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PURPOSE: Data are limited on sodium glucose co-transport 2 inhibitors (SGLT2-is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among real-world cohorts of underrepresented patients. We examined these therapies and glycemic control in US adults with diabetes mellitus (DM) by atherosclerotic cardiovascular disease (ASCVD) risk and sociodemographic factors. METHODS: In the NIH Precision Medicine Initiative All of Us Research Program, we categorized DM as (1) moderate risk, (2) high risk, and (3) with ASCVD. We examined proportions on DM therapies, including SGLT2-i or GLP-1 RA, and at glycemic control by sociodemographic factors and CVD risk groups. RESULTS: Our 81,332 adults aged ≥ 18 years with DM across 340 US sites included 22.3% non-Hispanic Black, 17.2% Hispanic, and 1.8% Asian participants; 31.1%, 30.3%, and 38.6% were at moderate risk, high risk, or with ASCVD, respectively. Those with DM and ASCVD were most likely on SGLT2-i (8.6%) or GLP-1 RA (11.9%). SGLT2-i use was

The results of large cardiovascular studies indicate that SGLT-2 inhibitors may increase the risk of leg amputations. This study aims to investigate whether dapagliflozin therapy affects peripheral vascular oxygenation, i.e., microcirculation in the foot, as measured by transcutaneous oxygen pressure (TcPO2) in patients with type 2 diabetes (T2DM) and peripheral arterial disease (PAD) compared to patients without PAD. The patients with PAD were randomized into two groups. In the first 35 patients with PAD, dapagliflozin was added to the therapy; in the other 26 patients with PAD, other antidiabetic drugs were added to the therapy. Dapagliflozin was added to the therapy in all patients without PAD. TcPO2 measurement, Ankle Brachial Index (ABI), anthropometric measurements, and laboratory tests were performed. After a follow-up period of 119.35 days, there was no statistically significant difference in the reduction of mean TcPO2 values between the group with T2DM with PAD treated with dapagliflozin and the group with T2DM with PAD treated with other antidiabetic drugs (3.88 mm Hg, SD = 15.13 vs. 1.48 mm Hg, SD = 11.55, p = 0.106). Patients with control TcPO2 findings suggestive of hypoxia (TcPO2 < 40 mm Hg) who were treated with dapagliflozin had a clinically significant decrease in mean TcPO2 of 10 mm Hg or more (15.8 mm Hg and 12.90 mm Hg). However, the aforementioned decrease in TcPO2 was not statistically significantly different from the decrease in TcPO2 in the group with PAD treated with other diabetic medications (p = 0.226, p = 0.094). Based on the available data, dapagliflozin appears to affect tissue oxygenation in T2DM with PAD. However, studies with a larger number of patients and a longer follow-up period are needed to determine the extent and significance of this effect. [ABSTRACT FROM AUTHOR]

Background and aims: Increases in both the prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity are closely related. Type 2 diabetes (T2DM) has been associated with metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis and hepatocellular carcinoma. Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of T2DM and has an important role in weight loss. Also, it may represent a new therapeutic option for the treatment of MASH in obese diabetic patients. The main outcomes were changes from baseline in liver steatosis and fibrosis at week 24. Material and methods: A total of one hundred eighty-seven patients with T2DM were eligible for this prospective study; ninety-five subjects were treated with oral semaglutide, and ninety-two patients were treated with dapagliflozin as an add-on to metformin. All the subjects were evaluated using Vibration Controlled Transient Elastography (VCTE) from June to December 2022. Results: From our cohort, 54% of the patients were females, with a mean age of 59.92 ± 11.89 years and a mean body mass index (BMI) of 29.53 ± 5.33 kg/m2. Following a six-month medication period, we observed a substantial reduction in anthropometric measurements, including the BMI, waist circumference (WC), and waist-to-hip ratio (WtHr), in both groups. Regarding HbA1c, a notable decrease was observed in the semaglutide group (p < 0.001) when compared to the dapagliflozin group (p = 0.011). In addition, the liver stiffness measurement (LSM) according to VCTE improved significantly in the semaglutide group participants from 8.07 ± 2.90 kPa at baseline to 6.51 ± 3.09 kPa after medication (p < 0.001). Conclusion: The superior metabolic effects of semaglutide, correlated to dapagliflozin, may contribute to a more efficient decrease in hepatic stress and injury, leading to a substantial enhancement of liver function in T2DM patients. Further investigations conducted over an ideal timeframe are necessary to confirm the evidence presented in this study. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: A precision medicine approach in type 2 diabetes could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the recently developed Bayesian causal forest (BCF) method to develop and validate an individualised treatment selection algorithm for two major type 2 diabetes drug classes, sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA). Methods: We designed a predictive algorithm using BCF to estimate individual-level conditional average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA, based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England (Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2252 people with type 2 diabetes from Scotland (SCI-Diabetes [Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were replicated in clinical trial data (HARMONY programme: liraglutide [n=389] and albiglutide [n=1682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on glycaemic response on weight change, tolerability and longer-term risk of new-onset microvascular complications, macrovascular complications and adverse kidney events. Results: Model development identified marked heterogeneity in glycaemic response, with 4787 (17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>0.3%) with SGLT2i over GLP1-RA and 5551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1-RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an independent Scottish dataset identified clear differences in glycaemic outcomes between those predicted to benefit from each therapy. Sex, with women markedly more responsive to GLP1-RA, was identified as a major treatment effect modifier in both the UK observational datasets and in clinical trial data: HARMONY-7 liraglutide (GLP1-RA): 4.4 mmol/mol (95% credible interval [95% CrI] 2.2, 6.3) (0.4% [95% CrI 0.2, 0.6]) greater response in women than men. Targeting the two therapies based on predicted glycaemic response was also associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications. Conclusions/interpretation: Precision medicine approaches can facilitate effective individualised treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical features for treatment selection could support low-cost deployment in many countries. [ABSTRACT FROM AUTHOR]

Introduction and objective Obesity poses a significant public health challenge due to its association with an elevated risk of various chronic diseases, including cardiovascular conditions, type 2 diabetes, and overall mortality. While lifestyle modifications such as dietary changes and increased physical activity remain cornerstone interventions in obesity management, pharmacological treatments have emerged as an adjunctive approach to address this complex condition. The review aims to compare the effectiveness of current pharmacotherapy and show upcoming methods of treatment of obesity. Review methods The review was conducted by searching scientific publications in PubMed, Google Scholar, Clinicaltrials.gov, Summaries of Product Characteristics, URPL, FDA, and EMA databases. The articles on medications available in Poland for treating obesity and the latest clinical trials of upcoming drugs were analyzed, followed by a concise review of the collected data. Abbreviated description of the state of knowledge Currently, in the Polish market, medications available for obesity treatment include orlistat, the combination of naltrexone and bupropion, liraglutide, tirzepatide, and available as part of the target import - semaglutide. Promising clinical trials are being conducted on further medications for weight reduction, including retatrutide, orforglipron, cagrilintide, and amycretin. Regrettably, new and effective medications due to their high cost and insufficient funding. Summary New pharmacotherapy options for obesity, particularly anti-diabetic medications, are rapidly advancing. Glucagon-like peptide-1 (GLP-1) analogs have shown promising results in weight reduction, surpassing previous medications such as orlistat or naltrexone. Recent drugs offer weight loss ranging up to 25%. More studies are underway on novel and increasingly effective medications.

(1) Background: This single-center retrospective study aimed to evaluate whether sodium–glucose cotransporter-2 inhibitors (SGLT2-i) therapy may have a nephroprotective effect to prevent contrast-induced acute kidney injury (CI-AKI) in patients with heart failure (HF) undergoing iodinated contrast medium (ICM) invasive procedures. (2) Methods: The population was stratified into SGLT2-i users and SGLT2-i non-users according to the chronic treatment with gliflozins. The primary endpoint was CI-AKI incidence during hospitalization. Secondary endpoints were all-cause mortality and the need for continuous renal replacement therapy (CRRT). (3) Results: In total, 86 patients on SGLT2-i and 179 patients not on SGLT2-i were enrolled. The incidence of CI-AKI in the gliflozin group was lower than in the non-user group (9.3 vs. 27.3%, p < 0.001), and these results were confirmed after propensity matching analysis. Multivariable logistic regression showed that only SGLT2-i treatment was an independent preventive factor for CI-AKI (OR: 0.41, 95% CI: 0.16–0.90, p = 0.045). The need for CRRT was reported only in five patients in the non-SGLT2-i-user group compared to zero patients in the gliflozin group (p = 0.05). (4) Conclusions: SGLT2-i therapy was associated with a lower risk of CI-AKI in patients with HF undergoing ICM invasive procedures. [ABSTRACT FROM AUTHOR]

Background: Certain glucagon-like peptide-1 receptor (GLP-1) agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2-inhibitors) can reduce cardiovascular risk in individuals with type 2 diabetes and cardiovascular disease (CVD). However, these medications can be expensive, potentially limiting their use. Objectives: The primary objective was to characterize the use of cardioprotective GLP-1 agonists and SGLT2-inhibitors among adults with diabetes with and without CVD. The secondary objective was to investigate the association of socioeconomic factors and health care utilization with the use of these medications. Methods: Adults aged ≥20 years old with self-reported diabetes, A1c ≥6.5%, or fasting glucose ≥126 mg/dL were identified using the 2015 to March 2020 National Health and Nutrition Examination Survey. The primary outcome was the use of cardioprotective GLP-1 agonists or SGLT2-inhibitors compared in individuals with and without CVD. Secondary analyses included identification of socioeconomic factors and health care utilization associated with the use of cardioprotective antidiabetic medications, stratified by CVD status. Weighted analyses were conducted to account for the complex survey design. Results: Use of cardioprotective antidiabetic medications was higher in adults with CVD compared to those without CVD (7.8% vs. 4.6%, P = 0.02), which was driven by the use of cardioprotective SGLT2-inhibitors (4.6% versus 1.9%, P = 0.002). Lower income level and less frequent health care visits within the past year were associated with lower likelihood of using these medications. Conclusion and Relevance: Despite preferential use in individuals with diabetes and CVD, the prevalence of cardioprotective antidiabetic medication use remains relatively low. Disparities in use appear to exist based on income level and health care utilization. [ABSTRACT FROM AUTHOR]

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Introduction Cardiovascular diseases (CVD) are a significant worldwide health issue, impacting millions of patients and being the primary cause of global illness and death. The combination of SGLT2 inhibitors with weight loss and physical activity can significantly reduce cardiovascular risk. Beyond their primary antihyperglycemic effects, SGLT2 inhibitors elicit pleiotropic benefits including weight loss and favorable alterations in lipid metabolism, culminating in a cardioprotective metabolic environment. Aim of the study The aim of the study is to investigate the pleiotropic benefits of SGLT2 inhibitors, including their effects on weight loss, lipid metabolism, and cardiovascular health, in individuals. Materials and methods This study presents the current state of knowledge about metabolic and cardiovascular benefits associated with SGLT2 inhibitors in various scientific articles. PubMed database was searched for articles written in English. The search included the keywords „SGLT2-inhibitors”; “SGLT2-inhibitors mechanism of action”; „heart failure”; „cardiovascular events”. Results SGLT2 inhibitors enhance glycemic control, decrease body weight and visceral fat, and ameliorate several metabolic abnormalities linked to metabolic syndrome, including lipid profile. Clinical investigations have underscored the cardiovascular benefits conferred by SGLT2 inhibitors. Reductions in major adverse cardiovascular events and heart failure-related hospitalizations have been consistently observed, irrespective of diabetic status. Guidelines now advocate for the incorporation of SGLT2 inhibitors as first-line therapies for HFrEF and HFpEF. This endorsement underscores the transformative impact of SGLT2 inhibitors on cardiovascular outcomes.

The results of large cardiovascular studies indicate that SGLT-2 inhibitors may increase the risk of leg amputations. This study aims to investigate whether dapagliflozin therapy affects peripheral vascular oxygenation, i.e., microcirculation in the foot, as measured by transcutaneous oxygen pressure (TcPO2) in patients with type 2 diabetes (T2DM) and peripheral arterial disease (PAD) compared to patients without PAD. The patients with PAD were randomized into two groups. In the first 35 patients with PAD, dapagliflozin was added to the therapy; in the other 26 patients with PAD, other antidiabetic drugs were added to the therapy. Dapagliflozin was added to the therapy in all patients without PAD. TcPO2 measurement, Ankle Brachial Index (ABI), anthropometric measurements, and laboratory tests were performed. After a follow-up period of 119.35 days, there was no statistically significant difference in the reduction of mean TcPO2 values between the group with T2DM with PAD treated with dapagliflozin and the group with T2DM with PAD treated with other antidiabetic drugs (3.88 mm Hg, SD = 15.13 vs. 1.48 mm Hg, SD = 11.55, p = 0.106). Patients with control TcPO2 findings suggestive of hypoxia (TcPO2 < 40 mm Hg) who were treated with dapagliflozin had a clinically significant decrease in mean TcPO2 of 10 mm Hg or more (15.8 mm Hg and 12.90 mm Hg). However, the aforementioned decrease in TcPO2 was not statistically significantly different from the decrease in TcPO2 in the group with PAD treated with other diabetic medications (p = 0.226, p = 0.094). Based on the available data, dapagliflozin appears to affect tissue oxygenation in T2DM with PAD. However, studies with a larger number of patients and a longer follow-up period are needed to determine the extent and significance of this effect.

Abstract Recent type 2 diabetes guidance from the UK’s National Institute for Health and Care Excellence (NICE) proposes offering SGLT2-inhibitor therapy to people with established atherosclerotic cardiovascular disease (ASCVD) or heart failure, and considering SGLT2-inhibitor therapy for those at high-risk of cardiovascular disease defined as a 10-year cardiovascular risk of > 10% using the QRISK2 algorithm. We used a contemporary population-representative UK cohort of people with type 2 diabetes to assess the implications of this guidance. 93.1% of people currently on anti-hyperglycaemic treatment are now recommended or considered for SGLT2-inhibitor therapy under the new guidance, with the majority (59.6%) eligible on the basis of QRISK2 rather than established ASCVD or heart failure (33.6%). Applying these results to the approximately 2.20 million people in England currently on anti-hyperglycaemic medication suggests 1.75 million people will now be considered for additional SGLT2-inhibitor therapy, taking the total cost of SGLT2-inhibitor therapy in England to over £1 billion per year. Given that older people, those of non-white ethnic groups, and those at lower cardiovascular disease risk were underrepresented in the clinical trials which were used to inform this guidance, careful evaluation of the impact and safety of increased SGLT2-inhibitor prescribing across different populations is urgently required. Evidence of benefit should be weighed against the major cost implications for the UK National Health Service.

Background and aims: Increases in both the prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity are closely related. Type 2 diabetes (T2DM) has been associated with metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis and hepatocellular carcinoma. Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of T2DM and has an important role in weight loss. Also, it may represent a new therapeutic option for the treatment of MASH in obese diabetic patients. The main outcomes were changes from baseline in liver steatosis and fibrosis at week 24. Material and methods: A total of one hundred eighty-seven patients with T2DM were eligible for this prospective study; ninety-five subjects were treated with oral semaglutide, and ninety-two patients were treated with dapagliflozin as an add-on to metformin. All the subjects were evaluated using Vibration Controlled Transient Elastography (VCTE) from June to December 2022. Results: From our cohort, 54% of the patients were females, with a mean age of 59.92 ± 11.89 years and a mean body mass index (BMI) of 29.53 ± 5.33 kg/m2. Following a six-month medication period, we observed a substantial reduction in anthropometric measurements, including the BMI, waist circumference (WC), and waist-to-hip ratio (WtHr), in both groups. Regarding HbA1c, a notable decrease was observed in the semaglutide group (p < 0.001) when compared to the dapagliflozin group (p = 0.011). In addition, the liver stiffness measurement (LSM) according to VCTE improved significantly in the semaglutide group participants from 8.07 ± 2.90 kPa at baseline to 6.51 ± 3.09 kPa after medication (p < 0.001). Conclusion: The superior metabolic effects of semaglutide, correlated to dapagliflozin, may contribute to a more efficient decrease in hepatic stress and injury, leading to a substantial enhancement of liver function in T2DM patients. Further investigations conducted over an ideal timeframe are necessary to confirm the evidence presented in this study.

Si la prévalence du diabète ne cesse d'augmenter dans le monde entier, avec 537 millions d'adultes âgés de 20 à 79 ans ayant un diabète en 2021, le développement de nouvelles classes thérapeutiques améliorant non seulement l'équilibre glycémique mais aussi la fonction rénale et la prévention cardiovasculaire a révolutionné la prise en charge des patients. Aujourd'hui, le traitement du diabète n'est plus seulement le traitement de la glycémie. Dans ce contexte, la stratégie thérapeutique individualisée a été entièrement revue, avec notamment les sulfamides hypoglycémiants indiqués beaucoup plus tard dans la stratégie thérapeutique, tandis que les inhibiteurs du SGLT2 sont indiqués très rapidement chez les patients ayant une néphropathie et une cardiopathie ischémique ou une insuffisance cardiaque chronique, et les analogues du GLP-1 chez les patients obèses et en prévention cardiovasculaire primaire et secondaire. Quant aux règles hygiéno-diététiques et à la metformine, elles restent à la base du traitement. La connaissance des effets antidiabétiques en termes d'efficacité et de risque hypoglycémique, des effets cardiovasculaires, néphroprotecteurs et pondéraux est indispensable pour optimiser la prise en charge des patients diabétiques aujourd'hui. While the prevalence of diabetes continues to rise worldwide, with 537 million adults aged 20–79-years-old having diabetes in 2021, the development of new therapeutic classes improving not only glycemic control but also kidney function and cardiovascular prevention has revolutionized patient care. Today, the treatment of diabetes is no longer just the treatment of blood sugar level. In this context, the individualized therapeutic strategy has been completely reviewed, with in particular sulfamides indicated much later in the therapeutic strategy, while SGLT2 inhibitors are indicated very early in patients with kidney disease and/or with ischemic heart disease or chronic heart failure, and GLP-1 analogues in obese patients and/or in primary or secondary cardiovascular prevention. As for lifestyle rules and metformin, they remain the cornerstone of treatment. Knowledge of antidiabetic effects in terms of efficacy and hypoglycemic risk, of cardiovascular, nephroprotective and weight effects is essential to optimize the management of diabetic patients today. [ABSTRACT FROM AUTHOR]

Neutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) and severe congenital neutropenia type 4 (SCN4), associated with deficiencies of the glucose-6-phosphate transporter (G6PT/SLC37A4) and the phosphatase G6PC3, respectively, are the result of the accumulation of 1,5-anhydroglucitol-6-phosphate in neutrophils. This is an inhibitor of hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol in blood. 1,5-AG is presumed to be reabsorbed in the kidney by a sodium-dependent-transporter of uncertain identity, possibly SGLT4/SLC5A9 or SGLT5/SLC5A10. Lowering blood 1,5-AG with an SGLT2-inhibitor greatly improved neutrophil counts and function in G6PC3-deficient and GSD1b patients. Yet, this effect is most likely mediated indirectly, through the inhibition of the renal 1,5-AG transporter by glucose, when its concentration rises in the renal tubule following inhibition of SGLT2. To identify the 1,5-AG transporter, both human and mouse SGLT4 and SGLT5 were expressed in HEK293T cells and transport measurements were performed with radiolabelled compounds. We found that SGLT5 is a better carrier for 1,5-AG than for mannose, while the opposite is true for human SGLT4. Heterozygous variants in SGLT5, associated with a low level of blood 1,5-AG in humans cause a 50–100% reduction in 1,5-AG transport activity tested in model cell lines, indicating that SGLT5 is the predominant kidney 1,5-AG transporter. These and other findings led to the conclusion that (1) SGLT5 is the main renal transporter of 1,5-AG; (2) frequent heterozygous mutations (allelic frequency > 1%) in SGLT5 lower blood 1,5-AG, favourably influencing neutropenia in G6PC3 or G6PT deficiency; (3) the effect of SGLT2-inhibitors on blood 1,5-AG level is largely indirect; (4) specific SGLT5-inhibitors would be more efficient to treat these neutropenias than SGLT2-inhibitors. [ABSTRACT FROM AUTHOR]

Recent type 2 diabetes guidance from the UK's National Institute for Health and Care Excellence (NICE) proposes offering SGLT2-inhibitor therapy to people with established atherosclerotic cardiovascular disease (ASCVD) or heart failure, and considering SGLT2-inhibitor therapy for those at high-risk of cardiovascular disease defined as a 10-year cardiovascular risk of > 10% using the QRISK2 algorithm. We used a contemporary population-representative UK cohort of people with type 2 diabetes to assess the implications of this guidance. 93.1% of people currently on anti-hyperglycaemic treatment are now recommended or considered for SGLT2-inhibitor therapy under the new guidance, with the majority (59.6%) eligible on the basis of QRISK2 rather than established ASCVD or heart failure (33.6%). Applying these results to the approximately 2.20 million people in England currently on anti-hyperglycaemic medication suggests 1.75 million people will now be considered for additional SGLT2-inhibitor therapy, taking the total cost of SGLT2-inhibitor therapy in England to over £1 billion per year. Given that older people, those of non-white ethnic groups, and those at lower cardiovascular disease risk were underrepresented in the clinical trials which were used to inform this guidance, careful evaluation of the impact and safety of increased SGLT2-inhibitor prescribing across different populations is urgently required. Evidence of benefit should be weighed against the major cost implications for the UK National Health Service. [ABSTRACT FROM AUTHOR]

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels. [ABSTRACT FROM AUTHOR]

Hypertension poses a significant burden in the general population, being responsible for increasing cardiovascular morbidity and mortality, leading to adverse outcomes. Moreover, the association of hypertension with dyslipidaemia, obesity, and insulin resistance, also known as metabolic syndrome, further increases the overall cardiovascular risk of an individual. The complex pathophysiological overlap between the components of the metabolic syndrome may in part explain how novel antidiabetic drugs express pleiotropic effects. Taking into consideration that a significant proportion of patients do not achieve target blood pressure values or glucose levels, more efforts need to be undertaken to increase awareness among patients and physicians. Novel drugs, such as incretin-based therapies and renal glucose reuptake inhibitors, show promising results in decreasing cardiovascular events in patients with metabolic syndrome. The effects of sodium-glucose co-transporter-2 inhibitors are expressed at different levels, including renoprotection through glucosuria, natriuresis and decreased intraglomerular pressure, metabolic effects such as enhanced insulin sensitivity, cardiac protection through decreased myocardial oxidative stress and, to a lesser extent, decreased blood pressure values. These pleiotropic effects are also observed after treatment with glucagon-like peptide-1 receptor agonists, positively influencing the cardiovascular outcomes of patients with metabolic syndrome. The initial combination of the two classes may be the best choice in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors because of their complementary mechanisms of action. In addition, the novel mineralocorticoid receptor antagonists show significant cardio-renal benefits, as well as anti-inflammatory and anti-fibrotic effects. Overall, the key to better control of hypertension in patients with metabolic syndrome is to consider targeting multiple pathogenic mechanisms, using a combination of the different therapeutic agents, as well as drastic lifestyle changes. This article will briefly summarize the association of hypertension with metabolic syndrome, as well as take into account the influence of antidiabetic drugs on blood pressure control. [ABSTRACT FROM AUTHOR]

Aims: Previous observational studies on glucose-lowering drugs and risk of stroke in type 2 diabetes yielded conflicting results. The aim was to examine the association of glucose-lowering drugs with incident stroke and transient ischaemic attacks (TIA) in newly diagnosed type 2 diabetes. Methods: We conducted a retrospective cohort analysis of the disease analyzer, which comprises a representative panel of 1248 general and internal medicine practices throughout Germany (01/2000–12/2019: 9.8 million patients). Incident non-fatal stroke/TIA was defined based on ICD-10 codes (I63, I64; G45) in newly diagnosed type 2 diabetes. Cox regression models were fitted to obtain hazard ratios (HR; 95%CI) for stroke/TIA adjusting for potential confounders (age, sex, health insurance, coronary heart disease, myocardial infarction, heart failure, polyneuropathy, blood pressure, eGFR) and anthropometric and metabolic intermediators (BMI, HbA1c, HDL- and LDL-cholesterol, triglycerides, lipid-lowering drugs). Result: 312,368 persons with newly diagnosed type 2 diabetes without previous stroke/TIA (mean age: 64 years; 52% males) were included. There were 16,701 events of non-fatal stroke/TIA corresponding to an incidence rate of 9.3 (95%CI 9.1–9.4) per 1000 person-years. Using Cox regression, adjusted HR for stroke/TIA (per 1 year of treatment) of 0.59 (0.54–0.64) for SGLT2 inhibitors and of 0.79 (0.74–0.85) for GLP-1 receptor agonists were estimated. DPP-4 inhibitors (0.84; 0.82–0.86), metformin (0.90; 0.89–0.91), insulin (0.92; 0.91–0.93) and sulfonylureas (0.98; 0.96–0.99) also showed moderately reduced HR for stroke/TIA. Sex-specific regression analyses yielded similar results (HR). Conclusions: Treatment with SGLT2 inhibitors or GLP-1 receptor agonists might reduce non-fatal stroke/TIA in persons with newly diagnosed type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a major cause of recurrent hospitalization and death worldwide. Sodium-glucose cotransporter-2 inhibitors including Dapagliflozin are anti-diabetic drugs with promising cardiovascular (CV) effects. We performed systematic review and meta-analysis of randomized controlled trials investigating the effects of Dapagliflozin in heart failure patients. Methods: We searched PubMed, Scopus and ScienceDirect databases. A total of 1,567 studies from January 2017 to September 10, 2022, were screened. After applying exclusion criteria, 22 studies were retrieved for full-text screening, and 9 of them were eligible for this meta-analysis. Effect estimates for dichotomous variables were expressed as risk ratio (RR) and 95% CI. The primary outcomes were the incidence of all-cause mortality, hospitalization due to HF and CV death. This review was registered on PROSPERO with ID CRD42022347793. Results: A total of 14,032 patients were included. The overall risk ratio of all-cause mortality favored the dapagliflozin group over the placebo/standard therapy group (RR= 0.89, 95% CI: 0.82 - 0.97, P=0.006) and the pooled studies were not heterogenous (I2= 0%). Additionally, Dapagliflozin significantly reduced the hospitalization due to heart failure (RR= 0.76, 95% CI: 0.70 – 0.84, P> 0.00001, I2= 0%), cardiovascular death (RR= 0.87, 95% CI: 0.78 – 0.97, P= 0.01, I2= 0%) and their composite outcomes. Conclusion: Dapagliflozin reduces the risk of all-cause mortality, heart failure hospitalizations and cardiovascular death in a wide range of heart failure patients.

Initially intended as an adjunct treatment for type 2 diabetes mellitus (T2DM), SGLT2-inhibitors (SGLT2i) have transformed into an unexpected pillar of the heart failure (HF) regimen. The past several years have witnessed a meteoric rise of this drug class, starting with the serendipitous results of trials assessing the safety of the glucose-lowering therapy in a broad range of cardiovascular patients and culminating with the demonstration of a reduction in hospitalizations for heart failure and cardiovascular mortality in dedicated heart failure populations. The heart failure benefits of SGLT2i are independent of a patient’s glycemic status, but the salient mechanisms of cardioprotection remain a subject of robust debate and ongoing research. Cardiologists as well as physicians of other disciplines should become familiar with the main indications, benefits, and clinical consideration of implementation. In this review, we will discuss the advance of SGLT2i in heart failure, ranging from the results of large randomized clinical trials to potential mechanisms of action.

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

Neutropenia and neutrophil dysfunction found in deficiencies in G6PC3 and in the glucose‐6‐phosphate transporter (G6PT/SLC37A4) are due to accumulation of 1,5‐anhydroglucitol‐6‐phosphate (1,5‐AG6P), an inhibitor of hexokinase made from 1,5‐anhydroglucitol (1,5‐AG), an abundant polyol present in blood. Lowering blood 1,5‐AG with an SGLT2 inhibitor greatly improved neutrophil counts and function in G6PC3‐deficient mice and in patients with G6PT‐deficiency. We evaluate this treatment in two G6PC3‐deficient children. While neutropenia was severe in one child (PT1), which was dependent on granulocyte cololony‐stimulating factor (GCSF), it was significantly milder in the other one (PT2), which had low blood 1,5‐AG levels and only required GCSF during severe infections. Treatment with the SGLT2‐inhibitor empagliflozin decreased 1,5‐AG in blood and 1,5‐AG6P in neutrophils and improved (PT1) or normalized (PT2) neutrophil counts, allowing to stop GCSF. On empagliflozin, both children remained infection‐free (>1 year – PT2; >2 years – PT1) and no side effects were reported. Remarkably, sequencing of SGLT5, the gene encoding the putative renal transporter for 1,5‐AG, disclosed a rare heterozygous missense mutation in PT2, replacing the extremely conserved Arg401 by a histidine. The higher urinary clearance of 1,5‐AG explains the more benign neutropenia and the outstanding response to empagliflozin treatment found in this child. Our data shows that SGLT2 inhibitors are an excellent alternative to treat the neutropenia present in G6PC3‐deficiency. [ABSTRACT FROM AUTHOR]

Background: Fournier’s gangrene (FG) is a rare necrotising soft tissue infection localised in the genital areas with possible dramatic outcomes. Recently, sodium glucose co-transporter-2 (SGLT2) inhibitors were identified as a risk factor. Methods: We present a case report of a 57-year-old female patient with type 2 diabetes mellitus (T2DM) in treatment with empagliflozin which led to the development of FG. Moreover, we performed a systematic review assessing the association between empagliflozin use and FG. Results: The female patient with 15-years treated diabetes presented a massive FG after 6 months from starting empagliflozin. Over the period of two months, she was successfully treated in a low-income setting. The systematic review included two studies with a total of 9915 participants. Although no participant had FG, there was an increased rate of urinary and genital infection in patients treated with empagliflozin compared to those treated with other antidiabetics or placebo. Conclusions: FG should be considered as a possible complication in patients using SGLT2. Patients should be educated to report early signs of genital infection and healthy behaviours as well as a balanced diet should be promoted to aid in the prevention of FG.

Heart failure (HF) and nonalcoholic fatty liver disease (NAFLD) are 2 conditions that have become important global public health problems. Emerging evidence supports a strong and independent association between NAFLD and the risk of new-onset HF, and there are multiple potential pathophysiological mechanisms by which NAFLD may increase risk of new-onset HF. The magnitude of this risk parallels the underlying severity of NAFLD, especially the level of liver fibrosis. Patients with NAFLD develop accelerated coronary atherosclerosis, myocardial alterations (mainly cardiac remodeling and hypertrophy), and certain arrhythmias (mainly atrial fibrillation), which may precede and promote the development of new-onset HF. This brief narrative review aims to provide an overview of the association between NAFLD and increased risk of new-onset HF, discuss the underlying mechanisms that link these 2 diseases, and summarize targeted pharmacological treatments for NAFLD that might also reduce the risk of HF. [ABSTRACT FROM AUTHOR]

Initially intended as an adjunct treatment for type 2 diabetes mellitus (T2DM), SGLT2-inhibitors (SGLT2i) have transformed into an unexpected pillar of the heart failure (HF) regimen. The past several years have witnessed a meteoric rise of this drug class, starting with the serendipitous results of trials assessing the safety of the glucose-lowering therapy in a broad range of cardiovascular patients and culminating with the demonstration of a reduction in hospitalizations for heart failure and cardiovascular mortality in dedicated heart failure populations. The heart failure benefits of SGLT2i are independent of a patient's glycemic status, but the salient mechanisms of cardioprotection remain a subject of robust debate and ongoing research. Cardiologists as well as physicians of other disciplines should become familiar with the main indications, benefits, and clinical consideration of implementation. In this review, we will discuss the advance of SGLT2i in heart failure, ranging from the results of large randomized clinical trials to potential mechanisms of action. [ABSTRACT FROM AUTHOR]

Objective: Sodium glucose cotransporter 2 inhibitors (SGLT2-is) are antidiabetic drugs that improve glycemic control by limiting urinary glucose reuptake in the proximal tubule. SGLT2-is might suppress atherosclerotic processes and ameliorate the prognosis of patients with diabetes mellitus diagnosed with or at high risk of atherosclerotic cardiovascular disease (ASCVD). In this mini review, we examine the role of SGLT2-is in the development and progression of atherosclerosis throughout its spectrum, from subclinical atherosclerosis to ASCVD. Data Sources—PubMed and Google Scholar were searched for publications related to SGLT2-is and atherosclerosis. All types of articles were considered, including clinical trials, animal studies, in vitro observations, and reviews and meta-analyses. Data were examined according to their impact and clinical relevance. Synopsis of Content—We first review the underlying mechanisms of SGLT2-is on the development and progression of atherosclerosis, including favorable effects on lipid metabolism, reduction of systemic inflammation, and improvement of endothelial function. We then discuss the putative impact of SGLT2-is on the formation, composition, and stability of atherosclerotic plaque. Furthermore, we evaluate the effects of SGLT2-is in subclinical atherosclerosis assessed by carotid intima media thickness and pulse wave velocity. Subsequently, we summarize the effects of SGLT2- is in ASCVD events, including ischemic stroke, angina pectoris, myocardial infarction, revascularization, and peripheral artery disease, as well as major adverse cardiovascular events, cardiovascular mortality, heart failure, and chronic kidney disease. Moreover, we examine factors that could modify the role of SGLT2-is in atherosclerosis, including sex, age, diabetes, glycemic control, ASCVD, and SGLT2-i compounds. Additionally, we propose future directions that can improve our understanding of SGLT2-is and atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective: Sodium glucose cotransporter 2 inhibitors (SGLT2-is) are antidiabetic drugs that improve glycemic control by limiting urinary glucose reuptake in the proximal tubule. SGLT2-is might suppress atherosclerotic processes and ameliorate the prognosis of patients with diabetes mellitus diagnosed with or at high risk of atherosclerotic cardiovascular disease (ASCVD). In this mini review, we examine the role of SGLT2-is in the development and progression of atherosclerosis throughout its spectrum, from subclinical atherosclerosis to ASCVD.Data Sources—PubMed and Google Scholar were searched for publications related to SGLT2-is and atherosclerosis. All types of articles were considered, including clinical trials, animal studies, in vitro observations, and reviews and meta-analyses. Data were examined according to their impact and clinical relevance.Synopsis of Content—We first review the underlying mechanisms of SGLT2-is on the development and progression of atherosclerosis, including favorable effects on lipid metabolism, reduction of systemic inflammation, and improvement of endothelial function. We then discuss the putative impact of SGLT2-is on the formation, composition, and stability of atherosclerotic plaque. Furthermore, we evaluate the effects of SGLT2-is in subclinical atherosclerosis assessed by carotid intima media thickness and pulse wave velocity. Subsequently, we summarize the effects of SGLT2-is in ASCVD events, including ischemic stroke, angina pectoris, myocardial infarction, revascularization, and peripheral artery disease, as well as major adverse cardiovascular events, cardiovascular mortality, heart failure, and chronic kidney disease. Moreover, we examine factors that could modify the role of SGLT2-is in atherosclerosis, including sex, age, diabetes, glycemic control, ASCVD, and SGLT2-i compounds. Additionally, we propose future directions that can improve our understanding of SGLT2-is and atherosclerosis.

Diabetes mellitus (DM) is a common cause of chronic kidney disease (CKD), leading to the need for renal replacement therapy (RRT). RRT includes hemodialysis (HD), peritoneal dialysis (PD), kidney transplantation (KT), and medical management. As CKD advances, the management of DM may change as medication clearance, effectiveness, and side effects can be altered due to decreasing renal clearance. Medications like metformin that were safe to use early in CKD may build up toxic levels of metabolites in advanced CKD. Other medications, like sodium-glucose co-transporter 2 inhibitors, which work by excreting glucose in the urine, may not be able to work effectively in advanced CKD due to fewer working nephrons. Insulin breakdown may take longer, and both formulation and dosing may need to be changed to avoid hypoglycemia. While DM control contributes to CKD progression, effective DM control continues to be important even after patients have been placed on RRT. Patients on RRT are frequently taken care of by a team of providers, including the primary care physician, both in and outside the hospital. Non-nephrologists who are involved with the care of a patient treated with RRT need to be adept at managing DM in this population. This paper aims to outline the management of type 2 DM in advanced CKD., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mallappallil et al.)

Acute pancreatitis is a condition seldom encountered with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors. They are beneficial in the treatment of various conditions and offer great promise. Despite this, they are associated with several adverse effects, necessitating vigilance and further research. This case study reports a 69-year-old male with multiple comorbidities who presented with epigastric pain radiating to the back. Laboratory tests revealed elevated AST, ALT, GGT and lipase. The patient was diagnosed with acute pancreatitis secondary to the SGLT2 inhibitor therapy regimen. Cessation of dapagliflozin resulted in a complete resolution of symptoms. There is credible evidence to suggest the presence of an association between SGLT2 inhibitors and acute pancreatitis, although extensive research is warranted to consolidate this association., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Khakhar et al.)

Background: Sacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF). Methods: We compared the treatment arms (sacubitril/valsartan, vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on vericiguat and the HFrEF subgroup of DECLARE-TIMI 58. Results: There was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat. Conclusions: Based on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to vericiguat. Registration Number: PROSPERO ID 186351. [ABSTRACT FROM AUTHOR]

Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[(18)F]fluoro-D-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.

Purpose: SGLT2-inhibitors (SGLT-2i) have been linked to the risk of potential life-threatening diabetic ketoacidosis (DKA). The U.S. Food and Drug Administration and the European Medicines Agency issued warnings in 2015 and 2016 respectively on the predisposing factors to the development of DKA in individuals on an SGLT2i. New predisposing factors to DKA are still being discovered with the use of SGLT-2i. The list by FDA and EMA is yet to be updated. This article aims to provide a holistic list that includes the newer factors that have been implicated in the development of DKA. The overall aim is to guide physicians in prescribing this class of drugs for type 2 diabetes mellitus (T2D). Method: A search was done using PUBMED, Google Scholar, and Directory of Open Access Journals with the following words: SGLT-2 Inhibitors AND Ketoacidosis were entered. We included articles from 2000 to 2020, those in English, those involving any of the approved SGLT2i medications in T2D patients, and studies that focused on DKA linked to SGLT-2i. These articles were reviewed, and relevant data extracted and compiled. Results and conclusion: The review has revealed that predisposing factors include (excess) alcohol consumption, female gender, starvation due to illness or fasting, withholding the use of SGLT2i for less than 48 h peri-operatively, and the existence of a variations in the expression of SGLT2 receptors. Patients should be advised on "sick day rules," and if a patient becomes unwell while on an SGLT2i, they should be advised to withhold the medication for the duration of the intercurrent illness. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a well-recognized microvascular complication of diabetes. Growing evidence suggests that, in addition to retinal vascular damage, there is significant damage to retinal neural tissue in DR. Studies reveal neuronal damage before clinically evident vascular lesions and DR is now classified as a neurovascular complication. Hyperglycemia causes retinal damage through complex metabolic pathways leading to oxidative stress, inflammation, vascular damage, capillary ischemia, and retinal tissue hypoxia. Retinal hypoxia is further worsened by high oxygen consumption in the rods. Persistent hypoxia results in increases in vascular endothelial growth factor (VEGF) and other pro-angiogenic factors leading to proliferative DR/macular edema and progressive visual impairment. Optimal glucose control has favorable effects in DR. Other treatments for DR include laser photocoagulation, which improves retinal oxygenation by destroying the high oxygen consuming rods and their replacement by low oxygen consuming glial tissue. Hypoxia is a potent stimulator of VEGF, and intravitreal anti-VEGF antibodies are effective in regressing macular edema and in some studies, retinal neovascularization. In this review, we highlight the complex pathophysiology of DR with a focus on retinal oxygen/fuel consumption and hypoxic damage to retinal neurons. We discuss potential mechanisms through which sodium-glucose cotransporter 2 (SGLT2) inhibitors improve retinal hypoxia-through ketone bodies, which are energetically as efficient as glucose and yield more ATP per molecule of oxygen consumed than fat, with less oxidative stress. Retinal benefits would occur through improved fuel energetics, less hypoxia and through the anti-inflammatory/oxidative stress effects of ketone bodies. Well-designed studies are needed to explore this hypothesis. [ABSTRACT FROM AUTHOR]

Heart failure (HF) continues to be a serious public health challenge despite significant advancements in therapeutics and is often complicated by multiple other comorbidities. Of particular concern is type 2 diabetes mellitus (T2DM) which not only amplifies the risk, but also limits the treatment options available to patients. The sodium-glucose linked cotransporter subtype 2 (SGLT2)-inhibitor class, which was initially developed as a treatment for T2DM, has shown great promise in reducing cardiovascular risk, particularly around HF outcomes – regardless of diabetes status. There are ongoing efforts to elucidate the true mechanism of action of this novel drug class. Its primary mechanism of inducing glycosuria and diuresis from receptor blockade in the renal nephron seems unlikely to be responsible for the rapid and striking benefits seen in clinical trials. Early mechanistic work around conventional therapeutic targets seem to be inconclusive. There are some emerging theories around its effect on myocardial energetics and calcium balance as well as on renal physiology. In this review, we discuss some of the cutting-edge hypotheses and concepts currently being explored around this drug class in an attempt better understand the molecular mechanics of this novel agent. [ABSTRACT FROM AUTHOR]

Background: Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia.Objectives: The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients.Methods: In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life.Results: Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O2 consumption (1.1 ± 2.6 ml/min/kg vs. -0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. -145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. -35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21 ± 18 vs. 2 ± 15; p < 0.001).Conclusions: Empagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222). [ABSTRACT FROM AUTHOR]

Obesity is a multifactorial chronic disease characterized by an excess of adipose tissue, affecting people of all ages. In the last 40 years, the incidence of overweight and obesity almost tripled worldwide. The accumulation of "visceral" adipose tissue increases with aging, leading to several cardio-metabolic consequences: from increased blood pressure to overt arterial hypertension, from insulin-resistance to overt type 2 diabetes mellitus (T2DM), dyslipidemia, chronic kidney disease (CKD), and obstructive sleep apnea. The increasing use of innovative drugs, namely glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2-i), is changing the management of obesity and its related cardiovascular complications significantly. These drugs, first considered only for T2DM treatment, are now used in overweight patients with visceral adiposity or obese patients, as obesity is no longer just a risk factor but a critical condition at the basis of common metabolic, cardiovascular, and renal diseases. An adipocentric vision and approach should become the cornerstone of visceral overweight and obesity integrated management and treatment, reducing and avoiding the onset of obesity-related multiple risk factors and their clinical complications. According to recent progress in basic and clinical research on adiposity, this narrative review aims to contribute to a novel clinical approach focusing on pathophysiological and therapeutic insights., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sarzani, Landolfo, Di Pentima, Ortensi, Falcioni, Sabbatini, Massacesi, Rampino, Spannella and Giulietti.)

Abstract Background Sodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms. Methods Neuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used. Results Dapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p

Susan C Bolge,1 Natalia M Flores,2 Shu Huang,3 Jennifer Cai1 1Janssen Scientific Affairs, LLC, Titusville, NJ, 2Kantar Health, Foster City, CA, 3Kantar Health, New York, NY, USA Purpose: This study describes how health care providers approach canagliflozin for the treatment of patients with type 2 diabetes mellitus (T2DM) in the real world.Patients and methods: An Internet-based questionnaire was completed by 101 endocrinologists, 101 primary care physicians, and 100 nurse practitioners/physician assistants (NP/PAs). Health care providers were required to have experience prescribing or managing patients using canagliflozin to be included in the study. Health care providers compared canagliflozin with other T2DM medication classes on clinical characteristics, costs, and patient satisfaction. Confidence in canagliflozin was also measured. Health care providers reported their canagliflozin prescribing experience and good candidate characteristics for treatment. Finally, providers reported on patient outcomes among those receiving canagliflozin. All variables were compared across provider type.Results: Health care providers reported higher favorability for canagliflozin for blood pressure and body weight compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and higher favorability for effect on blood pressure, body weight, treatment satisfaction, and glycosylated hemoglobin (HbA1c) compared with sulfonylureas (SUs), with differences observed for effect on blood pressure. Health care providers reported being very/extremely confident (55%–74%) with canagliflozin as a second- to fourth-line treatment. The top 3 characteristics reported by the providers, in terms of describing a good candidate for canagliflozin, include those concerned about their weight, insurance coverage/affordability, and avoiding injectable treatments. Finally, providers reported often/always observing patients’ lowering or controlling HbA1c (82%–88%) and improvement in overall quality of life (QoL; 50%–53%) with canagliflozin treatment. No differences were observed across provider type for confidence, good candidate characteristics, or patient outcomes.Conclusion: Health care providers reported favorable experiences with canagliflozin and witnessed improvements in patients’ clinical outcomes and QoL. Keywords: diabetes, SGLT2-inhibitors, management goals, real-world evidence, prescribing experience

The treatment landscape for patients with established or at high risk for cardiovascular disease and type 2 diabetes mellitus has entirely changed over the past decade, with the introduction of several anti-hyperglycemic agents. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are two anti-hyperglycemic classes which have been of special interest after multiple large cardiovascular disease (CVD) outcomes studies have demonstrated superiority of these agents compared to placebo for major adverse CVD events and in some cases, hospitalization for heart failure. Despite the dramatic results of these trials, only recently have we began to understand the mechanisms underlying these CVD benefits. Here we review the underlying mechanisms which have the greatest plausibility for both of these agents including the impact of ventricular loading conditions, direct effects on cardiac structure and function, myocardial energetics and sodium/hydrogen exchange for SGLT2 inhibitors, and the anti-atherosclerotic, anti-inflammatory, and modulation of endothelial function for GLP-1 agonists. [ABSTRACT FROM AUTHOR]

The SGLT2 inhibitor empagliflozin reduced cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in diabetic patients. We have recently demonstrated the efficacy of empagliflozin in ameliorating HF and improving cardiac function in a non-diabetic porcine model of HF mediated via a switch in myocardial metabolism that enhances cardiac energetics. Therefore, we hypothesized that the cardiac benefits of empagliflozin can also be extended to non-diabetic HF patients. The EMPA-TROPISM clinical trial is a randomized, double-blind, parallel group, placebo-controlled, trial comparing the efficacy of and safety of empagliflozin in non-diabetic HF patients. Eighty patients with stable HF for over 3 months, LVEF < 50%, and New York Heart Association functional class II to IV symptoms will be randomized to empagliflozin 10 mg for 6 months or placebo. All patients will undergo cardiac magnetic resonance (CMR), cardiopulmonary exercise test (CPET), 6-min walk test, and quality of life questionnaires. The primary outcome is the change in left ventricular end-diastolic volume measured by CMR. Secondary end-points include change in peak VO2 (CPET); change in LV mass, in LVEF, in myocardial mechanics (strains), in left atrium volumes, in RV function and volumes, in interstitial myocardial fibrosis, and in epicardial adipose tissue (CMR); change in the distance in the 6-min walk test; and changes in quality of life (Kansas Cardiomyopathy questionnaire [KCCQ-12] and the 36-Item Short Form Survey [SF-36]). Safety issues (e.g., hypoglycemia, urinary infections, ketoacidosis,...) will also be monitored. In summary, EMPA-TROPISM clinical trial will determine whether the SGLT2 inhibitor empagliflozin improves cardiac function and heart failure parameters in non-diabetic HF patients (EMPA-TROPISM [ATRU-4]: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic activity; NCT 03485222). [ABSTRACT FROM AUTHOR]