Bioinspired nanotopographical carriers have emerged as innovative cancer therapy strategies, mimicking natural processes to enhance targeted delivery and reduce systemic toxicity. This study presents the development of virus-like mesoporous silica nanoparticles (MSN) as a delivery platform for repurposed metformin (MTF) in a topical multi-stimuli responsive system for melanoma treatment. Metformin-loaded virus-like MSN (MTF-MSN) were fabricated and incorporated into a thermo-responsive gelling system. The particles were evaluated for morphology, zeta potential (ZP), particle size (PS), entrapment efficiency (EE%), Fourier-transform infrared (FT-IR) spectroscopy, MTT cytotoxicity assay, in vitro release, and in a melanoma in vivo model. The particles exhibited a spherical morphology, a zeta potential of +31.9 ± 1.45 mV, and a particle size of 197 ± 3.47 nm, ideal for skin penetration. MTF-MSN demonstrated significant antiproliferative activity against melanoma A375 cells, with lower IC50 values (192 μg/mL) compared to free MTF (>300 μg/mL). Sustained, pH-sensitive MTF release was observed over 48 h at pH 7.4 and 6 h at pH 5.5. In vivo studies showed enhanced anti-cancer efficacy of MTF-MSN, evidenced by elevated caspase-3 and Neurofibromin Type-1 (NF-1) levels, along with suppressed angiogenesis markers VEGF and NRAS. The MTF-MSN-treated group exhibited superior outcomes compared to free MTF and controls (p < 0.05). This innovative bioinspired MTF-MSN hydrogel system optimizes MTF delivery for melanoma therapy, pioneering advancements in drug repurposing and nano-oncology.

Sulfonylureas (SU) are commonly prescribed as oral hypoglycemic agents for the management of diabetes mellitus (DM). We postulated that SU possess antimicrobial properties due to their structural resemblance to the antimicrobial agent sulfamethoxazole. Using data from Taiwan's National Health Insurance Research Database, we enrolled patients diagnosed with DM between 2000 and 2013 and followed them for a three-year period. Patients who consistently used SU were categorized into the SU cohort, while those who had never used SU formed the non-sulfonylurea (non-SU) cohort. The primary study endpoints were diagnoses of pneumonia and urinary tract infections (UTIs). Within the database, we identified a total of 15,458,554 patients with DM, with 754,601 (4.88%) in the SU cohort and 2,244,436 (14.52%) in the non-SU cohort. After individual matching based on age, gender, index day, and propensity score of comorbidities, we included 663,056 patients in each cohort. The cumulative incidence of pneumonia and UTI was 29,239 (4.41%) and 60,733 (9.16%) in the SU cohort, respectively, and 24,599 (3.71%) and 56,554 (8.53%) in the non-SU cohort, respectively. Our findings indicated that the use of SU increased the risk of pneumonia (1.26-1.60 times) and UTI (1.13-1.22 times), while also potentially offsetting the protective effects of metformin. This pharmacoepidemiological study represents a concerted effort to assess latent drug properties that may have a significant impact on the clinical management of patients with DM.

Background/Objectives: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by fibrosis and vascular damage, significantly increasing the risk of heart failure (HF). Methods: This cross-sectional study included 61 SSc patients (92% female, mean age 63 ± 13 years), excluding those with pulmonary arterial hypertension, referred to a tertiary pulmonary hypertension center. HF stages were classified according to updated guidelines. Clinical, echocardiographic, hemodynamic, and functional capacity data were analyzed in relation to HF stages. Results: A total of 48% of patients had pre-symptomatic HF (5% stage A, 43% stage B), while 38% had symptomatic HF (stage C). Advanced HF stages were significantly associated with older age (p = 0.02) and multiorgan involvement (p = 0.045) but not with SSc subtype or autoantibodies. Structural and functional echocardiographic abnormalities were prevalent (77% and 10%, respectively). Markers of elevated ventricular filling pressure such as left atrial volume (p = 0.011) and E/e' ratio (p = 0.03) correlated with HF severity. Functional impairment was observed with lower 6 min walk test (6MWT) distance (p = 0.017), reduced VO2 peak (p = 0.015), and increased VE/VCO2 slope (p = 0.002). Resting pulmonary artery wedge pressure did not correlate with HF stage (p = 0.93). VE/VCO2 slope and 6MWT were independently associated with HF severity. Conclusions: Preclinical and symptomatic HF are highly prevalent in SSc patients. HF staging was linked to disease severity, age, and cardiovascular risk factors. Functional capacity tests (6MWT and CPET) serve as valuable tools for HF risk stratification. These findings highlight the critical need for comprehensive cardiovascular assessment and targeted management strategies to mitigate HF progression in SSc patients.

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.

The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1Ras) for prevention of heart failure (HF) in patients with type 2 diabetes (T2DM) without HF and for risk of death in patients with T2DM with HF has not been fully elucidated in routine clinical practice.

Using the real-world global electronic medical record TriNetX database, individuals with T2DM and with or without HF who initiated either GLP1Ras or sitagliptin from 2017 to 2020 were retrospectively analyzed. In individuals with T2DM without HF, the primary outcome was a composite of all-cause mortality and a new diagnosis of HF within three years. In individuals with T2DM with HF, the primary outcome was all-cause mortality within three years. Propensity-score (PS) matching was used to adjust for over 100 baseline characteristics.

A total of 65,598 individuals with T2DM without HF starting a GLP1Ras were PS matched with 65,598 starting sitagliptin. GLP1Ras were associated with a lower incidence of the composite endpoint (10.5 % versus 11.8 %, hazard ratio [HR] 0.82, [0.80-0.85], p < 0.001), mortality (HR 0.66 [0.63-0.69]) and new diagnosis of HF (HR 0.92 [0.88-0.96]). There were 6002 individuals in each group matched for T2DM and HF. Mortality was lower in the GLP1Ras group (17.6 % versus 22.8 %, HR 0.70 [0.65-0.76], p < 0.001). Results were consistent across subgroups.

In this global real-world data analysis, GLP1Ra use was associated with a lower risk of death and HF in individuals with T2DM without HF, and lower risk of death in those with HF.

Diabetes poses a serious global challenge, given its increasing prevalence, detrimental effects on public health, and substantial economic burden. Since 1950s, tens of drugs have been approved by the United States (US) Food and Drug Administration (FDA). In the past decade, the medical community and regulatory agencies have moved away from the glucose-centric paradigm and increasingly call for a holistic approach to assess different treatments' benefits and harms.

This study aimed to assess the medication efficiency and technological progress of Type 2 Diabetes (T2D) drugs, by considering their physiological outcomes, including both benefits (i.e., glucose lowering and weight loss) and adverse effects (mortality), relative to dosing frequency.

To derive medication efficiency, this study utilized data from the US FDA and prominent meta-analyses. Given that both the benefits and adverse effects of medications are multidimensional, this study employed a nonparametric frontier method, the data envelopment analysis (DEA) model, to integrate these factors into a measure of medication efficiency. Physiological outcomes could assume both positive and negative values. Adverse effects were regarded undesirable outputs. The DEA model was built under the framework of directional distance function and was able to handle negative and undesirable values which naturally arose in the case of T2D medications.

The paper presented a ranking of 20 T2D drugs in terms of medication efficiency. Three of them were able to attain the highest medication efficiency, all of which were in the GLP-1 class, including oral Semaglutide, subcutaneous Semaglutide and Dulaglutide. However, the other two GLP-1 drugs, Lixisenatide and Liraglutide, were less efficient. The average medication efficiency of drugs approved post-2010 was significantly higher than pre-2010 drugs. High dose frequency, low HbA1c reduction and insignificant weight loss were the main driving factors behind inefficiencies. Overall, medication efficiency provided an alternative perspective on treatment effectiveness other than conventional measures such as cost-effectiveness.

Radiation-induced intestinal injury (RIII) constitutes a challenge in radiotherapy. Ionizing radiation (IR) induces DNA and mitochondrial damage by increasing reactive oxygen species (ROS). Sodium-glucose cotransporter 1 (SGLT1) is abundant in the gastrointestinal tract and the protective effects of inhibited SGLT1 in kidney and cardiovascular disease have been widely reported. However, the function of SGLT1 in RIII remains unclear. Herein, we reported that IR induced intestinal epithelial cell damage along with upregulation of SGLT1 in vivo and in vitro, which was alleviated by inhibition of SGLT1. Specifically, maintaining intestinal cell homeostasis was detected through cellular proliferation, apoptosis, and DNA damage assays, promoting epithelial regeneration and lifespan extension. Considering the importance of mitochondrial function in cell fate, we next confirmed that SGLT inhibition maintains mitochondrial homeostasis through enhanced mitophagy in intestinal epithelial cells. Finally, based on the bioinformatics analysis and cell validation, we demonstrated that inhibition of SGLT1 suppresses the PI3K/AKT/mTOR pathway to enhance mitophagy activation post-irradiation. In addition, we preliminarily demonstrate that SGLT inhibitors do not affect the radiosensitivity of tumors. Hence, our findings suggest that inhibition of SGLT is a promising therapeutic strategy to protect against RIII. To the best of our knowledge, this is the first report on the potential effect of SGLT1 inhibition in RIII.

Although the benefits of sodium-glucose cotransporter 2 inhibitor (SGLT2i) use in chronic kidney disease (CKD) are well established, the effects of these therapeutic agents in patients with advanced CKD are less certain. We hypothesised that the continued use of these drugs, even when renal function deteriorates to stage 4 CKD or worse, is safe and associated with improved cardiorenal survival.

This is a retrospective cohort study utilising data from medical records from two institutions. All patients with type 2 diabetes mellitus who were prescribed an SGLT2i between 1 January 2016 and 31 December 2021, who subsequently had eGFR <30 ml/min per 1.73 m2 recorded on two occasions at least 90 days apart, were identified. The date on which the eGFR first reached any level less than 30 ml/min per 1.73 m2 was defined as the index date. Individuals were then categorised into the SGLT2i continuation group or the discontinuation group according to the use of SGLT2i after the index date. Inverse probability of treatment weighting (IPTW) was performed to minimise confounding. Outcomes of interest included heart failure outcomes, cardiovascular outcomes, renal outcomes and safety outcomes.

According to the eligibility criteria, 337 patients in the continuation group and 358 in the discontinuation group were identified. After IPTW, continuation of SGLT2i use was associated with significantly lower risks of the composite of major adverse cardiovascular events compared with discontinuation of SGLT2i use (HR 0.65 [95% CI 0.43, 0.99]), largely driven by reduced risk of myocardial infarction during follow-up (subdistribution HR [SHR] 0.43 [95% CI 0.21, 0.89]). The incidences of an eGFR decline of 50% or more (SHR 0.58 [95% CI 0.42, 0.81]) and all-cause hospital admission (SHR 0.77 [95% CI 0.64, 0.94]) were also significantly lower in the continuation group. None of the studied safety outcomes were significantly different when comparing the two groups. Blood haemoglobin levels were significantly higher in the continuation group at the end of follow-up (114.6 g/l vs 110.4 g/l, with a difference of 4.12 g/l; p=0.047).

In patients with CKD who were treated with an SGLT2i, continuation of SGLT2i use after eGFR declined to 30 ml/min per 1.73 m2 or less was associated with lower risks of cardiovascular and renal events compared with discontinuation of SGLT2i use. Continued use of SGLT2i throughout the course of CKD should be considered to optimise patient outcomes.

Type 2 diabetes is one of the most prevalent chronic diseases worldwide, significantly impacting patients' quality of life. Current treatment options like metformin (MET) effectively counteract hyperglycemia but fail to alleviate diabetes-associated complications such as retinopathy, neuropathy, nephropathy, hepatopathy, and cardiovascular diseases.

To propose the supplementation of cholecalciferol (CHO) and taurine (TAU) to enhance MET efficacy in controlling diabetes while minimizing the risk of associated complications.

The study involved sixty rats, including ten non-diabetic control rats and fifty experimental rats with type 2 diabetes induced by streptozotocin. The experimental rats were further subdivided into positive control and treatment subgroups. The four treatment groups were randomly allocated to a single MET treatment or MET combined with supplements either CHO, TAU, or both.

Diabetic rats exhibited elevated levels of glucose, insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), glycated hemoglobin%, lipid markers, aspartate aminotransferase, and malondialdehyde, along with reduced levels of antioxidant enzymes (catalase and superoxide dismutase). The administration of CHO and TAU supplements alongside MET in diabetic rats led to a noticeable recovery of islet mass. The antioxidative, anti-inflammatory, and anti-apoptotic properties of the proposed combination therapy significantly ameliorated the aforementioned abnormalities.

The supplementation of CHO and TAU with MET showed the potential to significantly improve metabolic parameters and protect against diabetic complications through its antioxidative, anti-inflammatory, and anti-apoptotic effects.

Diabetic nephropathy is a severe complication of diabetes. Treatment of diabetic nephropathy is an important challenge due to persistent hyperglycemia and elevated levels of reactive oxygen species (ROS) in the kidney. Herein, we designed a glycopolymersome that can treat type 2 diabetic nephropathy by effectively inhibiting hyperglycemia and ROS-associated diabetic nephropathy pathogenesis. The glycopolymersome is self-assembled from phenylboronic acid derivative-containing copolymer, poly(ethylene oxide)45-block-poly[(aspartic acid)13-stat-glucosamine24-stat-(phenylboronic acid)18-stat-(phenylboronic acid pinacol ester)3] [PEO45-b-P(Asp13-stat-GA24-stat-PBA18-stat-PAPE3)]. PBA segment can reversibly bind blood glucose or GA segment for long-term regulation of blood glucose levels; PAPE segment can scavenge excessive ROS for renoprotection. In vitro studies confirmed that the glycopolymersomes exhibit efficient blood glucose responsiveness within 2 h and satisfactory ROS-scavenging ability with 500 μM H2O2. Moreover, the glycopolymersomes display long-acting regulation of blood glucose levels in type 2 diabetic nephropathy mice within 32 h. Dihydroethidium staining revealed that these glycopolymersomes reduced ROS to normal levels in the kidney, which led to 61.7% and 76.6% reduction in creatinine and urea levels, respectively, along with suppressing renal apoptosis, collagen accumulation, and glycogen deposition in type 2 diabetic nephropathy mice. Notably, the polypeptide-based glycopolymersome was synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs), thereby exhibiting favorable biodegradability. Overall, we proposed a new glycopolymersome strategy for 'drug-free' treatment of diabetic nephropathy, which could be extended to encompass the design of various multifunctional nanoparticles targeting diabetes and its associated complications.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

Glucagon-like peptide 1 receptor agonists have been shown to reduce all-cause and cardiovascular mortality in patients with Type 2 diabetes mellitus (T2DM). The probable increase in heart rate hinders its early usage in acute myocardial infarction patients. In our study, we aimed to find out whether the use of liraglutide in patients with acute myocardial infarction as early as at the time of hospitalization would increase the heart rate.

This was an observational retrospective study. From December 2020 to August 2021, 200 patients with acute myocardial infarction were included in our study and divided into three groups: T2DM + liraglutide group (n = 46), T2DM + non-liraglutide group (n = 42), and non-T2DM group (n = 112). The primary outcomes were the differences in heart rate. Secondary outcomes were differences in systolic and diastolic blood pressure.

There were no significant differences in heart rate among the three groups at admission, the day before the first shot of liraglutide, and before discharge. There was also no significant difference in heart rate between diabetic patients with acute myocardial infarction and those on liraglutide during the hospital stay. And there were no differences of beta-blocker dosages among the three groups. Liraglutide did not affect the blood pressure during acute myocardial infarction.

Liraglutide did not increase the heart rate in diabetic patients during acute myocardial infarction and did not lead to an increase in the dose of beta-blockers in the patients. It also had no effect on blood pressure and showed better efficacy in lowering glucose levels without additional hypoglycemic events.

Cardiovascular diseases are caused by pathological cardiac remodeling, which involves fibrosis, inflammation and cell dysfunction. This includes autophagy, apoptosis, oxidative stress, mitochondrial dysfunction, changes in energy metabolism, angiogenesis and dysregulation of signaling pathways. These changes in heart structure and/or function ultimately result in heart failure. In an effort to prevent this, multiple cardiovascular outcome trials have demonstrated the cardiac benefits of sodium‑glucose cotransporter type 2 inhibitors (SGLT2is), hypoglycemic drugs initially designed to treat type 2 diabetes mellitus. SGLT2is include empagliflozin and dapagliflozin, which are listed as guideline drugs in the 2021 European Guidelines for Heart Failure and the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guidelines for Heart Failure Management. In recent years, multiple studies using animal models have explored the mechanisms by which SGLT2is prevent cardiac remodeling. This article reviews the role of SGLT2is in cardiac remodeling induced by different etiologies to provide a guideline for further evaluation of the mechanisms underlying the inhibition of pathological cardiac remodeling by SGLT2is, as well as the development of novel drug targets.

Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use.

Cardiometabolic risk prediction models that incorporate metabolic syndrome traits to predict cardiovascular outcomes may help identify high-risk populations early in the progression of cardiometabolic disease.

The purpose of this study was to examine whether a modified cardiometabolic disease staging (CMDS) system, a validated diabetes prediction model, predicts major adverse cardiovascular events (MACE).

We developed a predictive model using data accessible in clinical practice [fasting glucose, blood pressure, body mass index, cholesterol, triglycerides, smoking status, diabetes status, hypertension medication use] from the REGARDS (REasons for Geographic And Racial Differences in Stroke) study to predict MACE [cardiovascular death, nonfatal myocardial infarction, and/or nonfatal stroke]. Predictive performance was assessed using receiver operating characteristic curves, mean squared errors, misclassification, and area under the curve (AUC) statistics.

Among 20,234 REGARDS participants with no history of stroke or myocardial infarction (mean age 64 ± 9.3 years, 58% female, 41% non-Hispanic Black, and 18% diabetes), 2,695 developed incident MACE (13.3%) during a median 10-year follow-up. The CMDS development model in REGARDS for MACE had an AUC of 0.721. Our CMDS model performed similarly to both the ACC/AHA 10-year risk estimate (AUC 0.721 vs 0.716) and the Framingham risk score (AUC 0.673).

The CMDS predicted the onset of MACE with good predictive ability and performed similarly or better than 2 commonly known cardiovascular disease prediction risk tools. These data underscore the importance of insulin resistance as a cardiovascular disease risk factor and that CMDS can be used to identify individuals at high risk for progression to cardiovascular disease.

To determine the comparative effectiveness regarding major cardiovascular events of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).

We assembled a cohort of commercially insured adult patients with T2DM in the United States (derived from Optum Clinformatics DataMart 2003-2021) who were new users of GLP-1 receptor agonists or SGLT-2 inhibitors. We compared risks of non-fatal myocardial infarction or stroke in patients with and without CKD, and further categorized by CKD stage: stages G1 or G2 [estimated glomerular filtration rate (eGFR) ≥60 ml/min] and A2 (urine albumin to creatinine ratio 30 to <300 mg/g) or A3 (urine albumin to creatinine ratio ≥300 mg/g), stage G3a (eGFR 45 to <60 ml/min/1.73 m2 ) and stage G3b (eGFR 30 to <45 ml/min/1.73 m2 ). We used proportional hazards regression after inverse probability of treatment weighting to compute hazard ratios and 95% confidence intervals.

After accounting for the probability of treatment, patients with T2DM and CKD treated with SGLT-2 inhibitors experienced a 14% lower risk of non-fatal myocardial infarction or stroke (hazard ratio 0.86, 95% confidence interval 0.78-0.94) relative to those treated with GLP-1 receptor agonists.

Recognizing the potential for residual confounding, selection bias and immortal time bias, commercially insured patients in the United States with T2DM and CKD treated with SGLT-2 inhibitors experienced significantly lower risks of non-fatal myocardial infarction or stroke relative to those treated with GLP-1 receptor agonists.

This study was conducted to investigate the combined effect of genetic variation in the C3 gene and environmental factors on the risk of type 2 diabetes mellitus(T2DM) and coronary artery disease(CAD) in a population from Xinjiang, China.

We conducted a hospital-based case-control study with 896 participants (217 with T2DM+CAD and 679 healthy controls). A polymerase chain reaction-ligase detection reaction was used to identify and genotype TagSNPs in the C3 gene, and the influence of the interaction of two SNP loci (rs1047286 and rs11569562) with the environment on T2DM combined with CAD was evaluated through clinical data, statistical analysis of gene frequencies, and the formation of a gene-environment interaction model.

We find that rs11569562 GG is an independent protective factor for T2DM and CAD (OR=0.353, p=0.012), and the variants at its locus may be closely associated with Activated Partial Thromboplastin Time (APTT), lipoprotein a (Lp(a)), Apolipoprotein A (APOA), Aspartate Aminotransferase (AST), Aspartate Aminotransferase (ALT) and AST/ALT levels (all P < 0.05); its GG genotype has significantly lower Gensini score and number of stenoses than the GA and AA genotypes. Multifactorial dimensionality reduction (MDR) finds a strong correlation between rs11569562 and AST (antagonistic effect) (4.44%); the role of rs11569562's influence remains strong in terms of the independent effects of each attribute (1.72%).

In this study, we find that variants in the C3 gene loci rs11569562 are associated with the incidence of type 2 diabetes mellitus combined with coronary heart disease in a Chinese population. It is expected to be an independent predictor of type 2 diabetes mellitus combined with coronary heart disease in the Chinese population. Rs11569562 may be associated with lipid levels and coagulation molecules.

This trial registered on in 2014 at the China Clinical Trials Registry (ChiCTR-TRC-14005114).

Diabetic retinopathy, nephropathy, and neuropathy are significant microvascular complications of diabetes mellitus, contributing to substantial morbidity and mortality worldwide. This comprehensive review examines the clinical relationship between these complications, focusing on shared pathophysiological mechanisms, bidirectional relationships, and implications for patient management. The review highlights the importance of understanding the interconnected nature of diabetic complications and adopting a holistic approach to diabetes care. Insights gleaned from this review underscore the necessity for early detection, timely intervention, and integrated care models involving collaboration among healthcare professionals. Furthermore, the review emphasizes the need for continued research to elucidate underlying mechanisms, identify novel therapeutic targets, and assess the efficacy of integrated care strategies in improving patient outcomes. By fostering interdisciplinary collaboration and knowledge exchange, future research endeavors hold the potential to advance our understanding and management of diabetic complications, ultimately enhancing patient care and quality of life.

Despite type 2 diabetes guidelines recommending against the use of sulfonylureas in older adults and for the use of sodium-glucose cotransporter-2 inhibitors (SGLT2) and glucagon-like peptide-1 agonists (GLP1s) in patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure (HF), real-world guideline-concordant prescribing remains low. While some factors such as cost have been suggested, an in-depth analysis of the factors associated with guideline-concordant prescribing is warranted.

To quantify the extent of guideline-concordant prescribing in an integrated health care delivery system and examine provider and patient level factors that influence guideline-concordant prescribing.

We performed a cross-sectional study.

Participants were included if they had a diagnosis of type 2 diabetes, were prescribed a second-line diabetes medication between January 1, 2018 and December 31, 2020 and were at least 65 years old at the time of this second-line prescription.

Our outcome of interest was guideline-concordant prescribing. The definition of guideline-concordant prescribing was based on American Diabetes Association and American Geriatric Society recommendations as well as expert consensus. Factors affecting guideline concordant prescribing included patient demographics and provider characteristics among others.

We included 1,693 patients of which only 50% were prescribed guideline-concordant medications. In a subgroup of 843 patients with cardiorenal conditions, only 30% of prescriptions were guideline concordant. Prescribing of guideline-concordant prescriptions was more likely among pharmacists than physicians (RR 1.34, 95% CI 1.19-1.51, p<0.001) and in endocrinology practices compared to primary care practices (RR 1.41 95% CI 1.16-1.72, p=0.007). Additionally, guideline concordant prescribing increased over time (42% in 2018 vs 53% in 2019 vs 53% in 2020, p<0.001).

Guideline-concordant prescribing remains low in older adults, especially among those with cardiorenal conditions. Future studies should examine barriers to prescribing guideline-concordant medications and interventions to improve guideline-concordant prescribing.

The fight against aging is an eternal pursuit of humankind. The aging rate of patients with type 2 diabetes mellitus (T2DM) is higher than that of healthy individuals. Reducing the aging rate of patients with T2DM and extending their life expectancy are challenges that endocrinologists are eager to overcome. Many studies have shown that antidiabetic medications have potent anti-aging potential. Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere shortening is a hallmark of aging. This review summarizes clinical trials that have explored the association between antidiabetic medications and telomere length (TL) in patients with T2DM and explore the mystery of delaying aging in patients with T2DM from the perspective of telomeres. Various antidiabetic medications may have different effects on TL in patients with T2DM. Metformin and sitagliptin may protect telomeres in patients with T2DM, while exogenous insulin may promote telomere shortening in patients with T2DM. The effect of acarbose and glyburide on TL in patients with T2DM is still uncertain due to the absence of evidence from longitudinal studies.

Metformin shows beneficial effects on cardiometabolic health in diabetic individuals. However, the beneficial effects in the general population, especially in non-diabetic individuals are unclear. We aim to estimate the effects of perturbation of seven metformin targets on cardiometabolic health using Mendelian randomization (MR).

Genetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA1c) level were used to proxy therapeutic effects of seven metformin-related drug targets. Eight cardiometabolic phenotypes under metformin trials were selected as outcomes (average N = 466,947). MR estimates representing the weighted average effects of the seven effects of metformin targets on the eight outcomes were generated. One-sample MR was applied to estimate the averaged and target-specific effects in 338,425 non-diabetic individuals in UK Biobank.

Genetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA1c level, was associated with 37.8% lower risk of coronary artery disease (CAD) (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.46-0.84), lower levels of body mass index (BMI) (β = -0.22, 95% CI = -0.35 to -0.09), systolic blood pressure (SBP) (β = -0.19, 95% CI = -0.28 to -0.09) and diastolic blood pressure (DBP) levels (β = -0.29, 95% CI = -0.39 to -0.19). One-sample MR suggested that the seven metformin targets showed averaged and target-specific beneficial effects on BMI, SBP and DBP in non-diabetic individuals.

This study showed that perturbation of seven metformin targets has beneficial effects on BMI and blood pressure in non-diabetic individuals. Clinical trials are needed to investigate whether similar effects can be achieved with metformin medications.

Funding information is provided in the Acknowledgements.

All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1.

A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD).

Here we show an association of circulating ET-1 level with higher risk for all-cause mortality (HR: 2.06; 95% CI 1.5-2.83), CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality (adjusted HR: 0.05; 95% CI 0.01-0.38) and CV death (adjusted HR: 0.06; 95% CI 0.01-0.44) in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD.

Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1.

The objective of this review was to assess the risk of lower limb amputation (LLA) in type 2 diabetic patients based on the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase 4 inhibitors (DPP4i) or glucagon-like peptide-1 receptor agonists (GLP1a).

PubMed, CENTRAL, Scopus, Web of Science, and Embase were referenced for articles published up to 5 February 2023. All types of studies comparing the drugs for LLA risk and reporting hazard ratios (HR) were included.

Thirteen studies with 2,095,033 patients were included. Meta-analysis of eight studies comparing SGLT2i with Dipeptidyl peptidase inhibitors (DPPi) showed that there was no difference in the risk of LLA between the two drug groups (HR: 0.98 95% CI: 0.73, 1.31 I² = 89%). The outcomes were unchanged on sensitivity analysis. Another pooled analysis of six studies found no significant difference in the risk of LLA between SGLT2i and GLP1a users (HR: 1.26; 95% CI: 0.99, 1.60; I² = 69%). The exclusion of a single study showed an increased risk of LLA with SGLT2i (HR: 1.35; 95% CI: 1.14, 1.60; I² = 14%).

The current updated meta-analysis found no significant difference in the risk of LLA between SGLT2i and DPP4i users. A tendency of increased risk of LLA was noted with SGLT2i as compared to GLP1a. Further studies shall increase the robustness of current findings.

Most blood vessels are surrounded by adipose tissues known as perivascular adipose tissue (PVAT). Emerging experimental data have implicated the potential involvement of PVAT in the pathogenesis of cardiovascular disease: PVAT might be a source of inflammatory mediators under pathological conditions such as metabolic disorders, chronic inflammation, and aging, leading to vascular pathologies, while having vasculo-protective roles in a healthy state. PVAT has been also gaining attention in human disease conditions. Recent integrative omics approaches have greatly enhanced our understanding of the molecular mechanisms underlying the diverse functions of PVAT. This review summarizes recent progress in PVAT research and discusses the potential of PVAT as a target for the treatment of atherosclerosis.

In this review, we summarise new insights into diagnostic approaches and treatment strategies for coronary artery disease (CAD) in patients with diabetes mellitus (DM). Despite the improvements in therapy, the clinical management of DM patients remains challenging as they develop more extensive CAD at a younger age and consistently have worse clinical outcomes than non-DM patients. Current diagnostic modalities as well as revascularisation treatments mainly focus on ischemic lesions. However, the impact of plaque morphology and composition are emerging as strong predictors of adverse cardiac events even in the absence of identified ischemia. In particular, the presence of vulnerable plaques such as thin-cap fibroatheroma (TCFA) lesions has been identified as a very strong predictor of future adverse events. This emphasises the need for an approach combining both functional and morphological methods in the assessment of lesions. In particular, optical coherence tomography (OCT) has proven to be a valuable asset by truly identifying TCFAs. New treatment strategies should consist of individualised and advanced medical regimens and may evolve towards plaque sealing through percutaneous treatment.

Type 2 diabetes mellitus (DM) represents, with its macro and microvascular complications, one of the most critical healthcare issues for the next decades. Remarkably, in the context of regulatory approval trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) proved a reduced incidence of major adverse cardiovascular events (MACEs), i.e., cardiovascular death and heart failure (HF) hospitalizations. The cardioprotective abilities of these new anti-diabetic drugs seem to run beyond mere glycemic control, and a growing body of evidence disclosed a wide range of pleiotropic effects. The connection between diabetes and meta-inflammation seems to be the key to understanding how to knock down residual cardiovascular risk, especially in this high-risk population. The aim of this review is to explore the link between meta-inflammation and diabetes, the role of newer glucose-lowering medications in this field, and the possible connection with their unexpected cardiovascular benefits.

BACKGROUNDElevated circulating branched chain amino acids (BCAAs), measured at a single time point in middle life, are strongly associated with an increased risk of developing type 2 diabetes mellitus (DM). However, the longitudinal patterns of change in BCAAs through young adulthood and their association with DM in later life are unknown.METHODSWe serially measured BCAAs over 28 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective cohort of apparently healthy Black and White young adults at baseline. Trajectories of circulating BCAA concentrations from years 2-30 (for prevalent DM) or years 2-20 (for incident DM) were determined by latent class modeling.RESULTSAmong 3,081 apparently healthy young adults, trajectory analysis from years 2-30 revealed 3 distinct BCAA trajectory groups: low-stable (n = 1,427), moderate-stable (n = 1,384), and high-increasing (n = 270) groups. Male sex, higher body mass index, and higher atherogenic lipid fractions were more common in the moderate-stable and high-increasing groups. Higher risk of prevalent DM was associated with the moderate-stable (OR = 2.59, 95% CI: 1.90-3.55) and high-increasing (OR = 6.03, 95% CI: 3.86-9.43) BCAA trajectory groups in adjusted models. A separate trajectory group analysis from years 2-20 for incident DM after year 20 showed that moderate-stable and high-increasing trajectory groups were also significantly associated with higher risk of incident DM, after adjustment for clinical variables and glucose levels.CONCLUSIONBCAA levels track over a 28-year span in most young adults, but serial clinical metabolomic measurements identify subpopulations with rising levels associated with high risk of DM in later life.FUNDINGThis research was supported by the NIH, under grants R01 HL146844 (JTW) and T32 HL069771 (MRC). The CARDIA study is conducted and supported by the NIH National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), the University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I).

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to improve cardiovascular and renal outcomes in patients with established cardiovascular disease, chronic kidney disease (CKD), and heart failure (HF) with reduced or preserved ejection fraction. Clinical benefit has been substantiated in patients with and without type 2 diabetes (T2D). Consequently, SGLT2is have an increasingly important role in HF and CKD management that extends beyond T2D treatment. Their pleiotropic pharmacological effects underlying their cardiovascular and renal benefits are not completely understood but include significant effects beyond blood glucose reduction. SGLT2is inhibit the reabsorption of glucose and sodium in the proximal tubule which, in addition to lowering blood glucose, activates tubuloglomerular feedback, leading to reduced glomerular hydrostatic pressure and the mitigation of glomerular filtration rate loss. SGLT2is have diuretic and natriuretic effects, leading to decreased blood pressure, preload, and left ventricular (LV) filling pressure, and improvements in other surrogates of afterload. In HF, SGLT2is mitigate the risks of hyperkalemia and ventricular arrhythmia and improve LV dysfunction. SGLT2is also reduce sympathetic tone and uric acid levels, increase hemoglobin levels, and are postulated to have anti-inflammatory properties. This narrative review discusses the multifactorial and interrelated pharmacological mechanisms underlying the cardiovascular and renal benefits of SGLT2is.

To report the rationale for using PB-201, a partial glucokinase activator (GKA), for a Phase 3 study (NCT05102149) assessing its efficacy and safety in a Chinese population and to describe the design of this GKA Phase 3 trial, the first to involve both an active control and a placebo control arm.

This is an ongoing, multicentre, randomized, double-blind, three-arm placebo and active control study to be carried out among 672 Chinese treatment-naive participants with type 2 diabetes mellitus (T2DM) to assess the efficacy and safety of PB-201 for approximately 60 weeks, including a screening period and a safety follow-up period.

The primary objective of this study was to monitor change in glycated haemoglobin levels with PB-201 in treatment-naive T2DM participants from baseline to 24 weeks in comparison with vildagliptin and placebo. The key secondary objective was to assess the efficacy and safety of PB-201 following treatment for a time period of 52 weeks.

This pivotal study will offer critical information regarding the efficacy and safety of PB-201 in Chinese treatment-naive T2DM participants that would help to establish robust evidence for the benefit-risk evaluation of this drug.

Chronic low-grade inflammation has been identified as a major contributor in the development of atherosclerosis. Nuclear Factor-κappa B (NF-κB) is a critical transcription factors family of the inflammatory pathway. As a major catalytic subunit of the IKK complex, IκB kinase β (IKKβ) drives canonical activation of NF-κB and is implicated in the link between inflammation and atherosclerosis, making it a promising therapeutic target. Various natural product derivatives, extracts, and synthetic, show anti-atherogenic potential by inhibiting IKKβ-mediated inflammation. This review focuses on the latest knowledge and current research landscape surrounding anti-atherosclerotic drugs that inhibit IKKβ. There will be more opportunities to fully understand the complex functions of IKKβ in atherogenesis and develop new effective therapies in the future.

To evaluate the impact of adding a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in people with type 2 diabetes (T2D) in basal-bolus (BB) insulin regimen, on insulin requirement, HbA1c, weight loss up to 24 months.

Data on subjects with T2D on BB who initiated a GLP-1 RA have been retrospectively collected. HbA1c, body weight, and insulin dose were recorded at baseline, 6, 12, and 24 months after initiation of GLP-1 RA therapy. A linear mixed model for repeated measures was used to evaluate the changes in HbA1c, body weight, and insulin requirement over time.

We included 156 subjects (63.5% males; age 62 ± 11 years, HbA1c 70 ± 22.0 mmol/mol; 8.6 ± 4.2%). Compared to baseline, HbA1c and body weight were significantly lower at 6 months after introducing a GLP-1RA and remained stable up to 24 months (all p < 0.0001 vs. baseline). At 24 months, 81% of subjects discontinued prandial insulin, while 38.6% discontinued basal insulin as well. Insulin requirement at baseline (aOR 0.144; 95% CI, 0.046-0.456; P = 0.001) was the only significant predictor of prandial insulin discontinuation.

Replacing prandial insulin with GLP-1 RA is a valuable strategy to simplify the BB insulin regimen while improving glycaemic control and promoting weight loss in subjects with T2D.

This study aimed to assess the real-world outcomes of people with diabetes mellitus treated with glucagon-like peptide-1 receptor agonists (GLP1RAs) compared with those treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in terms of major adverse cardiovascular and limb events. Peripheral artery disease is a common cause of morbidity in people with diabetes. Previous cardiovascular outcome trials have demonstrated the benefits of GLP1RAs and SGLT2is for reducing various cardiovascular events, but the safety and efficacy of these drugs on limb outcomes remain subject to debate and ambiguity.

A retrospective cohort study was conducted in which data were collected from the Taiwan National Health Insurance Research Database. In total, 379,256 individuals with diabetes receiving either GLP1RA or SGLT2i with treatment initiated between 1 May 2016 and 31 December 2019 were identified. The primary outcome was major adverse limb events (MALE), defined as the composite of newly diagnosed critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for peripheral artery disease, and non-traumatic amputation. The secondary outcome was major adverse cardiac events, which was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Other examined outcomes included death from any cause and hospitalisation for heart failure. Propensity score matching was performed at a 1:4 ratio between the GLP1RA and SGLT2i groups to mitigate possible selection bias.

A total of 287,091 patients were eligible for analysis, with 81,152 patients treated with SGLT2i and 20,288 patients treated with GLP1RA after matching. The incidence of MALE was significantly lower in the GLP1RA group than in the SGLT2i group (3.6 vs 4.5 events per 1000 person-years; subdistribution HR 0.80; 95% CI 0.67, 0.96), primarily due to a lower incidence of critical limb ischaemia. The reduced risks of MALE associated with GLP1RA use were particularly noticeable in people with diabetic peripheral neuropathy (subdistribution HR 0.66 vs 1.11; p for interaction 0.006).

In people with diabetes, GLP1RA use was associated with significantly reduced risks of MALE compared with SGLT2i within the first 2 years after initiation, especially among people with diabetic neuropathy.

We aim to assess the relationship between hyperglycemia and long-term prognosis in CAD patients without known diabetes.

In this retrospective observational study, we enrolled 11,384 CAD patients without known diabetes. Newly detected diabetes was defined as HbA1c ≥ 6.5 %, and prediabetes was defined as HbA1c ranging from 5.7 to 6.4 %.The association between hyperglycemia and long-term all-cause mortality was examined using Cox proportional hazards regression analysis.

According to HbA1c level, 8207 (72.1 %) patients had hyperglycemia, including 13.0 % with diabetes and 59.1 % with prediabetes. During a median follow-up of 4.9 years, 1157(10.2 %) patients died. Compared with normoglycemia, hyperglycemia was associated with increased risk for long-term mortality (adjusted hazard ratio for diabetes and prediabetes: 1.23 [95 % confidence interval (CI): 1.00 to 1.51] and 1.17 [95 % CI: 1.01 to 1.36], respectively).

Hyperglycemia detected by HbA1c was common in CAD patients without known diabetes and was associated with increased long-term mortality. It is necessary to routinely use HbA1c to assess glucose metabolic status in CAD patients and treat hyperglycemia as early as possible to reduce the risk of adverse outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms 'glucagon-like peptide-1 receptor agonist', 'glucagon receptor agonist', 'glucose-dependent insulinotropic peptide', 'dual or co-agonist', and 'tirzepatide'. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.

The current study was to evaluate the effects of canagliflozin and metformin on insulin resistance and visceral adipose tissue in people with newly-diagnosed type 2 diabetes.

This is an open-label, parallel and controlled study. Participants were divided into canagliflozin (100 mg/qd) or metformin (1000 mg/bid) groups. At baseline and after 12 weeks' therapy, insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], subcutaneous and visceral adipose tissue, fasting blood glucose (FBG), glycated hemoglobin A1c (HbA1c), C-reactive protein (CRP) and nitric oxide (NO) were evaluated and compared.

There was no significant between-group difference in baseline characteristics. After 12 weeks' therapy, in canagliflozin group (n = 67), compared to baseline, FBG, HbA1c and HOMA-IR were decreased, accompanying with reduction of visceral adipose tissue. Compared to metformin group (n = 73), FBG, HbA1c and HOMA-IR were lower in canagliflozin group, accompanying with less visceral adipose tissue and lower serum CRP level and higher NO level. After multivariable regression analysis, age, visceral adipose tissue and CRP remained associated with increased insulin resistance, while canagliflozin treatment and higher NO level were associated with reduced insulin resistance. Body mass index, waist/hip ratio, CRP and HOMA-IR remained associated with increased visceral adipose tissue, while canagliflozin treatment and higher NO level were associated with reduced visceral adipose tissue. There was no difference in adverse event between these two groups.

Canagliflozin reduces visceral adipose tissue and improves blood glucose, insulin resistance and systemic inflammation in people with newly-diagnosed type 2 diabetes.

Glucagon-like peptide 1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are two novel classes of hypoglycemic agents. The relative cardiovascular effectiveness between these two drug classes in patients with type 2 diabetes (T2D) is unestablished due to the absence of large cardiovascular outcome trials directly comparing DPP-4i with GLP-1RA. We aimed to incorporate large propensity score-matched cohort studies to conduct a meta-analysis, to determine the relative effectiveness of GLP-1RA versus DPP-4i on cardiovascular endpoints in T2D patients. Compared to DPP-4i, GLP-1RA was associated with the significantly lower risks of major adverse cardiovascular events [MACE] (HR 0.76, 95% CI 0.63-0.92), cardiovascular mortality (HR 0.59, 95% CI 0.37-0.95), myocardial infarction (HR 0.89, 95% CI 0.80-0.98), stroke (HR 0.86, 95% CI 0.76-0.96), and all-cause mortality (HR 0.63, 95% CI 0.42-0.96) in T2D patients; whereas these two drug classes had the similar risk of hospitalization for heart failure [HHF] (HR 0.95, 95% CI 0.77-1.16). Meta-regression analyses showed that six factors (i.e., mean age, female proportion, cardiovascular disease proportion, heart failure proportion, and the proportions of receiving metformin and insulin at baseline) did not significantly affect the effects of GLP-1RA on MACE and HHF (P ≥ 0.076). This meta-analysis provides the direct evidence regarding the relative cardiovascular effectiveness of GLP-1RA versus DPP-4i from real-world studies, and its findings suggest that among T2D patients GLP-1RA should be considered in preference to DPP-4i as for preventing atherosclerotic cardiovascular events and death in clinical practice.

Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the general population. Energy metabolism disturbance is one of the early abnormalities in CVDs, such as coronary heart disease, diabetic cardiomyopathy, and heart failure. To explore the role of myocardial energy homeostasis disturbance in CVDs, it is important to understand myocardial metabolism in the normal heart and their function in the complex pathophysiology of CVDs. In this article, we summarized lipid metabolism/lipotoxicity and glucose metabolism/insulin resistance in the heart, focused on the metabolic regulation during neonatal and ageing heart, proposed potential metabolic mechanisms for cardiac regeneration and degeneration. We provided an overview of emerging molecular network among cardiac proliferation, regeneration, and metabolic disturbance. These novel targets promise a new era for the treatment of CVDs.

Lin et al. recently did a network meta-analysis based on cardiovascular (CV) outcome trials (CVOTs) of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and those of glucagon-like peptide-1 receptor agonists (GLP1RAs). Due to the absence of CVOTs directly comparing SGLT2is with GLP1RAs, Lin et al.'s network meta-analysis identified the indirect evidence that SGLT2is vs. GLP1RAs reduced hospitalization for heart failure (HHF) but did not reduce CV death and all-cause mortality (ACM) in patients with type 2 diabetes (T2D). We did another meta-analysis incorporating those CV outcome cohort studies directly comparing SGLT2is with GLP1RAs, and identified that SGLT2is vs. GLP1RAs were significantly associated with the lower risks of not only HHF but also CV death and ACM. These findings may suggest that SGLT2is should be considered over GLP1RAs in terms of preventing CV and all-cause death and HHF in T2D patients.

Several cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking.

We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed.

A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control.

SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles.

CRD42020206600.