Ajay Kumar Gupta

Importance: Randomised-controlled trials (RCTs) suggest glucagon-like-peptide-1 receptor agonists (GLP-1RAs) reduce the risk of stroke in type 2 diabetes (T2DM); however, the mechanisms remain unclear. If benefits were driven principally by blood pressure (BP) lowering, similar effects on cognitive impairment may be expected. Evaluating data from trials with robust ascertainment and prespecified stroke and/or cognitive outcomes may provide greater clarity. Objective: To confirm the effect of GLP-1RAs on stroke risk in RCTs with prespecified, adjudicated stroke endpoints; to explore whether risk reduction is associated with trial-level changes in systolic BP (SBP), glycated haemoglobin (HbA1c), or body weight; to establish whether a parallel cognitive signal exists. Data Sources: PubMed, Cochrane, Embase, and CINAHL, from inception to August 2026 (PROSPERO CRD420261305938). Study Selection: RCTs comparing GLP-1RAs with placebo/usual care in adults, with ≥12 months follow-up, and prespecified stroke and/or cognitive outcomes. Data Extraction and Synthesis: Hazard ratios (HRs) for stroke were pooled using inverse-variance random-effect meta-analysis. Univariable meta-regression related logHR for stroke to trial-level between-group differences in SBP, HbA1c and weight, with permutation-based inference and leave-one-out sensitivity analyses. The pooled effect was benchmarked against that predicted from achieved SBP differences. Heterogeneous cognitive outcomes were synthesized narratively. Main Outcomes and Measures: Adjudicated stroke events and prespecified cognitive endpoints. Results: Among 7 RCTs (n=50,617), GLP-1RA therapy was associated with 17% lower stroke risk (pooled HR 0.83; [95% CI 0.75-0.92]; p<.001). Meta regression showed an association with SBP (β = 0.371; [95% CI 0.013-0.729]; p=.043), but not HbA1c (0.432; [-0.064-0.928]; p=.088) or weight (0.109; [-0.038-0.256]; p=.148). The mean between-group SBP difference (∼1.45 mmHg) predicts a stroke reduction of roughly 4%, versus the 17% observed, leaving approximately three quarters of the log-effect unexplained by BP lowering. Four trials (n=4,206) in established neurodegenerative disease showed no cognitive benefit. Conclusions and Relevance: GLP-1RA therapy reduces stroke risk by 17% among individuals with T2DM at high cardiovascular risk, a benefit not fully accounted for by conventional cardiometabolic risk factor change. Additional mechanisms warrant evaluation. The absence of cognitive signal suggests the benefit may have cerebrovascular origin, but whether GLP-1RAs prevent vascular cognitive impairment in cardiometabolic populations remains untested.

Background: Despite the broad availability of antihypertensive drugs, approximately 40% of hypertensive patients fail to achieve the recommended blood pressure (BP) levels and may require alternative treatment(s). At present, renal denervation is the only proven non-pharmacological device-based alternative treatment available, but it is a costly, invasive, hospital-based procedure that is unlikely to be widely available. Transcutaneous autonomic neuromodulation (tAN)—if shown to be safe, acceptable, and efficacious—can offer a non-invasive, inexpensive, self-administered device-based innovative adjunct or alternative to pharmacological therapy. Methods: SCRATCH-HTN is a double-blind, sham-controlled trial, with 63 participants randomised on a 2:1 basis to receive either tAN or sham-tAN treatment. Hypertensive patients on medication were included if they had elevated systo-diastolic BPs on daytime ambulatory BP monitoring (ABPM) [systolic BP (SBP) of ≥135 and <170 mmHg and mean daytime diastolic BP (DBP) of ≥85 and <115 mmHg]. Participants were trained to self-administer tAN therapy for 30 min every day for first 14 days and then once a week for 10 weeks. The primary endpoint was change in daytime ambulatory SBP from baseline to 3 months. Secondary endpoints included change in 24-h ambulatory and office SBP and DBP, BP variability, heart rate variability, quality of life, and sleep quality from baseline to end of treatment. Other exploratory outcomes included evaluation of impact on functional exercise (6-min walk test), structural and functional changes in the heart, cognitive function, and central blood pressures. A subgroup of patients underwent detailed autonomic functional assessment at the start and end of the study. Conclusion: The SCRATCH-HTN trial is a phase 2a study testing the safety, acceptability, and potential efficacy of tAN treatment for improving blood pressure control in patients with elevated BP despite medication. It also explores the effects of tAN on sleep, exercise tolerance, heart rate variability, central BP, cardiac structure, and autonomic function. If effective, it could offer a transformative approach to hypertension management. Study Protocol Registration: Clinicaltrials.gov , identifier NCT05179343 and ISRCTN (14509154).

Aims/Introduction: At least a quarter of acute stroke and myocardial infarction (MI) survivors experience subsequent major depressive disorder, which adversely impacts adherence to secondary prevention strategies and is associated with a reduced quality of life and increased risk of recurrence of cardiovascular event and mortality. Purpose: To provide a comprehensive review of evidence from randomized controlled trials (RCTs) evaluating pharmacological and non-pharmacological interventions to help mitigate depression after non-fatal stroke or MI. Methods and results: PubMed database was searched on 17 April 2025 for all trials evaluating the efficacy of interventions to help treat depression amongst those with recent stroke or MI and have reported effects on depressive symptoms (as a primary outcome) using validated tools. Studies were included if RCT design and if intervention duration were 4 weeks or longer, compared against routine care/no active treatment, and published since 1st January 2000. Risk of bias was assessed using Cochrane Risk of Bias tool. 53 RCTs were included. 44 studies were in post-stroke patients, and 9 were in post-MI patients. 16 evaluated pharmacological and 37 evaluated non-pharmacological (sub-divided into 8 types) interventions. The findings suggest that some selective-serotonin reuptake inhibitors (escitalopram) and serotonin–norepinephrine reuptake inhibitors (duloxetine, milnacipran) are effective in reducing severity of depression amongst stroke survivors. Non-pharmacological interventions such as psychological interventions (e.g. behavioural therapies), device-based stimulation (vagus nerve, transcranial), and some physical activity/exercise interventions appear efficacious in those with recent stroke but there is a substantial evidence gap for the efficacy of these interventions amongst MI survivors. Conclusion(s): A holistic, multidisciplinary, and tailored approach encompassing pharmacological treatments together with non-pharmacological interventions (psychological therapy, device-based stimulation, and physical activity/exercise) is beneficial in reducing depression severity or risk amongst those with recent stroke, but there is a lack evidence for the long-term efficacy amongst those with recent MI. Registration: The study and its protocol were registered in PROSPERO (CRD420251028582).

There is limited evidence of the strategies to mitigate burnout among all health care professionals (HCPs). To evaluate the effectiveness of all interventions to mitigate burnout among HCPs. PubMed and Scopus (up to 14 May 2025). Independent study selection (2 people) of randomized controlled trials (RCTs) and cluster RCTs of interventions to mitigate burnout (vs. no active intervention) among HCPs. Independent extraction with validation by second reviewer. Continuous data for burnout outcomes extracted for emotional exhaustion (EE), depersonalization, personal accomplishment (PA), and single-concept burnout measurement. Separate random-effects models were stratified by role. 93 RCTs and 6 cluster RCTs evaluating individual-level interventions were included (9330 participants). Among physicians, professional coaching was probably effective in reducing some aspects of burnout (EE standardized mean difference [SMD], -0.37 [95% CI, -0.62 to -0.13], low certainty; and depersonalization SMD, -0.30 [CI, -0.42 to -0.19], moderate certainty), but mindfulness-based interventions may not be effective (EE SMD, -0.46 [CI, -1.28 to 0.35], very low certainty; depersonalization SMD, -0.09 [CI, -0.30 to 0.12], moderate certainty). However, mindfulness-based interventions may reduce burnout among nurses and midwives (EE SMD, -0.90 [CI,-1.46 to -0.34], low certainty) and among a mixture of HCP roles (EE SMD, -0.40 [-0.65 to -0.16], low certainty; depersonalization SMD, -0.33 [CI, -0.53 to -0.14], low certainty; and PA SMD, 0.48 [CI, 0.29 to 0.67], moderate certainty). Mindfulness-based and professional coaching interventions were generally more than 4 weeks in duration. Most trials were unblinded with subjective outcomes. There was substantial heterogeneity among interventions and populations despite stratifying by role. Although mindfulness-based interventions may reduce burnout in nurses and midwives and among a mixture of HCPs, professional coaching probably reduces burnout among physicians, particularly when sustained for more than 4 weeks. Barts Charity. (PROSPERO: CRD42024552385).

Background: Despite the broad availability of antihypertensive drugs, approximately 40% of hypertensive patients fail to achieve the recommended blood pressure (BP) levels and may require alternative treatment(s). Currently, renal denervation is the only proven non-pharmacological device-based alternative treatment available but is a costly hospital-based invasive procedure that is unlikely to be widely available. Transcutaneous autonomic neuromodulation (tAN), if safe, acceptable and efficacious, can offer a non-invasive, inexpensive, self-administered device-based innovative adjunct or alternative to pharmacological therapy. Methods: SCRATCH-HTN is a double-blind, sham-controlled trial, with 63 participants randomised on a 2:1 basis to receive either tAN or sham-tAN treatment. Hypertensive patients on medications were included if they had elevated systo-diastolic BPs on daytime ambulatory BP monitoring (ABPM) (systolic BP (SBP) of ≥135 and <170 mmHg and mean daytime diastolic BP (DBP) of ≥85 and < 115 mmHg). Participants were trained to self-administer tAN therapy for 30 minutes every day for first 14 days, and then once a week for 10 weeks. The primary endpoint was the change in daytime ambulatory SBP from baseline to 3 months. Secondary endpoints included the change in 24-hour ambulatory and office SBP and DBP, BP variability, heart rate variability, quality of life, and sleep quality from baseline to end-of-treatment. Other exploratory outcomes included evaluation of impact on functional exercise (6-minute walk test), structural and functional changes in the heart, cognitive function and central blood pressures. In a subgroup of patients detailed autonomic functional assessment was conducted at the start and end of the study. Conclusion: The SCRATCH-HTN trial is a phase 2a study testing the safety, acceptability, and potential efficacy of tAN treatment for improving blood pressure control in patients with elevated BP despite medication. It also explores tAN’s effects on sleep, exercise tolerance, heart rate variability, central BP, cardiac structure, and autonomic function. If effective, it could offer a transformative approach to hypertension management. Registration: clinicaltrials.gov ( NCT05179343 ).

Objective: To determine the annual trends over two decades in hypertension diagnosis, true hypertension prevalence, and control and use of antihypertensive drugs in England. Design: Annual, representative, nationwide Health Surveys for England from 2003 to 2021. Setting: Nationally representative sample consisting of participants from private households, identified through stratified, national, multistage sampling. Participants: 67 242 people older than 16 years surveyed between 2003 and 2021. Results: Between 2003 and 2021, the prevalence of measured hypertension decreased significantly from 37.8% in 2003 to 33.2% in 2018 (average annual percentage change (AAPC) −0.9%, 95% confidence interval −1.6% to −0.6%). Mean population systolic and diastolic blood pressure decreased significantly between 2003 to 2019 (systolic blood pressure from 128.7 to 124.0 mm Hg, AAPC −0.15%, −0.21% to −0.11%; diastolic blood pressure from 73.7 to 71.8 mm Hg, AAPC −0.12%, −0.20% to −0.04%). The prevalence of those with undiagnosed hypertension in the community decreased from 32.6% in 2003 to 23.7% in 2011, gradually worsening thereafter, with a steep increase in 2021 when 32.4% of those with hypertension were undiagnosed (AAPC −1.04%, −1.92% to −0.22%). Among people diagnosed (known) with hypertension, the proportion of those with blood pressure controlled to target increased across the study period (AAPC 1.66%, 0.04% to 2.27%), but this was mainly driven by the significant increase from 47.3% in 2003 to 56.5% in 2009 (AAPC 3.62%, 1.52% to 5.74%). A plateau was observed from 2011 onwards when there was no further significant improvement in the proportion of people with diagnosed (known) hypertension and blood pressure controlled to target. People with diagnosed (known) but uncontrolled hypertension showed a small but significant decrease in the mean number (standard deviation) of antihypertensive drugs used during the study period from 2.17 (0.86) in 2003 to 2.14 (0.96) in 2021 (AAPC −0.18%, −0.68% to −0.03%). Those with diagnosed (known) and controlled hypertension had no significant change in the mean number of drugs used. Conclusions: These findings indicate that there was a significant improvement in hypertension prevalence and control in the 2000s, with a plateau after 2011. The prevalence of undiagnosed hypertension in the community reduced in the early 2000s and 2010s, but has since returned to the same level as two decades ago.

Background Current guidelines recommend a blood pressure (BP) goal ≤130/80 mm Hg in peripheral artery disease (PAD) even though few PAD patients were enrolled in the landmark BP-lowering trials. Moreover, intensive BP control can worsen limb perfusion and none of the trials adjudicated limb events. Methods Using data from a longitudinal registry of US Veterans, we identified 91,296 patients (>2.7 million BP values) with a new diagnosis of PAD during 2015-2020. Multivariable Cox regression models evaluated the association between longitudinal BP values (time-varying exposure) and risk of cardiovascular (CV: myocardial infarction, stroke) and limb (chronic limb threatening ischemia, major amputation) events. Results Mean age was 70.5 years, 97.3% were men and 18.5% were Black race. At baseline, the mean (SD) systolic BP was 133 (19) mm Hg and diastolic BP was 73 (11) mm Hg. Over a median 4.1 years, the incidence of CV and limb events was 4.6 per-100 patient-years and 5.0 per 100-patient-years, respectively. In adjusted Cox models, systolic BP ≥140 mm Hg was strongly associated with higher risk of CV events with increasing risk across BP categories (130-139 mm Hg [reference]; 140-149 mm Hg: hazard ratio [HR]: 1.28 [95%CI: 1.16-1.41]; 150-159 mm Hg: HR 1.54 [1.39-1.72]; >160 mm Hg: 2.22 [2.02-2.44]). However, there was no association between systolic BP below 130 mm Hg and risk of CV events. In contrast, the association between systolic BP and limb events was U-shaped with the highest hazard of limb events at both low (Conclusion Current recommendations for BP goal in PAD patients are associated with optimizing risk of CV events but associated with a higher risk of limb events. Our findings highlight the need to better define BP goals for PAD patients, especially those at an increased risk of limb events.