The effects of the sodium-glucose co-transporter 2 inhibitor empagliflozin on renal and cardiovascular disease have not been tested in a dedicated population of people with chronic kidney disease ...(CKD).
The EMPA-KIDNEY trial is an international randomized, double-blind, placebo-controlled trial assessing whether empagliflozin 10 mg daily decreases the risk of kidney disease progression or cardiovascular death in people with CKD. People with or without diabetes mellitus (DM) were eligible provided they had an estimated glomerular filtration rate (eGFR) ≥20 but <45 mL/min/1.73 m2 or an eGFR ≥45 but <90 mL/min/1.73 m2 with a urinary albumin:creatinine ratio (uACR) ≥200 mg/g. The trial design is streamlined, as extra work for collaborating sites is kept to a minimum and only essential information is collected.
Between 15 May 2019 and 16 April 2021, 6609 people from eight countries in Europe, North America and East Asia were randomized. The mean age at randomization was 63.8 years standard deviation (SD) 13.9), 2192 (33%) were female and 3570 (54%) had no prior history of DM. The mean eGFR was 37.5 mL/min/1.73 m2 (SD 14.8), including 5185 (78%) with an eGFR <45 mL/min/1.73 m2. The median uACR was 412 mg/g) (quartile 1-quartile 3 94-1190), with a uACR <300 mg/g in 3194 (48%). The causes of kidney disease included diabetic kidney disease n = 2057 (31%), glomerular disease n = 1669 (25%), hypertensive/renovascular disease n = 1445 (22%), other n = 808 (12%) and unknown causes n = 630 (10%).
EMPA-KIDNEY will evaluate the efficacy and safety of empagliflozin in a widely generalizable population of people with CKD at risk of kidney disease progression. Results are anticipated in 2022.
Preclinical studies support a protective role for omega-3 fatty acids (FAs) on diabetic retinopathy (DR), but these observations have not been confirmed in randomized trials. We present randomized ...evidence for the effects of omega-3 FAs on DR outcomes.
A substudy of the A Study of Cardiovascular Events iN Diabetes (ASCEND) double-blind, randomized, placebo-controlled trial of 1 g omega-3 fatty acids (containing 460 mg eicosapentaenoic acid and 380 mg docosahexaenoic acid) daily for the primary prevention of serious cardiovascular events, in 15 480 UK adults at least 40 years of age, with diabetes.
Fifteen thousand four hundred eighty adults at least 40 years of age from the United Kingdom with diabetes from the ASCEND cohort.
Linkage to electronic National Health Service Diabetic Eye Screening Programme records in England and Wales and confirmation of participant-reported eye events via medical record review. Log-rank and stratified log-rank methods were used for intention-to-treat analyses of time until the main outcomes of interest.
The primary efficacy endpoint was time to the first postrandomization recording of referable disease, a composite of referable retinopathy (R
or R
) or referable maculopathy (M
) based on the grading criteria defined by the United Kingdom National Screening Committee. Secondary and tertiary outcomes included the referable disease outcome stratified by the severity of DR at baseline, any progression in retinopathy grade, and incident diabetic maculopathy.
Linkage data were obtained for 7360 participants (48% of those who were randomized in ASCEND). During their mean follow-up of 6.5 years, 548 participants (14.8%) had a referable disease event in the omega-3 FAs group, compared with 513 participants (13.9%) in the placebo group (rate ratio, 1.07; 95% confidence interval, 0.95-1.20; P = 0.29). There were no statistically significant between-group differences in the proportion of events for either of the secondary or tertiary outcomes.
Representing the largest prospective test of its kind to date, these data exclude any clinically meaningful benefits of 1 g daily omega-3 FAs on DR.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Despite optimized risk factor control, people with prior cardiovascular disease remain at high cardiovascular disease risk. We assess the immediate- and longer-term impacts of new vascular and ...nonvascular events on quality of life (QoL) and hospital costs among participants in the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) trial in secondary prevention.
Data on demographic and clinical characteristics, health-related quality of life (QoL: EuroQoL 5-Dimension-5-Level), adverse events, and hospital admissions during the 4-year follow-up of the 21 820 participants recruited in Europe and North America informed assessments of the impacts of new adverse events on QoL and hospital costs from the UK and US health systems' perspectives using generalized linear regression models. Reductions in QoL were estimated in the years of event occurrence for nonhemorrhagic stroke (-0.067 United Kingdom, -0.069 US), heart failure admission (-0.072 United Kingdom, -0.103 US), incident cancer (-0.064 United Kingdom, -0.068 US), and noncoronary revascularization (-0.071 United Kingdom, -0.061 US), as well as in subsequent years following these events. Myocardial infarction and coronary revascularization (CRV) procedures were not found to affect QoL. All adverse events were associated with additional hospital costs in the years of events and in subsequent years, with the highest additional costs in the years of noncoronary revascularization (£5830 United Kingdom, $14 133 US Medicare), of myocardial infarction with urgent CRV procedure (£5614, $24722), and of urgent/nonurgent CRV procedure without myocardial infarction (£4674/£4651 and $15 251/$17 539).
Stroke, heart failure, and noncoronary revascularization procedures substantially reduce QoL, and all cardiovascular disease events increase hospital costs. These estimates are useful in informing cost-effectiveness of interventions to reduce cardiovascular disease risk in secondary prevention.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252953; https://www.Isrctn.com. Unique identifier: ISRCTN48678192; https://www.clinicaltrialsregister.eu. Unique identifier: 2010-023467-18.
Aspirin and omega-3 fatty acids (FAs) have potential disease-modifying roles in diabetic retinopathy (DR) and age-related macular degeneration (AMD), but randomized evidence of these effects is ...limited. We present the rationale and baseline characteristics of ASCEND-Eye, a sub-study of the double-blind, 2x2 factorial design, randomized placebo-controlled ASCEND (A Study of Cardiovascular Events iN Diabetes) trial of 100 mg aspirin daily and, separately, 1g omega-3 FAs daily for the primary prevention of serious cardiovascular events, in 15,480 British adults, aged 40 years or older with diabetes.
Eye events will be derived from three sources: 1) participant follow-up questionnaires from ASCEND, 2) electronic NHS Diabetic Eye Screening Programme (DESP) data and 3) responses to the National Eye Institute's Visual Function Questionnaire-25 (NEI-VFQ-25) sent to a subset of participants after the main trial ended. Analytic cohorts and outcomes relevant to these data sources are described. The primary outcome is referable diabetic eye disease, a secondary outcome is incident AMD events.
Participant-reported events were ascertained for the full cohort of randomized individuals who were followed up over 7.4 years in ASCEND (n = 15,480). Linked DESP data were available for 48% of those (n = 7360), and 57% completed the NEI-VFQ-25 (n = 8839). The baseline characteristics of these three cohorts are presented.
Establishing the risks and benefits of drugs commonly taken by people with diabetes, the elderly, or both, and finding new treatments for DR and AMD is important. ASCEND-Eye provides the opportunity to evaluate the effect of aspirin and, separately, omega-3 FAs for both conditions.
Eudract No. 2004-000991-15; Multicentre Research Ethics Committee Ref No. 03/8/087; ClinicalTrials.gov No. NCT00135226; ISRCTN No. ISRCTN60635500.
1 Department of Cardiovascular Sciences, 2 Faculty of Medicine, University of Leicester; 3 Department of Medical Physics, University Hospitals of Leicester, NHS Trust, Leicester; and 4 School of ...Medicine, University of East Anglia, Norwich, United Kingdom
Submitted 8 March 2007
; accepted in final form 25 April 2007
Assessment of dynamic cerebral autoregulation (CA) requires continuous recording of arterial blood pressure (ABP). In humans, noninvasive ABP recordings with the Finapres device have often been used for this purpose. We compared estimates of dynamic CA derived from Finapres with those from invasive recordings in the aorta. Measurements of finger noninvasive ABP (Finapres), intra-aortic ABP (Millar catheter), surface ECG, transcutaneous CO 2 , and bilateral cerebral blood flow velocity (CBFV) in the middle cerebral arteries were simultaneously and continuously recorded in 27 patients scheduled for percutaneous coronary interventions. Phase, gain, coherence, and CBFV step response from both the Finapres and intra-arterial catheter were estimated by transfer function analysis. A dynamic autoregulation index (ARI) was also calculated. For both hemispheres, the ARI index and the CBFV step response recovery at 4 s were significantly greater for the Finapres-derived estimates than for the values obtained from aortic pressure. The transfer function gain for frequencies <0.1 Hz was significantly smaller for the Finapres estimates. The phase frequency response was significantly greater for the Finapres estimates at frequencies >0.1 Hz, but not at lower frequencies. The Finapres gives higher values for the efficiency of dynamic CA compared with values derived from aortic pressure measurements, as indicated by biases in the ARI index, CBFV step response, gain, and phase. Despite the significance of these biases, their relatively small amplitude indicates a good level of agreement between indexes of CA derived from the Finapres compared with corresponding estimates obtained from invasive measurements of aortic ABP.
cerebral blood flow velocity; central arterial pressure
Address for reprint requests and other correspondence: R. B. Panerai, Dept. of Medical Physics, Leicester Royal Infirmary, Leicester LE1 5WW, UK (e-mail: rp9{at}le.ac.uk )
A multicenter, randomized trial involving participants with diabetes and no evident cardiovascular disease at trial entry showed that aspirin led to a lower risk of serious vascular events than ...placebo but also caused a higher risk of major bleeding.
In this trial involving patients with diabetes without evidence of cardiovascular disease, the risk of serious vascular events was similar in those who received n−3 fatty acid supplements and those ...who received placebo.
Abstract only Background: There is definitive evidence that lowering LDL-cholesterol with statins as monotherapy, or in combination with ezetimibe or PCSK9 inhibitors, prevents not only first but ...also subsequent major coronary events (i.e. coronary death, myocardial infarction or coronary revascularization). Consequently, prolonged treatment produces greater absolute reductions in morbidity, mortality and economic costs. Inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib lowers LDL-cholesterol levels, as well as substantially increasing HDL-cholesterol, but it is not yet known if it produces benefits on first and subsequent occlusive vascular events and deaths. Methods: The HPS3/TIMI55-REVEAL trial has assessed the effects of adding the CETP inhibitor anacetrapib to atorvastatin on vascular morbidity and mortality in 30,449 individuals who had a history of atherosclerotic vascular disease. Study treatment was continued for a median of 4.1 years. Information was recorded on first and subsequent cardiovascular events that occurred during the scheduled treatment period. Results: The main trial results are to be presented at the European Society of Cardiology Congress in August 2017. For the American Heart Association Congress, it is proposed to present more detailed results on the effects of anacetrapib on first and subsequent occlusive vascular events. Within this high-risk population of individuals with pre-existing vascular disease, 3443 (11%) had a first major coronary event and 1097 subsequent events were reported during the scheduled treatment period. Conclusions: Unblinded results of the cumulative effects of anacetrapib on first and subsequent rates of coronary and other occlusive vascular events will be available for presentation.
OBJECTIVETo compare estimates of cardiac baroreceptor sensitivity (BRS) obtained by the Finapres device and from the direct measurement of arterial blood pressure (ABP) values from the ascending ...aorta, using both spectral analysis and sequence analysis.
DESIGNA cohort study of 45 coronary artery disease patients undergoing routine percutaneous coronary procedures.
METHODSContinuous supine recordings of resting ABP in the finger (Finapres), ascending aorta (Millar catheter-tip transducer) and electrocardiogram were obtained. Beat-to-beat values of systolic ABP (Finapres and aortic) and R–R interval were used to estimate the cardiac BRS from spontaneous sequences and by spectral analysis, using the alpha index for the low-frequency band (0.05–0.15 Hz). The influence of β-blockers on BRS estimates was also investigated.
RESULTSNo significant difference was observed between estimates of BRS derived from the Finapres (BRSFIN) and aortic ABP (BRSAO) by the spectral analysis method (Finapres bias 0.30 ± 2.52 ms/mmHg). For sequence analysis, BRSFIN was significantly higher than BRSAO (7.80 ± 4.52 versus 6.44 ± 3.46 ms/mmHg), but the bias (1.36 ± 3.10 ms/mmHg) was not significantly different from spectral analysis. No significant differences in BRS were found between β-blocker users (n = 24) and non-users (n = 10) for either the processing method or source of ABP recording.
CONCLUSIONSpectral analysis of cardiac BRS showed a better agreement between estimates obtained from the Finapres and aortic ABP.
Findings from cardiovascular outcome trials suggest that treatment with fenofibrate may reduce the progression of diabetic retinopathy. However, no dedicated large-scale randomised trials have yet ...investigated this hypothesis.
LENS is a streamlined randomised double-masked placebo-controlled trial, based in Scotland, assessing whether treatment with fenofibrate (145 mg tablet daily or, in the context of impaired renal function, on alternate days) in people with early retinopathy reduces progression to referable diabetic retinopathy (defined in NHS Scotland's Diabetic Eye Screening grading scheme as referable background or proliferative retinopathy, or referable maculopathy in either eye) or treatment with retinal laser, intravitreal injections or vitrectomy. Adults with diabetes mellitus and non-referable retinopathy (mild background retinopathy in both eyes or observable background retinopathy in one/both eyes at the most recent NHS retinal screening assessment; or observable maculopathy in one/both eyes in the previous 3 years) were eligible. Potential participants were identified from routinely collected healthcare data and followed up using regular contact from the research team and linkage to national electronic morbidity, mortality, biochemistry and retinal screening records. Study treatment was mailed to participants.
Between 18 September 2018 and 27 July 2021, 1151 participants were randomised. Their mean age was 61 (SD 12) years, 312 (27%) were female and 305 (26%) had type 1 diabetes. 96% had bilateral mild background retinopathy and 10% had observable maculopathy.
LENS will provide a robust evaluation of the efficacy of treating people at risk of progression of diabetic retinopathy with fenofibrate. Results are anticipated in mid-2024.
NCT03439345; ISRCTN15073006; EuDRACT 2016-002656-24.
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