Initiation Of Sodium-glucose Cotransporter-2 Inhibitors Research Articles

Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction

BackgroundNo study has compared the cardiovascular outcomes for sodium–glucose cotransporter-2 inhibitors (SGLT2i) head-to-head against other glucose-lowering therapies, including dipeptidyl peptidase 4 inhibitor (DDP4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA)—which also have cardiovascular benefits—in patients with heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction.MethodsMedicare fee-for-service data (2013–2019) were used to create four pair-wise comparison cohorts of type 2 diabetes patients with: (1a) HFrEF initiating SGLT2i versus DPP4i; (1b) HFrEF initiating SGLT2i versus GLP-1RA; (2a) HFpEF initiating SGLT2i versus DPP4i; and (2b) HFpEF initiating SGLT2i versus GLP-1RA. The primary outcomes were (1) hospitalization for heart failure (HHF) and (2) myocardial infarction (MI) or stroke hospitalizations. Adjusted hazards ratios (HR) and 95% CIs were estimated using inverse probability of treatment weighting.ResultsAmong HFrEF patients, initiation of SGLT2i versus DPP4i (cohort 1a; n = 13,882) was associated with a lower risk of HHF (adjusted Hazard Ratio [HR (95% confidence interval)], 0.67 (0.63, 0.72) and MI or stroke (HR: 0.86 [0.75, 0.99]), and initiation of SGLT2i versus GLP-1RA (cohort 1b; n = 6951) was associated with lower risk of HHF (HR: 0.86 [0.79, 0.93]), but not MI or stroke (HR: 1.02 [0.85, 1.22]). Among HFpEF patients, initiation of SGLT2i versus DPP4i (cohort 2a; n = 17,493) was associated with lower risk of HHF (HR: 0.65 [0.61, 0.69]) but not MI or stroke (HR: 0.90 [0.79, 1.02]), and initiation of SGLT2i versus GLP-1RA (cohort 2b; n = 9053) was associated with lower risk of HHF (0.89 [0.83, 0.96]), but not MI or stroke (HR: 0.97 [0.83, 1.14]). Results were robust across range of secondary outcomes (e.g., all-cause mortality) and sensitivity analyses.ConclusionsBias from residual confounding cannot be ruled out. Use of SGLT2i was associated with reduced risk of HHF against DPP4i and GLP-1RA, reduced risk of MI or stroke against DPP4i within the HFrEF subgroup, and comparable risk of MI or stroke against GLP-1RA. Notably, the magnitude of cardiovascular benefit conferred by SGLT2i was similar among patients with HFrEF and HFpEF.

Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with CKD and Type 2 Diabetes: Population-Based US Cohort Study.

Limited information exists regarding the safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with CKD treated in routine care. We evaluated the safety of SGLT2i in patients with CKD and type 2 diabetes treated in US routine practice. Using claims data from Medicare and two large US commercial databases (April 2013-December 2021), we included 96,128 adults with CKD stages 3-4 and type 2 diabetes who newly filled prescriptions for SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA). Safety outcomes included diabetic ketoacidosis (DKA), lower limb amputations, nonvertebral fractures, genital infections, hypovolemia, AKI, hypoglycemia, and severe urinary tract infections (UTIs). Hazard ratios (HRs) and incidence rate differences per 1000 person-years were estimated after 1:1 propensity score matching, adjusted for >120 baseline characteristics. Compared with GLP-1RA, SGLT2i initiators had a higher risk of nonvertebral fractures (HR, 1.30 [95% confidence interval (CI), 1.03 to 1.65]; incidence rate difference, 2.13 [95% CI, 0.28 to 3.97]), lower limb amputations (HR, 1.65 [95% CI, 1.22 to 2.23]; incidence rate difference, 2.46 [95% CI, 1.00 to 3.92]), and genital infections (HR, 3.08 [95% CI, 2.73 to 3.48]; incidence rate difference, 41.26 [95% CI, 37.06 to 45.46]). Similar risks of DKA (HR, 1.07 [95% CI, 0.74 to 1.54]; incidence rate difference, 0.29 [95% CI, -0.89 to 1.46]), hypovolemia (HR, 0.99 [95% CI, 0.86 to 1.14]; incidence rate difference, 0.20 [95% CI, -2.85 to 3.25]), hypoglycemia (HR, 1.08 [95% CI, 0.92 to 1.26]; incidence rate difference, 1.46 [95% CI, -1.31 to 4.23]), and severe UTI (HR, 1.02 [95% CI, 0.87 to 1.19]; incidence rate difference, 0.35 [95% CI, -2.51 to 3.21]) were observed. SGLT2i had lower risk for AKI (HR, 0.93 [95% CI, 0.87 to 0.99]; incidence rate difference, -6.75 [95% CI, -13.69 to 0.20]). In US patients with CKD and type 2 diabetes receiving routine care, SGLT2i use was associated with higher risks of genital infections and potentially lower limb amputations and nonvertebral fractures.

Changes in the use of glucose-lowering drugs: A Danish nationwide study.

To investigate changes in the pattern of drugs used to treat type 2 diabetes in Denmark from 2005 to 2021. A nationwide, population-based drug utilization study based on medical databases covering the Danish population was conducted. We assessed incident and prevalent use patterns among all 441 205 individuals initiating at least one non-insulin, glucose-lowering drug. The rate of new users of non-insulin, glucose-lowering drugs increased from 2005, peaked in 2011, decreased to stable levels during 2013 to 2019, then increased dramatically during 2020-2021. The prevalence of use increased from 2.1% (in 2005) to 5.0% (in 2021) of the entire adult population. In 2021, metformin comprised 39% of all glucose-lowering drug consumption, followed by insulin (17%), sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (17%), glucagon-like peptide-1 receptor agonists (GLP-1RAs) (16%) and dipeptidyl peptidase-4 inhibitors (7.5%). Overall, 56% of users were on monotherapy, 28% used dual therapy, while 13% and 2.8% used three and four drug classes, respectively. Both the intensity and diversity of therapies increased substantially over time, with 15 different treatment regimens each covering more than 1% of users in 2021. General practitioners prescribed 88% of all glucose-lowering drugs. Marked shifts towards GLP-1RA initiation by general practitioners and SGLT-2i initiation by specialists were observed, and changing user profiles suggested increasing use for non-diabetes indications. The rate of new users of non-insulin, glucose-lowering drugs has increased in recent years and the prevalence of glucose-lowering drug use increases steadily. Glucose-lowering drugs are mainly prescribed by general practitioners, and the intensity, diversity and indications of glucose-lowering treatment are increasing.

1153 SODIUM GLUCOSE COTRANSPORTER-2 INHIBITORS ELIGIBILITY IN PATIENTS WITH HEART FAILURE ACROSS THE SPECTRUM OF EJECTION FRACTION

Abstract Background Large randomized clinical trials demonstrated that sodium–glucose co-transporter-2 (SGLT2) inhibitors reduced adverse cardiovascular outcomes in patients with heart failure (HF) with both reduced (HFrEF) and preserved (HFpEF) ejection fraction. Despite the high potential to change clinical practice, the strict trial selection criteria might reduce external validity of these findings. Purpose The aim of the study was to evaluate the proportion of outpatients with HF that would be eligible for SGLT2 inhibitors across the spectrum of left ventricular ejection fraction (LVEF) in a contemporary real-world population. Methods We retrospectively evaluated patients with chronic stable HF followed-up at the outpatient clinic of our institution. HFrEF (LVEF <40%) patients’ eligibility was assessed according to the entry criteria of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials and to US Food and Drug Administration (FDA) label criteria (only dapagliflozin). In HFpEF group (LVEF>40%), Eligibility to SGLT2 inhibitors was based both strict and pragmatic (most likely influencing treatment decisions in clinical practice) EMPEROR- Preserved inclusion/exclusion criteria (empagliflozin). Results A total of 642 HF patients (441 HFrEF; 201 HFpEF) was studied. Among HFrEF patients, according to the major inclusion and exclusion criteria from DAPA-HF and EMPEROR-Reduced trials, 198 (45%) patients would be candidates for initiation of both dapagliflozin and empagliflozin, 61 (14%) would be eligible only to dapagliflozin and 23 (5%) only to empagliflozin, On the other hand, in HFpEF patients, 125 (62%) patients would be candidates for initiation of empagliflozin based on the EMPEROR-Preserved trial selection criteria. No significant differences were found between diabetic and non-diabetic patients in both HFrEF (p=0.23) and HFpEF (p=0.37). In patients not suitable for gliflozins treatment the major determinant of ineligibility was the failure to achieve the predefined NTproBNP inclusion threshold. Excluding NTproBNP as per FDA label criteria, dapagliflozin eligibility increased to 86%. Similarly, applying EMPEROR-Preserved criteria most likely influencing treatment decisions in clinical practice (symptomatic HF; eGFR <20 mL/min/1.73 m2; symptomatic hypotension; history of ketoacidosis) the proportion of HFpEF patients potentially eligible to empagliflozin rose to 85%. Conclusions In our real-world analysis the proportion of HF patients potentially candidate for initiation of SGLT2 inhibitors is consistent across the entire spectrum of LVEF. Our findings might herald an extensive use of gliflozins in HF treatment, with a consequent strong beneficial impact on cardiovascular outcomes in eligible patients.

Initiation of sodium-glucose cotransporter-2 inhibitors at lower HbA1c threshold attenuates eGFR decline in type 2 diabetes patients with and without cardiorenal disease: A propensity-matched cohort study

AimTo examine the association of initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) at lower glycemic threshold with decline in estimated-glomerular filtration rate (eGFR). MethodsWe analyzed a prospective cohort of Chinese patients with type 2 diabetes from Hong Kong. Patients initiating SGLT2i at HbA1c < 7.5 % (lower-HbA1c) versus ≥ 7.5 % (higher-HbA1c) were matched using 1:1 propensity score. We compared annual eGFR changes in the lower-HbA1c and higher-HbA1c groups using linear mixed-effect models. Binary logistic regression was used to explore associations of SGLT2i initiation at lower HbA1c with odds of rapid eGFR decline (>4% per year). ResultsAmong 3384 patients with a median follow-up of 1.9 years, the mean age was 60.2 ± 11.5 years and 62.1 % were male. The lower-HbA1c and higher-HbA1c groups had baseline HbA1c (%) of 6.9 ± 0.5 and 9.0 ± 1.3 respectively, with similar pre-index annual eGFR decline. The lower-HbA1c group had a slower post-index annual eGFR decline than the higher-HbA1c group (-0.99 versus −1.63 mL/min/1.73 m2, p < 0.001). Overall, the lower-HbA1c group had lower odds of rapid eGFR decline (OR = 0.15, 95 % CI: 0.07–0.29). Greater renoprotection from SGLT2i initiation at lower-HbA1c was observed in those with baseline eGFR < 60 mL/min/1.73 m2, albuminuria and/or treatment with renin-angiotensin-system inhibitors or insulin. ConclusionsIn this real-world study, SGLT2i initiation at HbA1c < 7.5 % was associated with slower eGFR decline especially in high risk patients, supporting the potential renal benefits of SGLT2i initiation at lower glycemic thresholds.

The effect of sodium glucose transporter 2 inhibitor in diabetic macular edema. A pilot study

AbstractPurpose: To investigate if the oral administration of sodium‐glucose cotransporter 2 (SGLT2) inhibitors may have a relevant role modifying the diabetic macular edema (DME) in naïve eyes of diabetic patients.Methods: We conducted a single‐arm pilot study including 6 eyes from 4 patients with type 2 DM with de novo DME who had never been treated with intravitreal injections of VEGF. We performed a first visit to ensure adequate metabolic control and blood pressure of the patients. Later, we add 100 mg/day of oral canagliflozin with an increase of 300 mg of canagliflozin at second month. In this study, visual acuity (VA) and central retinal thickness (CRT, μm) prior to and at 3 months after the initiation of SGLT2 inhibitors were retrospectively compared.Results: 3 of 4 patients maintained or improved their visual acuity. Only one patient worsened their visual accuracy in both eyes at week 12, and since this case exceeded the preset limit of 5 letters, the progression of DME was considered, requiring rescue with intravitreal anti‐VEGF treatment, according to the pre‐established protocol. After 12 weeks of follow‐up, median CRT improved from 317.5 to 302 μm (mean 15.5 μm).Maximum ILM‐EPR height of edema also reduced from 482 to 438 μm (mean 42.1 μm) None of the four patients reported severe adverse effects.Conclusions: To our knowledge, this pilot study is the first to evaluate the effect of oral canagliflozin in a series of patients with DME who have not previously received intraocular therapy or undergone vitreoretinal surgery. Based on our preliminary results, we could speculate that SGLT2i inhibitors may be useful to decrease DME within 12 weeks of treatment, with improvement of visual accuracy avoiding invasive treatments. Larger clinical studies are needed to confirm this relationship.

Abstract 11127: Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Heart Failure With Preserved Ejection Fraction and Type 2 Diabetes

Introduction: Limited information exists on the effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among patients with heart failure with preserved ejection fraction (HFpEF) in routine clinical care. Further, it remains uncertain if all agents in the SGLT2i class confer similar benefits in HFpEF. Methods: We compared initiators of SGLT2i versus sitagliptin, a DPP-4 inhibitor, using US Medicare data (04/2013-12/2018). Patients were required to have a diagnosis of type 2 diabetes (T2D) and HFpEF, identified using a validated prediction model. The primary outcome was a composite of all-cause mortality or worsening HF, i.e., outpatient use of intravenous diuretics or hospitalization for heart failure (HHF). Hazard ratios (HR) were estimated using Cox regression adjusting for 121 confounders. To address potential unmeasured confounding, we calibrated our results using estimates for HHF from a meta-analysis of HF RCTs of SGLT2i. Results: We included 33,475 patients with HFpEF and T2D (6,924 initiated SGLT2i and 26,551 initiated sitagliptin). Initiation of SGLT2i was associated with a lower risk of the primary composite outcome (adjusted HR 0.60; 95% CI 0.54-0.68), all-cause mortality (0.62; 0.53-0.74) and worsening HF (0.58; 0.52-0.66). We observed similar associations with the primary outcome for 3 SGLT2i agents (p-value for interaction 0.28) and across subgroups based on demographics, comorbidities, and HF treatments (Figure). Bias calibrated HR were 0.79 (0.69-92) for the primary composite outcome and 0.81 (0.63-1.03) for all-cause mortality suggesting our results cannot be fully explained by residual confounding. Conclusions: In routine US clinical practice, SGLT2i demonstrated robust clinical effectiveness in older adults with HFpEF and T2D without apparent heterogeneity across the class. Given the observational nature of the study, potential confounding and HFrEF/HFpEF misclassification cannot be entirely ruled out.

Abstract 10019: Access to Specialty Cardiovascular Care and Uptake of Cardioprotective Anti-Hyperglycemic Agents Among Adults With Type 2 Diabetes: A Cohort Study

Background: Sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are the only cardioprotective anti-hyperglycemic medications, but have had limited use. We evaluated whether access to specialty cardiovascular care improves the uptake of these cardioprotective medications in type 2 diabetes (T2D). Methods: In a retrospective cohort study between Jan 2019 and Dec 2020, beneficiaries with Medicare Advantage or commercial insurance were followed using Optum Labs’ de-identified administrative claims for the initiation of SGLT-2i and GLP-1RA among eligible adults with T2D across specialty visits. Eligibility included atherosclerotic cardiovascular disease (ASCVD), heart failure, or diabetic nephropathy for SGLT-2i and ASCVD for GLP-1RA. Detailed demographic and comorbidity information was obtained from the year before cohort enrollment. Results: Among eligible individuals for SGLT-2i (N=294,988) and GLP-1RA (N=198,525), 10.4% and 16.7% initiated these medications during the study period, respectively. Overall, 57% of those with an indication for SGLT-2i and 64% for GLP-1RA had at least one visit with a cardiologist. After accounting for differences in clinical characteristics and comorbidities, those with a visit with a cardiologist had higher odds of initiating SGLT-2i (OR = 1.26 [1.21-1.30]) and GLP-1RA (OR=1.05 [1.01-1.10]). However, these were not higher than those receiving care from family medicine and internal medicine providers and were substantially lower than those receiving care from an endocrinologist (Figure). Conclusion: In 2019-2020, among insured individuals with compelling CV indications, despite broad access to cardiovascular care, receiving care from cardiologists was only modestly associated with uptake of novel therapies. Efforts to improve the use of these medications are less likely to benefit from efforts to broaden access to specialty cardiovascular care.

Impact of early initiation of sodium-glucose cotransporter 2 inhibitor on cardiovascular outcomes in people with diabetes and known or at risk of atherosclerotic cardiovascular disease: Propensity score matched analysis.

We aimed to evaluate the impact of early initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) with known or at risk of atherosclerotic cardiovascular disease (ASCVD). T2D with first prescription of SGLT2i (Dx-to-Rx time) ≤12 months were matched with &gt;12 months using propensity score derived from logistic regression. T2D were divided into 3 groups: (i) known ASCVD; (ii) additional CV risk factor(s) and; (iii) without ASCVD or additional CV risk factors. Incidence rates of 3-point major adverse cardiovascular events (MACE, including non-fatal stroke, non-fatal myocardial infarction and CV death) were compared between Dx-to-Rx time ≤12 months and &gt;12 months across 3 subgroups. Median follow-up was 2.8 years (IQR 2.2 to 3.4). Among 29,309 T2D (mean age 57.6±11.4 years, 59.0% men), 23.6% had established ASCVD and 66.6% had additional CV risk factors. Overall, 19.0% of patients had Dx-to-Rx time ≤12 month which was associated with lower rates of MACE [hazard ratio (HR) = 0.27, 95%CI: 0.17-0.42]. Benefits of early initiation of SGLT2i was observed in patients with additional CV risk factors or known ASCVD but not in those without CV risk factors or ASCVD (P for interaction = 0.001). Early initiation of SGLT2 inhibitor was associated with lower MACE rates in T2D with known or at risk of ASCVD.

ODP242 Safety of SGLT2-Inhibitors in Patients with Multiple Myeloma and Diabetes

Abstract Background An estimated 10-20% of patients with multiple myeloma (MM) have type 2 diabetes (T2DM). About half of patients with MM will experience renal insufficiency,the risk of which increases in the setting of T2DM. While sodium-glucose cotransporter 2 inhibitors (SGLT2i) are beneficial in patients with chronic kidney disease (CKD) due to diabetic or hypertensive nephropathy, the role of SGLT2i in MM-related CKD is unknown. Moreover, as MM therapies target the immune system, concurrent use with SGLT2i may increase the risk of adverse events such as infections. The current work is the first to examine the potential benefit and safety of SGLT2i in patients with MM and T2DM. Methods This study was approved by the Institutional Review Board. A retrospective cohort study was performed on patients aged 18 years or older with MM who received SGLT2i therapy between March 2013 and December 2020 at a quaternary academic medical center. Electronic medical records were reviewed for the following data: demographics, comorbidities, MM parameters, medication and medical history, SGLT2i usage and duration, and hemoglobin A1c(HbA1c) and serum creatinine pre- and post-SGLT2i initiation. Data are presented as mean ± standard deviation or counts and percentages, and was analyzed using SPSS software (version 25. 0, IBM Corp). Results In total, 50 patients were identified. Patients who were diagnosed with MM after initiation of SGLT2i (n= 12), did not have any MM data available (n=1), or for whom SGLT2i usage could not be verified (n= 4) were excluded. Thirty-three patients were included in the final analysis. The mean age was 63 (±7.8) years, 63.6% were male, and 87.9% had active MM or MM in remission. Most had received stem-cell transplantation (55. 0%) and multiple lines of chemotherapy (63.6%) prior to SGLT2i initiation. The average HbA1c was 7.4% (±1.2%) and 20% of patients had CKD prior to SGLT2i initiation. The overall SGLT2i discontinuation rate was 42.4%, and the mean duration of therapy was 2.2(±1.5) years. Notably, 21.4% of discontinuation events were due to an increase in creatinine; however, for the entire cohort, there were no statistically significant changes in serum creatinine, total body weight, HbA1c, or 24-hour urine protein at 15 months’ follow-up. Other reasons for SLGT2i discontinuation included loss to follow-up, change of health insurance coverage for SGLT2i, and unrelated hospital admission. Genitourinary infection was not cited as a reason for any SGLT2i discontinuation. Conclusion SGLT2i therapy may be safe in patients with MM and T2DM, but no benefit was found with respect to serum creatinine, HbA1c, or 24-hour urine protein. Prospective research is required to further evaluate the potential benefit and safety of SGLT2i therapy in this population. Presentation: No date and time listed

Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States

Information regarding disparities in initiating sodium/glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) in patients with chronic kidney disease (CKD) is limited. We examined sociodemographic and clinical factors associated with the initiation of SGLT2i, GLP-1RA, or second-generation sulfonylureas in a Medicare Fee-For-Service patient population with CKD and type 2 diabetes. Retrospective cohort study. The 20% random sample of Medicare Fee-For-Service claims, 2012-2018. Patients' sociodemographic and clinical factors. Use of SGLT2i, GLP-1RA, or sulfonylureas. Patients with a newly initiated prescription of SGLT2i, GLP-1RA, or second-generation sulfonylureas from January 1, 2013, to December 31, 2018, were identified. Multinomial logistic regression model was used to evaluate demographic and clinical factors associated with the initiation of SGLT2i, GLP-1RA, or second-generation sulfonylureas. The study cohort comprised 53,029 adults (aged greater than or equal to 18 years) with CKD and type 2 diabetes, of whom 10.0%, 17.4%, and 72.6% had a first prescription for SGLT2i, GLP-1RA, and sulfonylurea, respectively. Patients aged greater than or equal to 75 years versus those aged 65-74 years had lower odds to start SGLT2i or GLP-1RA compared with sulfonylureas. Black patients were associated with lower odds of initiation of SGLT2i (OR, 0.67; 95% CI, 0.61-0.74) and GLP-1RA (OR, 0.73; 95% CI, 0.68-0.79), compared with White patients. Hispanic and Asian patients had lower odds of initiation of GLP-1RA. Patients with cardiovascular disease or hyperlipidemia had higher odds to start SGLT2i or GLP-1RA. CKD and type 2 diabetes diagnosis; CKD stage; and patient clinical status were identified with diagnosis or procedure codes. There is potential for residual confounding with the use of retrospective data. The results of this study identified disparities in the use of SGLT2i and GLP-1RA in patients with CKD. Black and older patients were significantly less likely to be initiated on SGLT2i or GLP-1RA than on second-generation sulfonylureas.

Impact of Inpatient Initiation of Sodium-Glucose Cotransporter-2 Inhibitors on Prescription Rates in Patients With Heart Failure With Reduced Ejection Fraction

Despite large, randomized controlled trials and guideline recommendations, patients with heart failure with reduced ejection fraction (HFrEF) continue to receive suboptimal guideline-directed medical treatment (GDMT). This study aimed to evaluate the potential effect of inpatient initiation of sodium-glucose cotransport-2 (SGLT2) inhibitors on postdischarge prescribing rates and the downstream impact on clinical outcomes. The INitiation of SGlt2i in Hospital for HFrEF (INSIGHT-HF) study was a retrospective analysis of hospitalized patients older than 18 years with a left ventricular ejection fraction (LVEF) ≤40% conducted from July 2020 and July 2021. Our primary outcome was SGLT2i prescription rates at 30days. Among 2,663 eligible patients with documented HFrEF, 177 (6.6%) had SGLT2i initiated during their index hospitalization. The rate of SGLT2i prescriptions at 30days was significantly higher in those with inpatient initiation of SGLT2i compared with those who did not start while inpatient (96% vs 14.7%, p <0.0001). The heart failure readmission rate in the first 30days was significantly lower in those with inpatient initiation of SGLT2i compared with those who did not start during hospitalization. (9.3% vs 22.7%, p=0.04). Cardiovascular mortality was numerically, but not significantly, different between groups (4% vs 10.7%, p=0.21). Inpatient initiation of an SGLT2i was associated with a significantly higher postdischarge rate of SGLT2i prescriptions and significantly lower heart failure readmission rates at 30days. In conclusion, these findings highlight the importance of initiating SGLT2i during inpatient hospitalization to improve the quality of care in patients with HFrEF.

Physicians' Considerations and Practice Recommendations Regarding the Use of Sodium-Glucose Cotransporter-2 Inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), although initially developed as glucose-lowering drugs, provide significant beneficial effects on cardiorenal outcomes, including heart failure, regardless of type 2 diabetes status. Integration of SGLT-2is into clinical practice requires practical guidance for physicians about their use. To overcome physicians’ clinical inertia for SGLT-2i use, including addressing safety, potentially a barrier to their use, a roundtable discussion with physicians from three specialties (cardiology, endocrinology, and nephrology) was conducted. This review summarizes the physicians’ clinical experience and recommendations about SGLT-2i use across different patient populations, taking into consideration the beneficial effects of SGLT-2is and their safety. The key aspects discussed regarding SGLT-2i safety include acute effects on kidney function (estimated glomerular filtration rate acute dip upon SGLT-2i initiation and acute kidney injury), volume depletion, diabetic ketoacidosis, genitourinary infections, hyperkalemia, and hypoglycemia. To mitigate any potential risks related to SGLT-2i safety, physicians can make minor adjustments to an individual patient’s treatment plan, while retaining the SGLT-2i cardiorenal benefits for effective disease management. Recognition by physicians that the benefits of SGLT-2i use on clinical outcomes outweigh the risks will result in the integration of SGLT-2is into clinical practice and lead to improved patient care and outcomes.

Sodium-glucose co-transporter-2 inhibitors after acute myocardial infarction in type 2 diabetes patients: a population-based investigation from South Korea

Abstract Background Whether the early use of sodium-glucose co-transporter-2 (SGLT2) inhibitors has cardioprotective effects following acute myocardial infarction (AMI) is unknown. Purpose We aimed to evaluate the association between the early initiation of SGLT2 inhibitors and cardiac event rates in diabetes patients with AMI undergoing percutaneous coronary intervention (PCI). Methods Based on the National Health Insurance claims data in South Korea, patients aged 18 years or older who had undergone PCI for the diagnosis of AMI between 2014 and 2018 were analyzed. Patients treated with SGLT2 inhibitors or other glucose-lowering drugs were matched based on a propensity score. The primary endpoint was a composite of all-cause mortality and hospitalizations for heart failure (HF). Major adverse cardiac events (MACE; a composite of all-cause death, non-fatal MI, and ischemic stroke) were compared as the secondary endpoint. Results After 1:2 propensity score matching, a total of 26,814 patients were assigned to the SGLT2 inhibitors group (938 patients) and the no use of SGLT2 inhibitors group (1,876 patients), respectively. During a median follow-up of 2.1 years, compared to no use of SGLT2 inhibitors, the early use of SGLT2 inhibitors was associated with lower risks of both the primary endpoint (9.8% vs. 13.9%, adjusted hazard ratio [HR] = 0.68, 95% confidence interval [CI]: 0.54 to 0.87, p=0.002) and secondary endpoint (9.1% vs. 11.6%, adjusted HR = 0.77, 95% CI: 0.60 to 0.99, p=0.04) (Figure 1). All-cause mortality and hospitalizations for HF were significantly lower in the early use of SLGT2 inhibitors group (adjusted HR = 0.55; 95% CI: 0.37 to 0.80; p=0.002; and HR = 0.74; 95% CI: 0.56 to 0.98; p=0.03, respectively). The incidence of non-fatal MI and ischemic stroke were not statistically different (Figure 2). Conclusions The early use of SGLT2 inhibitors in diabetes patients treated with PCI for AMI was associated with a significantly lower risk of cardiovascular events including all-cause mortality, hospitalizations for HF, and MACE. Our results suggest that the use of SGLT2 inhibitors could expand to the acute phase of AMI survivors with diabetes to reduce mortality and the subsequent development of congestive HF and ischemic events. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): This work was partly supported by the Research Institute of Medical Science, The Catholic University of Korea, Eunpyeong St. Mary's Hospital, Seoul, Republic of Korea.

Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: A perspective based on the updated evidence.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA, which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine 'sick day' guidance should be re-examined based on current evidence with a call for further research in this area. Furthermore, high-quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies.

Evaluation of Loop Diuretic Dosing Following Sodium-Glucose Cotransporter 2 Inhibitor Initiation in Patients With Heart Failure

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated cardiovascular benefits in patients with heart failure, many of which take loop diuretics. There are no evidence-based recommendations identifying which patients may require loop diuretic dose decreases or how to adjust loop diuretic doses when SGLT2is are initiated. Objectives: The main objective of this study was to investigate the frequency and degree of adjustments in loop diuretic doses after SGLT2i initiation in patients with heart failure. Methods: In this retrospective evaluation, patients seen in the UCHealth system with a diagnosis of heart failure who were prescribed a loop diuretic before initiation of SGLT2i were identified. We described loop diuretic dose changes at the time of SGLT2i initiation, at 6 months after initiation, and at 1 year after initiation. We also described de-escalation of maintenance medications that can contribute to hypotension at these time points. Data were evaluated using descriptive statistics. Results: A total of 100 patients were included. Loop diuretic dose was reduced empirically upon SGLT2i initiation in 2.0% of patients. Reduction of loop diuretic dose within the first 6 months of starting an SGLT2i occurred in 8.0% of patients. From baseline to 12 months after starting SGLT2i therapy, 14.0% of patients had loop diuretic dose reduction. Conclusions: Most of our patients with HF did not have change in loop diuretic dose after initiation of an SGLT2i. In patients who did have loop diuretic dose reduction, most occurred within 6 months after starting SGLT2i therapy rather than empirically at time of initiation.

Association of acute increases in serum creatinine with subsequent outcomes in patients with type 2 diabetes mellitus treated with sodium-glucose cotransporter 2 inhibitor or dipeptidyl peptidase-4 inhibitor.

The frequency of an acute increase in serum creatinine (sCr) of >30%, following treatment of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and its clinical implications in patients with type 2 diabetes remains unclear. We used medical data from a multicentre health care provider in Taiwan and recruited 11 657 and 8117 diabetic patients with baseline/follow-up sCr data available within 12 weeks of SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) treatment from 1 June 2016 to 31 December 2018. Participants receiving SGLT2i or DPP4i were categorized by initial sCr change into three groups: >30% sCr increase, 0-30% increase, or no-sCr increase. Participants receiving SGLT2i were associated with a higher proportion of sCr increase of 0-30% (52.7 vs. 42.6%) but a lower proportion of sCr increase of >30% (5.9 vs. 9.6%) when compared with DPP4i. In contrast to DPP4i, the mean estimated glomerular filtration rate over time became stable after 24 weeks in three categories of sCr increase following SGLT2i initiation. Compared with no sCr increase, an initial sCr increase of >30% was associated with a higher risk of major adverse cardiovascular events {adjusted hazard ratio (aHR): 2.91, [95% confidence interval (95% CI):1.37-6.17]}, heart failure hospitalization (HHF) [aHR:1.91, (95% CI:1.08-3.40)], and composite renal outcome [aHR:1.53, (95% CI:1.05-2.25)] in the SGLT2i group; an initial sCr increase of >30% associated with a higher risk of HHF and composite renal outcome in the DPP4i group after multivariate adjustment. Overall, participants receiving SGLT2i were associated with a lower risk of HHF [aHR:0.64, (95% CI:0.48-0.85)] and composite renal outcomes [aHR:0.40, (95% CI:0.34-0.48)] compared with DPP4i after multivariate adjustment, and the treatment benefit was persistent across three categories of sCr increase (P interaction>0.05). A modest increase in serum creatinine (<30%) was common following SGLT2i initiation, and was not associated with worse clinical outcomes, therefore should not stop therapy prematurely, but a larger increase in creatinine following drug therapy was not typical and should raise concern and review of the patient.

Significant reduction in chronic kidney disease progression with sodium-glucose cotransporter-2 inhibitors compared to dipeptidyl peptidase-4 inhibitors in adults with type 2 diabetes in a UK clinical setting: An observational outcomes study based on international guidelines for kidney disease.

To confirm the reno-protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors on the onset and progression of chronic kidney disease (CKD) in routine clinical practice. We conducted a retrospective cohort study using the Clinical Practice Research Datalink Aurum database linked to Hospital Episode Statistics. The primary outcome was risk of the composite CKD endpoint based on the recent consensus guidelines for kidney disease: >40% decline in estimated glomerular filtration rate (eGFR), kidney death or end-stage kidney disease (ESKD; a composite of kidney transplantation, maintenance of dialysis, sustained low eGFR <15 ml/min/1.73m² or diagnosis of ESKD). Secondary outcomes were components of the composite CKD endpoint, analysed separately. Patients were propensity-score-matched 1:1 for SGLT2 inhibitor versus DPP-4 inhibitor use. A total of 131 824 people with type 2 diabetes (T2D) were identified; 79.0% had no known history of CKD. During a median follow-up of 2.1 years, SGLT2 inhibitor initiation was associated with lower risk of progression to composite kidney endpoints than DPP-4 inhibitor initiation (7.48 vs. 11.77 events per 1000 patient-years, respectively). Compared with DPP-4 inhibitor initiation, SGLT2 inhibitor initiation was associated with reductions in the primary composite CKD endpoint (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.56-0.74), all-cause mortality (HR 0.74, 95% CI 0.64-0.86) and ESKD (HR 0.37, 95% CI 0.25-0.55), reduced the rate of sustained low eGFR (HR 0.33, 95% CI 0.19-0.57), and reduced diagnoses of ESKD in primary care (HR 0.04, 95% CI 0.01-0.18). Results were consistent across subgroup and sensitivity analyses. In adults with T2D, initiation of an SGLT2 inhibitor was associated with a significantly reduced risk of CKD progression and death compared with initiation of a DPP-4 inhibitor.

Real-World Prescription Patterns and Barriers Related to the Use of Sodium-Glucose Cotransporter 2 Inhibitors among Korean Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease.

BackgroundTo evaluate prescription trends and clinical factors of the sodium-glucose cotransporter 2 inhibitors (SGLT2i) use according to the presence of atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) in Korean patients with type 2 diabetes mellitus (T2DM).MethodsPrescription patterns of SGLT2i use between 2015 and 2019 were determined using the Korean National Health Insurance Service database of claims.ResultsOf all patients with T2DM (n=4,736,493), the annual prescription rate of SGLT2i increased every year in patients with ASCVD (from 2.2% to 10.7%) or HF (from 2.0% to 11.1%). After the first hospitalization for ASCVD (n=518,572), 13.7% (n=71,259) of patients initiated SGLT2i with a median of 10.6 months. After hospitalization for HF (n=372,853), 11.2% (n=41,717) of patients initiated SGLT2i after a median of 8.8 months. In multivariate regression for hospitalization, older age (per 10 years, odds ratio [OR], 0.57; 95% confidence interval [CI], 0.56 to 0.57), lower household income (OR, 0.93; 95% CI, 0.92 to 0.95), rural residents (OR, 0.95; 95% CI, 0.93 to 0.97), and dipeptidyl peptidase-4 inhibitor (DPP-4i) users (OR, 0.82; 95% CI, 0.81 to 0.84) were associated with lesser initiation of SGLT2i in ASCVD. Additionally, female gender (OR, 0.97; 95% CI, 0.95 to 0.99) was associated with lesser initiation of SGLT2i in HF.ConclusionThe prescription rate of SGLT2i increased gradually up to 2019 but was suboptimal in patients with ASCVD or HF. After the first hospitalization for ASCVD or HF, older age, female gender, low household income, rural residents, and DPP-4i users were less likely to initiate SGLT2i.

124-LB: Incidence and Risk Factors of Erythrocytosis following Initiation of Sodium–Glucose Cotransporter 2 Inhibitors in Men with Type 2 Diabetes in Real-World Setting

Background: Analyses of prospective trials consistently demonstrated that therapy with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in type 2 diabetes (T2D) results in mild but significant increase in hematocrit (Hct) . We sought to determine if SGLT-2i therapy poses risk of erythrocytosis (ERY) in routine clinical practice. Methods: This was a retrospective study of T2D US Veterans who were prescribed an SGLT-2i and had adequate adherence based on the proportion of days covered &amp;gt;80% during 3/2013-12/2019 and baseline Hct&amp;lt;50%. ERY incidence was defined as first Hct&amp;gt;54% within 180 days of an SGLT-2i initiation. The detailed patient data were obtained using the VA Informatics and Computing Infrastructure (VINCI) database. Odds ratio (OR) of ERY risk was calculated by logistic regression models adjusted for case-mix. Results: We identified 9402 patients (76.0% Whites/14.7% Blacks) with baseline mean±SD age 65.0±8.9 yrs, BMI 34.1±6.3 kg/m2, Hct 41.5±4.1 % and hemoglobin A1c 8.5±1.2 %. By the end of observation period, mean Hct increased from the baseline by 1.74% [95% CI 1.68-1.80] in the entire cohort and 61 patients (0.65% of the cohort) developed ERY. We found that BMI, tobacco use, or obstructive sleep apnea (OSA) were not associated with risk of developing ERY. However, concomitant use of testosterone replacement therapy (TRT) was associated with significant ERY risk compared with SGLT-2i users not on TRT in both unadjusted analyses (OR 12.28 [95% CI 5.29-25.10]) and after adjustments for age, race, BMI, OSA, and tobacco use (OR 7.26 [95% CI 2.95-16.04]) . The risk of ERY was independent of baseline Hct or modality of TRT (topical vs. injectable) . Conclusions: For the first time, we demonstrated that SGLT-2i initiation in men with T2D in real world clinical setting can result in detectable risk of erythrocytosis. It appears that concomitant TRT can significantly influence that risk. We recommend monitoring for Hct changes following SGLT-2i initiation and, particularly, in those persons who receive testosterone therapy. Disclosure A. R. Gosmanov: Research Support; AbbVie Inc., Kowa Research Institute, Inc., Speaker’s Bureau; AstraZeneca. D. E. Gemoets: None. M. A. Green: None. K. Schumacher: None.