STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk): a Delphi study by the EuGMS Task and Finish Group on Fall-Risk-Increasing Drugs.

BACKGROUND: Healthcare professionals are often reluctant to deprescribe fall-risk-increasing drugs (FRIDs). Lack of knowledge and skills form a significant barrier and furthermore, there is no consensus on which medications are considered as FRIDs despite several systematic reviews. To support clinicians in the management of FRIDs and to facilitate the deprescribing process, STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk) and a deprescribing tool were developed by a European expert group. METHODS: STOPPFall was created by two facilitators based on evidence from recent meta-analyses and national fall prevention guidelines in Europe. Twenty-four panellists chose their level of agreement on a Likert scale with the items in the STOPPFall in three Delphi panel rounds. A threshold of 70% was selected for consensus a priori. The panellists were asked whether some agents are more fall-risk-increasing than others within the same pharmacological class. In an additional questionnaire, panellists were asked in which cases deprescribing of FRIDs should be considered and how it should be performed. RESULTS: The panellists agreed on 14 medication classes to be included in the STOPPFall. They were mostly psychotropic medications. The panellists indicated 18 differences between pharmacological subclasses with regard to fall-risk-increasing properties. Practical deprescribing guidance was developed for STOPPFall medication classes. CONCLUSION: STOPPFall was created using an expert Delphi consensus process and combined with a practical deprescribing tool designed to optimise medication review. The effectiveness of these tools in falls prevention should be further evaluated in intervention studies.

Cost-Effectiveness of Antihypertensive Therapy in Patients Older Than 80 Years: Cohort Study and Markov Model.

BACKGROUND: Blood pressure and antihypertensive treatment (AHT) generally increase with age, but there is uncertainty concerning the value of treatment at very advanced ages. OBJECTIVES: To estimate the cost-effectiveness of AHT in people aged 80 years and older. METHODS: A Markov model compared AHT with no blood pressure treatment for prevention of cardiovascular disease. Outcomes were new stroke, coronary heart disease, and diabetes, with falls included as a potential complication of AHT. Costs were evaluated from a health system perspective. Incidence, mortality, and costs of healthcare utilization were estimated from linked primary and secondary care electronic health records for 98 220 individuals aged 80 years and older. Clinical effectiveness estimates were from the Hypertension in the Very Elderly Trial. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, AHT was associated with an additional 725 quality-adjusted life-years (QALYs) and £4.3 million per 1000, with an incremental cost-effectiveness ratio (ICER) of £5977 per QALY. The ICER was most sensitive to the cost of falls and relative risk reduction in stroke incidence. Probabilistic sensitivity analysis gave 95% uncertainty intervals: £5057 to £8398 per QALY in men and £4955 to £8218 per QALY in women. AHT for secondary prevention in participants with coronary heart disease gave an ICER of £9903 per QALY. CONCLUSIONS: AHT is estimated to be cost-effective in individuals aged 80 years and older, even if health benefits are smaller or side effects costlier than in the base case. Benefits and harms for vulnerable subgroups require further evaluation.

Systolic Blood Pressure Trajectory, Frailty, and All-Cause Mortality >80 Years of Age: Cohort Study Using Electronic Health Records.

BACKGROUND: Clinical trials show benefit from lowering systolic blood pressure (SBP) in people ≥80 years of age, but nonrandomized epidemiological studies suggest lower SBP may be associated with higher mortality. This study aimed to evaluate associations of SBP with all-cause mortality by frailty category >80 years of age and to evaluate SBP trajectories before death. METHODS: A population-based cohort study was conducted using electronic health records of 144 403 participants ≥80 years of age registered with family practices in the United Kingdom from 2001 to 2014. Participants were followed for ≤5 years. Clinical records of SBP were analyzed. Frailty status was classified using the e-Frailty Index into the categories of fit, mild, moderate, and severe. All-cause mortality was evaluated by frailty status and mean SBP in Cox proportional-hazards models. SBP trajectories were evaluated using person months as observations, with mean SBP and antihypertensive treatment status estimated for each person month. Fractional polynomial models were used to estimate SBP trajectories over 5 years before death. RESULTS: During follow-up, 51 808 deaths occurred. Mortality rates increased with frailty level and were greatest at SBP <110 mm Hg. In fit women, mortality was 7.7 per 100 person years at SBP 120 to 139 mm Hg, 15.2 at SBP 110 to 119 mm Hg, and 22.7 at SBP <110 mm Hg. For women with severe frailty, rates were 16.8, 25.2, and 39.6, respectively. SBP trajectories showed an accelerated decline in the last 2 years of life. The relative odds of SBP <120 mm Hg were higher in the last 3 months of life than 5 years previously in both treated (odds ratio, 6.06; 95% confidence interval, 5.40-6.81) and untreated (odds ratio, 6.31; 95% confidence interval, 5.30-7.52) patients. There was no evidence of intensification of antihypertensive therapy in the final 2 years of life. CONCLUSIONS: A terminal decline of SBP in the final 2 years of life suggests that nonrandomized epidemiological associations of low SBP with higher mortality may be accounted for by reverse causation if participants with lower blood pressure values are closer, on average, to the end of life.

Feasibility and efficacy of a multi-factorial intervention to prevent falls in older adults with cognitive impairment living in residential care (ProF-Cog). A feasibility and pilot cluster randomised controlled trial.

BACKGROUND: Falls are common in people with dementia living in residential care. The ProF-Cog intervention was developed to address fall risk factors specific to this population. The aim of this study was to evaluate the safety, acceptability, and feasibility of the intervention and provide an estimate of its efficacy. METHODS: This was a cluster randomised controlled pilot study undertaken in care homes in London, UK. All permanent residents living in participating homes who were not terminally ill were invited to participate. The intervention included an assessment of falls risk factors followed by a tailored intervention which could include dementia care mapping, comprehensive geriatric assessment, occupational therapy input and twice-weekly exercise for 6 months as required to target identified risk factors. The control group received usual care without a falls risk assessment. Standing balance was the primary outcome. This and other outcome measures were collected at baseline and after 6 months. Falls were recorded for this period using incident reports. Changes were analysed using multi-level modelling. Adherence to the interventions, adverse events and trial feasibility were recorded. RESULTS: Nine care homes enrolled in the study with a total 191 participants (51% of those eligible); five homes allocated to the intervention with 103 participants, and four homes to the usual care control group with 88 participants. The intervention was safe with only one reported fall whilst undertaking exercise. Adherence to agreed recommendations on activity and the environment was modest (21 and 45% respectively) and to exercise was poor (41%). Balance scores (score range 0-49) analysed on 100 participants decreased by a mean of 3.9 in the control and 5.1 in the intervention groups, a non-significant difference (p = 0.9). In other measures, both groups declined equally and there was no difference in falls rates (IRR = 1.59 95%, CI 0.67-3.76). CONCLUSION: The intervention was safe but not clinically effective. Poor adherence suggests it was not an acceptable or feasible intervention. TRIAL REGISTRATION: ISRCTN00695885 . Registered 26th March 2013.

Kicking Back Cognitive Ageing: Leg Power Predicts Cognitive Ageing after Ten Years in Older Female Twins.

BACKGROUND: Many observational studies have shown a protective effect of physical activity on cognitive ageing, but interventional studies have been less convincing. This may be due to short time scales of interventions, suboptimal interventional regimes or lack of lasting effect. Confounding through common genetic and developmental causes is also possible. OBJECTIVES: We aimed to test whether muscle fitness (measured by leg power) could predict cognitive change in a healthy older population over a 10-year time interval, how this performed alongside other predictors of cognitive ageing, and whether this effect was confounded by factors shared by twins. In addition, we investigated whether differences in leg power were predictive of differences in brain structure and function after 12 years of follow-up in identical twin pairs. METHODS: A total of 324 healthy female twins (average age at baseline 55, range 43-73) performed the Cambridge Neuropsychological Test Automated Battery (CANTAB) at two time points 10 years apart. Linear regression modelling was used to assess the relationships between baseline leg power, physical activity and subsequent cognitive change, adjusting comprehensively for baseline covariates (including heart disease, diabetes, blood pressure, fasting blood glucose, lipids, diet, body habitus, smoking and alcohol habits, reading IQ, socioeconomic status and birthweight). A discordant twin approach was used to adjust for factors shared by twins. A subset of monozygotic pairs then underwent magnetic resonance imaging. The relationship between muscle fitness and brain structure and function was assessed using linear regression modelling and paired t tests. RESULTS: A striking protective relationship was found between muscle fitness (leg power) and both 10-year cognitive change [fully adjusted model standardised ß-coefficient (Stdß) = 0.174, p = 0.002] and subsequent total grey matter (Stdß = 0.362, p = 0.005). These effects were robust in discordant twin analyses, where within-pair difference in physical fitness was also predictive of within-pair difference in lateral ventricle size. There was a weak independent effect of self-reported physical activity. CONCLUSION: Leg power predicts both cognitive ageing and global brain structure, despite controlling for common genetics and early life environment shared by twins. Interventions targeted to improve leg power in the long term may help reach a universal goal of healthy cognitive ageing.

Cognitive change in older women using a computerised battery: a longitudinal quantitative genetic twin study.

Cognitive performance is known to change over age 45, especially processing speed. Studies to date indicate that change in performance with ageing is largely environmentally mediated, with little contribution from genetics. We estimated the heritability of a longitudinal battery of computerised cognitive tests including speed measures, using a classical twin design. 324 (127 MZ, 197 DZ) female twins, aged 43-73 at baseline testing, were followed-up after 10 years, using seven measures of the Cambridge Automated Neuropsychological Test battery, four of which were measures of response latency (speed). Results were analysed using univariate and bivariate structural equation modelling. Heritability of longitudinal change was found in 5 of the 7 tests, ranging from 21 to 41%. The genetic aetiology was remarkably stable. The first principle component of change was strongly associated with age (p < 0.001) and heritable at 47% (27-62%). While estimates for heritability increased in all measures over time compared to baseline, these increases were statistically non-significant. This computerised battery showed significant heritability of age-related change in cognition. Focus on this form of change may aid the search for genetic pathways involved in normal and pre-morbid cognitive ageing.

Therapeutic benefit of the anesthesiologist-patient relationship.

The psychologic effect of the preoperative visit by an anesthetist has been compared with the effect of pentobarbital for preanesthetic medication. Patients receiving pentobarbital 1 hour before an operation became drowsy but it could not be shown that they became calm. Patients who had received a visit by an anesthetist before operation (informing them about the events which were to occur on the day of operation and about the anesthetic to be administered) were not drowsy but were more likely to be calm on the day of operation. The importance of the preoperative visit probably explains, in part, the difficulties previous investigators have had in showing sedative effects from the barbiturates and narcotics before operation. The tremendous emotional significance to a patient of illness or an operation may explain why physicians are able to exert such influence upon their patients.

The Hypertension in the Very Elderly Trial - latest data.

Early trials in the field of hypertension focused on adults in their fifties and sixties. However, with the passage of time, a progressive effort has been made to expand the evidence base for treatment in older adults. 2008 saw publication of data from the Hypertension in the Very Elderly Trial which demonstrated significant mortality and morbidity benefits from antihypertensive therapy in octogenarians. More recently, additional data from this cohort has been published suggesting that appropriate anti-hypertensive therapy may lead to a reduction in incident cognitive impairment and fractures, whilst a 1 year open label extension of the main study confirmed many of the original trial findings. This review provides an overview of the Hypertension in the Very Elderly Trial whilst also discursively evaluating the latest data.

Risk: benefit of treating high blood pressure in older adults.

Older people (those aged 65 years or over) comprise over 15% of the UK's population and this cohort is growing. Whilst at greatest risk from systemic arterial hypertension (hypertension), its resultant end organ damage and clinically significant cardiovascular disease, this group was initially neglected in clinical trials and thereby denied treatment, with the lack of evidence cited as justification. However since the 1960s, when the first landmark trials in severe diastolic hypertension were published, there has been a progressive attempt to understand the pathophysiology of hypertension and to expand the evidence base for treatment in older adults. In contrast to the participants of the very first randomized trials who had a mean age of 51 years, the recent Hypertension in the Very Elderly Trial demonstrated significant mortality and morbidity benefits from the treatment of both mixed systolic and diastolic hypertension, as well as isolated systolic hypertension in octogenarians. This review highlights the progressive evidence base behind the relative risks and benefits of treating hypertension in older adults.

Development and validation of a fall-related impulsive behaviour scale for residential care.

INTRODUCTION: impulsivity in older people with cognitive impairment has yet to be examined rigorously as a risk factor for falls. The objective of this study was to evaluate the psychometric properties of a new fall-related impulsive behaviour scale (FIBS) for a cognitively impaired population living in residential care. METHODS: one hundred and nine care home residents (84.5 ± 8.3 years) were assessed on the FIBS and a range of behavioural, physical and neuropsychological measures. Participants were then prospectively followed up for falls for 6 months. RESULTS: the internal reliability (Cronbach's α = 0.77) and test-retest reliability (intra-class correlation coefficient = 0.93) of the FIBS were both good. Construct validity was supported by significant correlations between the FIBS and the neuropsychiatric inventory (r = 0.43, P < 0.001), wandering (r = 0.33, P = 0.001) and global cognition (r = -0.2, P = 0.04). Compared with residents with FIBS scores <1, those with FIBS scores of ≥ 1 were nearly three times more likely to fall in the following 6 months, AOR = 2.92 (95% CI: 1.03-8.29). CONCLUSION: the FIBS is a simple, valid and reliable scale for assessing fall-related impulsivity in care home residents and can be recommended for use in this group for both research and clinical purposes.

United States anesthesiologists over 50: retirement decision making and workforce implications.

BACKGROUND: Anesthesiology is among the medical specialties expected to have physician shortage. With little known about older anesthesiologists' work effort and retirement decision making, the American Society of Anesthesiologists participated in a 2006 national survey of physicians aged 50-79 yr. METHODS: Samples of anesthesiologists and other specialists completed a survey of work activities, professional satisfaction, self-defined health and financial status, retirement plans and perspectives, and demographics. A complex survey design enabled adjustments for sampling and response-rate biases so that respondents' characteristics resembled those in the American Medical Association Physician Masterfile. Retirement decision making was modeled with multivariable ordinal logistic regression. Life-table analysis provided a forecast of likely clinical workforce trends over an ensuing 30 yr. RESULTS: Anesthesiologists (N = 3,222; response rate = 37%) reported a mean work week of 49.4 h and a mean retirement age of 62.7 yr, both values similar to those of other older physicians. Work week decreased with age, and part-time work increased. Women worked a shorter work week (mean, 47.9 vs. 49.7 h, P = 0.024), partly due to greater part-time work (20.2 vs. 13.1%, P value less than 0.001). Relative importance of factors reported among those leaving patient care differed by age cohort, subspecialty, and work status. Poor health was cited by 64% of anesthesiologists retiring in their 50s as compared with 43% of those retiring later (P = 0.039). CONCLUSIONS: This survey lends support for greater attention to potentially modifiable factors, such as workplace wellness and professional satisfaction, to prevent premature retirement. The growing trend in part-time work deserves further study.

Ageing, genes, environment and epigenetics: what twin studies tell us now, and in the future.

Compared with younger people, older people are much more variable in their organ function, and these large individual differences contribute to the complexity of geriatric medicine. What determines this variability? Is it due to the accumulation of different life experiences, or because of the variation in the genes we are born with, or an interaction of both? This paper reviews key findings from ageing twin cohorts probing these questions. Twin studies are the perfect natural experiment to dissect out genes and life experiences. We discuss the paradox that ageing is strongly determined by heritable factors (an influence that often gets stronger with time), yet longevity and lifespan seem not to be so heritable. We then focus on the intriguing question of why DNA sequence-identical twins might age differently. Animal studies are increasingly showing that epigenetic modifications occurring in early development and adulthood, might be key to ageing phenomena but this is difficult to investigate longitudinally in human populations, due to ethical problems of intervention and long lifespan. We propose that identical twin studies using new and existing cohorts may be useful human models in which to investigate the interaction between the environment and genetics, mediated by epigenetic modifications.

Trajectory of Total Cholesterol in the Last Years of Life Over Age 80 Years: Cohort Study of 99,758 Participants.

Background: Epidemiological studies suggest that lower total cholesterol (TC) may be associated with higher mortality. This study aimed to evaluate whether a decline in TC before death might account for the association of TC with mortality over age 80 years. Methods: Cohort study using primary care electronic health records of 99,758 participants aged 80-105 years from the UK Clinical Practice Research Datalink. Hazard ratios for all-cause mortality were adjusted for age, gender, frailty, comorbidity, blood pressure, and smoking. Fractional polynomial models were fitted to evaluate longitudinal trends in TC before death or end-of-study. Adjusted odds ratios were estimated using generalized estimating equations. Results: There were 63,630 women and 36,128 men, mean age 86 years, with 29,200 deaths. There were 41,164 treated with statins at cohort entry. Compared with TC values of 4.5-5.4 mmol/L, TC values <3.0 mmol/L were associated with higher mortality (statin treated hazard ratios 1.53, 95% confidence interval 1.43-1.64, p < .001; not treated, 1.41, 1.29-1.54, p < .001). A secular decline in TC values accelerated in the last 2 years of life. In the last quarter of follow-up, the adjusted odds of TC < 3.0 mmol/L for those who died, compared with surviving participants, were 3.33 (2.84-3.91, p < .001) for untreated and 1.88 (1.68-2.11, p < .001) for statin-treated participants. Conclusions: TC values show a terminal decline in the last years of life. Reverse causation may contribute to the association of lower TC with higher mortality in nonrandomized studies.

Incidence and mortality of fractures by frailty level over 80 years of age: cohort study using UK electronic health records.

OBJECTIVE: This study aimed to estimate the association of frailty with incidence and mortality of fractures at different sites in people aged over 80 years. DESIGN: Cohort study. SETTING: UK family practices from 2001 to 2014. PARTICIPANTS: 265 195 registered participants aged 80 years and older. MEASUREMENTS: Frailty status classified into 'fit', 'mild', 'moderate' and 'severe' frailty. Fractures, classified into non-fragility and fragility, including fractures of femur, pelvis, shoulder and upper arm, and forearm/wrist. Incidence of fracture, and mortality within 90 days and 1 year, were estimated. RESULTS: There were 28 643 fractures including: non-fragility fractures, 9101; femur, 12 501; pelvis, 2172; shoulder and upper arm, 4965; and forearm/wrist, 6315. The incidence of each fracture type was higher in women and increased with frailty category (femur, severe frailty compared with 'fit', incidence rate ratio (IRR) 2.4, 95% CI 2.3 to 2.6). Fractures of the femur (95-99 years compared with 80-84 years, IRR 2.7, 95% CI 2.6 to 2.9) and pelvis (IRR 2.9, 95% CI 2.5 to 3.3) were strongly associated with age but non-fragility and forearm fractures were not. Mortality within 90 days was greatest for femur fracture (adjusted HR, compared with forearm fracture 4.3, 95% CI 3.7 to 5.1). Mortality was higher in men and increased with age (HR 5.3, 95% CI 4.3 to 6.5 in those over 100 years compared with 80-84 years) but was less strongly associated with frailty category. Similar associations with fractures were seen at 1-year mortality. CONCLUSIONS: The incidence of fractures at all sites was higher in women and strongly associated with advancing frailty status, while the risk of mortality after a fracture was greater in men and was associated with age rather than frailty category.

Declining blood pressure and intensification of blood pressure management among people over 80 years: cohort study using electronic health records.

BACKGROUND: Management of high blood pressure (BP) in people over 80 years is controversial, but there is limited information available concerning the uptake of hypertension treatment at this age. OBJECTIVE: To evaluate use of antihypertensive drugs and changes in SBP and DBP from 2001 to 2014 in men and women aged 80 years and over. METHODS: Cohort study using primary care electronic health records of 265 225 participants from the UK Clinical Practice Research Datalink. Records of BP and antihypertensive medications were analysed. Linear trends were estimated by frailty category in multiple regression models. RESULTS: Data were analysed for 116 401 men and 148 824 women. The proportion with BP recorded increased from 51% in 2001 to 78% in 2014. The proportion of patients prescribed antihypertensive medications increased from 64 to 76%. Mean SBP declined from 150 (SD 20) mmHg in 2001 to 135 (16) mmHg in 2014. In 'fit' participants, the decline in SBP was 12.4 (95% confidence interval 11.9-13.0) mmHg/decade in those treated for hypertension and 8.5 (7.8-9.1) mmHg in those not treated. The decline in SBP was smaller as frailty increased. The proportion of all participants with BP less than 140/90 mmHg increased from 14 to 44% in the study period. CONCLUSION: In octogenarians, BP treatment has intensified between 2001 and 2014. BP values have declined in both treated and untreated participants, with a substantial increase in the proportion achieving conventional BP targets.

Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects.

Cognitive impairment is associated with increased blood concentrations of homocysteine and high blood viscosity. Previous studies have shown that vitamin B supplementation reduces homocysteine and enhances cognitive function in patients with mild dementia and low serum folic acid. However, whether folic acid enhances cognitive function in elderly subjects without dementia and normal serum folic acid is unknown. Twenty-four healthy elderly subjects (age 73.0+/-5.6 years, mean+/-S.D.) with normal serum folic acid (6.3+/-2.4 microg/l) and Mini Mental State Examination (MMSE) >27/30 were randomized to 4-week treatment with folic acid 5mg/day or placebo in a randomized, placebo-controlled, parallel-group study. Continuous Attention Test (CAT), Four-Choice Reaction Time (FCRT), Digit-Symbol Substitution (DSS), Scanning Memory Sets (SMS), and blood viscosity for different shear rates were measured before and after treatment. Folic acid supplementation induced a significant increase in serum folic acid levels (+13.8 versus +1.6 microg/l, p<0.001) and fall in homocysteine levels (-1.91 versus -0.41 micromol/l, p=0.05) compared to placebo. However, there was no significant change in CAT, FCRT, DSS, SMS, and blood viscosity between the two groups. Short-term folic acid supplementation does not enhance psychomotor performance or reduce blood viscosity in healthy elderly subjects with normal serum folic acid levels and preserved cognitive function.

Longitudinal Trends in Hypertension Management and Mortality Among Octogenarians: Prospective Cohort Study.

The role of hypertension management among octogenarians is controversial. In this long-term follow-up (>10 years) study, we estimated trends in hypertension prevalence, awareness, treatment, and control among octogenarians, and evaluated the relationship of systolic blood pressure (SBP) ranges with mortality. Data were based on the English Longitudinal Study of Ageing (ELSA). Outcome measures were hypertension prevalence, awareness, treatment and control, and cardiovascular disease, and all-cause mortality events. Participants were separated into 8 categories of SBP values (<110, 110-119, 120-129, 130-139, 140-149, 150-159, 160-169, and >169 mm Hg). Among 2692 octogenarians, mean SBP levels declined from 147 mm Hg in 1998/2000 to 134 mm Hg in 2012/2013. The decline was of lower magnitude in the 50 to 79 years old subgroup (n=22007). Hypertension prevalence and awareness were 40% and 13%, respectively, higher among octogenarians than the 50 to 79 years of age subgroup, but hypertension treatment rates were similar (≈90%). Around 47% of the treated octogenarians achieved conventional BP targets (<140/90 mm Hg), increasing to 59% when assessed against revised targets (<150/90 mm Hg). All-cause mortality rates were higher (hazard ratio, 1.55; 95% confidence interval, 0.89-2.72) at lower extremes of SBP values (<110 mm Hg). The lowest cardiovascular disease and all-cause mortality risk among treated octogenarians was observed for an SBP range of 140 to 149 mm Hg (1.04, 0.60-1.78) and 160 to 169 mm Hg (0.78, 0.51-1.21). An increasing trend in hypertension awareness and treatment was observed in a large sample of community-dwelling octogenarians. The results do not support the view that more stringent BP targets may be associated with lower mortality.

Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes.

BACKGROUND: Endothelial dysfunction and arterial stiffening are commonly observed in type 2 diabetes. These abnormalities might be secondary to increased plasma concentrations of homocysteine. We sought to determine whether oral folic acid supplementation, by lowering homocysteine levels, enhanced endothelial function and reduced arterial stiffness in type 2 diabetes. METHODS: Twenty-six type 2 diabetic patients (age 56.5 +/- 0.9 years, diabetes duration 5.5 +/- 0.6 years, means +/- SEM) with no history of cardiovascular disease received 5 mg/d of oral folic acid or placebo for 4 weeks in a double-blind, randomized controlled, parallel group trial. The following parameters were measured before and after treatment: 1) endothelial function (forearm arterial blood flow during local intra-arterial administration of endothelium-dependent [acetylcholine 1.5, 4.5, and 15 microg/min] and endothelium-independent [sodium nitroprusside 1, 2, and 4 microg/min] vasodilators); and 2) carotid-radial and carotid-femoral pulse wave velocity. RESULTS: Folic acid reduced plasma homocysteine concentrations and enhanced endothelium-dependent vasodilatation during each acetylcholine infusion rate (mean and 95% confidence interval post versus pretreatment differences in forearm arterial blood flow ratio between the infused and control arm +0.19 (0.03-0.35), P < .01; +0.39 (0.02-0.81), P < .05; and +0.40 (0.09-0.89), P < .05, respectively). Endothelium-independent vasodilatation and pulse wave velocity were not affected. No significant changes in forearm arterial blood flow and pulse wave velocity were observed in the placebo group. Multiple regression analysis showed that changes in folic acid, but not homocysteine, concentrations independently described changes in maximal endothelium-dependent vasodilatation. CONCLUSIONS: Short-term oral folic acid supplementation significantly enhances endothelial function in type 2 diabetic patients, independent of homocysteine lowering.