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Diabetic nephropathy, also known as diabetic kidney disease (DKD), remains a challenge in clinical practice as this is the major cause of kidney failure worldwide. Clinical trials do not answer all the questions raised in clinical practice and real‐world evidence provides complementary insights from randomized controlled trials. Real‐life longitudinal data highlight the need for improved screening and management of diabetic nephropathy in primary care. Adherence to the recommended guidelines for comprehensive care appears to be suboptimal in clinical practice in patients with DKD. Barriers to the initiation of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors for patients with DKD persist in clinical practice, in particular for the elderly. Attainment of blood pressure targets often remains an issue. Initiation of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in routine clinical practice is associated with a reduced risk of albuminuria progression and a possible beneficial effect on kidney function. Real‐world evidence confirms a beneficial effect of SGLT2 inhibitors on the decline of glomerular filtration, even in the absence of albuminuria, with a lower risk of acute kidney injury events compared to GLP‐1RA use. In addition, SGLT2 inhibitors confer a lower risk of hyperkalaemia after initiation compared with dipeptidyl peptidase‐4 inhibitors in patients with DKD. Data from a large population indicate that diuretic treatment increases the risk of a significant decline in glomerular filtration rate in the first few weeks of treatment after SGLT2 inhibitor initiation. The perspective for a global approach targeting multifaceted criteria for diabetic individuals with DKD is emerging based on real‐world evidence but there is still a long way to go to achieve this goal. [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]

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce the risk of hospitalizations from heart failure and cardiovascular mortality. However, SGLT2i therapy's potential effects on the risks of dementia and Parkinson's disease are not well established, with conflicting results based on observational studies. Hence, we sought to evaluate the association between SGLT2i and the risk of dementia and Parkinson's disease in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. We performed a systematic literature search on PubMed, and Clinicaltrial.gov for relevant randomized controlled trials from inception until March 2024 without any language restrictions. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model. A total of 12 randomized controlled trials with 74,442 patients (40,784 in the SGLT2i group and 33,658 in the control group) were included in the analysis. The mean age of patients in SGLT2i and control was 65.3 and 65.2 years, respectively. Pooled analysis showed that there is no significant association between SGLT2i use and the risk of dementia (OR 1.37; 95% CI, 0.70-2.69; P =.36), dementia Alzheimer's type (OR 1.99; 95% CI, 0.59-6.71; P =. 27), vascular dementia (OR 0.40; 95% CI, 0.09-1.85; P =. 24), and Parkinson's disease (OR 0.63; 95% CI, 0.25-1.61; P =. 33) when compared with the control groups. Our study suggests that there is no significant association between SGLT2i use and the risk of dementia, its subtypes, and Parkinson's disease when compared with the control groups. [Display omitted] Central illustration showing the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and risk of dementia. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic retinopathy (DR), a microvascular complication of type 2 diabetes mellitus (T2DM), is a leading cause of blindness and has detrimental effects on patients' quality of life. We compared the risk of DR diagnosis with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM in Japan. Methods: This Japanese retrospective cohort study used the JMDC Claims Database (data collected from January 2015 to September 2022). Patients with T2DM and no record of microvascular or macrovascular diseases who were newly treated with an SGLT2i (23,061 patients) or a DPP-4i (53,986 patients) were matched 1:1 using propensity score (10,166 per matched group). Incidence rates (IRs) and cumulative IRs of DR diagnosis were calculated for each treatment group; hazard ratio (HR) and its 95% confidence interval (CI) were calculated using Cox proportional hazard models to compare the risk between the groups. Results: The IR of DR diagnosis was 46.23 and 57.12 per 1000 person-years in the SGLT2i and DPP-4i groups, respectively, with a significantly lower risk in the SGLT2i group than in the DPP-4i group (HR 0.83, 95% CI 0.75–0.92, P = 0.0003). Conclusions: In this study, the risk of DR diagnosis was lower with SGLT2i compared with DPP-4i in patients with T2DM without microvascular and macrovascular diseases in Japan. Findings suggest that early SGLT2i treatment may be beneficial in preventing DR development in early-stage T2DM. Graphical abstract available for this article. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the utilization and costs of non‐insulin glucose‐lowering drugs (GLDs) in Australia from 2013 to 2023. Materials and Methods: We conducted a retrospective analysis of the Australian Pharmaceutical Benefits Scheme (PBS) administrative dataset of 118 727 494 GLD prescriptions. The main outcome measures were the annual number of GLD prescriptions dispensed, accounting for type 2 diabetes mellitus (T2DM) prevalence and healthcare system costs, adjusted for inflation. Results: Utilization of GLDs doubled from 6.4 million prescriptions in 2013 to 15.6 million in 2023. The average annual percent increase in utilization was 8.1%, compared to the average annual increase in prevalence of T2DM of 1.8%. The biggest change was in sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, for which there was an average annual increase in utilization of 59.4% (95% confidence interval [CI] 51.7%, 68.2%; p < 0.05) from 2014 (first full year of PBS listing), followed by glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), which showed an increase of 31.4% (95% CI 28.5%, 33.8%; p < 0.05) annually (2013 to 2023). Dipeptidyl peptidase‐4 inhibitor utilization tripled, with an average annual increase of 10.9% (95% CI 8.1%, 13.8%; p < 0.05), but this plateaued from 2020. Metformin utilization increased by 4.7% (95% CI 2.0%, 6.9%; p < 0.05) annually. In contrast, sulphonylurea, glitazone and acarbose utilization declined. Total GLD costs increased threefold over the same period. Despite only accounting for 11.7% of utilization, GLP‐1RAs contributed to 35% of the costs. Conclusion: Utilization of GLDs doubled, and associated costs tripled over the past 11 years, with no sign of either utilization or costs plateauing, predominantly due to increased GLP‐1RA and SGLT2 inhibitor prescribing. [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]

Aims/hypothesis: Although the benefits of sodium–glucose cotransporter 2 inhibitor (SGLT2i) use in chronic kidney disease (CKD) are well established, the effects of these therapeutic agents in patients with advanced CKD are less certain. We hypothesised that the continued use of these drugs, even when renal function deteriorates to stage 4 CKD or worse, is safe and associated with improved cardiorenal survival. Methods: This is a retrospective cohort study utilising data from medical records from two institutions. All patients with type 2 diabetes mellitus who were prescribed an SGLT2i between 1 January 2016 and 31 December 2021, who subsequently had eGFR <30 ml/min per 1.73 m2 recorded on two occasions at least 90 days apart, were identified. The date on which the eGFR first reached any level less than 30 ml/min per 1.73 m2 was defined as the index date. Individuals were then categorised into the SGLT2i continuation group or the discontinuation group according to the use of SGLT2i after the index date. Inverse probability of treatment weighting (IPTW) was performed to minimise confounding. Outcomes of interest included heart failure outcomes, cardiovascular outcomes, renal outcomes and safety outcomes. Results: According to the eligibility criteria, 337 patients in the continuation group and 358 in the discontinuation group were identified. After IPTW, continuation of SGLT2i use was associated with significantly lower risks of the composite of major adverse cardiovascular events compared with discontinuation of SGLT2i use (HR 0.65 [95% CI 0.43, 0.99]), largely driven by reduced risk of myocardial infarction during follow-up (subdistribution HR [SHR] 0.43 [95% CI 0.21, 0.89]). The incidences of an eGFR decline of 50% or more (SHR 0.58 [95% CI 0.42, 0.81]) and all-cause hospital admission (SHR 0.77 [95% CI 0.64, 0.94]) were also significantly lower in the continuation group. None of the studied safety outcomes were significantly different when comparing the two groups. Blood haemoglobin levels were significantly higher in the continuation group at the end of follow-up (114.6 g/l vs 110.4 g/l, with a difference of 4.12 g/l; p=0.047). Conclusions/interpretation: In patients with CKD who were treated with an SGLT2i, continuation of SGLT2i use after eGFR declined to 30 ml/min per 1.73 m2 or less was associated with lower risks of cardiovascular and renal events compared with discontinuation of SGLT2i use. Continued use of SGLT2i throughout the course of CKD should be considered to optimise patient outcomes. [ABSTRACT FROM AUTHOR]

The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident. [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]

Background: Cirrhotic refractory ascites (RA) patients have few alternatives for treatment. Empagliflozin is now known to have natriuretic and neurohormonal modulatory effects. This research investigated the safety and efficacy of empagliflozin in the management of RA when added to the standard of care (SoC) compared to SoC alone. Methods: Patients were randomized to receive either a fixed dose of 10 mg of empagliflozin plus standard of care (SoC) or SoC alone. Patients were followed up for 3 months. The primary endpoint was achieving no need for large-volume paracentesis (LVP). Results: Forty-two patients were randomized equally, and intention-to-treat was performed. There was a statistically significant decrease in the need for LVP in the empagliflozin group compared to the SoC group (100% in the SoC vs. 42.9% in the empagliflozin group, p < 0.001). By the end of the study, the total resolution of ascites was reported in approximately 24% of patients. Muscle cramps and newly developed hyponatremia were more common in the empagliflozin group, but they were mild. Acute kidney injury was more common in the SoC group. Conclusions: Empagliflozin may be an effective option for use as an add-on therapy in the management of RA, with an accepted safety profile. Trial registration: The trial was registered at www.clinicaltrials.gov under the identifier NCT05430243. The registration was submitted on 18/06/2022. It is available at https://clinicaltrials.gov/study/NCT05430243. [ABSTRACT FROM AUTHOR]

Background: The therapeutic effects of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, on cardiovascular outcome are not fully understood. This study aimed to evaluate the efficacy and safety of ertugliflozin on cardiac function in people with type 2 diabetes and pre-heart failure. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial involving individuals with type 2 diabetes inadequately controlled with antidiabetic medications. Participants with left ventricular hypertrophy, E/e' >15, or impaired left ventricular global longitudinal strain (LVGLS) were randomized 1:1 to receive either ertugliflozin (5 mg once daily) or a placebo. The primary outcome was the change in LVGLS. Secondary outcomes included changes in left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Prespecified exploratory outcomes, including angiotensin-converting enzyme 2 (ACE2) and angiotensin (1–7) levels, were also assessed. Results: A total of 102 individuals (mean age, 63.9 ± 9.2 years; 38% women) were included. The ertugliflozin group showed a significant improvement in LVGLS (− 15.5 ± 3.1% to − 16.6 ± 2.8%, P = 0.004) compared to the placebo group (− 16.7 ± 2.7% to − 16.4 ± 2.6%, P = 0.509), with a significant between-group difference (P = 0.013). Improvements in LVMI and LVEF were also observed. Additionally, significant reductions in HbA1c, systolic blood pressure, whole-body and visceral fat, uric acid, proteinuria, N-terminal pro–B-type natriuretic peptide, and lipoprotein(a) were noted. ACE2 and angiotensin (1–7) levels significantly increased in the ertugliflozin group compared to the placebo group and correlated with changes in LVGLS [r = 0.456, P < 0.001 for ACE2; r = 0.541, P < 0.001 for angiotensin (1–7)]. Adverse events were similar between the two groups. Conclusions: This study demonstrated that ertugliflozin has beneficial effects on left ventricular function in individuals with type 2 diabetes and pre-heart failure, and it provided insights into potential underlying mechanisms. Clinical trial registration: ClinicalTrials.gov Identifier: NCT03717194. [ABSTRACT FROM AUTHOR]

Background: Patients with low-to-normal body mass index (BMI; < 25.0 kg/m2) were underrepresented in major randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes. The present study aims to investigate the effectiveness of SGLT2 inhibitors for cardiovascular outcomes among patients with type 2 diabetes and low-to-normal BMI, using finer stratification than previous trials. Methods: This cohort study with a target trial emulation framework was conducted using insurance claims and health screening records of more than 30 million working-age citizens in Japan acquired from April 1, 2015 to March 31, 2022. 139,783 new users of SGLT2 inhibitors matched to 139,783 users of dipeptidyl protease (DPP) 4 inhibitors with stratification by BMI category (< 20.0, 20.0–22.4, 22.5–24.9, 25.0–29.9, 30.0–34.9, and 35.0 ≤ kg/m2). The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure. Secondary outcomes were the components of the primary outcome. Cox proportional hazard models were used to compare SGLT2 inhibitors with DPP4 inhibitors in the whole population and subgroups defined by the BMI category. Results: Among participants, 17.3% (n = 48,377) were female and 31.0% (n = 86,536) had low-to-normal BMI (< 20.0 kg/m2, 1.9% [n = 5,350]; 20.0–22.4 kg/m2, 8.5% [n = 23,818]; and 22.5–24.9 kg/m2, 20.5% [n = 57,368]). Over a median follow-up of 24 months, the primary outcome occurred in 2.9% (n = 8,165) of participants. SGLT2 inhibitors were associated with a decreased incidence of the primary outcome in the whole population (HR [95%CI] = 0.92 [0.89 to 0.96]), but not in patients with low-to-normal BMI (< 20.0 kg/m2, HR [95%CI] = 1.08 [0.80 to 1.46]; 20.0–22.4 kg/m2, HR [95%CI] = 1.04 [0.90 to 1.20]; and 22.5–24.9 kg/m2, HR [95%CI] = 0.92 [0.84 to 1.01]). Conclusions: The protective effect of SGLT2 inhibitors on cardiovascular events among patients with type 2 diabetes appeared to decrease with lower BMI and was not significant among patients with low-to-normal BMI (< 25.0 kg/m2). These findings suggest the importance of considering BMI when initiating SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: In recent decades, an increase in the incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has been observed. Pediatric‐onset T2DM differs from the adult‐onset form, particularly regarding the durability of glycemic control and earlier appearance of complications. However, the scarcity of approved treatments and comprehensive studies on T2DM management in youth persists. Ongoing clinical trials seek to ascertain the efficacy and safety of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) in patients aged between 10 and 24 years with T2DM. Therefore, we aimed to perform a meta‐analysis exploring the efficacy and safety of SGLT2i in pediatric patients and young adults with T2DM. Methods: We searched PubMed, Embase, Cochrane, and Web of Science for randomized controlled clinical trials on the efficacy and safety of SGLT2i in children, adolescents, and young adults with T2DM compared with placebo. Statistical analysis was performed using RevMan 5.4 and R statistical software 4.2.1. Heterogeneity was assessed with I2 statistics. Results: We included three studies totaling 334 patients followed for 37.79 weeks. Reduction in HbA1C (MD = −0.93; 95% CI = −1.36 to −0.49; p < 0.0001; I2 = 0%) was significantly higher in SGLT2i group compared with placebo. The proportion of patients requiring rescue or discontinuation of study medication due to lack of efficacy was statistically lower in SGLT2i group compared with placebo (RR = 0.64; 95% CI = 0.43–0.94; p = 0.02; I2 = 0%). SGLT2i and placebo were similar in terms of any adverse event (RR = 1.10; 95% CI = 0.96–1.27; p = 0.17; I2 = 0%), serious side effects (RR = 1.06; 95% CI = 0.44–2.57; p = 0.90; I2 = 0%), and individual adverse effects. Conclusion: In children, adolescents, and young adults with T2DM, SGLT2i appears to be effective and safe for glycemic control. [ABSTRACT FROM AUTHOR]

The article discusses the potential of empagliflozin, a drug used for type 2 diabetes, as a treatment for the syndrome of inappropriate antidiuresis (SIAD). Empagliflozin works by inducing glycosuria, leading to increased renal electrolyte-free water excretion. Studies have shown that empagliflozin can increase serum sodium levels in patients with SIAD, making it a promising treatment option. However, further research is needed to fully understand its efficacy and safety in different patient populations. [Extracted from the article]

Introduction: Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with reninangiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection. Methods: Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8 weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment. Results: Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice. Discussion: Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade. [ABSTRACT FROM AUTHOR]

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

Introduction: Kuwait has a large expatriate community who experience both restricted access to public health services and lower income than Kuwaiti citizens. Given these conditions, we examined differences in characteristics and management of chronic kidney disease (CKD) between Kuwaitis and expatriates. Methods: Clinical and laboratory data for adult CKD Stages 3–5 not on dialysis (CKD 3–5 ND) patients with native kidneys attending nephrology clinics in all Ministry of Health hospitals collected from January 1, 2022, to December 31, 2022. Cohort was then divided into Kuwaiti patients and expatriates patients for comparison. Results: We collected data from 2,610 patients (eGFR: 30.8 ml/min/1.73m2; age: 62.6 years; males: 56.7%; Kuwaitis: 62.1%). Kuwaitis were older (63.94 vs. 60.3 years, p < 0.001), with lower mean eGFR (30.4 vs. 31.5 ml/min/1.73m2, p = 0.052) than non-Kuwaitis, however, Kuwaitis had lower mean blood pressure (137.2/76.5 vs. 139.1/78.9 mmHg, p = 0.006), lower HbA1c in diabetics (7.59 vs. 7.82%, p = 0.010), and better lipid profile despite higher body mass indexes (29.6 vs. 28.9 kg/m2, p = 0.002). Both groups had high diabetes mellitus and hypertension rates. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were used in only 22.6% and renin-angiotensin-aldosterone system inhibitors (RAASi) in only 46.2%. Conclusion: CKD 3–5 ND is caused by diabetes mellitus in 56.6% of cases, and the majority have hypertension. In our study, non-Kuwaitis had higher eGFR; however, restricted public healthcare access and lower income can lead to an unhealthy diet and suboptimal care, which may cause higher blood pressure, higher HbA1c, and a higher dyslipidemia rate. RAASi and SGLT2i utilization must increase to combat CKD, and antihypertensive selection must improve. [ABSTRACT FROM AUTHOR]

Background and Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently become a standard treatment for heart failure and renal failure. The number of patients using these drugs is expected to increase further. However, no adverse drug event profiles have been published for the use of SGLT2i in patients without diabetes. To analyze and clarify the differences in adverse event profiles associated with the use of SGLT2i in patients with diabetes or heart failure using the Japanese Adverse Drug Event Report (JADER) database, a Japanese reporting system for adverse events. Methods: The JADER database, containing reports submitted between April 2004 and January 2024, was used. Our study focused on patients with diabetes or heart failure, analyzing adverse events associated with empagliflozin and dapagliflozin. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated for signal detection. Results: We identified risks of adverse drug events such as ketoacidosis, urinary tract infection, dehydration, and acidosis in both patient groups. However, the risks of cerebral infarction and ischemic heart disease were identified only in patients with diabetes, while risks of renal dysfunction, hypoglycemia, and sepsis were identified only in those with heart failure. Conclusion: Adverse events should be managed appropriately for patients using SGLT2i, as the adverse event profiles differ between those with diabetes and those with heart failure. Understanding these differences is crucial for improving patient safety and optimizing treatment outcomes. [ABSTRACT FROM AUTHOR]

The article focuses on the use of SGLT2 inhibitors in patients with HNF1A-MODY, a type of monogenic diabetes. Topics include the typical treatment regimen for HNF1A-MODY, the observed clinical outcomes from adding SGLT2 inhibitors to existing therapies, and the specific HNF1A genetic variants found in the study participants.

The use of SGLT2 inhibitors (SGLT2is) has been found in large clinical studies to slow the progression of chronic kidney disease (CKD) and to lower the risk of acute kidney injury (AKI). Recent reports suggest that SGLT2is may also reduce the likelihood of developing radiocontrast-associated nephropathy (CAN) following contrast-enhanced imaging and intravascular interventions. This review underscores potential pitfalls and confounders in these studies and calls for caution in adopting their conclusions regarding the safety and renoprotective potency of SGLT2is, in particular in patients at high risk, with advanced CKD and hemodynamic instability undergoing coronary intervention. This caution is particularly warranted since both SGLT2is and contrast media intensify medullary hypoxia in the already hypoxic diabetic kidney and their combination may lead to medullary hypoxic damage, a principal component of CAN. Further studies are needed to evaluate this dispute, particularly in patients at high risk, and to reveal whether SGLT2is indeed provide renal protection or are hazardous during contrast-enhanced imaging and vascular interventions. [ABSTRACT FROM AUTHOR]

Both sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes. This target trial emulation study compares the risk for dementia among older adults who use SGLT2 inhibitors and the GLP-1 RA dulaglutide. Visual Abstract. Sodium–Glucose Cotransporter-2 Inhibitors, Dulaglutide, and Risk for Dementia: Both sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes. This target trial emulation study compares the risk for dementia among older adults who use SGLT2 inhibitors and the GLP-1 RA dulaglutide. Background: Both sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain. Objective: To compare the risk for dementia between SGLT2 inhibitors and dulaglutide (a GLP-1 RA). Design: Target trial emulation study. Setting: Nationwide health care data of South Korea obtained from the National Health Insurance Service between 2010 and 2022. Patients: Patients aged 60 years or older who have T2D and are initiating treatment with SGLT2 inhibitors or dulaglutide. Measurements: The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year before the date of dementia diagnosis, assuming that the time between the onset of dementia and diagnosis was 1 year. The 5-year risk ratios and risk differences comparing SGLT2 inhibitors with dulaglutide were estimated in a 1:2 propensity score–matched cohort adjusted for confounders. Results: Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was −0.91 percentage point (95% CI, −2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16). Limitation: Residual confounding is possible; there was no adjustment for hemoglobin A 1c levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly. Conclusion: Under conventional statistical criteria, a risk for dementia between 2.5 percentage points lower and 0.6 percentage point greater for SGLT2 inhibitors than for dulaglutide was estimated to be highly compatible with the data from this study. However, whether these findings generalize to newer GLP-1 RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required. Primary Funding Source: Ministry of Food and Drug Safety of South Korea. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium‐glucose co‐transporter‐2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP‐1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow‐up of 6 months. Additionally, THP‐1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF‐α and IFN‐γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2‐related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM‐treated THP‐1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM‐treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression. [ABSTRACT FROM AUTHOR]

Aims: To provide an overview of the primary outcomes and key clinical implications of the CANVAS Program and CREDENCE trial, which were event‐driven, double‐blind randomized controlled trials that established the efficacy and safety of canagliflozin in those with type 2 diabetes (T2D) and high cardiovascular risk (CV) or albuminuric chronic kidney disease (CKD). Methods and Results: The CANVAS programme (CANVAS and CANVAS‐R trials) randomized 10 142 people with T2D and high CV risk to canagliflozin or placebo and followed them for a median of 126 weeks. The primary efficacy outcome was met, with canagliflozin treatment associated with a 14% reduction in major adverse CV events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.75 to 0.97; p < 0.001) as compared to placebo. The CREDENCE trial randomized 4401 individuals with T2D and albuminuric CKD to canagliflozin or placebo and followed them for 109 weeks. The CREDENCE trial also met its primary endpoint; canagliflozin treatment was associated with a 30% reduction in the composite of kidney failure, sustained doubling of serum creatinine level, or death from kidney or CV causes (HR 0.70, 95% CI 0.59 to 0.82; p < 0.001). Substantial reductions in hospitalization for heart failure (CANVAS: HR 0.67, 95% CI 0.52 to 0.87; CREDENCE: HR 0.61, 95% CI 0.47 to 0.80) and other key CV and kidney outcomes were also identified. Relative clinical benefits were consistent across subgroups defined by baseline age, sex, kidney function and history of CV disease but absolute benefits were greatest in those at highest baseline risk. Total serious adverse events were less common with canagliflozin treatment. Concerns about amputation and fracture risk observed in the CANVAS Program were not seen in CREDENCE and appear to have been spurious chance findings. Conclusion: Canagliflozin reduced important CV, kidney and mortality outcomes in those with T2D and high CV risk or CKD across diverse patient groups, with a good safety profile. Taken together with the other sodium‐glucose cotransporter‐2 inhibitor CV and renal outcomes trials, these landmark findings have changed the treatment landscape for patients worldwide. [ABSTRACT FROM AUTHOR]

Sodium‐glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio‐renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio‐renal diseases and SGLT2 inhibitors has been explored through landmark trials and real‐world evidence (RWE) studies, demonstrating significant reductions in cardio‐renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real‐world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio‐renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower‐limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio‐renal protective effects in real‐world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long‐term effects and safety profiles. [ABSTRACT FROM AUTHOR]

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

There has been concern over whether to use sodium-glucose-cotransporter-2 (SGLT-2) inhibitors in patients that use catheters due to the concern for increased urinary tract infections (UTIs). The concern is that patients who use catheters are already at an increased risk for UTIs and that SGLT-2-inhibitors may promote bacterial growth due their mechanism of action, ie. increasing glycosuria. The objective of this study was to evaluate whether using empagliflozin, a SGLT-2-inhibitor, in patients who also use catheters, increases their risks for UTIs. A retrospective chart review of electronic health records at a single-center was completed of all Veterans who received an empagliflozin prescription and were also using catheters between October 1, 2015 and September 30, 2022. Veterans were included if they were using catheters for at least 2 months prior to starting empagliflozin and were on both therapies for at least 2 months concurrently. The primary outcome for this study is the number of UTIs occurring prior to and after beginning empagliflozin treatment. Additional secondary outcomes included change in A1c, change in body mass index (BMI), UTI-hospitalizations, and fungal infections. Of the 91 patients with concurrent empagliflozin and catheter-use, only 25 Veterans were included. There was an occurrence of.09 UTIs/month pre-empagliflozin compared to.07 post-empagliflozin (P =.61). There was an observed trend in Veterans with Type 2 Diabetes having an increased rate of UTIs. There was no statistically significant difference found in UTI rates when comparing catheters alone to concurrent catheter and empagliflozin-use. [ABSTRACT FROM AUTHOR]

Aim: To investigate the clinical significance of body weight changes on kidney outcomes among individuals with diabetes using sodium–glucose cotransporter‐2 (SGLT2) inhibitors. Materials and Methods: This is a retrospective cohort study using a nationwide epidemiological database, and we conducted an analysis involving 11 569 individuals with diabetes who were newly prescribed SGLT2 inhibitors. The main outcome was the rate of decline in estimated glomerular filtration rate (eGFR), determined through a linear mixed‐effects model with an unstructured covariance structure. Results: The median age of the patients was 52 (Q1–Q3: 47–58) years, and the median fasting plasma glucose and glycated haemoglobin (HbA1c) levels were 144 (Q1–Q3: 124–175) mg/dL and 7.4 (Q1–Q3: 6.8–8.3)%, respectively. The median estimated eGFR was 77.7 (Q1–Q3: 67.2–89.1) mL/min/1.73 m2. The median follow‐up period was 1.7 (Q1–Q3: 1.0–2.6) years. Participants were stratified into three groups based on the body mass index change rate tertiles between baseline and 1 year after (tertile 1: <−4.55%, tertile 2: −4.55% to −1.43%, tertile 3: >−1.43%). The annual change in eGFR was −0.78 (−0.94 to −0.63) mL/min/1.73 m2 in tertile 1, −0.95 (−1.09 to −0.81) mL/min/1.73 m2 in tertile 2, and −1.65 mL/min/1.73 m2 (−1.84 to −1.47) in tertile 3 (pinteraction < 0.001). A variety of sensitivity analyses confirmed the relationship between the 1‐year body mass index decrease and favourable kidney outcomes after SGLT2 inhibitor administration. Conclusions: Our analysis of a nationwide epidemiological cohort revealed that kidney outcomes following the initiation of SGLT2 inhibitors would be more favourable, with greater body weight loss observed after the initiation of SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Aim: This nationwide cohort study evaluated the impact of sodium–glucose co‐transporter‐2 inhibitors (SGLT2i) on patients with type 2 diabetes mellitus (T2DM) after ischaemic stroke (IS), aiming to compare clinical outcomes between SGLT2i‐treated patients and those not receiving SGLT2i. Materials and Methods: Utilizing Taiwan's National Health Insurance Research Database, we identified 707 patients with T2DM treated with SGLT2i and 27 514 patients not treated with SGLT2i after an IS, respectively, from 1 May 2016 to 31 December 2019. Propensity score matching was applied to balance baseline characteristics. The follow‐up period extended from the index date (3 months after the index acute IS) until the independent occurrence of the study outcomes, 6 months after discontinuation of the index drug, or the end of the study period (31 December 2020), whichever came first. Results: After propensity score matching, compared with the non‐SGLT2i group (n = 2813), the SGLT2i group (n = 707) exhibited significantly lower recurrent IS rates (3.605% per year vs. 5.897% per year; hazard ratio: 0.55; 95% confidence interval: 0.34–0.88; p = 0.0131) and a significant reduction in all‐cause mortality (5.396% per year vs. 7.489% per year; hazard ratio: 0.58; 95% confidence interval: 0.39–0.85; p = 0.0058). No significant differences were observed in the rates of acute myocardial infarction, cardiovascular death, heart failure hospitalization, or lower limb amputation. Conclusions: Our findings indicate significantly lower risks of recurrent IS and all‐cause mortality among patients with T2DM receiving SGLT2i treatment. Further studies are required to validate these results and investigate the underlying mechanisms behind the observed effects. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%–48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA‐KIDNEY, DAPA‐CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA‐KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real‐world studies. International guidelines recommend first‐line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon‐like peptide‐1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin‐to‐creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under‐recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self‐testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High‐tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high‐risk individuals, self‐screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy. [ABSTRACT FROM AUTHOR]

Aim: Glucagon‐like peptide 1 receptor agonists (GLP1RA) and sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are both recommended for patients with diabetes, yet their effects on the development or progression of diabetic retinopathy (DR) are largely unknown. Methods: In this retrospective cohort study, data were collected from a nationwide database. Patients with diabetes who initiated treatment with a GLP1RA or SGLT2i between 1 May 2016 and 31 December 2017, were identified. Patients were divided into those with or without a previous diagnosis of DR and then categorized into the GLP1RA and the SGLT2i groups according to drug use. The primary outcome of interest in the DR group was the composite of new‐onset proliferative DR, vitreous haemorrhage and tractional retinal detachment (RD). In the non‐DR group, the primary outcome was the composite of newly diagnosed DR of any severity, vitreous haemorrhage and RD. Results: In total, 97 413 patients were identified. After matching, 1517 patients were treated with a GLP1RA and 3034 with an SGLT2i in the DR cohort. In the non‐DR cohort, 9549 initiated a GLP1RA and 19 098 initiated an SGLT2i. In patients with pre‐existing DR, the incidence of any DR progression event was significantly higher in the GLP1RA group than the SGLT2i group (subdistribution hazard ratio 1.50, 95% confidence interval 1.01‐2.23), primarily because of the increased risk of tractional RD. In patients without DR at baseline, the risks of all ocular outcomes were similar between the GLP1RA and SGLT2i groups. Conclusions: In patients with diabetes mellitus and established DR, GLP1RA treatment was associated with increased risks of DR progression compared with SGLT2i use. [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: Bone fragility is a critical issue in the treatment of elderly people with type 2 diabetes (T2D). In the Canagliflozin Cardiovascular Assessment Study, the subjects with T2D who were treated with canagliflozin showed a significant increase in fracture events compared to a placebo group as early as 12 weeks post-initiation. In addition, it has been unclear whether sodium-glucose co-transporter 2 (SGLT2) inhibitors promote bone fragility. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to prospectively evaluate the short-term effect of the SGLT2 inhibitor luseogliflozin on bone strength and microarchitecture in elderly people with T2D. Methods: This was a single-center, randomized, open-label, active-controlled pilot trial for ≥ 60-year-old Japanese individuals with T2D without osteoporosis. A total of 22 subjects (seven women and 15 men) were randomly assigned to a Lusefi group (added luseogliflozin 2.5 mg) or a control group (added metformin 500 mg) and treated for 48 weeks. We used the second-generation HR-pQCT (Xtreme CT II®, Scanco Medical, Brüttisellen, Switzerland) before and 48 weeks after the treatment to evaluate the subjects' bone microarchitecture and estimate their bone strength. Results: Twenty subjects (Lusefi group, n = 9; control group, n = 11) completed the study, with no fracture events. As the primary outcome, the 48-week changes in the bone strength (stiffness and failure load) estimated by micro-finite element analysis were not significantly different between the groups. As the secondary outcome, the changes in all of the cortical/trabecular microarchitectural parameters at the radius and tibia from baseline to 48 weeks were not significantly different between the groups. Conclusions: In the pilot trial, we observed no negative effect of 48-week luseogliflozin treatment on bone microarchitecture or bone strength in elderly people with T2D. Trial Registration: UMIN-CTR no. 000036202 and jRCT 071180061. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial pleiotropic effects, contributing to improved cardiovascular and renal outcomes for patients with and without diabetes. The impact of SGLT2is on arrhythmic burden remains largely unexplored through randomized trials. Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, we investigated the effects of ertugliflozin on arrhythmic burden among patients with heart failure with an ejection fraction less than 50%. All patients had an implantable cardioverter-defibrillator (ICD) with or without a cardiac resynchronization therapy device (CRT-D) and were randomized (1:1) to receive either ertugliflozin 5 mg once daily or placebo. The primary end point was the number of incident sustained (>30 seconds) ventricular tachycardia or ventricular fibrillation events from baseline to week 52. Secondary end points included the total number of non-sustained ventricular tachycardias, appropriate ICD therapies, changes in N-terminal pro-brain-type natriuretic peptide (NTproBNP) levels, and the number of heart failure hospitalizations. Results: Randomization was prematurely terminated, after class IA guideline recommendations were published for SGLT2is in patients with heart failure regardless of the ejection fraction. The final analysis included 46 patients (11% of the originally planned sample size). The yearly rate of the primary end point was 3.5 (95% confidence interval [CI] 2.8 to 4.4) with ertugliflozin compared with 13.3 with placebo (95% CI 11.8 to 14.8; rate ratio 0.16, 95% CI 0.04 to 0.61; P<0.001). There were no apparent differences in appropriate ICD therapies, hospitalizations, NTproBNP levels, or predefined adverse and serious adverse events. Conclusions: Ertugliflozin reduced sustained ventricular tachycardia or ventricular fibrillation events in adults with heart failure and an ICD compared with placebo; however, our trial ended early and thus results should be interpreted with caution. (Funded by Investigator-initiated Studies Program of Merck Sharp & Dohme Corp and Pfizer; EudraCT number, 2020-002581-14; ClinicalTrials.gov number NCT04600921.) [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]

Background: Polycystic ovarian syndrome (PCOS) has been a common metabolic and endocrinal disorder, prevalent amongst women belonging to the reproductive age group. The aim of this systematic review was to assess the safety and efficacy profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin, and Licogliflozin) for the treatment of women suffering from PCOS. Methods: A literature search in PubMed, Science Direct, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted for randomized clinical trials of SGLT-2 inhibitors in PCOS patients by applying predetermined inclusion and exclusion criteria. The articles in English language were included. Results: Four randomized controlled trials including 146 subjects were included in the review. The clinical studies indicated a significant decrease in the levels of total testosterone, free androgen index, total body fat, homeostasis model assessment-estimated insulin resistance (HOMA-IR), body mass index (BMI), dehydroepiandrosterone sulfate (DHEAS) and fasting plasma glucose (FPG). However, no significant difference was reported in levels of sex hormone-binding globulin (SHBG). Overall, there was improvement in metabolic and endocrine profiles, suggesting a potentially beneficial impact of SGLT2 inhibitors in the management of PCOS. Conclusion: There is a requirement for large extensive clinical trials to demonstrate the efficacy of SGLT-2 inhibitors in PCOS patients. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV). Methods: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico–medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI. Results: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: −0.20×10−3 mm2/s [95% CI −0.30, −0.10], p<0.001; empagliflozin: −0.15×10−3 mm2/s [95% CI −0.26, −0.04], p=0.01). No significant change was observed in the combination-therapy group (−0.05×10−3 mm2/s [95%CI −0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of −0.13×10−3 mm2/s (95% CI −0.22, −0.04; p=0.01). Compared with placebo, TKV decreased by −3% (95% CI −5%, −0.3%; p=0.04), −3% (95% CI −5%, −0.4%; p=0.02) and −5% (95% CI −8%, −2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c. Conclusions/interpretation: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis. Trial registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38 [ABSTRACT FROM AUTHOR]

Background: While Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective in managing diabetes and reducing cardiovascular risk, concerns about their association with lower limb complications, including, osteomyelitis, ulcers, and peripheral artery disease (PAD), persist. This study employs Mendelian Randomization (MR) to assess the causal relationship between SGLT2 inhibitors and these lower limb safety outcomes. Methods: A two-sample drug-target MR approach was used, complemented by a one-sample MR and genetic association analysis. Six SNPs were selected as instrumental variables to proxy the effect of SGLT2 inhibition. Primary outcomes were major limb safety outcomes, including osteomyelitis, lower limb ulcers, PAD, and cellulitis. The primary analytical method was the generalized inverse variance-weighted (IVW) approach, along with several sensitivity analyses. Results: The MR analysis indicated no significant causal association between genetically proxied SGLT2 inhibition and most of the studied lower limb safety outcomes. However, a significant association with PAD was observed, necessitating careful interpretation due to discrepancies between IVW and MR-Egger results. Sensitivity analyses supported these findings, showing little evidence of heterogeneity or directional pleiotropy. Conclusion: This study suggests that SGLT2 inhibitors may not be significantly associated with an increased risk of most lower limb safety outcomes, including osteomyelitis, lower limb ulcers, and cellulitis, in patients with type 2 diabetes. However, the complex relationship with PAD highlights the need for further research. These findings contribute to the understanding of the safety profile of SGLT2 inhibitors, supporting their continued use in diabetes management while underlining the importance of continuous safety monitoring. [ABSTRACT FROM AUTHOR]

This article discusses three different studies related to heart failure and valvular heart disease. The first study examines the use of intravenous ferric carboxymaltose (FCM) in patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency. The study found that FCM improved exercise capacity and had fewer serious adverse events compared to a placebo. However, the study was small and did not assess other symptoms or quality of life. The second study compares transcatheter aortic valve implantation (TAVI) with surgery in low-risk patients with aortic stenosis. The study found that the rate of death, stroke, or rehospitalization at one year was similar between the two treatments. However, TAVI had different risks and outcomes for patients with bicuspid aortic stenosis. The third study explores sex differences in severe native valvular heart disease. It found that women were older, more symptomatic, and had poorer concordance with recommended treatment compared to men. However, survival at six months was similar between men and women. Overall, these studies provide valuable insights into the treatment and management of heart failure and valvular heart disease, but further research is needed to fully understand their impact. [Extracted from the article]

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana. [ABSTRACT FROM AUTHOR]

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

Aim Materials and Methods Results Conclusions To assess the cost‐effectiveness of diabetic nephropathy treatment with sodium‐glucose cotransporter‐2 (SGLT2) inhibitors in Japanese clinical practice, considering diabetes‐related complications.A population‐based Monte Carlo simulation was used to estimate the cost‐effectiveness for people with diabetic nephropathy who initiated pharmacotherapy with an SGLT2 inhibitor plus conventional treatment or conventional treatment alone, based on quality‐adjusted life‐years (QALYs) and healthcare costs. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation study (CREDENCE) and the Japanese Society for Dialysis Research statistical survey were the primary sources of probability and mortality, while Japanese Health Insurance Claims Data were the cost source. The state transition model included diabetic nephropathy, hospitalization due to cardiovascular disease, dialysis, and death. One‐way and probabilistic sensitivity analyses were used to explore model uncertainty.Using the threshold of JPY 5 000 000 per QALY, SGLT2 inhibitor plus conventional treatment was more cost‐effective than conventional treatment alone, with an incremental cost‐effectiveness ratio of JPY 654 309 per QALY. Treating 100 000 people, SGLT2 inhibitor plus conventional treatment prevented 2234 deaths and reduced 5793 fewer heart failure cases, 3967 fewer myocardial infarctions and stroke events. Sensitivity analysis affirmed the robustness of these results for patients aged under 70 years.The SGLT2 inhibitor treatment appeared to be cost‐effective for the overall population of our study and particularly for younger patients (<70 years old). For older patients (≥70 years old), the cost‐effectiveness was less clear and may require further evaluation. Decision‐makers should consider this age‐based heterogeneity when making recommendations about SGLT2 inhibitor treatment. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is commonly found in persons living with HIV (PLWH) even when antiretroviral therapy suppresses HIV viremia. However, studying this condition has been challenging because an appropriate animal model is not available. In this article, we studied calcium transient in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in culture to simulate the cardiomyocyte relaxation defect noted in PLWH and HFpEF and assess whether various drugs have an effect. We show that treatment of hiPSC-CMs with inflammatory cytokines (such as interferon-γ or TNF-α) impairs their Ca2+ uptake into sarcoplasmic reticulum and that SGLT2 inhibitors, clinically proven as effective for HFpEF, reverse this effect. Additionally, treatment with mitochondrial antioxidants (like mito-Tempo) and certain antiretrovirals resulted in the reversal of the effects of these cytokines on calcium transient. Finally, incubation of hiPSC-CMs with serum from HIV patients with and without diastolic dysfunction did not alter their Ca2+-decay time, indicating that the exposure to the serum of these patients is not sufficient to induce the decrease in Ca2+ uptake in vitro. Together, our results indicate that hiPSC-CMs can be used as a model to study molecular mechanisms of inflammation-mediated abnormal cardiomyocyte relaxation and screen for potential new interventions. [ABSTRACT FROM AUTHOR]

Background: In 2019, coronavirus disease 2019 (COVID-19) emerged in China, spreading globally with significant impacts in Japan, including the Delta and Omicron variants. The research identified risk factors such as age, chronic diseases, and lifestyle choices, emphasizing the need for further study on the association between underlying health conditions, treatments, and COVID-19 severity in Japan. Methods: This study used a nationwide medical database to analyze the association between COVID-19 underlying conditions and pharmacological interventions to identify risk factors for disease severity. We examined the Japanese COVID-19 dataset from Medical Data Vision, selecting patients diagnosed with COVID-19 between January 2020 and December 2022. Logistic regression was used to calculate the odds ratios (ORs) for intensive care unit treatment- or ventilator use-related risk factors. Results: Among 650,317 patients (mean age: 52.1 ± 20.9 years; male individuals: 324,127; female individuals: 326,190), factors that significantly increased the severe disease risk (OR [95% confidence interval]) included age > 65 years (1.31 [1.27–1.36]), hypertension (1.34 [1.28–1.41]), cardiovascular disease (1.74 [1.67–1.81]), and use of beta-blockers (2.09 [2.00–2.17]), calcium blockers (1.97 [1.89–2.06]), angiotensin-converting enzyme inhibitors (1.41 [1.33–1.49]), low-dose aspirin (1.38 [1.32–1.45]), and insulin (7.14 [6.87–7.43]). Conversely, factors that reduced the severe disease risk included female sex and the use of sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor agonists, and alpha-glucosidase inhibitors. Conclusions: Patients using cardiovascular medications faced a higher risk, whereas those receiving diabetes treatment had a lower risk. Appropriate pharmacotherapy and risk factor identification can aid in the prevention of severe COVID-19. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Real‐world data show that guidelines are insufficiently implemented, and particularly guideline‐directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines.A 22‐question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non‐cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin‐converting enzyme inhibitors/angiotensin receptor–neprilysin inhibitor (ACEi/ARNi) (91.2%), beta‐blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium–glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1–3 months by 52%, 3–6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time‐to‐initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach.Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions To identify the prevalence of cardiovascular disease (CVD) and obesity in patients with type 2 diabetes (T2D) in Germany and to evaluate if antidiabetic treatment patterns varied by comorbidity status.Patients with T2D (aged ≥18 years) were identified during the study period (2014–2020) from medical claims of 4.5 million publicly insured German residents and divided into different cohorts based on CVD and/or obesity diagnosis. Annual prevalence and incidence were estimated for each study year, while characteristics and treatments were assessed in 2020. Data were extrapolated to the German population by age and sex.The prevalence of T2D in 2020 was 11.4%. Among patients with T2D, 53.0% had CVD, 39.3% had obesity, and 20.9% had CVD and obesity. Since 2014, CVD increased by 1.4%, obesity by 4.5%, and CVD with obesity by 2.7% in patients with T2D. The incidence of T2D in 2020 was 1.0% (42.9% had CVD, 37.9% had obesity, and 15.8% had CVD and obesity). Among the prevalent T2D population in 2020, 4.9% received glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), 9.7% received sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, and 13.0% received GLP‐1 RAs and/or SGLT2 inhibitors. Of those with CVD, 12.9% received GLP‐1 RAs and/or SGLT2 inhibitors (without CVD, 13.2%). Of those with obesity, 19.4% received GLP‐1RAs and/or SGLT2 inhibitors (without obesity, 9.0%).In this retrospective claims database study, more than two thirds of patients with T2D also had CVD, obesity, or both CVD and obesity. GLP‐1 RA and SGLT2 inhibitor use remained low. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Materials and Methods Results Conclusions Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co‐transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear.This multicenter, open‐label, randomized, parallel‐group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half‐life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure.At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time‐shift effect of the short half‐life tofogliflozin and salt restriction on urinary time.The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half‐life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most prevalent arrhythmia among adults worldwide, frequently co-occurring with comorbidities such as Heart Failure (HF) and Type 2 Diabetes Mellitus (T2DM). This association contributes to increased morbidity and mortality, elevated healthcare costs, and diminished quality of life. Consequently, preventing or delaying the onset and recurrence of AF is crucial for reducing the incidence of complications. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), due to their multifaceted pharmacological actions, have been proposed as potential therapeutic agents in the management of AF. However, current evidence from both animal models and clinical studies remains inconclusive. This narrative literature review aims to provide a comprehensive analysis of existing evidence on the impact of SGLT2is on the prevalence, incidence of new-onset, and recurrence of AF in diabetic populations and patients with HF. Numerous observational studies, predominantly retrospective, suggest a consistent reduction in AF risk with SGLT2is, while randomized controlled trials (RCTs) have yielded mixed results, with some demonstrating benefits and others not reaching statistical significance. The heterogeneity in study outcomes, population characteristics, follow-up duration, and specific SGLT2is used, as well as potential biases, underscore the need for further extensive and rigorous RCTs to establish definitive conclusions and elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]