Type 2 diabetes mellitus (T2DM) is a global health crisis, with cardiovascular disease (CVD) accounting for 75% of mortality in this population. Despite advances in managing traditional risk factors, such as low-density lipoprotein cholesterol (LDL) cholesterol reduction (IMPROVE-IT, FOURIER), antithrombotic therapies (PEGASUS, COMPASS), and triglyceride-lowering agents (REDUCE-IT), a substantial residual cardiovascular risk persists, driven in part by chronic low-grade systemic inflammation. Chronic low-grade inflammation is a central driver of cardiovascular-kidney-metabolic (CKM) syndrome in T2DM, perpetuating residual cardiovascular risk despite optimal management of traditional risk factors. This narrative review synthesizes evidence on how inflammation accelerates coronary heart disease (CHD), heart failure (HF), stroke, diabetic kidney disease (DKD), and peripheral artery disease (PAD). We evaluate the anti-inflammatory mechanisms of current therapies such as statins, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, as well as emerging agents like colchicine and interleukin (IL)-1β/IL-6 inhibitors, emphasizing their differential efficacy across CKM traits. By integrating pathophysiological insights with clinical trial data, we propose biomarker-guided strategies to target inflammation as a modifiable risk factor, offering a roadmap to bridge the gap in diabetes-related cardiovascular care.

Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and 'real-world' studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).

Considering the important role of obesity and related factors in different societies on increasing the burden of non-communicable diseases, in this review we will investigate the possible effects of Beinaglutide on these risk factors.

In order to identify all randomized controlled trials that investigated the effects of Beinaglutide on cardiometabolic factors, a systematic search was conducted in the original databases using predefined keywords until July 2024. The pooled weighted mean difference (WMD) and 95% confidence intervals were computed using the random-effects model.

   A quantitative meta-analysis results from seven studies with 872 participants showed that Beinaglutide has a significant lowering effect on weight (WMD: -3.74 kg; 95% CI: -5.03, -2.45), body mass index (BMI) (WMD:-1.64 kg/m2; 95% CI: -2.10, -1.17), waist circumference (WC) (WMD: -3.19 cm; 95% CI: -4.65 to -1.73), triglyceride (TG) levels (WMD: -0.14 mmol/l with; 95% CI: -0.25, -0.04), and systolic blood pressure (SBP) (WMD: -1.76 mm/Hg; 95% CI: -2.61, -0.91). In addition, body weight loss was greater in doses < 0.4 mg compared to doses ≥ 0.4 mg.

The results of this meta-analysis show that Beinaglutide is effective in reducing parameters related to obesity, TG as well as SBP.

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a novel risk factor for cardiovascular diseases. CHIP is characterized by the expansion of hematopoietic stem cell clones harboring somatic mutations in genes such as TET2, DNMT3A, and ASXL1, which are implicated in inflammation, atrial remodeling, and hypercoagulability. These mutations foster a pro-inflammatory and pro-thrombotic environment conducive to arrhythmogenesis, thereby linking CHIP to the development and progression of atrial fibrillation (AF). Mechanistic insights indicate that CHIP contributes to atrial fibrosis, disrupts calcium signaling, and exacerbates oxidative stress, all of which heighten susceptibility to AF. Clinical studies, including epidemiological and Mendelian randomization analyses, further support the association between CHIP and an increased risk of both incident and progressive AF, with specific mutations such as TET2 and ASXL1 identified as significant contributors. Additionally, CHIP has been linked to adverse outcomes in AF, including elevated rates of heart failure, thromboembolism, and mortality. Understanding CHIP's role in AF pathophysiology offers opportunities for the development of precision medicine approaches, providing novel avenues for early intervention and targeted AF treatment. This review synthesizes current mechanistic and clinical evidence on the role of CHIP in AF, emphasizes its potential as a biomarker for risk stratification, and explores emerging therapeutic strategies targeting CHIP-associated pathways.

American culture encourages overconsumption, fueled by ubiquitous availability and pervasive marketing of ultra-processed foods and other addictive substances. This chronic overindulgence has contributed to rising rates of obesity, type 2 diabetes (T2D), substance abuse, mental health disorders and premature mortality. Glucose-like peptide-1 agonists (GLP-1RAs) affect the brain's reward pathway that mediates addiction to foods and various other substances. Evolving data suggest that tirzepatide and semaglutide may be the first effective "anti-consumption" agents with potential applications in reducing food cravings, obesity, alcohol consumption, nicotine addiction, recreational drug use, and even uncontrollable shopping behaviors. Tirzepatide and semaglutide, unlike prior weight-loss drugs, are effective and relatively safe/well-tolerated medications that are associated with reduced risks for myocardial infarction, stroke, cardiovascular death, heart failure, progressive kidney and liver disease, obstructive sleep apnea, debilitating osteoarthritis, polycystic ovarian syndrome, neurodegenerative disease and premature mortality. Observational studies show that GLP-1RAs are associated with spontaneous nonvolitional reductions in use of alcohol, nicotine, and recreational drugs. Because obesity and substance abuse are so prevalent in the United States, GLP-1RA drugs may be uniquely helpful in addressing overconsumption and addiction issues thereby improving overall health and life expectancy.

Tirzepatide, a long-acting, glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, reduced urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes and high cardiovascular risk in the SURPASS-4 trial. To examine the generalizability of these findings, we assessed change from baseline in UACR for tirzepatide (5, 10, and 15 mg) compared with active and placebo treatment in a broad population from the SURPASS-1-5 trials.

This post hoc analysis examined data from the overall pooled SURPASS-1-5 population and subgroups defined by baseline UACR ≥30 mg/g. A mixed model for repeated measures was used to analyze on-treatment data from baseline to the end-of-treatment visit. Study identifier was included in the model as a covariate.

The adjusted mean percent change from baseline in UACR for tirzepatide 5, 10, or 15 mg compared with all pooled comparators was -19.3% (95% CI -25.5, -12.5), -22.0% (-28.1, -15.3), and -26.3 (-32.0, -20.0), respectively, at week 40/42. Results were similar across pooled placebo, active, and insulin comparator studies. UACR lowering appeared more pronounced in subgroups with UACR ≥30 mg/g. Mediation analysis findings suggested that approximately one-half of the reduction in albuminuria associated with tirzepatide may be weight loss related. There was no difference in eGFR between tirzepatide and pooled comparators at week 40/42.

In this post hoc analysis in people with type 2 diabetes, including those with chronic kidney disease, tirzepatide was associated with a clinically relevant decreased UACR versus comparators, suggesting a potential kidney-protective effect.

The global rise in diabetes prevalence has significantly contributed to the increasing burden of atherosclerotic cardiovascular disease (ASCVD), a leading cause of morbidity and mortality in this population. Diabetes accelerates atherosclerosis through mechanisms such as hyperglycemia, oxidative stress, chronic inflammation, and epigenetic dysregulation, leading to unstable plaques and an elevated risk of cardiovascular events. Despite advancements in controlling traditional risk factors like dyslipidemia and hypertension, a considerable residual cardiovascular risk persists, highlighting the need for innovative therapeutic approaches. Emerging treatments, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, epigenetic modulators, and RNA-based therapies, are showing promise in addressing the unique challenges of diabetes-associated ASCVD. Precision medicine strategies, such as nanoparticle-based drug delivery and cell-specific therapies, offer further potential for mitigating cardiovascular complications. Advances in multiomics and systems biology continue to deepen our understanding of the molecular mechanisms driving diabetes-associated atherosclerosis. This review synthesizes recent advances in understanding the pathophysiology and treatment of diabetes-related atherosclerosis, offering a roadmap for future research and precision medicine approaches to mitigate cardiovascular risk in this growing population.

Type 2 diabetes (T2D), as well as obesity, are risk factors for chronic kidney disease (CKD) and end-stage renal disease. The renal impacts of glucose-lowering and weight-lowering drugs and their potential benefits in preventing CKD often guide clinicians in choosing them appropriately. Only limited data based on randomized controlled trials (RCTs) is currently available on the renal effects and safety profile of tirzepatide.

To explore the renal benefits and safety of tirzepatide vs controls.

RCTs involving patients receiving tirzepatide for any indication in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases. The co-primary outcomes were percent change from baseline (CFB) in urine albumin-to-creatinine ratio (UACR) and absolute CFB in estimated glomerular filtration rate (eGFR; in mL/min/1.73 m2); the secondary outcome was tirzepatide's renal safety profile. RevMan web was used to conduct meta-analysis using random-effects models. Outcomes were presented as mean differences (MD) or risk ratios with 95% confidence intervals.

Fifteen RCTs (n = 14471) with mostly low risk of bias (RoB) were included. Over 26-72 weeks, tirzepatide 10 mg [MD -26.95% (-40.13, -13.76), P < 0.0001] and 15 mg [MD -18.03% (-28.58, -7.47), P = 0.0008] were superior to placebo in percent reductions of UACR. Tirzepatide, at all doses, outperformed insulin in percent reductions of UACR. Compared to the placebo, the percent UACR reduction was greater in subjects with T2D than those with obesity but without T2D (MD -33.25% vs -7.93%; P = 0.001). The CFB in eGFR with all doses of tirzepatide was comparable [5 mg: MD 0.36 (-1.41, 2.14); 10 mg: MD 1.17 (-0.22, 2.56); 15 mg: MD 1.42 (-0.04, 2.88)]; P > 0.05 for all] vs insulin. Tirzepatide (pooled and separate doses) did not increase the risks of adverse renal events, urinary tract infection, nephrolithiasis, acute kidney injury, and renal cancer compared to the placebo, insulin, and glucagon-like peptide-1 receptor agonists.

Short-term data from RCTs with low RoB suggests that tirzepatide positively impacts UACR without detrimental effects on eGFR in subjects with T2D and obesity without T2D, with a reassuring renal safety profile. Larger RCTs are warranted to prove the longer-term renal benefits of tirzepatide, which might also prevent eGFR decline and worsening of CKD.

The study objective was to describe characteristics and utilization patterns of tirzepatide users with type 2 diabetes (T2D) using the Healthcare Integrated Research Database in the USA.

Adults (≥18 years) included had T2D diagnosis; ≥1 tirzepatide claim (May 2022-January 2023; first claim date = index date); and continuous medical and pharmacy enrollment during the 6-month baseline and follow-up periods from the index date. Baseline demographics, clinical characteristics, and 6-month follow-up dosing and treatment patterns were summarized descriptively.

The study included 15,665 patients with T2D initiating tirzepatide (mean age: 53.2 years; 58.5% women; 76.7% non-Hispanic white). During the 6-month baseline period, hypertension (69.2%), dyslipidemia (69.2%), overweight/obesity (58.4%), and obstructive sleep apnea (22.8%) were commonly reported comorbidities. Over half of the patients (51.2%) had used glucagon-like peptide-1 (GLP-1) receptor agonist (RA) before initiating tirzepatide. The mean glycated hemoglobin (HbA1c) was 7.6% (n = 5175), and 58.4% of these patients had HbA1c ≥7%. The mean body mass index (BMI) was 38.7 kg/m2 (n = 3459), and 87.8% of these patients either had Class 1, 2, or 3 obesity. Among patients with a single prescription on each fill date (N = 14,986), 84.1% initiated tirzepatide at ≤5 mg dose. During sixth prescription refill (n = 7304), 56.5% were receiving tirzepatide doses of <10 mg. During the 6-month follow-up period, 69.6% of patients had ≥1 dose escalation and 17.2% had ≥1 dose de-escalation. The mean time to first dose escalation was 59.1 days and first dose de-escalation was 104.8 days. Tirzepatide adherence (proportion of days covered [PDC] ≥80%) was 57.5% and persistence (45-day gap) was 73.3% at 6 months. Of patients who discontinued tirzepatide (n = 4177; 26.7%), 29.1% re-initiated tirzepatide (45-day gap).

Patients with T2D initiating tirzepatide had multimorbidity; uncontrolled diabetes; and mean BMI was consistent with Class 2 obesity. Patients showed favorable tirzepatide adherence and persistence profiles, and the majority remained at <10 mg doses during the 6-month follow-up period.

Effective therapeutic approaches for the treatment of diabetic nephropathy (DN) with irreversible deterioration of renal function are currently lacking. In this study, we aimed to investigate the ability of the glucagon-likepeptide-1 (GLP-1)/ gastric inhibitory polypeptide (GIP) dual agonist, tirzepatide to alleviate DN in mice and its underlying mechanisms.

We investigated the reno-protective effect of semaglutide and tirzepatide in a mouse model of DN, an insulin-treated positive control group was also included. Indicators of diabetic kidney injury and oxidative stress biomarkers were also assessed. RNA-seq analysis of renal tissue was conducted to explore the potential mechanism of action of tirzepatide and in vitro cell experiments were performed to validate its pathway.

In DN mice, one-third the dose of tirzepatide was consistent with that of semaglutide in lowering glucose, body weight, and urine albumin-to-creatine ratio (UACR) and in improving antioxidative stress activities, while insulin treatment could not effectively restore the UACR. RNA-seq analysis revealed that the PI3K-AKT signaling pathway was significantly enriched after tirzepatide treatment compared with that in the DN model. Confirmatory experiments demonstrated that tirzepatide regulated oxidative stress and the PI3K-AKT pathway in mouse podocyte cell-5 cells exposed to high glucose. Further mechanistic validation suggested that the antioxidative activity of tirzepatide was reversed by PI3K inhibitor.

These findings expand the potential effects and mechanics of tirzepatide in the treatment of DN, which may provide a novel therapeutic approach and therapeutic target for DN treatment.

Chronic kidney disease (CKD) attributed to diabetes, termed diabetic kidney disease (DKD), is increasing with the rising global prevalence of diabetes. Patterns of DKD onset and progression have shifted in recent years because of population aging and advances in the treatment of diabetes. Prevention of the onset and progression of micro/macro-albuminuria is possible through comprehensive and strict management of lifestyle, blood glucose, blood pressure, and lipids in people with diabetes and early DKD. Renin-angiotensin system (RAS) inhibitors have also been shown to effectively slow the progression of CKD in people with diabetes and micro/macro-albuminuria. However, the effect of improving kidney outcomes with RAS inhibitors in people with advanced DKD is limited, and the residual risk remains very high. A recent rapid expansion of treatment options include sodium-glucose co-transporter-2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, which have demonstrated additional protective effects for the kidneys when used in addition to the standard therapy with RAS inhibitors, even in people with advanced DKD. Early diagnosis and therapeutic intervention can be expected to delay progression to end-stage kidney failure. This perspective outlines the diagnostic and therapeutic evolution of DKD to date.

Atrial fibrosis is a hallmark of atrial cardiomyopathy and plays a pivotal role in the pathogenesis of atrial fibrillation (AF), contributing to its onset and progression. The mechanisms underlying atrial fibrosis are multifaceted, involving stretch-induced fibroblast activation, oxidative stress, inflammation, and coagulation pathways. Variations in fibrosis types-reactive and replacement fibrosis-are influenced by patient-specific factors such as age, sex, and comorbidities, complicating therapeutic approaches. The heterogeneity of fibrosis leads to distinct electrophysiological abnormalities that promote AF via reentrant activity and enhanced automaticity mechanisms. Despite advancements in imaging, such as late gadolinium enhancement CMR and electroanatomical mapping, challenges in accurately quantifying fibrosis persist. Emerging therapeutic strategies include antifibrotic agents targeting the renin-angiotensin-aldosterone system, novel pathways like TGF-β signaling, and cardio-metabolic drugs like SGLT2 inhibitors and GLP-1 receptor agonists. Innovative interventions, including microRNA modulation and lipid nanoparticle-based therapies, show promise but require validation. Knowledge gaps remain in correlating clinical outcomes with fibrosis patterns and optimizing diagnostic tools. Future research should focus on precise phenotyping, integrating advanced imaging with molecular biomarkers, and conducting robust trials to evaluate antifibrotic therapies' efficacy in reducing AF burden and related complications.

This study aimed to explore the association of globulin and albumin-to-globulin ratio (AGR) with diabetic kidney disease (DKD) and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

This study used data from the China National Diabetic Chronic Complications Study in Shaanxi Province. From April to May 2019, T2DM patients at disease surveillance sites in Shaanxi Province were investigated using a stratified multi-stage sampling method. The participants completed questionnaire surveys, anthropometric and blood pressure measurements, laboratory tests, and fundus photograph examinations. Multivariate Logistic regression and restricted cubic spline model were used to analyze the association of globulin and AGR with DKD and DR, and subgroup analysis was performed according to age, sex, and diabetes duration to test the stability of the results.

A total of 1494 T2DM patients were enrolled in this study, including 495 patients with DKD (33.1%) and 341 patients with DR (22.8%). After adjusting for all covariates, globulin and AGR were linearly associated with DKD. For every 1g/L increase in globulin level, the risk of DKD increased by 7% (OR=1.07, 95% CI=1.04, 1.10). For every 1 unit increase in AGR, the risk of DKD was reduced by 55% (OR=0.45, 95% CI=0.28, 0.72). Subgroup analysis showed that the association between globulin and DKD was consistent across all subgroups, and the association between AGR and DKD was consistent across subgroups of age and diabetes duration; however, only in males, higher AGR was associated with a reduced risk of DKD. No association was found between globulin and AGR with DR.

Globulin is an independent risk factor and AGR is an independent protective factor for DKD. Screening for DKD should be performed in T2DM patients with high globulin and low AGR levels, especially in men.

Several new treatments have recently been shown to have heart and kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, it is unclear how the different molecular pathways affected by the therapies may overlap. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone in mice with comorbid diabetes, focusing on the regulation of expression of the glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor (GIPR) and glucagon receptor (GCGR), which are targets of approved or investigational therapies in diabetes.

Male C57BL/6J mice were fed a high fat diet for 26 weeks. Twelve weeks into the high fat diet feeding period, mice received an intraperitoneal injection of streptozotocin before being followed for the remaining 14 weeks (DMHFD mice). After 26 weeks, mice were fed a high fat diet containing finerenone (100 mg/kg diet) or high fat diet alone for a further 2 weeks. Cell culture experiments were performed in primary vascular smooth muscle cells (VSMCs), NRK-49 F fibroblasts, HK-2 cells, and MDCK cells.

DMHFD mice developed albuminuria, glomerular mesangial expansion, and diastolic dysfunction (decreased E/A ratio). Glp1r and Gcgr were predominantly expressed in arteriolar VSMCs and distal nephron structures of mouse kidneys respectively, whereas Gipr was the predominant of the three transcripts in mouse hearts. Kidney Glp1r and Gcgr and cardiac Gipr mRNA levels were reduced in DMHFD mice and this reduction was negated or attenuated with finerenone. Mechanistically, finerenone attenuated upregulation of the profibrotic growth factor Ccn2 in DMHFD kidneys, whereas recombinant CCN2 downregulated Glp1r and Gcgr in VSMCs and MDCK cells respectively.

Through its anti-fibrotic actions, finerenone reverses Glp1r and Gcgr downregulation in the diabetic kidney. Both finerenone and GLP-1R agonists have proven cardiorenal benefits, whereas receptor co-agonists are approved or under development. The current findings provide preclinical rationale for the combined use of finerenone with the GLP-1R agonist family. They also provide mechanism of action insights into the potential benefit of finerenone in people with diabetes for whom GLP-1R agonists or co-agonists may not be indicated.

This study aims to review relevant research and assess the diagnostic value of serum cystatin C (CysC) for post-cardiac surgery acute kidney injury (PCSAKI).

We searched databases (PubMed, Embase, Cochrane, WanFang, CNKI, VIP) for literature published up to January 10, 2024. Quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Extracted data from eligible studies and summarized sensitivity, specificity, and area under the curve (AUC) values.

A total of 24 studies involving 3,427 patients were included. The estimated diagnostic sensitivity of CysC for PCSAKI was 0.67 (95% CI, 0.57-0.76), with a specificity of 0.87 (95% CI, 0.81-0.91). The positive likelihood ratio (+LR) was 5.17 (95% CI, 3.45-7.73), and the negative likelihood ratio (-LR) was 0.38 (95% CI, 0.28-0.51). The diagnostic odds ratio (DOR) was 14 (95% CI, 7-26), the diagnostic score (DS) was 2.62 (95% CI, 1.99-3.24), and AUC was 0.86 (95% CI, 0.83-0.89). The sub-analysis results indicate that gender distribution, serum storage temperature, CysC detection method, and detection time all have a significant impact on sensitivity and specificity.

CysC has high specificity and good sensitivity in diagnosing PCSAKI during the perioperative period, with better detection results 24 hours before surgery, making it suitable for early detection. However, whether and how CysC is commonly used in clinical diagnosis still requires further research and clinical trials.

Obstructive sleep apnea (OSA) is a prevalent condition associated with increased cardiovascular risk, particularly in individuals with comorbid obesity and type 2 diabetes (T2D). Despite the widespread use of continuous positive airway pressure (CPAP) for OSA management, adherence remains suboptimal, and CPAP has not consistently demonstrated reductions in surrogate cardiovascular events. Recently, attention has focused on glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors as potential therapeutic agents for mitigating cardiovascular risk in OSA patients. These agents, originally developed for T2D management, have demonstrated pleiotropic effects, including significant weight loss, blood pressure reduction, and amelioration of endothelial dysfunction and arterial stiffness, along with anti-inflammatory benefits, which may be particularly beneficial in OSA. Emerging clinical evidence suggests that GLP-1RAs and SGLT2 inhibitors can reduce OSA severity and improve daytime sleepiness, potentially reversing the adverse cardiovascular effects observed in OSA. This review explores the pathophysiological mechanisms linking OSA with cardiovascular disease and evaluates the potential therapeutic roles of GLP-1RAs and SGLT2 inhibitors in addressing cardiovascular risk in OSA patients. Further research, including long-term clinical trials, is necessary to establish the effectiveness of these therapies in reducing cardiovascular events and improving patients' reported outcomes in this population.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD). Most supportive evidence of a kidney-protective effect of the GLP-1RA class of medications has been derived from kidney-related outcomes reported from cardiovascular outcome trials (CVOTs). GLP-1RAs have been shown to reduce albuminuria, mitigate cardiovascular risk, and possibly attenuate estimated glomerular filtration rate (eGFR) decline. The kidney-protective effects of GLP-1RAs are thought to be attributed to their anti-inflammatory, antioxidant, and vasodilatory properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure in people with T2DM. The Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) is the first major trial assessing the potential of a GLP-1RA to slow progression of kidney disease in people with established CKD to clinically important kidney end points. On March 5, 2024, the top line result from FLOW was announced with semaglutide 1.0 mg being reported to reduce the primary end point of the trial by a significant 24% compared with placebo. Here, we summarize the kidney outcomes reported from CVOTs for the GLP-1RA class of medication and briefly describe kidney outcomes from other major GLP-1RAs trials. We also discuss a potential role of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, as a kidney-protective agent.

Obesity is a significant predisposing factor for heart failure with preserved ejection fraction (HFpEF). Although a substantial proportion of individuals with HFpEF also have obesity, those with obesity are under-represented in clinical trials for heart failure. In turn, current guidelines provided limited recommendations for the medical management of this patient population. Both obesity and diabetes induce a pro-inflammatory state that can contribute to endothelial dysfunction and coronary microvascular impairment, finally resulting in HFpEF. Additionally, obesity leads to increased epicardial and chest wall adiposity, which enhances ventricular interdependence. This condition is further aggravated by plasma and blood volume expansion and excessive vasoconstriction, ultimately worsening HFpEF. Despite the well-documented benefits of GLP-1 receptor agonists in subjects with diabetes, obesity, or both, their role in obesity-related HFpEF remains unclear. In light of the recently published literature, this review aims to investigate the potential mechanisms and synthesize the available clinical evidence regarding the role of GLP-1 receptor agonists in patients with obesity-related HFpEF.

We sought to determine whether treatment with tirzepatide in type 2 diabetes mellitus (T2DM) patients can increase the odds for achieving normoglycemia, compatible with glycated hemoglobin levels lower than 5.7 %. We demonstrated that treatment with tirzepatide versus control increased the odds for achievement of normoglycemia by >16 times.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes (T2DM) with chronic kidney disease (CKD). This class of medication has demonstrated promising results in reducing albuminuria, preserving estimated glomerular filtration rate (eGFR), and mitigating cardiovascular (CV) risk, making them potential therapeutic options for individuals with CKD. The kidney protective effects of GLP-1RAs extend beyond glycaemic control, and are thought to be attributed to their anti-inflammatory, antioxidant, and natriuretic properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure, or reduce CV and kidney related death in people with T2DM and CKD. The Research Study to See How Semaglutide (a once weekly subcutaneous administered GLP-1RA) Works Compared to Placebo in People with Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) was recently stopped because of efficacy. The primary end point for the FLOW trial consists of a composite endpoint of (i) onset of chronic kidney failure; (ii) death from kidney failure; (iii) cardiovascular death; and (iv) onset of a persistent ≥50% reduction in eGFR from baseline. It has also been reported by the sponsors of the trial that the primary end point of the trial was reduced by 24% with both CKD and CV outcomes contributing to risk reduction. In anticipation of the results of the FLOW trial being published, we review the current evidence surrounding kidney outcomes and proposed kidney protective pathways associated with GLP-1RA use.

To investigate effects of tirzepatide, a dual receptor agonist for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), on eating behaviors.

Eating behaviors were evaluated by using a validated questionnaire survey in 33 Japanese patients with type 2 diabetes mellitus (T2DM) (mean age: 51.8 years) who were treated with tirzepatide (2.5 mg/week for 4 weeks and then 5.0 mg/week) for 6 months (M).

Treatment with tirzepatide significantly decreased median hemoglobin A1c (HbA1c) (baseline/3 M/6 M: 7.3 %/6.0 %/5.8 %), mean body weight (BW) (baseline/3 M/6 M: 87.7 kg/82.0 kg/79.6 kg) and mean relative score of eating behaviors (baseline/3 M/6 M: 57.0/50.7/45.9). In the GLP-1 receptor agonist (GLP-1RA) naïve group (n = 20, men/women: 13/7), HbA1c and BW were continuously decreased up to 6 M. Changes in eating behaviors were mainly observed in the first 3 M. In the GLP-1RA non-naïve group (n = 13, men/women: 8/5), reductions in HbA1c and BW were predominant in the first 3 M, and changes in eating behaviors were observed up to 6 M. There were no significant correlations of changes in scores of eating behaviors with changes in glycemic control or those in BW.

Tirzepatide ameliorates eating behaviors as well as glycemic management and obesity in Japanese patients with T2DM, and the patterns of improvement are partially dependent on prior exposure to GLP-1RAs.

Elevated urine albumin-to-creatinine ratio (UACR) is an established risk factor for microvascular disease in the general population. However, it is unclear whether UACR is associated with arterial stiffness in diabetes. We aimed to assess the relationship between UACR levels and the risk of arterial stiffness in patients with diabetes.

From July 2021 to February 2023, a total of 1039 participants were assessed for the risk of arterial stiffness, which was evaluated by brachial-ankle pulse wave velocity (baPWV). The value of UACR≥30 mg/g was defined as high UACR. The UACR level had an abnormal distribution and was log2-transformed for analyses to reduce skewness and volatility. High baPWV was evaluated as categorical variables divided by the highest quartile of the values by sex. The relationship between UACR and arterial stiffness was analyzed by linear curve fitting analyses. Multiple logistic regression models were used to analyze the crude and adjusted odds ratio (OR) of UACR for high baPWV with 95% confidence interval (CI). In addition to applying non-adjusted and multivariate-adjusted models, interaction and stratified analyses were also carried out.

The baPWV level was significantly higher in the high UACR group compared with that in the normal UACR group (1861.84 ± 439.12 cm/s vs 1723.13 ± 399.63 cm/s, p<0.001). Adjusted smoothed plots suggested that there are linear relationships between log2-transformed UACR and high baPWV, and Spearman correlation coefficient was 0.226 (0.176-0.276, p<0.001). The OR (95% CI) between log2-transformed UACR and high baPWV were 1.26 (1.19-1.33, p<0.001), and 1.16 (1.08-1.25, p<0.001) respectively in diabetic patients before and after adjusting for potential confounders.

The elevated UACR was associated with arterial stiffness in Chinese patients with diabetes.

Kidneys have an amazing ability to adapt to adverse situations, both acute and chronic. In the presence of injury, the kidney is able to activate mechanisms such as autoregulation or glomerular hyperfiltration to maintain the glomerular filtration rate (GFR). While these adaptive mechanisms can occur in physiological situations such as pregnancy or high protein intake, they can also occur as an early manifestation of diseases such as diabetes mellitus or as an adaptive response to nephron loss. Although over-activation of these mechanisms can lead to intraglomerular hypertension and albuminuria, other associated mechanisms related to the activation of inflammasome pathways, including endothelial and tubular damage, and the hemodynamic effects of increased activity of the renin-angiotensin-aldosterone system, among others, are recognized pathways for the development of albuminuria. While the role of albuminuria in the progression of chronic kidney disease (CKD) is well known, there is increasing evidence of its negative association with cardiovascular events. For example, the presence of albuminuria is associated with an increased likelihood of developing heart failure (HF), even in patients with normal GFR, and the role of albuminuria in atherosclerosis has recently been described. Albuminuria is associated with adverse outcomes such as mortality and HF hospitalization. On the other hand, it is increasingly known that the systemic effects of congestion are mainly preceded by increased central venous pressure and transmitted retrogradely to organs such as the liver or kidney. With regard to the latter, a new entity called congestive nephropathy is emerging, in which increased renal venous pressure can lead to albuminuria. Fortunately, the presence of albuminuria is modifiable and new treatments are now available to reverse this common risk factor in the cardiorenal interaction.