David Preiss

Aims: The LENS trial demonstrated that fenofibrate slowed the progression of diabetic retinopathy compared to placebo in participants with early diabetic eye disease. We assessed its cost‐effectiveness for reducing the progression of diabetic retinopathy versus standard care from a UK National Health Service perspective.Methods: Resource use and outcome data were collected over follow‐up for participants enrolled in LENS. Mean costs were compared at 2 years and per 6‐month follow‐up (median 4.0 years). Within the trial, cost‐effectiveness was assessed in terms of the incremental cost per case of referable disease averted. A microsimulation model, with inputs derived primarily from LENS trial data, was used to assess the incremental cost per quality‐adjusted life year (QALY).Results: Fenofibrate resulted in a mean (95% confidence interval) reduction in health service costs of ‐£254 (−1062 to 624) at 2 years and ‐£101 (−243 to 42) per 6‐month follow‐up. This was accompanied by a 4.4% (1.3% to 8.0%) absolute reduction in any referable diabetic retinopathy or treatment thereof at 2 years, and a 27% (9%–42%) relative reduction over follow‐up. Modelled over 10 years, fenofibrate use cost an additional £6 per patient for an expected QALY gain of 0.02, costing £406 per QALY versus standard care under base case assumptions. The probability of cost‐effectiveness varied from 70% to 79% at a threshold of £20,000 per QALY, depending on the price discount applied to anti‐VEGF drugs.Conclusions: Fenofibrate is likely to offer a cost‐effective treatment for slowing the progression of diabetic retinopathy in people with early to moderate diabetic retinopathy or maculopathy.

Key Points: Frailty, multimorbidity, and polypharmacy overlap and are associated with higher risk of adverse health outcomes in CKD. Empagliflozin was safe, well tolerated, and effectively reduced cardiorenal and hospitalization risk irrespective of these characteristics. Absolute benefits appeared greater in the most frail participants in this post hoc analysis of EMPA-KIDNEY. Background: Sodium-glucose cotransporter-2 inhibitors are recommended treatment for adults with CKD, but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk–benefit profile in a post hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. Methods: The EMPA-KIDNEY trial randomized 6609 patients with CKD (eGFR ≥20 to 2, or ≥45 to 2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed them for 2 years (median). Additional characteristics analyzed in subgroups were multimorbidity, polypharmacy, and health-related quality of life at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. Results: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility, and diabetes and then eGFR and other comorbidities. Empagliflozin was generally well tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio, 0.72; 95% confidence interval, 0.64 to 0.82) and all-cause hospitalization by 14% (hazard ratio, 0.86; 95% confidence interval, 0.78 to 0.95), with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy, or health-related quality of life. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. Conclusions: These findings support the use of sodium-glucose cotransporter-2 inhibitors in CKD, irrespective of frailty, multimorbidity, or polypharmacy. Clinical Trial registration number: NCT03594110. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2024_09_23_CJASNSeptember19992.mp3

Background Low physical activity (PA) has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported PA measures. This report aims to investigate the relationship of PA with NAFLD using accelerometer-derived step count from a large prospective cohort study. Methods The wrist-worn accelerometer sub-study of the UK Biobank (N=∼100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. Results Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000 step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%–14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%–7%) lower risk. There was evidence for some mediation by adiposity. Conclusion Physical activity, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.

Significance Statement: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived “Fluid Overload” at recruitment. Empagliflozin induced a prompt and sustained reduction in “Fluid Overload,” irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. Background: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived “Fluid Overload” and adiposity in a CKD population. Methods: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute “Fluid Overload” (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. Results: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute “Fluid Overload” was 0.4±1.7 L. Compared with placebo, the overall mean absolute “Fluid Overload” difference among those allocated empagliflozin was −0.24 L (95% confidence interval [CI], −0.38 to −0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of −0.49 L (95% CI, −0.69 to −0.30, including the −0.24 L “Fluid Overload” difference) and a −0.30 L (95% CI, −0.57 to −0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (−0.28 kg [95% CI, −1.41 to 0.85]). The between-group difference in weight was −0.7 kg (95% CI, −1.3 to −0.1). Conclusions: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. Trial Registration: Clinicaltrials.gov: NCT03594110; EuDRACT: 2017-002971-24 (https://eudract.ema.europa.eu/).

Background Antiplatelet therapy (APT) can substantially reduce the risk of further vascular events in individuals with established atherosclerotic cardiovascular disease (ASCVD). However, knowledge regarding the extent and determinants of APT use is limited. Objectives Estimate the extent and identify patient groups at risk of suboptimal APT use at different stages of the treatment pathway. Methods Retrospective cohort study using linked NHS Scotland administrative data of all adults hospitalised for an acute ASCVD event (n=150 728) from 2009 to 2017. Proportions of patients initiating, adhering to, discontinuing and re-initiating APT were calculated overall and separately for myocardial infarction (MI), ischaemic stroke and peripheral arterial disease (PAD). Multivariable logistic regression and Cox proportional hazards models were used to assess the contribution of patient characteristics in initiating and discontinuing APT. Results Of patients hospitalised with ASCVD, 84% initiated APT: 94% following an MI, 83% following an ischaemic stroke and 68% following a PAD event. Characteristics associated with lower odds of initiation included female sex (22% less likely than men), age below 50 years or above 70 years (aged Conclusions APT use remains suboptimal for the secondary prevention of ASCVD, particularly among women and older patients, and following ischaemic stroke and PAD hospitalisations.

Objective To estimate the extent of suboptimal statin use for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD) at different stages of the treatment pathway and identify patient groups at risk of suboptimal treatment. Methods National retrospective cohort study using linked National Health Service Scotland administrative data of adults hospitalised for an ASCVD event (n=167 978) from 2009 to 2017. Proportions of patients initiating, adhering to, discontinuing and reinitiating statins were calculated. We separately examined treatment following myocardial infarction (MI), ischaemic stroke and peripheral arterial disease (PAD) hospitalisations. Multivariable logistic regression and Cox proportional hazards models were used to assess the roles of patient characteristics in the likelihood of initiating and discontinuing statins. Results Of patients hospitalised with ASCVD, only 81% initiated statin therapy, 40% of whom used high-intensity statin. Characteristics associated with lower odds of initiation included female sex (28% less likely than men), age below 50 years or above 70 years (Conclusions Statin use remains suboptimal for the secondary ASCVD prevention, particularly in women and older patients, and following ischaemic stroke and PAD hospitalisations. Improving this would offer substantial benefits to population health at low cost.

Background: Cholesterol guidelines typically prioritize primary prevention statin therapy based on 10-year risk of cardiovascular disease. The advent of generic pricing may justify expansion of statin eligibility. Moreover, 10-year risk may not be the optimal approach for statin prioritization. We estimated the cost-effectiveness of expanding preventive statin eligibility and evaluated novel approaches to prioritization from a Scottish health sector perspective. Methods: A computer simulation model predicted long-term health and cost outcomes in Scottish adults aged ≥40 years. Epidemiologic analysis was completed using the Scottish Heart Health Extended Cohort, Scottish Morbidity Records, and National Records of Scotland. A simulation cohort was constructed with data from the Scottish Health Survey 2011 and contemporary population estimates. Treatment and cost inputs were derived from published literature and health service cost data. The main outcome measure was the lifetime incremental cost-effectiveness ratio (ICER), evaluated as cost (GBP 2020) per quality-adjusted life year (QALY) gained. Three approaches to statin prioritization were analyzed: 10-year risk scoring using the ASSIGN score, age-stratified (Age-Strat) risk thresholds to increase treatment rates in younger individuals, and absolute risk reduction (ARR)-guided therapy to increase treatment rates in individuals with elevated cholesterol levels. For each approach, two policies were considered: one which treats the same number of individuals as an ASSIGN score ≥20% (ASSIGN 20, Age-Strat 20, ARR 20) and one which treats the same number as an ASSIGN score ≥10% (ASSIGN 10, Age-Strat 10, ARR 10). Results: Compared to ASSIGN 20, reducing the risk threshold for statin initiation to 10% expanded eligibility from 804,000 (32% of CVD-free adults aged ≥40 years) to 1,445,500 individuals (58%). This policy would be cost-effective (ICER: £12,300/QALY, 95% CI: £7,690/QALY-£26,500/QALY). Incremental to ASSIGN 20, ARR 20 produced around 8,800 QALYs and was cost-effective (£7,050/QALY, 95% CI: £4,560/QALY-£10,700/QALY). Incremental to ASSIGN 10, ARR 10 produced around 7,950 QALYs and was cost-effective (£11,700/QALY, 95% CI: £9,250/QALY-£16,900/QALY). Both age-stratified risk threshold strategies were dominated (i.e., more expensive and less effective than alternative treatment strategies). Conclusions: Generic pricing has rendered preventive statin therapy cost-effective for many adults. Absolute risk reduction-guided therapy is more effective than 10-year risk scoring and is cost-effective.

Diabetic eye disease (retinopathy and maculopathy) remains a leading cause of blindness and impaired vision, and it is also the only major cause that is increas