W. David Strain

Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study

BACKGROUND Guidelines suggest setting individualised targets for glycaemic control in elderly patients with type 2 diabetes, despite no evidence. We aimed to assess the feasibility of setting and achieving individualised targets over 24 weeks along with conventional HbA1c reduction using vildagliptin versus placebo. METHODS In this multinational, double-blind, 24 week study, we enrolled drug-naive or inadequately controlled (glycosylated haemoglobin A1c [HbA1c] ≥7·0% to ≤10·0%) patients with type 2 diabetes aged 70 years or older from 45 outpatient centres in Europe. Investigators set individualised treatment targets on the basis of age, baseline HbA1c, comorbidities, and frailty status before a validated automated system randomly assigned patients (1:1) to vildagliptin (50 mg once or twice daily as per label) or placebo. Coprimary efficacy endpoints were proportion of patients reaching their investigator-defined HbA1c target and HbA1c reduction from baseline to study end. The study is registered with ClinicalTrials.gov, number NCT01257451, and European Union Drug Regulating Authorities Clinical Trials database, number 2010-022658-18. FINDINGS Between Dec 22, 2010, and March 14, 2012, we randomly assigned 139 patients each to the vildagliptin and placebo groups. 37 (27%) of 137 patients in the placebo group achieved their individualised targets by education and interactions with the study team alone and 72 (52·6%) of 137 patients achieved their target in the vildagliptin group (adjusted odds ratio 3·16, 96·2% CI 1·81-5·52; p<0·0001). This finding was accompanied by a clinically relevant 0·9% reduction in HbA1c from a baseline of 7·9% with vildagliptin and a between-group difference of -0·6% (98·8% CI -0·81 to -0·33; p<0·0001). The overall safety and tolerability was similar in the vildagliptin and placebo groups, with low incidence of hypoglycaemia and no emergence of new safety signals. INTERPRETATION This study is the first to introduce and show the feasibility of using individualised HbA1c targets as an endpoint in any type 2 diabetes population. Individualised glycaemic target levels are achievable with vildagliptin without any tolerability issues in the elderly type 2 diabetes population. FUNDING Novartis Pharma AG.

Human endothelial function and microvascular ageing

Age is a primary risk factor for cardiovascular disease, and this is an increasingly important public health concern because of an increase in the absolute number and proportion of the population at an older age in many countries. A key component of cardiovascular ageing is reduced function of the vascular endothelium, and this probably contributes to the impaired microvessel function observed with ageing in multiple vascular beds. In turn, impaired microvessel function is thought to contribute to the pathophysiology of cardiovascular and metabolic diseases. Here we review evidence that the first signs of altered endothelial and microvessel function can appear in childhood and at all stages of the human lifespan; low‐birth‐weight babies have reduced endothelial function in skin microvessels at 3 months, and by age 10 years their brachial artery endothelial function is reduced in comparison with normal‐birth‐weight babies. In overweight/obese adolescent children with clustering of traditional cardiovascular disease risk factors, endothelial function is reduced compared with normal‐weight children, and this appears to persist into early adulthood. Adult ageing is associated with impaired microvessel endothelial function and an increase in capillary blood pressure. Biological and lifestyle factors that influence microvessel function include body fat and visceral adiposity, sex hormone status, diet and physical activity. The mechanisms underlying age‐associated changes in microvessel function are uncertain but may involve alterations in nitric oxide, prostanoid, endothelium‐derived hyperpolarizing factor(s) and endothelin‐1 pathways.

IN VITRO AND PRELIMINARY IN VIVO VALIDATION OF ECHO PARTICLE IMAGE VELOCIMETRY IN CAROTID VASCULAR IMAGING

Noninvasive, easy-to-use and accurate measurements of wall shear stress (WSS) in human blood vessels have always been challenging in clinical applications. Echo particle image velocimetry (Echo PIV) has shown promise for clinical measurements of local hemodynamics and wall shear rate. Thus far, however, the method has only been validated under simple flow conditions. In this study, we validated Echo PIV under in vitro and in vivo conditions. For in vitro validation, we used an anatomically correct, compliant carotid bifurcation flow phantom with pulsatile flow conditions, using optical particle image velocimetry (optical PIV) as the reference standard. For in vivo validation, we compared Echo PIV-derived 2-D velocity fields obtained at the carotid bifurcation in five normal subjects against phase-contrast magnetic resonance imaging (PC-MRI)-derived velocity measurements obtained at the same locations. For both studies, time-dependent, 2-D, two-component velocity vectors; peak/centerline velocity, flow rate and wall shear rate (WSR) waveforms at the common carotid artery (CCA), carotid bifurcation and distal internal carotid artery (ICA) were examined. Linear regression, correlation analysis and Bland-Altman analysis were used to quantify the agreement of different waveforms measured by the two techniques. In vitro results showed that Echo PIV produced good images of time-dependent velocity vector maps over the cardiac cycle with excellent temporal (up to 0.7 ms) and spatial (∼0.5 mm) resolutions and quality, comparable with optical PIV results. Further, good agreement was found between Echo PIV and optical PIV results for velocity and WSR measurements. In vivo results also showed good agreement between Echo PIV velocities and phase contrast MRI velocities. We conclude that Echo PIV provides accurate velocity vector and WSR measurements in the carotid bifurcation and has significant potential as a clinical tool for cardiovascular hemodynamics evaluation.

Microcirculation on a Large Scale: Techniques, Tactics and Relevance of Studying the Microcirculation in Larger Population Samples

Please cite this paper as: Strain, Adingupu, and Shore (2012). Microcirculation on a Large Scale: Techniques, Tactics and Relevance of Studying the Microcirculation in Larger Population Samples. Microcirculation 19(1), 37–46.

Attenuated Systemic Microvascular Function in Men with Coronary Artery Disease is Associated with Angina but not Explained by Atherosclerosis

Refractory angina is the occurrence of clinical symptoms despite maximal therapy. We investigated associations between microvascular function, atherosclerotic burden, and clinical symptoms in subjects with CAD.

Outcomes of Treated Hypertension at Age 80 and Older: Cohort Analysis of 79,376 Individuals.

To estimate outcomes according to attained blood pressure (BP) in the oldest adults treated for hypertension in routine family practice.

ALBUMIN:CREATININE RATIO PREDICTS MORTALITY AFTER STROKE: ANALYSIS OF THE THIRD NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY

1. Inouye SK, Fearing MA, Marcantonio ER. Delirium. In: Halter JB, Ouslander JG, Tinetti ME et al., editors. Hazzard’s Geriatric Medicine and Gerontology, 6th Ed. New York: McGraw Hill Medical, 2009, pp 647–658. 2. Reichel W, Arenson C, Scherger JE. Essential principles in the care of the elderly. In: Arenson C, Busby-Whitehead J, Brummel-Smith K et al., editors. Reichel’s Care of the Elderly: Clinical Aspects of Aging, 6th Ed. Cambridge: Cambridge University Press, 2009, pp 1–13. 3. Benbadis SR, Sila CA, Cristea RL. Mental status changes and stroke. J Gen Intern Med 1994;9:485–487. 4. Dasgupta M, Hillier LM. Factors associated with prolonged delirium: A systematic review. Int Psychogeriatr 2010;22:373–394. 5. McManus J, Pathansali R, Stewart R et al. Delirium post-stroke. Age ageing 2007;36:613–618. 6. Caeiro L, Ferro JM, Albuquerque R et al. Delirium in the first days of acute stroke. J Neurol 2004;251:171–178. 7. Sheng AZ, Shen Q, Cordato D et al. Delirium within three days of stroke in a cohort of elderly patients. J Am Geriatr Soc 2006;54:1192–1198. 8. Lanna ME, Madeira DM, Alves G et al. Vascular dementia by thalamic strategic infarct. Arq Neuropsiquiatr 2008;66:412–414. 9. McManus J, Pathansali R, Hassan H et al. The course of delirium in acute stroke. Age ageing 2009;38:385–389.

Proton-Pump Inhibitors and Long-Term Risk of Community-Acquired Pneumonia in Older Adults: PPIs and pneumonia

To estimate associations between long‐term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care.

Understanding the barriers and improving care in type 2 diabetes: Brazilian perspective in time to do more in diabetes

BackgroundType 2 diabetes mellitus (T2DM) is a complex disease, particularly in a continental country like Brazil. We attempted to understand and evaluate the perceptions and routines of Brazilians with T2DM and physicians, compared with other countries.MethodsWe compared the results from a 20-min online survey in Brazil with simultaneously collated data from India, Japan, Spain, UK and USA.ResultsIn total, 652 adults with T2DM and 337 treating physicians were enrolled, of whom 100 patients and 55 physicians were from Brazil. The numbers of primary care physicians from the five countries were 221 versus 43 in Brazil, diabetes specialists were 61 versus 12. There was disconnect between the opinions of physicians and people with diabetes globally. Further, there were differences between clinical practices in Brazil versus the rest of the world, in many areas Brazilians were performing better.ConclusionsCommunication between patients and physicians should be clearer. There is an urgent need to identify the deficits in education, in order to address the clinical inertia within the diabetes management team. There is a necessity to understand the specific requirements of the Brazilian population in order to contextualise international guidelines and implement local changes in practice.

Cardiovascular Outcome Studies in Diabetes: How Do We Make Sense of These New Data?

Poorly controlled diabetes is characterized by premature cardiovascular mortality and morbidity. The mechanisms linking hyperglycemia with accelerated atherosclerotic disease have not been fully elucidated; however, are thought to be mediated through vascular inflammation, oxidative stress and endothelial dysfunction. The advent of incretin-based therapy, whether by increasing endogenous glucagon-like peptide (GLP)-1 and glucose-dependent inhibitory polypeptide by inhibition of their breakdown using di-peptidyl peptidase 4 inhibitors, or augmenting GLP-1 activity using either exendin-4-based drugs or synthetic GLP-1 analogs promised not just improvements in glycemic control, but improvements in endothelial function, lipid profiles and markers of vascular inflammation. As such, it was anticipated they would demonstrate cardiovascular benefit in those with diabetes, indeed early meta-analyses suggested cardiovascular events would be reduced. To date, however, this benefit has failed to materialize, indeed the cardiovascular outcome trials, whilst meeting their primary endpoint of cardiovascular safety, have failed to demonstrate any improvements in stroke or myocardial infarction. This review will explore the data and attempt to answer the question: what went wrong?