The sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated potential benefits, including anti-inflammatory effects, reverse left ventricular remodeling, improved myocardial fibrosis, and enhanced microcirculation. However, the potential of these drugs to improve cardiac remodeling and function in non-diabetic patients without heart failure remains unclear.

This study aims to evaluate the impact of the SGLT2 inhibitor (empagliflozin) on inflammatory markers and maximum oxygen consumption (VO2 max) in non-diabetic patients experiencing acute ST-segment elevation myocardial infarction (STEMI) and undergoing percutaneous coronary intervention (PCI).

The expression levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), high-sensitivity C-reactive protein (hs-CRP), and VO2 max were measured and compared before and after surgery in both groups.

Baseline levels of TNF-α, IL-10, and hs-CRP did not differ significantly between the two groups prior to treatment. One month post-treatment, both groups demonstrated reductions in TNF-α and hs-CRP levels relative to preoperative values, with the experimental group showing significantly lower levels of TNF-α and hs-CRP compared to the control group (P < 0.05). Additionally, the VO2 max values measured one week post-surgery revealed a statistically significant difference between the two groups (t = 2.4, P = 0.03).

Empagliflozin administration in non-diabetic patients with STEMI undergoing emergency PCI may effectively reduce inflammatory markers and improve oxygen consumption capacity. These findings suggest a potential cardioprotective role for empagliflozin in this patient population.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors showed time-varying effects in heart failure and reduced ejection fraction (HFrEF), but corresponding cost-effectiveness in different timeframes remained poorly understood. This study estimated the time-varying cost-effectiveness of SGLT2 inhibitors in HFrEF from the perspective of the Chinese healthcare system.

Based on real-world individual patient data, a 2-year microsimulation model was constructed to evaluate the cost-effectiveness of adding SGLT2 inhibitors to standard therapy compared with standard therapy alone among patients with HFrEF. A published prediction model informed transition probabilities for all-cause death and hospitalization for heart failure. The time-varying effects of SGLT2 inhibitors, medical costs, and utility values were derived from the published literature. Scenario analyses in different timeframes were conducted to assess the trend of cost-effectiveness over time.

Compared with standard therapy alone, SGLT2 inhibitors plus standard therapy were found cost-effective at a willingness-to-pay (WTP) threshold of $12,741 per quality-adjusted life year (QALY) gained in 2 years. The incremental cost-effectiveness ratio (ICER) decreased from $12,346.07/QALY at 0.5 years to $9,355.66/QALY at 2 years. One-direction sensitivity analysis demonstrated that the cost-effectiveness of SGLT2 inhibitors was most sensitive to the cost of SGLT2 inhibitors, the cost of hospitalization for heart failure, the cost of standard therapy for heart failure, and the baseline risks of all-cause death and hospitalization for heart failure. Probabilistic sensitivity analysis proved the robustness of the results.

Adding SGLT2 inhibitors to standard therapy was found to be cost-effective in Chinese patients with HFrEF. Longer treatment appeared to be more economically favorable, but further explorations are warranted.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce cardiovascular death and heart failure (HF) hospitalizations in patients with reduced and mildly reduced or preserved ejection fraction. This study assesses the effectiveness of SGLT2 inhibitors in reducing HF readmission rates and examines prescription patterns in hospitalized patients.

This single-center retrospective cross-sectional study evaluated the impact of SGLT2 inhibitors on HF readmission rates when initiated during index hospitalization or within 14 days of discharge. Patients were divided into an SGLT2 group and a non-SGLT2 group, with 6-month readmission rates compared to the groups.

Of the 234 patients, 85 (36.3%) were prescribed SGLT2 inhibitors, while 149 (63.7%) were not. SGLT2 inhibitors were prescribed less frequently to patients with chronic kidney disease (CKD) and patients admitted under cardiology services were more likely to receive SGLT2 inhibitors. Among those prescribed SGLT2 inhibitors, the median ejection fraction was significantly lower compared to those not prescribed, while the median estimated glomerular filtration rate was higher. There were 107 total readmissions (45.7%), with most (55%) occurring within 30 days of the index hospitalization. Total readmissions and 30-day readmissions were significantly lower in the SGLT2 inhibitor group (31.8% vs 53.7%, p = 0.001) and (33.33% vs 62.50%, p = 0.029), respectively. Heart failure readmissions were also lower in the SGLT2 group (29.6% vs 21.3%, p = 0.37).

Our study demonstrated a significant reduction in heart failure readmission rates among patients prescribed with SGLT2 inhibitors. However, we also observed a gap in the prescription of SGLT2 inhibitors.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a cutting-edge class of oral antidiabetic therapeutics that operate through selective inhibition of glucose reabsorption in proximal renal tubules, consequently augmenting urinary glucose excretion and attenuating blood glucose levels. Extensive clinical investigations have demonstrated their profound cardiovascular efficacy. Parallel basic science research has elucidated the mechanistic pathways through which diverse SGLT-2 inhibitors beneficially modulate pulmonary vascular cells and arterial remodeling. Specifically, these inhibitors exhibit promising potential in enhancing pulmonary vascular endothelial cell function, suppressing pulmonary smooth muscle cell proliferation and migration, reversing pulmonary arterial remodeling, and maintaining hemodynamic equilibrium. This comprehensive review synthesizes current literature to delineate the mechanisms by which SGLT-2 inhibitors enhance pulmonary vascular cell function and reverse pulmonary remodeling, thereby offering novel therapeutic perspectives for pulmonary vascular diseases.

Cardiovascular-Kidney-Metabolic syndrome, introduced by the American Heart Association in 2023, represents a complex and interconnected spectrum of diseases driven by shared pathophysiological mechanisms. However, this framework notably excludes the liver-an organ fundamental to metabolic regulation. Building on this concept, Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome incorporates the liver's pivotal role in this interconnected disease spectrum, particularly through its involvement via metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the increasing prevalence of CRHM syndrome, unified management strategies remain insufficiently explored. This review addresses the following critical question: How can novel anti-diabetic agents, including sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual gastric inhibitory polypeptide (GIP)/GLP-1RA, offer an integrated approach to managing CRHM syndrome beyond the boundaries of traditional specialties? By synthesizing evidence from landmark clinical trials, we highlight the paradigm-shifting potential of these therapies. SGLT2is, such as dapagliflozin and empagliflozin, have emerged as cornerstone guideline-directed treatments for heart failure (HF) and chronic kidney disease (CKD), providing benefits that extend beyond glycemic control and are independent of diabetes status. GLP-1RAs, e.g., semaglutide, have transformed obesity management by enabling weight reductions exceeding 15% and improving outcomes in atherosclerotic cardiovascular disease (ASCVD), diabetic CKD, HF, and MASLD. Additionally, tirzepatide, a dual GIP/GLP-1RA, enables unprecedented weight loss (>20%), reduces diabetes risk by over 90%, and improves outcomes in HF with preserved ejection fraction (HFpEF), MASLD, and obstructive sleep apnea. By moving beyond the traditional organ-specific approach, we propose a unified framework that integrates these agents into holistic management strategies for CRHM syndrome. This paradigm shift moves away from fragmented, organ-centric management toward a more unified approach, fostering collaboration across specialties and marking progress in precision cardiometabolic medicine.

No clear consensus exists regarding the safest anti-diabetic drugs with the least adverse events on bone health. This umbrella systematic review therefore aims to assess the published meta-analysis studies of randomized controlled trials (RCTs) conducted in this field.

All relevant meta-analysis studies of RCTs assessing the effects of anti-diabetic agents on bone health in patients with diabetes mellitus (DM) were collected in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). English articles published until 15 March 2023 were collected through the search of Cochrane Library, Scopus, ISI Web of Sciences, PubMed, and Embase using the terms "Diabetes mellitus", "anti-diabetic drugs", "Bone biomarker", "Bone fracture, "Bone mineral density" and their equivalents. The methodological and evidence quality assessments were performed for all included studies.

From among 2220 potentially eligible studies, 71 meta-analyses on diabetic patients were included. Sodium-glucose cotransporter-2 inhibitors (SGLT-is) showed no or equivalent effect on the risk of fracture. Dipeptidyl peptidase-4 inhibitors (DPP-4is) and Glucagon-like peptide-1 receptor agonists (GLP-1Ras) were reported to have controversial effects on bone fracture, with some RCTs pointing out the bone protective effects of certain members of these two medication classes. Thiazolidinediones (TZDs) were linked with increased fracture risk as well as higher concentrations of C-terminal telopeptide of type I collagen (CTx), a bone resorption marker.

The present systematic umbrella review observed varied results on the association between the use of anti-diabetic drugs and DM-related fracture risk. The clinical efficacy of various anti-diabetic drugs, therefore, should be weighed against their risks and benefits in each patient.

Atherosclerotic cardiovascular disease remains a prominent global cause of mortality, with coronary artery disease representing its most prevalent manifestation. Recently, a novel class of antidiabetic medication, namely sodium-glucose cotransporter-2 (SGLT2) inhibitors, has been reported to have remarkable cardiorenal advantages for individuals with type 2 diabetes mellitus (DM), and they may reduce cardiorenal risk even in individuals without pre-existing DM. Currently, there is no evidence regarding the safety and efficacy of these drugs in acute coronary syndrome (ACS), regardless of diabetes status. This review aims to comprehensively present the available preclinical and clinical evidence regarding the potential role of SGLT2 inhibitors in the context of ACS, as adjuncts to standard-of-care treatment for this patient population, while also discussing potential short- and long-term cardiovascular benefits.

A literature search was performed through MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, and Scopus until February 26, 2024. Eligible were preclinical and clinical studies, comprising randomized controlled trials (RCTs), real-world studies, and meta-analyses.

Evidence from preclinical models indicates that the use of SGLT2 inhibitors is associated with a blunted ischemia-reperfusion injury and decreased myocardial infarct size, particularly after prior treatment. Although RCTs and real-world data hint at a potential benefit in acute ischemic settings, showing improvements in left ventricular systolic and diastolic function, decongestion, and various cardiometabolic parameters such as glycemia,body weight, and blood pressure, the recently published DAPA-MI (Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure) trial did not establish a clear advantage regarding surrogate cardiovascular end points of interest. SGLT2 inhibitors appear to provide a benefit in reducing contrast-induced acute kidney injury events in patients with ACS undergoing percutaneous coronary intervention. However, data on other safety concerns, such as treatment discontinuation because of hypotension, hypovolemia, or ketoacidosis, are currently limited.

Despite the well-established cardiovascular benefits observed in the general population with type 2 DM and, more recently, in other patient groups irrespective of diabetes status, existing evidence does not support the use of SGLT2 inhibitors in the context of ACS. Definitive answers to this intriguing research question, which could potentially expand the therapeutic indications of this novel drug class, require large-scale, well-designed RCTs.

To examine cardiovascular and kidney benefits and harms of sodium-glucose co-transporter-2 (SGLT-2) inhibitors stratified by risk in adults with chronic kidney disease regardless of diabetes status.

Systematic review and meta-analysis.

Ovid Medline, Embase, and Cochrane Central from database inception to 15 June 2024.

Randomised controlled trials that compared SGLT-2 inhibitors with placebo or standard care with no SGLT-2 inhibitors in adults with chronic kidney disease with a follow-up duration of ≥12 weeks were eligible. Secondary analyses based on subpopulations from randomised controlled trials and publications not in English language were excluded.

Random effects meta-analyses were conducted, with effect estimates presented as risk ratios with 95% confidence intervals (CIs). Absolute treatment effects were estimated over a five year duration for individuals with varied risks of cardiovascular and kidney complications based on the Kidney Disease Improving Global Outcomes (KDIGO) risk stratification system. Certainty of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

Evidence from 13 randomised controlled trials (29 614 patients) informed treatment effect estimates. In relative terms, SGLT-2 inhibitors reduced all cause death (risk ratio 0.85 (95% CI 0.74 to 0.98)), cardiovascular death (0.84 (0.74 to 0.96)), kidney failure (0.68 (0.60 to 0.77)), non-fatal stroke (0.73 (0.57 to 0.94)), non-fatal myocardial infarction (0.75 (0.60 to 0.93)), and admission to hospital for heart failure (0.68 (0.60 to 0.78)). No credible subgroup effects were found from diabetes status, heart failure status, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, and follow-up duration. Absolute effect estimates across these outcomes over a five year period varied across risk groups based on baseline risks of cardiovascular and kidney events. Effects of SGLT-2 inhibitors in the group at low risk included seven fewer all- cause deaths, four fewer admissions to hospital for heart failure per 1000 individuals, and no effects on kidney failure. Effects in the higher risk group included 48 fewer all cause deaths, 58 fewer kidney failures, and 25 fewer admissions to hospital for heart failure per 1000 individuals. Although SGLT-2 inhibitor use was associated with a relative increase in the risk of harms, including genital infection (2.66 (95% CI 2.07 to 3.42)), ketoacidosis (2.27 (1.30 to 3.95)), and symptomatic hypovolaemia (1.29 (1.15 to 1.44)), absolute differences for all harm outcomes were small.

Among people who have chronic kidney disease either with type 2 diabetes or not, SGLT-2 inhibitors improved cardiovascular and kidney outcomes with varying degrees of absolute benefit depending on an individual's baseline risks of cardiovascular and kidney-related sequelae. Absolute benefits and harms stratified by risk and associated with SGLT-2 inhibitors should inform individual decision making at the patient level.

PROSPERO CRD42022325483.

Studies examining the safety and effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus glucagon-like peptide-1 receptor agonists (GLP-1RAs) among community-dwelling adults may not generalize to nursing home (NH) residents, who are typically older and more multimorbid. We compared the safety and cardiovascular effectiveness of SGLT2is and GLP-1RAs among US NH residents.

Eligible individuals were aged ≥66 years with type 2 diabetes mellitus and initiated an SGLT2i or GLP-1RA in an NH between 2013 and 2018. Safety outcomes included fall-related injuries, hypoglycaemia, diabetic ketoacidosis (DKA), urinary tract infection or genital infection, and acute kidney injury in the year following treatment initiation. Cardiovascular effectiveness outcomes included death, major adverse cardiovascular events and hospitalization for heart failure. Per-protocol adjusted hazard ratios (HR) were calculated using stabilized inverse probability of treatment and censoring weighted cause-specific hazard regression models accounting for 127 covariates.

The study population included 7710 residents (31.08% SGLT2i, 68.92% GLP-1RA). Compared with GLP-1RA initiators, SGLT2i initiators had higher rates of DKA (HR 1.95, 95% confidence limits 1.27, 2.99) and death (HR 1.18, 95% confidence limits 1.02, 1.36). Rates of urinary tract infection or genital infection, acute kidney injury, major adverse cardiovascular events, and heart failure were also elevated, while rates of fall-related injuries and hypoglycaemia were reduced, but all estimates were imprecise and highly compatible with no difference.

SGLT2is do not have superior, and may have inferior, effectiveness compared with GLP-1RAs for cardiovascular and mortality outcomes in NH residents. Residents initiating SGLT2is should be monitored closely for DKA.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a novel class of glucose-lowering drugs, have revolutionized the management of heart failure with reduced and preserved ejection fraction, regardless of the presence of diabetes, and are currently incorporated in the heart failure guidelines. While these drugs have consistently demonstrated their ability to decrease heart failure hospitalizations in several landmark clinical trials, their cardioprotective effects are far from having been completely elucidated. In the past decade, a growing body of experimental research has sought to address the molecular and cellular mechanisms of SGLT2i in order to provide a better understanding of the off-target acute and chronic cardiac benefits, beyond the on-target renal effect responsible for blood glucose reduction. The present narrative review addresses the direct cardioprotective effects of SGLT2i, delving into the off-target mechanisms of the drugs currently approved for heart failure therapy, and provides insights into future perspectives.

Heart failure (HF) is a leading cause of hospitalization and death worldwide. The Steady Movement with Innovating Leadership for Heart Failure (SMILE HF) aims to evaluate the clinical characteristics, management, hospital course, and long-term outcomes of patients hospitalized for acute HF in South Korea.

This prospective, observational multicenter cohort study was conducted on consecutive patients hospitalized for acute HF in nine university hospitals since September 2019. Enrolment of 2000 patients should be completed in 2024, and follow-up is planned through 2025.

Interim analysis of 1,052 consecutive patients was performed to understand the baseline characteristics. The mean age was 69±15 years; 57.6% were male. The mean left ventricular ejection fraction was 39±15%. The prevalences of HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction were 50.9%, 15.3%, and 29.2%. Ischemic cardiomyopathy (CMP) was the most common etiology (32%), followed by tachycardia-induced CMP (12.8%) and idiopathic dilated CMP (9.5%). The prescription rate of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers/angiotensin receptor/neprilysin inhibitor, beta-blockers, spironolactone, and sodium-glucose cotransporter-2 inhibitors at discharge were 76.8%, 66.5%, 50.0%, and 17.5%, respectively. The post-discharge 90-day mortality and readmission rates due to HF aggravation were 2.0% and 6.4%, respectively. Our analysis reveals the current state of acute HF in South Korea.

Our interim analysis provides valuable insights into the clinical characteristics, management, and early outcomes of acute HF patients in South Korea, highlighting the current state and treatment patterns in this population.

Background: Several studies have shown that sodium-dependent glucose transporter 2 inhibitors can be used in the treatment of heart failure. This article summarized systematic reviews of sodium-dependent glucose transporter 2 inhibitors in the treatment of heart failure in order to evaluate efficacy and safety. Methods: We systematically searched eight electronic databases from inception to July 2023. We used Assessment of Multiple Systematic Reviews 2 to evaluate the methodological quality, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 to assess report quality, Risk of Bias in Systematic Review to assess the risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation to rate the quality of evidence. Outcome: A total of 36 systematic reviews were included. Our results were classified as clear evidence of benefit: hospitalization for heart failure; possible benefit: cardiovascular death (mortality) and renal outcome composite; clear evidence of no effect or equivalence: atrial arrhythmias, ventricular arrhythmia, atrial fibrillation, and hypotension; possible harm: genital infection; insufficient evidence to draw a conclusion: atrial flutter, major adverse cardiovascular events, urinary tract infection, acute kidney injury, hypoglycemia, and bone fracture. Conclusions: Sodium-dependent glucose transporter 2 inhibitors are beneficial for the treatment of heart failure, especially in terms of heart failure hospitalization.

This study aimed to investigate the association between clinical and laboratory parameters and response to therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2D).

We retrospectively analyzed the medical records of people with T2D in whom SGLT2i was started. Clinical and laboratory parameters were recorded before, 3 and 6 months after starting treatment. Specific criteria were applied to classify participants into good and poor responders in terms of weight loss (primary outcome) and glycemic control (secondary outcome), separately.

Fifty individuals (64% men) with a mean age of 65.8 ± 8.5 years were included in the analysis. 86% and 64% of the participants were classified into good response categories for glycemic control and weight loss, respectively. Good responders in terms of glycemic control had lower high-density lipoprotein cholesterol levels at baseline compared to poor responders (43.3 vs 57.4 mg/dl, p = 0.044). In the logistic regression analysis, a higher baseline weight was associated with a better response to therapy in terms of weight loss (p = 0.04).

Our findings suggest that specific clinical and laboratory parameters are associated with response to SGLT2i treatment and can contribute to a more personalized approach to T2D care.

Use of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces hospitalization in heart failure (HF) patients across the spectrum of ejection fraction, but no study has comprehensively explored their impact on quality of life (QoL) with respect to different subgroup populations. We aimed to explore the QoL impact of SGLT2i use in HF patients across the spectrum of ejection fraction and over time.

We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) covering the period from 2019 to February 2022. We included placebo-controlled randomized controlled trials (RCTs) enrolling HF patients that evaluated QoL as an outcome. Two reviewers independently assessed studies for eligibility, extracted data, and assessed risk of bias (RoB), using the Cochrane RoB2 tool, and certainty of evidence, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Primary and secondary outcomes were the mean difference in QoL, and clinically important improvement in QoL, as defined in the original study, respectively. We conducted subgroup analyses based on ejection fraction category, SGLT2i agent, and timing of QoL measurement.

From 1477 identified reports, we included 14 RCTs (n = 23,361). The mean age was 68 years, and 34% were female. All included RCTs reported QoL using the Kansas City Cardiomyopathy Questionnaire (KCCQ). SGLT2i use improved KCCQ-overall summary score, compared with placebo (mean difference 2.0, 95% confidence interval 1.6-2.5; high certainty). More patients receiving an SGLT2i achieved a clinically important QoL improvement (risk ratio 1.14, 95% confidence interval 1.02-1.28; moderate certainty). Similar improvements were observed in the KCCQ clinical summary and total symptom subscores, and across all subgroups and timeframes.

Use of an SGLT2i consistently provides a clinically important improvement in QoL among patients with HF, regardless of ejection fraction, with noticeable improvements seen as early as week 2.

Heart failure is a continuously developing syndrome of cardiac insufficiency caused by diseases, which becomes a major disease endangering human health as well as one of the main causes of death in patients with cardiovascular diseases. The occurrence of heart failure is related to hemodynamic abnormalities, neuroendocrine hormones, myocardial damage, myocardial remodeling etc, lead to the clinical manifestations including dyspnea, fatigue and fluid retention with complex pathophysiological mechanisms. Currently available drugs such as cardiac glycoside, diuretic, angiotensin-converting enzyme inhibitor, vasodilator and β receptor blocker etc are widely used for the treatment of heart failure. In particular, natural products and related active ingredients have the characteristics of mild efficacy, low toxicity, multi-target comprehensive efficacy, and have obvious advantages in restoring cardiac function, reducing energy disorder and improving quality of life. In this review, we mainly focus on the recent advance including mechanisms and active ingredients of natural products for the treatment of heart failure, which will provide the inspiration for the development of more potent clinical drugs against heart failure.

Heart failure (HF) is a chronic condition with considerable clinical burden for patients and economic burden for healthcare systems. Treatment for HF is typically based on ejection fraction (EF) phenotype. The cost-effectiveness of empagliflozin + standard of care (SoC) compared to SoC has been examined for HF phenotypes below or above 40% EF separately, but not across the full spectrum of EF in Spain.

The results of two preexisting, validated, and published phenotype-specific Markov cohort models were combined using a population-weighted approach, reflecting the incidence of each phenotype in the total HF population in Spain. A probabilistic sensitivity analysis was performed by sampling each model's probabilistic results.

Empagliflozin + SoC compared to SoC resulted in increased life-years (LYs) (6.48 vs. 6.35), quality-adjusted LYs (QALYs) (4.80 vs. 4.63), and healthcare costs (€19,090 vs. €18,246), over a lifetime time horizon for the combined HF population in Spain. The incremental cost-effectiveness ratio (ICER) was €5,089/QALY. All subgroup, scenario, and probabilistic ICERs were consistently below €10,000/QALY.

Empagliflozin is the first treatment with established efficacy and cost-effectiveness for HF patients across EF from the perspective of healthcare payers in Spain. Empagliflozin also proved to be cost-effective for all subgroups of patients included in the analysis.

Mitochondria are cellular power stations and essential organelles for maintaining cellular homeostasis. Dysfunctional mitochondria have emerged as a key factor in the occurrence and development of cardiovascular disease. This review focuses on advances in the relationship between mitochondrial dysfunction and cardiovascular diseases such as atherosclerosis, heart failure, myocardial ischemia reperfusion injury, and pulmonary arterial hypertension. The clinical value and challenges of mitochondria-targeted strategies, including mitochondria-targeted antioxidants, mitochondrial quality control modulators, mitochondrial function protectors, mitochondrial biogenesis promoters, and recently developed mitochondrial transplants, are also discussed.

Durable progression-free survivors (dPFSors) over 2 years have been reported among patients with melanoma or non-small-cell lung cancer (NSCLC) who received PD-(L)1 therapy. However, risk of progression still exists and the optimal imaging surveillance interval is unknown.

Individual patient data for progression-free survival (PFS) were extracted from PD-1 blockade clinical trials with a follow-up of at least 5 years. Patients with a PFS of at least 2 years were considered as dPFSors. Conditional risks of progression/death (P/D) every 3, 4, 6, and 12 months in each subsequent year were calculated. We prespecified three different levels of risk between scans (10%, 15%, or 20%) to allow clinicians and patients to decide on the scanning interval on the basis of considerations of imaging frequency and risk tolerance. An interval is considered acceptable if the upper bound of the 95% CI of the risk at each scan is lower than a prespecified level.

Of 1,495 and 3,752 patients with melanoma and NSCLC, 474 (31.7%) and 586 (15.6%) were dPFSors, respectively. Among them, the PFS probability for an additional 3 years was 76.4% and 48.1%, respectively. Not more than 8% of patients had P/D in any quarter in the 3 years. With a risk threshold of 10%, melanoma dPFSors can be scanned every 6 months during the third year and then every 12 months in years 4 and 5. The interval for NSCLC would be every 3 months in the third year and every 4 months in years 4 and 5. The higher risk tolerance of 15% and 20% would allow for less frequent scans.

On the basis of their own risk tolerance level, our findings allow clinicians and dPFSors make data-driven decisions regarding the imaging surveillance schedule beyond every 3 months.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, there remains uncertainty about the efficiency of GLP-1 RAs in patients with heart failure (HF).

Randomized placebo-controlled trials (RCTs) that reported the effect of GLP-1 RAs on prognosis in patients with HF were identified by searching databases. The primary outcome was defined as MACE. Trail Sequential Analysis (TSA) was used to evaluate the reality and authenticity.

Nine RCTs involving 8920 patients with HF were included. GLP-1 RAs significantly reduced the risk of MACE compared with placebo (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.77-0.98) in HF coexisting with T2DM. The benefit was not observed in all-cause death (HR 0.99, 95% CI 0.84-1.15), hospitalization for heart failure (HR 1.04, 95% CI 0.89-1.22), cardiovascular death (HR 0.95, 95% CI 0.79-1.16), myocardial infarction (HR 0.88, 95% CI 0.71-1.08), stroke (HR 1.03, 95% CI 0.75-1.43) and death or hospitalization for HF (HR 1.07, 95% CI 0.78-1.46). GLP-1 RAs did not improve the change in LVEF (mean difference [MD]): - 0.86, p = 0.12, left-ventricular end-diastolic volume (LVEDV) (MD: 3.54, p = 0.11), left-ventricular end-systolic volume (LVESV) (MD: 2.78, p = 0.07) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) (MD: - 140.36, p = 0.08). However, GLP-1 RAs significantly increased the change in the 6-min walk test (MWT) distance (MD: 19.74, p = 0.002). In the subgroup analyses, human GLP-1 RAs, but not nonhuman GLP-1 RAs, reduced the risk of MACE in patients with HF (p interaction = 0.11). Grading of Recommendations Assessment, Development and Evaluation (GRADE) showed moderate certainty for MACE, all-cause death and hospitalization for HF. Trail Sequential Analysis revealed that there may be a high possibility of false positive results for MACE.

Compared with placebo, GLP-1 RAs may reduce the risk of MACE in patients with HF coexisting with T2DM, with a more significant efficiency of human GLP-1 RAs. More RCTs are needed to assess the cardiovascular benefits of GLP-1 RAs in HF, regardless of T2DM.

The protocol for this meta-analysis is registered on PROSPERO [CRD42022357886].

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) imposes a high disease burden on patients, primarily because of multimorbidity and frequent hospitalizations. Recently, the American College of Cardiology Expert Consensus recommended treating all patients diagnosed with HFpEF with a sodium-glucose cotransporter 2 inhibitor, such as dapagliflozin or empagliflozin, to reduce the risk of cardiovascular death and hospitalization and improve health status. However, managing HFpEF can be expensive, highlighting the need to assess therapeutic alternatives that can minimize health care costs while optimizing patient outcomes. OBJECTIVE: To compare the cost-effectiveness of dapagliflozin vs empagliflozin in managing patients with HFpEF from the US health care system perspective. METHODS: We developed a Markov model to simulate a cohort of patients with HFpEF (defined as having a left ventricular ejection fraction ≥ 50%) treated with dapagliflozin or empagliflozin. Transition probabilities between 3 health states (HFpEF, hospitalization for heart failure, and death), costs, and quality of life weight input variables were obtained from the literature. In the base-case analysis, we estimated total expected costs, quality-adjusted life-years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) over a lifetime horizon. All future expected costs and QALYs were discounted at the annual rate of 3%. We conducted sensitivity analyses to demonstrate the robustness of the cost-effectiveness model findings. RESULTS: Dapagliflozin had an incremental expected lifetime cost of $29,896 compared with empagliflozin, resulting in an ICER of $36,902/QALY. Value-based price threshold analysis suggested that for empagliflozin to be cost-effective, it would need a 29% discount on its annual price. In a probabilistic sensitivity analysis, dapagliflozin would be the most preferred cost-effective option at willingness-to-pay thresholds of $50,000/QALY about 72% of the time. CONCLUSIONS: This cost-effectiveness analysis showed that, from the US health care system perspective, dapagliflozin was more cost-effective than empagliflozin, and its uptake may enhance long-term outcomes in patients with HFpEF.

Emerging evidence has consistently demonstrated that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) hospitalization and cardiovascular (CV) death among patients with HF. However, it remains unclear how long a patient needs to live to potentially benefit from SGLT2 inhibitors in this population.

To estimate the time to benefit from SGLT2 inhibitors among patients with HF.

This comparative effectiveness study systematically searched PubMed for completed randomized clinical trials about SGLT2 inhibitors and patients with HF published until September 5, 2022; 5 trials with the year of publication ranging from 2019 to 2022 were eventually included. Statistical analysis was performed from April to October 2022.

Addition of SGLT2 inhibitors or placebo to guideline-recommended therapy.

The primary outcome was the time to first event of CV death or worsening HF, which was broadly comparable across the included trials.

Five trials consisting of 21 947 patients with HF (7837 [35.7%] were female; mean or median age older than 65 years within each trial) were included. SGLT2 inhibitors significantly reduced the risk of worsening HF or CV death (hazard ratio [HR], 0.77 [95% CI, 0.73-0.82]). Time to first nominal statistical significance (P < .05) was 26 days (0.86 months), and statistical significance was sustained from day 118 (3.93 months) onwards. A mean of 0.19 (95% CI, 0.12-0.35) months were needed to prevent 1 worsening HF or CV death per 500 patients with SGLT2 inhibitors (absolute risk reduction [ARR], 0.002). Likewise, 0.66 (95% CI, 0.43-1.13) months was estimated to avoid 1 event per 200 patients with SGLT2 inhibitors (ARR, 0.005), 1.74 (95% CI, 1.07-2.61) months to avoid 1 event per 100 patients (ARR, 0.010), and 4.96 (95% CI, 3.18-7.26) months to avoid 1 event per 50 patients (ARR, 0.020). Further analyses indicated a shorter time to benefit for HF hospitalization and among patients with diabetes or HF with reduced ejection fraction.

In this comparative effectiveness research study of estimating the time to benefit from SGLT2 inhibitors among patients with HF, a rapid clinical benefit in reducing CV death or worsening HF was found, suggesting that their use may be beneficial for most individuals with HF.

Given the cumulative evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on chronic heart failure, demand is emerging for further information on their effects in patients who are hospitalized for acute heart failure. However, there is still limited evidence about the class effect of SGLT2is on acute heart failure. We investigated whether initiating treatment with SGLT2is after an episode of acute heart failure reduces the risks of post-discharge heart failure readmission or cardiovascular mortality among patients with type 2 diabetes.

A retrospective cohort study was conducted in a cohort of patients with type 2 diabetes who hospitalized for heart failure, using Korean Health Insurance Review & Assessment database (2015-2020). The exposure was defined as initiation of SGLT2is during hospitalization or at discharge. We assessed hazards of post-discharge heart failure readmission and cardiovascular death at 1-year, and 30-, 60-, and 90-day from the date of discharge in the SGLT2is users and non-users. Cox proportional hazards models with propensity score-based inverse probability of treatment weighting were used to estimate hazard ratios and 95% confidence intervals.

Among 56,343 patients with type 2 diabetes hospitalized for heart failure, 29,290 patients were included in the study cohort (mean [SD] age, 74.1 [10.8] years; 56.1% women); 818 patients (2.8%) were prescribed SGLT2is during index hospitalization or at discharge. Patients with a prescription for SGLT2i vs. those without prescription had lower rates of heart failure readmission or cardiovascular death at 1 year (22.4% vs. 25.3%; adjusted hazard ratio, 0.90 [95% confidence interval, 0.87-0.93]), and also at 30 days (7.0% vs. 7.7%%; 0.74 [0.69-0.79]).

Among patients with type 2 diabetes, initiating SGLT2i treatment after an episode of acute heart failure was significantly associated with a reduced combined risk of heart failure readmission and cardiovascular mortality in a nationwide cohort reflecting routine clinical practice.

Evidence suggests that adding dapagliflozin to the prior standard of care is cost-effective compared with the standard of care alone. The latest guideline by the American Heart Association/American College of Cardiology/Heart Failure Society of America now recommends the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with heart failure with reduced ejection fraction (HFrEF). However, the relative cost-effectiveness of different SGLT2 inhibitors, including dapagliflozin and empagliflozin, has not been fully characterized. Therefore, we conducted a cost-effectiveness analysis to compare dapagliflozin and empagliflozin in patients with HFrEF from the US health care perspective.

To compare the cost-effectiveness of dapagliflozin and empagliflozin in treating HFrEF, we used a state-transition Markov model. This model was used to estimate the expected lifetime costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) for both medications. The model incorporated patients who were 65 years of age at entry and simulated their health outcomes over a lifetime horizon. The perspective of the analysis was based on the US health care system. To determine the health state transition probabilities, we used a network meta-analysis. All future costs and QALYs were discounted at an annual rate of 3%, and the costs were presented in 2022 US dollars.

The base case analysis found that the incremental expected lifetime cost of treating patients with dapagliflozin vs empagliflozin was $37,684, resulting in an ICER of $44,763 per QALY. A price threshold analysis indicated that for empagliflozin to be the most cost-effective SGLT2 inhibitor at a willingness-to-pay threshold of $50,000 per QALY, it may require a 12% discount on its current annual prices.

The findings of this study indicate that dapagliflozin may offer greater lifetime economic value when compared with empagliflozin. Given that the current clinical practice guideline does not recommend one SGLT2 inhibitor over the other, it is essential to implement scalable strategies to ensure affordable access to both medications. By doing so, patients and health care practitioners can make informed decisions about their treatment options without being constrained by financial barriers.

The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This study aimed to evaluate the comparative effectiveness of SGLT2i vs. sitagliptin in older adults with HF and type 2 diabetes and to investigate whether there were any differences between agents within the SGLT2i class or for reduced and preserved ejection fraction.

Using Medicare claims data (April 2013 to December 2019), 16 253 SGLT2i initiators vs. 43 352 initiators of sitagliptin aged ≥65 years with type 2 diabetes and HF were included. The primary outcome was a composite of all-cause mortality, hospitalization for HF or urgent visit requiring intravenous diuretics; secondary outcomes included its individual components. Propensity score fine stratification weighted Cox regression was used to adjust for 100 pre-exposure characteristics. Mean age was 74 years; 49.8% were women. Initiation of SGLT2i vs. sitagliptin was associated with a lower risk of the primary composite outcome [adjusted hazard ratio (HR) 0.72; 95% confidence interval 0.67-0.77]. The adjusted HRs were 0.70 (0.63-0.78) for all-cause mortality, 0.64 (0.58-0.70) for hospitalization for HF, and 0.77 (0.69-0.86) for urgent visit requiring intravenous diuretics. Similar associations with the primary composite outcome were observed for all three agents within the SGLT2i class, for reduced and preserved ejection fraction, and subgroups based on demographics, comorbidities, and other HF treatments. Bias-calibrated HRs for the primary endpoint using negative and positive control outcomes ranged between 0.81 and 0.89, suggesting that the observed benefit could not be fully explained by residual confounding.

In routine US clinical practice, SGLT2i demonstrated robust clinical effectiveness in older adults with HF and type 2 diabetes compared with sitagliptin, with no evidence of heterogeneity across the SGLT2i class or across ejection fraction.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM. Methods: We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388). Conclusion: Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.

Eligibility for glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but whether treatment benefits differ by risk levels is not clear.

To investigate whether patients with varying risks differ in cardiovascular and renal benefits from GLP-1RA and SGLT2i with use of meta-analysis and meta-regression.

We performed a systematic review using PubMed through 7 November 2022.

We included reports of GLP-1RA and SGLT2i confirmatory randomized trials in adult patients with safety or efficacy end point data.

Hazard ratio (HR) and event rate data were extracted for mortality, cardiovascular, and renal outcomes.

We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary HRs were significant for cardiovascular mortality (GLP-1RA 0.87 and SGLT2i 0.86), major adverse cardiovascular events (0.87 and 0.88), heart failure (0.89 and 0.70), and renal (0.84 and 0.65) outcomes. For stroke, efficacy was significant for GLP-1RA (0.84) but not for SGLT2i (0.92). Associations between control arm cardiovascular mortality rates and HRs were nonsignificant. Five-year absolute risk reductions (0.80-4.25%) increased to 11.6% for heart failure in SGLT2i trials in patients with high risk (Pslope < 0.001). For GLP1-RAs, associations were nonsignificant.

Analyses were limited by lack of patient-level data, consistency in end point definitions, and variation in cardiovascular mortality rates for GLP-1RA trials.

Relative effects of novel diabetes drugs are preserved across baseline cardiovascular risk, whereas absolute benefits increase at higher risks, particularly regarding heart failure. Our findings suggest a need for baseline risk assessment tools to identify variation in absolute treatment benefits and improve decision-making.

The triglyceride-glucose (TyG) index is a simple and reliable indicator of insulin resistance, and is associated with the development and poor outcomes of cardiovascular disease. Subclinical left ventricular dysfunction (SLVD) is frequently detected in approximately one-third of diabetes patients, but it has not been established whether the TyG index correlates with SLVD. We carried out this research to evaluate the relationship between the TyG index and SLVD in type 2 diabetes mellitus patients.

This was a cross-sectional and observational study of 183 type 2 diabetes mellitus inpatients at Nanjing Drum Tower Hospital, Nanjing, China. The TyG index and homeostasis model assessment 2 estimates for insulin resistance (HOMA2-IR) were calculated from biochemical measurements, and speckle-tracking echocardiography was carried out. According to global longitudinal strain (GLS) by echocardiography, participants were categorized into the SLVD (GLS <18%) group or the non-SLVD (GLS ≥18%) group.

In comparison with non-SLVD participants, SLVD participants had higher insulin resistance, as reflected by elevated TyG and HOMA2-IR indices, as well as a higher body mass index, waist circumference and triglyceride level (P < 0.05 for each). When grouped by TyG index tertiles, an elevated TyG index was correlated with other cardiometabolic risk factors, as well as a decrease in GLS. In the multivariate logistic regression analyses, the TyG index was an independent risk factor for SLVD in type 2 diabetes mellitus patients (odds ratio 2.047, 95% confidence interval 1.07-3.914, P  = 0.03), whereas HOMA2-IR was not.

The TyG index is independently associated with SLVD in type 2 diabetes mellitus patients and is a more reliable indicator of SLVD than HOMA2-IR.

Emerging evidence points to a positive impact of sodium glucose co-transporter 2 (SGLT-2) inhibitors on cardiac structure and function, acutely (as early as 15 days) and chronically (up to 2 years). Accordingly, data from clinical studies appear to support the beneficial effects of this class of drugs on the cardiovascular system. However, the extent to which such effects may directly and/or indirectly be responsible for the beneficial actions of this class of drugs remains unclear. Based on the data in the literature, the actions of SGLT-2 inhibitors on the cardiac tissue in the absence of SGLT-2 co-transporter sites would suggest possible direct effects on calcium/calmodulin-dependent kinase II (CaMKII), voltage-gated, Na_v1.5 channels and sodium-calcium exchanger 1 (NCX1), Na⁺/H⁺ exchanger (NHX), the late I_Na associated with calcium transient, the rapid (I_Kr) and slow (I_Ks) delayed rectifier K⁺ currents, phosphorylated levels of myofilament regulatory proteins, xanthine oxidase activity and sarco(endo)plasmic reticulum calcium ATPase and/or intracellular, and/or possible genomic sites in the cardiac myocytes. Collectively, the experimental and clinical evidence as to the effects of SGLT-2 inhibitors on cardiac and vascular tissues appear multifaceted in nature with no consensus for definitive site(s) of actions. It is clear that further investigations both in animals and humans, in vitro and in vivo are needed to shed more light on the true nature of the pharmacological actions of this class of compounds, and the extent of their beneficial effects as reported in a population with heart failure.

Type 2 diabetes mellitus (T2DM) has caused a huge clinical and economic burden worldwide. The management strategy of T2DM has been mentioned in many guidelines. However, controversy still exists in the recommendation of anti-hyperglycemic agents. To this end, this protocol has been written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). We will make an overview of systematic reviews based-on network meta-analysis firstly that report on safety and efficacy of different category of anti-hyperglycemic agents for T2DM patients. We will identify network meta-analysis by applying a robust and standardized search strategy within Embase, PubMed, Web of Science, and Cochrane Database of Systematic Reviews. Hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) will be defined as the primary outcomes. We will assess the methodological quality of included reviews by applying the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR-2) tool, and quality of evidence for all outcomes will be judged by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). This will provide an accessible narrative synthesis to clinicians, patients, policy makers, and developers of clinical guidelines based on published high-quality network meta-analysis. We will submit our results for peer-review publication and presentation at domestic and international conferences. We will also disseminate our results through established clinical networks and consumer networks, using pamphlet where appropriate. Ethics approval is not required for this overview as we will analysis published network meta-analysis only. Trial registration number: INPLASY202070118.

The life history theory assumes that all organisms are under selective pressure to harvest external resources and allocate them to maximise fitness: only organisms making the best use of energy obtain the greatest fitness benefits. The trade-off of energy spans four functions: maintenance, growth, reproduction, and defence against pathogens. The innovative antihyperglycaemic agents glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease bodyweight and have the potential to counter low-grade inflammation. These key activities could rewire two components of the life history theory operative in adulthood-ie, maintenance and defence. In this Personal View, we postulate that the benefits of these medications on the cardiovascular system, beyond their glucose-lowering effects, could be mediated by the reduction of the maintenance cost driven by obesity and efforts spent on blunting low-grade inflammation.

Individuals with type 2 diabetes mellitus (DM) have an increased risk of pneumonia and septic shock. Traditional glucose-lowering drugs have recently been found to be associated with a higher risk of infections. It remains unclear whether sodium-glucose cotransporter 2 inhibitors (SGLT2is), which have pleiotropic/anti-inflammatory effects, may reduce the risk of pneumonia and septic shock in DM.

MEDLINE, Embase, and ClinicalTrials.gov were searched from inception up to May 19, 2022, for randomized, placebo-controlled trials of SGLT2i that included patients with DM and reported outcomes of interest (pneumonia and/or septic shock). Study selection, data extraction, and quality assessment (using the Cochrane Risk of Bias Assessment Tool) were conducted by independent authors. A fixed-effects model was used to pool the relative risk (RRs) and 95% CI across trials.

Out of 4568 citations, 26 trials with a total of 59 264 patients (1.9% developed pneumonia and 0.2% developed septic shock) were included. Compared with placebo, SGLT2is significantly reduced the risk of pneumonia (pooled RR 0.87, 95% CI 0.78-0.98) and septic shock (pooled RR 0.65, 95% CI 0.44-0.95). There was no significant heterogeneity of effect size among trials. Subgroup analyses according to the type of SGLT2i used, baseline comorbidities, glycemic control, duration of DM, and trial follow-up showed consistent results without evidence of significant treatment-by-subgroup heterogeneity (all Pheterogeneity > .10).

Among DM patients, SGLT2is reduced the risk of pneumonia and septic shock compared with placebo. Our findings should be viewed as hypothesis generating, with concepts requiring validation in future studies.