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BACKGROUND: We examined the real-world comparative safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. other newer anti-glycemic medications (dipeptidyl peptidase-4 inhibitors [DPP4i], glucagon-like peptide-1 receptor agonists [GLP1a]) in patients with and without chronic kidney disease (CKD). METHODS: Among US Veterans with diabetes receiving care from the Veterans Affairs (VA) healthcare system over 2004-19, we identified incident users of SGLT2i vs. DPP4i vs. GLP1a monotherapy. In analyses stratified by CKD status, defined by estimated glomerular filtration rate and albuminuria, we examined associations of SGLT2i vs. DPP4i vs. GLP1a use with risk of infection-related (primary outcome) and genitourinary infection hospitalizations (secondary outcome) using multivariable Cox models. FINDINGS: Among 92,269 patients who met eligibility criteria, 52% did not have CKD, whereas 48% had CKD. In the overall and non-CKD cohorts, compared to DPP4i use, SGLT2i use was associated with lower infection-related hospitalization risk (HRs [95% CIs] 0.74 [0.67-0.81] and 0.77 [0.67, 0.88], respectively), whereas GLP1a use demonstrated comparable risk. However, in the CKD cohort SGLT2i and GLP1a use were each associated with lower risk (HRs [95% CIs] 0.70 [0.61, 0.81] and 0.91 [0.84, 0.99], respectively). Propensity score-matched analyses showed similar findings in the non-CKD and CKD cohorts. In the overall, non-CKD, and CKD cohorts, SGLT2i use was associated with lower genitourinary infection hospitalization risk whereas GLP1a use showed comparable risk vs. DPP4i use. INTERPRETATION: In a national cohort of Veterans with diabetes, compared with DPP4i use, SGLT2i use was associated with lower infection-related and genitourinary infection hospitalization risk. FUNDING: VA Health Services Research and Development, USA.

BACKGROUND: To investigate the individual profile of each SGLT2 (sodium-glucose cotransoporter-2) inhibitor in patients with different backgrounds. METHODS AND RESULTS: This study included 21 placebo-controlled randomized controlled trials with a total of 96 196 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. The primary efficacy end point was the composite of cardiovascular death and hospitalizations for heart failure. The secondary efficacy end points were all-cause death, cardiovascular death, hospitalizations for heart failure, kidney disease progression, and acute kidney injury. We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease. Safety end points were also assessed among SGLT2 inhibitors in the overall cohort. In the overall cohort, there were no significant differences in the primary efficacy outcome among the SGLT2 inhibitors, while empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53-0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56-0.96]) were associated with lower risk of acute kidney injury than sotagliflozin. The presence or absence of diabetes did not alter the results. In patients with chronic kidney disease, there were no differences in the efficacy outcomes among SGLT2 inhibitors, while in patients without chronic kidney disease, empagliflozin was associated with lower risk of the primary outcome compared with ertugliflozin (HR, 0.77 [95% CI, 0.60-0.98]). For safety outcomes, no significant differences were observed in amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis. CONCLUSIONS: The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.

BACKGROUND: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved empagliflozin for reducing cardiovascular mortality and heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). However, limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and potential cost-effectiveness based on a nationwide prospective HF registry. METHODS: A total of 3,108 HFrEF and 2,070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analyzed. Eligibility was estimated by inclusion and exclusion criteria of EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trials and by FDA & EMA label criteria. The cost-utility analysis was done using a Markov model to project the lifetime medical cost and quality-adjusted life year (QALY). RESULTS: Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The incremental cost-effectiveness ratio of empagliflozin was calculated at US$6,764 per QALY in the overall population, which is far below a threshold of US$18,182 per QALY. The cost-effectiveness benefit was more evident in patients with HFrEF (US$5,012 per QALY) than HFpEF (US$8,971 per QALY). CONCLUSION: There is a large discrepancy in real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. Empagliflozin is cost-effective in HF patients regardless of ejection fraction in South Korea health care setting. The efficacy and safety of empagliflozin in real-world HF patients should be further investigated for a broader range of clinical applications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01389843.

There is a bidirectional pathophysiological interaction between the heart and the kidneys, and prolonged physiological stress to the heart and/or the kidneys can cause adverse cardiorenal complications, including but not limited to subclinical cardiomyopathy, heart failure and chronic kidney disease. Whilst more common in individuals with Type 2 diabetes, cardiorenal complications also occur in the absence of diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially approved to reduce hyperglycaemia in patients with Type 2 diabetes. Recently, these agents have been shown to significantly improve cardiovascular and renal outcomes in patients with and without Type 2 diabetes, demonstrating a robust reduction in hospitalisation for heart failure and reduced risk of progression of chronic kidney disease, thus gaining approval for use in treatment of heart failure and chronic kidney disease. Numerous potential mechanisms have been proposed to explain the cardiorenal effects of SGLT2i. This review provides a simplified summary of key potential cardiac and renal mechanisms underlying the cardiorenal benefits of SGT2i and explains these mechanisms in the clinical context. Key mechanisms related to the clinical effects of SGLT2i on the heart and kidneys explained in this publication include their impact on (1) tissue oxygen delivery, hypoxia and resultant ischaemic injury, (2) vascular health and function, (3) substrate utilisation and metabolic health and (4) cardiac remodelling. Knowing the mechanisms responsible for SGLT2i-imparted cardiorenal benefits in the clinical outcomes will help healthcare practitioners to identify more patients that can benefit from the use of SGLT2i.

Sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) and glucagon‐Like peptide‐1 receptor agonists (GLP‐1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP‐1 RA or dual gastric inhibitory polypeptide (GIP)/GLP‐1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP‐1‐based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP‐1‐based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP‐1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP‐1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease‐modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP‐1 RA or dual GIP/GLP‐1 RA should be considered for most patients with T2D who do not have contraindications. [ABSTRACT FROM AUTHOR]

Background: Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) represent a deep revolution of the therapeutic approach to heart failure (HF), preventing its insurgence but also improving the management of the disease and slowing its natural progression. To date, few studies have explored the effectiveness of SGLT2i and, in particular, Dapagliflozin in a real-world population. Therefore, in this observational prospective study, we evaluated Dapagliflozin's effectiveness in a real-world HF population categorized in the different hemodynamic profiles. Methods: From January 2022 to June 2023, we enrolled 240 patients with chronic HF and reduced ejection fraction (HFrEF) on optimal medical therapy, according to 2021 ESC guidelines, that added treatment with Dapagliflozin from the HF Clinics of 6 Italian University Hospitals. Clinical, biochemical, and echocardiographic parameters were collected before and after 6 months of Dapagliflozin introduction. Moreover, the HFrEF population was classified according to hemodynamic profiles (A: SV ≥ 35 ml/m2; E/e′ < 15; B: SV ≥ 35 ml/m2; E/e′ ≥ 15; C: SV < 35 ml/m2; E/e′ < 15; D: SV < 35 ml/m2; E/e′ ≥ 15). Then, we compared the Dapagliflozin population with two retrospective HF cohorts, hereinafter referred to as Guide Line 2012 (GL 2012) group and Guide Line 2016 (GL 2016) group, in accordance with the HF ESC guidelines in force at the time of patients enrolment. Precisely, we evaluated the changes to baseline in clinical, functional, biochemical, and echocardiographic parameters and compared them to the GL 2012 and GL 2016 groups. Results: Dapagliflozin population (67.18 ± 11.11 years) showed a significant improvement in the echocardiographic and functional parameters (left ventricular ejection fraction [LVEF], LV end-diastolic volume [LVEDV], LVEDV index, stroke volume index [SVi], left atrium volume index [LAVi], filling pressure [E/e′ ratio], tricuspid annular plane systolic excursion [TAPSE], tricuspid annular S′ velocity [RVs'], fractional area change [FAC], inferior vena cava [IVC diameter], pulmonary artery systolic pressure [sPAP], NYHA class, and quality of life) compared to baseline. In particular, TAPSE and right ventricle diameter (RVD1) ameliorate in congestive profiles (B and D); accordingly, the furosemide dose significantly decreased in these profiles. Comparing the three populations, the analysis of echocardiographic parameters (baseline vs follow-up) highlighted a significant decrease of sPAP in the Dapagliflozin population (p < 0.05), while no changes were recorded in the GL 2012 and GL 2016 population. Moreover, at the baseline evaluation, the GL 2012 and 2016 groups needed a higher significant dose of furosemide compared to Dapagliflozin group. Finally, Dapagliflozin patients had significantly fewer rehospitalizations (1.25%) compared with the other two groups (GL 2012 18.89%, p 0.0097; GL 2016 15.32%, p 0.0497). Conclusions: We demonstrate that Dapagliflozin is rapidly effective in an HFrEF real-world population; furthermore, the more significant effect is recorded in HFrEF patients with a congestive profile (B and D), supporting the introduction of Dapagliflozin in patients with a congestive profile and a worse prognosis. In conclusion, our data suggest evaluating the patient's hemodynamic state beyond LVEF in HFrEF. [ABSTRACT FROM AUTHOR]

The article explores the impact of sotagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease stages 3 and 4. The study found that sotagliflozin increased haemoglobin levels in patients with and without anaemia, with a significant effect on resolving anaemia in those with baseline anaemia. The results suggest that sotagliflozin may be a potential treatment for anaemia in this population, in addition to its known cardiorenal protective effects. The study also highlights the safety and tolerability of sotagliflozin in patients with type 2 diabetes and chronic kidney disease. [Extracted from the article]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors—to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function—are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951 ; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977) [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Both pioglitazone and glucagon‐like peptide 1 receptor agonists (GLP1RA) alone improve metabolic dysfunction‐associated steatohepatitis (MASH) in randomized clinical trials, whereas preclinical studies suggested MASH benefits with sodium glucose co‐transporter 2 inhibitors (SGLT2i). In the real world, patients with type 2 diabetes often require multiple agents for glycaemic control. Here, we investigated the benefits of combining these agents on risks of MASH.Longitudinal changes in FibroScan‐aspartate aminotransferase (FAST) score were measured in 888 patients with type 2 diabetes. Use of pioglitazone, GLP1RA and/or SGLT2i was defined as continuous prescriptions of ≥180 days prior to their last reassessment FibroScan. Multivariable logistic regression analysis was conducted to evaluate the associations between use of these agents and FAST score changes.Over a median follow‐up of 3.9 years, the increasing number of these agents used was significantly associated with more reductions in FAST score (p for trend <0.01). Dual combination was independently associated with a higher likelihood of achieving low FAST score at reassessment than single use of any of these agents (odds ratio [OR] 2.84, p = 0.01). Among the different drug combinations, using SGLT2i and pioglitazone (median dose 15 mg daily) together, as compared to not using any of these three agents, was associated with a higher likelihood of both low FAST score at reassessment (OR 6.51, p = 0.008) and FAST score regression (OR 12.52, p = 0.009), after adjusting for changes in glycaemic control and body weight during the study.Combining SGLT2i and pioglitazone is a potentially useful strategy to ameliorate ‘at‐risk’ MASH in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: While randomized controlled trials data on the long‐term effect of glucose‐lowering drugs (GLDs) on liver‐related outcomes are lacking, population‐based studies have evaluated the associations of GLDs with liver‐related outcomes in individuals with type 2 diabetes (T2D). we aimed to conduct a systematic review of population‐based studies evaluating the effects of GLDs on liver‐related outcomes in people with T2D. Methods: PubMed, Web of Science, and Embase databases were systematically searched for population‐based studies testing the associations of GLDs with liver‐related outcomes in individuals with T2D and no liver disease other than non‐alcoholic fatty liver disease (NAFLD) from inception to 23 February 2024. GLDs included SGLT2is, TZDs, insulin, GLP‐1 RAs and dipeptidyl peptidase‐4 inhibitors (DPP4Is). Results: Ten cohort studies, comprising 1,274,641 participants, met the inclusion criteria. The median follow‐up period ranged from 8.9 to 76 months. Of all the GLDs under investigation, SGLT2is were associated with the strongest reduction in NAFLD incidence, cirrhosis, and composite liver‐related events compared to other medications. TZDs were associated with a reduced risk of developing NAFLD and cirrhosis but were not significantly associated with a lower incidence of hepatocellular carcinoma. GLP‐1 RAs demonstrated a significant association with reduced liver‐related mortality. Conclusions: Observational data from population‐based studies suggest that GLDs such as SGLT2is are associated with beneficial long‐term liver‐related outcomes in T2D patients with NAFLD. Additional studies, including randomized controlled trials with long‐term follow‐up, are needed to confirm these findings. Registration Number: PROSPERO CRD442024536872. [ABSTRACT FROM AUTHOR]

Aim: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. Methods: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co‐primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three‐point major adverse CV events, its individual components, and all‐cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. Results: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19‐13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction >.05). Conclusion: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a growing public health concern, affecting at least 1 in 7 adults in the United States, and accounting for a large proportion of healthcare spending. The risk of mortality rises steeply with declining kidney function, mostly due to cardiovascular-related deaths. Since CKD is asymptomatic in the early stages, diagnosis is sometimes delayed. However, early diagnosis is important for timely initiation of interventions to reduce disease progression, and to avoid the need for hospitalizations, dialysis, or kidney transplantation. This review focuses on the impact of sodium glucose transporter 2 inhibitors (SGLT2i) on CKD based on mechanistic and clinical trial evidence. These agents affect the kidneys through changes in sodium transport and metabolic factors that interfere with the primary pathological mechanisms shared by most kidney diseases. Following clinical trials of SGLT2i in patients with type 2 diabetes which demonstrated reductions in the risk of major adverse CV events, death, and hospitalizations for heart failure (HHF), and in patients with heart failure (HF) with and without diabetes which showed reductions in death and HHF, recent trials in patients with CKD have provided overwhelming support for the use of SGLT2i as foundational therapy across a broad spectrum of patients with CKD, regardless of diabetes status, primary kidney disease (except polycystic kidney disease), or kidney function. While clinical trials in CKD generally recruit patients with a high risk of events, patients at lower risk could also benefit from SGLT2i in terms of reduction of CKD progression, HF, and death, as well as other beneficial effects including reductions in blood sugar, body weight, and blood pressure. Plain Language Summary: Chronic kidney disease (CKD) is a serious health problem that affects at least 1 in 7 adults in the United States. However, around 9 out of 10 adults with CKD are not aware that they have the condition. This is because people with CKD often have no symptoms, especially in the early stages of their condition. People with CKD have a higher risk of death and heart and/or kidney complications compared with people without the condition. It is important that doctors diagnose CKD as early as possible, so they can advise people about lifestyle changes and treatments that help to slow the progression of their CKD. Early diagnosis and intervention can reduce the chance that someone with CKD will be admitted to the hospital or eventually need dialysis or a kidney transplant. This article looked at a group of medicines called sodium-glucose cotransporter 2 (SGLT2) inhibitors that can be used to treat people with CKD. SGLT2 inhibitors were first developed to treat people with type 2 diabetes (T2D); however, further research has shown that these medicines can help to protect the kidneys and the heart in people with CKD with and without T2D. SGLT2 inhibitors can help to slow the decline in kidney function and lower the risk of death and hospitalizations in people with CKD. Research has shown that a wide range of people with CKD could benefit from treatment with SGLT2 inhibitors. This article describes how SGLT2 inhibitors can affect the body and the benefits of these medicines in people with CKD. [ABSTRACT FROM AUTHOR]

Heart failure (HF), which has a high morbidity and mortality rate, is nevertheless a common and crippling ailment, especially in older populations. The complicated pathophysiology of heart failure (HF), which includes oxidative stress, endothelial dysfunction, fibrosis, and inflammation, is frequently not sufficiently treated despite advances in medication. Inhibitors of the sodium-glucose co-transporter 2 (SGLT2) have become a key treatment for HF in patients with varying left ventricular ejection fractions (LVEF). SGLT2 inhibitors have been shown in recent clinical trials to considerably lower hospitalization rates for heart failure, cardiovascular mortality, and all-cause mortality. The mechanisms of SGLT2 inhibitors, such as better ventricular loading, increased heart metabolic efficiency, and decreased inflammation and necrosis, are covered in this review. Additionally, we provide an overview of four important clinical trials--DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER--highlighting their effectiveness in lowering unfavorable cardiovascular outcomes for patients with heart failure who have preserved (HFpEF), slightly reduced (HFmrEF), or reduced (HFrEF). The results validate the need of SGLT2 inhibitors in allinclusive HF treatment plans by highlighting their adaptability and safety in a range of clinical contexts. [ABSTRACT FROM AUTHOR]

Purpose: Owing to the absence of the most recent evidence on the efficacy and safety of luseogliflozin, our study aimed to conduct a systematic review and meta-analysis of luseogliflozin in patients with type 2 diabetes mellitus. Methods: A comprehensive search of electronic databases like PubMed, Cochrane CENTRAL, and Google Scholar was performed from the inception to the 31st of August 2023 to identify the randomized controlled trials (RCTs) that examined the glucose and body weight lowering efficacy and safety outcomes of luseogliflozin in comparison with control or other active treatments. The fixed or random-effect model was used based on the heterogeneity identified using the I2 statistic and Cochran's Q test. Results: Out of 50 non-duplicate articles identified through database searching, 8 RCTs (11 studies) with 1922 patients were included in this study. The efficacy outcomes like HbA1c (MD: −0.59%; 95% CI: −0.90, −0.29; P < 0.001), FPG (MD: −16.01 mg/dL; 95% CI: −19.46, −12.57; P < 0.001), PPG (MD: −36.63 mg/dL; 95% CI: −43.71, −29.55; P < 0.001) and body weight (MD: −1.66 kg; 95% CI: −2.23, −1.12; P < 0.001) were significantly reduced with luseogliflozin compared to the control group. Regarding the safety outcomes, there was no statistically significant difference between the two groups for hypoglycemia (OR: 1.14; 95% CI: 0.70, 1.84; P = 0.60). However, pollakiuria (OR: 4.08; 95% CI: 1.71, 9.69; P < 0.001) and any ADRs (OR: 2.04; 95% CI: 1.33, 3.14; P < 0.001) were significantly higher in the luseogliflozin group compared to the control. Conclusion: The current study identified a significant improvement in efficacy outcomes of HbA1c, FPG, PPG, and body weight in the luseogliflozin group. Non-significant safety results may be due to a smaller population size and fewer studies. Hence, long-term multicentric RCTs are needed to identify the safety and efficacy in a diversified population. [ABSTRACT FROM AUTHOR]

Objective: Implantable cardioverter defibrillators (ICDs) are the standard treatment for patients with reduced left ventricular ejection fraction (LVEF ≤35%) to reduce the risk of sudden cardiac death. Loop diuretics can cause electrolyte imbalances, leading to an increased incidence of ICD shocks. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown cardiovascular benefits in patients with heart failure (HF), but their effects on ventricular arrhythmias and ICD shocks, particularly in patients receiving different doses of loop diuretics, are not fully understood. This study evaluated the effects of furosemide dose and SGLT2i use on ICD shocks in HF patients with reduced left ventricular ejection fraction (HFrEF). Materials and Methods: HFrEF patients using oral furosemide and undergoing ICD implantation in our clinic were followed for 12 months to monitor ICD shocks for ventricular arrhythmias. They were grouped according to daily oral furosemide dose and SGLT2i use. Results: Out of 175 patients, the use of high-dose furosemide (>80 mg/day) was significantly higher in the ICD shock group compared to the non-shock group (38.8% vs. 16.7%, p = 0.001), while the use of SGLT2i was lower (19.4% vs. 45.4%, p < 0.001). ICD shocks occurred in 67.6% of patients on high-dose furosemide without SGLT2i and 30.0% with SGLT2i (p < 0.001). Multivariate analysis identified the absence of SGLT2i as an independent predictor of ICD shocks. Conclusions: SGLT2i was associated with reduced ventricular arrhythmias and ICD shocks in HF patients, even when high doses of furosemide were used. The absence of SGLT2i in HF treatment was an independent predictor of ICD shocks. [ABSTRACT FROM AUTHOR]

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition. [ABSTRACT FROM AUTHOR]

Although sodium–glucose transport protein-2 (SGLT2) inhibitors (SGLT2i) do not increase the risk of acute kidney injury (AKI) in general, they may pose a risk in patients undergoing angiography. This prospective cohort study aimed to evaluate the safety and efficacy of SGLT2i for post-contrast AKI (PC-AKI) in patients with type 2 diabetes mellitus (T2DM). Following screening, 306 patients with T2DM selected to undergo coronary arterial angiography with or without percutaneous intervention were enrolled. Patients were divided into the SGLT2i exposure and non-exposure groups. The primary outcome was PC-AKI, defined as an increase in serum creatinine levels > 0.5 mg/dL (44.2 µmol/L), or 25% above the baseline, within 48–72 h after exposure to contrast medium. The incidence of PC-AKI in the overall T2DM population was 5.2% (16/306). Following 1:1 propensity score matching, the incidence of PC-AKI was significantly higher in the SGLT2i group than in the non-SGLT2i group (10.7% vs. 2.9%; P = 0.027), with an odds ratio of 4.5 (95% confidence interval: 1.0–20.2; P = 0.047). Furthermore, PC-AKI occurred at a higher rate among short-term users of SGLT2i than long-term users (20.5% vs. 3.4%, P = 0.018). Thus, our findings suggest an increased risk of PC-AKI associated with short-term SGLT2i therapy in patients with T2DM. [ABSTRACT FROM AUTHOR]

Aim: To investigate the efficacy and safety of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 (SGLT2) inhibitors in liver transplant (LT) recipients with diabetes. Methods: A single‐centre, retrospective analysis of prospectively collected data from an LT recipient database (1990–2023) was conducted. We included adults with pre‐existing diabetes and post‐transplant diabetes, newly started on GLP‐1RAs and/or SGLT2 inhibitors after LT. Metabolic and biochemical parameters and outcomes were collected for up to 12 months after starting medications and were compared to those in patients receiving dipeptidyl peptidase‐4 (DPP‐4) inhibitors. Statistical analysis included descriptive statistics and linear mixed models. Results: We included participants on GLP‐1RAs (n = 46), SGLT2 inhibitors (n = 87), combination therapy (n = 12), and a DPP‐4 inhibitor comparator (n = 217). Both GLP‐1RAs and combination therapy decreased mean glycated haemoglobin (HbA1c) levels, and combination therapy remained significant when adjusted for DPP‐4 inhibitor treatment (−3.5%, 95% CI [−6.1, −0.95]; p = 0.0089) at 12 months. All three groups had significant decreases in mean weight and body mass index, but these remained significant in the GLP‐1RA (−5.2 kg, 95% CI [−8.7, −1.7], p = 0.0039 and 1.99 kg/m2, 95% CI [−3.4, −0.6], p = 0.0048) and combination therapy groups (−5.4 kg, 95% CI [−10.5, −0.36], p = 0.04 and −3.4 kg/m2, 95% CI [−5.5, −1.3], p = 0.0015) when adjusted for DPP‐4 inhibitor treatment at 12 months. Alanine aminotransferase levels decreased with GLP‐1RA and combination therapy. There were two (1.4%) cases of graft rejection. Conclusion: We found that GLP‐1RAs, SGLT2 inhibitors, and their combination, led to significant weight loss in LT recipients with diabetes. Combination therapy, in particular, lowered HbA1c and alanine aminotransferase levels compared to DPP‐4 inhibitors. Further studies are needed to assess long‐term safety and efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Lowering blood glucose is important to prevent long-term microvascular complications in adults with type 2 diabetes mellitus (T2DM). Various evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors are beneficial for microvascular diseases. This study was designed to investigate whether SGLT2 inhibitors have an effect on eye disorders. Methods: We searched PubMed, Web of Science, and ClinicalTrials.gov for randomized, double-blind, placebo-controlled trials with at least 24 weeks of follow-up up to 20 December 2023. Mantel-Haenszel statistical method, risk ratios (RRs) and 95% confidence intervals (CIs) were used to analyze the binary variables. Results: We included a total of 40 studies covering 104,586 participants. T2DM was present in 84.5% of the subjects. SGLT2 inhibitors had no significant effect on overall eye events compared to placebo (RR 0.99; 95%CI 0.86–1.15; p = 0.91), nor did subgroup analysis. We did not observe significant heterogeneity (I2 = 0; p = 0.99). Analysis of all secondary outcomes showed that SGLT2 inhibitors did not cause a significantly different effect from placebo. Meta-analysis in the entire T2DM population showed results consistent with those in the overall population. Conclusion: SGLT2 inhibitors did not have a significant effect on eye disorders during treatment, regardless of baseline conditions and duration of treatment. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) represents the most lethal complication in both type 1 and type 2 diabetes. The disease progresses without obvious symptoms and is often refractory when apparent symptoms have emerged. Although the molecular mechanisms underlying the onset/progression of DKD have been extensively studied, only a few effective therapies are currently available. Pathogenesis of DKD involves multifaced events caused by diabetes, which include alterations of metabolisms, signals, and hemodynamics. While the considerable efficacy of sodium/glucose cotransporter-2 (SGLT2) inhibitors or angiotensin II receptor blockers (ARBs) for DKD has been recognized, the ever-increasing number of patients with diabetes and DKD warrants additional practical therapeutic approaches that prevent DKD from diabetes. One plausible but promising target is the mechanistic target of the rapamycin complex 1 (mTORC1) signaling pathway, which senses cellular nutrients to control various anabolic and catabolic processes. This review introduces the current understanding of the mTOR signaling pathway and its roles in the development of DKD and other chronic kidney diseases (CKDs), and discusses potential therapeutic approaches targeting this pathway for the future treatment of DKD. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate potential predictors of effectiveness of SGLT2 inhibitors (SGLT2i) in individuals with type 1 diabetes (T1D) on sensor-augmented pump (SAP) therapy. Methods: We included individuals with T1D receiving SAP therapy at our hospital who were newly initiated on SGLT2i between 2019 and 2020 and were followed for at least 1 year. Data on BMI, blood tests, and continuous glucose monitoring (CGM) were compared before and 12 months after initiation of SGLT2i. Predictors of incremental increases in time in range (ΔTIR) were explored using a multiple regression analysis. Cutoff values for the predictors were determined using an ROC curve analysis. Results: A total of 17 individuals (females, 70.6%; median age, 44.0 years) were included, excluding three individuals who discontinued SGLT2i due to side effects. During follow-up, their median BMI decreased significantly (P = 0.013), while no significant change was seen in their total daily dose of insulin, basal-to-total insulin ratio. Again, their HbA1c, TIR, and time above range (TAR) improved significantly (P = 0.004, P = 0.003, and P = 0.003, respectively), while their time below range (TBR) showed no significant change. The predictor of increased ΔTIR was high urinary albumin-to-creatinine ratio (UACR) at baseline (P = 0.026) only, with the cutoff value determined to be 28.0 mg/g Cr or higher (AUC = 0.82, P = 0.003). Conclusions: It may be suggested that individuals with T1D on SAP therapy and having near-microalbuminuria or higher could be expected to show significant improvement in TIR. [ABSTRACT FROM AUTHOR]

Background: Real-world data on the implementation and prognostic impact of glucose-lowering drugs with proven cardiovascular benefits in patients with type 2 diabetes (T2D) following acute coronary syndrome (ACS) are limited. We investigated the utilization and treatment patterns of sodium–glucose contrasporter-2 inhibitors (SGLT2Is) and glucagon-like peptide-1 recepto-agonists (GLP1RAs) in patients with T2D experiencing ACS and analyzed their association with mortality and major adverse cardiovascular events (MACEs) including recurrent ACS, acute revascularization, heart failure, or ischemic stroke. Methods: We carried out a retrospective analysis of 9756 patients with T2D from a nationwide healthcare organization in Israel who were hospitalized with ACS between 01/2019 and 01/2022. Drug prescriptions were estimated pre-hospitalization, 90 days, and 1 year following hospitalization. The association between SGLT2I and/or GLP1RA treatment with MACE and mortality was investigated using a time-dependent Cox regression analysis with multivariable adjustment. Results: The prescription rates (pre-hospitalization, 90 days, and 1 year post-hospitalization) of GLP1RAs were 13%, 13.2%, and 18%, and those of SGLT2Is were 23.9%, 33.6%, and 42.7%, respectively. At 1 year, 13.9% of patients were prescribed both treatments. The use of SGLT2Is and/or GLP1RAs was higher in younger age groups and increased from 2019 to 2021 (38.1% to 59.2%). The adjusted hazard ratio for the association of pre- or post-hospitalization SGLT2I and/or GLP1RA treatment with mortality and MACE was 0.724 (0.654–0.801) and 0.974 (0.909–1.043), respectively. Conclusions: In the real-world practice of treating patients with T2D experiencing ACS, the implementation of SGLT2Is, particularly GLP1RAs, was suboptimal when prescribed both early and 1 year following hospitalization, emphasizing the need to improve medical care. Treatment with SGLT2Is and/or GLP1RAs was associated with a favorable impact on mortality but not MACE. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is the ninth-leading cause of cancer-related deaths worldwide. Diabetic patients have an increased risk and mortality rates for PC. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin (Met) are widely used anti-diabetic medications. Both Met and SGLT2 inhibitors have anticancer properties in PC, but nothing is known concerning their combined effect. So, we investigated the in vitro effect of SGLT2 inhibitors combined with Met. Canagliflozin and dapagliflozin possessed cytotoxic, antiproliferative, and pro-apoptotic properties in the tested PC cell lines. In PANC-1 cells, the antimigratory and pro-apoptotic effects were enhanced when dapagliflozin was combined with Met, and G1 cell cycle arrest was enhanced when dapagliflozin or canagliflozin was combined with Met. In AsPC-1 cells, the cytotoxic effect and the G1 cell cycle arrest were enhanced when canagliflozin and dapagliflozin, respectively, were combined with Met. Only the cytotoxic effects of SGLT2 inhibitors, but not the combination treatments, involved PI3K and JNK-dependent pathways in AsPC-1 cells. In conclusion, combination treatments increased the anticancer effects in a cell type-dependent way in the two investigated cell lines. Additionally, the cytotoxic effect of SGLT2 inhibitors was dependent on the PI3K and JNK pathways in AsPC-1 cells, but Met appears to act via a distinct mechanism. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The aim of this study was to examine contemporary trends in the use of, time to, and type of first add‐on anti‐hyperglycaemic therapy to metformin in Australia.We used the dispensing records of a 10% random sample of Pharmaceutical Benefits Scheme (PBS) eligible people. We included people aged 40 years and older initiating metformin from 1 January 2018 to 31 December 2020. Our primary outcome was first add‐on anti‐hyperglycaemic medicine within 2 years of metformin initiation. We analysed time to dispensing of first add‐on therapy. All analyses were stratified by metformin initiation year.Overall, 38 747 people aged 40 years and older initiated metformin between 2018 and 2020. Approximately one‐third (n = 12 946) of people received add‐on therapy with the proportion increasing slightly by year of metformin initiation (32.3% in 2018 to 34.8% in 2020). Amongst people with add‐on therapy following metformin initiation, sodium‐glucose cotransporter 2 inhibitor (SGLT2i) use increased from 28.8% (2018) to 35.0% (2020), and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) increased from 3.0% to 9.6%, respectively. Dipeptidyl peptidase‐4 inhibitors and sulfonylureas as first add‐on therapy decreased and insulin remained stable. One‐third of people with add‐on therapy initiated the therapy on the same day metformin was initiated, i.e. initial combination therapy.Amongst people initiating metformin from 2018 to 2020, there was an increasing proportion of SGLT2i and GLP‐1 RA being used as first add‐on therapy. However, the overall prevalence of add‐on therapy was low. Advocacy to promote add‐on therapy with cardiorenal beneficial medicines is critical to reduce type 2 diabetes morbidity and mortality. [ABSTRACT FROM AUTHOR]

Aims: People with type 2 diabetes (T2D) face high risks of heart failure (HF) hospitalizations that are often recurrent, especially as kidney function declines. We examined the effects of canagliflozin on total HF events by baseline kidney function in patients with T2D at high cardiovascular risk and/or with chronic kidney disease. Methods and results: Leveraging pooled participant‐level data from the CANVAS programme (n = 10 142) and CREDENCE trial (n = 4401), first and total HF hospitalizations were examined. Cox proportional hazards models were built for the time to first HF hospitalization, and proportional means models based on cumulative mean functions were used for recurrent HF hospitalizations. Treatment effects were evaluated overall as well as within baseline estimated glomerular filtration rate (eGFR) strata (<45, 45–60, and >60 ml/min/1.73 m2). HF hospitalizations were independently and blindly adjudicated. Among 14 540 participants with available baseline eGFR values, 672 HF hospitalizations occurred over a median follow‐up of 2.5 years. Among participants who experienced a HF hospitalization, 357 had a single event (201 in placebo‐treated patients and 156 in canagliflozin‐treated patients), 77 had 2 events, and 39 had >2 events. Canagliflozin reduced risk of first HF hospitalization (hazard ratio 0.58, 95% confidence interval [CI] 0.48–0.70) consistently across baseline eGFR strata (pinteraction = 0.84). Canagliflozin reduced total HF hospitalizations overall (mean event ratio 0.63, 95% CI 0.54–0.73) and across eGFR subgroups (pinteraction = 0.51). Canagliflozin also reduced cardiovascular death and total HF hospitalizations (mean event ratio 0.72, 95% CI 0.65–0.80) and across eGFR subgroups (pinteraction = 0.82). The absolute risk reductions were numerically larger, and numbers needed to treat were smaller when evaluating total events versus first events alone. These observed HF benefits were highly consistent across the range of eGFR, with larger absolute benefits in participants who had worse kidney function at baseline. Conclusions: In individuals with T2D at high cardiovascular risk and/or with chronic kidney disease, canagliflozin reduced the total burden of HF hospitalizations, with consistent benefits observed across the kidney function spectrum. Clinical Trial Registration: ClinicalTrials.gov Identifier: CANVAS (NCT01032629), CANVAS‐R (NCT01989754), CREDENCE (NCT02065791). [ABSTRACT FROM AUTHOR]

Introduction: In peritoneal dialysis (PD), managing peritoneal glucose uptake is a clinical challenge, as the uptake leads to peritoneal ultrafiltration loss. Peritoneal expression of sodium-glucose co-transporter 2 (SGLT2) suggests that SGLT2 inhibitors, a class of antidiabetic agents, may offer a solution. Methods: In 12 PD patients, we examined the influence of dapagliflozin, an SGLT2 inhibitor, on peritoneal equilibration test. Results: The volume of drainage and the total glucose content in drainage were larger in the test with dapagliflozin than in that without dapagliflozin (2.41 ± 0.16 vs. 2.23 ± 0.20 L, p = 0.011 and 16.9 ± 3.8 vs. 14.5 ± 3.7 g, p = 0.005, respectively). Conclusion: SGLT2 inhibitors could reduce peritoneal glucose uptake and improve fluid removal in clinical PD. [ABSTRACT FROM AUTHOR]

Background: Sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) are novel agents for heart failure (HF) and are now recommended in guidelines. Understanding general physicians' perspectives can help to optimise utilisation of this new medication. Aim: To understand the clinical concerns and barriers from general physicians about prescribing SGLT2is in a general medicine cohort. Methods: A questionnaire exploring clinicians' experience, comfort level and barriers to prescribing SGLT2is in patients with HF, incorporating two clinical scenarios, was disseminated to Internal Medicine Society of Australia and New Zealand members over a 2‐month period. Results: Ninety‐eight participants responded to the questionnaire (10.8% response rate). Most respondents (66.3%) were senior medical staff. Most participants worked in metropolitan settings (64.3%) and in public hospital settings (83.7%). For HF with reduced ejection fraction, 23.5% of participants reported prescribing SGLT2is frequently (defined as prescribing SGLT2is frequently over 75% of occasions). For HF with preserved ejection fraction, 57.1% of participants reported prescribing SGLT2is less than 25% of the time. Almost half of the participants (44%) expressed a high level of familiarity with therapeutic knowledge of SGLT2is, while 47% indicated high familiarity with potential side effects. Patient complexity, cost of medications and discontinuity of care were identified as important barriers. Euglycemic diabetic ketoacidosis was the side effect that caused the most hesitancy to prescribe SGLT2is in 48% of the respondents. Conclusion: General physicians in Australia and Aotearoa New Zealand are familiar with the therapeutic knowledge and side effects of SGLT2is. Patient complexity, medication cost and discontinuity of care were significant barriers to the use of SGLT2is for HF among general physicians. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the impact of dapagliflozin on reducing major adverse cardiovascular events (MACE) and all-cause mortality in patients with COVID-19 and to assess whether it was associated with clinical improvement. Methods: Between March 2020 and July 2022, 446 diabetic patients hospitalized with COVID-19 were included in the study and were divided into two groups in terms of dapagliflozin use: 120 patients in the dapagliflozin group and 326 patients in the other oral antidiabetic (non-dapagliflozin) group. Results: Six (5%) deaths occurred in the dapagliflozin group and 58 (17.8%) in the non-dapagliflozin group (p=0.001). Lower rates of ICU admission were observed in the dapagliflozin group (8 (6.7%) vs. 67 (20.6%) patients) (p = 0.001). MACE occurred in 23 patients (19.2%) in the dapagliflozin group and 70 (21.5%) in the non-dapagliflozin group (p = 0.689). Higher age (p = 0.001) and higher urea (p = 0.019) were associated with increased risk of mortality. Dapagliflozin users had 3.937-fold lower risk of mortality (OR, 0.254; 95% CI, 0.093–0.697; p = 0.008). Multivariable logistic regression revealed that advanced age, active smoking, presence of peripheral artery disease, lower left ventricular ejection fraction, and glucose level were independently associated with MACE. Conclusion: We demonstrated that dapagliflozin treatment may be related with a reduced risk of mortality and lower ICU admission rates in diabetic patients hospitalized with COVID-19. Despite the limitations of the study, dapagliflozin could benefit COVID-19 patients with cardiometabolic risk factors, but further studies that control for our limitations are necessary. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the effects of sodium-glucose co-transporter inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and dipeptidyl peptidase-4 inhibitors (DPP4i) on individuals subjected to diabetes and COVID-19. Methods: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched to cover studies (except for case reports and review studies) published until August 30, 2022. The primary outcome was the mortality of people with diabetes and COVID-19. The secondary outcomes comprised the requiring intensive care unit (ICU) admission and mechanical ventilation. Two reviewers independently screened studies, abstracted data, and assessed risk-of-bias. Furthermore, the network meta-analyses (NMA) were conducted. Results: A total of 12 trials were involved in the analysis. The OR and 95% CI of mortality for SGLT2i compared with SGLT2i + GLP-1RA and DPP4i reached 0.41 (0.17,0.97) and 0.69 (0.49,0.98), respectively. The OR and 95% CI of requiring mechanical ventilation for SGLT2i compared with the DPP4i reached 0.85 (0.75,0.97). Conclusions: As revealed by the result of this study, SGLT2i is associated with the lower mortality rate in people with diabetes and COVID-19 among novel glucose-lowering drugs. And SGLT2i is linked to lower requiring mechanical ventilation. These findings can have a large impact on clinicians' decisions amid the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

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The article explores the potential benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of acute myocardial infarction (AMI). SGLT2i medications have shown promise in reducing cardiovascular events in patients with diabetes. Observational studies and recent trials have shed light on the role of SGLT2i in this critical setting. While SGLT2i have positive effects on various organs, potential side effects should be acknowledged and patients should be monitored carefully. The trials evaluated the efficacy of dapagliflozin and empagliflozin in AMI patients, with dapagliflozin showing statistically superior outcomes in cardio-metabolic factors and empagliflozin showing a significant reduction in heart failure hospitalization rates. Further research is needed to fully understand the potential benefits of SGLT2 inhibitors in AMI patients. [Extracted from the article]

Aims/hypothesis: Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis. Methods: Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013–2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument. Results: Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA1c reduction was similar between SGLT2i and DPP4i (−0.3 mmol/mol [−1.6, 1.1], −0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (−4 mmol/mol [4.8, −3.1], −0.4% [−0.4, −0.3]). Conclusions/interpretation: Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract Background Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) represent a deep revolution of the therapeutic approach to heart failure (HF), preventing its insurgence but also improving the management of the disease and slowing its natural progression. To date, few studies have explored the effectiveness of SGLT2i and, in particular, Dapagliflozin in a real-world population. Therefore, in this observational prospective study, we evaluated Dapagliflozin's effectiveness in a real-world HF population categorized in the different hemodynamic profiles. Methods From January 2022 to June 2023, we enrolled 240 patients with chronic HF and reduced ejection fraction (HFrEF) on optimal medical therapy, according to 2021 ESC guidelines, that added treatment with Dapagliflozin from the HF Clinics of 6 Italian University Hospitals. Clinical, biochemical, and echocardiographic parameters were collected before and after 6 months of Dapagliflozin introduction. Moreover, the HFrEF population was classified according to hemodynamic profiles (A: SV ≥ 35 ml/m2; E/e′

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are integral to diabetes treatment, facilitating renal glucose excretion and offering benefits in cardiovascular risk reduction, kidney function preservation, and weight management. However, their integration into diabetes care presents challenges due to associated adverse effects. This review assesses the efficacy of SGLT2 inhibitors in diabetes management. A comprehensive literature search using PubMed and Google Scholar yielded pertinent studies. Clinical evidence demonstrates the effectiveness of SGLT2 inhibitors in glycemic control and in reducing cardiovascular risks in diabetes patients. Moreover, these agents exhibit positive effects on cardiovascular and renal functions. Despite their therapeutic promise, careful consideration is warranted when integrating SGLT2 inhibitors into diabetes care. Common adverse effects such as genitourinary infections, hypoglycemia, and sporadic diabetic ketoacidosis necessitate rigorous patient monitoring and education. Nonetheless, SGLT2 inhibitors offer a comprehensive approach to diabetes management, showing efficacy across multiple domains. In summary, SGLT2 inhibitors play a crucial role in diabetes care, offering benefits beyond glycemic control. However, their use requires careful patient selection, education, and monitoring to manage associated risks effectively. Awareness of potential adverse effects is essential for optimizing the therapeutic benefits of SGLT2 inhibitors in T2DM (type 2 diabetes mellitus) management.

The article briefly describes the stages of creating the main methods of acute myocardial infarction (MI) and its complications treatment. It is noted that currently existing clinical guidelines (CG) were formed at the end of the first decade of the XXI century; since then there have been no principal changes in the CG due to the lack of fundamentally new approaches to the acute MI treatment, its immediate and long-term outcomes. Compliance with the current CG has significantly reduced hospital mortality in acute MI and improved long-term outcomes. However, today, despite compliance with the CG, the absolute hospital mortality rates for acute MI remain quite high, and the long-term prognosis of patients’ lives is very unfavorable. A number of major randomized clinical trials that ended in 2023-2024 and studied fundamentally new approaches to the treatment of acute MI and its long–term outcomes are analyzed. It is noted that none of these studies gave a positive result. A new study with beta-blockers, which proved its positive effect on the mortality of patients with acute MI in the 80s of the twentieth century, gave negative results. This may indicate that a number of acute MI treatment methods, the effectiveness of which was proven several decades ago, have now lost their significance. It is concluded that despite compliance with modern CG, the residual risk of death after acute MI remains quite high. It is necessary to develop principally new methods of treating this disease.

Abstract Although sodium–glucose transport protein-2 (SGLT2) inhibitors (SGLT2i) do not increase the risk of acute kidney injury (AKI) in general, they may pose a risk in patients undergoing angiography. This prospective cohort study aimed to evaluate the safety and efficacy of SGLT2i for post-contrast AKI (PC-AKI) in patients with type 2 diabetes mellitus (T2DM). Following screening, 306 patients with T2DM selected to undergo coronary arterial angiography with or without percutaneous intervention were enrolled. Patients were divided into the SGLT2i exposure and non-exposure groups. The primary outcome was PC-AKI, defined as an increase in serum creatinine levels > 0.5 mg/dL (44.2 µmol/L), or 25% above the baseline, within 48–72 h after exposure to contrast medium. The incidence of PC-AKI in the overall T2DM population was 5.2% (16/306). Following 1:1 propensity score matching, the incidence of PC-AKI was significantly higher in the SGLT2i group than in the non-SGLT2i group (10.7% vs. 2.9%; P = 0.027), with an odds ratio of 4.5 (95% confidence interval: 1.0–20.2; P = 0.047). Furthermore, PC-AKI occurred at a higher rate among short-term users of SGLT2i than long-term users (20.5% vs. 3.4%, P = 0.018). Thus, our findings suggest an increased risk of PC-AKI associated with short-term SGLT2i therapy in patients with T2DM.

The immune system can lead to a variety of renal diseases through direct or indirect mechanisms. In immune-mediated nephropathy, though standardized treatment, there are still a small number of patients with further decline in renal function, which may even progress to renal failure; sodium-glucose cotransporter protein 2 (SLC5A2,SGLT2) inhibitors not only can significantly reduce blood glucose, but also have an additional protective effect on the kidneys and the heart; this review concludes the potential mechanism of the renal protective effect of SGLT2i and the new advances in the recent years in common immune-mediated nephropathies, which can provide new theoretical references to optimize the therapeutic strategy of common immune-mediated nephropathies. [ABSTRACT FROM AUTHOR]

Since the publication of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure (HF), results of several randomized controlled clinical trials have been published that have a direct impact on day-to-day clinical practice in the treatment of HF patients. These studies provided knowledge that made it necessary to update recommendations for the treatment of HF patients before the publication of the next planned full guideline. Based on the above, the 2023 focused update addresses changes warranted by new evidence in the original guideline's recommendations for addressing the HF. The recommendations for the following sections of the 2021 ESC HF Guideline have been updated: 1) chronic HF: HF with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF); 2) acute HF; 3) comorbidities and prevention of HF. This article details the updated recommendations and the results of the studies that underpinned the updated recommendations.

Atrial cardiomyopathy and remodeling play pivotal roles in the development of atrial fibrillation (AF) and heart failure (HF), involving complex changes in atrial structure and function. These changes facilitate the progression of AF and HF by creating a dynamic interplay between mechanical stress and electrical disturbances in the heart. Sodium–glucose cotransporter 2 inhibitors (SGLT2is), initially developed for the management of type 2 diabetes, have demonstrated promising cardiovascular benefits, being currently one of the cornerstone treatments in HF management. Despite recent data from randomized clinical trials indicating that SGLT2is may significantly influence atrial remodeling, their overall effectiveness in this context is still under debate. Given the emerging evidence, this review examines the molecular mechanisms through which SGLT2is exert their effects on atrial remodeling, aiming to clarify their potential benefits and limitations. By exploring these mechanisms, this review aims to provide insights into how SGLT2is can be integrated into strategies for preventing the progression of atrial remodeling and HF, as well as the development of AF.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is common in type 2 diabetes mellitus (T2D), leading to high morbidity and mortality. Managing HFpEF in diabetic patients is challenging with limited treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown potential cardiovascular benefits. This meta-analysis compares the effects of GLP1-RA and SGLT2 inhibitors on HFpEF in T2D patients. Methods We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating GLP1-RA and SGLT2 inhibitors’ impact on HFpEF in T2D patients. Databases searched included PubMed, MEDLINE, and Cochrane Library up to July 2024. Primary outcomes were changes in left ventricular ejection fraction (LVEF), myocardial fibrosis (extracellular volume fraction, ECV), and functional capacity (6-minute walk test, 6MWT). Secondary outcomes included HbA1c, body weight, and systolic blood pressure (SBP). Results Twelve studies with 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774) were included. Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo (GLP1-RA: mean difference [MD] 2.8%, 95% confidence interval [CI] 1.5 to 4.1, p

Abstract New anti-diabetic medications, including glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitors are recommended in guidelines to reduce cardio-renal events in type 2 diabetes mellitus (T2DM), independent of glucose control. Yet they might be underused in real world. This study aims to address the knowledge gap, prescription patterns and barriers faced by Chinese doctors. Cardio-Metabolic Survey was a cross-sectional study conducted among doctors managing diabetic patients in clinical practice, via a designated online questionnaire from May 1st, to Dec. 31th, 2022. A total of 358 doctors from 57 hospitals across Beijing participated in this survey, 34.9% from tertiary hospitals. Only 30–40% doctors demonstrated somewhat understanding of the mechanism and clinical applications of GLP-1RA or SGLT2 inhibitors. There is no difference in understanding of these two medications overall (p = 0.336). However, doctors in tertiary hospitals have a higher understanding of GLP-1RA and SGLT2 inhibitors compared to those in non-tertiary hospitals (p = 0.049, and 0.008, respectively). 40.2% doctors have never prescribed GLP-1RA, and 36.6% for SGLT2 inhibitors. The frequency of prescribing SGLT2 inhibitors was significantly higher than prescribing GLP-1RA (p = 0.005). The main barriers on prescription include high cost, poor adherence, side effects concern, and insufficient knowledge about these medications. Chinese doctors currently have limited understanding and low prescription frequency for GLP-1RA and SGLT2 inhibitors. Multifaceted approaches are needed to improve doctors' knowledge and strengthen their ability to manage T2DM effectively.

Abstract Background International longitudinal studies have indicated an increasing incidence of diabetic ketoacidosis (DKA). We aim to examine the incident trends, demographic differences, length of stay and mortality for DKA in adults with type 1 diabetes (T1D) and type 2 diabetes (T2D) in Victoria, Australia from 2002 to 2016. Methods Age and sex adjusted incident trends, length of stay and mortality for DKA was retrospectively obtained using the Victorian Admitted Episode Dataset between 2002 and 2016. Data for adults with T1D and T2D was obtained from the National Diabetes Services Scheme (NDSS). Joinpoint regression analysis was used to identify changes in linear trends that were described as average annual percentage change (AAPC). Results There were 23,628 DKA presentations in Victoria between 2002 and 2016. For T1D there was an increase in DKA presentations (AAPC + 6.8%) from 2003 to 2016 and for T2D there was a decline from 2003 to 2011 (APC − 3.5%), increase from 2011 to 2014 (APC + 38.5%), and a decrease from 2014 to 2016 (APC − 20.9%). Length of stay was longer for people with T2D than T1D (P

Abstract Background/Objective The research on sodium-glucose cotransporter 2 (SGLT2) inhibitors has been increasing rapidly in the last decade, as well as indications for their use. This study aimed to analyze the methodological characteristics of clinical trials on SGLT2 inhibitors registered on ClinicalTrials.gov. Design We conducted a cross-sectional study of trials on SGLT2 inhibitors registered on ClinicalTrials.gov up to November 11, 2022. We included clinical trials that tested SGLT2 inhibitors for any clinical condition, as a single or combined SGLT2 therapy, compared to any other medication or placebo and mapped their characteristics. Results We identified 1102 eligible trials on 14 different SGLT2 inhibitors. The first trial registration was in 2005. There were 993 (90%) interventional and 109 (10%) observational trials. Most trials were in Phase 1 (29%), Phase 3 (23%), or Phase 4 (24%). Interventional trials were mostly randomized (85%); almost half of them did not use masking (44%). Trials on empagliflozin, dapagliflozin, and canagliflozin accounted for 75% of all trials. More than 60% of trials included patients with diabetes mellitus, 13% included only healthy subjects, and 12% included patients with heart diseases. Overall, these trials included more than 9.5 million participants (~ 312,000 of which in interventional studies). Almost 65% of all clinical trials were industry-funded. Most trials were completed (60%) and 35% of those reported results. For trials that are obligated to report results by the Food and Drugs Administration (FDA), 88% of them did so. Trials fully or partially funded by industry more frequently published results compared to non-industry funded trials (46.1% vs. 11.2%; p

Sodium–glucose cotransporter 2 (SGLT2) inhibitors regulate plasma glucose levels in patients with type 2 diabetes mellitus (T2DM) by inhibiting renal glucose reabsorption. This study investigated the impact of empagliflozin (EMPA), an SGLT2 inhibitor, on hypothalamic energy regulation. To directly investigate the role of SGLT2 inhibitors in the hypothalamus, we administered EMPA through intracerebroventricular (i.c.v.) injections into the murine ventricles. After dental cementing the i.c.v. cannula onto the skull, the mice were given 5 days to recover before receiving vehicle or EMPA (50 nM/2 μL) injections. In a high-fat diet (HFD)-induced obesity model, we determined the gene expression levels of agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) in the hypothalamus. Additionally, we assessed FoxO1 expression, which regulates AgRP and POMC gene transcription in hypothalamic cell lines. We found that EMPA directly influenced the expression of endogenous mRNA of POMC and AgRP, which are critical for energy homeostasis, and modulated their transcription in high-fat diet-induced obese mice. Additionally, EMPA affected the expression of FoxO1, a key transcriptional regulator of glucose homeostasis, thereby regulating the transcriptional activity of POMC and AgRP. These results indicate that EMPA significantly influences hypothalamic energy homeostasis, highlighting its potential as a regulator in obesity and T2DM management.

With around one billion of the world’s population affected, the era of the metabolic-associated fatty liver disease (MAFLD) pandemic has entered the global stage. MAFLD is a chronic progressive liver disease with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC), and for which to date there are almost no approved pharmacologic options. Because MAFLD has a very complex etiology and it also affects extrahepatic organs, a multidisciplinary approach is required when it comes to finding an effective and safe active substance for MAFLD treatment. The optimal drug for MAFLD should diminish steatosis, fibrosis and inflammation in the liver, and the winner for MAFLD drug authorisation seems to be the one that significantly improves liver histology. Saroglitazar (Lipaglyn®) was approved for metabolic-dysfunction-associated steatohepatitis (MASH) in India in 2020; however, the drug is still being investigated in other countries. Although the pharmaceutical industry is still lagging behind in developing an approved pharmacologic therapy for MAFLD, research has recently intensified and many molecules which are in the final stages of clinical trials are expected to be approved in the coming few years. Already this year, the first drug (Rezdiffra™) in the United States was approved via accelerated procedure for treatment of MAFLD, i.e., of MASH in adults. This review underscores the most recent information related to the development of drugs for MAFLD treatment, focusing on the molecules that have come furthest towards approval.

Abstract Background Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. Methods Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. Results Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. Conclusion This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Abstract Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2 is encoded by SLC5A2 (Solute Carrier Family 5 Member 2), which is highly expressed in renal cortex, but also in the testes where glucose uptake may be essential for spermatogenesis and androgen synthesis. We postulated that in healthy males, SGLT2 inhibitor therapy may affect gonadal function. We examined the impact on gonadal and steroid hormones in a post-hoc analysis of a double-blind, randomized, placebo-controlled research including 26 healthy males who were given either placebo or empagliflozin 10 mg once daily for four weeks. After one month of empagliflozin, there were no discernible changes in androgen, pituitary gonadotropin hormones, or inhibin B. Regardless of BMI category, the administration of empagliflozin, a highly selective SGLT2 inhibitor, did not alter serum androgen levels in men without diabetes. While SGLT2 is present in the testes, its inhibition does not seem to affect testosterone production in Leydig cells nor inhibin B secretion by the Sertoli cells.

Background: Heart failure with preserved ejection fraction (HFpEF) is common in type 2 diabetes mellitus (T2D), leading to high morbidity and mortality. Managing HFpEF in diabetic patients is challenging with limited treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown potential cardiovascular benefits. This meta-analysis compares the effects of GLP1-RA and SGLT2 inhibitors on HFpEF in T2D patients. Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating GLP1-RA and SGLT2 inhibitors' impact on HFpEF in T2D patients. Databases searched included PubMed, MEDLINE, and Cochrane Library up to July 2024. Primary outcomes were changes in left ventricular ejection fraction (LVEF), myocardial fibrosis (extracellular volume fraction, ECV), and functional capacity (6-minute walk test, 6MWT). Secondary outcomes included HbA1c, body weight, and systolic blood pressure (SBP). Results: Twelve studies with 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774) were included. Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo (GLP1-RA: mean difference [MD] 2.8%, 95% confidence interval [CI] 1.5 to 4.1, p < 0.001; SGLT2 inhibitors: MD 3.2%, 95% CI 2.0 to 4.4, p < 0.001). SGLT2 inhibitors significantly reduced myocardial fibrosis (MD -3.5%, 95% CI -4.2 to -2.8, p < 0.001) more than GLP1-RA (MD -2.3%, 95% CI -3.0 to -1.6, p < 0.001). Functional capacity improved significantly with both treatments (GLP1-RA: MD 45 m, 95% CI 30 to 60, p < 0.001; SGLT2 inhibitors: MD 50 m, 95% CI 35 to 65, p < 0.001). Secondary outcomes showed reductions in HbA1c (GLP1-RA: MD -1.1%, 95% CI -1.4 to -0.8, p < 0.001; SGLT2 inhibitors: MD -1.0%, 95% CI -1.3 to -0.7, p < 0.001) and body weight (GLP1-RA: MD -2.5 kg, 95% CI -3.1 to -1.9, p < 0.001; SGLT2 inhibitors: MD -2.0 kg, 95% CI -2.6 to -1.4, p < 0.001). Both treatments significantly lowered SBP (GLP1-RA: MD -5.2 mmHg, 95% CI -6.5 to -3.9, p < 0.001; SGLT2 inhibitors: MD -4.8 mmHg, 95% CI -6.0 to -3.6, p < 0.001). Conclusions: GLP1-RA and SGLT2 inhibitors significantly benefit HFpEF management in T2D patients. SGLT2 inhibitors reduce myocardial fibrosis more effectively, while both improve LVEF, functional capacity, and metabolic parameters. These therapies should be integral to HFpEF management in diabetic patients. Further research is needed on long-term outcomes and potential combined therapy effects. [ABSTRACT FROM AUTHOR]