From molecules to the clinic—pathophysiology of sodium-glucose cotransporter 2 inhibitors and their emerging role in urology: A comprehensive review from the European Association of Urology Section of Endourology

The aim is to explore the possibilities of improving the effectiveness in preventing cardiovascular diseases and heart failure using sodium-glucose co-transporter 2 inhibitors. Materials and methods: The analysis of the existing clinical and experimental data on the effect of sodium-glucose co-transporter 2 (SGLT-2) inhibitors on the cardiovascular system, the condition of kidneys, cardiovascular risk factors. Review: SGLT-2 inhibitors are the first class of glucose-lowering agents in large-scale studies (EMPA-REG OUTCOME, CANVAS, CVD-REAL, CVD-REAL2) which have demonstrated the ability to improve cardiorenal outcomes and reduce the risk of hospitalization with heart failure in patients with diabetes. In addition to hypoglycaemic action, SGLT-2 inhibitors show a number of pleiotropic effects, which are potentially capable of reducing cardiovascular risk: diuretic effect, decrease in: blood pressure, arterial wall stiffness, waist and body weight, expression of albuminuria, etc. The use of drugs of this class opens great prospects not only in terms of glycaemic control, but also in the prevention of cardiovascular complications of diabetes. Conclusions: 1. When choosing glucose-lowering agents in patients with type 2 diabetes, it is necessary to take into account their impact on the risk of development and the course of heart failure. 2. SGLT-2 inhibitors ought to be considered as a preferred method of treatment for type 2 diabetes in patients with heart failure or with a risk of heart failure that meets the latest recommendations of the European and American Diabetes Association.

Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like-peptide-1 receptor (GLP-1-R) agonists are novel therapeutic agents used for the management of type 2 diabetes mellitus (T2DM). Recently, large-scale randomized clinical trials have been conducted to assess the cardiovascular safety of these medications. The findings of these trials have revealed that both SGLT2 inhibitors and GLP-1-R agonists exhibit favorable cardioprotective effects, including reduction in cardiovascular and all-cause mortality, a decreased risk of chronic kidney disease progression, a decrease in hospitalization for heart failure (HF), an effect shown by SGLT2 inhibitors, and stroke prevention, an effect shown by GLP-1-R agonists. Based on the results from above studies, the European and American Diabetes Associations have issued new recommendations strongly endorsing the use of SGLT2 inhibitors and GLP-1-R agonists in combination with metformin for patients with T2DM who have additional cardiovascular (CV) comorbidities or risk factors. The primary aim of this combined therapy is to prevent CV events. Although both medication groups offer beneficial effects, they demonstrate slightly different profiles. SGLT2 inhibitors have exhibited better effects regarding a reduced incidence of HF, whereas GLP-1-R agonists have shown a reduced risk of CV events, particularly stroke. Moreover, recent European Society of Cardiology as well as American College of Cardiology and American Heart Association guidelines of HF treatment stressed the importance of SGLT2 inhibitor administration in patients with HF regardless of T2DM. In this context, we present and discuss the outcomes of the most recent trials investigating the impact of SGLT2 inhibitors and GLP-1-R agonists on renal and cardiovascular outcomes in patients, both with and without T2DM. Additionally, we explore the synergistic effects of combining SGLT2 inhibitors and GLP-1-R agonists in patients with cardiovascular disease.

Patient phenotype profiling in heart failure with preserved ejection fraction to guide therapeutic decision making. A scientific statement of the Heart Failure Association, the European Heart Rhythm Association of the European Society of Cardiology, and the European Society of Hypertension.

ABSTRACTA substantial number of patients with autosomal dominant polycystic kidney disease (ADPKD) undergo a nephrectomy, especially in workup for a kidney transplantation. Currently, there is no evidence-based algorithm to guide clinicians about which patients should undergo nephrectomy, the optimal timing of this procedure, or the preferred surgical technique. This systematic review-based consensus statement aimed to answer important questions regarding nephrectomy in ADPKD. A literature review was performed and extended to a meta-analysis when possible. For this purpose, PubMed and EMBASE were searched up to May 2024. Fifty-four publications, describing a total of 2391 procedures, were included. In addition, an exploratory questionnaire was sent to urologists, nephrologists, and transplant surgeons. These sources were used to develop practice points about indications, complications, mortality, and timing and technique of nephrectomy. In addition, data on renal embolization as a potential alternative to nephrectomy were explored and summarized. To reach consensus, practice points were defined and improved in three Delphi survey rounds by experts of the European Renal Association Working Group Genes & Kidney and the European Association of Urology Section of Transplantation Urology. A total of 23 practice points/statements were developed, all of which reached consensus. Among others, it was deemed that nephrectomy can be performed successfully for various indications and is an intermediate risk procedure with acceptable mortality and minimal impact on kidney graft function when performed before, in the same session or after transplantation. The complication rate seems to increase when the procedure is performed as an emergency. During the workup for transplantation, patient complaints should be assessed routinely by questionnaires to indicate symptom burden. Deciding on the need for nephrectomy and exploring potential alternatives such as kidney embolization should be a process of shared decision-making, preferably after multidisciplinary consultation.

Getting to the heart of the matter in type 2 diabetes

Journal of Diabetes NEWS

Recent large clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, with the aim of verifying cardiovascular safety, have revealed that these medications have a preventative advantage on adverse cardiovascular outcomes, including worsening of heart failure and deterioration of nephropathy, in patients with type 2 diabetes (T2D). These observed benefits do not seem to correlate with the glucose-lowering effect, and the underlying mechanism is being intensively investigated. Given the results from recent studies, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that patients with T2D and clinical cardiovascular disease (CVD) with inadequate glucose control despite treatment with metformin should receive an SGLT2 inhibitor or GLP-1 receptor agonist. In this review we summarize the results of recent cardiovascular outcome trials and discuss the potential clinical advantage of SGLT2 inhibitors and GLP-1 receptor agonists. We also present practical implications of these glucose-lowering agents for reducing the risk of adverse cardiovascular events and progressive renal comorbidity in patients with T2D and CVD.

SGLT2 inhibitor or GLP-1 receptor agonist in type 2 diabetes?

BackgroundGood adherence by physicians to treatment guidelines for type II diabetes mellitus (T2DM) could improve therapy outcome for patients. In this retrospective, cross-sectional study, we assessed physicians’ adherence to evidence-based guidelines for T2DM management in adult patients (aged ≥18 years) with either confirmed atherosclerotic cardiovascular disease (ASCVD) or those at high risk of developing ASCVD at the Thumbay Academic Health Center, United Arab Emirates (UAE).MethodsRelevant data was obtained from patients’ medical records, assessed, and compared based on the 2018 diabetes guidelines of the American Diabetes Association and European Association for the Study of Diabetes.ResultsA total of 218 patients (186 males and 32 females) were included in the analysis. Of these, 122 were prescribed either sodium-glucose co-transporter-2(SGLT2) inhibitors or glucagon-like peptide 1 (GLP-1) receptor agonists and 34 were prescribed both. The overall adherence to the guidelines was 56%, which was significantly influenced by body mass index (BMI), hemoglobin A1c (HbA1c) levels, and estimated average glucose (eAG).ConclusionsAdherence to guidelines was significantly high when treating patients with elevated levels of HbA1c and eAG, suggesting that physicians are more likely to prescribe SGLT2 inhibitors or/and GLP-1 receptor agonists to such patients. Physicians’ adherence to guidelines was significantly correlated with patients’ BMI and the levels of HbA1c and eAG. To the best of our knowledge, this is the first study conducted on diabetes and its risk factors in UAE.

The advent of new antihyperglycaemic drugs has not only brought a greater variety of drugs used to control glycaemia, but has introduced changes in other important aspects of Type 2 diabetes (T2DM) therapy, cardioprotection and renoprotection. All new antihyperglycaemic drugs: sodium glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 agonists), and dipeptidyl peptidase-4 (DPP-4) inhibitors were subjects of Cardiovascular Outcome Trials - CVOTs. Cardiovascular protection is not considered to be class specific, especially in the GLP-1 agonist group, but more likely drug specific. Based on the result of CVOTs, some drugs received from Food and Drug Administration labelled indications of reduction of the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (liraglutide, semaglutide, dulaglutide, canagliflozin, empagliflozin, dapagliflozin). Cardiology and diabetology societies acknowledged CVOTs results in various ways. American Diabetes Associations (ADA) and European Association for the Study of Diabetes (EASD) still consider metformin as first-line drug but introduced precise criteria for utilization of GLP-1 agonists and SGLT2 inhibitors for primary as well as secondary cardiovascular (CV) prevention. The Canadian Diabetes Association (Diabetes Canada) recognized the use of an antihyperglycaemic agent with demonstrated CV outcome benefit in secondary prevention only. The European Society of Cardiology (ESC) favoured cardiovascular protection effects and chosen GLP-1 agonists and SGLT2 inhibitors to be firstline therapy in a treatment-naïve patient with atherosclerotic cardiovascular disease (ASCVD). National Institute for Health and Care Excellence (NICE) did not change the previous position of utilisation of novel antihyperglycemic drugs only for achieving adequate glycaemic control either as monotherapy when metformin is contraindicated or not tolerated or as add-on therapy in dual and triple combinations of antihyperglycemic drugs.

In October 2022, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) updated the previous consensus report for management of hyperglycemia in type 2 diabetes (T2DM). In January 2023, ADA Standards of Care in Diabetes with pharmacologic approaches to achieve a glycemic target were published to align with the consensus report by ADA and EASD. This recent consensus report and ADA Standards of Care in Diabetes emphasized weight management as an important aspect of the holistic approach to management of T2DM. In addition, it included numerous results of cardiorenal trials involving glucagon-like peptide 1 (GLP-1) receptor agonist and sodium glucose cotransporter 2 (SGLT2) inhibitor in type 2 diabetes. This information was added to address broader recommendations for cardiorenal risk reduction, in particular for organ (heart and kidney)-specific protection. This review summarizes the 2022 ADA-EASD consensus report and 2023 ADA standards of care for diabetes regarding management of hyperglycemia in T2DM.

The global prevalence of "diabesity"-diabetes related to obesity-is increasing steadily over the past few decades because of the obesity epidemic. Although bariatric surgery is an effective treatment option for patients with diabesity, its limited availability, invasiveness, relatively high costs and the potential for surgical and postsurgical complications restrict its widespread use. Therefore, medical management is the only option for a majority of patients with diabesity. Diabetes control with several anti-diabetic agents, including insulin, causes weight gain with probability of worsening diabesity. Rational use of anti-diabetic medications with weight loss potential in varying combinations may help to address this key issue for long-term management of diabesity. There is no consensus on such an approach from different professional bodies like American Diabetes Association, European Association for Study of Diabetes, or International Diabetes Federation. We attempt to discuss the key issues and realistic targets for diabesity management in this paper. Rational use of anti-diabetic combinations can mitigate worsening of diabesity to some extent while managing patients. Retrospective studies showed that combination therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose co-transporter 2 (SGLT-2) inhibitors, when administered along with other anti-diabetic medications, offer the best therapeutic benefit in the medical management of diabesity. Different combinations of other anti-diabetic drugs with minimum weight gain potential were also found useful. Because of insufficient evidence based on prospective randomised controlled trials (RCTs), future research should focus on evolving the appropriate rational drug combinations for the medical management of diabesity.

Potential Place of SGLT2 Inhibitors in Treatment Paradigms for type 2 Diabetes Mellitus

Background: Basic simulation training in endourology was established with the endoscopic stone treatment step 1 (EST-s1), which is now recognized worldwide for training and examination. Following on from EST-s1, the endoscopic stone treatment step 2 (EST-s2) was started by the European Association of Urology (EAU) sections. Objective: We describe the methodology used in the development of EST-s2 assessment curriculum. Materials and Methods: The "full-life cycle curriculum development" template was followed for curriculum development, focusing on intermediate training of EST protocol with complex endourologic tasks. A cognitive task analysis (CTA) was run in accordance with EAU Urolithiasis guidelines. The protocol and its details underwent a first consensus by Delphi method with EAU Urolithiasis Section experts in March 2017. Once the outcome and metrics were decided, curriculum development was carried out. Purpose-built stones were developed, and simulator system requirement was defined. Preliminary testing was done in European Urology Residents Education Programme 2019 and in phase five the protocol was finalized with full tutor instruction sheet. Results: The EST-s2/A curriculum development took 38 months and involved EAU Uro-technology and urolithiasis sections with coordination from the European School of Urology training group. Starting from the initial CTA, a 1277-word revision with preliminary task description was produced. Nine intermediate skills were identified and included in the final training protocol. The training content and session evaluations were carried out by 26 experts and 16 final year trainees, respectively. Although the experts agreed that EST-s2/A protocol was well structured (96%), covered the complex endourologic maneuvers (92%), and was useful to optimize and improve hands-on-training (HoT) sessions (92%), the overall evaluation was scored 4.25/5 by trainees. Conclusion: We describe the development methodology for intermediate EST curriculum, which also provides a roadmap on developing other HoT protocols in future. Patients Summary: In this report we described the development of the novel intermediate training curriculum for EST, called EST-s2, which took 3 years of collaborative work inside the EAU. This article is aimed to strengthen the standards in curriculum development and clearly describe the background of this new EAU official endourology protocol.

10-yr Outcomes of Senior Clinical Fellowship in Robot-assisted Radical Cystectomy (RARC) with focus on Intracorporeal Ileal Conduit Urinary Diversion: Aggregated Learning Curve Assessment and Achievement of the EAU-Robotic Urology Section (ERUS) RARC Curriculum