Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major cardiovascular events among individuals with heart failure regardless the ejection fraction. The effect of SGLT2 inhibitors on health-related quality of life (HRQoL) and physical capacity are still unclear.

To investigate the effects of SGLT2 inhibitors on HRQoL and physical capacity in patients with heart failure.

We systematically searched PubMed, Embase, and Cochrane Central databases for randomized controlled trials (RCTs) comparing SGLT2 inhibitors to placebo in this population. The outcomes analyzed were mean changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and its domains: total symptoms score (TSS), physical limitations score (PLS), clinical summary score (CSS) and overall summary score (OSS), as well as the six-minute walk test (6MWT) and peak oxygen uptake (peak VO2).

Eighteen RCTs with 23,848 participants were included. There was a statistical significant improvement in KCCQ TSS (MD: 3.33; 95% CI 1.84 to 4.81; p < 0.001) in HFrEF, HFpEF and non-diabetic subgroups. Consistent findings were found in KCCQ PLS, KCCQ CSS, and KCCQ OSS. The distance covered in the 6MWT was significant higher (MD: 12.8; 95% CI 1.06 to 24.54; p = 0.03) and peak VO2 was increased (MD: 1.06; 95% CI 0.57 to 1.55; p < 0.001).

SGLT2 inhibitors improve HRQoL and functional capacity in patients with HF regardless the ejection fraction and co-diagnosis of diabetes.

Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.

Background/Objectives: Emerging evidence suggests an association between glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors with altered risk of damage in the inner ear system. However, limited research exists on the relationship between these medications and subsequent irreversible hearing loss. We conducted this network meta-analysis (NMA) to evaluate the comparative risk of hearing loss associated with such medications. Methods: In this NMA, we used a confirmatory approach to specifically focus on particular adverse effects of interest (i.e., incidence of hearing loss here) based on the Cochrane recommendation. A Bayesian-based NMA of randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors was conducted. The primary outcome was the hearing loss events. Results: Our NMA of 29 RCTs with 145,895 participants found that only two exendin-4 derivatives-lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week)-showed increased hearing loss events compared to controls. No other GLP-1 receptor agonists or SGLT2 inhibitors demonstrated significantly elevated hearing loss risk. Lixisenatide ranked highest in risk among all investigated regimens. Conclusions: This comprehensive NMA identifies a significant association between exendin-4 derivatives (lixisenatide and efpeglenatide) and potential ototoxicity. Clinicians should carefully consider this potential ototoxicity when prescribing exendin-4 derivatives, particularly in patients with pre-existing hearing loss risk factors.

Cellular senescence is the permanent cessation of cell proliferation and growth. Senescent cells accumulating in tissues and organs with aging contribute to many chronic diseases, mainly through the secretion of a pro-inflammatory senescence-associated secretory phenotype (SASP). Senotherapeutic (senolytic or senomorphic) strategies targeting senescent cells or/and their SASP are being developed to prolong healthy lifespan and treat age-related pathologies. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that promote the renal excretion of glucose, resulting in lower blood glucose levels. Beyond their glucose-lowering effects, SGLT2 inhibitors have demonstrated protective effects against cardiovascular and renal events. Moreover, SGLT2 inhibitors have recently been associated with the inhibition of cell senescence, making them a promising therapeutic approach for targeting senescence and aging. This review examines the latest research on the senotherapeutic potential of SGLT2 inhibitors.

Cardiac fibrosis and remodeling are critical contributors to heart failure, particularly in the context of diabetes, where hyperglycemia (HG) exacerbates pathological fibroblast activity. Despite the known cardiovascular benefits of canagliflozin (CANA), its specific effects on human cardiac fibroblasts (HCFs) under HG conditions remain unexplored. We investigated whether CANA could mitigate HG-induced detrimental responses in HCFs. Dose-response assays revealed that 100 nM CANA significantly reduced HG-induced proliferation and migration of HCFs. Furthermore, CANA attenuated mitochondrial reactive oxygen species (ROS) production, a key driver of myofibroblast differentiation, and suppressed HG-induced expression of SMAD2, a critical activator of cardiac fibroblasts. Additionally, HG disrupted calcium (Ca2+) homeostasis, which was ameliorated by CANA treatment. These findings collectively demonstrate that CANA exerts protective effects on HCFs by improving mitochondrial function, restoring Ca2+ handling, and reducing fibroblast proliferation, migration, and activation under HG conditions.

Heart failure is a growing health-care concern affecting tens of millions of individuals globally. Although traditional therapeutic strategies have focused on reducing the risk for hospitalization and mortality, the importance of patient-reported outcomes (PROs) in patients with heart failure is increasingly being recognized. Regulatory agencies consider PROs part of their evaluation of drugs and devices, and professional society guidelines may recommend interventions that improve PROs. However, for several reasons, the effect of interventions on PROs reported in heart failure trials currently is difficult to interpret. There is no consensus on the timing and frequency of PRO assessments. Moreover, it has been difficult to establish a minimal clinically important difference, that is, the minimal change in a PRO score that is meaningful to a patient. In addition, traditional methods of analyzing and reporting PROs such as comparison of mean differences across groups or responder analysis are prone to statistical artifacts and misinterpretation. This article presents an in-depth discussion of these issues, with the Kansas City Cardiomyopathy Questionnaire used as an example, to facilitate the use of PROs in heart failure research, regulatory, and clinical settings.

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies.

We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA.

Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.

This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease.

PROSPERO CRD42021252381.

Early initiation of empagliflozin, a sodium-glucose cotransporter 2 inhibitor, in acute heart failure (AHF) patients increases urine output, reduces hospital stays, and enhances quality of life post-hospital discharge.

This trial aims to investigate the effectiveness and safety of early canagliflozin initiation compared to empagliflozin in hospitalized AHF patients with volume overload.

This was a multicenter, prospective, open-labeled, randomized equivalence trial. AHF diabetic and non-diabetic patients were randomized within 24 h from hospital admission to either receive 100 mg canagliflozin or 10 mg empagliflozin in addition to the standardized protocol for an intravenous loop diuretic. The primary outcome was the median of daily diuresis during the hospitalization period.

Hospitalized AHF patients were enrolled (71 patients per group). The median daily diuresis during the hospitalization period was 4200 ml in the canagliflozin group, which was statistically equivalent to empagliflozin (4117 ml) with a difference of 83 ml, which falls within the predefined equivalence margin (±10) % of the median of daily diuresis of empagliflozin; Δ = ±411.7 mL), confirming equivalence via bootstrap TSOT p < 0.001. No difference was observed in diuretic response, dyspnea score, orthodema congestion score or length of hospital stay. The NT-proBNP level at day 30 post-discharge and the change in KCCQ-TSS from baseline to day 90 were statistically comparable between both groups, without differences in safety event incidence.

Canagliflozin could be a part of usual care for hospitalized AHF patients and an alternative to empagliflozin without safety concerns.

Wearable accelerometers allow continuous assessment of physical activity during normal living conditions and may be useful in evaluating the effects of treatment for heart failure. We explored the relationships between accelerometer measures of physical activity and 6-minute walk distance and patient-reported measures of functional limitation in participants across the entire spectrum of left ventricular ejection fraction in the DETERMINE (Dapagliflozin EffecT on ExeRcise capacity using a 6-MINutE walk test in patients with heart failure) trials.

A subgroup of patients in the DETERMINE trials wore a waist-based accelerometer during 7-day periods at 3 points during the trial: between screening and randomization and during weeks 8 and 14. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) at baseline and at weeks 8 and 16.

Of the 817 patients randomized, 319 (39%) had adequate baseline accelerometer data. Patients with lower levels of physical activity had lower (ie, worse) KCCQ scores and 6MWD, higher NT-proBNP levels and BMIs, worse kidney function, and a greater likelihood of diabetes and atrial fibrillation. Baseline accelerometer values had weak correlations with KCCQ summary scores (Pearson r = 0.06-0.21) and weak to moderate correlations with 6MWD (Pearson r = 0.20-0.31). The change from baseline to 16 weeks in accelerometer-measured physical activity correlated weakly with the change in KCCQ summary scores (Pearson r = 0-0.18) and 6MWD (r = 0.01-0.10).

In the DETERMINE trials, accelerometer-based measures of physical activity correlated modestly with KCCQ summary scores and 6MWD. Accelerometer-based assessments of physical activity may provide additional information complementing that obtained from standard measures of functional limitation in patients with heart failure.

SGLT-2 inhibitors, initially developed for type 2 diabetes, demonstrate profound cardiorenal and metabolic benefits. This review synthesizes evidence from clinical trials and mechanistic studies to elucidate their roles in cardiovascular diseases, chronic kidney disease, and non-alcoholic fatty liver disease. Key findings include a notable reduction in cardiovascular death/heart failure hospitalization, a marked decrease in heart failure hospitalization risk, and significant improvements in renal and hepatic outcomes. Emerging mechanisms, such as autophagy induction, ketone utilization, and anti-inflammatory effects, underpin these benefits. Ongoing trials explore their potential in non-diabetic populations, positioning SGLT-2 inhibitors as transformative agents in multisystem disease management.

Currently, there is no relevant study comparing sodium-dependent glucose transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and dipeptidyl peptidase inhibitor (DPP4i) head to head to evaluate their comprehensive impact on heart failure patients.

We conducted a comprehensive literature search across multiple databases. Utilizing the risk of bias tool from the Cochrane Collaboration, the methodological quality of included studies was critically assessed and potential publication bias was examined via funnel plots.

All results are presented as mean difference; 95% confidence interval (MD; 95% CI). The network meta-analysis indicated that in regards to left ventricular function, there is a big difference in the left ventricular ejection fraction (LVEF) of Empagliflozin 25 mg (13.64; 0.26, 27.01) compared to Canagliflozin 100 mg; and significant differences in the left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) of Dapagliflozin 10 mg (-0.76; -1.27, -0.25 and -0.95; -1.86, -0.05), Vildagliptin 50 mg (-1.05; -1.47, -0.63 and -1.12; -2.19, -0.05), and Sitagliptin 100 mg (-1.34; -2.31, -0.38 and -1.89; -3.50, -0.27) compared to Empagliflozin 10 mg. In terms of the quality of life, there are significant differences in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the Quality of life score of Sitagliptin 100 mg (408.08; 213.59, 602.57 and 3.74; 1.57, 5.92) compared to Dapagliflozin 5 mg. In terms of the cardiovascular outcome events, there is a significant difference in the heart failure rehospitalization rate of Dapagliflozin 10 mg (0.45; 0.25, 0.82) and Empagliflozin 10 mg (0.48; 0.28, 0.81) compared to Liraglutide 1.8 mg. Further significant differences are found in the all-cause mortality of Dapagliflozin 10 mg (0.81; 0.66, 0.98) compared to Vildagliptin 50 mg; the cardiovascular death of Albiglutide 30 mg (0.49; 0.28, 0.86) compared to Exenatide 2 mg; and the arrhythmic events of Liraglutide 1.8 mg (0.49; 0.26, 0.90) compared to Empagliflozin 10 mg. The network meta-analysis of SGLT2i, GLP-1RA, and DPP4i as a class of drugs showed that GLP-1RA is superior to SGLT2i in improving LVEF and reducing myocardial infarction/acute coronary syndrome, whereas DPP4i is superior to SGLT2i in improving LVEDV and LVESV.

GLP-1RA is superior to SGLT2i in improving LVEF and reducing myocardial infarction/acute coronary syndrome, whereas DPP4i is superior to SGLT2i in improving LVEDV and LVESV. Key message What is already known on this topic-It has been confirmed that three new hypoglycemic drugs have a protective effect on the cardiovascular system. Studies have shown that sodium-dependent glucose transporter 2 inhibitors (SGLT2i) can improve cardiovascular outcomes and enhance the quality of life of heart failure patients. Currently, SGLT2i is widely used in the clinical treatment of heart failure, and related studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase inhibitor (DPP4i) also play important roles in the treatment of heart failure. What this study adds-However, there is no relevant research on whether these drugs' clinical efficacy is dose-dependent. How this study might affect research, practice, or policy-This study included different doses of hypoglycemic drugs and used a network meta-analysis method to comprehensively evaluate the effects of three hypoglycemic drugs on heart function, quality of life, and prognosis in heart failure patients, providing a basis for clinical practice.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to lower the risk of re-hospitalization and cardiovascular mortality among heart failure (HF) patients. Nevertheless, the impact of these agents on ventricular arrhythmias (VAs) has not been thoroughly investigated. To assess the beneficial impact of SGLT2 inhibitors on VAs in patients at various stages of HF, a systematic review and meta-analysis of randomized controlled trials involving SGLT2 inhibitors in this patient population was performed.

A comprehensive search of the PubMed, Embase, Ovid, ProQuest, Scopus, and Cochrane databases was performed for clinical trials published up to November 21, 2024. The primary outcomes of interest were incidences of VAs and sudden cardiac death (SCD) between the groups receiving SGLT2 inhibitors and the control drugs. For the outcomes observed in the populations of the included trials and in specific subgroups, hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled and meta-analysed across the analyses.

A total of 23 randomized trials (22 placebo-controlled trials and 1 active-controlled trial) involving 74,380 patients (37,372 receiving SGLT2 inhibitors and 37,008 in the control group) were included. The analysed SGLT2 inhibitors included canagliflozin, dapagliflozin, empagliflozin, bexagliflozin, sotagliflozin, and ertugliflozin. The participants were non-advanced HF patients, including at-risk for HF, pre-HF, and symptomatic HF, with follow-up duration ranging from 12 to 296 weeks. Compared with the control, treatment with SGLT2 inhibitors was associated with significantly reduced risk of VAs (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74-0.98; P = 0.02) and SCD (RR 0.79, 95% CI 0.64-0.98; P = 0.03). Subgroup analyses indicated that longer follow-up (≥ 1 year) taking SGLT2 inhibitors can still reduce the risk of VAs (RR 0.79, 95% CI 0.65-0.96; P = 0.02) and SCD (RR 0.80, 95% CI 0.65-0.99; P = 0.04).

SGLT2 inhibitors have beneficial effects on lowering risks of VAs and SCD in patients with type 2 diabetes, cardiovascular diseases, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF), with longer follow-up duration reinforcing these findings. However, future prospective trials are needed to verify the effects of SGLT2 inhibitors on VAs and SCD.

PROSPERO (CRD42024601914).

Background: In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated significant cardiovascular and renal benefits in patients with heart failure (HF), in addition to their established antidiabetic effects. However, their role in arrhythmia prevention remains unclear. This study aimed to assess the effect of SGLT2 inhibitors on the incidence of supraventricular tachycardia (SVT) and ventricular tachycardia (VT) in patients with HF with reduced ejection fraction (HFrEF) during an extended follow-up period. Methods: This retrospective cohort study was conducted between January 2019 and November 2024 at the Ulm University Heart Center. All patients exhibited severely reduced left ventricular function and underwent primary prophylactic implantable cardioverter-defibrillator (ICD) implantation. Half of the cohort initiated SGLT2 inhibitor therapy alongside optimal medical HF treatment (the SGLT2 group). Patients were followed for approximately three years (846.2 ± 520.0 days) and the incidence of SVT and VT was analyzed using intracardiac Holter records of the ICD. Results: The study population consisted of 78 patients with a mean age of 66.6 ± 12.9 years. Over the follow-up period, a significant prolongation in the time to first occurrence of SVT was observed in the SGLT2 group (Log-Rank p = 0.03), suggesting a potential protective effect of SGLT2 inhibitors. However, regarding VT, additional SGLT2 inhibitor therapy did not show an additional benefit to optimal medical HF treatment. Conclusions: This study suggests that SGLT2 inhibitors may play a beneficial role in reducing the incidence of SVT in patients with HFrEF. These results highlight the importance of further investigating the antiarrhythmic potential of SGLT2 inhibitors through large-scale, prospective studies to better understand their clinical implications and mechanisms of action.

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a commonly used outcome in heart failure trials. While comparing means between treatment groups improves statistical power, mean treatment effects do not necessarily reflect the clinical benefit experienced by individual patients.

To evaluate the association between mean KCCQ treatment effects and the proportions of patients experiencing clinically important improvements across a range of clinical trials and heart failure etiologies.

A patient-level analysis of 11 randomized clinical trials, including 9977 patients, was performed to examine the association between mean treatment effects and the KCCQ Overall Summary Score (OSS) and the absolute differences in the proportions of patients experiencing clinically important (≥5 points) and moderate to large (≥10 points) improvements. There was no target date range, and included studies were those for which patient-level data were available. Validation was performed in 7 additional trials. The data were analyzed between July 1 and September 15, 2023.

Proportion of patients experiencing an improvement of 5 or more and 10 or more points in their KCCQ score (with each domain transformed to a range of 0 to 100 points, where higher scores represent better health status).

Group mean KCCQ-OSS differences were strongly correlated with absolute differences in clinically important changes (Spearman correlations 0.76-0.92). For example, a mean KCCQ-OSS treatment effect of 2.5 points (half of a minimally important difference for an individual patient) was associated with an absolute difference of 6.0% (95% prediction interval [PI], 4.0%-8.1%) in the proportion of patients improving 5 or more points and 5.0% (95% PI, 3.1%-7.0%) in the proportion improving 10 or more points, corresponding to a number needed to treat of 17 (95% PI, 12-25) and 20 (95% PI, 14-33), respectively.

Inferences about clinical impacts based on population-level mean treatment effects may be misleading, since even small between-group differences may reflect clinically important treatment benefits for individual patients. Results of this study suggest that clinical trials should explicitly describe the distributions of KCCQ change at the patient level within treatment groups to support the clinical interpretation of their results.

Sodium glucose transporter type 2 (SGLT2) inhibitors have been introduced into human medicine where their beneficial effects go beyond the expected improvement in blood glucose control. These drugs appear to prevent progression of both cardiovascular and kidney diseases, not only in diabetic but also in non-diabetic human patients. As these drugs have received conditional approval for use in diabetic cats and are being used in other veterinary species, the intriguing question as to whether they will have similar cardioprotective and nephroprotective effects in dogs and cats is being asked. The primary mechanism(s) by which SGLT2 inhibitors are cardio- and nephroprotective remain to be fully characterized. This paper reviews these suggested mechanisms in the context of the pathophysiology of progressive cardiovascular and kidney diseases in dogs and cats with the goal of predicting which categories of non-diabetic veterinary patients these drugs might be of most benefit.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Heart failure (HF) is a life-threatening condition with severe incapacitating consequences. Many body organs and systems may be affected, which may also hinder the quality of life and finances at the individual and societal levels. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have also emerged as potentially useful drugs in the HF domain and other medical fields, in addition to their glucose-lowering effect. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the authors searched Google Scholar, PubMed, and Scopus websites for SGLT2i and SGLT2i-related terms and their impact on HF events, major adverse cardiovascular events (MACEs), renal composite outcomes, and improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, involving human adult populations. Two reviewers conducted the literature search, and disagreements were resolved through mutual consensus and input from a third reviewer. A literature search was conducted from 1st February to 20th February 2024. We included studies published after 2018 to focus only on the latest advancements. Randomized controlled trials, observational studies, or systematic reviews of these studies were included in our study. Of the 44 initial articles identified, only 14 met the inclusion and exclusion criteria. The outcomes revealed the superiority of SGLT2i therapeutics over placebo in all four domains mentioned above. A total of 234,509 patients from 11 papers with moderate heterogeneity (P = 0.07; I2 = 42%) evaluating the effect of SGLT2i in comparison to placebo on HF events were considered; of these, 128,477 patients received the intervention drug, and 106,032 individuals were assigned to the control group. The absolute numbers of HF events were 6845 and 8877, respectively. The study showed an overall benefit of SGLT2i in patients with heart failure due to their ability to major adverse cardiovascular events (MACE) in comparison to placebo (OR: 0.92; 95% CI: 0.89-0.96; P < 0.00001). This systematic review confirmed previous findings related to the use of SGLT2i as adjunctive therapy for HF and amelioration of KCCQ scores and as a protective agent against MACE and renal impairment progression.

Canagliflozin (CANA) is a sodium glucose cotransporter-2 inhibitor that reduces blood glucose levels. Sodium glucose cotransporter-2 is primarily expressed in the kidney, but not in any bone cells, therefore effects on the skeleton are likely to be non-cell autonomous. Originally developed to treat type II diabetes, CANA use has expanded to treat cardiovascular and renovascular disease. Clinical trials examining CANA in diabetic patients have produced contradictory reports on fracture risk, but there are limited data of CANA in nondiabetic conditions. In nondiabetic preclinical models, short-term treatment with CANA negatively affected trabecular bone whereas long-term treatment reduced cortical bone mineralization in male but not female mice. To investigate the skeletal effects of an intermediate period of CANA treatment, we treated male and female C57BL/6 J mice with CANA (180 ppm) for 6 months. Age at treatment initiation was also evaluated, with cohorts starting CANA prior to skeletal maturity (3-months-old) or in adulthood (6-months-old). Longitudinal assessments of bone mineral density revealed early benefits of CANA treatment in female mice. At euthanasia, both trabecular and cortical bone morphology were improved by CANA treatment in males and females. Bone formation was reduced at the endosteal surface. CANA decreased osteoblast number in male mice and bone marrow adiposity in females. Overall, more skeletal benefits were recorded in CANA-treated females than males. Urinary calcium output increased with CANA treatment, but parathyroid hormone was not changed. Despite reduced fasting blood glucose, body composition and whole-body metabolism were minimally changed by CANA treatment. For all outcome measures, limited differences were recorded based on age at treatment initiation. This study demonstrated that in nondiabetic C57BL/6 J mice, an intermediate period of CANA treatment improved bone morphology, but reduced osteoblast and bone marrow adipocyte number as well as serum procollagen type 1 N-terminal pro-peptide in a sex-specific manner.

Chronic kidney disease and end-stage kidney disease (ESKD) are well-established risk factors for cardiovascular disease (CVD), the leading cause of mortality in the dialysis population. Conventional therapies, such as statins, blood pressure control, and renin-angiotensin-aldosterone system blockade, have inadequately addressed this cardiovascular risk, highlighting the unmet need for effective treatment strategies. Sodium-glucose transporter 2 (SGLT2) inhibitors have demonstrated significant renal and cardiovascular benefits among patients with type 2 diabetes, heart failure, or CKD at risk of progression. Unfortunately, efficacy data in dialysis patients is lacking as ESKD was an exclusion criterion for all major clinical trials of SGLT2 inhibitors. This review explores the potential of SGLT2 inhibitors in improving cardiovascular outcomes among patients with ESKD, focusing on their direct cardiac effects.

Recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population. SGLT2 inhibitors may provide cardiovascular benefits to dialysis patients, not only indirectly by preserving the remaining kidney function and improving anemia but also directly by lowering intracellular sodium and calcium levels, reducing inflammation, regulating autophagy, and alleviating oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells. This review examines the current clinical evidence and experimental data supporting the use of SGLT2 inhibitors, discusses its potential safety concerns, and outlines ongoing clinical trials in the dialysis population. Further research is needed to evaluate the safety and effectiveness of SGLT2 inhibitor use among patients with ESKD.

This study aimed to quantify the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a therapeutic approach for heart failure.

A systematic literature review was conducted to collect pharmacokinetics (PK) and pharmacodynamics (PD) data on empagliflozin, dapagliflozin, and canagliflozin. Population pharmacokinetic models were developed separately for each drug, along with PK/PD turnover models for SGLT2 inhibitors, to describe the time course of NT-proBNP and simulate its changes over 52 weeks.

A total of 42 publications were included in this study. The results showed that baseline NT-proBNP levels, estimated glomerular filtration rate levels, and body weight significantly influenced the therapeutic effects of SGLT2 inhibitors. Among the studied drugs, canagliflozin demonstrated a greater reduction in NT-proBNP at comparable baseline levels.

Baseline NT-proBNP concentration, renal function, and body weight were covariates affecting the efficacy of SGLT2 inhibitors in reducing NT-proBNP. Canagliflozin showed the most favorable treatment outcomes at similar baseline levels. This model-based meta-analysis approach may support further drug development for SGLT2 inhibitors.

Inadequate representation of women and racial minorities in heart failure (HF) clinical trials continues to limit the generalizability of the results. This could create a disparity in treatment for future heart failure therapies and devices. The study aims to assess the representation of women and racial minorities in recent heart failure studies involving sodium-glucose cotransporter-2 (SGLT-2) inhibitors.

PubMed was used to search randomized controlled trials (RCTs) looking at SGLT-2 inhibitors and heart failure, which were published from inception to August 2024.

A total of 43 RCTs with 27,703 participants were identified. The studies were published between 2018 and 2024. Seven studies (41 %) were multi-country, with 45 countries represented. The overall proportion of women enrolled in the studies was 35.6 %. The proportion of women was 24.06 % in studies that recruited only patients with HFrEF, 44.33 % in those that recruited only patients with HFpEF, and 41.4 % in those that recruited both HFrEF and HFpEF. Data on race was partially reported in 25 studies (58 %). 76 % of the pharmaceutical industry-funded studies reported race data. However, only 33.3 % of the unfunded or non-industry-funded studies reported race data. In the studies that reported race data, 72.91 % were Caucasians, 15.48 % were Asians, 5.62 % were African-American and 4.1 % were mixed race or others.In the bivariate analysis, race was more likely to be reported in studies done in the US (p < 0.001), multi-country studies (p = 0.013), and studies sponsored by pharmaceutical companies. More than a third of the study participants were more likely to be women in more recently published studies than older studies (p < 0.001). Additionally, more than a third of the study participants were more likely to be women in studies done in the US (p = 0.055). The multivariate analysis showed an increased odds of having more than a third of the study participants being women in more recently published studies (OR 1.83, 95 % CI 1.06-3.17, p = 0.031) and in studies done in the US (OR 7.69, 95 % CI 1.53-38.59, p = 0.013).

Our study found that women and racial minority individuals have remained underrepresented in recent heart failure studies. Although some progress has been made over the years, more work is needed to improve data reporting and address barriers to enrollment for women and racial minority individuals in clinical trials.

Historically marginalized communities are disproportionately affected by cardiometabolic diseases yet are underrepresented in clinical trials that investigate needed interventions. This review investigates the barriers to equitable inclusion in clinical trials, identifying opportunities for improvement at the institutional, trial, community, and individual level. It proposes a social determinants-based approach that serves as a toolkit to target these barriers using structural, economic, community, healthcare access, and technology solutions, supporting constructive improvement in the clinical trial recruitment process.

The Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i) are a class of anti-diabetic medications that confer cardio-renal-metabolic (CRM) benefits. Emerging evidence also suggests that these agents provide better benefits for chronic pulmonary conditions, especially chronic obstructive pulmonary disease (COPD).

We aimed to assess the association between SGLT2i use and outcomes in patients with COPD and concomitant Type 2 Diabetes Mellitus (T2DM).

We conducted a retrospective cohort study on adults with T2DM and COPD in a primary care clinic from January 01, 2019 to 01/01//2023. Patients were categorized into two groups based on SGLT2i use. We collected demographic information and outcomes such as emergency room (ER) visits, hospitalizations secondary to COPD exacerbation over the period of four years and time to hospitalization and ER visits. Chi-square analysis was used for categorical variables, whereas an unpaired t-test was used for continuous variables. Cox regression was performed to identify significant prognostic factors of hospitalization and ER visits. A Kaplan-Meir analysis was used to visualize the probability of non-hospitalization and the probability of not visiting the ER. Statistical significance was set at p-value <0.05.

Of the 220 patients screened, 94 met the inclusion criteria, of which 20 patients (21.3 %) had SGLT2i use at admission, and 74 (78.7 %) did not. Baseline demographic information were well-matched between the two groups. SGLT2i use was associated with a significant reduction in ER visits (70 % vs. 97.3 %, p-0.001) and the number of hospitalizations (55 % vs 87.8 %, p-0.001). Further multivariate analysis showed lower hazards of hospitalization (adjusted HR-0.156; CI:0.073 to 0.331) and ER visits (HR)-0.232; CI:0.118 to 0.453) in patients on SGLT2i.

In patients with T2DM with COPD, SGLT2i use was associated with reduced ER visits and hospitalizations related to COPD. This protective effect of SGLT2i could be explained by reduced systemic proinflammatory markers and increased anti-inflammatory markers via inhibition of Node like receptor protein 3(NLRP3) inflammasome activation in multiple tissues, including the lungs.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1β/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.

Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.

To evaluate the comparative effects of dapagliflozin versus placebo in patients with heart failure (HF), focusing on functional capacity, symptoms, and safety outcomes.

Despite advancements in heart failure (HF) therapy, HF is still a significant cause of recurrent hospitalization and death worldwide. Dapagliflozin has demonstrated potential in lowering hospitalizations and mortality associated with heart failure; however, its impact on functional capacity, particularly the 6-min walk distance (6MWD), and the comprehensive assessment of safety outcomes in diverse HF populations, including those with preserved or reduced ejection fraction (HFpEF and HFrEF, respectively), requires further investigation.

PubMed, Web of Science, Cochrane Library, and Scopus databases were comprehensively searched to identify randomized controlled trials (RCTs) investigating the efficacy of dapagliflozin in comparison with control interventions for heart failure. The primary outcome was a change in the 6MWD, KCCQ score, and safety measures included hospitalization, all-cause mortality, and adverse events.

In our meta-analysis of ten studies involving 12,695 patients with heart failure, dapagliflozin showed significantly improved Kansas City Cardiomyopathy Questionnaire (KCCQ) scores [risk ratio (RR) of 2.75, 95% confidence interval (CI) (1.95-3.569), p < 0.00001] and no significant differences in 6-min walk distance [6MWD; RR of 3.59, 95% CI (- 1.44 to 8.63), p = 0.16]. Dapagliflozin demonstrated a notable reduction in hospitalization for heart failure [RR of 0.76, 95% CI (0.68-0.84), p < 0.00001], significant overall reduction on the effect of any cause mortality [RR of 0.90, 95% CI (0.83-0.99), p = 0.03). There was, however, no significant effect on adverse events [RR of 0.96, 95% CI (0.98-1.03), p = 0.39).

Our meta-analysis of ten trials concluded that dapagliflozin significantly improved KCCQ scores in both HFrEF and HFpEF. The improvement in 6MWD was not statistically significant but trended toward dapagliflozin. Dapagliflozin also showed a mortality benefit in patients with reduced ejection fraction; however, in patients with preserved ejection fraction, the result was not statistically significant. There was also a statistically significant reduction in heart failure hospitalizations across all classes.

Heart failure with preserved ejection fraction (HFpEF), a complex disease that is increasingly prevalent due to population aging, pose significant challenges in its treatment. The present study utilized the HFpEF rat model and H9C2 cells as research subjects to thoroughly investigate the potential mechanisms of alarin in protecting cardiac function in HFpEF. The study shows that under HFpEF conditions, oxidative stress significantly increases, leading to myocardial structural damage and dysfunction of calcium ion channels, which ultimately impairs diastolic function. Alarin, through its interaction with NADPH oxidase 1 (NOX1), effectively alleviates oxidative stress and modulates the activities of type 2 ryanodine receptor (RyR2) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), thereby facilitating the restoration of Ca2+ homeostasis and significantly improving cardiac function in the HFpEF model. This research not only uncovers the cardioprotective effects of alarin and its underlying molecular mechanisms but also provides new insights and potential therapeutic targets for HFpEF treatment strategies, suggesting a promising future for alarin and related therapies in the management of this debilitating condition.

Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms.

We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-β) to investigate the effect of DAPA.

In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels.

In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.

Patients with chronic kidney disease (CKD) are at a high risk of cardiovascular (CV) complications. In these patients, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce CV events. Mineralocorticoid receptor antagonists (MRAs) exert similar benefits in diabetic CKD, though their effects in non-diabetic CKD remain unclear. This study aimed to evaluated whether the combination of Dapagliflozin (DAPA) and Eplerenone (EPLE) would have positive effects on cardiorenal functions in a non-diabetic CKD model. CKD was induced in rats via 5/6 nephrectomy, followed by treatment with DAPA (5 mg/kg/day PO), EPLE (100 mg/kg/day PO) or the combination for 3 months following CKD induction. Cardiorenal functions were assessed after the treatment period. All treated groups showed reduced kidney fibrosis though plasma creatinine and urea levels remained unchanged. Compared to untreated CKD, EPLE or DAPA/EPLE reduced left ventricle (LV) end-diastolic pressure and LV end-diastolic pressure volume relationship, whereas DAPA alone did not achieve significant reductions. Compared to untreated CKD, EPLE and DAPA/EPLE improved cardiac perfusion but DAPA alone did not. Cardiac fibrosis in CKD was blunted by either DAPA or EPLE alone, with the combination showing an additive effect. In conclusion, co-treatment with DAPA and EPLE enhances diastolic function, cardiac perfusion and reduces myocardial fibrosis in non-diabetic CKD rats.

Cardiovascular clinical trials continue to under-represent children, older adults, females and people from ethnic minority groups relative to population disease distribution. Here we describe strategies to foster trial representativeness, with proposed actions at the levels of trial funding, design, conduct and dissemination. In particular, trial representativeness may be increased through broad recruitment strategies and site selection criteria that reflect the diversity of patients in the catchment area, as well as limiting unjustified exclusion criteria and using pragmatic designs that minimize research burden on patients (including embedded and decentralized trials). Trial communications ought to be culturally appropriate; engaging diverse people with lived experience in the co-design of some trial elements may foster this. The demographics of trialists themselves are associated with participant demographics; therefore, trial leadership must be actively diversified. Funding bodies and journals increasingly require the reporting of sociodemographic characteristics of trial participants, and regulatory bodies now provide guidance on increasing trial diversity; these steps may increase the momentum towards change. Although this Perspective focuses on the cardiovascular trial context, many of these strategies could be applied to other fields.

This scoping review examines the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on health-related quality of life (HRQoL) and exercise capacity in heart failure patients with preserved ejection fraction (HFpEF). Five randomized controlled trials were analyzed, revealing consistent improvements in HRQoL metrics, such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores and exercise capacity, measured by the six-minute walk distance (6MWD). The findings suggest that SGLT-2 inhibitors significantly enhance physical functioning and overall well-being in HFpEF patients. These benefits align with existing literature on SGLT-2 inhibitors' efficacy in heart failure with reduced ejection fraction (HFrEF), indicating broader applicability across heart failure phenotypes. However, the review highlights the need for long-term studies to confirm sustained benefits and further investigate the underlying mechanisms. Methodological improvements, such as standardized outcome measures, are also recommended to enhance future research robustness. Clinically, these findings advocate for incorporating SGLT-2 inhibitors into HFpEF management strategies, emphasizing their potential to improve patient outcomes and quality of life. Future research should focus on diverse patient populations and long-term effects to optimize the therapeutic use of SGLT-2 inhibitors in HFpEF.

This Series paper provides an overview of digital tools in heart failure care, encompassing screening, early diagnosis, treatment initiation and optimisation, and monitoring, and the implications these tools could have for research. The current medical environment favours the implementation of digital tools in heart failure due to rapid advancements in technology and computing power, unprecedented global connectivity, and the paradigm shift towards digitisation. Despite available effective therapies for heart failure, substantial inadequacies in managing the condition have hindered improvements in patient outcomes, particularly in low-income and middle-income countries. As digital health tools continue to evolve and exert a growing influence on both clinical care and research, establishing clinical frameworks and supportive ecosystems that enable their effective use on a global scale is crucial.

Wearable accelerometers can quantify the frequency and intensity of physical activity during everyday life and may provide complementary data to established functional outcome measures on the effect of heart failure therapies on functional limitations.

In a voluntary substudy of the DETERMINE trials (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure), patients wore a waist-worn triaxial accelerometer for as long as possible (ideally for 24 h/d for 7 days) at 3 points during the trial, between the screening visit and randomization (baseline data), and during weeks 8 and 14 to 16. Accelerometer outcomes included the change from baseline to week 16 in the total number of steps, time spent in light-to-vigorous physical activity, time spent in moderate-to-vigorous physical activity, movement intensity during walking, number of vector magnitude units' and total activity counts.

Adequate baseline and week 16 accelerometer data were available for 211 of 817 (26%) randomized patients (defined as ≥10 hours of wear time for ≥3 days). Dapagliflozin had a favorable effect on the mean change from baseline at 16 weeks in the number of steps (between-group difference, 778 [95% CI, 240-1315]), time spent in moderate-to-vigorous physical activity (0.16 [95% CI, 0.03-0.29] hours), and in the mean vector magnitude units (25 [95% CI, 0.1-49] counts per minute). There were no between-group differences in the other accelerometer outcomes of interest.

In this exploratory analysis of the DETERMINE trials, dapagliflozin had a beneficial effect on selected accelerometer-based measures of physical activity in patients with heart failure across the entire left ventricular ejection fraction spectrum, yet did not improve 6-minute walk distance, as previously reported. These data suggest that accelerometer-based measurements of everyday activity may provide complementary information to 6-minute walk distance and identify beneficial effects of treatment not detected by 6-minute walk distance.

URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224.

Hypertension is the predominant risk factor for cardiovascular disease related morbidity and mortality among Black adults in the United States. It contributes significantly to the development of heart failure and increases the risk of death following heart failure diagnosis. It is also a leading predisposing factor for hypertensive disorders of pregnancy and peripartum cardiomyopathy in Black women. As such, all stakeholders including health care providers, particularly primary care clinicians (including physicians and advanced practice providers), patients, and communities must be aware of the consequences of uncontrolled hypertension among Black adults. Appropriate treatment strategies should be identified and implemented to ensure timely and effective blood pressure management among Black individuals, particularly those with, and at risk for heart failure.

The effectiveness and safety of a novel class of hypoglycemic medications known as sodium-glucose cotransporter 2 (SGLT2) inhibitors have not been completely established in relation to acute heart failure (AHF). Consequently, we sought to compare the prognostic and safety outcomes of patients administered SGLT2 inhibitors for the treatment of AHF.

An extensive search of the Web of Science, PubMed, and EMBASE was conducted for randomized controlled trials and observational studies that have evaluated the use of SGLT2 inhibitors in AHF from the inception of these drugs to the present. We compiled data related to cardiovascular safety and prognosis. Aggregated risk ratios (RR), mean differences (MD), or standardized mean differences (SMD) were generated for all outcomes, with 95% confidence intervals (CIs), to evaluate the predictive significance of SGLT2 inhibitors in patients with AHF.

We identified 4,053 patients from 13 studies. Patients experienced a substantial reduction in all-cause mortality (RR = 0.82, 95% CI: 0.70-0.96, P = 0.01), readmission rates (RR = 0.85, 95% CI: 0.74-0.98, P = 0.02), the number of heart failure exacerbation events (RR = 0.69, 95% CI: 0.50-0.95, P = 0.02), and the number of rehospitalization events due to heart failure (RR = 0.71, 95% CI: 0.58-0.86, P < 0.05) in the SGLT2 inhibitors-treatment group compared to a placebo or standard care (control group). SGLT2 inhibitors improved patient quality of life (SMD = -0.24, 95% CI: -0.40 to -0.09, P = 0.002). SGLT2 inhibitors were associated with enhanced diuresis in patients with AHF (MD = 2.83, 95% CI: 1.36-4.29, P < 0.05). Overall, treatment with SGLT2 inhibitors significantly reduced the level of serum NT-proBNP (MD = -497.62, 95% CI: -762.02 to -233.21, P < 0.05) and did not increase the incidence of adverse events (RR = 0.91, 95% CI: 0.82-1.01, P = 0.06).

This meta-analysis suggests that treatment with SGLT2 inhibitors is associated with a better prognosis in patients with AHF than in patients not treated with SGLT2 inhibitors. It is safe and effective to initiate SGLT2 inhibitors in patients with AHF.

https://www.doi.org/10.37766/inplasy2024.9.0015, identifier (INPLASY202490015).

Decentralized clinical trials (DCTs) are becoming increasingly popular. Digital clinical trial platforms are software environments where users complete designated clinical trial tasks, providing investigators and trial participants with efficient tools to support trial activities and streamline trial processes. In particular, digital platforms with a modular architecture lend themselves to DCTs, where individual trial activities can correspond to specific platform modules. While design features can allow users to customize their platform experience, the real strengths of digital platforms for DCTs are enabling centralized data capture and remote monitoring of trial participants and in using digital technologies to streamline workflows and improve trial management. When selecting a platform for use in a DCT, sponsors and investigators must consider the specific trial requirements. All digital platforms are limited in their functionality and technical capabilities. Integrating additional functional modules into a central platform may solve these challenges, but few commercial platforms are open to integrating third-party components. The lack of common data standardization protocols for clinical trials will likely limit the development of one-size-fits-all digital platforms for DCTs. This viewpoint summarizes the current role of digital platforms in supporting decentralized trial activities, including a discussion of the potential benefits and challenges of digital platforms for investigators and participants. We will highlight the role of the digital platform in the development of DCTs and emphasize where existing technology is functionally limiting. Finally, we will discuss the concept of the ideal fully integrated and unified DCT and the obstacles developers must address before it can be realized.

Gliflozins are recommended as first-line treatment in patients with heart failure and/or cardiovascular comorbidities and are demonstrated to reduce atrial fibrillation (AF) occurrence. However, it is not well known which gliflozin yields the larger cardioprotection in terms of AF occurrence reduction. Hence, we aimed to compare data regarding AF recurrence associated with different gliflozins.

An accurate search of online scientific libraries (from inception to June 1, 2023) was performed. Fifty-nine studies were included in the meta-analysis involving 108 026 patients, of whom 60 097 received gliflozins and 47 929 received placebo.

Gliflozins provided a statistically significant reduction of AF occurrence relative to standard of care therapy in the overall population (relative risks [RR]: 0.8880, 95% CI: [0.8059; 0.9784], p = .0164) and in patients with diabetes and cardiorenal diseases (RR: 0.8352, 95% CI: [0.7219; 0.9663], p = .0155). Dapagliflozin significantly decreased AF occurrence as compared to placebo (0.7259 [0.6337; 0.8316], p < .0001) in the overall population, in patients with diabetes (RR: 0.2482, 95% CI: [0.0682; 0.9033], p = .0345), with diabetes associated with cardiorenal diseases (RR: 0.7192, 95% CI: [0.5679; 0.9110], p = .0063) and in the subanalysis including studies with follow-up ≥1 year (RR: 0.7792, 95% CI: [0.6508; 0.9330], p = .0066). No significant differences in terms of AF protection were found among different gliflozins.

Dapagliflozin use was associated with significant reduction in AF risk as compared to placebo in overall population and patients with diabetes, whereas the use of other gliflozins did not significantly reduce AF occurrence.

Increases in pulmonary capillary wedge pressure (PCWP) during exercise reduce pulmonary artery (PA) compliance, increase pulsatile right ventricular (RV) afterload, and impair RV-PA coupling in patients with heart failure with preserved ejection fraction (HFpEF). The effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on pulmonary vascular properties and RV-PA coupling are unknown.

To test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF.

Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction (CAMEO-DAPA) randomized clinical trial demonstrated improvement in PCWP at rest and exercise over 24 weeks with dapagliflozin compared with placebo with participants recruited between February 2021 and May 2022. This secondary analysis evaluates the effects of dapagliflozin on pulsatile pulmonary vascular load and RV-PA coupling using simultaneous echocardiography and high-fidelity invasive hemodynamic testing with exercise. This was a single-center study including patients with hemodynamically confirmed HFpEF with exercise PCWP of 25 mm Hg or greater.

Dapagliflozin or placebo for 24 weeks.

Pulsatile pulmonary vascular load (PA compliance and elastance) and right ventricular performance (PA pulsatility index, RV systolic velocity [s']/PA mean) during rest and exercise.

Among 37 randomized participants (mean [SD] age, 67.4 [8.5] years; 25 female [65%]; mean [SD] body mass index, 34.9 [6.7]; calculated as weight in kilograms divided by height in meters squared), there was no effect of dapagliflozin on PA loading or RV-PA interaction at rest. However, with exercise, dapagliflozin improved PA compliance (placebo-corrected mean difference, 0.57 mL/mm Hg; 95% CI, 0.11-1.03 mL/mm Hg; P = .02) and decreased PA elastance (stiffness; -0.17 mm Hg/mL; 95% CI, -0.28 to -0.07 mm Hg/mL; P = .001). RV function during exercise improved, with increase in PA pulsatility index (0.33; 95% CI, 0.08-0.59; P = .01) and increase in exercise RV s' indexed to PA pressure (0.09 cm·s-1/mm Hg; 95% CI, 0.02-0.16 cm·s-1/mm Hg; P = .01). Improvements in pulsatile RV load and RV-PA coupling were correlated with reduction in right atrial (RA) pressure (PA elastance Pearson r = 0.55; P =.008; RV s'/PA elastance Pearson r = -0.60; P =.002) and PCWP (PA elastance Pearson r = 0.58; P <.001; RV s'/PA elastance Pearson r = -0.47; P = .02). Dapagliflozin increased resistance-compliance time (dapagliflozin, median [IQR] change, 0.06 [0.03-0.15] seconds; placebo, median [IQR] change, 0.01 [-0.02 to 0.05] seconds; P =.046), resulting in higher PA compliance for any exercise pulmonary vascular resistance.

Results of this randomized clinical trial reveal that treatment with dapagliflozin for 24 weeks reduced pulsatile pulmonary vascular load and enhanced dynamic RV-PA interaction during exercise in patients with HFpEF, findings that are related to the magnitude of PCWP reduction. Benefits on dynamic right ventricular-pulmonary vascular coupling may partially explain the benefits of SGLT2 inhibitors in HFpEF.

ClinicalTrials.gov Identifier: NCT04730947.