acute cerebrovascular events. Evidence from the peripheral circulation suggests that vascular dysfunction may be a central mechanism. However, the effects of PM2.5 on cerebrovascular function and hemodynamics are unknown. METHODS: We used transcranial Doppler ultrasound to measure beat-to-beat blood flow velocity in the middle cerebral artery at rest and in response to changes in end-tidal CO2 (cerebral vasoreactivity) and arterial blood pressure (cerebral autoregulation) in 482 participants from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. We used linear mixed effects models with random subject intercepts to evaluate the association between cerebrovascular hemodynamic parameters and mean PM2.5 levels 1 to 28 days earlier adjusting for age, race, medical history, meteorologic covariates, day of week, temporal trends, and season. RESULTS: An interquartile range increase (3.0 µg/m(3)) in mean PM2.5 levels during the previous 28 days was associated with an 8.6% (95% confidence interval, 3.7%-13.8%; P<0.001) higher cerebral vascular resistance and a 7.5% (95% confidence interval, 4.2%-10.6%; P<0.001) lower blood flow velocity at rest. Measures of cerebral vasoreactivity and autoregulation were not associated with PM2.5 levels. CONCLUSIONS: In this cohort of community-dwelling seniors, exposure to PM2.5 was associated with higher resting cerebrovascular resistance and lower cerebral blood flow velocity. If replicated, these findings suggest that alterations in cerebrovascular hemodynamics may underlie the increased risk of particle-related acute cerebrovascular events.

Residential proximity to nearest major roadway and cognitive function in community-dwelling seniors: results from the MOBILIZE Boston Study.

OBJECTIVES: To evaluate the association between residential distance to nearest major roadway, as a marker of long-term exposure to traffic pollution, and cognitive function in older adults. DESIGN: Prospective cohort study with median follow-up of 16.8 months. SETTING: Community. PARTICIPANTS: Seven hundred sixty-five community-dwelling seniors. MEASUREMENTS: The Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), category and letter fluency tests, and Clock-in-the-Box Test were administered during home visits on two occasions. The residential distance to the nearest major roadway was calculated, and generalized estimating equations were used to evaluate the association between performance on each test and residential distance to nearest major roadway, adjusting for participant demographics, education, socioeconomic status, and past medical history. RESULTS: Shorter distance to major roadway was associated with statistically significantly poorer performance on the immediate and delayed recall components of the HVLT-R, TMT Part B, TMT delta, and letter and category fluency tests. Generally, participants residing less than 100 m from a major roadway performed worst. Performance improved monotonically with increasing distance. CONCLUSION: In this cohort of community-dwelling older adults, residential proximity to a major roadway was associated with poorer performance on cognitive tests of verbal learning and memory, psychomotor speed, language, and executive functioning. If causal, these results add to the growing evidence that living near major roadways is associated with adverse health outcomes.