Background COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness.Methods DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593.

'The extent to which an individual's medication-taking behaviour and/or execution of lifestyle changes, corresponds with agreed recommendations from a healthcare provider', is a highly complex behaviour, defined as adherence. However, intentional non-adherence is regularly observed and results in negative outcomes for patients along with increased healthcare provision costs. Whilst this is a consistent issue amongst adults of all ages, the burden of chronic disease is greatest amongst older adults. As a result, the absolute prevalence of intentional non-adherence is increased in this population. This non-systematic review of intentional non-adherence to medication highlights the extent of the problem amongst older adults. It notes that age, per se, is not a contributory factor in intentionally non-adherent behaviours. Moreover, it describes the difference in methodology required to identify such behaviours in contrast to reports of non-adherence in general: the use of focus groups, semi-structured, one-to-one interviews and questionnaires as opposed to pill counts, electronic medication monitors and analysis of prescription refill rates. Using Leventhal's Common-Sense Model of Self-Regulation, it emphasizes six key factors that may contribute to intentional non-adherence amongst older adults: illness beliefs, the perceived risks (e.g. dependence, adverse effects), benefits and necessity of potential treatments, the patient-practitioner relationship, inter-current physical and mental illnesses, financial constraints and pharmaceutical/pharmacological issues (poly-pharmacy/regimen complexity). It describes the current evidence for each of these aspects and notes the paucity of data validating Leventhal's model in this regard. It also reports on interventions that may address these issues and explicitly acknowledges the lack of evidence-based interventions available to healthcare practitioners. As a result, it highlights five key areas that require urgent research amongst older adults: (1) the overlap between intentional and unintentional non-adherence, particularly amongst those who may be frail or isolated; (2) the potential correlation between symptomatic benefit and intentional vs. unintentional non-adherence to medication; (3) an evaluation of the source of prescribing (i.e. a long-standing provider vs. an acute episode of care) and the patient-prescriber relationship as determinants of intentional and unintentional non-adherence; (4) the decision-making processes leading to selective intentional non-adherence amongst older adults with multiple medical problems; and (5) the development and evaluation of interventions designed to reduce intentional non-adherence, specifically addressing each of the aspects listed above.

Aims Coronavirus disease 2019 (COVID‐19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium‐glucose cotransporter‐2 inhibitor, has shown significant cardio‐ and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high‐risk patients with COVID‐19. Materials and methods DARE‐19 (NCT04350593) is an investigator‐initiated, collaborative, international, multicentre, randomized, double‐blind, placebo‐controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all‐cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID‐19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID‐19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all‐cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID‐19 will be assessed. Conclusions DARE‐19 will evaluate whether dapagliflozin can prevent COVID‐19‐related complications and all‐cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE‐19 is the first large randomized controlled trial investigating use of sodium‐glucose cotransporter 2 inhibitors in patients with COVID‐19.

BackgroundEthnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a “black versus white” approach; in doing so, they ignore the United Kingdom's largest ethnic minority: Asians from South Asia.Study designThe primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual therapy on the basis of self-defined ethnicity. A multicenter, prospective, open-label, randomized study with 2 parallel, independent trial arms (mono- and dual therapy), AIM-HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3-treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3-period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4-treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4-period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure.ConclusionAIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first- and second-line antihypertensive therapies for multiethnic populations.

Background and objectivesPatients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR.Design, setting, participants, & measurementsThe DARE-19 trial randomized 1250 patients who were hospitalized (231 [18%] had eGFR <60 ml/min per 1.73 m2) with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. Dual primary outcomes (time to new or worsened organ dysfunction or death, and a hierarchical composite end point of recovery [change in clinical status by day 30]), and the key secondary kidney outcome (composite of AKI, KRT, or death), and safety were assessed in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2.ResultsThe effect of dapagliflozin versus placebo on the primary prevention outcome (hazard ratio, 0.80; 95% confidence interval, 0.58 to 1.10), primary recovery outcome (win ratio, 1.09; 95% confidence interval, 0.97 to 1.22), and the composite kidney outcome (hazard ratio, 0.74; 95% confidence interval, 0.50 to 1.07) were consistent across eGFR subgroups (P for interaction: 0.98, 0.67, and 0.44, respectively). The effects of dapagliflozin on AKI were also similar in participants with eGFR <60 ml/min per 1.73 m2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m2 (hazard ratio, 0.69; 95% confidence interval, 0.37 to 1.29). Dapagliflozin was well tolerated in participants with eGFR <60 and ≥60 ml/min per 1.73 m2.ConclusionsThe effects of dapagliflozin on primary and secondary outcomes in hospitalized participants with COVID-19 were consistent in those with eGFR below/above 60 ml/min per 1.73 m2. Dapagliflozin was well tolerated and did not increase the risk of AKI in participants with eGFR below or above 60 ml/min per 1.73 m2.

Prescribing for older adults represents a signifi cant challenge as the UK population ages. Physiological decline and the rising prevalence of frailty increase the likelihood of altered pharmacodynamics and pharmacokinetics, suboptimal prescribing and adverse effects among this growing cohort of the population. In the fi rst of two articles, we begin by considering these issues and posit four key questions which should be considered when prescribing for older adults. Does this agent refl ect the priorities of the patient? Are there alternatives -with greater effi cacy, effectiveness or tolerability -that might be considered? Are the dose, frequency and formulation appropriate? How does this prescription relate to concurrent medication? We also describe current drug therapies in two disease states with a predilection for older adults: Alzheimer's disease (AD) and osteoporosis. Using these examples we highlight the limitations of evidencebased medicine and guidelines in this cohort of the population, illustrating the reliance on sub-group analysis to demonstrate the effi cacy of drug therapies for older adults in osteoporosis and the underutilisation of appropriate treatments for patients with AD as a result of fl awed guidelines.

In this, the second of two articles, we continue our evaluation of drug therapies in older adults. Having previously described the pharmacokinetic and pharmacodynamic consequences of physiological ageing, along with the challenge of appropriate prescribing, we proposed four key questions which should be considered when prescribing for this cohort of the population. Does this agent refl ect the priorities of the patient? Are there alternatives -with greater effi cacy, effectiveness or tolerability -that might be considered? Are the dose, frequency and formulation appropriate? How does this prescription relate to concurrent medication? We also highlighted the reliance on subgroup analysis to demonstrate the effi cacy of drug therapies for older adults in osteoporosis and the underutilisation of appropriate treatments for patients with Alzheimer's disease as a result of fl awed guidelines. Here we describe current drug therapies in systolic heart failure, noting the limited inclusion of older adults in key trials, while also reviewing the pharmacological treatment of orthostatic hypotension. In doing so, we advocate the intermittent use of midodrine as a fi rst-line treatment for orthostasis in older adults, counter to the generic guidelines produced by various learned societies, but in keeping with the scant trial data available.

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.