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Aim: Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have revolutionized clinical medicine, but their association with urinary tract infection (UTI) risk remains debated. This study investigates the influence of dapagliflozin on UTI outcomes, focusing on kidney injury. Materials and Methods: Female non‐diabetic C57BL/6J and C3H/HeOuJ mice, along with diabetic db/db mice, were orally administered dapagliflozin (1 mg/kg or 10 mg/kg) for 7 days before transurethral uropathogenic Escherichia coli (UPEC) infection. Mice were killed either 24 h after UTI or after six additional days of dapagliflozin treatment. UPEC titers were enumerated, and kidney histopathology, injury, fibrosis and function were assessed. Results: Vehicle‐ and dapagliflozin‐treated C57BL/6J mice exhibited similar urine and bladder UPEC titers, with minimal kidney burden 24 h after UTI. In C3H/HeOuJ mice, UPEC burden was comparable in vehicle‐ and 1 mg/kg dapagliflozin‐treated groups both 24 h and 7 days after UTI. However, C3H/HeOuJ mice receiving 10 mg/kg dapagliflozin had increased UPEC titers in the urine, bladder and kidneys at both endpoints. Kidney injury and fibrosis markers, as well as kidney function, were similar in vehicle and dapagliflozin groups. In diabetic db/db mice receiving dapagliflozin, UPEC strain UTI89 titers were reduced 7 days after UTI compared to vehicle‐treated mice, but no difference in UPEC titers was observed when mice were infected with UPEC strain CFT073. Kidney injury and fibrosis markers and kidney function remained similar across treatment groups. Conclusions: Dapagliflozin does not consistently influence UTI susceptibility and shows limited impact on kidney injury or fibrosis, suggesting SGLT2 inhibitors have minimal effects on UTI‐related kidney complications. [ABSTRACT FROM AUTHOR]

The growing prevalence of overweight/obesity, the persistence of inadequate glycemic control among the majority of affected individuals, and the still unacceptably high risk of cardiovascular morbidity and mortality among population with type 1 diabetes mellitus (T1D), impose an urgent need for the introduction of non-insulin glucose-lowering agents in the therapeutic armamentarium. Given that their antihyperglycemic mechanism of action is independent of endogenous insulin secretion and that the observed cardio-renal benefits are unrelated to their glucose-lowering properties, one can speculate that the use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) could provide benefits in T1D, similar to the ones observed among individuals with type 2 diabetes mellitus, chronic kidney disease (CKD), and heart failure. Available evidence from randomized controlled trials suggests that treatment with SGLT2is as adjunct to insulin in T1D results in modest reductions in glycated hemoglobin and body weight. Additionally, SGLT2is ameliorate albuminuria, and thus delay or prevent the development of CKD in T1D. However, use of SGLT2is is associated with an increased risk of diabetic ketoacidosis (DKA) in T1D. This commentary aims at providing a framework for practical recommendations regarding the potential use of SGLT2is in adults with T1D, based on the individual's risk level for DKA development, the presence of inadequate glycemic control and related cardio-renal complications. [ABSTRACT FROM AUTHOR]

Abstract Background Non-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive. Methods A nested case–control study was conducted using Taiwan’s National Health Insurance Research Database for 2011–2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual’s age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed. Results There were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46–1.52] and 0.85 [0.63–1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38–0.97]). Conclusion GLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure.

Background: Non-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive. Methods: A nested case–control study was conducted using Taiwan's National Health Insurance Research Database for 2011–2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual's age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed. Results: There were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46–1.52] and 0.85 [0.63–1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38–0.97]). Conclusion: GLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor agonists (GLP1Ra) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce major adverse cardiovascular events (MACE). We assessed whether the effect differs in patients with and without cardiovascular (CV) disease, and rated the certainty of evidence by conducting a systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials. Certainty of the evidence (CoE) was rated using the Grading of Recommendations, Assessment, Development, and Evaluation guidelines. The reduction in the risk of MACE was significant for both medications (high CoE), and the effect was similar in patients with and without CV disease (moderate CoE). GLP1Ra and SGLT2i reduced the risk of CV death (with high and moderate CoE, respectively), and the effects were consistent in the subgroups, but with very low CoE. While SGLT2i reduced the risk of fatal or non-fatal MI with a consistent effect in the subgroups, GLP1Ra reduced the risk of fatal or non-fatal stroke (with high CoE). In conclusion, GLP1Ra and SGLT2 inhibitors reduce the MACE to a similar extent in patients with and without CV disease, but have a differential effect on the reduction of fatal or non-fatal MI and stroke. [ABSTRACT FROM AUTHOR]

Aim: To estimate individual treatment effects (ITEs) of sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) on lowering the risk of developing chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) and to identify those most probable to benefit from treatment. Methods: This study followed a T2D cohort from Ramathibodi Hospital, Thailand, from 2015 to 2022. A counterfactual model was constructed to predict factual and counterfactual risks of CKD if patients did/did not receive SGLT2is. ITEs were estimated by subtracting the factual risk from the counterfactual risk of CKD. Results: There were 1619 and 15 879 patients included in the SGLT2i and non‐SGLT2i groups, respectively. The estimated ITEs varied from −1.19% to −17.51% with a median of −4.49%, that is, 50% of patients had a 4.49% or greater lower CKD risk if they received an SGLT2i. Patients who gained the greatest benefit from SGLT2is were more probable to be male, aged at least 60 years, with a history of diabetes duration of at least 3 months, hypertension, peripheral arterial disease, diabetic retinopathy and low high‐density lipoprotein cholesterol. Conclusions: Our prediction model provides individualized information that helps target T2D patients who may benefit more from SGLT2is. This could help clinical decision making and implementation of personalized medicine in clinical practice, especially in resource‐limited settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Repurposing the diabetes drug dapagliflozin and the natural agent silymarin, this study tackled the liver damage caused by the chemotherapy drug cisplatin. Thirty female Wistar rats were treated with cisplatin alone, silymarin, dapagliflozin, or their combination for 45 days. The results were promising; cisplatin-induced liver damage, marked by elevated ALT, AST, and TB levels, and decreased TP and albumin levels, was significantly mitigated by dapagliflozin and silymarin. The combination of both showed promising results as well, restoring the liver enzyme levels and tissue structure. This novel approach not only highlights the powerful hepatoprotective effects of dapagliflozin and silymarin but also opens new avenues for safer chemotherapy treatments. Further mechanistic research could turn these findings into clinical practice, offering new hope for cancer patients undergoing cisplatin-based therapy. Recognizing the challenges posed by chemotherapy, specifically the hepatotoxic effects of drugs like cisplatin, this study aimed to examine the hepatoprotective potential of dapagliflozin to mitigate cisplatin-induced hepatotoxicity in a rat model. This study focused on repurposing drugs such as dapagliflozin and natural agents like silymarin as potential interventions to address cisplatin-induced hepatotoxicity. Thirty adult female Wistar rats were distributed into five groups and treated with cisplatin alone, silymarin, dapagliflozin, or a combination of dapagliflozin and silymarin accordingly for 45 days. Body weight, fasting blood glucose levels, liver function tests, and histopathological analysis were conducted to evaluate the hepatoprotective effects. Cisplatin-induced hepatotoxicity significantly (p < 0.05) increased the serum levels of ALT, AST, TB, and reduced the TP and albumin levels. Dapagliflozin administration led to significant reductions in ALT, AST, TB, and increased albumin levels. Silymarin demonstrated comparable effects. Combining dapagliflozin and silymarin showed synergistic effects, further reducing the liver enzymes and improving albumin levels. Histopathological examination supported these findings, revealing the restoration of liver structure with dapagliflozin and silymarin treatment. Dapagliflozin and silymarin exhibited substantial hepatoprotective benefits against cisplatin-induced hepatotoxicity in rats. The combination therapy demonstrated synergistic effects, highlighting a potential therapeutic approach for mitigating chemotherapy-induced liver damage. Further research into molecular mechanisms and clinical translation is warranted, offering hope for improved clinical outcomes in cancer patients undergoing cisplatin-based chemotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) share a bidirectional link, and the innovative antidiabetic molecules GLP-1 Ras and SGLT-2is have proven cardiac and renal benefits, respectively. This study aimed to evaluate CV risk categories, along with lipid-lowering and antidiabetic treatments, in patients with T2DM from a real-life setting in Romania. Material and Methods: A cross-sectional evaluation was conducted on 405 consecutively admitted patients with T2DM in an ambulatory setting, assessing them according to the 2019 ESC/EAS guidelines for moderate, high, and very high CV risk categories. Results: The average age of the group was 58 ± 9.96 years, with 38.5% being female. The mean HbA1C level was 7.2 ± 1.7%. Comorbidities included HBP in 88.1% of patients, with a mean SBP and DBP of 133.2 ± 13.7 mm Hg and 79.9 ± 9 mm Hg, respectively, and obesity in 66.41%, with a mean BMI of 33 ± 6.33 kg/m2. The mean LDL-C levels varied by CV risk category: 90.1 ± 34.22 mg/dL in very high risk, 98.63 ± 33.26 mg/dL in high risk, and 105 ± 37.1 mg/dL in moderate risk. Prescribed treatments included metformin (100%), statins (77.5%), GLP-1 Ras (29.4%), and SGLT-2is (29.4%). Conclusions: In Romania, patients with T2DM often achieve glycemic control targets but fail to meet composite targets that include glycemic, BP, and lipid control. Additionally, few patients benefit from innovative glucose-lowering therapies with proven cardio-renal benefits or from statins. [ABSTRACT FROM AUTHOR]

Heart failure is a major global healthcare concern. The condition is associated with high morbidity, high mortality and a reduced quality of life. The prognosis of heart failure is poor, with a 5-year survival rate close to 50%. Pharmacological treatment is a cornerstone of heart failure care, helping to improve outcomes and quality of life for people living with the condition. The sodium–glucose co-transporter-2 (SGLT2) inhibitors dapagliflozin and empagliflozin have been approved for patients who have heart failure with reduced ejection fraction, mildly reduced ejection fraction and preserved ejection fraction. This article discusses the evidence base, mechanism of action, clinical indications and practical considerations for the use of SGLT2 inhibitors in the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi‐imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost‐effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium–glucose co‐transporter‐2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF. [ABSTRACT FROM AUTHOR]

We evaluated the effects on glycemic control and body weight of a GLP1-RA in obese type 2 diabetic patients treated with SGLT2-inhibitors and other hypoglycemic agents and/or insulin, in a real-world setting. A cohort of 583 type 2 diabetic outpatients treated with a SGLT2 inhibitor and/or other anti-diabetic medications were examined. Because patients had suboptimal glycemic control, the GLP1-RA Dulaglutide was added to ongoing medications. At 6 months, 334 patients had a follow-up visit. Patients were classified in terms of cardiovascular risk (CVR) employing the ESC-EASD 2019 criteria, with the AWARE app. The study’s primary endpoints were changes in: 1) HbA1c level, 2) BMI, and 3) body weight after six months of treatment. Secondary endpoints were evaluation of Dulaglutide addition in type 2 diabetic patients: 1) with more or less than ten years of T2DM; 2) more or less than 75 years of age and in different subgroups of CVR. In the 334 patients which had a 6 months follow-up visit, age was 65,9+9,8; 33.5 % (112) were females and 66.5 % (222) were males. After six months of Dulaglutide treatment, we found a significant reduction in HbA1c levels (8.0+10.5 mmol/mol; p

Hua Liu,1,2,&ast; Yang-Min Hao,1,2,&ast; Sheng Jiang,1,2,&ast; Maiheliya Baihetiyaer,1,2 Cheng Li,3 Guo-Yao Sang,4 Zhiming Li,5 Guo-Li Du1,2,6 1State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang, People’s Republic of China; 2Department of Endocrinology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 3Data Statistics and Analysis Center of Operation Management Department, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 4Laboratory Medicine Diagnostic Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 5Department of Ultrasound, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 6Bazhou People’s Hospital, Korla, Xinjiang Uygur Autonomous Region, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guo-Li Du, Email genemagic@126.comPurpose: This study aims to investigate the relationship between Sodium Glucose Co-transporter-2 inhibitors (SGLT2i) treatment and fibrosis in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD) combined with Type 2 Diabetes Mellitus (T2DM) and Major Adverse Cardiovascular and Cerebrovascular Events (MACCEs).Methods: A case–control study was conducted, involving 280 patients with MASLD combined with T2DM treated at the First Affiliated Hospital of Xinjiang Medical University from January 2014 to October 2023. Among these patients, 135 received SGLT2i treatment. The association between the Fibrosis-4 (FIB-4) index and the occurrence of MACCEs, as well as the association between the Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) scores and MACCEs, were evaluated.Results: The FIB-4 index and APRI scores were significantly lower in the SGLT2i treatment group compared to the non-SGLT2i group (1.59 vs 1.25, P< 0.001). SGLT2i treatment tended to reduce the occurrence of MACCEs compared to non-SGLT2i treatment (45.5% vs 38.5%, P=0.28). All patients who developed MACCEs in the non-SGLT2i treatment group had higher FIB-4 index (1.83 vs 1.35, P=0.003). Additionally, after SGLT2i treatment for a median duration of 22 months, patients showed significant reductions in blood glucose, APRI, and FIB-4 index.Conclusion: SGLT2i treatment significantly reduces the occurrence of MACCEs and liver fibrosis in patients with MASLD combined with T2DM. The FIB-4 index may serve as a potential surrogate marker for predicting the occurrence of MACCEs.Keywords: MASLD, type 2 diabetes mellitus, sodium-glucose co-transporter-2 inhibitors, MACCEs, FIB-4 index

Simple Summary: This study explored the liver-protective effects of dapagliflozin and silymarin, alone and combined, against liver damage caused by carbon tetrachloride (CCl4) in rats. Thirty rats were divided into five groups. All groups except the normal control group were given CCl4 to induce liver damage. The other groups received treatments with gum acacia, silymarin, dapagliflozin, or a combination of dapagliflozin and silymarin for 14 days. The results show that both dapagliflozin and silymarin, alone and combined, significantly reduced liver damage markers in the blood compared to the group that only received CCl4. Additionally, these treatments lowered levels of inflammatory substances and increased antioxidant enzyme levels in the liver. The combination of dapagliflozin and silymarin was especially effective, suggesting they work well together to protect the liver. This study highlights the potential of dapagliflozin and silymarin in preventing liver damage by influencing specific protective pathways in the body. This study was aimed to investigate the hepatoprotective potential of dapagliflozin and silymarin alone and in combination to combat carbon tetrachloride (CCl4)-induced hepatotoxicity and the anticipated mechanisms. Thirty female Wistar rats were randomly allocated into five different groups. All the experimental animals except the normal control (Group I) were administered CCl4. Additionally, Groups II, III, IV, and V were treated with gum acacia, silymarin, dapagliflozin, and a combination of dapagliflozin and silymarin, respectively, for 14 days. Dapagliflozin, silymarin alone, and in combination, significantly reduced (p < 0.05) serum levels of ALT, AST, AST:ALT ratio, and total bilirubin compared to CCl4-intoxicated control rats. There was a notable reduction (p < 0.05) observed in the levels of IL-1beta, IL-6, TNF-alpha, nitrites, and 4-hydroxynonenal, accompanied by an elevation in catalase, superoxide dismutase, glutathione peroxidase, nuclear erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in liver homogenates of the groups treated with dapagliflozin, silymarin alone, and in combination, as compared to the CCl4-intoxicated control group. Dapagliflozin in combination with silymarin showed a synergistic hepatoprotective effect. Our study reveals the profound hepatoprotective potential of dapagliflozin alone and in combination with silymarin in CCl4-intoxicated Wistar rats by modulating the Nrf2 and HO-1 signaling pathways. [ABSTRACT FROM AUTHOR]

Aims: To conduct a meta‐analysis of randomized controlled trials (RCTs) to assess the effect of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors on inflammatory biomarkers. Methods: Medline, Embase and the Cochrane Library were searched for RCTs investigating the effect of SGLT2 inhibitors on inflammatory biomarkers, adipokine profiles and insulin sensitivity. Results: Thirty‐eight RCTs were included (14 967 participants, 63.3% male, mean age 62 ± 8.6 years) with a median (interquartile range) follow‐up of 16 (12–24) weeks. Meta‐analysis showed that SGLT2 inhibitors significantly improved adiponectin, interleukin‐6, tumour necrosis factor receptor‐1 (vs. placebo alone: standardized mean difference [SMD] 0.34 [95% confidence interval {CI} 0.23, 0.45], mean difference [MD] −0.85 pg/mL [95% CI −1.32, −0.38], SMD −0.13 [95% CI −0.20, −0.06], respectively), leptin and homeostatic model assessment of insulin resistance index (vs. control: SMD −0.20 [95% CI −0.33, −0.07], MD −0.83 [95% CI −1.32, −0.33], respectively). There were no significant changes in C‐reactive protein (CRP), tumour necrosis factor‐α, plasminogen activator inhibitor‐1, fibroblast growth factor‐21 or monocyte chemoattractant protein‐1. Conclusions: Our analysis shows that SGLT2 inhibitors likely improve adipokine biomarkers and insulin sensitivity, but there is little evidence that SGLT2 inhibitors improve other inflammatory biomarkers including CRP. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) and kidney disease are the main causes of morbidity and mortality in type 2 diabetes mellitus (T2DM). Globally, the incidence of T2DM continues to rise. A substantial increase in the burden of CVD and renal disease, alongside the socioeconomic implications, would be anticipated. Adopting a purely glucose-centric approach focusing only on glycemic targets is no longer adequate to mitigate the cardiovascular risks in T2DM. In the past decade, significant advancement has been achieved in expanding the pharmaceutical options for T2DM, with novel agents such as the sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide receptor agonists (GLP-1 RAs) demonstrating robust evidence in cardiorenal protection. Combinatorial approaches comprising multiple pharmacotherapies combined in a single agent are an emerging and promising way to not only enhance patient adherence and improve glycemic control but also to achieve the potential synergistic effects for greater cardiorenal protection. In this review, we provide an update on the novel antidiabetic agents in the past decade, with an appraisal of the mechanisms contributing to cardiorenal protection. Additionally, we offer a glimpse into the landscape of T2DM management in the near future by providing a comprehensive summary of upcoming agents in early-phase trials. [ABSTRACT FROM AUTHOR]

Originally developed for use in type 2 diabetes mellitus (T2DM), sodium–glucose co-transporter-2 (SGLT2) inhibitors demonstrated diverse cardiovascular- and kidney-protective effects in large outcome trials. Their subsequent approval as a treatment for chronic kidney disease (CKD) marked a pivotal shift in the landscape of CKD management. Further to this, the approval of dapagliflozin and empagliflozin for use in patients with CKD with and without T2DM afforded new treatment opportunities for this population. SGLT2 inhibitors provide an effective treatment for CKD with a favorable safety profile. However, their uptake has been slow, especially among patients without T2DM, owing perhaps to a lack of certainty and familiarity among health care professionals. As the landscape of CKD management continues to evolve, health care professionals should remain knowledgeable about these changes, and implement new guideline recommendations promptly to avoid therapeutic inertia. SGLT2 inhibitors are recommended for patients with CKD with or without T2DM and are foundational agents to support cardiovascular, kidney, and metabolic health. In this review, we provide evidence-based answers to questions that may be asked in the clinic regarding the use of SGLT2 inhibitors to treat CKD.

Background: Contemporary evidence supports the cardiovascular and renal benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2is) in patients with diabetes. While metformin has traditionally been recommended as a first-line treatment, its exact role in improving cardiovascular outcomes remains uncertain. This study aims to evaluate the impact of combination therapy with metformin on the cardiovascular and renal outcomes in high-risk, treatment-naïve diabetic patients who have undergone SGLT2i therapy. Methods: Using the National Health Insurance Research Database in Taiwan, a retrospective cohort study was conducted. Treatment-naïve patients with diabetes and established atherosclerotic cardiovascular disease (ASCVD) undertaking SGLT2i therapy from 1 January 2016 to 31 December 2021 were included. Patients were categorized based on the concomitant use of metformin. Propensity score matching was employed to minimize confounding factors. The primary outcome was major adverse cardiovascular events (MACEs), with secondary outcomes including cardiovascular death, hospitalization for heart failure, and renal outcomes. Results: In total, 10,151 treatment-naïve diabetic patients with ASCVD were identified, with 2570 in the only SGLT2i therapy group and 7581 in the SGLT2i plus metformin group. In total, 2262 pairs were analyzed after propensity score adjustment. The risk of MACEs (36.6 vs. 42.1 events per 1000 person-years; hazard ratio 0.87, 95% confidence interval 0.70–1.09) and other outcomes did not significantly differ between the two treatment groups. Conclusions: In high-risk, treatment-naïve diabetic patients, initiating SGLT2i therapy alone or in combination with metformin resulted in comparable cardiovascular and renal outcomes. These findings suggest that metformin might not be mandatory as a first-line treatment for achieving cardiovascular benefits in such patients. [ABSTRACT FROM AUTHOR]

Recent advances in type 2 diabetes (T2D) research have highlighted the benefits of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, including cardiovascular and renal protection. However, uptake rates of these drugs remain low in patients with T2D, particularly in subpopulations most likely to benefit from them. This review considers the potential barriers to prescribing SGLT-2 inhibitors in T2D in clinical practice and outlines potential multidisciplinary recommendations to overcome these barriers. Safety concerns and a lack of clarity in and divergence of guidelines around the introduction of SGLT-2 inhibitors into treatment regimens may represent a barrier to uptake from the clinicians perspective, including a general lack of understanding of the benefits associated with SGLT-2 inhibitors. Patient characteristics, such as socioeconomic status, may influence uptake because of the cost of SGLT-2 inhibitors, especially in the United States, where health insurance coverage could be a concern. SGLT-2 inhibitor prescription rates vary between clinical specialty (endocrinology, primary care, cardiology, and nephrology) and country, with cardiologists the lowest prescribers, and endocrinologists the highest. Primary care practitioners may experience more challenges in following SGLT-2 inhibitor-related guidelines than diabetes specialists as there may be fewer opportunities for education on how this drug class improves cardiovascular and renal outcomes in patients with T2D. Uptake rates appear to vary between countries because of differences in guidelines and health insurance systems. The amendment of SGLT-2 inhibitor-related guidelines for more multidisciplinary use and the implementation of patient and clinician education may encourage uptake of these drugs, potentially improving long-term health outcomes among patients with T2D.

Abstract Introduction Evidence for dual antidiabetic therapy in type 2 diabetes mellitus patients with cirrhosis is limited. This study compared 5-year mortality, composite hepatic decompensation risk, and hepatocellular carcinoma occurrence in patients with diabetes and cirrhosis who were either on metformin monotherapy or on dual metformin and sodium-glucose co-transporter-2 inhibitor (SGLT2-I) therapy. Methods This retrospective study used the TriNetX Research Network to identify propensity score-matched patients treated with either metformin or dual metformin and SGLT2-I therapy. Our outcomes were all-cause mortality, a composite of hepatic decompensation events, and hepatocellular carcinoma (HCC) occurrence over 5 years. We estimated hazard ratios within each cohort with 95% confidence intervals (CI) and Kaplan-Meier estimates for time-to-event distributions with Log-rank tests. We were able to stratify our cohorts by age, sex, race, and ethnicity. We further investigated a subset of diabetic patients with cirrhosis due to MASH. Results In our propensity score-matched cohorts of type 2 diabetes patients with cirrhosis, those on dual metformin and SGLT2-I therapy had decreased risk for mortality (HR 0.57, 95%CI 0.41–0.81), reduced composite risk of becoming decompensated (HR 0.63, 95%CI 0.43–0.93) and less than half the risk for developing HCC (HR 0.43, 95%CI 0.21–0.88) compared to those on mono metformin therapy. We did not find a difference between mono or dual therapy treatment for mortality, decompensation, or HCC risks in the subset of patients with MASH cirrhosis. Conclusion Dual metformin and SGLT2-I treatment in type 2 diabetes patients with cirrhosis are associated with improved mortality and hepatic complications.

Introduction: Evidence for dual antidiabetic therapy in type 2 diabetes mellitus patients with cirrhosis is limited. This study compared 5-year mortality, composite hepatic decompensation risk, and hepatocellular carcinoma occurrence in patients with diabetes and cirrhosis who were either on metformin monotherapy or on dual metformin and sodium-glucose co-transporter-2 inhibitor (SGLT2-I) therapy. Methods: This retrospective study used the TriNetX Research Network to identify propensity score-matched patients treated with either metformin or dual metformin and SGLT2-I therapy. Our outcomes were all-cause mortality, a composite of hepatic decompensation events, and hepatocellular carcinoma (HCC) occurrence over 5 years. We estimated hazard ratios within each cohort with 95% confidence intervals (CI) and Kaplan-Meier estimates for time-to-event distributions with Log-rank tests. We were able to stratify our cohorts by age, sex, race, and ethnicity. We further investigated a subset of diabetic patients with cirrhosis due to MASH. Results: In our propensity score-matched cohorts of type 2 diabetes patients with cirrhosis, those on dual metformin and SGLT2-I therapy had decreased risk for mortality (HR 0.57, 95%CI 0.41–0.81), reduced composite risk of becoming decompensated (HR 0.63, 95%CI 0.43–0.93) and less than half the risk for developing HCC (HR 0.43, 95%CI 0.21–0.88) compared to those on mono metformin therapy. We did not find a difference between mono or dual therapy treatment for mortality, decompensation, or HCC risks in the subset of patients with MASH cirrhosis. Conclusion: Dual metformin and SGLT2-I treatment in type 2 diabetes patients with cirrhosis are associated with improved mortality and hepatic complications. [ABSTRACT FROM AUTHOR]

Ertugliflozin, a sodium-glucose cotransporter-2 inhibitor, seems to improve glycemic control in type 2 diabetes mellitus (T2DM). We aim to evaluate the efficacy of Ertugliflozin across multiple time intervals (18, 26, and 52 weeks) in T2DM patients. A literature search was conducted on electronic databases. Data was extracted from eligible studies at both 5 mg and 15 mg doses in monotherapy and as add-on therapy. Cochrane RevMan was used to perform the meta-analysis. Ertugliflozin, at both 5 mg and 15 mg doses, demonstrated a significant improvement in HbA1c levels at 18 weeks 5 mg [P = 0.00001], 15 mg [P = 0.05], and at 26 weeks in monotherapy 5 mg [P = 0.006], monotherapy 15 mg [P = 0.006], 5 mg as add-on therapy [P = 0.00001], 15 mg add-on therapy [P = 0.00001] respectively. At 52 weeks, the reduction in HbA1c was significant in 15 mg add-on therapy [P = 0.0001]. Additionally, ertugliflozin as an add-on therapy also led to a significant reduction in FPG, body weight, and systolic blood pressure. Ertugliflozin showed clinical efficacy in improving glycemic control, fasting plasma glucose, body weight, and systolic blood pressure in T2DM patients over the studied time intervals compared to placebo. [ABSTRACT FROM AUTHOR]

Background: To estimate the contemporary prevalence of established cardiovascular disease (CVD) in adults with type 2 diabetes (T2D) in Mexico. Methods: CAPTURE was a multinational, non-interventional, cross-sectional study across 13 countries from five continents. Standardized demographic and clinical data were collected from adults with T2D attending a single routine healthcare visit in primary or specialized care between December 2018 and September 2019. Data from Mexico are analyzed in this study. Results: Of the 9,823 patients included in the CAPTURE study, 820 (8.3%) participants were from Mexico, mainly attended in private centers (29.3% in 6 specialized diabetes treatment centers and 70.7% in 26 primary care centers). The median age was 63.0 years, 52.6% were women, the duration of diabetes was 11.8 years and the average HbA1c 7.5%. The weighted prevalence [95% CI] of CVD and atherosclerotic CVD was 36.9% [34.1–39.6] and 29.5% [26.7–32.3], respectively. Additionally, the prevalence of coronary heart disease, heart failure, peripheral arterial disease and cerebrovascular disease was 23.1% [20.6–25-7], 8.4% [6.8–10.0], 5.0% [3.5–6.5] and 3.9% [2.6–5.2], respectively. Glucose lowering drugs were used in 88.5% of patients, being metformin the most commonly drug used (79.4%), followed by sulfonylureas (26.3%). SGLT-2 inhibitors and GLP1 receptor agonists were used in 15.5% and 3.9%, respectively. Conclusions: In Mexico, nearly four out of ten patients with T2D mainly attended in private centers have CVD, particularly atherosclerotic CVD. Most patients were not taking glucose lowering drugs with proven CV benefit. [ABSTRACT FROM AUTHOR]

Background: The 2018 Australian Heart Failure (HF) guidelines strongly recommended commencing sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) in HF patients with type 2 diabetes mellitus (T2DM). The uptake of SGLT‐2is for HF patients with T2DM in our health service is unknown. Aims: To determine the adoption of the 2018 HF guidelines by assessing the temporal trends of SGLT‐2is' usage in HF patients with T2DM at Metro South Health (MSH) hospitals, in South‐East Queensland. Methods: Retrospective analysis of all HF patients (ejection fraction (EF) < 50%) with T2DM who were managed within MSH hospitals between June 2018 and June 2021. Results: A total of 666 patients met the inclusion criteria with 918 HF encounters. Mean age was 72 years and 71% were male (473/666). Mean EF was 30% (SD ± 11%), and mean estimated glomerular filtration rate was 48 mL/min/1.73 m2 (SD ± 25). Fifty‐four per cent (362/666) had contraindications to SGLT‐2is. Among those without contraindications, there was a five‐fold increase in the utility of SGLT‐2is, 7% (2/29) before versus 38% (103/275) after implementation of the HF guidelines (P < 0.001). Patients on SGLT‐2is were younger (64 years vs 69 years, P = 0.002) and had a lower number of HF hospitalisations (1.1 vs 2.1, P = 0.01). Conclusions: During the study period, 54% of our HF patients with T2DM were not on SGLT‐2is due to prescribing guidelines/limitations in the Australian context. We observed a five‐fold significant increase in the uptake of SGLT‐2is before and after implementation of HF guidelines among patients without contraindications to SGLT‐2is. There were significantly fewer HF hospitalisations among patients on SGLT‐2is compared to those without. [ABSTRACT FROM AUTHOR]

Early and intensive treatment of type 2 diabetes (T2D) has been associated with lower risk of diabetes-related complications. Control of overweight and obesity, which are strongly associated with T2D and many of its complications, is also key in the management of the disease. New therapies allow for individualised glycaemic control targets with greater safety. Thus, in patients with a higher cardiovascular and renal risk profile, current guidelines encourage early treatment with metformin together with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors with proven cardiovascular benefit. GLP-1 RAs combine highly efficacious glucose-lowering activity with a reduced risk of hypoglycaemia. Recently, tirzepatide, a first-in-class drug that activates both glucose-dependent insulinotropic polypeptide and GLP-1 receptors, has demonstrated very high efficacy in glycated haemoglobin (HbA1c) and weight reduction in clinical trials. Tirzepatide has the potential to help people with T2D reach recommended glycaemic and weight targets (HbA1c < 7% and > 5% weight reduction) and to allow some patients to reach HbA1c measurements close to normal physiological levels and substantial weight reduction. In 2022, tirzepatide was approved by the US Food and Drug Administration and the European Medicines Agency for treatment of people with T2D and is currently in development for chronic weight management. Plain Language Summary: In people newly diagnosed with type 2 diabetes, early and intensive treatment of the disease can help control blood sugar and reduce the risk of later complications. The need to control weight in people with obesity and diabetes has also recently become a priority. New drugs developed in recent years allow for better and more individualised management of blood sugar without the risk of blood sugar levels dropping too low. In patients at risk of kidney or heart disease, the current recommendation is early treatment with metformin and drugs with proven cardiovascular benefit. Tirzepatide is a new drug that has also demonstrated very high efficacy in reducing blood glucose and body weight. It has the potential to help people with type 2 diabetes achieve their goals and prevent other diabetes-related complications. It is likely that some patients will even be able to bring their blood glucose to normal levels and lose substantial amounts of weight. The US and European regulatory agencies approved tirzepatide in 2022 for the treatment of type 2 diabetes and it is currently being tested for chronic weight management. [ABSTRACT FROM AUTHOR]

Abstract Background Sodium-glucose co-transporter-2 inhibitors displayed cardiovascular benefits in type 2 diabetes mellitus in previous studies; however, there were some heterogeneities regarding respective cardiovascular outcomes within the class. Furthermore, their efficacies in Asians, females, and those with low cardiovascular risks were under-represented. Thus, we compared the cardiovascular outcomes between new users of dapagliflozin and empagliflozin in a broad range of patients with type 2 diabetes mellitus using a nationwide population-based real-world cohort from Korea. Methods Korean National Health Insurance registry data between May 2016 and December 2018 were extracted, and an active-comparator new-user design was applied. The primary outcome was a composite of heart failure (HF)-related events (i.e., hospitalization for HF and HF-related death), myocardial infarction, ischemic stroke, and cardiovascular death. The secondary outcomes were individual components of the primary outcome. Results A total of 366,031 new users of dapagliflozin or empagliflozin were identified. After 1:1 nearest-neighbor propensity score matching, 72,752 individuals (mean age approximately 56 years, 42% women) from each group were included in the final analysis, with a follow-up of 150,000 ~ person-years. Approximately 40% of the patients included in the study had type 2 diabetes mellitus as their sole cardiovascular risk factor, with no other risk factors. The risk of the primary outcome was not different significantly between dapagliflozin and empagliflozin users (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.855–1.006). The risks of secondary outcomes were also similar, with the exception of the risks of HF-related events (HR 0.84, 95% CI 0.714–0.989) and cardiovascular death (HR 0.76, 95% CI 0.618–0.921), which were significantly lower in the dapagliflozin users. Conclusions This large-scale nationwide population-based real-world cohort study revealed no significant difference in composite cardiovascular outcomes between new users of dapagliflozin and empagliflozin. However, dapagliflozin might be associated with lower risks of hospitalization or death due to HF and cardiovascular death than empagliflozin in Asian patients with type 2 diabetes mellitus.

Abstract Background Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. Methods A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013–2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. Results Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71–1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39–0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. Conclusion SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect.

Cardiovascular disease (CVD) and kidney disease are the main causes of morbidity and mortality in type 2 diabetes mellitus (T2DM). Globally, the incidence of T2DM continues to rise. A substantial increase in the burden of CVD and renal disease, alongside the socioeconomic implications, would be anticipated. Adopting a purely glucose-centric approach focusing only on glycemic targets is no longer adequate to mitigate the cardiovascular risks in T2DM. In the past decade, significant advancement has been achieved in expanding the pharmaceutical options for T2DM, with novel agents such as the sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide receptor agonists (GLP-1 RAs) demonstrating robust evidence in cardiorenal protection. Combinatorial approaches comprising multiple pharmacotherapies combined in a single agent are an emerging and promising way to not only enhance patient adherence and improve glycemic control but also to achieve the potential synergistic effects for greater cardiorenal protection. In this review, we provide an update on the novel antidiabetic agents in the past decade, with an appraisal of the mechanisms contributing to cardiorenal protection. Additionally, we offer a glimpse into the landscape of T2DM management in the near future by providing a comprehensive summary of upcoming agents in early-phase trials.

Aim: To describe the development of the AWARE App, a novel web application for the rapid assessment of cardiovascular risk in Type 2 Diabetes Mellitus (T2DM) patients. We also tested the feasibility of using this App in clinical practice. Methods: Based on 2019 European Society of Cardiology/European Association for the Study of Diabetes criteria for cardiovascular risk stratification in T2DM, the AWARE App classifies patients into very high (VHCVR), high (HCVR) and moderate (MCVR) cardiovascular risk categories. In this retrospective clinical study, we employed the App to assess the cardiovascular risk of T2DM patients, while also collecting data about current glycaemic control and pharmacological treatment. Results: 2243 T2DM consecutive patients were evaluated. 72.2% of the patients were VHCVR, 8.9% were HCVR, 0.8% were MCVR while 18.2% did not fit into any of the risk categories and were classified as "moderate-to-high" (MHCVR). Compared with the other groups, patients with VHCVD were more frequently ≥ 65 years old (68.9%), with a longer disease duration (≥ 10 years [56.8%]), a history of cardiovascular disease (41.4%), organ damage (35.5%) and a higher numbers of cardiovascular risk factors. Patients with MHCVD generally had disease duration < 10 years (96%), younger age (50–60 years [55%]), no history of cardiovascular disease, no organ damage, and 1–2 cardiovascular risk factors (89%). Novel drugs such as Glucagon Like Peptyde 1 Receptor Agonists or Sodium-Glucose Linked Transporter 2 inhibitors were prescribed only to 26.3% of the patients with VHCVR and to 24.7% of those with HCVR. Glycaemic control was unsatisfactory in this patients population (HbA1c 7.5 ± 3.4% [58.7 ± 13.4 mmol/mol]). Conclusions: The AWARE App proved to be a practical tool for cardiovascular risk stratification of T2DM patients in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Background As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. Methods A retrospective, pharmacovigilance study of the FDA’s global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (

Background: Sodium-glucose co-transporter-2 inhibitors displayed cardiovascular benefits in type 2 diabetes mellitus in previous studies; however, there were some heterogeneities regarding respective cardiovascular outcomes within the class. Furthermore, their efficacies in Asians, females, and those with low cardiovascular risks were under-represented. Thus, we compared the cardiovascular outcomes between new users of dapagliflozin and empagliflozin in a broad range of patients with type 2 diabetes mellitus using a nationwide population-based real-world cohort from Korea. Methods: Korean National Health Insurance registry data between May 2016 and December 2018 were extracted, and an active-comparator new-user design was applied. The primary outcome was a composite of heart failure (HF)-related events (i.e., hospitalization for HF and HF-related death), myocardial infarction, ischemic stroke, and cardiovascular death. The secondary outcomes were individual components of the primary outcome. Results: A total of 366,031 new users of dapagliflozin or empagliflozin were identified. After 1:1 nearest-neighbor propensity score matching, 72,752 individuals (mean age approximately 56 years, 42% women) from each group were included in the final analysis, with a follow-up of 150,000 ~ person-years. Approximately 40% of the patients included in the study had type 2 diabetes mellitus as their sole cardiovascular risk factor, with no other risk factors. The risk of the primary outcome was not different significantly between dapagliflozin and empagliflozin users (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.855–1.006). The risks of secondary outcomes were also similar, with the exception of the risks of HF-related events (HR 0.84, 95% CI 0.714–0.989) and cardiovascular death (HR 0.76, 95% CI 0.618–0.921), which were significantly lower in the dapagliflozin users. Conclusions: This large-scale nationwide population-based real-world cohort study revealed no significant difference in composite cardiovascular outcomes between new users of dapagliflozin and empagliflozin. However, dapagliflozin might be associated with lower risks of hospitalization or death due to HF and cardiovascular death than empagliflozin in Asian patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. Methods: A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013–2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. Results: Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71–1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39–0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. Conclusion: SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect. [ABSTRACT FROM AUTHOR]

Aims: We investigated evidence from randomised, placebo‐controlled trials of novel glucose‐lowering therapies; sodium‐glucose co‐transporter‐2 inhibitors (SGLT2i), dipeptidyl peptidase‐4 inhibitors (DPP4i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RA), on physical function in people with type 2 diabetes (T2D). Methods: PubMed, Medline, Embase and Cochrane library were searched from 1 April 2005 to 20 January 2022. The primary outcome was change in physical function in groups receiving a novel glucose‐lowering therapy versus placebo at the trial end‐point. Results: Eleven studies met our criteria including nine for GLP‐1RA and one each for SGLT2i and DPP4i. Eight studies included a self‐reported measure of physical function, seven with GLP‐1RA. Pooled meta‐analysis showed an improvement of 0.12 (0.07, 017) points in favour of novel glucose‐lowering therapies, mainly GLP‐1RA. These findings were consistent when assessed individually for commonly used subjective assessments of physical function; namely the Short‐Form 36 item‐questionnaire (SF‐36; all investigating GLP‐1RA) and the Impact of Weight on Quality of Life‐Lite (IWQOL‐LITE; all, except one, exploring GLP‐1RA) with estimated treatment differences (ETDs) of 0.86 (0.28, 1.45) and 3.72 (2.30, 5.15) respectively in favour of novel GLTs. For objective measures of physical function (VO2max and 6‐minute walk test (6MWT)) no significant between‐group differences between the intervention and the placebo were found. Conclusions: GLP‐1RAs showed improvements in self‐reported outcomes of physical function. However, there is limited evidence to draw definitive conclusions especially because of lack of studies exploring the impact of SGLT2i and DPP4i on physical function. There is a need for dedicated trials to establish the association between novel agents and physical function. [ABSTRACT FROM AUTHOR]

Introduction: Albuminuria, or elevated urinary albumin-to-creatine ratio (UACR), is a biomarker for chronic kidney disease that is routinely monitored in patients with type 2 diabetes (T2D). Head-to-head comparisons of novel antidiabetic drugs on albuminuria outcomes remain limited. This systematic review qualitatively compared the efficacy of novel antidiabetic drugs on improving albuminuria outcomes in patients with T2D. Methods: We searched the MEDLINE database until December 2022 for Phase 3 or 4 randomized, placebo-controlled trials that evaluated the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on changes in UACR and albuminuria categories in patients with T2D. Results: Among 211 records identified, 27 were included, which reported on 16 trials. SGLT2 inhibitors and GLP-1 RAs decreased UACR by 19–22% and 17–33%, respectively, versus placebo (P < 0.05 for all studies) over median follow-up of ≥ 2 years; DPP-4 inhibitors showed varying effects on UACR. Compared with placebo, SGLT2 inhibitors decreased the risk for albuminuria onset by 16–20% and for albuminuria progression by 27–48% (P < 0.05 for all studies) and promoted albuminuria regression (P < 0.05 for all studies) over median follow-up of ≥ 2 years. Evidence on changes in albuminuria categories with GLP-1 RA or DPP-4 inhibitor treatment were limited with varying outcome definitions across studies and potential drug-specific effects within each class. The effect of novel antidiabetic drugs on UACR or albuminuria outcomes at ≤ 1 year remains poorly studied. Conclusion: Among the novel antidiabetic drugs, SGLT2 inhibitors consistently improved UACR and albuminuria outcomes in patients with T2D, with continuous treatment showing long-term benefit. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to estimate the prevalence of cardiovascular disease and investigate cardiovascular risk management among type 2 diabetes (T2D) patients in the city of Meknes. Materials and methods: In a non-interventional cross-sectional study, we enrolled adult outpatients (= 18 years old) with T2D from the endocrinology and diabetology consultation of the Military Hospital of Meknes from June 2021 to January 2022. Informed consent was signed by all participants in the study. Assessment of cardiovascular risk was based on European Society of Cardiology (ESC) Guidelines on cardiovascular disease prevention in clinical practice of 2021. Clinical, biological and therapeutic data were compared between patients with and without cardiovascular disease. Data were analyzed using SPSS version 18 statistical software. Results: One hundred eighty T2D patients were enrolled. The mean age was 59.42 ± 8.72 years. The prevalence of cardiovascular disease was 13.3%. The prescription of statin (p < 0.001), antihypertensive treatment (p < 0.001) and platelet aggregation inhibitors (p < 0.001) was significantly higher in patients with cardiovascular disease. Overall, 5.6% patients were prescribed a blood glucose-lowering agent with demonstrated cardiovascular benefit. This prescription was higher in patients with cardiovascular disease (5 (20.8%) vs. 5 (3.2%); p = 0.004). It was found that 7.2% patients had an optimal cardiovascular risk factor management. Conclusions: The prevalence of cardiovascular disease among T2D patients is high in the city of Meknes. Despite an optimal prescription of cardiovascular medications, comprehensive control of cardiovascular risk factors is not achieved in most patients. The use of blood glucose-lowering agents with demonstrated cardiovascular benefit was low but significantly higher among patients with cardiovascular disease. [ABSTRACT FROM AUTHOR]

Crescentic IgA nephropathy (IgAN) with rapidly progressive glomerulonephritis (RPGN) is often associated with rapidly declining kidney function. Up to this date, specific therapy for crescentic IgAN is still unknown. Accumulating evidence suggests that sodium-glucose co-transporter-2 inhibitors (SGLT-2i) may have a role in standard therapy of glomerular diseases. However, it is unclear at what point in the natural history of specific glomerular diseases SGLT-2i can be beneficial. We report the clinical and histological features of a patient with crescentic IgAN that presented as an RPGN, who received intensive immunosuppression and renal replacement therapeutic (RRT). At the third month, the patient presented with significant improvement in his kidney function. At that point, we decided to start dapagliflozin in addition to his renin-angiotensin system (RAS) blocker, basing our decision on its proven renal benefits such as slowing the rate of decline in kidney function and reducing albuminuria. At the eighth month, the patient’s renal function gradually improved from serum Cr of 6.07 to 2.1 mg/dL; and urine albumin to creatinine ratio (UACR) declined from 5655 mg/g to 200 mg/g. The use of SGLT-2i in primary and secondary nondiabetic glomerular disease appears promising. It is crucial and necessary to accumulate more evidence for a more complete understanding of the mechanisms of the actions of SGLT-2i in non-diabetic glomerular disease.

Aim: To investigate changes in the pattern of drugs used to treat type 2 diabetes in Denmark from 2005 to 2021. Materials and Methods: A nationwide, population‐based drug utilization study based on medical databases covering the Danish population was conducted. We assessed incident and prevalent use patterns among all 441 205 individuals initiating at least one non‐insulin, glucose‐lowering drug. Results: The rate of new users of non‐insulin, glucose‐lowering drugs increased from 2005, peaked in 2011, decreased to stable levels during 2013 to 2019, then increased dramatically during 2020‐2021. The prevalence of use increased from 2.1% (in 2005) to 5.0% (in 2021) of the entire adult population. In 2021, metformin comprised 39% of all glucose‐lowering drug consumption, followed by insulin (17%), sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) (17%), glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) (16%) and dipeptidyl peptidase‐4 inhibitors (7.5%). Overall, 56% of users were on monotherapy, 28% used dual therapy, while 13% and 2.8% used three and four drug classes, respectively. Both the intensity and diversity of therapies increased substantially over time, with 15 different treatment regimens each covering more than 1% of users in 2021. General practitioners prescribed 88% of all glucose‐lowering drugs. Marked shifts towards GLP‐1RA initiation by general practitioners and SGLT‐2i initiation by specialists were observed, and changing user profiles suggested increasing use for non‐diabetes indications. Conclusions: The rate of new users of non‐insulin, glucose‐lowering drugs has increased in recent years and the prevalence of glucose‐lowering drug use increases steadily. Glucose‐lowering drugs are mainly prescribed by general practitioners, and the intensity, diversity and indications of glucose‐lowering treatment are increasing. [ABSTRACT FROM AUTHOR]

Diabetic patients have a two- to four-fold increase in the risk of heart failure (HF), and the co-existence of diabetes and HF is associated with poor prognosis. In randomized clinical trials (RCTs), compelling evidence has demonstrated the beneficial effects of sodium-glucose co-transporter-2 inhibitors on HF. The mechanism includes increased glucosuria, restored tubular glomerular feedback with attenuated renin–angiotensin II–aldosterone activation, improved energy utilization, decreased sympathetic tone, improved mitochondria calcium homeostasis, enhanced autophagy, and reduced cardiac inflammation, oxidative stress, and fibrosis. The RCTs demonstrated a neutral effect of the glucagon-like peptide receptor agonist on HF despite its weight-reducing effect, probably due to it possibly increasing the heart rate via increasing cyclic adenosine monophosphate (cAMP). Observational studies supported the markedly beneficial effects of bariatric and metabolic surgery on HF despite no current supporting evidence from RCTs. Bromocriptine can be used to treat peripartum cardiomyopathy by reducing the harmful cleaved prolactin fragments during late pregnancy. Preclinical studies suggest the possible beneficial effect of imeglimin on HF through improving mitochondrial function, but further clinical evidence is needed. Although abundant preclinical and observational studies support the beneficial effects of metformin on HF, there is limited evidence from RCTs. Thiazolidinediones increase the risk of hospitalized HF through increasing renal tubular sodium reabsorption mediated via both the genomic and non-genomic action of PPARγ. RCTs suggest that dipeptidyl peptidase-4 inhibitors, including saxagliptin and possibly alogliptin, may increase the risk of hospitalized HF, probably owing to increased circulating vasoactive peptides, which impair endothelial function, activate sympathetic tones, and cause cardiac remodeling. Observational studies and RCTs have demonstrated the neutral effects of insulin, sulfonylureas, an alpha-glucosidase inhibitor, and lifestyle interventions on HF in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular morbidity and delay the progression of kidney disease in patients with type 2 diabetes mellitus (T2DM). However, the mechanisms underpinning these benefits are not entirely clear. More specifically, it is uncertain whether these agents exert cardiorenal protective effects through a direct action on the vascular wall. The aim of the present study was to evaluate the effects of SGLT2 inhibitors on markers of subclinical vascular damage. Methods: In total, 40 adult patients with T2DM and glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 and age- and gender-matched patients with T2DM and GFR > 60 mL/min/1.73 m2 were consecutively enrolled. Indices of arterial stiffness (pulse wave velocity, augmentation index (AIx), AIx adjusted to a heart rate of 75 beats/min (Alx@75) and central systolic, diastolic, pulse and mean pressure), carotid atherosclerosis (stenosis, intima-media thickness (cIMT) and maximal plaque thickness) and peripheral arterial disease (ankle brachial index (ABI)) were determined. The chi-squared and Mann–Whitney U-test were used to detect differences in categorical and continuous variables between groups, respectively. Results: In total, 15 patients were treated with SGLT2 inhibitors and 25 patients were not receiving these agents. Serum low-density lipoprotein cholesterol levels were lower in the former whereas other cardiovascular risk factors, the prevalence of established cardiovascular disease, anthropometric and demographic characteristics, and vital signs did not differ between the 2 groups. The AIx was lower in patients treated with SGLT2 inhibitors (21.9 ± 11.3 vs. 29.7 ± 12% in patients not treated with SGLT2 inhibitors; p < 0.05). The AIx@75 was also lower in the former (21.3 ± 10.9 and 32.6 ± 11.3%, respectively, p < 0.005). Other markers of arterial stiffness were similar in the 2 groups. In addition, markers of carotid atherosclerosis and the ABI did not differ between patients treated and not treated with SGLT2 inhibitors. Conclusions: Treatment with SGLT2 inhibitors appears to reduce arterial stiffness. Accordingly, these agents might improve cardiovascular outcomes not only in patients with T2DM and established cardiorenal disease but also in lower-risk patients. [ABSTRACT FROM AUTHOR]

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Background: As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. Methods: A retrospective, pharmacovigilance study of the FDA's global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). Results: We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51–68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 − 487.3] vs adj.ROR = 250.2 [79.3 − 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 − 58.8] vs adj.ROR = 88.0 [27.0 − 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 − 34.8] vs adj.ROR = 23.3 [19.2 − 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 − 11.2] vs adj.ROR = 8.6 [7.2 − 10.3]), nocturia (adj.ROR = 5.5 [3.7 − 8.2] vs adj.ROR = 6.7 [2.8 − 15.7]), dehydration (adj.ROR = 2.5 [2.3 − 2.8] vs adj.ROR = 2.6 [2.1 − 3.3]), and fractures (adj.ROR = 1.7 [1.4 − 2.1] vs adj.ROR = 1.5 [1.02 − 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (Pinteraction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 − 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 − 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. Conclusion: In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted. [ABSTRACT FROM AUTHOR]

Introduction: There is limited published literature on longitudinal utilization of glucose-lowering agents (GLAs) among patients with type 2 diabetes (T2D) and cardiovascular disease (CVD or risk of CVD). This retrospective, observational study aimed to provide updated evidence on patient characteristics and utilization of GLAs among patients with T2D and CVD or risk of CVD in the United States. Methods: This was a cross-sectional evaluation of patients with T2D aged 50–89 years with annual continuous enrolment in a Medicare Advantage and Prescription Drug plan, identified from administrative claims data (Humana Research Database). Patients with T2D and atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) (CVD cohort), or T2D and an additional CVD risk factor without pre-existing CVD (CVD risk cohort) were identified from 2015 to 2019. Patients were followed from their first observed ASCVD/HF diagnosis or CVD risk factor for each year they were continuously enrolled or until occurrence of a CVD diagnosis (CVD risk cohort only). Use of GLA classes were reported by year, cohort, and age groups (50–64 years and ≥ 65 years). Results: The percentage of patients on sodium-glucose co-transporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and GLP-1 RAs with proven cardiovascular benefit, respectively, increased from 2015 to 2019 among ≥ 65 years (CVD cohort: 1.1–3.4%, 1.6–4.0%, and 1.2–3.8%; CVD risk cohort: 1.4–3.7%, 2.0–4.3%, and 1.5–4.1%); and among 50–64 years (CVD cohort: 2.6–7.3%, 4.3–10.1%, and 3.4–9.4%; CVD risk cohort: 3.3–6.8%, 4.6–9.6%, and 3.5–8.9%). Conclusions: Although use of SGLT-2is and GLP-1 RAs increased over time, overall utilization of these agents in patients with T2D and ASCVD/HF or at risk for ASCVD/HF remained low, especially for those aged ≥ 65 years. Plain Language Summary: Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are types of glucose-lowering medications for patients with type 2 diabetes (T2D). The American Diabetes Association, the American Association of Clinical Endocrinologists, and American College of Endocrinology have recommended these medications for patients who have been diagnosed with T2D and atherosclerotic cardiovascular disease or heart failure (ASCVD/HF). The purpose of this study was to find out how many patients in a US-based health insurance population with T2D and ASCVD/HF were treated with SGLT-2is, GLP-1 RAs, and other glucose-lowering medications from 2015 to 2019. Using insurance claims data, we identified 50- to 89-year-old patients with T2D and either ASCVD/HF or at least one risk factor for ASCVD/HF. We tracked the number of patients with T2D and either ASCVD/HF or ASCVD/HF risk factors who were using different glucose-lowering medications. Glucose-lowering medications were used in most patients (60–78%), but fewer than 11% of patients aged 50–64 years, and fewer than 5% of patients over 65 years of age were prescribed SGLT-2i and GLP-1 RA medications, despite clinical guidelines recommending their use for the above-mentioned indications. Increasing awareness among healthcare providers may be required to ensure patients with T2D and ASCVD/HF or ASCVD/HF risk factors are prescribed the guideline-recommended cardioprotective glucose-lowering agents. [ABSTRACT FROM AUTHOR]

To identify the impact of sodium-glucose co-transporter-2 (SGLT2) inhibitors on anthropometric indices and metabolic markers in individuals without diabetes who are overweight/obese. Clinical trials investigating the safety and efficacy of SGLT2 inhibitors in overweight or obese adults were sought in PubMed, Scopus, Google Scholar, and EMBASE databases. The overall intervention effect was estimated using a random-effect meta-analysis. Jadad scale was used to assess the risk of bias. The heterogeneity of the studies was assessed using the Cochran's test (Q test) and I2 Index. Analyses of meta-regression were carried out to identify possible sources of heterogeneity among the trials. The analyses were all conducted using Stata, and p <.05 was set as the statistically significant level. Of the five clinical trials that were included in the meta-analysis, five, four, three, and two clinical trials met the eligibility criteria for evaluating the efficacy of SGLT2 inhibitors on the weight, waist circumference (WC) and blood pressure, body mass index (BMI), and lipid and glucose profile, respectively. According to the results, SGLT2 inhibitors lowered BMI (WMD = −0.47 [95% CI: −0.63, −0.31]; p <.001), and WC (WMD = −3.25 [95% CI: −6.36, −0.14]; p =.04), but had no significant influence on blood pressure, lipid, and glucose profile of overweight/obese patients compared to the control groups. The SGLT2 inhibitors appear to ameliorate some anthropometric and metabolic markers. There is, however, a limited number of studies, and further research is required for a firm conclusion. CRD42022306415. [ABSTRACT FROM AUTHOR]

Background and Hypothesis: In chronic kidney disease (CKD) the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is impaired. Runcaciguat, an sGC activator, activates heme-free sGC, restoring cGMP production. This phase 2a trial studied the efficacy, safety, and tolerability of runcaciguat in CKD patients with or without sodium-glucose co-transporter-2 inhibitor (SGLT2i)., Methods: Patients with CKD and established atherosclerotic cardiovascular disease or heart failure, plus type 2 diabetes (T2D) and/or hypertension, were enrolled. All were receiving stable maximum tolerated renin - angiotensin system inhibitors with or without SGLT2i. They were randomized 3:1 to runcaciguat once daily, titrated weekly (30-120 mg if tolerated), or placebo for 8 weeks. The primary efficacy endpoint was urine albumin-to-creatinine ratio (UACR) (average of post-randomization Days 22, 29, and 57 vs baseline). CONCORD was separately powered for CKD and T2D with stable SGLT2i comedication, CKD and T2D without SGLT2i, and non-diabetic CKD., Results: Of 243 patients randomized, 229 were included in the full analysis set (FAS) and 170 in the per-protocol set (PPS). In the PPS, UACR decreased by - 45.2% versus placebo with runcaciguat in patients with CKD without SGLT2i (P < 0.001) and by - 48.1% versus placebo in patients with CKD taking SGLT2i (P = 0.02) In the FAS, the relative reductions were - 46.9% (P < 0.001) and - 44.8% (P = 0.01), respectively. No significant difference was observed between patients with or without SGLT2i. In non-diabetic CKD, UACR was reduced versus baseline with runcaciguat, but the change was not statistically significant (P = 0.10). Serious treatment-emergent adverse events were reported in 7% of patients receiving runcaciguat and 8% receiving placebo., Conclusion: Runcaciguat improved albuminuria in patients with CKD, irrespective of concomitant SGLT2i. Runcaciguat was well tolerated. sGC activation may represent a novel kidney-protective treatment in CKD patients (funded by Bayer AG; ClinicalTrials.gov number, NCT04507061)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Purpose: To evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter2(SGLT-2) inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM)., Methods: To construct an exhaustive database of randomized controlled trials (RCTs) concerning SGLT-2 inhibitors and GLP-1 agonists, a methodical search was undertaken across a range of databases, such as Embase, PubMed, and the Cochrane Central Register of Controlled Trials, from their inception to January 2023. Following this, a meta-analysis was executed to amalgamate the collected data, which allowed for the calculation of standardized mean differences (SMDs), odds ratios (ORs), and 95 % confidence intervals (CIs) for a spectrum of outcomes. This analytical approach was designed to yield a quantitative evaluation of the therapeutic efficacy and safety profile of SGLT-2 inhibitors and GLP-1 agonists for the treatment of diabetes mellitus., Results: When compared to GLP-1 agonist therapy alone, the combination therapy did not significantly reduce fasting plasma glucose (FPG) levels (95 % confidence interval [CI]: -0.27, 0.10; p = 0.35), body weight (95 % CI: -0.18, 0.18; p = 1.00), Glycosylated Hemoglobin, Type A1C (HbA1c) (95 % CI: -0.29, 0.07; p = 0.22), or systolic blood pressure (SBP) values (95 % CI: -0.29, 0.06; p = 0.21). In contrast, when compared to SGLT-2 inhibitor therapy alone, combination therapy significantly decreased FPG by 0.24 mmol/L (95 % CI: -0.43, -0.05; p = 0.01), HbA1c by 0.45 % (95 % CI: -0.72, -0.18; p = 0.001), and SBP by 0.12 mmHg (95 % CI: -0.24, 0.00; p = 0.05). However, the combination therapy failed to demonstrate a significant reduction in body weight when compared with either SGLT-2 inhibitor therapy (95 % CI: -0.20, 0.05; p = 0.24) or GLP-1 agonist therapy (95 % CI: -0.18, 0.18; p = 1.00). Additionally, the combination therapy did not increase the incidence of hypoglycemia. It should be noted that data regarding mortality and cardiovascular outcomes were limited., Conclusions: The combination treatment of SGLT-2 inhibitors and GLP-1 receptor agonists effectively reduces HbA1c, FPG, and SBP without elevating the risk of hypoglycemia when compared to monotherapy with SGLT-2 inhibitors. However, these beneficial effects were not observed when the combination therapy was compared with GLP-1 receptor agonist treatment alone., Competing Interests: Conflict of interest statement We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence the work submitted, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “ the Efficacy and Safety of the Combination or Monotherapy With GLP-1 Receptor Agonists and SGLT-2 Inhibitors in Type 2 Diabetes Mellitus:An update Systematic Review and Meta-analysis ”., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Renin-angiotensin-aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are key drugs in the management of patients with cardiovascular diseases (CVD), particularly those with hypertension, diabetes, chronic kidney disease and heart failure (HF), given their demonstrated effectiveness in reducing the risk of both surrogate and hard endpoints. Despite their positive impact on the outcome, patients with RAASi and MRAs are particularly vulnerable to hyperkalaemia, with approximately 50 % of these individuals experiencing two or more recurrences annually. The common practice of reducing the dose or discontinuing the treatment with RAASi and MRAs in conditions of hyperkalaemia results in suboptimal management of these patients, with a potential impact on their mortality and morbidity risk. Recent guidelines from cardiovascular and renal international societies increasingly recognize the need for alternative strategies to manage the risk of hyperkalaemia, allowing the continuation of RAASi and MRA therapies. In this review, we summarise the new potential options available to manage hyperkalaemia in patients with CVD and the recommendations of the most recent guidelines on the topic., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The present study aimed to analyse the published data and to realize an update about the use and pathogenesis of the novel antidiabetic drugs, respectively, dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 Ra), and sodium-glucose co-transporter-2 inhibitors (SGLT-2i), in patients with type 2 diabetes mellitus (T2DM) and coronavirus disease (COVID-19). Literature research in the PubMed and Web of Science database was performed in order to identify relevant published clinical trials and meta-analyses that include information about the treatment with novel antidiabetic agents in patients with T2DM and COVID-19. A total of seven articles were included, and their primary and secondary outcomes were reported and analysed. DPP-4i has mixed results on mortality in T2DM patients with COVID-19 but with an overall slightly favourable or neutral effect, whereas GLP-1 Ra seems to have a rather beneficial impact, while SGLT-2i may be useful in acute illness. Even if there are limited data, they seem to have favourable efficacy and safety profiles. The available evidence is heterogenous and insufficient to evaluate if the benefits of non-insulin novel antidiabetic drugs in COVID-19 treatment are due to the improvement of glycaemic control or to their intrinsic anti-inflammatory effects but highlights their beneficial effects in the pathogenesis and evolution of the disease. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a progressively deteriorating medical condition that significantly reduces both the patients' life expectancy and quality of life. Even though real progress was made in the past decades in the discovery of novel pharmacological treatments for HF, the prevention of premature deaths has only been marginally alleviated. Despite the availability of a plethora of pharmaceutical approaches, proper management of HF is still challenging. Thus, a myriad of experimental and clinical studies focusing on the discovery of new and provocative underlying mechanisms of HF physiopathology pave the way for the development of novel HF therapeutic approaches. Furthermore, recent technological advances made possible the development of various interventional techniques and device-based approaches for the treatment of HF. Since many of these modern approaches interfere with various well-known pathological mechanisms in HF, they have a real ability to complement and or increase the efficiency of existing medications and thus improve the prognosis and survival rate of HF patients. Their promising and encouraging results reported to date compel the extension of heart failure treatment beyond the classical view. The aim of this review was to summarize modern approaches, new perspectives, and future directions for the treatment of HF. [ABSTRACT FROM AUTHOR]

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in developed countries, with its incidence growing parallel to the epidemics of obesity and type 2 diabetes mellitus (T2DM). Sodiumglucose co-transporter-2 inhibitors (SGLT2i) are becoming a cornerstone in the management of cardiovascular health and some studies suggest the potential role in NAFLD. However, patients under treatment with SGLT2i are at risk of developing genitourinary fungal infections (GFIs). Moreover, both NAFLD and SGLT2i have a strong influence on the immune system, and therefore the risk of infections other than GFIs could be increased in NAFLD patients treated with SGLT2i. We aimed to examine the possible association of SGLT2i with infections and hepatic outcomes in NAFLD patients. Methods: We conducted a case-control study including NAFLD patients with T2DM visited at the Liver Unit outpatient clinic from 2016 to 2021 with a minimum follow-up of 6 months by selecting 65 patients receiving SGLT2i and 130 matched patients with other types of antidiabetic treatment. Results: During follow-up, GFIs were significantly higher in the SGLT2i group (15.4% vs. 3.8%; p=0.008), whereas there were no differences in the occurrence of overall infections (41.5% vs. 30%; p=0.1) nor in other types of specific infections. In the multivariable analysis, treatment with SGLT2i was not independently associated with higher odds of overall infection. On the other hand, SGLT2i patients showed a significantly lower incidence of hepatic events (1.5% vs. 10.7%; p=0.02). There were no significant different in all-cause mortality between cases and controls. Conclusions: NAFLD patients with T2DM receiving SGLT2i more frequently presented GFIs, whereas the incidence of other types of infections was not found to be higher than in other patients with NAFLD and T2DM treated with other drugs. Moreover, SGLT2i-treated patients had a lower occurrence of hepatic events. Further studies are warranted to validate our data. [ABSTRACT FROM AUTHOR]