Type 2 diabetes patients requiring empagliflozin in Southeast of Iran: Frequency and guideline adherence (2022–2023) / Pacientes con diabetes tipo 2 que requieren empagliflozina en el sureste de Irán: frecuencia y cumplimiento de las directrices (2022-2023)

Introduction: Empagliflozin plays a beneficial role in individuals with type 2 diabetes at high risk of cardiovascular complications. This study aimed to assess the prevalence of individuals with type 2 diabetes who required empagliflozin based on clinical guidelines between the years 2022 and 2023. Material and methods: This study was a descriptive-analytical cross-sectional study conducted on a target population of patients with type 2 diabetes. Patient data, including demographic characteristics, smoking status, hypertension, hyperlipidemia, renal insufficiency, retinopathy, and proteinuria, were collected. The indication for prescribing empagliflozin was determined based on the risk of cardiovascular complications. Results: A total of 398 individuals with type 2 diabetes with a mean age of 58.4 years were examined. Overall, 87.4% of the patients had an indication for empagliflozin prescription. The indication for empagliflozin prescription was significantly higher in men, individuals with hyperlipidemia, those over 55 years of age, obese individuals, and smokers. The mean age, body mass index, and triglyceride levels were higher in candidates for empagliflozin prescription. Male candidates for empagliflozin had significantly higher rates of smoking and systolic blood pressure compared to females. Conclusions: The findings of this study demonstrated that a significant percentage of individuals with type 2 diabetes had an indication for empagliflozin prescription based on clinical and laboratory criteria. (AU)

Introducción: La empagliflozina tiene un papel beneficioso en las personas con diabetes tipo 2 con alto riesgo de complicaciones cardiovasculares. Este estudio tuvo como objetivo evaluar la prevalencia de pacientes con este padecimiento que requerían empagliflozina según las guías clínicas entre los años 2022 y 2023. Material y métodos: Se trata de un estudio transversal descriptivo-analítico realizado en una población objetivo de personas con diabetes tipo 2. Se recogieron los datos de los pacientes, incluyendo las características demográficas, el hábito tabáquico, la hipertensión, la hiperlipidemia, la insuficiencia renal, la retinopatía y la proteinuria. La indicación para prescribir empagliflozina se determinó en función del riesgo de complicaciones cardiovasculares. Resultados: Se examinaron un total de 398 individuos con diabetes tipo 2 con una edad media de 58,4 años. En general, 87,4% de estos tenía una indicación para la prescripción de empagliflozina, la cual fue significativamente mayor en los hombres, aquellos con hiperlipidemia, obesidad, los mayores de 55 años y los fumadores. La edad media, el índice de masa corporal y los niveles de triglicéridos fueron mayores en los candidatos a la prescripción de este medicamento. Los candidatos masculinos a este fármaco tenían tasas significativamente más altas de tabaquismo y presión arterial sistólica, en comparación con las mujeres. Conclusiones: Los resultados de este estudio demostraron que un porcentaje significativo de personas con diabetes tipo 2 tenía una indicación para la prescripción de empagliflozina según los criterios clínicos y de laboratorio. (AU)

Targeting the endothelium by combining endothelin-1 antagonism and SGLT-2 inhibition: better together?

Endothelin A and B receptors, together with sodium-glucose cotransporter-2 (SGLT-2) channels are important targets in improving endothelial function and intervention with inhibitors has been the subject of multiple mechanistic and clinical outcome trials over recent years. Notable successes include the treatment of pulmonary hypertension with endothelin receptor antagonists, and the treatment of heart failure and chronic kidney disease with SGLT-2 inhibitors. With distinct and complementary mechanisms, in this review, we explore the logic of combination therapy for a number of diseases which have endothelial dysfunction at their heart.

Epidemiology of Heart Failure and the Discovery of the Cardioprotective Effects of SGLT2 Inhibitors.

In this video, Javed Butler, MD, introduces the series on the use of SGLT2 inhibitors in heart failure. He discusses the epidemiology of heart failure and the effects of SGLT2 inhibitors on heart failure outcomes. Jonathan Rich, MD, joins to summarize the effects of SGLT2 inhibitors from dedicated trials in patients with heart failure.

Summary and Panel Discussion.

In this video, Javed Butler, MD, Jonathan Rich, MD, Rachel Pessah-Pollack, MD, and John E. Anderson, MD, summarize the key points of the enhanced publication "Role of SGLT2 Inhibitors in the Management of Heart Failure With and Without Type 2 Diabetes." The panel then delves deeper into some of the topics raised.

Use of SGLT2 Inhibitors in Patients With HF With and Without Type 2 Diabetes: An Endocrinologist's Perspective.

In this video, Javed Butler, MD, and Rachel Pessah-Pollack, MD, discuss the use of SGLT2 inhibitors in patients with and without type 2 diabetes.

Managing Patients on SGLT2 Inhibitors in Primary Care.

In this video, Javed Butler, MD, and John E. Anderson, MD, discuss the management of patients on SGLT2 inhibitors in the primary care setting.

Recent advances in understanding the mechanisms in skeletal muscle of interaction between exercise and frontline antihyperglycemic drugs.

Regular exercise and antihyperglycemic drugs are front-line treatments for type-2 diabetes and related metabolic disorders. Leading drugs are metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 receptor agonists. Each class has strong individual efficacy to treat hyperglycemia, yet the combination with exercise can yield varied results, some of which include blunting of expected metabolic benefits. Skeletal muscle insulin resistance contributes to the development of type-2 diabetes while improvements in skeletal muscle insulin signaling are among key adaptations to exercise training. The current review identifies recent advances into the mechanisms, with an emphasis on skeletal muscle, of the interaction between exercise and these common antihyperglycemic drugs. The review is written toward researchers and thus highlights specific gaps in knowledge and considerations for future study directions.

Treating Type 2 Diabetes With Early, Intensive, Multimodal Pharmacotherapy: Real-World Evidence From an International Collaborative Database.

Aims: We compared the glycaemic and cardiorenal effects of combination therapy involving metformin, pioglitazone, sodium-glucose-linked-cotransporter-2 inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP-1RA) versus a more conventional glucocentric treatment approach combining sulphonylureas (SU) and insulin from the point of type 2 diabetes (T2D) diagnosis. Methods: We performed a retrospective cohort study using the Global Collaborative Network in TriNetX. We included individuals prescribed metformin, pioglitazone, an SGLT2i, and a GLP-1 RA for at least 1-year duration, within 3 years of a T2D diagnosis, and compared with individuals prescribed insulin and a SU within the same temporal pattern. Individuals were followed up for 3 years. Results: We propensity score-matched (PSM) for 26 variables. A total of 1762 individuals were included in the final analysis (n = 881 per cohort). At 3-years, compared to the insulin/SU group, the metformin/pioglitazone/SGLT2i/GLP-1 RA group had a lower risk of heart failure (HR 0.34, 95% CI 0.13-0.87, p = 0.018), acute coronary syndrome (HR 0.29, 95% CI 0.12-0.67, p = 0.002), stroke (HR 0.17, 95% CI 0.06-0.49, p < 0.001), chronic kidney disease (HR 0.50, 95% CI 0.25-0.99, p = 0.042), and hospitalisation (HR 0.59, 95% CI 0.46-0.77, p < 0.001). Conclusions: In this real-world study, early, intensive polytherapy, targeting the distinct pathophysiological defects in T2D, is associated with significantly more favourable cardiorenal outcomes, compared to insulin and SU therapy.

Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.

Evaluation of Drug-Drug Interaction Between Henagliflozin and Hydrochlorothiazide in Healthy Chinese Volunteers.

Purpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Conclusion: Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. Trial Registration: ClinicalTrials.gov NCT06083116.

The Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Atrial Electromechanical Conduction Time.

OBJECTIVE: This study aims to explore the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, a newer class of oral antidiabetic drugs, on atrial electromechanical delay (EMD) in patients with type 2 diabetes mellitus (DM). This is particularly relevant given the significantly higher incidence of atrial fibrillation (AF) in diabetic patients compared to the general population. Atrial electromechanical delay is recognized as an important factor influencing the development of atrial fibrillation. METHODS: This study included 30 type 2 DM patients (53.3% female, mean age 60.07 ± 10.03 years), initiating treatment with SGLT-2 inhibitors. The patients were assessed using echocardiography at baseline and again at 6 months, focusing on basic echocardiographic parameters and atrial electromechanical delay times (EMD) measured via tissue Doppler imaging. RESULTS: No significant changes were observed in intra-atrial EMD times. However, significant reductions were noted in interatrial EMD times, decreasing from 15.13 ± 5.87 ms to 13.20 ± 6.12 ms (P = 0.029). Statistically significant shortening occurred in lateral pulmonary acceleration (PA) times (from 58.73 ± 6.41 ms to 54.37 ± 6.97 ms, P < 0.001), septal PA times (from 50.90 ± 6.02 ms to 48.23 ± 5), and tricuspid PA times (from 43.60 ± 6.28 ms to 41.30 ± 5.60 ms, P = 0.003). Additionally, there was a significant reduction in the E/e' ratio from 8.13 ± 4.0 to 6.50 ± 2.37 (P = 0.003). CONCLUSION: SGLT-2 inhibitors might positively influence atrial electromechanical conduction, reducing DM-related functional impairments and the risk of arrhythmias, particularly AF.

Multidisciplinary proactive e-consults to improve guideline-directed medical therapies for patients with diabetes and chronic kidney disease: an implementation study.

INTRODUCTION: We hypothesized that multidisciplinary, proactive electronic consultation (MPE) could overcome barriers to prescribing guideline-directed medical therapies (GDMTs) for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: We conducted an efficacy-implementation pilot study of MPE for T2D and CKD for primary care provider (PCP)-patient dyads at an academic health system. MPE included (1) a dashboard to identify patients without a prescription for sodium-glucose cotransporter-2 inhibitors (SGLT2i) and without a maximum dose prescription for renin-angiotensin-aldosterone system inhibitors (RAASi), (2) a multidisciplinary team of specialists to provide recommendations using e-consult templates, and (3) a workflow to deliver timely e-consult recommendations to PCPs. In-depth interviews were conducted with PCPs and specialists to assess feasibility, acceptability, and appropriateness of MPE and were analyzed using an iterative qualitative analysis approach to identify major themes. Prescription data were extracted from the electronic health record to assess preliminary effectiveness to increase GDMT. RESULTS: 20 PCPs agreed to participate, 18 PCPs received MPEs for one of their patients with T2D and CKD, and 16 PCPs and 2 specialists were interviewed. Major themes were as follows: appropriateness of prioritization of GDMT for T2D and CKD, acceptability of the content of the recommendations, PCP characteristics impact experience with MPE, acceptability and appropriateness of multidisciplinary collaboration, feasibility of MPE to overcome patient-specific barriers to GDMT, and appropriateness of workflow. At 6 months postbaseline, 7/18 (39%) patients were newly prescribed an SGLT2i, and 7/18 (39%) patients were either newly prescribed or had increased dose of RAASi. CONCLUSIONS: MPE was an acceptable and appropriate health system strategy to identify and address gaps in GDMT among patients with T2D and CKD. Adopting MPE could enhance GDMT, though PCPs raised feasibility concerns which could be improved with program enhancements, including follow-up e-consults for reinforcement, and administrative support for navigating system-level barriers.

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD. METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations. RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively. CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post-authorization safety study.

PURPOSE: This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. METHODS: Data from two large US claims databases were analyzed in an observational study of patients with T2D receiving metformin who were newly prescribed empagliflozin versus sulfonylurea (SU). Because dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with the risk of acute pancreatitis in some studies, patients on these agents were excluded. Using pooled analyses of data from the two databases (2014-2021), patients initiating empagliflozin were matched 1:1 within database to patients initiating SU using propensity scores (PS) that incorporated relevant demographic and clinical characteristics. Prespecified sensitivity analyses were performed for design parameters. RESULTS: The analyses identified 72 661 new users of empagliflozin and 422 018 new users of SUs, with both patient groups on concurrent metformin therapy. Baseline characteristics within treatment groups appeared to be similar across the 72 621 matched pairs. After mean follow-up of ~6 months, incidence rates of acute pancreatitis in the pooled matched cohort were 10.30 (95% confidence interval [CI] 9.29-11.39) events per 1000 patient-years (PY) for empagliflozin and 11.65 (95% CI 10.59-12.77) events per 1000 PY for SUs. On a background of metformin, patients newly initiating empagliflozin did not have an increased risk of acute pancreatitis compared with those initiating an SU (pooled PS matched hazard ratio 0.88 [0.76-1.02]) across 75621.42 PY of follow-up. CONCLUSIONS: The results of this voluntary post-approval safety study provide additional evidence that the use of empagliflozin for the treatment of T2D is not associated with an increased risk of acute pancreatitis.

Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia.

Background: A phenomenon known as legacy effect was observed that poor glycemic control at early stage of patients with newly-diagnosed type 2 diabetes (T2D) increases the risk of subsequent cardiovascular diseases (CVD). Early use of some novel anti-hyperglycemic agents, such as sodium-glucose transport protein 2 inhibitors (SGLT-2i), may attenuate this effect, but the evidence is limited. Methods: Two retrospective cohorts of newly diagnosed T2D patients from 2010-2023 were assembled using the Yinzhou Regional Health Care Database (YRHCD) with different definitions of the early exposure period - the 1-year exposure cohort and 2-year exposure cohort, which were comprised of subjects who had HbA1c measurement data within 1 year and 2 years after their T2D diagnosis, respectively. Using Cox proportional hazards models, we examined the association between high HbA1c level (HbA1c>7%) during the early exposure period and the risk of subsequent CVD. This analysis was performed in the overall cohort and three subpopulations with different treatments during the early exposure period, including patients initiating SGLT-2i or glucagon-like peptide-1 receptor agonists (GLP-1RA), patients using dipeptidyl peptidase-4 inhibitors (DPP-4i), and patients without using SGLT-2i, GLP-1RA, and DPP-4i. Besides, subgroup analyses were performed by stratifying patients into age <55 and ≥55 years. Results: A total of 21,477 and 22,493 patients with newly diagnosed T2D were included in the two final cohorts. Compared with patients with mean HbA1c ≤ 7% during the early exposure period, those with HbA1c>7% had higher risks of incident CVD, with a HR of 1.165 (95%CI, 1.056-1.285) and 1.143 (95%CI, 1.044-1.252) in 1-year and 2-year exposure period cohort. Compared to non-users, in patients initiating SGLT-2i/GLP-1RA within 1 or 2 years after T2D diagnosis, higher HbA1c level at baseline was not associated with CVD in both two cohorts. In subgroup analyses, results were generally consistent with the main analysis. Conclusions: Poor glycemic control in the early stage of T2D increased later CVD risk in Chinese adults with newly diagnosed T2D. Compared to non-users, this association was smaller and non-significant in patients receiving SGLT-2i/GLP-1RA during the early stage of T2D, indicating early use of these drugs may have the potential to mitigate legacy effects of hyperglycemia.

Is GFR decline induced by SGLT2 inhibitor of clinical importance?

BACKGROUND: Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. METHODS: We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. RESULTS: Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. CONCLUSIONS: Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. TRIAL REGISTRATION: clinicaltrials.gov (NCT02752113).

Dapagliflozin added to metformin reduces perirenal fat layer in type 2 diabetic patients with obesity.

Sodium-glucose co-transporters type 2 inhibitors (SLGT2i) are highly effective in controlling type 2 diabetes, but reported beneficial cardiovascular effects suggest broader actions on insulin resistance. Weight loss may be initially explained by glycosuria-induced net caloric output and secondary volumetric reduction, but its maintenance could be due to loss of visceral fat mass. Structured ultrasound (US) imaging of abdominal adipose tissue ("eco-obesity") is a recently described methodology used to measure 5 consecutive layers of abdominal fat, not assessable by DEXA or CT scan: superficial subcutaneous (SS), deep subcutaneous (DS), preperitoneal (PP), omental (Om) and right perirenal (RK). PP, Om and RK are predictors of metabolic syndrome (MS) with defined cut-off points. To assess the effect of SLGT2i on every fat depot we enrolled 29 patients with type 2 Diabetes (HbA1c 6.5-9%) and Obesity (IMC > 30 kg/m2) in an open-label, randomized, phase IV trial (EudraCT: 2019-000979-16): the Omendapa trial. Diabetes was diagnosed < 12 months before randomization and all patients were treatment naïve. 14 patients were treated with metformin alone (cohort A) and 15 were treated with metformin + dapaglifozin (cohort B). Anthropometric measures and laboratory tests for glucose, lipid profile, insulin, HOMA, leptin, ultrasensitive-CRP and microalbuminuria (MAL) were done at baseline, 3rd and 6th months. At 6th month, weight loss was -5.5 ± 5.2 kg (5.7% from initial weight) in cohort A and -8.4 ± 4.4 kg (8.6%) in cohort B. Abdominal circumference showed a -2.7 ± 3.1 cm and -5.4 ± 2.5 cm reduction, respectively (p = 0.011). Both Metformin alone (-19.4 ± 20.1 mm; -21.7%) or combined with Dapaglifozin (-20.5 ± 19.4 mm; -21.8%) induced significant Om fat reduction. 13.3% of cohort A patients and 21.4% of cohort's B reached Om thickness below the cut-off for MS criteria. RK fat loss was significantly greater in cohort B group compared to cohort A, at both kidneys. Only in the Met + Dapa group, we observed correlations between Om fat with leptin/CRP/MAL and RK fat with HOMA-IR. US is a useful clinical tool to assess ectopic fat depots. Both Metformin and Dapaglifozin induce fat loss in layers involved with MS but combined treatment is particularly effective in perirenal fat layer reduction. Perirenal fat should be considered as a potential target for cardiovascular dapaglifozin beneficial effects.