Use Of Sodium-glucose Cotransporter-2 Inhibitors Research Articles

Efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with acute heart failure: a systematic review and meta-analysis.

The effectiveness and safety of a novel class of hypoglycemic medications known as sodium-glucose cotransporter 2 (SGLT2) inhibitors have not been completely established in relation to acute heart failure (AHF). Consequently, we sought to compare the prognostic and safety outcomes of patients administered SGLT2 inhibitors for the treatment of AHF. An extensive search of the Web of Science, PubMed, and EMBASE was conducted for randomized controlled trials and observational studies that have evaluated the use of SGLT2 inhibitors in AHF from the inception of these drugs to the present. We compiled data related to cardiovascular safety and prognosis. Aggregated risk ratios (RR), mean differences (MD), or standardized mean differences (SMD) were generated for all outcomes, with 95% confidence intervals (CIs), to evaluate the predictive significance of SGLT2 inhibitors in patients with AHF. We identified 4,053 patients from 13 studies. Patients experienced a substantial reduction in all-cause mortality (RR = 0.82, 95% CI: 0.70-0.96, P = 0.01), readmission rates (RR = 0.85, 95% CI: 0.74-0.98, P = 0.02), the number of heart failure exacerbation events (RR = 0.69, 95% CI: 0.50-0.95, P = 0.02), and the number of rehospitalization events due to heart failure (RR = 0.71, 95% CI: 0.58-0.86, P < 0.05) in the SGLT2 inhibitors-treatment group compared to a placebo or standard care (control group). SGLT2 inhibitors improved patient quality of life (SMD = -0.24, 95% CI: -0.40 to -0.09, P = 0.002). SGLT2 inhibitors were associated with enhanced diuresis in patients with AHF (MD = 2.83, 95% CI: 1.36-4.29, P < 0.05). Overall, treatment with SGLT2 inhibitors significantly reduced the level of serum NT-proBNP (MD = -497.62, 95% CI: -762.02 to -233.21, P < 0.05) and did not increase the incidence of adverse events (RR = 0.91, 95% CI: 0.82-1.01, P = 0.06). This meta-analysis suggests that treatment with SGLT2 inhibitors is associated with a better prognosis in patients with AHF than in patients not treated with SGLT2 inhibitors. It is safe and effective to initiate SGLT2 inhibitors in patients with AHF. https://www.doi.org/10.37766/inplasy2024.9.0015, identifier (INPLASY202490015).

Long-Term Mortality and SGLT2 Inhibitors in Type 2 Diabetes with and without Renal Impairment: An Observational Cohort Study

Aim: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a vital part of management of type 2 diabetes, as they have been shown to have both cardiovascular and renal benefits along with an improved survival rate in several randomized clinical trials. We designed a retrospective cohort study to investigate the impact of SGLT2 inhibitors on mortality among type 2 diabetes patients. Methods: Patients with type 2 diabetes who presented to the Dasman Diabetes Institute in Kuwait were followed from January 1st, 2015, until January 20th, 2023. To control for non-random allocation of SGLT2 inhibitors and measured confounders, we performed one-to-one propensity score matching and evaluated outcomes in the matched cohorts using a Cox proportional hazards model. The primary treatment variable was SGLT2 inhibitor use; time to mortality from any cause was used as the outcome of interest. Results: 1,551 patients were taking SGLT2 inhibitors, and 1,687 patients were not. After propensity score matching, 845 patients were on SGLT2 inhibitors, and 845 patients were not. In post-matching analysis, all-cause mortality was higher among patients who did not take SGLT2 inhibitors compared to patients taking SGLT2 inhibitors (5.2 vs. 2.1%, p = 0.0012). The hazard ratio of all-cause mortality in patients taking SGLT2 inhibitors was 0.42 (95% confidence interval [95% CI], 0.24–0.72). Additional adjustment of matching factors did not change the results. Conclusion: This observational study demonstrated substantial long-term reduction in mortality risk among patients with type 2 diabetes treated with SGLT2 inhibitors. This is irrespective of the stage of their renal diseases or GLP1 agonist.

The Year in Hungarian Cardiology 2023: Heart failure

The year 2023 proved to be a productive period with many remarkable scientific papers published from Hungary in the field of heart failure (HF). Our aim with this brief review is to highlight the results of the most prominent landmark randomized clinical trials as well as other relevant influential publications with significant contribution from Hungarian authors. Several clinical trials were published in 2023 with the primary focus on optimizing medical management. Papers described the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in HF in association with renal dysfunction, COVID-19 infection, and evaluating their economic impact. A comprehensive manuscript analysed the geographic differences in patient characteristics, treatments, and outcomes in the PARADISE-MI trial population. With regards to glucagon-like peptide-1 (GLP-1) receptor agonists, the STEP-HFpEF landmark clinical trial reported a favourable effect for semaglutide in patients with HFpEF and obesity. The intermittent administration of levosimendan did not improve post-hospitalization clinical stability in a population with advanced HF. In the field of cardiac resynchronization therapy (CRT), results of the BUDAPEST-CRT Upgrade trial was published in the European Heart Journal. This was the first prospective, randomized controlled trial to demonstrate that CRT upgrade in patients with intermittent or permanent RV pacing and HFrEF reduces morbidity and mortality. Several papers focused on the greater field of cardiomyopathies, including medical therapies, diuretic use, and cardiotoxicity. Finally, it is important to mention that an issue of Cardiologia Hungarica was published that was entirely dedicated to HF.

Value of the triglyceride-glucose index and related parameters in heart failure patients.

The triglyceride-glucose (TyG) index, proven to be a crucial insulin resistance biomarker (better than the Homeostasis Model Assessment for Insulin Resistance), is simple and non-invasive. Recently, indisputable evidence has shown that the TyG index is strongly associated with cardiovascular disease [CVD, including atherosclerosis, heart failure (HF), and hypertension] prognosis and mortality. Nevertheless, the value of the TyG index in HF patients treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) has not been systematically evaluated. Therefore, in this review, we summarized the value of the TyG index and its related parameters as markers of CVD, especially HF. Furthermore, we addressed the use of SGLT2is and GLP-1 receptor antagonists in HF patients. Finally, we summarized the mechanism of the "obesity paradox."

Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

Sodium-Glucose Cotransporter-2 Inhibitors in Odontogenic Infections

On top of improving glycemic control, sodium-glucose cotransporter-2 inhibitors have been shown to reduce cardiovascular mortality &amp; heart failure hospitalization. Sodium-glucose cotransporter-2 inhibitors have also been gaining momentum as effective reno-protective agents. Recent evidences have shown that sodium-glucose cotransporter-2 inhibitors are transforming the management of heart failure and chronic kidney disease in patients without type 2 diabetes mellitus. In view of the cardioprotective and reno-protective outcomes, as well as the potential benefits that outweigh adverse effects, it is no doubt that there will be continued increased use of sodium-glucose cotransporter-2 inhibitors. However, with use of sodium-glucose cotransporter-2 inhibitors comes risk of adverse effects, in particular diabetic ketoacidosis. Although uncommon, diabetic ketoacidosis is a potentially life-threatening acute metabolic complication. Diabetic ketoacidosis developing during sodium-glucose cotransporter-2 inhibitors use can present with normal blood glucose concentrations (euglycemia). This atypical presentation can delay diagnosis and hence, treatment. It is therefore crucial for dental practitioners to be cognizant of the increased risk of euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors use, especially during periods of reduced oral intake, such as in patients with odontogenic infection. Euglycemic diabetic ketoacidosis is a diagnosis of exclusion and should be considered as a differential in an ill patient on sodium-glucose cotransporter-2 inhibitors, despite normal blood glucose or absent urine ketones. We report a case of starvation ketosis in a patient with well-controlled type 2 diabetes mellitus, after excisional biopsy of right cervical lymph node and extractions of two lower right molars. Although the patient did not develop euglycemic diabetic ketoacidosis peri-operatively, it was an important diagnosis to exclude considering his high-risk profile of developing euglycemic diabetic ketoacidosis and the potential sequelae of missing the diagnosis.

Identifying Barriers and Facilitators for Increasing Uptake of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in British Columbia, Canada, using the Consolidated Framework for Implementation Research.

Care gaps remain in modern health care despite the availability of robust, evidence-based medications. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated profound benefits in improving both cardiovascular and kidney outcomes in patients, the uptake of these medications remain suboptimal, and the causes have not been systematically explored. The purpose of this study was to use the Consolidated Framework for Implementation Research (CFIR) to describe the barriers and facilitators faced by clinicians in British Columbia, Canada, when prescribing an SGLT2 inhibitor. To achieve this, we conducted semistructured interviews using the CFIR with practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Semistructured interviews. British Columbia, Canada. Actively practicing family physicians, nephrologists, endocrinologists, and cardiologists in British Columbia. Twenty-one clinicians were interviewed using questions derived from the CFIR. The audio recordings were transcribed verbatim, and each transcription was individually analyzed in duplicate using thematic analysis. The analysis focused on identifying barriers and facilitators to using SGLT2 inhibitors in clinical practice and coded using the CFIR constructs. Once the transcriptions were coded, overarching themes were created. Five overarching themes were identified to the barriers and facilitators to using SGLT2 inhibitors: current perceptions and beliefs, clinician factors, patient factors, medication factors, and health care system factors. The current perceptions and beliefs were that SGLT2 inhibitors are efficacious and have distinct advantages over other agents but are underutilized in British Columbia. Clinician factors included varying levels of knowledge of and comfort in prescribing SGLT2 inhibitors, and patient factors included intolerable adverse events and additional pill burden, but many were enthusiastic about potential benefits. Multiple SGLT2 inhibitor related adverse events like mycotic infections and euglycemic diabetic ketoacidosis and the difficulty in obtaining reimbursement for these medications were also identified as a barrier to prescribing these medications. Facilitators for the use of SGLT2 inhibitors included consensus among colleagues, influential leaders, and peers in support of their use, and endorsement by national guidelines. The experience from the clinicians regarding costs and the reimbursement process is limited to British Columbia as each province has its own procedures. There may be responder bias as clinicians were approached through purposive sampling. This study highlights different themes to the barriers and facilitators of using SGLT2 inhibitors in British Columbia. The identification of these barriers provides a specific target for improvement, and the facilitators can be leveraged for the increased use of SGLT2 inhibitors. Efforts to address and optimize these barriers and facilitators in a systematic approach may lead to an increase in the use of these efficacious medications.

Sodium-Glucose Cotransporter-2 Inhibitors Utilization and Outcomes in Patients with Chronic Kidney Disease at a Tertiary Centre

Sodium-glucose cotransporter-2 (SGLT2) inhibitor is an antidiabetic agent with cardiac and renal protective properties. Its renal protective property is a result of the inhibition of tubular sodium reabsorption and reduction in the intraglomerular pressure. The use of SGLT2 inhibitor in chronic kidney disease (CKD) independent of diabetic status is emerging. However, the real-world data of SGLT2 inhibitor utilisation in CKD is limited. We conducted a descriptive study of patients with CKD, who were prescribed with SGLT2 inhibitor in our Nephrology Clinic. A total of 156 patients were initiated on SGLT2 inhibitor from 2017 to 2022. Among them, 58.3% were male, with a mean age of 61 + 13 years, and 86.5% had diabetes mellitus, with estimated mean glomerular filtration rate (eGFR) of 46.41 + 21.14 ml/min/1.73m2, and proteinuria of 2.22 + 2.62 g/day. A total of 85.9% of patients were on renin-angiotensin-system (RAS) blockers, whereby those who were not prescribed with RAS were mostly CKD stage 4. Among the non-diabetic patients, 81% had glomerulonephritis, half of which was IgA nephropathy, and 42.9% were on immunosuppressants. There was a significant retardation of eGFR decline over a six-month-duration after the initiation of SGLT2 inhibitor from -3.46 + 6.56 ml/min/1.73m2 to -0.77 + 7.97 ml/min/1.73m2 (p=0.001). The retardation of eGFR decline was more pronounced in more advanced CKD stages. However, the proteinuria reduction was insignificant over a six-month-duration (-0.03 + 2.31 g/day). There were no adverse events reported. In conclusion, SGLT2 inhibitor retarded the eGFR decline with minimal proteinuria reduction in short-term. Nonetheless, long-term efficacy and safety data of SGLT2 inhibitor in local populations requires further evaluation.

Acute kidney injury as a risk factor for atrial fibrillation after coronary artery bypass grafting — effects of sodium-glucose cotransporter-2 inhibitors

Aim. To identify predictors of paroxysmal atrial fibrillation (pAF) in patients with stable angina after coronary artery bypass grafting (CABG), as well as to evaluate the effect of sodium-glucose cotransporter 2 (SGLT-2) inhibitors.Material and methods. We examined 92 patients with stable angina who received CABG, aged 64±7 years (men, 78,3%). Among this cohort, 81,5% of patients had multivessel coronary artery disease, carbohydrate metabolism disorders — 35,6%, hypertension — 96,7%, chronic kidney disease (CKD) — 23,9%, preprocedural pAF — 10,9%, previous myocardial infarction (MI) — 54,3%. Off-pump CABG was performed in 31,5%, including bilateral inthernal thoracic artery grafting — in 50%. Cardiopulmonary bypass time was 68 (55-83) minutes. The number of grafts was 2,7±0,7. In addition, 18,5% of individuals received SGLT-2 inhibitors. Serum creatinine content was determined by the Jaffe method, and CKD was diagnosed with glomerular filtration rate &lt;60 ml/min. Acute kidney injury (AKI) was assessed according to the KDIGO criteria (2012).Results. The number of patients who had pAF after CABG was 29,3%, AKI — 16,3%. There were following parameters associated with pAF after CABG: creatinine (100;82-142 in patients with pAF and 83;69-105 μmol/l — without pAF, p=0,032) and urea (7,8;5,8-9,7 in patients with pAF and 5,9;4,7-9,1 mmol/l — without pAF, p=0,025) one day after the intervention; postoperative AKI was revealed in 33,3% and 9,2% (p=0,004), while the number of patients taking SGLT-2 inhibitors was 3,7% and 24,6% (p=0,019) in those with and without pAF, respectively. The probability of pAF after CABG increased by an average of 5,5 times with AKI. Patients with pAF after CABG compared to patients without pAF have a higher rate of AKI, intraoperative MI, and cardiac death.Conclusion. The number of patients with pAF after CABG was 29,3%, AKI — 16,3%. Post-CABG pAF predictor was postoperative AKI. The use of SGLT-2 inhibitors was associated with a lower incidence of pAF after intervention. Patients with pAF after CABG have a poor inhospital prognosis.

Safety of sodium-glucose cotransporter 2 inhibitors drugs among heart failure patients: a systematic review and meta-analysis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce morbidity and mortality for heart failure (HF) patients and are recommended as cornerstones for their medical therapy. Utilization in clinical practice remains low for multiple reasons, one of which may be adverse events. We investigated the incidence of these events to see if they are associated with SGLT2i use. A systematic search was performed in databases, including PubMed, Embase, Cochrane Library, Clinicaltrials.gov, and WHO's International Clinical Trials Registry Platform. Relevant randomized controlled trial studies assessing the safety outcomes of SGLT2i in HF patients were included in this study. We conducted the common-effect meta-analysis to estimate the relative risk (RR) and 95% confidence interval (CI) of safety outcomes in SGLT2i compared with placebo. Eighteen studies were included in the meta-analysis composed of 12925 HF patients taking an SGLT2i and 12747 taking a placebo. The meta-analysis indicated that the all-cause mortality and serious adverse events (SAEs) were lower in the SGLT2i group (RR, 0.91; 95% CI, 0.85-0.97; P=0.005, I2=0%; and RR, 0.92; 95% CI, 0.90-0.95; P<0.001, I2=43%, respectively). Volume depletion and genitourinary infections were more prevalent in the SGLT2i group (RR, 1.17; 95% CI, 1.06-1.28; P=0.001, I2=0%; and RR, 1.27; 95% CI, 1.13-1.43; P<0.001, I2=17%, respectively). Our meta-analysis demonstrated that using SGLT2is in HF patients was correlated with reduced mortality and SAEs, with a more prominent effect in HF with reduced ejection fraction patients and those taking dapagliflozin.

Comparison of SGLT2 inhibitors vs. DPP4 inhibitors for patients with metabolic dysfunction associated fatty liver disease and diabetes mellitus

PurposeThis study aimed to examine the potential benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and diabetes mellitus (DM) using a real-world database.MethodsWe analyzed individuals with MAFLD and DM newly initiated on SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors from a large-scale administrative claims database. The primary outcome was the change in the fatty liver index (FLI) assessed using a linear mixed-effects model from the initiation of SGLT2 or DPP4 inhibitors. A propensity score-matching algorithm was used to compare the change in FLI among SGLT2 and DPP4 inhibitors.ResultsAfter propensity score matching, 6547 well-balanced pairs of SGLT2 and 6547 DPP4 inhibitor users were created. SGLT2 inhibitor use was associated with a greater decline in FLI than DPP4 inhibitor use (difference at 1-year measurement, − 3.8 [95% CI − 4.7 to − 3.0]). The advantage of SGLT2 inhibitor use over DPP4 inhibitor use for improvement in FLI was consistent across subgroups. The relationship between SGLT2 inhibitors and amelioration of FLI was comparable between individual SGLT2 inhibitors.ConclusionsOur analysis using large-scale real-world data demonstrated the potential advantage of SGLT2 inhibitors over DPP4 inhibitors in patients with MAFLD and DM.

Impact of Sodium-Glucose Cotransporter 2 Inhibitor on Recurrence After Catheter Ablation for Atrial Fibrillation in Patients With Diabetes: A Propensity-Score Matching Study and Meta-Analysis.

The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and atrial fibrillation (AF) recurrence after catheter ablation among patients with diabetes and AF remains unclear. Patients with AF undergoing initial catheter ablation with a history of diabetes from the China AF registry were included. Patients using SGLT2i were identified and matched by propensity score with non-SGLT2i patients in a 1:3 ratio. The main outcome was AF recurrence during the 18-month follow-up. A total of 138 patients with diabetes with SGLT2i therapy and 387 without SGLT2i were analyzed. AF recurrence occurred in 37 patients (26.8%) in the SGLT2i group and 152 patients (39.3%) in the non-SGLT2i group during a total of 593.3 person-years follow-up. The SGLT2i group was associated with lower AF recurrence compared with the non-SGLT2i group (hazard ratio, 0.63 [95% CI, 0.44-0.90], P=0.007). A total of 4 studies were analyzed in our meta-analysis demonstrating that SGLT2i was associated with lower AF recurrence after catheter ablation (odds ratio, 0.61 [95% CI, 0.54-0.69]; P<0.001, I2=0.0%). Our prospective study coupled with a meta-analysis demonstrated a lower risk of AF recurrence with the use of SGLT2i among patients with diabetes after AF ablation.

Urinary tract infections and genital mycotic infections associated with SGLT‑2 inhibitors: an analysis of the FDA Adverse Event Reporting System

ABSTRACT Background Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents, including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Risk of urinary tract infections (UTIs) and genital mycotic infections (GMIs) associated with SGLT‑2 inhibitors is of great clinical significance. The study aimed to assess the association between SGLT-2 inhibitors and occurrences of UTIs and GMIs using the FDA Adverse Event Reporting System (FAERS) database. Methods We used OpenVigil 2.1-MedDRA-v24 to query the FAERS database. Disproportionality analysis was performed to detect adverse event signals. Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) were calculated to measure the disproportionality. Results A total of 45,256 reports related to the use of SGLT-2 inhibitors, including 1,714 UTI cases and 438 GMI cases, were retrieved. Potential positive signals for UTIs and GMIs were identified for canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin in adult patients of all ages and both sexes. Conclusions Data mining in the FAERS database suggests strong association between SGLT-2 inhibitors and UTIs/GMIs. These findings provide real-world evidence on the potential risk of UTIs/GMIs related to SGLT-2 inhibitors.

How Would You Manage This Patient With Heart Failure With Preserved Ejection Fraction? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

The proportion of patients with new-onset heart failure who have preserved rather than reduced left ventricular ejection fraction (HFpEF and HFrEF) has been increasing over recent decades. In fact, HFpEF now outweighs HFrEF as the predominant heart failure subtype and likely remains underdiagnosed in the community. This is due in part to an aging population and a rise in other risk factors for HFpEF, including obesity and associated cardiometabolic disease. Whereas the diagnosis of HFrEF is relatively straightforward, the diagnosis of HFpEF is often more challenging because there can be other causes for symptoms, including dyspnea and fatigue, and cardinal physical examination findings of elevated jugular venous pressure or pulmonary congestion may not be evident at rest. In 2022, the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America published a comprehensive guideline on heart failure that included recommendations for the management of HFpEF. The use of diuretics for the management of congestion remained the only class 1 (strong) recommendation. New recommendations included broader use of sodium-glucose cotransporter-2 inhibitors (SGLT2i, class 2a), and angiotensin receptor-neprilysin inhibitors (class 2b). In 2023, the American College of Cardiology published an expert consensus decision pathway for the management of HFpEF that suggests treatment strategies based on sex assigned at birth, ejection fraction, clinical evidence of congestion, and candidacy for SGLT2i therapy. Here, 2 experts, a cardiologist and a geriatrician, discuss their approach to the diagnosis and management of HFpEF and how they would apply guidelines to an individual patient.

Sodium-Glucose Co-Transporter-2 Inhibitor Use in the Setting of Myeloproliferative Neoplasms: Impact on Hemoglobin/Hematocrit Levels and Thrombosis Risk

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are FDA-approved for diabetes mellitus, heart failure and chronic renal disease. Clinical trials on their anti-diabetic and cardiorenal protective effects showed an association with erythrocytosis. We have previously reported on the benign nature of SGLT-2I associated JAK2-unmutated erythrocytosis ( Blood 2021). Recently, we described the same phenomenon in the setting of a previously unrecognized myeloproliferative neoplasm (MPN), which led to unmasking of underlying MPN and thrombosis in 3 (33%) of 9 informative cases ( AJH 2023). The main objective of the current study was to assess the erythropoietic and thrombotic impact of SGLT-2I therapy in patients with a well-established MPN diagnosis, prior to treatment initiation. Methods: The Mayo Clinic MPN database was queried to identify patients prescribed SGLT2-I after diagnosis of essential thrombocythemia (ET), polycythemia vera (PV) or myelofibrosis (MF). Baseline Hgb/Hct at SGLT-2I initiation, peak Hgb/Hct, absolute change in Hgb/Hct levels, and thrombosis during treatment were recorded. Results: SGLT-2I use in essential thrombocythemia Eleven patients with ET (median age; 72 years, 55% males, 73% JAK2 mutated, 64% with thrombosis history) received SGLT-2I. Active treatments included aspirin ( n=10), cytoreductive therapy ( n=10) and systemic anticoagulation ( n=4). All 11 patients displayed increase in Hgb/Hct following SGLT-2I treatment. Baseline median (range) values for Hgb/Hct were 12.8 g/dL (9.5-14.9)/38.9% (30.3-44.6); median (range) peak Hgb/Hct levels during SGLT-2I therapy, were 14.5 g/dL (11-16.4)/44.4% (34.8-51.1), with median (range) increase in Hgb/Hct of 1.5 g/dL (1-4)/5.1% (2.6-13.8); 2 patients (18%), exceeded the proposed ICC Hgb/Hct diagnostic threshold for PV (Patient 7 and 8) (Figure 1). JAK2 mutation/VAF (p=0.54/ 0.20), or serum erythropoietin (Epo) (p=0.48) did not correlate with changes in Hgb/Hct levels. One patient experienced thrombosis, despite treatment with hydroxyurea and aspirin and Hgb/Hct levels below the threshold of concern (11.4 g/dL/37.7%). SGLT-2I use in polycythemia vera Nine patients with PV (median age 74 years, 66% males, JAK2 median VAF 14%, two patients with thrombosis history) received SGLT-2I. Concomitant treatments included aspirin ( n=9), cytoreductive therapy ( n=8), and systemic anticoagulation ( n=3). Phlebotomy intensity, defined as the number of phlebotomies, six months prior to and after SGLT-2I initiation, ranged from 0-3 and 0-12, respectively. Documented Hgb/Hct levels showed an increase in all 9 cases with baseline median (range) values for Hgb 14.1 g/dL (10.5-15.9) and Hct 42.7% (33.3-49.2) and peak median (range) values for Hgb/Hct, 15.4 g/dL (11.2-19.9)/46.7% (35.9-63.3). JAK2 VAF (p=0.85), and serum Epo (p=0.43) did not correlate with increase in Hct. Figure 2 highlights five patients (56%) with Hct exceeding 45% while on SGLT-2I; two patients (22%) had increased phlebotomy requirements; 6-month pre/post SGLT-2I phlebotomies for patient 5 and 9 were 3 and 6, and 0 and 12, respectively. Patient 9, experienced thrombosis in the context of uncontrolled Hgb/Hct level at 19.9 g/dl/63.3% and absence of cytoreductive therapy. SGLT-2I use in myelofibrosis Eight patients with myelofibrosis (primary 6, post-ET 2; median age 71 years; 50% males; 63% JAK2 mutated; MIPSS-70 2.0 int/high 6; on ruxolitinib 4),received SGLT-2I. Baseline median (range) values for Hgb/Hct were 10.6 g/dL (8.2-14.7)/27.5% (33.8-45.9); two (25%) patients displayed anemia with Hgb 8-10 g/dl. Peak median (range) values for Hgb/Hct were 11.5 g/dL (10.2-16.1)/35.3% (31.8-49.8), with median (range) baseline increase in Hgb/Hct of 1.6 g/dL (0.7-3.8)/4.3% (1-7.5). Patient 2 and 4 with baseline Hgb 8.2 g/dl and 9.4 g/dl, and not receiving ruxolitinib, had Hgb increase of 2 g/dl and 1 g/dl, respectively (Figure 3). One thrombotic event occurred during therapy with Hgb/Hct level of 11.6 g/dl/37.3%. Conclusion: The current study suggests that SGLT-2I therapy in MPN patients leads to increase in Hgb/Hct levels, regardless of disease subtype, and in some cases surpass the PV diagnosis and thrombosis risk thresholds. These observations mandate increased awareness to secure patient safety and diagnostic accuracy. The erythropoietic effect of SGLT-2I in MF suggests its potential use for MF-associated anemia.

Glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter 2 inhibitor use among adults with diabetes mellitus by cardiovascular-kidney disease risk: National Health and Nutrition Examination Surveys, 2015–2020

ObjectiveGlucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) lower adverse cardiac and kidney events among high-risk patients with diabetes mellitus (DM) and are now guideline-recommended as first-line therapy alongside metformin. However, the adoption of these new treatments from 2015 to 2020 among the highest-risk adults with DM remains unclear. MethodsWe performed a cross-sectional analysis of the National Health and Nutrition Examination Surveys (NHANES) 2015–2020 to estimate the use of GLP1-RAs and SGLT2Is among adults with DM overall and by level of cardiovascular and kidney risk (CKR). We defined high CKR by history of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), heart failure, or age ≥55 years with at least 2 ASCVD risk factors (i.e., obesity, hypertension, hyperlipidemia, or current smoker). ResultsOverall, 2,432 participants with DM (mean age 60.6 years, 46.8 % female, 58.8 % Non-Hispanic White) were included, of which 1,869 and 563 were with and without high CKR, respectively. Participants with vs. without high CKR were more likely to be older, have higher systolic blood pressure, lower estimated glomerular filtration rate, use oral antidiabetic agents, and have health insurance. Overall, the weighted prevalence of GLP1-RA or SGLT2I was 9.0 % (95 % confidence interval [CI] 6.9–11.0): 4.8 % (95 % CI 3.6–6.1) took GLP1-RAs, and 5.1 % (95 % CI 3.3–7.0) took SGLT2Is. Use of GLP1-RAs or SGLT2Is did not differ between participants with vs. without high CKR (adjusted prevalence ratio [aPR] 1.00; 95 % CI 0.98–1.02). Participants with ASCVD were more likely to be on a GLP1-RA or SGLT2I (aPR 1.28; 95 % CI 1.25–1.31), while adults with CKD were less likely (aPR 0.84; 95 % CI 0.82–0.86). ConclusionAmong US adults with DM, GLP1-RA and SGLT2I use was low regardless of CKR. Data since 2020 analyzing the utilization of GLP1-RAs and SGLT2Is among high-CKR patients with DM is needed to identify implementation strategies for increased utilization.

Sodium-glucose cotransporter 2 inhibitors are associated with reduced risk of mortality and readmissions in heart failure.

Compelling evidence from randomized trials has shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) are effective in heart failure (HF) across the spectrum of left ventricular ejection fractions. However, there are very few studies with real-world data. A retrospective cohort analysis was performed based on patient-level data from the Swedish Heart Failure Registry (SwedeHF) linked with three other national registers. Patients included had an index registration between 3 September 2013 and 31 December 2020 in SwedeHF and were on treatment with guideline-recommended therapy without or with SGLT2i 3months before or 6months after their index registration. Endpoints were mortality or readmissions. Association between the use of SGLT2i and endpoints was studied using adjusted Cox models. In the overall cohort, 796/22405 patients were included with/without SGLT2i. In patients with SGLT2i, 93.5% had diabetes mellitus. In the overall cohort, SGLT2i was statistically significantly associated with all-cause mortality {hazard ratio [HR]: 0.61 [95% confidence interval (CI) 0.48-0.79], P<0.0001}, cardiovascular mortality [HR: 0.29 (95% CI 0.17-0.50), P<0.0001], cardiovascular mortality or HF readmission [HR: 0.89 (95% CI 0.80-1.00), P=0.046], and all-cause readmissions [HR: 0.90 (95% CI 0.81-0.99), P=0.038]. Similar results were obtained for the diabetes cohort. However, no association with cause-specific readmissions was observed. This nationwide real-world study indicates that patients with HF, in which majority coexisted with diabetes mellitus, who received SGLT2i were statistically significantly associated with lower risk for all-cause mortality, cardiovascular mortality, cardiovascular mortality or HF readmissions, and all-cause readmissions, in line with the randomized trials assessing SGLT2i.

The effect of sodium-glucose co-transporter-2 (SGLT2) inhibitors on blood interleukin-6 concentration: a systematic review and meta-analysis of randomized controlled trials

BackgroundThe low-grade chronic inflammation in diabetes plays an important role in development of cardiovascular and renal complications. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recognized as protective agents for cardio-renal complications. Interleukin-6 (IL-6) is positively associated with the pathophysiology of metabolic-related pathologies. The aim of this meta-analysis is to investigate the effect of SGLT2 inhibitors on blood IL-6 concentration in randomized controlled trials (RCTs).MethodsEmbase, PubMed, and Scopus were systematically searched up to 1st of November 2023. The eligible studies were RCTs with adult population that had provided blood IL-6 for both control and intervention groups. Cochrane risk-of-bias tool were for study quality assessment. Data were analyzed using random effect model via Stata statistical software.ResultsEighteen studies with a total of 5311 patients were included. Of which 3222 and 2052 patients were in intervention and control arm, respectively. Of the total population, 49.7% were men. The study durations ranged from 8 to 52 weeks. The pooled analysis showed a significant association between the use of SGLT2 inhibitors and lower IL-6 levels (standardized mean difference (SMD) = -1.04, Confidence Interval (CI): -1.48; -0.60, I2 = 96.93%). Dapagliflozin was observed to have a higher IL-6-lowering effect (SMD = -1.30, CI: -1.89; -0.71, I2 = 92.52) than empagliflozin or canagliflozin. Sub-group analysis of control groups (SMD = -0.58 (-1.01, -0.15) and -1.35 (-2.00, -0.70 for the placebo and active control sub-groups, respectively) and duration of interventions (SMD = -0.78 (-1.28, -0.28) and -1.20 (-1.86, -0.55) for study duration of ≤ 12 and > 12 weeks, respectively) did not change the results. Meta-regression analysis showed a significant correlation between the level of HbA1c and IL-6-lowering efficacy of SGLT2 inhibitors.ConclusionIL-6 levels are significantly reduced with the use of SGLT2 inhibitors with HbA1c as the only marker influencing such reductions, and dapagliflozin had the highest potency. The anti-inflammatory effect of SGLT2 inhibitors supports their broader use to address diabetic complications related to inflammatory responses.

Association between hypoglycemic agent use and the risk of occurrence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus.

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern with increasing prevalence and associated health impacts. Although no approved drugs are available for the NAFLD treatment, several hypoglycemic agents have been investigated as promising therapeutic agents. We aimed to compare the risk of occurrence of NAFLD with respect to the use of different hypoglycemic agents in patients with type 2 diabetes. This retrospective cohort study used data from the National Health Insurance Service-National Sample Cohort of South Korea. Participants newly diagnosed with type 2 diabetes (2003-2019) were included in this study. Two new user-active comparator cohorts were assembled: Cohort 1, new users of thiazolidinediones (TZD) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and Cohort 2, new users of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and DPP-4i. The occurrence of NAFLD was defined based claims that include diagnostic codes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models in 1:3 propensity score (PS)-matched cohorts. For 65,224 patients newly diagnosed with type 2 diabetes, the overall prevalence of NAFLD was 42.6%. The PS-matched Cohort 1 included 6,351 and 2,117 new users of DPP-4i and TZD, respectively. Compared to DPP-4i, TZD use was associated with the decreased risk of NAFLD (HR, 0.66; 95% CI: 0.55-0.78). Cohort 2 consisted of 6,783 and 2,261 new users of DPP-4i and SGLT-2i, respectively; SGLT-2i use was associated with a decreased risk of NAFLD (HR, 0.93; 95% CI: 0.80-1.08). This population-based cohort study supports the clinical implications of prioritizing TZD and SGLT-2i over DPP-4i in reducing the risk of occurrence of NAFLD in patients with type 2 diabetes. However, the findings lacked statistical significance, highlighting the need for further verification studies.

Time to completely eradicate diabetic nephropathy

Abstract Diabetes mellitus (DM) is the most important cause of end-stage renal disease, blindness, autonomic neuropathy, and heart failure. These complications endanger life expectancy, quality of life, and health costs in patients suffering from DM. These complications start to develop, especially in type 2 DM (T2DM), before the onset of this disease. Accumulating evidence proves that complications of diabetes are due to hyperglycemia that develops many years before the patients fulfill the diagnostic criteria of T2DM. Pathologic changes of diabetic kidney disease (DKD) in these patients have already developed by the time of onset of frank DM but are still clinically silent. These facts can explain the failure of the different sodium–glucose cotransporter 2 inhibitors (SGLT2Is) to completely prevent renal events even in diabetic patients with apparently normal kidneys. Many studies have used different SGLT2Is in patients devoid of diabetes without the fear of hypoglycemia. Available evidence pushes toward the use of SGLT2Is as early as the onset of prediabetes. This approach would eradicate not only DKD but also other known complications. The use of these agents by the onset of T1DM might be also justifiable. The early use of SGLT2Is as early as the onset of prediabetes might abort the development of DKD completely. This review provides insights for prospective studies that would make this hope a reality.