Initiation Of Sodium-glucose Cotransporter-2 Inhibitors Research Articles

469-P: Sodium–Glucose Cotransporter 2 Inhibitors Decrease the Frequency of Antivascular Endothelial Growth Factor Agent Injection in Patients with Type 2 Diabetes Complicated by Diabetic Macular Edema

Aims: Diabetic macular edema (DME) leads to impaired vision. The first line of treatment is intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent. However, there are patients who are refractory to this. We reported patients whose DME were refractory to anti-VEGF agents and showed improvement by using sodium glucose cotransporter 2 inhibitors (SGLT2is) . The effectiveness of SGLT2is for DME was assessed using a health insurance claim database. Methods: The JMDC inc. database covering million Japanese patients between 2005-20was used for analysis. Patients with type 2 diabetes (T2D) with DME were included, and those who were undergo dialysis, had other ocular diseases that may be treated by anti-VEGF agents, or were not on treatment with any antidiabetic drug introduced after 2014 were excluded. Propensity score matching was performed between SGLT2i users and non-users. The frequency and the duration of intravitreal injection of anti-VEGF agent after the period from the start of SGLT2is or other antidiabetic drugs were analyzed. Results: In this study, 340 matched patients with T2D were analyzed. Initiation of SGLT2is revealed a decrease in the frequency of anti-VEGF agent injection (2.7 ± 4.1 vs. 3.8 ± 4.6 times, p < 0.001; the Wilcoxon signed rank test, p < 0.001, 95%CI -0.25 to -0.085; the Poisson regression, p < 0.001, HR 0.80, 95% CI 0.73 to 0.87; the recurrent event analysis) and an extension in the duration for the requirement of the first injection of anti-VEGF agent (the number of patients who received no anti-VEGF agents, 96 vs. 32, p < 0.001; the log-rank test) . Conclusion: Using SGLT2is for patients with T2D complicated by DME extended the duration for the requirement of the first anti-VEGF agent injection and decreased the frequency of anti-VEGF agent injection. SGLT2is may be an option for DME treatment. Disclosure R.Ishibashi: Research Support; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., YL Biologics, ZERIA Pharmaceutical Co.,Ltd. E.Kawakami: None. M.Koshizaka: None. Y.Maezawa: None. K.Yokote: None. Y.Takatsuna: None. T.Tatsumi: None. S.Yamamoto: None. Y.Inaba: None. Y.Shiko: None.

Sodium-glucose cotransporter 2 inhibitors for treatment of diabetes mellitus after kidney transplantation.

Diabetes mellitus in kidney transplant recipients is a risk factor for cardiovascular events and premature death. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are increasingly used in nontransplant populations to improve diabetes control and cardiovascular and renal benefits. Limited literature exists regarding the safety and efficacy of these agents in renal transplant recipients. We retrospectively reviewed all kidney transplant recipients within our health system who were prescribed a SGLT2i after transplantation for diabetes. The safety, tolerability, and effectiveness of SGLT2i were analyzed. Thirty-nine kidney transplant recipients were initiated on SGLT2i therapy, twenty-seven of which remained on therapy for at least 1year. Ten (25%) patients experienced an adverse event while on a SGLT2i, with urinary tract infections (UTI) being the most common. Seventeen patients (43%) discontinued the SGLT2i at the time of chart review, most commonly due to cost and kidney function decline. The median [IQR] hemoglobin A1c (HbA1c) at SGLT2i initiation of 8.4% [7.8-9.2] decreased to 7.5% [6.8-8.0%] after 3months and 7.5% [6.5-7.9] after 12 months. No meaningful change in kidney function or tacrolimus exposure was observed. SGLT2i may be a safe and effective treatment for diabetes in kidney transplant recipients. Cost is a barrier to SGLT2i therapy, and UTIs were the most frequently encountered adverse events in this cohort. More studies are needed to understand the safety profile and determine the effect of SGLT2i on diabetes-related comorbidities among kidney transplant recipients.

Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study.

Evidence on the risk for cardiovascular events associated with use of first-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited. To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin. Population-based cohort study. Claims data from 2 large U.S. commercial and Medicare databases (April 2013 to March 2020). Patients with T2D aged 18 years and older (>65 years in Medicare) initiating treatment with SGLT-2i or metformin during April 2013 to March 2020, without any use of antidiabetic medications before cohort entry, were identified. After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported. First-line SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin. Primary outcomes were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Safety outcomes including genital infections were assessed. Among 8613 first-line SGLT-2i initiators matched to 17226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months. Initiators receiving SGLT-2i showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality compared with metformin. Initiators receiving SGLT-2i had a higher risk for genital infections (HR, 2.19; CI, 1.91 to 2.51) and otherwise similar safety as those receiving metformin. Treatment selection was not randomized. As first-line T2D treatment, initiators receiving SGLT-2i showed a similar risk for MI/stroke/mortality, lower risk for HHF/mortality and HHF, and a similar safety profile except for an increased risk for genital infections compared with those receiving metformin. Brigham and Women's Hospital and Harvard Medical School.

Acute kidney injury following SGLT2 inhibitors among diabetic patients: a pharmacovigilance study.

The sodium-glucose cotransporter-2 (SGLT2) inhibitors have changed the treatment of type 2 diabetes mellitus. Several studies evaluated SGLT2 inhibitor-related acute kidney injury (AKI), but pharmacoepidemiology studies are needed to compare the adverse events in different SGLT2 inhibitors (SGLT2i). We used disproportionality analysis and Bayesian analysis in data mining to screen the AKI cases after initiating different SGLT2i among diabetic patients, based on the FDA's Adverse Event Reporting System (FAERS) updated to December 2020. We also investigated the onset time and fatality rates of SGLT2i-associated AKI, which was based on preferred terms (PTs) coded for the renal adverse events in the structure of the FARES database. We identified 2483 cases of AKI following SGLT2i regimens among diabetic patients. Most of them were 45-64years old (58.46%) and > 65years old (28.67%). Canagliflozin generated the largest number of AKI reports (n = 1650, 66.45%) in our study. Canagliflozin showed the strongest association among SGLT2i, evidenced by the highest reporting odds ratio (ROR = 3.70, two-sided 95% CI 3.51-3.91), proportional reporting ratio (PRR = 3.39, χ2 = 2635.06), and empirical Bayes geometric mean (EBGM = 3.18, one-sided 95% CI 3.04). The median onset time to AKI was 72.0 (interquartile range [IQR] 21.0-266.0) days after SGLT2i initiation. The general hospitalization rate of SGLT2i-associated AKI was 63.50%, and the fatality rate was 1.59%. The deceased patients (62.94 ± 10.69years) were significantly older than the survived ones (57.82 ± 11.84years) (P = 0.011). We compared AKI events in the real-world practice of various SGLT2i among diabetic cases from the FAERS database. It is essential to monitor kidney function during the early administration of SGLT2i. Concern should be paid for AKI in patients older than 65 taking SGLT2i.

MO1034: Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Alport Syndrome and Fsgs: A Case Series

Abstract BACKGROUND AND AIMS Most hereditary diseases of the glomerular filtration barrier still progress to end-stage renal failure (ESRF)—raising the urgent need for add-on therapies. Recent randomized clinical trials (RCTs) demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney diseases (CKD). SGLT2-mediated afferent arteriole vasoconstriction, additive to efferent arteriole vasodilatation by angiotensin-converting enzyme inhibitors (ACEis), is postulated to correct the haemodynamic overload of the glomerular filtration barrier. For that reason, we investigated the nephroprotective effect of SGLT2i in hereditary glomerular diseases. METHOD In 2020, this monocentric prospective case series was started in six patients with Alport syndrome or FSGS, who consented to off-label therapy with empagliflozin or dapagliflozin. To our knowledge, this is the first case series on the effect of SGLT2i in patients with hereditary causes of CKD. RESULTS We report data on the use of SGLT2i in a case series of patients with Alport syndrome and FSGS in respect of the early effect on the kidney function and safety of initiation of therapy. The follow-up was 3–11 months. The mean age was 40 years (standard deviation, SD ± 17), the mean duration of treatment was 4.5 months (SD ± 2.9). The mean serum creatinine before and after SGLT2i initiation was 1.46 (SD ± 0.42) and 1.58 (SD ± 0.55). The mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT2i was 1827 (SD ± 1560) and decreased to 1127 (SD ± 854) after SGLT2i initiation. The estimated glomerular filtration rate (eGFR) ‘dipped’ after initiation of SGLT2i in most patients. Overall, treatment was well tolerated, however, eGFR initially decreased by more than 30% in one patient with FSGS. The initial eGFR drop raises some safety concerns, which underlines the need to collect and evaluate the course of every patient with AS in which therapy with SGLT2i is started. CONCLUSION In conclusion, therapy with SGLT2i on top of ACEi was well tolerated and effective in terms of lowering albuminuria. As a proof of concept, SGLT2-mediated correction of the haemodynamic overload of the glomerular filtration barrier looks like a very promising therapeutic approach in hereditary diseases such as AS and FSGS. Specific RCTs are needed to confirm our findings in this genetically well-defined population with a tremendous unmet medical need for more effective, early on and safe nephroprotective therapies. Proteinuria is reported as a urinary albumin-creatinine ratio in mg/g creatinine. All male patients received SGLT2i additive to renin-angiotensin-aldosterone system (RAAS)-blockade. In the female patient, ACEi was stopped prior to the start of SGLT2i because of angioedema. In addition to ACEi and SGLT2i, one patient also received tacrolimus because of irritable bowel disease. (A) eGFR (CKD-EPI formula) at baseline and at follow-up. (B) UACr at baseline and at follow up. m, male; f, female; FSGS, focal segmental glomerulosclerosis; XLAS, X-linked Alport syndrome; IBD, irritable bowel disease; aHT, arterial hypertension; sHP, secondary hyperparathyroidism; eGFR, estimated glomerular filtration rate; UACr, urine-albumin-creatinine ratio; Crea, serum-creatinine

FC 128: Novel Glucose-Lowering Drugs and the Risk of Acute Kidney Injury in Routine Care: The Stockholm Creatinine Measurements (SCREAM) Project

Abstract BACKGROUND AND AIMS Little is known about the comparative effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium glucose cotransporter-2 inhibitors (SGLT2i) on risk of acute kidney injury (AKI) in routinely care, which may differ from the controlled setting of trials. METHOD We performed a population-based retrospective analysis using the Stockholm CREAtinine Measurements (SCREAM) database, with complete information on diagnoses, medication dispensation claims and laboratory test results for all Stockholm citizens accessing healthcare during 2008–2018. We used a new user active comparator design: new initiation of SGLT2i, GLP1-RA or DPP-4i. The outcome AKI was defined by ICD-10 diagnostic codes as well as KDIGO criteria for rapid creatinine elevations. A multinominal propensity score model with inverse probability treatment weights (IPTW) was used to adjust for 59 identified confounders. Weighted Cox regression was used to estimate adjusted hazard ratios and weighted Kaplan-Meier curves for adjusted absolute risks. RESULTS We included 17 043 participants who newly initiated DPP-4i (N = 10 345), GLP1-RA (N = 4384) or SGLT2i (N = 2314). Mean age was 63 years (38% women) and median eGFR 89 mL/min/1.73 m2. During a median follow-up of 2.5 years, 1361 participants experienced AKI. SGLT2i users had the lowest incidence rate of AKI, 17.4 per 1000 person years [95% confidence interval (95% CI) 13.3–22.4], followed by GLP1-RA users, 22.2 (95% CI 19.6–25) and DPP-4 users, 26.1 (95% CI 24.6–27.8). The adjusted 3-year absolute risk for AKI was 5.98 (95% CI 3.65–8.38) in the SGLT2i arm, compared with 6.45 (95% CI 5.26–7.62) in the GLP1-RA arm and 7.03 (95% CI 6.45–7.59) in the DPP-4i arm. The adjusted hazard ratio was 0.85 (95% CI 0.58–1.18) for SGLT2i versus DPP-4i, and 0.93 (95% CI 0.78–1.11) for GLP1-RA versus DPP-4i. CONCLUSION This study of routinely cared patients initiating novel glucose-lowering drugs observed similar occurrence of AKI between therapies.

Complications of Chronic Kidney Disease: Therapeutic Approaches and What Can Be Done to Halt Disease Progression?

Singapore is one of the most rapidly ageing societies in the world. Currently, Singapore ranks first in the world for the incidence of diabetes-induced end-stage renal disease (ESRD) and seventh for the incidence of kidney failures per million population. It is estimated that nearly one-quarter of Singapore’s population will have chronic kidney disease (CKD) by 2035. Disease management of CKD has been identified as a critical issue due to the rapid increase in cases among the elderly in recent years. Chronic kidney disease is associated with adverse clinical outcomes, and metabolic complications such as anaemia, cardiovascular events, and CKD-associated metabolic bone diseases present treatment management complexities to healthcare professionals. Early detection and management of CKD can avert complications before symptoms occur and prevent the progressive loss of kidney function over time. Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) are recommended for hypertension and proteinuria management in CKD patients with and without diabetes. However, neither of these agents alone reduces the risk of all-cause mortality; furthermore, combinational therapy of ACEI plus ARB is associated with renal dysfunction, stroke, and/or hyperkalaemia. Recently, the use of sodium–glucose cotransporter 2 inhibitors (SGLT2i) has been shown to provide favourable effects on the kidney and cardiovascular outcomes in patients with or without type 2 diabetes mellitus. Studies have shown that early initiation of SGLT2i may slow or halt the progression of CKD in patients with the risk of CKD and ESRD. This review discusses the mechanisms underlying the progression of CKD, its associated risk factors and summarises the management strategies as per Kidney Disease Outcomes Quality Initiative clinical practice guideline recommendations. This article also summarises the evidence regarding the use of SGLT2i in slowing the progression of CKD and improvement of health-related quality of life.

Change in Diuretic Dose After Initiation of a SGLT2 Inhibitor in Patients with Heart Failure with Reduced Ejection Fraction

<h3>Purpose</h3> This study was designed to evaluate the change in loop diuretic dose at three months post-initiation of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) in patients with heart failure with reduced ejection fraction (HFrEF). <h3>Methods</h3> This was a retrospective cohort study including 69 patients from January 2020 to September 2021. Patients were included if they were ≥ 18 years old, had an ejection fraction (EF) of ≤ 40%, were prescribed a loop diuretic, and were initiated on a SGLT2i as an outpatient. Patients were excluded if the SGLT2i was discontinued prior to follow-up or if there was insufficient data available in the patient's chart such as missing loop diuretic dose or lack of follow-up visit after SGLT2i initiation. The primary outcome was the change in loop diuretic dose from baseline to 3 months after SGLT2i initiation. Secondary outcomes included change in other diuretic medications, change in the patient's heart failure status based on the New York Heart Association (NYHA) classification, and the incidence of adverse effects at 3 months after SGLT2i. The primary outcome was analyzed using the Wilcoxon signed-rank test with a p-value <0.05 considered significant. <h3>Results</h3> This cohort was primarily male (69.6%) with a median age of 64 years, a median EF of 20%, and a median loop diuretic dose of 40 mg (22.8-80.0) of furosemide equivalents at baseline. The majority of patients had NYHA class II or III at baseline (79.7%). Most patients were on guideline directed medical therapy at baseline with 63 patients (91.3%) on a renin-angiotensin inhibitor, 67 patients (97.1%) on a beta blocker, and 45 patients (65.2%) on a mineralocorticoid receptor antagonist. At a median of 94 days after initiation of a SGLT2i, 26 patients (37.7%) required a reduction in their loop diuretic dose. The median loop diuretic dose at 94 days was 40 mg (20.0-60.0) of furosemide equivalents which is a significant change from baseline (p = 0.001). No significant differences were noted in the secondary outcomes (p >0.05). <h3>Conclusion</h3> While the median loop diuretic dose was similar before and after SGLT2i initiation there was a statistically significant number of patients who had their loop diuretic dose reduced. This study provides a real-world experience on the additional diuresis obtained with a SGLT2i and a potential guide to loop diuretic dose adjustments in HFrEF patients.

Sodium Glucose Co-Transporter 2 Inhibitor Use in Patients with Left Ventricular Assist Devices

Purpose Multiple studies have shown improved cardiovascular outcomes with a sodium glucose-co-transporter 2 inhibitor (SGLT2i) in patients with heart failure with reduced ejection fraction (HFrEF). There are no current data supporting safety or efficacy in the Left Ventricular Assist Device (LVAD) population. The purpose of this study is to assess use of SGLT2 inhibitors in LVAD patients. Methods A retrospective analysis of LVAD patients implanted since 2015 was completed. Patients prescribed SGLT2i were identified. Clinical and laboratory variables were assessed following SGLT2i initiation with median values calculated at three and six month intervals. Results A total of 15 patients were prescribed SGLT2i, dapagliflozin (n=10) or empagliflozin (n=5), following LVAD implantation with follow-up time of 8 months (IQR 7-11). Six patients were naïve to SGLT2i until after implant, with 9 re-started on their pre-implant SGLT2i. Ten of the 15 carry a diagnosis of Diabetes Mellitus. Mean arterial pressure was 87 mmHg (IQR 82-88, n=15) at initiation, 78 mm Hg (IQR 74-89, n=15) at three months, and 82 mmHg (IQR 73-91, n=13) at six months. Estimated glomerular filtration rate was 70 mL/min/1.73m2 (IQR 54-92, n=15) at initiation, 79.5 mL/min/1.73m2 (IQR 60-94, n=12) at three months, and 74 mL/min/1.73m2 (IQR 62-78, n=9) at six months. Pro-brain natriuretic peptide decreased from 2005 pg/mL (IQR 1208-3813, n=13) at initiation, to 1334 pg/mL at 3 months (IQR 876-3617, n=11), and 885 pg/mL (IQR 409-1164, n=8) at 6 months. Glycated hemoglobin at the time of initiation was 7.4% (IQR 6.4-7.9, n=12), 7% (IQR 6.8-8.2, n=9) at 3 months, and 6.8% (IQR 6.5-7.3, n=6) at 6 months. One of the 15 patients had SGLT2i therapy discontinued due to recurrent genital yeast infections. Eight of the 15 patients had 11 total unplanned hospitalizations due to: gastrointestinal bleeding (2), acute decompensated heart failure (5), driveline infection (1), arrhythmia (1), drug-related reaction (1), diabetic ketoacidosis (DKA) (1). The hospitalization for DKA occurred while receiving high-dose steroids, and SGLT2i was resumed without adverse effects. Conclusion SGLT2i were successfully initiated in a small cohort of LVAD patients without significant adverse events. Larger, prospective studies are needed to determine if the cardiovascular and renal benefits of SGLT2i carry over from HFrEF to LVAD patients. Multiple studies have shown improved cardiovascular outcomes with a sodium glucose-co-transporter 2 inhibitor (SGLT2i) in patients with heart failure with reduced ejection fraction (HFrEF). There are no current data supporting safety or efficacy in the Left Ventricular Assist Device (LVAD) population. The purpose of this study is to assess use of SGLT2 inhibitors in LVAD patients. A retrospective analysis of LVAD patients implanted since 2015 was completed. Patients prescribed SGLT2i were identified. Clinical and laboratory variables were assessed following SGLT2i initiation with median values calculated at three and six month intervals. A total of 15 patients were prescribed SGLT2i, dapagliflozin (n=10) or empagliflozin (n=5), following LVAD implantation with follow-up time of 8 months (IQR 7-11). Six patients were naïve to SGLT2i until after implant, with 9 re-started on their pre-implant SGLT2i. Ten of the 15 carry a diagnosis of Diabetes Mellitus. Mean arterial pressure was 87 mmHg (IQR 82-88, n=15) at initiation, 78 mm Hg (IQR 74-89, n=15) at three months, and 82 mmHg (IQR 73-91, n=13) at six months. Estimated glomerular filtration rate was 70 mL/min/1.73m2 (IQR 54-92, n=15) at initiation, 79.5 mL/min/1.73m2 (IQR 60-94, n=12) at three months, and 74 mL/min/1.73m2 (IQR 62-78, n=9) at six months. Pro-brain natriuretic peptide decreased from 2005 pg/mL (IQR 1208-3813, n=13) at initiation, to 1334 pg/mL at 3 months (IQR 876-3617, n=11), and 885 pg/mL (IQR 409-1164, n=8) at 6 months. Glycated hemoglobin at the time of initiation was 7.4% (IQR 6.4-7.9, n=12), 7% (IQR 6.8-8.2, n=9) at 3 months, and 6.8% (IQR 6.5-7.3, n=6) at 6 months. One of the 15 patients had SGLT2i therapy discontinued due to recurrent genital yeast infections. Eight of the 15 patients had 11 total unplanned hospitalizations due to: gastrointestinal bleeding (2), acute decompensated heart failure (5), driveline infection (1), arrhythmia (1), drug-related reaction (1), diabetic ketoacidosis (DKA) (1). The hospitalization for DKA occurred while receiving high-dose steroids, and SGLT2i was resumed without adverse effects. SGLT2i were successfully initiated in a small cohort of LVAD patients without significant adverse events. Larger, prospective studies are needed to determine if the cardiovascular and renal benefits of SGLT2i carry over from HFrEF to LVAD patients.

Multidisciplinary Approach To Incorporating Sodium-glucose Co-transporter 2 Inhibitors In Ambulatory Heart Failure Patients

<h3>Introduction</h3> : In recent years, sodium-glucose co-transporter 2 inhibitors (SGLT2i) gained an indication in heart failure (HF) with reduced ejection fraction. With reduced cardiovascular mortality and HF hospitalizations, SGLT2i are now recommended and incorporated into the 2021 Update of the 2017 ACC Expert Consensus Decision Pathway for Optimization of HF Treatment. <h3>Hypothesis</h3> Multidisciplinary screening of patients in the ambulatory setting can identify qualified patients and facilitate SGLT2i initiation. <h3>Methods</h3> A SGLT2i initiation pilot program was started at the REX HF Clinic. During the pilot, a Clinical Pharmacist (CP) screened candidates based on select baseline demographics that included primary indications and contraindications to SGLT2i. It was decided that preference would be given to titration of traditional guideline-directed medical therapy (GDMT) over SGLT2i initiation. The CP screened all patients, identified those that qualified, and shared findings with the HF providers. Recommendations were made with consideration of SGLT2i cost and insurance-preferred agent. The HF provider and patient discussed medication changes as part of the clinic visit. When a SGLT2i was prescribed, the CP provided education to the patient, facilitated affordability by providing manufacturer coupon cards or assistance program applications, and monitored patient response and safety. <h3>Results</h3> : Two hundred forty-one unique patients were screened from October 2020 to April 2021, of which 112 patients (46.4%) qualified for SGLT2i (see TABLE 1). Sixty-four of the 112 patients had titration of other GDMT (57.1%). Of the remaining 48 patients, 12 were started on SGLT2i, while 7 had a contraindication. No medication changes were made in 15 patients, mostly due to patient preference or cost concerns.

Identifying Barriers To SGLT2 Inhibitor Use In Eligible Patients With Heart Failure: A Real-world Experience From A Single Centre

Background Recent landmark trials investigating the use of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with reduced ejection fraction (HFrEF) have demonstrated significant reductions in cardiovascular mortality and heart failure hospitalization. As a result of these trials, recent updates to major societal guidelines have included a strong recommendation for the initiation of SGLT2 inhibitors in patients with HFrEF and HF symptoms. The routine initiation of SGLT2 inhibitors in eligible patients, however, has been limited by several factors including cost, increased pill burden, concomitant chronic kidney disease and adverse effects, among others. Real-world data investigating the use of SGLT2 inhibitors and perceived barriers to their initiation in eligible heart failure patients are currently lacking. Methods/Results This is a prospective, single center, observational study evaluating the use of SGLT2 inhibitors in a specialized heart function clinic. Patients seen in clinic from January 1, 2021 to April 30, 2021 were screened for eligibility of SGLT2 inhibitor initiation. Patient characteristics, background medical therapy and lab values of interest were recorded using paper charts and local electronic records. Providers were asked to record whether SGLT2 inhibitor therapy was successfully initiated and if not, the reason it was not prescribed. In total 286 of 496 (57.7%) patients screened were eligible for SGLT2 inhibitor therapy. Among eligible patients, average age was 63.0 years (SD +/- 13.5); 217 patients were male (75.9%) and 69 female (24.1%); 17 (5.9%) were NYHA class 1, 220 (76.9%) were NYHA class 2, 47 (16.4%) were NYHA class 3 and 2 (0.7%) were NYHA class 4. In total 113/286 eligible patients were prescribed SGLT2 inhibitors (39.5%). Of these 286 eligible patients, 265 had HFrEF, of which 101 were prescribed an SGLT2 inhibitor (38.1%). The most common reasons for not prescribing SGLT2 inhibitor therapy included: up-titration or initiation of other medications/defer to future visit in 110 patients (63.6%), patient preference or refusal in 15 patients (8.7%) and inability to afford the cost of medication in 11 patients (6.4%). Conclusion A substantial proportion (57.7%) of HF patients are eligible for an SGLT2 inhibitor. However, SGLT2 inhibitors are currently underutilized in eligible patients seen in a specialized heart function clinic predominantly due to up-titration or initiation of other HF therapies. Strategies should be undertaken to increase utilization of this new class of therapy for HF to reduce cardiovascular events. Recent landmark trials investigating the use of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with reduced ejection fraction (HFrEF) have demonstrated significant reductions in cardiovascular mortality and heart failure hospitalization. As a result of these trials, recent updates to major societal guidelines have included a strong recommendation for the initiation of SGLT2 inhibitors in patients with HFrEF and HF symptoms. The routine initiation of SGLT2 inhibitors in eligible patients, however, has been limited by several factors including cost, increased pill burden, concomitant chronic kidney disease and adverse effects, among others. Real-world data investigating the use of SGLT2 inhibitors and perceived barriers to their initiation in eligible heart failure patients are currently lacking. This is a prospective, single center, observational study evaluating the use of SGLT2 inhibitors in a specialized heart function clinic. Patients seen in clinic from January 1, 2021 to April 30, 2021 were screened for eligibility of SGLT2 inhibitor initiation. Patient characteristics, background medical therapy and lab values of interest were recorded using paper charts and local electronic records. Providers were asked to record whether SGLT2 inhibitor therapy was successfully initiated and if not, the reason it was not prescribed. In total 286 of 496 (57.7%) patients screened were eligible for SGLT2 inhibitor therapy. Among eligible patients, average age was 63.0 years (SD +/- 13.5); 217 patients were male (75.9%) and 69 female (24.1%); 17 (5.9%) were NYHA class 1, 220 (76.9%) were NYHA class 2, 47 (16.4%) were NYHA class 3 and 2 (0.7%) were NYHA class 4. In total 113/286 eligible patients were prescribed SGLT2 inhibitors (39.5%). Of these 286 eligible patients, 265 had HFrEF, of which 101 were prescribed an SGLT2 inhibitor (38.1%). The most common reasons for not prescribing SGLT2 inhibitor therapy included: up-titration or initiation of other medications/defer to future visit in 110 patients (63.6%), patient preference or refusal in 15 patients (8.7%) and inability to afford the cost of medication in 11 patients (6.4%). A substantial proportion (57.7%) of HF patients are eligible for an SGLT2 inhibitor. However, SGLT2 inhibitors are currently underutilized in eligible patients seen in a specialized heart function clinic predominantly due to up-titration or initiation of other HF therapies. Strategies should be undertaken to increase utilization of this new class of therapy for HF to reduce cardiovascular events.

Impact of SGLT2i Use on Functional Capacity in Heart Failure

<h3>Purpose</h3> Recently published trials have shown benefit for patients with heart failure with reduced or preserved ejection fraction with the addition of sodium glucose co-transporter 2 inhibitors (SGLT2i) to optimal medical therapy (OMT). Outcomes are limited to readmission and mortality but fail to elucidate a benefit in functional capacity. Data regarding the impact of SGLT2i on hemodynamic optimization has not demonstrated benefit in heart failure patients. The impact of SGLT2i on peak oxygen consumption measured by cardiopulmonary stress testing (CPET) has only been evaluated in animal models. Our aim was to evaluate the physiological impact of SGLT2i in the advanced heart failure population. <h3>Methods</h3> We performed a retrospective study between August 1, 2020 and August 15, 2021 to evaluate all patients with heart failure (preserved or reduced ejection fraction) undergoing CPET. Pre and post CPET were required after initiation of SGLT2i or after OMT. The SGLT2i group was compared to matched controls on OMT. <h3>Results</h3> A total of 13,213 patients were on SGLT2i during our study period. Of those, 2,063 (16%) had a diagnosis of heart failure with a total of 96 patients with CPET. 46 of these (48%) patients were in the SGLT2i group and 50 (52%) were matched controls on OMT. Median LVEF was 33% (IQR 25-40) in the SGLT2i group and 38% (IQR 25 -50) in the OMT group, p=0.10. Median duration between baseline and follow-up CPET in SGLT2i group was 352 days and 437 days in the OMT group, p=0.06. Pre and post comparison between OMT and SGLT2i was not different for exercise time (p=0.09), VE/VCO2 (p=0.11), RER (p=0.45), METS (p=0.25) or NYHA class (p=0.28). Less ARNI use (29 vs. 39, p=0.05), higher A1C (6.5 vs 5.7, p=0.01), similar GFR (65 vs 63, p=0.25) and less hypotensive blood pressure response at peak exercise (p<0.01) was noted in the SGLT2i group. Estimated GFR was not impacted by SGLT2i use (p=0.21) There was no significant difference in VO2 max at baseline (p=0.18) or follow-up (p=0.19) between the two groups. Change in VO2 max after SGLT2i was not significant (p=0.31). <h3>Conclusion</h3> The pluripotent mechanism of SGLT2i effect in heart failure is not clearly understood. Current outcomes have limited focus on readmission and mortality. Our data suggest that SGLT2i use does not improve functional capacity in heart failure. Optimization with SGLT2i is potentially due to a predominant effect on neurohormonal modulation and diuretic effect in addition to OMT.

Medication Optimization for New Initiators of Empagliflozin for Diabetic Kidney Disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are recommended agents for the treatment of diabetic kidney disease (DKD). Additionally, SGLT2 inhibitors lower blood glucose, decrease blood pressure, and can be useful for volume management. For these reasons, we hypothesized that initiating SGLT2 inhibitor therapy may be associated with deprescribing of other medications in patients with DKD. We compared medication lists at SGLT2 inhibitor initiation and 6 months post-initiation in 21 patients with DKD who were followed in our interprofessional outpatient nephrology clinic to evaluate deprescribing patterns in diabetes, hypertension, and diuretic medications. Six months of SGLT2 inhibitor therapy in patients with DKD was associated with deprescribing of high-risk diabetes agents, antihypertensives, and loop diuretics with minimal changes in A1C and fewer adverse events.

Safety and Efficacy of SGLT2i Post Orthotopic Heart Transplantation

<h3>Purpose</h3> Diabetes mellitus is common after orthotopic heart transplantation (OHT) due to steroid-induced hyperglycemia. Traditionally, it has been treated using parenteral insulin therapy. The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in OHT recipients is not well established. <h3>Methods</h3> A retrospective chart review was performed on all the patients who underwent OHT at our center to identify patients on SGT2i post OHT. Clinical outcomes pre and post SGLT2i therapy were compared using the student t-test. <h3>Results</h3> Out of the 455 patients who had OHT at our single institution, 26 patients were on SGLT2i post OHT (1 patient was dual organ recipient - heart and liver transplant). The baseline characteristics are reported in Table 1. The median days from OHT to initiation of SGLT2i was 780 days (range 40-4986 days), and the median duration of therapy post-OHT was 169 days (range 38-2474 days). There was a statistically significant improvement in the average hemoglobin A1c, weight, and body mass index after starting SGLT2i (Results table). There was a trend towards improving renal function. There was no incidence of systemic infection, hypoglycemia, amputation, or euglycemic diabetic ketoacidosis while on SGLT2i. Two patients were able to discontinue insulin therapy after starting SGLT2i. There was no incidence or progression of cardiac allograft vasculopathy during the therapy. Two patients experienced graft rejection (1Antibody Mediated Rejection and 1 Acute Cellular Rejection) with drop in left ventricular systolic function that recovered after appropriate treatment. <h3>Conclusion</h3> SGLT2i can be used safely in OHT recipients. The renal protective mechanism of SGLT2i could be helpful to combat the nephrotoxicity of calcineurin inhibitors (CNI) used for immunosuppression and help prolong the use of CNI. Further randomized studies are required to explore the complete benefits of SGLT2i in OHT recipients

Effects of SGLT2 inhibitors on patients with diabetic kidney disease: A preliminary study on the basis of podocyturia.

BackgroundThe aim of this study was to investigate the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the glomerulus through the evaluation of podocyturia in patients with diabetic kidney disease (DKD).MethodsThe study population was composed of 40 male patients with type 2 diabetes mellitus; 22 of them received SGLT2i (SGLT2i group), and the others who did not were the control. The DKD‐related parameters of patients were monitored before SGLT2i initiation, and then in the third and sixth month of the follow‐up period. Patients' demographic, clinical, laboratory, and follow‐up data were obtained from medical charts. Microalbuminuria was measured in 24‐h urine. The number of podocytes in the urine was determined by immunocytochemical staining of two different markers, namely podocalyxin (podx) and synaptopodin (synpo). Concentrations of urine stromal cell‐derived factor 1a and vascular endothelial growth factor cytokines were quantified with an enzyme‐linked immunosorbent assay kit.ResultsAt the end of the follow‐up period, decreases in glycosylated hemoglobin, glucose, systolic and diastolic blood pressure, uric acid level, and microalbuminuria, and improvement in body mass index level and weight loss were significant for the SGLT2i group. On the other hand, there was no significant difference in terms of these parameters in the control group. The excretion of synaptopodin‐positive (synpo+) and podocalyxin‐positive (podx+) cells was significantly reduced at the end of the follow‐up period for the SGLT2i group, while there was no significant change for the control.ConclusionsAt the end of the follow‐up period, male patients receiving SGLT2i had better DKD‐related parameters and podocyturia levels compared to baseline and the control group. Our data support the notion that SGLT2i might have structural benefits for glomerular health.

Real-world evaluation of insulin requirements after GLP1 agonist or SGLT2 inhibitor initiation and titration.

To describe insulin adjustments made following initiation of glucagon-like peptide 1 agonist (GLP1a) or sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy in patients within a primary care setting. This was a multicenter, retrospective cohort study conducted at an academic health system. Adults with type 2 diabetes mellitus initiated on a GLP1a or SGLT2i while on insulin and managed by an ambulatory care pharmacist were included. The primary endpoint was the percent change in total daily insulin dose at specified time points (2 weeks, 4 weeks, 6 weeks, 3 months, and 6 months) after agent initiation. The secondary endpoints included a glycosylated hemoglobin (HbA1c) value of less than 8%, change from baseline HbA1c, and safety profiles of GLP1a therapy and SGLT2i therapy. Of the 150 patients included, 123 were initiated on a GLP1a and 27 on an SGLT2i. After 6 months, GLP1a initiation had resulted in a mean 23.5% decrease (P < 0.001) in insulin dosage and SGLT2i resulted in a mean 0.2% increase (P = 0.20). Insulin dosage reduction with GLP1a use was significantly different between baseline and each time point (P < 0.001). About 72% of patients initiated on a GLP1a and 59% of those initiated on an SGLT2i achieved an HbA1c value of less than 8%. The mean absolute change from baseline in HbA1c concentration was -1.7% with GLP1a use and -1.5% with SGLT2i use (P < 0.001 for both comparisons with baseline values). Hypoglycemia occurred in 21% of patients on a GLP1a and 11% of those on an SGLT2i. After GLP1a initiation, the mean total daily insulin dose decreased by 23.5%; after SGLT2i initiation, insulin requirements increased by a mean of 0.2%. These results will help guide insulin adjustments after initiation of these medications.

Efficacy and safety of sodium-glucose cotransporter 2 inhibitors initiation in patients with acute heart failure, with and without type 2 diabetes: a systematic review and meta-analysis

BackgroundThere is uncertainty and limited data regarding initiation of sodium-glucose cotransporter 2 (SGLT2) inhibitors among patients hospitalized with acute heart failure (AHF). This systematic review and meta-analysis aim to establish the efficacy and safety of SGLT2 inhibitors initiated in patients hospitalized for AHF.MethodsPubMed/Medline, Embase, and Cochrane library were searched using the following terms: (“sglt2" and "acute heart failure") and (“sglt2" and "worsening heart failure") from inception till November 15th, 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of initiating an SGLT2 inhibitor compared with placebo in patients with AHF. Major cardiovascular and diabetes scientific meetings in 2021 were also searched for relevant studies. Prespecified efficacy outcomes were all-cause mortality, rehospitalization for heart failure, and improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ) scale score. Prespecified safety outcomes were acute kidney injury (AKI), hypotension, and hypoglycemia. Random effects odds ratio (OR) and mean difference with 95% confidence intervals (CIs) were calculated.ResultsThree RCTs with a total of 1831 patients were included. Initiation of SGLT2 inhibitors in patients with AHF reduced the risk of rehospitalization for heart failure (OR 0.52; 95% CI [0.42, 0.65]) and improved Kansas City Cardiomyopathy Questionnaire scores (mean difference 4.12; 95% CI [0.1.89, 6.53]). There was no statistically significant effect for initiation of SGLT2 inhibitors in patients with AHF on all-cause mortality (OR 0.70; 95% CI [0.46, 1.08]). Initiation of SGLT2 inhibitors in patients with AHF did not increase the acute kidney injury (OR 0.76; 95% CI [0.50, 1.16]), hypotension (OR 1.17; 95% CI [0.80, 1.71]), or hypoglycemia (OR 1.51; 95% CI [0.86, 2.65]).ConclusionInitiation of SGLT2 inhibitors in patients hospitalized for AHF during hospitalization or early post-discharge (within 3 days) reduces the risk of rehospitalization for heart failure and improves patient-reported outcomes with no excess risk of adverse effects.

Impact of socioeconomic position on initiation of SGLT-2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes - a Danish nationwide observational study.

SummaryBackgroundLow socioeconomic position may affect initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucacon-like-peptide-1 receptor agonists (GLP-1RA) among patients with type 2 diabetes (T2D). We examined the association between socioeconomic position and initiation of SGLT-2i or GLP-1RA in patients with T2D at time of first intensification of antidiabetic treatment.MethodsThrough nationwide registers, we identified all Danish patients on metformin who initiated second-line add-on therapy between December 10, 2012, and December 31, 2020. For each time period (2012-2014, 2015-2017, and 2018-2020), we used multivariable multinomial logistic regression to associate disposable income, as proxy for socioeconomic position, with the probability of initiating a specific second-line treatment at time of first intensification. We reported probabilities standardised to the distribution of demographics and comorbidities of patients included in the last period (2018-2020).FindingsWe included 48915 patients (median age 62 years; 61·7% men). In each time period, high-income patients were more often men and had less comorbidities as compared with low income-patients. In each time period, the standardised probability of initiating a SGLT-2i or a GLP-1RA was significantly higher in the highest income group compared with the lowest: 11·4% vs. 9·5% (probability ratio [PR] 1·21, 95 % confidence interval [CI] 1·01-1·44) in 2012-2014; 22·6% vs. 19.6% (PR 1·15, CI 1·05-1·27) in 2015-2017; and 65·8% vs. 54·8% (PR 1·20, CI 1·16-1·24) in 2018-2020. The differences by income were consistent across multiple subgroups.InterpretationDespite a universal healthcare system, low socioeconomic position was consistently associated with a lower probability of initiating a SGLT-2i or a GLP-1RA. These disparities may widen the future socioeconomic gap in cardiovascular outcomes.FundingThe work was funded by unrestricted grants from ‘Region Sjaelland Den Sundhedsvidenskabelige Forskningsfond’ and ‘Murermester Lauritz Peter Christensen og hustru Kirsten Sigrid Christensens Fond’.

Evolving channeling in prescribing SGLT-2 inhibitors as first-line treatment for type 2 diabetes.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are increasingly being considered as first-line treatment for type 2 diabetes (T2D). The benefits of SGLT-2i from cardiovascular outcome trials may lead to preferential prescribing of SGLT-2i to patients at high cardiovascular risk, possibly causing confounding in non-randomized studies of SGLT-2i as first-line treatment. We assessed evolving imbalances in characteristics of patients starting SGLT-2i versus metformin as first-line monotherapy. Using claims data from two US commercial health insurance and Medicare, we identified patients with T2D aged ≥18 years (>65 years in Medicare) initiating first-line SGLT-2i or metformin from 2013 through 2019. Standardized differences (SDs) for patient characteristics were assessed during four consecutive calendar time blocks (T1:4/2013-12/2014; T2:1/2015-6/2016; T3:7/2016-12/2017; and T4:1/2018-12/2019). We also estimated the propensity score of receiving SGLT-2i versus metformin within each time block and evaluated time trends in model discrimination with c-statistics. We identified 9113 initiators of first-line SGLT-2i and 810 348 initiators of first-line metformin. During T1, SGLT-2i initiators were younger (SD=-0.24) and less likely to have seen cardiologists (-0.07) with a similar prevalence of CVD (0.04) compared with metformin. During T4, patients were more balanced for age (-0.01). Cardiologist visits (0.08) and CVD (0.25) became more prevalent among SGLT-2i initiators. When comparing initiators of first-line SGLT-2i versus metformin, imbalances in patient characteristics evolved from 2013 through 2019, particularly channeling SGLT-2i to individuals at high cardiovascular risk. Evolving channeling in prescribing first-line SGLT-2i should be expected and accounted for in non-randomized comparative effectiveness research.

Predictors of cardio-kidney complications and treatment failure in patients with chronic kidney disease and type 2 diabetes treated with SGLT2\xa0inhibitors

BackgroundClinical practice guidelines recommend sodium-glucose co-transporter 2 inhibitors (SGLT2is) to mitigate adverse kidney and cardiovascular outcomes in patients with type 2 diabetes (T2D), including patients with comorbid chronic kidney disease (CKD), also referred to as diabetic kidney disease (DKD), who are at even higher risk. In this study, we sought to identify predictors of cardio-kidney events, cardio-kidney complications, and treatment failure (i.e., addition/initiation of a new T2D class, insulin, or discontinuation of SGLT2is) after new initiation of SGLT2is in patients with CKD and T2D (DKD).MethodsIn this retrospective cohort study, we identified adult patients with DKD who initiated SGLT2is between April 1, 2012, and June 30, 2019, in Optum claims data. Outcome rates per 1000 person-years (PY) are reported with 95% confidence intervals (CIs). Cox proportional hazards regression identified patient characteristics associated with each outcome.ResultsThe study population consisted of 6389 initiators of SGLT2is. The rate of CV hospitalization was 26.0 (95% CI 21.6, 30.4) per 1000 PY. Baseline characteristics associated with higher risk of CV hospitalization included age, atrial fibrillation, peripheral vascular disease (PVD), and cancer. The rate of kidney hospitalization was 12.0 (95% CI 9.0, 15.0) per 1000 PY. The risk increased significantly with baseline evidence of heart failure, hyperkalemia, respiratory failure, depression, and use of loop diuretics. In total, 55.0% of all SGLT2i initiators discontinued treatment during the follow-up period. The rate of treatment failure was 510.5 (95% CI 492.9, 528.1) per 1000 PY. Analysis of key time-dependent SGLT2i-associated adverse events showed that experiencing diabetic ketoacidosis and volume depletion were associated with risk of treatment failure.ConclusionsOur study demonstrated high rates of residual cardio-kidney outcomes and treatment failure in patients with DKD treated with SGLT2is. Patients with high baseline CV risk and the presence of certain conditions, such as atrial fibrillation, PVD, and heart failure, were at higher risk for cardio-kidney events. Further research is needed to assess the potential relationship between adverse events and SGLT2i treatment failure.