Search

Cardiorenal syndrome (CRS) is a complex clinical disorder characterized by the interplay between heart and kidney dysfunction. This condition is exacerbated by comorbidities such as diabetes mellitus, which contribute to glucose-mediated oxidative stress, further complicating the management of CRS. The management of CRS has evolved with the discovery of sodium-glucose-cotransporter-2 (SGLT2) inhibitors, which have been established as effective agents in reducing hyperglycemia and demonstrated cardiorenal protective effects. Concurrently, intermittent fasting has gained attention as an intervention without pharmacological treatment for its metabolic benefits, including improved glucose metabolism and insulin regulation and sensitivity, both with a potential reduction in oxidative stress. This review provides a summary of current findings on the roles of SGLT2 inhibitors and intermittent fasting in managing CRS, with a particular focus on glucose-mediated oxidative stress. We evaluate the mechanisms by which these interventions exert their effects, identify gaps in current research, and offer recommendations for future studies. While both SGLT2 inhibitors and intermittent fasting demonstrate potential in managing CRS, more research is needed to elucidate their long-term efficacy, safety, and potential synergistic effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diabetes is a complex global healthcare burden involving multiple organ systems with its prevalence on the rise. SGLT2 inhibitors enhance glucose excretion. The objective of our literature review was to determine the association between cutaneous adverse drug reactions (CADRs) and the use of SGLT2 inhibitors. We collected data on CADRs related to the use of SGLT2 inhibitors from all available published articles and studied their details to understand the patterns of their association. PubMed, Cochrane, Google, and Embase were searched for relevant articles. A total of 37 papers were included and studied. Most articles were case reports followed by pharmacovigilance studies, case series, and reviews. The cutaneous findings ranged from benign eruptions to severe reactions. The available literature suggests a strong link between the use of SGLT2 inhibitors and Fournier's gangrene/necrotizing fasciitis. T2DM patients using SGLT2 inhibitors have also developed fixed drug eruptions, drug-induced pruritus, and Sweet syndrome/acute febrile neutrophilic dermatosis, among other skin lesions. We found that SGLT2 inhibitors present a risk of developing CADRs. Raising awareness among healthcare providers regarding CADRs to SGLT2 inhibitors can reduce complications, minimize hospitalizations, and improve patient care in the vulnerable population of diabetes patients. [ABSTRACT FROM AUTHOR]

Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes. [ABSTRACT FROM AUTHOR]

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

Background: Clinical trials demonstrating improved cardiovascular outcomes with SGLT2 inhibitors have often had limited representation from Black and Hispanic populations. While the mechanisms of action are not well known, ethnicity- or gender-based receptor physiology may render SGLT2 inhibitors a better agent in certain populations over others. Methods: A medical records query yielded diabetic patients initiated on SGLT2 inhibitors between 2013 and 2020. Patients with coronary artery disease, cardiac arrhythmias, and heart failure were excluded. Transthoracic echocardiographic studies (TTE) before and after starting SGLT2 inhibitors were analyzed, and post-processing left ventricular global longitudinal strain (LV GLS) analysis was also performed on each echocardiographic study. Univariate outliers and patients with missing data were excluded. Results: Among 94 patients with TTE (mean age 60.7 years; 68% Hispanics, 22.3% Blacks; median follow up of 7 months), there were significant improvements in the mean LV GLS (−15.3 vs. −16.5; p = 0.01), LV mass (LVM) (198.4 ± 59.6 g vs. 187.05 ± 50.6 g; p = 0.04), and LV mass index (LVMI) (100.6 ± 26.6 g/m2 vs. 94.3 ± 25.4 g/m2; p = 0.03) before and after initiating SGLT2 inhibitors but no significant change in the ratio (MV E/E') of peak early diastolic mitral flow velocity (E) and spectral pulsed-wave Doppler-derived early diastolic velocity from the septal mitral annulus (E') (12.5 ± 5.7 vs. 12.7 ± 4.8; p = 0.38). Changes in HbA1c (r2 = 0.82; p = 0.026), LVM (r2 = 0.20; p = 0.04), and LVMI (r2 = 0.20; p = 0.04) were found to be independently associated with changes in values of LV GLS on follow-up echocardiograms, when compared to the pre-medication LV GLS number. Conclusion: Non-White diabetic patients receiving SGLT2 inhibitors against a backdrop of other cardioprotective medications demonstrate significant improvements in LV remodeling and LV GLS, driven in part by an improvement in glycemic control. Large, prospective studies are needed to explore the differences in the therapeutic actions of SGLT2 inhibitors among different populations. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation. CKD is a leading global health burden that is asymptomatic in early stages but can ultimately cause kidney failure. Its etiology is complex and involves dysregulated signaling pathways that lead to fibrosis. Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury. While current therapies are limited, the search for more effective diagnostic and treatment modalities is intensive. Although biopsy with histology is the most accurate method of diagnosis and staging, imaging techniques such as diffusion-weighted magnetic resonance imaging and shear wave elastography ultrasound are less invasive ways to stage fibrosis. Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression. Newer antifibrotic agents that suppress the downstream inflammatory mediators involved in the fibrotic process are in clinical trials, and potential therapeutic targets that interfere with TGF-β signaling are being explored. Small interfering RNAs and stem cell-based therapeutics are also being evaluated. Further research and clinical studies are necessary in order to avoid dialysis and kidney transplantation. [ABSTRACT FROM AUTHOR]

(1) Background: Sodium–glucose co-transporter 2 inhibitors (SGLT2is) increase uric acid excretion. The intensity of uricosuria is linked to glycosuria. (2) Methods: We aim to analyze the effect of SGLT2 inhibitors on urinary fractional excretion (FE) of uric acid and glucose in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in a single-center retrospective study with patients with T2DM and CKD who started on treatment with SGLT2is. Patients on renal replacement therapy or with glucagon-like peptide-1 (GLP1) analogs were excluded. Subgroup analysis was performed according to the estimated glomerular filtration rate (eGFR), the SGLT2i molecule, the main comorbidities, and concomitant treatment. As a secondary objective, the study analyzed the effect of SGLT2 inhibitors on uricemia levels. (3) Results: Seventy-three patients were analyzed, with a mean follow-up of 1.2 years. Uric acid and glucose FE significantly increased after the initiation of SGLT2is. This increase remained stable during the follow-up without differences among eGFR groups. No significant reduction in uricemia was observed. However, a trend towards a decrease was observed. (4) Conclusion: The use of SGLT2is in patients with CKD and T2DM is associated with an increase in uric acid FE, which maintains stability irrespective of glomerular filtration loss at least during 24 months of follow-up. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and older adult individuals. DM may accelerate the aging process, and the age-related declines in the estimated glomerular filtration rate (eGFR) can pose a challenge to diagnosing diabetic kidney disease (DKD) using standard diagnostic criteria especially with the absence of severe albuminuria among older adults. In the presence of CKD and DM, older adult patients may need multidisciplinary care due to susceptibility to various health issues, e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to older adults. We review the evidence that the benefits from these newer therapies apply equally to older and younger patients with CKD and diabetes type 2 and propose a comprehensive management. This framework will address nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), sodium glucose co-transporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and glucagon like peptide 1 receptor agonists (GLP1-RAs). [ABSTRACT FROM AUTHOR]

Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients. [ABSTRACT FROM AUTHOR]

This review paper presents a review of the evolution of this disease throughout the centuries, describes and summarizes the pathophysiologic mechanisms, briefly discusses the mechanism of action of diuretics, presents their role in decongesting heart failure in patients, and reveals the data behind ultrafiltration in the management of acutely or chronically decompensated heart failure (ADHF), focusing on all the available data and advancements in this field. Acutely decompensated heart failure (ADHF) presents a critical clinical condition characterized by worsening symptoms and signs of heart failure, necessitating prompt intervention to alleviate congestion and improve cardiac function. Diuretics have traditionally been the mainstay for managing fluid overload in ADHF. Mounting evidence suggests that due to numerous causes, such as coexisting renal failure or chronic use of loop diuretics, an increasing rate of diuretic resistance is noticed and needs to be addressed. There has been a series of trials that combined diuretics of different categories without the expected results. Emerging evidence suggests that ultrafiltration may offer an alternative or adjunctive approach. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a common occurrence in patients with diabetes mellitus (DM), occurring in approximately 40% of cases. DM is also an important risk factor for cardiovascular disease (CVD), but CKD is an important mediator of this risk. Multiple CVD outcomes trials have revealed a greater risk for CVD events in patients with diabetes with CKD versus those without. Thus, reducing the risk of CKD in diabetes should result in improved CVD outcomes. To date, of blood pressure (BP) control, glycemic control, and inhibition of the renin-angiotensin system (RASI), glycemic control appears to have the best evidence for preventing CKD development. In established CKD, especially with albuminuria, RASI slows the progression of CKD. More recently, sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP1RA) have revolutionized the care of patients with diabetes with and without CKD. SGLT2i and GLP1RA have proven to reduce mortality, heart failure (HF) hospitalizations, and worsening CKD in patients with diabetes with and without existing CKD. The future of limiting CVD in diabetes and CKD is promising, and more evidence is forthcoming regarding combinations of evidence-based therapies to further minimize CVD events. [ABSTRACT FROM AUTHOR]

In the current modern era of unhealthy lifestyles, non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and has become a serious global health problem. To date, there is no approved pharmacotherapy for the treatment of NAFLD, and necessary lifestyle changes such as weight loss, diet, and exercise are usually not sufficient to manage this disease. Patients with type 2 diabetes mellitus (T2DM) have a significantly higher risk of developing NAFLD and vice versa. Sodium–glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that have recently been approved for two other indications: chronic kidney disease and heart failure in diabetics and non-diabetics. They are also emerging as promising new agents for NAFLD treatment, as they have shown beneficial effects on hepatic inflammation, steatosis, and fibrosis. Studies in animals have reported favorable effects of SGLT2 inhibitors, and studies in patients also found positive effects on body mass index (BMI), insulin resistance, glucose levels, liver enzymes, apoptosis, and transcription factors. There are some theories regarding how SGLT2 inhibitors affect the liver, but the exact mechanism is not yet fully understood. Therefore, biomarkers to evaluate underlying mechanisms of action of SGLT2 inhibitors on the liver have now been scrutinized to assess their potential as a future in-label therapy for NAFLD. In addition, finding suitable non-invasive biomarkers could be helpful in clinical practice for the early detection of NAFLD in patients. This is crucial for a positive disease outcome. The aim of this review is to provide an overview of the most recent findings on the effects of SGLT2 inhibitors on NAFLD biomarkers and the potential of SGLT2 inhibitors to successfully treat NAFLD. [ABSTRACT FROM AUTHOR]

Our aim was to evaluate osteomyelitis and other major lower limb safety outcomes (i.e., peripheral artery disease or PAD, ulcers, atraumatic fractures, amputations, symmetric polyneuropathy, and infections) in patients affected by type 2 diabetes mellitus (T2DM) and treated with sodium-glucose cotransporter 2 inhibitors (SGLT2-is). We thus performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing SGLT2-is at approved doses for T2DM with a placebo or standard of care. MEDLINE, Embase, and Cochrane CENTRAL were searched through August 2022. Separate intention-to-treat analyses were implemented for each molecule to calculate Mantel-Haenszel risk ratios (RRMH) with 95% confidence intervals (CIs) through a random-effects model. We processed data from 42 RCTs for a total of 29,491 and 23,052 patients, respectively assigned to SGLT2-i and comparator groups. SGLT2-is showed a pooled neutral effect on osteomyelitis, PAD, fractures, and symmetric polyneuropathy, whereas slightly deleterious sway on ulcers (RRMH 1.39 [1.01–1.91]), amputations (RRMH 1.27 [1.04–1.55]), and infections (RRMH 1.20 [1.02–1.40]). In conclusion, SGLT2-is appear to not significantly interfere with the onset of osteomyelitis, PAD, lower limb fractures, or symmetric polyneuropathy, even though the number of these events proved consistently higher in the investigational groups; otherwise, local ulcers, amputations, and overall infections may be favoured by their employment. This study is registered with the Open Science Framework (OSF). [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) is one of the main public health care problems worldwide. It is associated with a marked increased risk of developing atherosclerotic vascular disease, heart failure, chronic kidney disease and death. It is essential to act during the early phases of the disease, through the intensification of lifestyle changes and the prescription of those drugs that have been shown to reduce these complications, with the aim not only of achieving an adequate metabolic control, but also a comprehensive vascular risk control. In this consensus document, developed by the different specialists that treat these patients (endocrinologists, primary care physicians, internists, nephrologists and cardiologists), a more appropriate approach in the management of patients with T2DM or its complications is provided. A particular focus is given to the global control of cardiovascular risk factors, the inclusion of weight within the therapeutic objectives, the education of patients, the deprescription of those drugs without cardiovascular benefit, and the inclusion of GLP-1 receptor agonists and SGLT2 inhibitors as cardiovascular protective drugs, at the same level as statins, acetylsalicylic acid, or renin angiotensin system inhibitors. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare genetic disorder caused by a deficiency in the α-galactosidase A enzyme, which results in the globotriaosylceramide accumulation in many organs, including the kidneys. Nephropathy is a major FD complication that can progress to end-stage renal disease if not treated early. Although enzyme replacement therapy and chaperone therapy are effective, other treatments such as ACE inhibitors and angiotensin receptor blockers can also provide nephroprotective effects when renal damage is also established. Recently, SGLT2 inhibitors have been approved as innovative drugs for treating chronic kidney disease. Thus, we plan a multicenter observational prospective cohort study to assess the effect of Dapagliflozin, a SGLT2 inhibitor, in FD patients with chronic kidney disease (CKD) stages 1–3. The objectives are to evaluate the effect of Dapagliflozin primarily on albuminuria and secondarily on kidney disease progression and clinical FD stability. Thirdly, any association between SGT2i and cardiac pathology, exercise capacity, kidney and inflammatory biomarkers, quality of life, and psychosocial factors will also be evaluated. The inclusion criteria are age ≥ 18; CKD stages 1–3; and albuminuria despite stable treatment with ERT/Migalastat and ACEi/ARB. The exclusion criteria are immunosuppressive therapy, type 1 diabetes, eGFR < 30 mL/min/1.73 m2, and recurrent UTIs. Baseline, 12-month, and 24-month visits will be scheduled to collect demographic, clinical, biochemical, and urinary data. Additionally, an exercise capacity and psychosocial assessment will be performed. The study could provide new insights into using SGLT2 inhibitors for treating kidney manifestations in Fabry disease. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is associated with increased morbidity and mortality, especially from cardiovascular (CV) causes, and especially in people with diabetes mellitus (DM). Already the presence of DM increases CV risk and potentiates the risk of CKD. Therefore, besides glycemic control, prevention and treatment of CKD to slow its progression are of clinical importance. A significant nephroprotective effect of novel antidiabetic drugs, namely sodium-glucose cotransporter 2 inhibitors (SGLT2-I) and glucagon-like peptide 1 receptor agonists (GLP1-RA), has been shown on top of their glucose-lowering effects and was confirmed in cardiovascular outcome trials. GLP1-RA mainly reduced the risk of macroalbuminuria, whereas SGLT2-I were also associated with a lower risk of declining glomerular filtration rate (GFR) over time. The nephroprotective effects of SGLT2-I are also evident in people without DM. According to current guidelines, SGLT2-I and/or GLP1-RA are recommended for people with DM who have chronic kidney disease and/or increased cardiovascular risk. However, other antidiabetic drugs offer nephroprotective properties, which will also be discussed in this review. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to describe the rates of adverse clinical outcomes, including all-cause mortality, heart failure (HF) hospitalization, myocardial infarction, and stroke, in patients newly diagnosed with HF to provide a comprehensive picture of HF burden. Methods: This was a retrospective and observational study, using the BIG-PAC database in Spain. Adults, newly diagnosed with HF between January 2013 and September 2019 with ≥1 HF-free year of enrolment prior to HF diagnosis, were included. Results: A total of 19,961 patients were newly diagnosed with HF (43.5% with reduced ejection fraction (EF), 26.3% with preserved EF, 5.1% with mildly reduced EF, and 25.1% with unknown EF). The mean age was 69.7 ± 19.0 years; 53.8% were men; and 41.0% and 41.5% of patients were in the New York Heart Association functional classes II and III, respectively. The baseline HF treatments included beta-blockers (70.1%), renin–angiotensin system inhibitors (56.3%), mineralocorticoid receptor antagonists (11.8%), and SGLT2 inhibitors (8.9%). The post-index incidence rates of all-cause mortality, HF hospitalization, and both combined were 102.2 (95% CI 99.9–104.5), 123.1 (95% CI 120.5–125.7), and 182 (95% CI 178.9–185.1) per 1000 person-years, respectively. The rates of myocardial infarction and stroke were lower (26.2 [95% CI 25.1–27.4] and 19.8 [95% CI 18.8–20.8] per 1000 person-years, respectively). Conclusions: In Spain, patients newly diagnosed with HF have a high risk of clinical outcomes. Specifically, the rates of all-cause mortality and HF hospitalization are high and substantially greater than the rates of myocardial infarction and stroke. Given the burden of adverse outcomes, these should be considered targets in the comprehensive management of HF. There is much room for improving the proportion of patients receiving disease-modifying therapies. [ABSTRACT FROM AUTHOR]

Background: The impact of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in addition to optimal medical therapy (OMT) on the right ventricular (RV) systolic function using advanced echocardiographic analysis among outpatients with heart failure and a reduced ejection fraction (HFrEF) has thus far been poorly investigated. Methods: This was a single-center, prospective, single-blinded study in which an echocardiographic expert was blinded to the allocation of the treatment. A total of 36 outpatients with HFrEF were randomized to either OMT or OMT+SGLT2i. Both groups underwent an echocardiographic examination of the RV systolic function at the baseline and at the 3-month follow-up (3mFU). Results: The patients in both groups did not significantly differ with respect to the relevant baseline comorbidities, therapy, and clinical characteristics. The patients receiving OMT+SGLT2i showed a significant improvement from the baseline to the 3mFU in all the measured RV echocardiographic parameters, while for the OMT group, a significant improvement after the 3mFU was observed for TAPSE and s'. The mean percent change from the baseline to the 3mFU was significant when comparing OMT+SGLT2i to the OMT group concerning RV FWS (+91% vs. +28%, p = 0.039), TR maxPG (−27% vs. +19%, p = 0.005), and TR Vmax (−17% vs. +13%, p = 0.008), respectively. Conclusions: Adding SGLT2i to OMT in patients with HFrEF resulted in a greater improvement in the RV systolic function from the baseline to the 3mFU compared to the OMT alone. [ABSTRACT FROM AUTHOR]

Objective: To estimate the prevalence, incidence, and describe the characteristics and management of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain. Methods: Adults with ≥1 inpatient or outpatient HF diagnosis between 1 January 2013 and 30 September 2019 were identified through the BIG-PAC database. Annual incidence and prevalence by EF phenotype were estimated. Characteristics by EF phenotype were described in the 2016 and 2019 HF prevalent cohorts and outcomes in the 2016 HF prevalent cohort. Results: Overall, HF incidence and prevalence were 0.32/100 person-years and 2.34%, respectively, but increased every year. In 2019, 49.3% had HFrEF, 38.1% had HFpEF, and 4.3% had HFmrEF (in 8.3%, EF was not available). Compared with HFrEF, patients with HFpEF were largely female, older, and had more atrial fibrillation but less atherosclerotic cardiovascular disease. Among patients with HFrEF, 76.3% were taking renin-angiotensin system inhibitors, 69.5% beta-blockers, 36.8% aldosterone antagonists, 12.5% sacubitril/valsartan and 6.7% SGLT2 inhibitors. Patients with HFpEF and HFmrEF took fewer HF drugs compared to HFrEF. Overall, the event rates of HF hospitalization were 231.6/1000 person-years, which is more common in HFrEF patients. No clinically relevant differences were found in patients with HFpEF, regardless EF (50- < 60% vs. ≥60%). Conclusions: >2% of patients have HF, of which around 50% have HFrEF and 40% have HFpEF. The prevalence of HF is increasing over time. Clinical characteristics by EF phenotype are consistent with previous studies. The risk of outcomes, particularly HF hospitalization, remains high, likely related to insufficient HF treatment. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) and heart failure (HF) are two chronic disorders that affect millions worldwide. Hyperglycemia can induce excessive generation of highly reactive free radicals that promote oxidative stress and further exacerbate diabetes progression and its complications. Vascular dysfunction and damage to cellular proteins, membrane lipids and nucleic acids can stem from overproduction and/or insufficient removal of free radicals. The aim of this article is to review the literature regarding the use of antidiabetic drugs and their role in glycemic control in patients with heart failure and oxidative stress. Metformin exerts a minor benefit to these patients. Thiazolidinediones are not recommended in diabetic patients, as they increase the risk of HF. There is a lack of robust evidence on the use of meglinitides and acarbose. Insulin and dipeptidyl peptidase-4 (DPP-4) inhibitors may have a neutral cardiovascular effect on diabetic patients. The majority of current research focuses on sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. SGLT2 inhibitors induce positive cardiovascular effects in diabetic patients, leading to a reduction in cardiovascular mortality and HF hospitalization. GLP-1 receptor agonists may also be used in HF patients, but in the case of chronic kidney disease, SLGT2 inhibitors should be preferred. [ABSTRACT FROM AUTHOR]

Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD. [ABSTRACT FROM AUTHOR]

Inhibitors of sodium–glucose cotransporter 2 (SGLT2) have emerged as practice-changing treatments for patients with type 2 diabetes, reducing both the risk of cardiovascular events and kidney events. However, regarding the latter, caution is warranted, as these kidney endpoints are defined using glomerular filtration rate estimations based on creatinine, the non-enzymatic product of creatine residing in muscles. Creatinine-based estimations of the glomerular filtration rate are only valid if the treatment has no effect on changes in muscle mass over time. Yet, circumstantial evidence suggests that treatment with SGLT2 inhibitors does result in a loss of muscle mass, rendering serum creatinine-based kidney endpoints invalid. Currently, it cannot be excluded that the described renoprotective effect of SGLT2 inhibitors is in part or in whole the consequence of a loss of muscle mass. Post-hoc analyses of existing trials or new trials based on kidney function markers independent of muscle mass can provide more definitive answers on the proposed renoprotective effects of SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Sodium–glucose co-transporter 2 inhibitors (iSGLT2) have been linked to a considerable reduction in cardiovascular risk in patients with type 2 diabetes (T2D), but the precise molecular mechanisms are still elusive. We aimed to evaluate the effects of the iSGLT2 empagliflozin on systemic inflammation and its potential antioxidant properties. This is an observational, prospective follow-up study of a cohort of fifteen patients with T2D who received 10 mg/day of empagliflozin according to standard clinical care. Measures at baseline, 12 and 24 weeks were taken. Metabolic and anthropometric parameters were evaluated. Production of mitochondrial superoxide, glutathione content, and glutathione s-reductase and catalase mRNA levels were measured in leukocytes. Serum levels of myeloperoxidase, hs-CRP and IL-10 were determined. In addition to decreased body weight and reduced glucose and HbA1c levels, we observed a reduction in superoxide production in leukocytes of diabetic patients and increased glutathione content, prominently after 24 weeks of empagliflozin treatment. Leukocyte expression of glutathione s-reductase and catalase, and serum levels of IL-10 were enhanced at 24 weeks of empagliflozin treatment. Concomitantly, reduced hs-CRP and myeloperoxidase levels were seen. This study provides evidence of the antioxidant and anti-inflammatory properties of empagliflozin treatment in humans, which may contribute to its beneficial cardiovascular effects. [ABSTRACT FROM AUTHOR]

Precision medicine is a scientific and medical practice for personalized therapy based on patients' individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications. [ABSTRACT FROM AUTHOR]

Background: Guidelines differ with regard to indications for initial combination pharmacotherapy for type 2 diabetes. Aims: To compare the efficacy and safety of (i) sodium-glucose cotransporter 2 (SGLT2) inhibitor combination therapy in treatment-naïve type 2 diabetes adults; (ii) initial high and low dose SGLT2 inhibitor combination therapy. Methods: PubMed, Embase and Cochrane Library were searched for randomised controlled trials (RCTs) of initial SGLT2 combination therapy. Mean difference (MD) for changes from baseline (HbA1c, weight, blood pressure) after 24–26 weeks of treatment and relative risks (RR, safety) were calculated using a random-effects model. Risk of bias and quality of evidence was assessed. Results: In 4 RCTs (n = 3749) there was moderate quality evidence that SGLT2 inhibitor/metformin combination therapy resulted in a greater reduction in HbA1c (MD (95% CI); −0.55% (−0.67, −0.43)) and weight (−2.00 kg (−2.34, −1.66)) compared with metformin monotherapy, and a greater reduction in HbA1c (−0.59% (−0.72, −0.46)) and weight (−0.57 kg (−0.89, −0.25)) compared with SGLT2 inhibitor monotherapy. The high dose SGLT2 inhibitor/metformin combination resulted in a similar HbA1c but greater weight reduction; −0.47 kg (−0.88, −0.06) than the low dose combination therapy. The RR of genital infection with combination therapy was 2.22 (95% CI 1.33, 3.72) and 0.69 (95% CI 0.50, 0.96) compared with metformin and SGLT2 inhibitor monotherapy, respectively. The RR of diarrhoea was 2.23 (95% CI 1.46, 3.40) with combination therapy compared with SGLT2 inhibitor monotherapy. Conclusions: Initial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy. [ABSTRACT FROM AUTHOR]