Topologically unique chiral noradamantanes are synthesized using a diphenylprolinol silyl ether-mediated domino Michael/epimerization/Michael/1,2-addition or Michael/epimerization/aldol/1,2-addition reaction with excellent enantioselectivity in a single reaction vessel. Three carbon-carbon bonds are formed, and six chiral centers, including one all-carbon quaternary center, are generated, five of which are fully controlled. These functionalized noradamantanes are 3D, cage-like molecules that can serve as valuable chiral building blocks for drug design.

The growing morbidity, mortality, and health care costs related to heart failure (HF) underscore the urgent need to prioritize its primary prevention. Whereas a risk-based approach for HF prevention remains in its infancy, several key opportunities exist to actualize this paradigm in clinical practice. First, the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America HF guidelines provided recommendations, for the first time, on the clinical utility of multivariable risk equations to estimate risk of incident HF. Second, the American Heart Association recently developed the PREVENT (Predicting Risk of Cardiovascular Disease Events) equations, which not only enable prediction of incident HF separately, but also include HF in the prediction of total cardiovascular disease. Third, the predominant phenotype of HF risk has emerged as the cardiovascular-kidney-metabolic syndrome. Fourth, the emergence of novel therapies that prevent incident HF (eg, sodium-glucose cotransporter-2 inhibitors) and target multiple cardiovascular-kidney-metabolic axes demonstrate growing potential for risk-based interventions. Whereas the concept of risk-based prevention has been established for decades, it has only been operationalized for atherosclerotic cardiovascular disease prevention to date. Translating these opportunities into a conceptual framework of risk-based primary prevention of HF requires implementation of PREVENT-HF (Predicting Risk of Cardiovascular Disease Events-Heart Failure) equations, targeted use of cardiac biomarkers (eg, natriuretic peptides) and echocardiography for risk reclassification and earlier detection of pre-HF, and definition of therapy-specific risk thresholds that incorporate net benefit and cost-effectiveness. This scientific statement reviews the current evidence for accurate risk prediction, defines strategies for equitable prevention, and proposes potential strategies for the successful implementation of risk-based primary prevention of HF.

The 10th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on December 5-6, 2024. This year, discussions about cardiovascular (CV) and kidney outcome trials centered on the recent findings from studies involving empagliflozin (EMPACT-MI), semaglutide (STEP-HFpEF-DM and FLOW), tirzepatide (SURMOUNT-OSA and SUMMIT), and finerenone (FINEARTS-HF). These studies represent significant advances in reducing the risk of major adverse cardiovascular events (MACE) and improving metabolic outcomes in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), and obstructive sleep apnea (OSA). The congress also comprised sessions on novel and established therapies for managing HFpEF, CKD, and obesity; guidelines for managing CKD and metabolic dysfunction-associated steatotic liver disease (MASLD); organ crosstalk and the development of cardio-kidney-metabolic (CKM) syndrome; precision medicine and person-centered management of diabetes, obesity, cardiovascular disease (CVD) and CKD; early detection of type 1 diabetes (T1D) and strategies to delay its onset; continuous glucose monitoring (CGM) and automated insulin delivery (AID); cardiovascular autonomic neuropathy (CAN) and the diabetic heart; and the role of primary care in the early detection, prevention and management of CKM diseases. The contribution of environmental plastic pollution to CVD risk, the increasing understanding of the efficacy and safety of incretin therapies in the treatment of CKM diseases, and the latest updates on nutrition strategies for CKM management under incretin-based therapies were also topics of interest for a vast audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians, who actively engaged in online discussions. The 11th CVOT Summit will be held virtually on November 20-21, 2025 ( http://www.cvot.org ).

Heart failure is the leading cardiovascular cause of hospitalization with an increasing prevalence, especially in older patients. About 50% of patients with heart failure have preserved ventricular function, a form of heart failure that, until a few years ago, was orphaned by pharmacological treatments effective in reducing hospitalization and mortality. New trials, which have tested the use of gliflozins in patients with heart failure with preserved ejection fraction (HFpEF), have for the first time demonstrated their effectiveness in changing the natural history of this insidious and frequent form of heart failure. Therefore, diagnosing those patients early is crucial to provide the best treatment. Moreover, the diagnosis is influenced by the patient's comorbidities, and some HFpEF patients have symptoms common to other rare diseases that, if unrecognized, develop an unfavourable prognosis. This position paper aims to provide the clinician with a useful tool for diagnosing and treating patients with HFpEF, guiding the clinician towards the most appropriate diagnostic and therapeutic pathway.

Coronary artery disease (CAD) confers a continued challenge to healthcare necessitating innovative therapies. Linagliptin, a dipeptidyl peptidase 4 inhibitor, has been shown in preclinical and clinical studies to have cardioprotective effects independent of its glycemic control. An important pathway by which linagliptin has been described to induce these effects is due to its immune regulation. This study aims to evaluate the immune modulation by linagliptin treatment in a porcine model of chronic myocardial ischemia.

Yorkshire swine underwent ameroid constrictor placement to the left circumflex artery, which induced chronic myocardial ischemia. Two wk later, swine either received no drug (n = 8) or 2.5 mg linagliptin daily (n = 8). Five weeks later, swine were sacrificed and left ventricular tissue was harvested. Protein expression and immune cell count was measured with immunoblotting and immunofluorescence, respectively. Data were statistically analyzed via Wilcoxon rank-sum test.

Linagliptin treatment was associated with decreased expression of inflammatory markers interleukin (IL)-1β (P = 0.0012), IL-6 (P = 0.0073), nuclear factor kappa B (NFκB) (P = 0.0106), transforming growth factor beta (P = 0.001), and IL-4 (P = 0.0419) in chronically ischemic myocardium. There was increased expression of phosphorylated NFκB at Ser536 (p=<0.0001) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (P = 0.0167). Interestingly, there was increased expression of cluster of differentiation (CD) 11c (P = 0.0002) and increased cell count of CD11c dendritic cells (P = 0.014).

Linagliptin treatment was associated with a reduction of proinflammatory cytokines in the setting of chronically ischemic myocardium, with identified modulation of the NFκB pathway. Following treatment, there was found to be an increase in CD11c expression, demonstrating an increase in dendritic cells as a possible immune modulating cell population within the ischemic myocardium.

Fotagliptin is a novel dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes (T2D). This trial aimed to assess the efficacy and safety of fotagliptin add-on to metformin in patients with T2D.

In this phase 3 randomised, double-blind, placebo-controlled study, patients with T2D who had inadequate glycaemic control using metformin alone were randomly allocated to fotagliptin or placebo at a 2:1 ratio for 24-week double-blind treatment period, followed by an open-label treatment with fotagliptin for all patients, making up a total of 52 weeks. All eligible patients were treated with a stable dose of metformin (≥1500 mg per day). The primary endpoint was the change in HbA1c level from baseline to week 24. Safety was assessed in all patients who received at least one dose of the study drug.

After 24 weeks, LS mean change of HbA1c from baseline was -0.81% with fotagliptin versus -0.28% with placebo. Estimated treatment difference for fotagliptin versus placebo of HbA1c was -0.53% (95% confidence interval [CI] -0.68% to -0.39%; p < 0.001). Significantly more patients on fotagliptin than on placebo achieved HbA1c < 7.0% after 24 weeks (38.7% vs. 16.9%; p < 0.001). The incidence of adverse events was similar between the two groups. No severe hypoglycaemia events were reported in patients treated with fotagliptin and metformin combined therapy.

In patients with T2D who experienced inadequate glycaemic control with metformin, fotagliptin achieved a superior and clinically meaningful improvement in glycaemic control compared with placebo.

Calcific aortic valve disease (CAVD) is a progressive disease, of which the 2-year mortality is >50% for symptomatic disease. However, there are currently no pharmacotherapies to prevent the progression of CAVD unless transcatheter or surgical aortic valve replacement is performed. The prevalence of diabetes among CAVD has increased rapidly in recent decades, especially among those undergoing aortic valve replacement. Diabetes and its comorbidities, such as hypertension, hyperlipidemia, chronic kidney disease and ageing, participated jointly in the initiation and progression of CAVD, which increased the management complexity in patients with CAVD. Except from hyperglycemia, the molecular links between diabetes and CAVD included inflammation, oxidative stress and endothelial dysfunction. Traditional cardiovascular drugs like lipid-lowering agents and renin-angiotensin system blocking drugs have proven to be unsuccessful in retarding the progression of CAVD in clinical trials. In recent years, almost all kinds of glucose-lowering medications have been specifically assessed for decelerating the development of CAVD. Based on the efficacy for atherosclerotic cardiovascular disease and CAVD, this review summarized current knowledge about glucose-lowering medications as promising treatment options with the potential to retard CAVD.

As a heterogeneous syndrome, heart failure with preserved ejection fraction (HFpEF) has become the leading form of heart failure worldwide. Increasing evidence has identified that diabetes mellitus (DM) increases the risk of HFpEF. Worse still, the coexistence of both diseases poses a great threat to human health by further worsening the cardiovascular system and accelerating the progression of diabetes. Although several studies have indicated that the novel antidiabetic drugs, including sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase 4 inhibitors (DPP4i) provide the cardiovascular benefits in T2DM patients with HFpEF, the elaborated roles and mechanisms are not fully understood. In this review, we summarize the state-of-the-art evidence regarding the epidemiology and pathophysiology of diabetic HFpEF, and the landscape of the novel antidiabetic drugs in the treatment of diabetic HFpEF, as well as discuss the relevant mechanisms, aiming to broaden the understanding of diabetic HFpEF and gain new insight into the treatment of this disease.

Patients diagnosed with type 2 diabetes have an increased risk of developing cardiovascular complications. The researchers are currently working on understanding how to prevent these progressions from occurring. Since 2006, dipeptidyl-peptidase-4 inhibitors have been made available to patients as a relatively new treatment for diabetes. These substances inhibit the enzyme known as dipeptidyl peptidase-4 (DPP-4), which in turn increases the levels of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This results in an increase in the effectiveness of insulin release after meals, which in turn has a positive impact on glycemic control. Regarding the safety of this category of medication in the treatment of cardiovascular disorders, there have been a great deal of debates. Emerging research suggests that DPP-4 inhibitors could be useful in the treatment of a variety of cardiovascular conditions, including coronary atherosclerosis, heart failure, and hypertension, among others. In order to investigate the possibility of using dipeptidyl-peptidase-4 inhibitors as a treatment option for cardiovascular disease, the molecular pathways that are thought to be responsible for their cardioprotective effect will be clarifies throughout the course of this review.

Patients with diabetes are at an increased risk of cardiovascular disease (CVD), including atherosclerotic CVD and heart failure. In addition, diabetes is associated with a higher risk of developing chronic kidney disease, which is considered to be one of the strongest risk factors for CVD and mortality. To address the increased cardiovascular risk of patients with diabetes, dedicated screening strategies for CVD are necessary; conversely, screening for diabetes needs to be performed in all patients with CVD to allow timely identification. Once diabetes is diagnosed, rapid implementation of treatment with therapies to reduce cardiovascular risk on top of standard of care is necessary. This review gives an overview of contemporary therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes.

Diabetic cardiomyopathy is a notable microvascular complication of diabetes, characterized primarily by myocardial fibrosis and functional abnormalities. Long-term hyperglycemia induces excessive activation and recruitment of immune cells and triggers the cascade of inflammatory responses, resulting in systemic and local cardiac inflammation. Emerging evidence highlights the significant roles of immunology in modulating the pathology of diabetic cardiomyopathy. As the primary effectors of inflammatory reactions, immune cells are consistently present in cardiac tissue and can be recruited under pathological hyperglycemia circumstances. A disproportionate favor to proinflammatory types of immune cells and the increased proinflammatory cytokine levels mediate fibroblast proliferation, phenotypic transformation, and collagen synthesis and ultimately rise to cardiac fibrosis and hypertrophy. Meanwhile, the severity of cardiac fibrosis is also strongly associated with the diverse phenotypes and phenotypic alterations of the immune cells, including macrophages, dendritic cells, mast cells, neutrophils, and natural killer cells in innate immunity and CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes in adaptive immunity. In this review, we synthesized the current analysis of the critical role played by the immune system and its components in the progression of diabetic cardiomyopathy. Finally, we highlight preclinical and clinical immune targeting strategies and translational implications.

Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.

The treatment of type 2 diabetes is based on four fundamental pillars: diet, exercise, therapeutic education, and pharmacological therapy. There are ten groups of antidiabetic drugs that can be classified according to their mechanism of action, effects on body weight, risk of hypoglycemia, and ability to reduce the development of complications. The choice of medication will be individualized based on the preferences and characteristics of the individual, taking into consideration the presence of cardiovascular disease, heart failure, chronic kidney disease, obesity, or non-alcoholic fatty liver disease. The type 2 diabetes mellitus treatment algorithm from the RedGDPS Foundation is an evidence-based tool that can help us select the most appropriate pharmacological therapy depending on the characteristics of each patient.

We previously demonstrated that sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, slowed down the progression of carotid atherosclerosis in type 2 diabetes participants who were treated with insulin and had no history of cardiovascular disease in the Sitagliptin Preventive study of Intima-Media Thickness Evaluation (SPIKE) trial. This was an extension of the SPIKE trial that examined if early sitagliptin initiation improved long-term cardiovascular outcomes.

In the SPIKE trial, 282 participants were randomized to either sitagliptin or conventional treatment to examine the effects of sitagliptin on carotid atherosclerosis. All participants who completed the SPIKE trial were recruited to this prospective, observational, cohort study and followed for up to 520 weeks. The primary endpoint was the first occurrence of a major cardiovascular event, which included acute myocardial infarction, stroke, or total mortality.

Events of composite primary outcome occurred in only a few participants in each group (15 [12.6%] in the sitagliptin group and eight in the conventional treatment group [6.7%]). The incidence rate of the primary outcome did not differ significantly between two groups. In post hoc Poisson regression analysis, there were no significant between-group differences in the incidence rates of composite recurrence events for the same outcomes as the primary endpoint.

Early initiation of sitagliptin as add-on therapy to insulin was not linked to reduced risk of composite cardiovascular disease. This may be due to low event numbers in both groups and/or relatively lower continuation rates of DPP-4 inhibitors in the sitagliptin group during the follow-up period.

The online version contains supplementary material available at 10.1007/s13340-024-00786-7.

Persons living with type 2 diabetes mellitus (T2DM) have a significantly greater risk of stroke (1.5 to 3 times higher than normoglycemic individuals). The traditional approach to primary and secondary stroke prevention has been control of risk factors. While this has resulted in prolongation of life in patients with diabetes, the risk for recurrent stroke in these patients still remains higher than in the normoglycemic population, and patients with T2DM post stroke have a poorer quality of life (increases in handicap and death).

Multiple publications on the pathophysiology which increases stroke in T2DM were reviewed as well as new publications looking at the effect of traditional and new risk factor modification on stroke are summarized.

Traditional risk factor modification is refined with recommended levels of lipids and blood pressure and methods of anticoagulation. More recently, studies with antidiabetic drugs (glucagon-like peptide 1 RA and pioglitazone) have been shown to prevent both primary and secondary stroke in patients with diabetes.

Worldwide, stroke is the second leading cause of death and the third leading cause of disability. Both risk and the outcomes are greatly worsened by the presence of T2DM. Newer recommendations can improve these outcomes.

Novel antidiabetic drugs, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have significantly transformed the management landscape for type 2 diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, owing to their well-established cardiorenal protective effects. Given the shared risk factors and comorbidities, it is relevant to consider the potential risk of venous thromboembolism (VTE) in individuals prescribed these novel antidiabetic medications. This literature review aims to summarize currently available evidence on VTE risk associated with novel antidiabetic drugs, including GLP-1 receptor agonists, dipeptidyl-peptidase IV (DPP-4) inhibitors, and SGLT2 inhibitors. Following a comprehensive search on PubMed using relevant keywords and backward reference searching, we identified 25 publications that directly reported on associations between these medications and VTE risk. Findings from these studies, including seven meta-analyses, reveal inconsistent results: some studies suggest that GLP-1 receptor agonists or DPP-4 inhibitors may be associated with increased risk of VTE, whereas SGLT2 inhibitors do not appear to be associated with VTE and may even be a protective factor. A notable limitation of the existing studies is the significant challenge posed by confounding in observational studies, while the randomized controlled trials (RCTs) often concluded with a limited number of VTE events, if it was studied. Furthermore, all identified studies focused on the risk of primary VTE, leaving an important knowledge gap regarding whether these novel antidiabetic drugs may influence the efficacy or safety of anticoagulants used for preventing VTE recurrence. Addressing these gaps presents an important avenue for future research.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors improve hyperglycemia, and SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACEs) among individuals with type 2 diabetes. It is not clear whether efficacy varies by age or sex.

To assess whether age or sex are associated with differences in the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors.

The MEDLINE and Embase databases and US and Chinese clinical trial registries were searched for articles published from inception to November 2022; in August 2024, the search was updated to capture the trial results. Two reviewers screened for randomized clinical trials of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors vs a placebo or active comparator in adults with type 2 diabetes.

Individual participant data and aggregate data were used to estimate age × treatment interactions and sex × treatment interactions in multilevel network meta-regression models.

Hemoglobin A1c (HbA1c) and MACEs.

Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA1c; mean age, 58.9 [SD, 10.8] years; 42.3% were female and 23 trials with 168 489 participants reported MACEs; mean age, 64.0 [SD, 8.6] years; 35.3% were female), individual participant data were obtained for 103 trials (103 reported HbA1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% [95% credible interval {CrI}, 0.10% to 0.38%] per 30-year increment in age), for dual therapy (AR, 0.17% [95% CrI, 0.10% to 0.24%]), and for triple therapy (AR, 0.25% [95% CrI, 0.20% to 0.30%]). The use of GLP-1 receptor agonists was associated with greater HbA1c lowering with increasing age for monotherapy (AR, -0.18% [95% CrI, -0.31% to -0.05%] per 30-year increment in age) and for dual therapy (AR, -0.24% [95% CrI, -0.40% to -0.07%]), but not for triple therapy (AR, 0.04% [95% CrI, -0.02% to 0.11%]). The use of DPP4 inhibitors was associated with slightly better HbA1c lowering in older people for dual therapy (AR, -0.09% [95% CrI, -0.15% to -0.03%] per 30-year increment in age), but not for monotherapy (AR, -0.08% [95% CrI, -0.18% to 0.01%]) or triple therapy (AR, -0.01% [95% CrI, -0.06% to 0.05%]). The relative reduction in MACEs with use of SGLT2 inhibitors was greater in older vs younger participants per 30-year increment in age (hazard ratio, 0.76 [95% CrI, 0.62 to 0.93]), and the relative reduction in MACEs with use of GLP-1 receptor agonists was less in older vs younger participants (hazard ratio, 1.47 [95% CrI, 1.07 to 2.02]). There was no consistent evidence for sex × treatment interactions with use of SGLT2 inhibitors and GLP-1 receptor agonists.

The SGLT2 inhibitors and GLP-1 receptor agonists were associated with lower risk of MACEs. Analysis of age × treatment interactions suggested that SGLT2 inhibitors were more cardioprotective in older than in younger people despite smaller reductions in HbA1c; GLP-1 receptor agonists were more cardioprotective in younger people.

The restricted mean survival time has been widely used in the field of medical research because of its clear physical and simple clinical interpretation. In this paper, we propose an efficient estimation that incorporates the auxiliary restricted mean survival information into the estimation of the proportional hazard (PH) model. Compared to conventional models that do not incorporate available auxiliary information, the proposed method improves efficiency in estimating regression parameters by utilizing the double empirical likelihood method. We prove that the estimator asymptotically follows a multivariate normal distribution with a covariance matrix that can be consistently estimated. To address scenarios where the PH assumption is violated, we also extended the method to the stratified Cox model. In addition, simulation studies show that the proposed estimators are more efficient than those derived from the conventional partial likelihood approach. A type 2 diabetes dataset is then used to evaluate the risk of antidiabetic drugs and demonstrate the proposed method.

Atherosclerotic cardiovascular disease (ASCVD) encompasses various phenotypes with elevated risks of major adverse cardiovascular events (MACEs). This study aimed to assess the comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) across diverse ASCVD phenotypes.

We conducted a systematic review and meta-analysis of randomized controlled trials evaluating GLP-1 RAs or SGLT2is against placebo or standard care in ASCVD patients. Primary outcomes included MACE, defined as cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. Risk ratios (RRs) with 95% confidence interval (CI) were calculated using a random-effects model.Twenty-six trials (151 789 patients) were included. Both GLP-1 RAs and SGLT2is significantly reduced MACE rates in ASCVD patients (RR 0.85; 95% CI 0.80-0.91 for both). GLP-1 RAs showed significant effectiveness in peripheral artery disease (RR 0.86; 95% CI 0.76-0.98) and post-acute cardiovascular events (RR 0.90; 95% CI 0.83-0.97). In ASCVD with heart failure, both drug classes reduced MACE (GLP-1 RAs: RR 0.73; 95% CI 0.63-0.84; SGLT2is: RR 0.86; 95% CI 0.78-0.95). SGLT2is significantly reduced MACE in ASCVD with chronic kidney disease (RR 0.84; 95% CI 0.72-0.99), particularly in severe albuminuria (RR 0.61; 95% CI 0.37-0.99).

GLP-1 RAs and SGLT2is exhibit distinct cardiovascular effectiveness profiles across ASCVD phenotypes. GLP-1 RAs show particular benefits in peripheral artery disease and post-acute cardiovascular events, while SGLT2is demonstrate unique advantages in ASCVD with comorbid chronic kidney disease. Both are effective in heart failure. These findings support tailored treatment strategies for diverse ASCVD participants based on specific comorbidities and risk factors.

To comprehensively evaluate the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i).

A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP-1RAs, or SGLT2i to placebo. Twenty-one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population-averaged odds ratios (ORs) with 95% CIs.

Twenty-six trials enrolling 198 177 participants were included. GLP-1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP-1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns.

Given the distinct benefit-risk profiles, the selection of glucose-lowering drugs should be individualized based on patient characteristics and risk factors.

To compare the risk of composite peripheral artery disease (PAD) surgical outcome, including peripheral revascularization and amputation procedures, between new users of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP-4is).

This retrospective cohort study of U.S. veterans age ≥18 years with diabetes who received care from the Veterans Health Administration was performed from 1 October 2000 to 31 December 2021. Data were linked to Medicare, Medicaid, and the National Death Index. New use of SGLT2i or DPP-4i medications as an add-on to metformin, sulfonylurea, or insulin treatment alone or in combination was evaluated for an association with PAD surgical procedure for peripheral revascularization and amputation. A Cox proportional hazards model for time-to-PAD event analysis compared the risk of a PAD event between SGLT2is and DPP-4is in a propensity score-weighted cohort with a competing risk of death and allowance for events to occur up to 90 days or 360 days after stopping SGLT2is.

The weighted cohort included 76,072 SGLT2i vs. 75,833 DPP-4i use episodes. The median age was 69 years, HbA1c was 8.4% (interquartile range [IQR] 7.5-9.4%), and the median diabetes duration was 10.1 (IQR 6.6-14.6) years. There were 874 and 780 PAD events among SGLT2i and DPP-4i users, respectively, for an event rate of 11.2 (95% CI 10.5-11.9) and 10.0 (9.4-10.6) per 1,000 person-years (adjusted hazard ratio [aHR] 1.18 [95% CI 1.08-1.29]). When PAD events were allowed for 360 days after SGLT2i use ended, the aHR was 1.16 (95% CI 1.06-1.26).

SGLT2i as an add-on diabetes therapy was associated with an increased cause-specific hazard of PAD surgeries compared with DPP-4i.

William Bayliss and Ernest Starling are not only famous as pioneers in cardiovascular physiology, but also responsible for the discovery of the first hormone (from the Greek 'excite or arouse'), the intestinal signalling molecule and neuropeptide secretin in 1902. Our research group focuses on neuropeptides and neuromodulators that influence cardiovascular autonomic control as potential biomarkers in disease and tractable targets for therapeutic intervention. Acute myocardial infarction (AMI) and chronic heart failure (CHF) result in high levels of cardiac sympathetic stimulation, which is a poor prognostic indicator. Although beta-blockers improve mortality in these conditions by preventing the action of the neurotransmitter noradrenaline, a substantial residual risk remains. Recently, we have identified the sympathetic co-transmitter neuropeptide-Y (NPY) as being released during AMI, leading to larger infarcts and life-threatening arrhythmia in both animal models and patients. Here, we discuss recently published data demonstrating that peripheral venous NPY levels are associated with heart failure hospitalisation and mortality after AMI, and all cause cardiovascular mortality in CHF, even when adjusting for known risk factors (including brain natriuretic peptide). We have investigated the mechanistic basis for these observations in human and rat stellate ganglia and cardiac tissue, manipulating NPY neurochemistry at the same time as using state-of-the-art imaging techniques, to establish the receptor pathways responsible for NPY signalling. We propose NPY as a new mechanistic biomarker in AMI and CHF patients and aim to determine whether specific NPY receptor blockers can prevent arrhythmia and attenuate the development of heart failure.

Elevated serum free fatty acid (FFA) concentration is associated with insulin resistance and is a hallmark of metabolic syndrome. A pathological feature of insulin resistance is impaired endothelial function.

To investigate the effect of FFA reduction with either acipimox, a nicotinic acid derivative that impairs lipolysis, or salsalate, a salicylate that reduces basal and inflammation-induced lipolysis, on insulin-mediated endothelium-dependent vasodilation.

This was a post hoc, combined analysis of two randomised, double-blind, placebo-controlled crossover trials. Sixteen subjects were recruited (6 with metabolic syndrome and 10 controls) and randomised to acipimox 250 mg orally every 6 h for 7 days or placebo. Nineteen subjects were recruited (13 with metabolic syndrome and 6 controls) and randomised to receive salsalate 4.5 g/day for 4 weeks or placebo. The primary outcome was the association between FFA concentration and insulin-mediated vasodilation, measured by venous-occlusion strain-gauge plethysmography at baseline and following FFA modulation with the study drugs.

At baseline, FFA concentration (R = -0.35, p = 0.043) and insulin sensitivity (HOMA-IR: R = -0.42, p = 0.016, Adipo-IR: R = -0.39, p = 0.025) predicted insulin-mediated vasodilation. FFA levels were significantly reduced after drug pretreatment (0.604 vs. 0.491 mmol/L, p = 0.036) while insulin levels, insulin sensitivity and inflammatory markers were unchanged. Despite a reduction in circulating FFA with drug therapy, neither insulin-stimulated vasodilation nor insulin sensitivity improved.

Short-term reduction of FFA concentration does not improve insulin-stimulated vasodilation in patients with metabolic syndrome.

ClinicalTrials.gov identifier: NCT00759291 and NCT00760019 (formerly NCT00762827).

Exposure to chronic psychosocial stress is a risk factor for metabolic cardiovascular disorders. Dipeptidyl peptidase-4 (DPP-4) plays essential roles in human pathobiology, and we recently showed that DPP-4 levels are increased by chronic stress in murine models. We here investigated the role of DPP-4 in stress-related cardiac injury and dysfunction in mice, focusing on oxidative stress and cardiac apoptosis. Male mice were randomly assigned to non-stress and two-week immobilized-stress groups for biological and morphological studies. On day 14 post-stress, stress had increased blood pressure, heart weight, cardiac myocyte size, and interstitial fibrosis, impaired cardiac diastolic function, and increased plasma levels of DPP-4 and glucose. The stressed mice also had increased levels of monocyte chemoattractant protein-1, inteleukin-6, gp91phox, matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of MMP-1/-2, caspase-8, and Bax genes and/or proteins and lowered levels of Bcl-2, p-Akt, and endothelial nitric oxide synthase (eNOS) proteins. DPP-4 inhibition by either a genetic or pharmacological approach ameliorated the stress-induced targeted molecular and morphological changes. In vitro, DPP-4 inhibition also mitigated the alterations in the targeted caspase-8, Bcl-2, eNOS, and p-Akt proteins in H9c2 cardiomyocytes in response to H2O2. DPP-4 inhibition appeared to improve the stress-induced cardiac injury and dysfunction in mice, possibly via the improvement of oxidative stress and apoptosis, suggesting that DPP-4 could become a novel therapeutic target for chronic psychological stress-related metabolic cardiovascular disorders.

Clinical trials showed that glucagon-like peptide-1 receptor agonist (GLP1-RA) significantly improved the control of diabetes and reduced body weight compared with dipeptidyl peptidase 4 inhibitor (DPP-4i). However, it is unclear whether GLP1-RA is effective compared with DPP-4i in patients with heart failure (HF) with type 2 diabetes (T2D). The purpose of this study was to evaluate the risk of GLP1-RA compared with DPP-4i in all-cause death and hospitalization in patients with HF and T2D.

This multicenter retrospective observational study using TriNetX, a global health care data and analytics platform, included patients with HF and T2D who had received GLP1-RA or DPP-4i from January 1, 2018, to December 31, 2022. Primary outcome was 12-month incidence of all-cause death. Secondary outcome was hospitalization. We used odds ratios (ORs) and 95% CIs to evaluate outcome measures.

Among 1 005 097 patients with HF and T2D, 57 965 initiated GLP1-RA and 77 098 initiated DPP-4i. After propensity score matching, the number of participants in both the GLP1-RA group and the DPP-4i group was 36 557. The proportion of 12-month incidence of all-cause death was lower in the GLP1-RA group than in the DPP-4i group (5.9% [2140/36 557] versus 8.5% [3103/36 557]; OR, 0.67 [95% CI, 0.63-0.71]).The proportion of 12-month incidence of hospitalization was also lower in the GLP1-RA group than in the DPP-4i group (42.3% [15 455/36 557] versus 48.5% [17 733/36 557]; OR, 0.78 [95% CI, 0.76-0.80]).

Use of GLP1-RA for patients with HF and T2D was associated with reduced 12-month incidence of all-cause death and hospitalization compared with DPP-4i.

Sodium glucose cotransporter 2 (SGLT2) inhibitors improve clinical outcomes in several populations including type 2 diabetes (T2D), chronic renal insufficiency, and heart failure (HF). However, limited data exist on their effects on atrial fibrillation (AF).

We conducted a retrospective cohort study using the National Health Insurance Service database. A total of 4,771 patients with T2D and AF who were newly prescribed SGLT2 inhibitors or DPP4 inhibitors were selected and matched in a 1:2 ratio by propensity score with 37 confounding variables. We assessed the effect of SGLT2 inhibitors on the composite outcome of either HF hospitalization or death.

Over a median follow-up of 31 months, patients on SGLT2 inhibitors were associated with a lower risk of hospitalizations for HF or mortality compared to those on DPP4 inhibitors (HR 0.61; 95% CI 0.44-0.85; P = 0.004). SGLT2 inhibitor use was also associated with a lower risk of mortality (HR 0.61; 95% CI 0.39-0.94; P = 0.025) and CV mortality (HR 0.43; 95% CI 0.21-0.86; P = 0.018), but not of MI (HR 1.22 [95% CI 0.72-2.09]; P = 0.461) or stroke (HR 1.00 [95% CI 0.75-1.33]; P = 0.980). The incidence of hospitalizations for HF, although statistically insignificant, tended to be lower in the SGLT2 inhibitor group (HR 0.63 [95% CI 0.39-1.02]; P = 0.062).

In a nationwide cohort of patients with T2D and AF, SGLT2 inhibitor was associated with a lower risk of mortality, which may suggest that SGLT2 inhibitors may be considered as the first-line antidiabetic medication in patients with T2D and AF.

Despite advancements in the neuroscience of consciousness, no new medications for disorders of consciousness (DOC) have been discovered in more than a decade. Repurposing existing US Food and Drug Administration (FDA)-approved drugs for DOC is crucial for improving clinical management and patient outcomes.

To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from March 2012 to October 2024 tested the model's predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 4047 patients in a coma from traumatic, vascular, or anoxic brain injury.

Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. After matching patients by age, sex, initial GCS score, coma etiology, and glycemic status, brain-injured patients with diabetes on incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, recovered from coma at significantly higher rates compared to both brain-injured patients with diabetes on non-incretin-based diabetes medications (95% confidence interval of 1.8-14.1% higher recovery rate, P = 0.0331) and brain-injured patients without diabetes (95% confidence interval of 2-21% higher recovery rate, P = 0.0272). Post matching, brain-injured patients with diabetes on incretin-based therapies also recovered at a significantly higher rate than patients treated with amantadine (95% confidence interval for the difference 2.4-25.1.0%, P = 0.0364). A review of preclinical studies identified several pathways through which saxagliptin and other incretin-based medications may aid awakening from both acute and chronic DOC: restoring monoaminergic and GABAergic neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-β, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage.

Our findings suggest incretin-based medications in general, and saxagliptin in particular, as potential novel therapeutic agents for DOC. Further prospective clinical trials are needed to confirm their efficacy and safety in DOC.

To characterize the geospatial distribution of the adoption of dipeptidyl-peptidase-4 inhibitor (DPP-4i) antidiabetics versus second generation sulfonylureas (SU).

Using Medicare claims data 2012-2017, two cohorts were built with new-users of either sitagliptin or saxagliptin each versus active comparator SU. For each ZIP Code tabulation area (ZCTA), the proportion DPP-4i prescribing was used in a local indicator of spatial association hotspot analysis. Multilevel logistic models were used to quantify the variation in medication use at the individual, ZCTA, state, and region levels.

DPP-4i utilization proportion was low (sitagliptin median = 0.22; interquartile range 0.15 to 0.33; saxagliptin median = 0.025; 0.00 to 0.069). Clustering was observed for sitagliptin (Moran's I = 0.32) and saxagliptin (Moran's I = 0.20). States and ZCTAs accounted for 8.1 % and 13.3 % of variation in sitagliptin and saxagliptin prescribing, respectively.

Variation across ZCTAs suggests neighborhood factors may be important determinants of prescribing.

Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n = 9) or LIN 2.5 mg (n = 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P < .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.

Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.

The impact of diabetes on incident cardiovascular disease in relation to the extent of atherosclerotic disease remains unclear. We aimed to investigate major adverse cardiovascular events (MACE) in patients with or without type 2 diabetes (T2DM) presenting with two extremes of atherosclerotic disease, those with angiographically documented minor coronary atherosclerotic lesions and those with symptomatic peripheral artery disease. We included 1238 patients from two prospective, long-term cohort studies. Patients underwent coronary angiography and/or sonography in order to assess the grade of atherosclerosis and were defined as having no signs of Atherosclerosis (n = 332; Group I), minor atherosclerosis (n = 425; Group II) and major atherosclerosis (n = 481; Group III). Cardiovascular events were recorded over a median follow-up period of 7.1 years (Q1 = 3.6 years, Q2 = 7.1 years, Q3 = 11.3 years), covering a total of 9533 patient years. We tested the hypothesis that T2DM infers the same relative risk increase irrespective of the atherosclerosis stage, considering 3-point MACE as the primary endpoint. Incident MACE was reported in 681 patients (51%). MACE occurred more frequently in patients with T2DM than in patients without T2DM (p < 0.001). Further, MACE occurred more frequently in group III (58.1%), than group II (34.1%) or group I (19.1%) (group I vs. group II vs. group III, p < 0.001). In a cox-regression-model, T2DM was a significant predictor of MACE in univariate analyses (HR = 2.43 [1.88-3.14], p < 0.001) and after multivariate adjustment for cardiovascular risk factors, as well as the different grades of atherosclerosis (HR = 1.37 [1.02-1.84], p = 0.034). Also, atherosclerosis grades predicted MACE (HR = 3.19 [2.75-3.70], p < 0.001) in univariate analyses, and also after multivariate adjustment for known cardiovascular risk factors, including T2DM (HR = 1.61 [1.31-1.98], p < 0.001). Finally, when testing for interactions between T2DM and stages of atherosclerosis on MACE we could not find any significant interaction (HR = 1.14 [0.86-1.52], p = 0.364). We conclude that T2DM infers an increased risk for MACE across anatomically and morphologically distinct stages of atherosclerosis.

Type 2 diabetes mellitus (T2DM) represents a major healthcare condition of the 21st century. It is characterised by persistently elevated blood glucose occurring as a result of peripheral insulin resistance and reduced insulin production which may lead to multiple long-term health conditions such as retinopathy, neuropathy, and nephropathy. The estimated number of individuals suffering from diabetes mellitus (DM) is expected to rise to 591 million by the year 2035 with 4.4 million in the United Kingdom (UK) alone, 90% of which is attributed to T2DM. Moreover, a significant proportion of individuals may have undetected diabetes mellitus, especially among those presenting with symptoms of ischaemic heart disease (IHD). This is particularly important in those individuals presenting with acute coronary syndromes (ACS) who are at the highest risk of complications and sudden cardiac death. Identifying abnormal levels of common biochemical markers of diabetes, such as capillary blood glucose or glycated haemoglobin (HbA1c) in these patients is important for early diagnosis, which will then allow for timely intervention to improve outcomes. However, a significant proportion of individuals who meet the criteria for the diagnosis of diabetes remain undiagnosed, representing missed opportunities for early intervention. This may result in a prolonged period of untreated hyperglycaemia, which can result resulting in significant further microvascular and macrovascular complications. There is an increased risk of IHD, heart failure, cerebrovascular accidents (CVA), and peripheral artery disease (PVD). These account accounting for 50% of deaths in patients with T2DM. Cardiovascular diseases in the context of diabetes particular represent a significant cause of morbidity and mortality with a two to three times higher risk of cardiovascular disease in individuals with T2DM than in those without the condition normo-glycaemia. In the United Kingdom UK alone, around 120 amputations, 770 CVA, 590 heart attacks, and more than 2300 presentations with heart failure per week are attributed to diabetes DM. with One 1 in six 6 hospital beds and around 10% of the healthcare budget may be being spent on managing diabetes DM or its complications. Therefore, it represents a significant burden on our healthcare system.