SGLT2 Research Articles

Age-dependent effects of SGLT2 inhibitors on stroke risk in geriatric patients with diabetes and atrial fibrillation

BackgroundAtrial fibrillation (AF) and diabetes mellitus (DM) are associated with an increased risk of ischemic stroke, particularly in geriatric populations. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefits, but their effects on stroke risk may vary by age. This study aimed to explore the age-dependent effects of SGLT2i on stroke risk in patients with AF and DM.MethodsThis historical longitudinal follow-up cohort study included 9,669 patients with AF and DM from the National Taiwan University Hospital database (2010–2020). Patients were stratified into three age groups (< 75, 75–89, and ≥ 90 years) to compare SGLT2i users and non-users within each age group. Cox proportional hazards models were used to evaluate stroke risk, adjusting for CHA₂DS₂-VASc score and oral anticoagulant use. Interaction analysis assessed age-specific SGLT2i effects.ResultsIn patients aged < 75 years, SGLT2i use significantly reduced stroke risk (HR 0.63, 95% CI 0.44–0.88, P < 0.05). Stroke risk was neutral in patients aged 75–89 years (HR 0.95, 95% CI 0.60–1.50), but significantly increased in those aged ≥ 90 years (HR 5.04, 95% CI 1.20–21.1, P < 0.05). Interaction analysis confirmed a significant age-dependent effect (aged ≥ 90 years x SGLT2i use HR 6.39, 95% CI 1.49–27.40, P < 0.05).ConclusionsThe impact of SGLT2i on stroke risk varies significantly by age. While protective in younger patients, SGLT2i may increase stroke risk in those aged ≥ 90 years. These findings highlight the importance of age-specific considerations in prescribing SGLT2i for patients with AF and DM.Graphical

SGLT2 inhibition, circulating biomarkers, and Alzheimer's disease: A Mendelian randomization study.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors is a novel category of medications for diabetes, exhibiting neuroprotective potential. However, evidence regarding whether the use of SGLT2 inhibitors effectively reduces the risk of Alzheimer's disease (AD) remains unclear. Our study employed Mendelian randomization (MR) analysis to investigate potential causal relationships between SGLT2 inhibition, metabolites, and AD. In our research, we used a two-sample MR method to explore the link between SGLT2 inhibitor use and AD, addressing both its late-onset and early-onset forms. Furthermore, we executed a two-step MR analysis to explore how circulating metabolites, primarily endogenous in nature due to SGLT2 inhibition, mediate the relationship between SGLT2 inhibition and AD. The genetic instruments for SGLT2 inhibition were pinpointed through their association with SLC5A2 gene expression and the decreased glycated hemoglobin (HbA1c) levels. Genetic analysis indicated that SGLT2 inhibition, which effectively reduces HbA1c by enhancing renal glucose excretion and improving glycemic control, was associated with a lower likelihood of developing AD for every 1 SD decrease in HbA1c (OR = 0.48, [0.36, 0.63], p < 0.001). Our MR analysis revealed that SGLT2 inhibition significantly affected 27 of the 123 metabolites examined, adhering to a Bonferroni correction threshold (p < 4.06 × 10-4). Among these 27 significant metabolites, citrate was also associated with AD, showing a significant association (0.81 [0.79, 0.83], p < 0.001). The study provides strong evidence linking SGLT2 inhibition with a lower AD risk, highlighting citrate's potential mediating role for subsequent clinical research.

Comparative Effectiveness of Individual Sodium-Glucose Cotransporter 2 Inhibitors

Evidence on cardiovascular benefits and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors is mainly from placebo-controlled trials. Therefore, the comparative effectiveness and safety of individual SGLT-2 inhibitors remain unknown. To compare the use of canagliflozin or dapagliflozin with empagliflozin for a composite outcome (myocardial infarction [MI] or stroke), heart failure hospitalization, MI, stroke, all-cause death, and safety outcomes, including diabetic ketoacidosis (DKA), lower-limb amputation, bone fracture, severe urinary tract infection (UTI), and genital infection and whether effects differed by dosage or cardiovascular disease (CVD) history. This comparative effectiveness study using target trial emulation included adults with type 2 diabetes (T2D) using 3 US claims databases using data from August 2014 through June 2020. The study was conducted from August 2023 to July 2024, with a follow-up period of up to 8 years, and the analysis was completed in July 2024. First dispensing of canagliflozin, dapagliflozin, or empagliflozin without any use of SGLT-2 inhibitors during the prior 365 days. Database-specific models were weighted using propensity score matching-weights to adjust for 129 confounders. Hazard ratios and 95% CIs for outcomes were estimated using weighted Cox proportional hazards models. HRs were pooled across databases using a fixed-effect meta-analysis. : Across the databases, 232 890 patients receiving canagliflozin, 129 881 patients receiving dapagliflozin, and 295 043 patients receiving empagliflozin were identified. Compared with empagliflozin initiators, those receiving canagliflozin or dapagliflozin were less likely to have diabetes-related conditions or a history of CVD at baseline. For MI/stroke risk, both canagliflozin (HR, 0.98; 95% CI, 0.91-1.05) and dapagliflozin (HR, 0.95; 95% CI, 0.89-1.03) were comparable to empagliflozin. For heart failure hospitalization, dapagliflozin initiators had a higher risk (HR, 1.19; 95% CI, 1.02-1.39), particularly at the low dose of 5 mg (HR, 1.30; 95% CI, 1.12-1.50). These findings were consistent across subgroups of CVD history. For safety events, compared with empagliflozin, canagliflozin initiators had a lower risk of genital infections (HR, 0.94; 95% CI, 0.91-0.97) but a higher risk of severe UTIs (HR, 1.13; 95% CI, 1.03-1.24), and dapagliflozin initiators had lower risks of genital infections (HR, 0.92; 95% CI, 0.89-0.95) and DKA (HR, 0.78; 95% CI, 0.68-0.90). This study found that individual SGLT-2 inhibitors demonstrated comparable cardiovascular effectiveness at clinically effective doses, though low-dose dapagliflozin showed a reduced benefit for heart failure hospitalization compared with empagliflozin.

Impact of dapagliflozin on metabolic phenotype, hormone levels, and fertility in female mice after prolonged high-fat diet.

A long-term high-fat diet (HFD) cause obesity and infertility through hypothalamic inflammation and insulin resistance, leading to metabolic abnormalities and ovulation dysfunction. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a treatment for type 2 diabetic patients, regulating adipose tissue metabolism, hypothalamic inflammation, and ovulation in women with polycystic ovary syndrome (PCOS). The study aimed to investigate the pharmacological effects of dapagliflozin on improving insulin resistance, energy metabolism, sex hormones, and fertility in female mice following prolonged consumption of HFD. At 6 weeks of age, female mice were fed a HFD and treated with dapagliflozin. Serum hormone concentrations and inflammatory factors in mice aged 28 weeks or 38 weeks were quantified using ultrasensitive enzyme-linked immunosorbent assays (ELISAs). Metabolic parameters were also assessed and documented at different stages of the experiment. At 34 weeks of age, half of the experimental mice in each of the four groups fed with standard chow were mated with male mice. Pregnancy rate, abortion rate, pregnancy-related deaths, and perinatal outcomes were systematically recorded. After 16 weeks of HFD feeding, dapagliflozin significantly attenuated visceral fat deposition, weight gain, glucose intolerance, and insulin resistance induced by the diet. However, these effects diminished after 32 weeks. Unexpectedly, neither HFD nor dapagliflozin treatment elicited any significant changes in serum IL-6 and TNFα levels. Throughout the experiment period, dapagliflozin exhibited favorable effects on reproductive function along with insulin sensitivity and luteinizing hormone (LH) release from the pituitary gland. In conclusion, this study demonstrates that dapagliflozin alleviated HFD-induced reproductive dysfunction independently of obesity, peripheral tissue insulin resistance, and systemic inflammation, suggesting its potential as a promising treatment for diet-related ovulation disorders.

Safety and efficacy of early initiation of sodium-glucose co-transporter inhibitors 2 in patients hospitalized for acute heart failure: A meta-analysis of randomized controlled trials.

Data on the early use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with acute heart failure (HF) are conflicting, and mostly evaluating soft endpoints (i.e., indices of congestion, renal function, ejection fraction, and diuresis). The aim was to perform a meta-analysis of randomized controlled trials (RCTs) to assess their impact after an HF decompensation event. Two electronic databases were screened for eligible studies. Efficacy endpoints were all-cause death, cardiovascular death, HF hospitalization, length of hospital stay, and N-terminal pro-B-type natriuretic peptide (nt-proBNP). Safety endpoints included acute kidney injury (AKI), volume depletion, ketoacidosis, hypotension, hypoglycemia, non-cardiovascular death, urinary tract infection, genital infections, serious adverse events (AE), and AE leading to treatment discontinuation. Two pre-specified subgroup analyses were planned according to the specific SGLT2i and clinical setting [i.e., acute myocardial infarction (MI) versus non-acute MI]. 16 RCTs enrolling 15,073 patients were considered. Early initiation of SGLT2i significantly reduced the risk of HF hospitalizations [Risk ratio (RR) 0.79, 95 % Confidence interval (CI) 0.72-0.87], AKI (RR 0.76, 95 % CI 0.59-0.99), and nt-proBNP levels (MD -354 pg/mL). No significant difference was detected for any of the other endpoints. In the pre-specified subgroup analysis, a significant interaction was found between the SGLT2i type and the risk of AKI, in favor of empagliflozin. In patients recently hospitalized for acute HF, early administration of SGLT2i was associated with fewer readmissions for HF and AKI, as well as decongestant effects, without raising any safety concern.

Euglycemic Ketoacidosis in a non-diabetic patient: a rare adverse effect of sodium-glucose co-transporter type-2 inhibitors. A review based on a case report

Euglycemic Ketoacidosis in a non-diabetic patient: a rare adverse effect of sodium-glucose co-transporter type-2 inhibitors. A review based on a case report

The efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients aged over 80years with heart failure.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) have demonstrated effectiveness in reducing cardiovascular death and heart failure hospitalization (HFH). However, the efficacy and safety of SGLT2 inhibitors in elderly patients with poor general status, such as very low bodyweight or low nutritional status, who are not included in randomized controlled trials, has not yet been examined. In a real-world setting, the introduction of SGLT2 inhibitors to such elderly patients is a very difficult decision to make. We therefore examined the efficacy and safety of these drugs in elderly heart failure patients in a real-world setting. In Kokura Memorial Hospital, a retrospective study was conducted on 1559 patients over 80years old hospitalized for HF between 2018 and 2023. Among them, 1326 were included in the non-SGLT2i group and 233 in the SGLT2i group. A multivariate Cox regression model was used to compare the risk of primary composite outcome (all-cause death and HFH) and secondary safety composite outcome (ischaemic stroke, urinary tract infection and dehydration) at 1year post-discharge between the two groups. The cumulative 1year incidence of the composite outcome was significantly higher in the non-SGLT2i group (47.3% vs. 31.6%, P<0.01). SGLT2 inhibitors independently reduced the risk of all-cause death [adjusted hazard ratio (HR): 0.58, 95% confidence interval (CI): 0.39-0.87, P<0.01] and HFH (adjusted HR: 0.69, 95% CI: 0.52-0.91, P<0.01), whereas the risk of safety composite events was not increased (adjusted HR: 0.80, 95% CI: 0.49-1.29, P=0.36). Subgroup analysis showed no significant interactions between age, diabetes, body mass index, left ventricular ejection fraction, clinical frailty scale, geriatric nutritional risk index and SGLT2 inhibitors consistently reduced composite outcomes across all strata. Similarly, SGLT2 inhibitors did not increase safety composite outcomes at any strata. SGLT2 inhibitors reduce the risk of all-cause death and HFH without increasing adverse events, even in patients over 80years old. It may be that SGLT2 inhibitors are effective and safe in patients who are basically hesitant to be introduced to SGLT2 inhibitors, such as those with high frailty, low nutritional status or very low bodyweight.

Glomerular diameter is associated with a reduction in urinary protein by treatment with dapagliflozin in patients with chronic kidney disease.

Several clinical trials showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors have protective effects against chronic kidney disease (CKD) in both patients with and those without type 2 diabetes mellitus. Since one of the renoprotective mechanisms of SGLT2 inhibitors is thought to be amelioration of glomerular hyperfiltration, we hypothesized that an enlarged glomerular diameter, which suggests increased single-nephron glomerular filtration rate, is associated with a reduction in urinary protein after treatment with an SGLT2 inhibitor. This study was a retrospective multicentered study including 28 adult patients with CKD who underwent kidney biopsy and were then treated with dapagliflozin, an SGLT2 inhibitor. The association of glomerular diameter with changes in urinary protein 4-8 weeks after the initiation of treatment with dapagliflozin was investigated. Maximum glomerular diameter was significantly and positively correlated with change in urinary protein-to-creatinine ratio (UPCR) (R2 = 0.44; P < 0.001). Maximum glomerular diameter was significantly larger in patients who achieved ≥ 30% reduction in UPCR after the initiation of treatment with dapagliflozin than in patients who achieved < 30% reduction in UPCR (219.4 ± 23.9 vs. 188.0 ± 29.0; P = 0.005). After adjustment of age, sex and estimated glomerular filtration rate, maximum glomerular diameter was independently associated with change in UPCR (β = 0.645, P < 0.001). Furthermore, maximum glomerular diameter was independently associated with ≥ 30% reduction in UPCR (odds ratio: 1.07, 95% confidential interval: 1.01-1.14). Glomerular diameter is independently associated with an early change in UPCR after the initiation of treatment with dapagliflozin in patients with CKD.

Dapagliflozin increased pancreatic beta cell proliferation and insulinogenic index in mice fed a high-fat and high-sodium chloride diet.

People in Eastern Asia, including Japan, traditionally consume higher amounts of sodium chloride than in the United States and Western Europe, and it is common knowledge that impaired insulin secretion-rather than insulin resistance-is highly prevalent in Asian people who have diabetes mellitus. We previously reported that mice fed a high-fat and high-sodium chloride (HFHS) diet had a relatively lower degree of obesity than mice fed a high-fat diet, but had a comparatively impaired insulin secretion. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to dampen down the sympathetic nervous system, which reportedly is activated by a high-sodium chloride diet. In this study, we examined the effects of dapagliflozin, a SGLT2 inhibitor, on glucose metabolism and insulin secretion in mice fed a HFHS diet. C57BL6/J mice were fed a HFHS diet for 6 weeks and subsequently divided into two treatment groups fed: (1) a HFHS diet mixed with dapagliflozin for up to 3 weeks (HFHS+Da) and (2) a HFHS diet without dapagliflozin (HFHS). Dapagliflozin improved glucose tolerance and the insulinogenic index accompanied by increased pancreatic beta cell proliferation. Furthermore, dapagliflozin decreased both the tyrosine hydroxylase-positive area in pancreatic islets and catecholamine excretion in urine. Our results suggest that dapagliflozin improved insulin secretion by suppressing sympathetic nerve activation in mice fed a HFHS diet.

Mapping the effectiveness and risks of GLP-1 receptor agonists.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. However, their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. Here, we used the US Department of Veterans Affairs databases to build a cohort of people with diabetes who initiated GLP-1RA (n = 215,970) and compared them to those who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989) or sodium-glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a control group composed of an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors (n = 536,068), and a control group of 1,203,097 individuals who continued use of non-GLP-1RA antihyperglycemics (usual care). We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes. Compared to usual care, GLP-1RA use was associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. There was an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis and drug-induced pancreatitis associated with GLP-1RA use compared to usual care. The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.

Dapagliflozin modulates hepatic lipid metabolism through the proprotein convertase subtilisin/kexin type 9/low density lipoprotein receptor pathway.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly secreted by the liver, and plays a crucial role in lipid metabolism disorder. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) can regulate lipid metabolism through various pathways, including reducing visceral fat accumulation, modulating serum lipoprotein levels and alleviating hepatic steatosis. However, the specific regulatory mechanisms remain unclear. We built a model of glucose and lipid metabolism disorder in vivo and in vitro, and explored the regulatory mechanism of dapagliflozin in regulating liver lipid metabolism. We found that the SGLT2i dapagliflozin significantly reduced serum levels of PCSK9, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice, while also improving hepatic steatosis. In vitro studies confirmed that dapagliflozin increased LDL receptor (LDLR) expression in HepG2 cells, enhancing their ability to uptake LDL-C. Further mechanistic studies revealed that the hepatocyte nuclear factor-1-alpha (HNF1α)/PCSK9/LDLR signalling pathway may be involved in dapagliflozin's regulation of lipid metabolism homeostasis.

Dapagliflozin attenuates skeletal muscle atrophy in diabetic nephropathy mice through suppressing Gasdermin D-mediated pyroptosis.

Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear. The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits. Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin. Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.

Utilization Trends of Glucose-Lowering Medications Among Adult Kidney Transplant Recipients with Type 2 Diabetes in the United States.

Background: To date, there are limited studies describing the use of glucose-lowering medications (GLMs) in adult kidney transplant recipients (KTRs), and the uptake of sodium glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP1RAs). Thus, we aimed to evaluate the use of GLMs, including SGLT2i and GLP1RA, among adult KTRs with type 2 diabetes (T2D). Methods: This is an ecologic study of adult KTR with T2D. Data were sourced from two large U.S. health insurance claim databases from 2014 to 2023. The proportions of any user and incident use of GLMs were reported in percentage. Any use of GLM was defined through prescription claims, and incident use was further defined as the absence of any prior dispensing within the preceding 365 days. Results: From 2014 to 2023, we identified 33,913 adult KTRs with T2D who were prescribed any GLMs. Any use of SGLT2i and GLP1RA increased throughout the study period (0.4% to 14.4% for SGLT2i, and 2.8% to 12.5% for GLP1RA). While insulin was the most frequently used GLM, ranging from 58% to 74%, the usage gradually declined over time. By 2023, SGLT2i and GLP1RA were initiated nearly as frequently as insulin (5.1% for SGLT2i, 5.7% for GLP1RA, and 5.7% for insulin). Compared with insulin initiators, SGLT2i initiators (n = 1009) had a higher prevalence of cardiovascular comorbidities and proteinuria, while GLP1RA initiators (n = 2149) had a higher prevalence of obesity. Conclusions: Any use of both SGLT2i and GLP1RA among KTRs with T2D increased over time with the incident use of SGLT2i and GLP1RA as high as insulin by 2023. Our findings emphasize the need for the effectiveness and safety analysis of SGLT2i and GLP1RA among KTRs with T2D.

Animal experiments and network pharmacology to explore the anti-inflammatory mechanism of dapagliflozin in the treatment of polycystic ovary syndrome

Background Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder associated with chronic low-grade inflammation of the ovary. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a class of antidiabetic drugs that can reduce the weight and hyperglycemia of type 2 diabetes patients. Dapagliflozin is a highly selective, orally active and reversible inhibitor of the human SGLT2. However, the role of dapagliflozin in regulating PCOS remains unclear. Methods In this study, 24 six-week-old female Sprague Dawley (SD) rats were randomly divided into control, letrozole, and letrozole + dapagliflozin groups. PCOS model rats were produced by gavage administration of letrozole for 21 days. The intervention was conducted after the gavage administration of dapagliflozin for 14 days to evaluate the estrous cycle and ovarian imaging changes of the rats in each group. We observed changes in the weight, ovarian weight, and ovarian morphology of the rats in each group. Pathological changes in the ovaries were examined by H&E staining, changes in ovarian tissue cell apoptosis were identified using TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and changes in inflammation-related factors were detected using immunohistochemistry and Western blotting analysis. Network pharmacology was used to predict the inflammatory targets and pathways affected by dapagliflozin in treating PCOS, and the potential interactions between dapagliflozin and inflammation-related target proteins were evaluated through molecular docking. Results Our results demonstrated that dapagliflozin treatment significantly improved PCOS symptoms, recovered ovarian morphology and physiological functions, and reduced the apoptosis of ovarian cells after drug intervention. Dapagliflozin treatment also reduced the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, indicating its anti-inflammatory properties. Furthermore, network pharmacology identified 26 intersecting target genes relevant to inflammation in PCOS, with subsequent molecular docking simulations revealing strong binding affinities of dapagliflozin to key targets, including AKT1 and TP53. Conclusions These findings suggest that dapagliflozin exerts beneficial effects on PCOS by ameliorating ovarian dysfunction and reducing inflammation. Dapagliflozin represents a promising therapeutic candidate for managing PCOS, warranting further clinical investigation to explore its full potential in treating this multifaceted disorder.

Pharmacologic Management of Heart Failure with Preserved Ejection Fraction (HFpEF) in Older Adults.

There are several pharmacologic agents that have been touted as guideline-directed medical therapy for heart failure with preserved ejection fraction (HFpEF). However, it is important to recognize that older adults with HFpEF also contend with an increased risk for adverse effects from medications due to age-related changes in pharmacokinetics and pharmacodynamics of medications, as well as the concurrence of geriatric conditions such as polypharmacy and frailty. With this review, we discuss the underlying evidence for the benefits of various treatments in HFpEF and incorporate key considerations for older adults, a subpopulation that may be at higher risk for adverse drug events. Key considerations for older adults include: the use of loop diuretics, mineralocorticoid receptor antagonists (MRAs), and sodium glucose co-transporter-2 (SGLT2) inhibitors for most; angiotensin receptor blockers/ angiotensin receptor-neprilysin inhibitors (ARB/ARNIs) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) as add-on therapies for some, though risk of geriatric conditions such as falls, malnutrition, and/or sarcopenia must be considered; and beta blockers for a smaller subset of patients (with consideration of deprescribing for some, though data are lacking on this approach). Naturally, when making clinical decisions for older adults with cardiovascular disease, it is critical to consider the complexity of their conditions, including cognitive and physical function and social and environmental factors, and ensure alignment of care plans with the patient's health goals and priorities.

Novel Therapies for Right Ventricular Failure.

Traditionally viewed as a passive player in circulation, the right ventricle (RV) has become a pivotal force in hemodynamics. RV failure (RVF) is a recognized complication of primary cardiac and pulmonary vascular disorders and is associated with a poor prognosis. Unlike treatments for left ventricular failure (LVF), strategies such as adrenoceptor signaling inhibition and renin-angiotensin system modulation have shown limited success in RVF. This review aims to reassure about the progress in RVF treatment by exploring the potential of contemporary therapies for heart failure, including angiotensin receptor andneprilysin inhibitors, sodium-glucose co-transporter 2 inhibitors, and soluble guanylate cyclase stimulators, which may be beneficial for treating RV failure, particularly when associated with left heart failure. Additionally, it examines novel therapies currently in the pipeline. Over the past decade, a new wave of RVF therapies has emerged, both pharmacological and device-centered. Novel pharmacological interventions targeting metabolism, calcium homeostasis, oxidative stress, extracellular matrix remodeling, endothelial function, and inflammation have shown significant promise in preclinical studies. There is also a burgeoning interest in the potential of epigenetic modifications as therapeutic targets for RVF. Undoubtedly, a deeper understanding of the mechanisms underlying RV failure, both with and without pulmonary hypertension, is urgently needed. This knowledge is not just a theoretical pursuit, but a crucial step that could lead to the development of pharmacological and cell-based therapeutic options that directly target the RV and pulmonary vasculature, aligning with the principles of precision medicine.

Long-term hemodynamic responses and reverse remodeling after pharmacotherapy in HFpEF versus HFrEF: a systematic review and meta-analysis.

Aims: The acute response to therapeutic afterload reduction differs between heart failure with preserved (HFpEF) versus reduced ejection fraction (HFrEF), with larger left ventricular (LV) stroke work augmentation in HFrEF compared to HFpEF. This may (partially) explain the neutral effect of HFrEF-medication in HFpEF. It is unclear whether such differences in hemodynamic response persist and/or differentially trigger reverse remodeling in case of long-term afterload reduction. Methods and results: A systematic search was performed, identifying 21 clinical trials investigating renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers and sodium-glucose cotransport 2 inhibitors that report data on afterload reduction, stroke volume and reverse remodeling in HFpEF and/or HFrEF. In both HFpEF and HFrEF, meta-analyses revealed limited long-term change in systolic/diastolic blood pressure (-5.6/-3.2 and -4.6/-1.4 mmHg, respectively) and LV afterload reduction (arterial elastance: -0.039 and -0.055 mmHg/mL, respectively). Long-term treatment did not result in increase in stroke volume, with the exception of beta-blockers in HFrEF. Indexed LV mass decreased slightly in both HFpEF and HFrEF (-2.8 and -2.3 g/m2, respectively). In HFrEF, treatment reduced LV end-diastolic and end-systolic volume (-8 and -6 ml, respectively), whereas in HFpEF there was no relevant change. Conclusion: Contrary to acute heart failure studies, long-term afterload reduction had little effect on blood pressure and stroke volume augmentation in both HFpEF and HFrEF. On the other hand, reverse remodeling was clearly present in HFrEF, but was essentially absent in HFpEF.

Sodium-glucose cotransporter-2 inhibitors in cardiovascular disease: a gaseous solution

Sodium-glucose cotransporter-2 inhibitors in cardiovascular disease: a gaseous solution

Post-hoc analysis of the tofogliflozin post-marketing surveillance study (J-STEP/LT): Tofogliflozin improves liver function in type 2 diabetes patients regardless of BMI.

Patients with type 2 diabetes are at high risk of developing steatotic liver disease (SLD). Weight loss has proven effective in treating metabolic dysfunction-associated steatotic liver disease (MASLD) in obese patients with type 2 diabetes, with sodium-glucose cotransporter 2 (SGLT2) inhibitors showing promising results. However, lean MASLD is more prevalent in Japan, necessitating alternative approaches to body weight reduction. We used the J-STEP/LT dataset including up to 3-year treatment data to analyze the effects of the SGLT2 inhibitor tofogliflozin on liver function and treatment safety and conducted a subgroup analysis based on body mass index (BMI; kg/m2, <20, 20-<23, 23-<25, 25-<30, and ≥30). This study included 4,208 participants. Tofogliflozin significantly reduced alanine aminotransferase (ALT) levels in participants with baseline ALT levels >30 U/L across all BMI groups, with median changes of -12, -16, -13, -15, and -15 U/L, respectively (P = 0.9291 for trends). However, median changes in body weight with tofogliflozin were -2.00, -2.75, -2.00, -3.00, and -3.80 kg, respectively (P < 0.0001 for trends), with no significant weight loss observed in the BMI <20 group. ALT levels were also significantly decreased in participants who did not lose weight. Safety assessments according to BMI and age categories revealed no clear differences in the frequency of adverse events. Tofogliflozin reduced ALT levels without substantial body weight reduction among lean participants. These findings suggest that SGLT2 inhibitors may be a viable treatment option for non-obese patients with type 2 diabetes and SLD.

Metabolomic Analysis of the Effects of Canagliflozin on HFpEF Rats and Its Underlying Mechanism.

Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF. We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions. Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content. Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.