Sodium-glucose Cotransporter 2 Inhibitor Therapy Research Articles

Comparative effectiveness of SGLT2i versus GLP1-RA on cardiovascular outcomes in routine clinical practice

BackgroundTo investigate the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular outcomes in routine clinical practice, which have never been directly compared in head-to-head outcome trials. MethodsWe compared outcomes of adults who newly started SGLT2i or GLP1-RA therapy in Stockholm, Sweden, during 2013–2019. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular (CV) death, myocardial infarction and stroke. Secondary outcomes included the individual MACE components and hospitalization for heart failure. Cox regression with propensity score overlap weighting was used to estimate hazard ratios (HRs) with 95% confidence intervals and adjust for 57 covariates. ResultsWe included 12,375 individuals, of which 5489 initiated SGLT2i and 6886 GLP1-RA therapy, followed for median 1.6 years. Mean age was 61 years and 37.6% were women. Compared with GLP1-RA, SGLT2i new users had similar risk of MACE risk (adjusted HR 1.04; 95% CI 0.83–1.31). The adjusted HRs (95% CI) for SGLT2i vs. GLP1-RA were 0.80 (0.59–1.09) for heart failure hospitalization, 0.95 (0.58–1.55) for cardiovascular death, 0.91 (0.67–1.24) for myocardial infarction and 1.71 (1.14–2.59) for ischemic stroke (5-year absolute risk difference for stroke 1.9% [95% CI 0.8–3.0]). ConclusionsIn a largely primary-prevention population of people undergoing routine care, no differences were observed in MACE risk among initiators of SGLT2i and GLP1-RA. However, compared with GLP1RA, the use of SGLT2i was associated with an increased risk of ischemic stroke that was small in absolute magnitude.

Three Sides to the Story: Adherence Trajectories During the First Year of SGLT2 Inhibitor Therapy Among Medicare Beneficiaries.

We aimed to understand the factors associated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) adherence and longitudinal adherence trajectories in older adults with type 2 diabetes. Using Medicare claims data (April 2013-December 2017), we identified 83,675 new SGLT2i users ≥66 years old with type 2 diabetes. We measured SGLT2i adherence as the proportion of days covered (PDC) during the first year of SGLT2i therapy. We used linear regression to assess the association between baseline covariates and PDC. Then we used group-based trajectory modeling to identify distinct longitudinal SGLT2i adherence groups and used a multivariable logistic regression model to examine the association between baseline covariates and membership in these adherence groups. Unadjusted mean PDC was 63%. Previous adherence to statins had the strongest positive association with PDC (regression coefficient 6.00% [95% CI 5.50, 6.50]), whereas female sex (-5.51% [-6.02, -5.00]), and Black race/ethnicity (-5.06% [-6.03, -4.09]) had the strongest negative association. We identified three adherence trajectory groups: low (23% of patients, mean PDC 17%), moderate (32%, mean PDC 50%), and high (45%, mean PDC 96%) adherence. More patients in the high adherence group were previously adherent to statins (odds ratio 1.43 [95% CI 1.39, 1.48]), and more women (1.28 [1.23, 1.32]) and Black patients (1.31 [1.23, 1.40]) were in the low adherence group. In a large population of older patients with type 2 diabetes, 45% were highly adherent during the first year of SGLT2i treatment. Female sex and Black race/ethnicity were most strongly associated with low adherence.

Prognostic Benefit of New Drugs for HFrEF: A Systematic Review and Network Meta-Analysis.

Background: The new heart failure (HF) therapies of sodium-glucose cotransporter 2 inhibitors (SGLT2i), vericiguat, and omecamtiv mecarbil do not act primarily through the neuro-hormonal blockade, but have shown clinical benefits in patients with HF with reduced ejection fraction (HFrEF). However, their respective efficacies remain unclear. Our aim was to evaluate the relative efficacy of new drugs for HFrEF. Methods: We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing SGLT2i, vericiguat, omecamtiv mecarbil, and placebo in HFrEF patients. The primary endpoint was the composite of cardiovascular death (CVD) or HF hospitalization (CVD-HF); secondary endpoints were CVD, all-cause death, and HF hospitalization (HFH). Results: Twelve RCTs (n = 23,861 patients) were included. A significant reduction in CVD-HF was observed with SGLT2i compared with placebo (risk ratio (RR) 0.77, 95% confidence interval (CI) 0.71–0.83), vericiguat (RR 0.84, 95% CI 0.75–0.93), and omecamtiv mecarbil (RR 0.80, 95% CI 0.72–0.88). No significant difference was observed between vericiguat and omecamtiv mecarbil (RR 0.95, 95% CI 0.87–1.04). SGLT2i were superior to placebo and omecamtiv mecarbil for all individual secondary endpoints (CVD, all-cause death, and HFH), and also to vericiguat for HFH. SGLT2i ranked as the most effective therapy for all endpoints, and vericiguat, omecamtiv mecarbil, and placebo ranked as the second, third, and last options, respectively, for the primary endpoint. Conclusions: In patients with HFrEF on standard-of-care therapy, SGLT2i therapy was associated with a reduced risk of CVD-HF compared to placebo, vericiguat, and omecamtiv mecarbil. Furthermore, SGLT2i were superior to placebo and omecamtiv mecarbil for CVD, all-cause death, and HFH, and also to vericiguat for HFH.

Hemochromatosis Gene Mutation in Persons Developing Erythrocytosis on Combined Testosterone and SGLT-2 Inhibitor Therapy.

In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) use alone in persons with type 2 diabetes (T2D) or testosterone replacement therapy (TRT) prescription alone in men with hypogonadism was shown to lead to a modest but significant increase in red blood cell mass. Recent evidence indicates that combined use of TRT and SGLT-2i in persons with T2D may be associated with risk of erythrocytosis. However, factor(s) that may lead to the development of erythrocytosis in these patients is unknown. We describe here 5 consecutive patients with hypogonadism on chronic TRT who developed erythrocytosis following addition of SGLT-2i empagliflozin for optimization of T2D management. In addition to the careful review of medical history, all patients underwent genetic screening for hereditary hemochromatosis. We have found that none of the patients had C282Y mutation in the HFE (Homeostatic Iron Regulator) gene and 4 out of 5 patients had heterozygosity in the H63D allele. Upon TRT discontinuation or its dose reduction or referral for scheduled phlebotomy, patients showed resolution of erythrocytosis. Our study reaffirms that practitioners should monitor for changes in hematocrit following the initiation of SGLT-2i in persons with T2D and hypogonadism on chronic TRT. Also, for the first time, we showed that in some of the patients receiving combined TRT and SGLT-2i H63D heterozygosity in the HFE gene may mediate the development of new-onset erythrocytosis.

Concomitant iGlarLixi and Sodium-Glucose Co-transporter-2 Inhibitor Therapy in Adults with Type 2 Diabetes: LixiLan-G Trial and Real-World Evidence Results

IntroductioniGlarLixi, the once-daily fixed-ratio combination of insulin glargine 100 U/ml and lixisenatide, robustly improves glycaemic control in adults with type 2 diabetes irrespective of previous treatment [oral antihyperglycaemic drugs (OADs), basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs)]. Sodium-glucose co-transporter-2 inhibitors (SGLT2is) are a recommended treatment option for people with type 2 diabetes with cardiovascular disease, kidney disease and/or heart failure because of their cardio- and renoprotective benefits. Herein, we assessed the effects of concomitant iGlarLixi and SGLT2i therapy.MethodsWe conducted subgroup analyses according to SGLT2i use in: (1) adults with suboptimally controlled type 2 diabetes on GLP-1 RAs and OADs switching to iGlarLixi in the 26-week LixiLan-G randomised controlled trial (RCT; NCT02787551) and (2) adults switching to or adding iGlarLixi in a 6-month, retrospective real-world evidence (RWE) observational study using data from the US Optum-Humedica electronic medical records database. Changes in HbA1c and hypoglycaemia prevalence and event rates were assessed.ResultsThere were no major differences in baseline characteristics for those who initiated iGlarLixi while already using SGLT2i (n = 346) and those initiating iGlarLixi without concomitant SGLT2i therapy (n = 1285). HbA1c reductions from baseline to time of assessment and hypoglycaemia prevalence and event rates were similar for iGlarLixi users regardless of SGLT2i therapy.ConclusionEvidence from an RCT and an RWE analysis supports the efficacy/effectiveness and safety of iGlarLixi when used concomitantly with SGLT2i.Trial RegistrationNCT02787551.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01180-1.

617 Effects of SGLT2 inhibitors on left and right ventricular function in a real-world diabetic population

Abstract Aims Heart failure (HF) is a pandemic and despite improvements in therapy, the mortality rate has remained unacceptably high. Sodium glucose cotransporter-2 inhibitors (SGLT2i) have emerged as a promising new class of glucose-lowering drugs, reducing HF-related outcomes across all ejection fraction ranges in clinical trials. However, few studies have assessed their efficacy using echocardiography imaging in a real-world setting. Methods and results Type 2 diabetes mellitus (T2DM) patients treated with SGLT2i from 2015 to 2020 were enrolled in a retrospective observational study. Clinical, biochemical, and echocardiographic data at baseline and 6 and 12 months after treatment initiation were collected. Of the 459 patients screened, 312 (68%) patients completed 1 year of SGLT2i therapy. Side effects were developed in 92 (20%) patients leading them to stop treatment pre-maturely, while 55 (12%) were lost to follow-up. From the 312 patients who completed 1 year of treatment, 83 patients had echocardiography data before initiation and after either 6 or 12 months of treatment and were included in the data analysis. Sample’s average age was 65.78 ± 8.53 years, 23 (27.7%) were females, and the mean BMI was 32.10 ± 6.29 kg/m2. At baseline patients had Hb1Ac 7.94 ± 1.80% and the mean duration of diabetes was 11.19 ± 8.54 years. 59 (71.1%) patients were asymptomatic (NYHA I) at baseline. The mean left ventricular ejection fraction (LVEF) at baseline was 48.40 ± 10.89%, while mean left ventricular end-diastolic volume (LVEDV) was 127.96 ± 41.84 ml. Mean pulmonary artery systolic pressure (PASP) was 33.63 ± 7.89 mmHg and mean tricuspid annular plane systolic excursion (TAPSE) was 20.18 ± 4.17 mm before treatment started. Mean E/e′ ratio at baseline was 9.75 ± 3.50. Mean septal wall thickness before therapy was initiated was 12.05 ± 1.80 mm while mean anterior wall thickness was 11.22 ± 1.52 mm. Almost all of the patients had at least one cardiovascular risk factor, hypertension being the most common (77, 92.8%), while 53 (63.9%) patients had a history of coronary artery disease (CAD), of which 42 (50.6%) had suffered a myocardial infarction. All-cause HF was present in 31 (37.3%) patients (19 HFrEF, 7 HFmrEF, 5 HFpEF). After a mean of 12.94 ± 7.91 months of SGLT2i treatment, left ventricular function was improved as LVEF was increased to 50.62 ± 10.04% (+2.22%, P = 0.018), while LVEDV was reduced to 123.24 ± 41.41 ml (−4.72 ml, P = 0.052). A trend towards improvement of the right ventricular function was also observed as TAPSE increased to 21.45 ± 3.92 mm (+1.27 mm, P = 0.076). PASP remained rather stable (−0.83 mm, P = 0.620), as well as the E/e′ ratio (−0.11, P = 0.857). Septal wall thickness was found unchanged (−0.16 mm, P = 0.449), as well as the anterior wall thickness (−0.63 mm, P = 0.143). After 1 year of treatment the number of asymptomatic patients remained stable (60, P = 0.863). Conclusions SGLT2i improved left ventricular systolic function in a sample of real-world diabetic patients, as shown by the changes in LVEF and LVEDV. A trend towards right ventricular function improvement was also recorded, demonstrated by the TAPSE increase. These findings highlight SGLT2i action on ventricular function and might be hypothesis generating to further elucidate their cardiovascular mechanism of action, beyond their already noted diuretic effect.

M18. Three-year cardiovascular outcome of SGLT-2 Inhibitor in patient with Type 2 Diabetes Mellitus: a Meta-Analysis of Randomized Control Trial

Abstract Aims SGLT-2 Inhibitor is an anti-diabetic drug. SGLT-2 Inhibitor has favourably effect in cardiovascular outcomes. However, the three-year cardiovascular outcomes of SGLT-2 Inhibitor in Type-2 Diabetes Mellitus remains unclear. We performed meta-analysis to evaluate cardiovascular outcomes in three-years of SGLT-2 Inhibitor therapy. Methods We performed a systematic literature search from various electronic databases. We used keywords “SGLT-2 Inhibitor”, “Type-2 Diabetes Mellitus”, and “Cardiovascular outcome”. Inclusion criteria for research is Randomized Control Trial and 3-year follow-up. Primary endpoint is Major Adverse Cardiovascular Event (MACE). Secondary endpoints are all-cause mortality, cardiovascular mortality and hospitalization of heart failure. Risk ratio (RR) with 95% confidence interval were used to report all outcomes. Results Total of two Randomized Control Trial was selected (EMPA-REG [Jardiance®] and VERTIS-CV [Steglatro®] trial) with 15.266 patients pooled in our analysis. Results of three-year primary outcome compared SGLT-2 Inhibitor with Placebo had no significant reduction in MACE (RR = 0.93 [95% CI, 0.81–1.07], p = 0.32; I2=56%). Result of secondary outcome showed no significant reduction in all-cause mortality (RR = 0.80 [95% CI, 0.60-1.08], p = 0.15; I2=85%) and cardiovascular mortality (RR = 0.77 [95% CI, 0.52–1.12], p = 0.17; I2=87%). However, there are significant reduction in hospitalization of heart failure (RR = 0.68 [95% CI, 0.57–0.82], p < 0.00001; I2=0%). Conclusion SGLT-2 Inhibitor in Type-2 Diabetes Mellitus has significant reduction in hospitalization of heart failure. However, no significant results were found in MACE, all-cause mortality, and cardiovascular mortality after 3-year follow-up.

Effect of Treatment With Sodium-Glucose Cotransporter 2 Inhibitor on the Initiation of Continuous Positive Airway Pressure Therapy in Type 2 Diabetic Patients With Obstructive Sleep Apnea Syndrome

Background: Obese patients with type 2 diabetes mellitus often develop obstructive sleep apnea syndrome (OSAS). In this study, continuous positive airway pressure (CPAP) was initiated in Japanese patients with type 2 diabetes mellitus who developed OSAS during treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the effect of the SGLT2 inhibitor therapy on the patients was investigated. Methods: The study was conducted in outpatients with type 2 diabetes mellitus with serum hemoglobin A1c (HbA1c) values of ? 6.5% who developed OSAS. The patients were divided into two groups according to whether they were receiving treatment with an SGLT2 inhibitor or with other oral hypoglycemic agents: the SGLT2 inhibitor group (n = 9) and non-SGLT2 inhibitor group (n = 7). The patients in the former group were under treatment with one of the following three SGLT2 inhibitors: luseogliflozin (2.5 mg/day), dapagliflozin (5 mg/day) and empagliflozin (10 mg/day). The patients took the drugs once daily, before or after breakfast. The patients were initiated on CPAP therapy for OSAS, and their weight, body mass index (BMI), serum HbA1c level, lipid profile, liver function parameters, serum uric acid, and apnea-hypopnea index (AHI) measured before the initiation of CPAP therapy (baseline) were compared with the values measured 3 months after the start of CPAP therapy. Results: The AHI decreased significantly after 3 months of CPAP therapy, as compared to that at the baseline, in both the SGLT2 inhibitor and non-SGLT2 inhibitor groups. There was no significant change in the serum HbA1c value after 3 months of CPAP therapy as compared to that at the baseline in either group. The body weight and BMI increased significantly after 3 months of CPAP therapy in the SGLT2 inhibitor group, but not in the non-SGLT2 inhibitor group. Conclusion: The body weight and BMI increased significantly after 3 months of CPAP therapy initiated for OSAS in the type 2 diabetic patients who were receiving SGLT2 inhibitor therapy. Thus, when CPAP therapy is adopted for an obese diabetic patient with OSAS, it should be borne in mind that the body weight may increase if the patient is receiving SGLT2 inhibitor treatment. J Clin Med Res. 2021;13(10-11):497-501 doi: https://doi.org/10.14740/jocmr4626

Effect of sodium-glucose cotransporter-2 inhibitors on cardiac remodelling: a systematic review and meta-analysis.

To examine the effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiac remodelling in patients with type 2 diabetes mellitus (T2DM) and/or heart failure (HF), and to explore the subsets of patients who may have greater benefit from SGLT2i therapy. Four electronic databases were searched for randomized controlled trials (RCTs) that evaluated the effects of SGLT2i on parameters reflecting cardiac remodelling in patients with T2DM and/or HF. Standardized mean differences (SMDs) or mean differences (MDs) were pooled. Subgroup analyses were performed according to the baseline HF and T2DM, HF type, SGLT2i agent, follow-up duration, and imaging modality. A total of 13 RCTs involving 1251 patients were analysed. Sodium-glucose cotransporter-2 inhibitors treatment significantly improved left ventricular (LV) ejection fraction [SMD, 0.35; 95% confidence interval (CI) (0.04, 0.65); P = 0.03], LV mass [SMD, -0.48; 95% CI (-0.79, -0.18); P = 0.002], LV mass index [SMD, -0.27; 95% CI (-0.49, -0.05); P = 0.02], LV end-systolic volume [SMD, -0.37; 95% CI (-0.71; -0.04); P = 0.03], LV end-systolic volume index [MD, -0.35 mL/m2; 95% CI (-0.64, -0.05); P = 0.02], and E-wave deceleration time [SMD, -0.37; 95% CI (-0.70, -0.05); P = 0.02] in the overall population. Subgroup analyses showed that the favourable effects of SGLT2i on LV remodelling were only significant in HF patients, especially HF with reduced ejection fraction (HFrEF), regardless of glycaemic status. Among the four included SGLT2i, empagliflozin was associated with a greater improvement of LV mass, LV mass index, LV end-systolic volume, LV end-systolic volume index, LV end-diastolic volume, and LV end-diastolic volume index (all P < 0.05). Sodium-glucose cotransporter-2 inhibitors treatment significantly reversed cardiac remodelling, improving LV systolic and diastolic function, LV mass and volume, especially in patients with HFrEF and amongst those taking empagliflozin compared with other SGLT2i. Reversed remodelling may be a mechanism responsible for the favourable clinical effects of SGLT2i on HF.

Impact of Sodium-glucose Cotransporter-2 Inhibitor Initiation in a Safety-net Hospital.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antihyperglycemic medications with cardiovascular disease and renal protective properties. While clinical trials supporting their efficacy, the utility among safety-net health system patients with low health literacy has not been evaluated. We sought to assess appropriate monitoring, safety and effectiveness of GLT2i initiation at a safety-net hospital. From May 2017 to July 2020, 150 patients were newly initiated on an SGLT2i therapy. We evaluated appropriate initiation, laboratory monitoring, impact on urine microalbumin, mean hemoglobin A1c (HbA1c), and systolic blood pressure (SBP). We also analyzed primary care versus subspecialty prescriber patterns. All patients did not have prohibitive renal dysfunction based on Food and Drug Administration labeling and the majority (N = 101, 67%) had renal function testing completed before initiation. Improvement in cardiovascular disease surrogate markers including SBP (mean, -3.12 mm Hg), albuminuria (mean, -3.98 mg/dL), and HbA1c (mean, -1.06%) were observed. A total of 94% of the cohort had serum chemistry panels drawn, yet only 4% were performed within the protocol-specified (14-day) period. Primary care and cardiology providers were the sole prescribers; despite the known renoprotective properties, no patients were initiated on SGLT2i therapy by a nephrologist. In conclusion, the benefits of SGLT2i drugs reducing SBP, albuminuria, and HbA1c observed in clinical trials were duplicated in our safety-net population. Therefore, ongoing education and promotion to providers to ensure broadened utilization and timely renal function monitoring appear warranted.

Abstract 9473: Implications of Removal of the Race Coefficient from Estimated Glomerular Filtration Rate Calculation on Sodium Glucose Co-transporter-2 Inhibitors Eligibility in Heart Failure and/or Chronic Kidney Disease

Introduction: The implications of race coefficient removal from the eGFR estimation equations on the pool of eligible Black patients with HFrEF and/or CKD for initiation of the Sodium Glucose Co-Transporter-2 inhibitors (SGLT2i) have not been evaluated. Hypothesis: To determine the change in eligibility by eGFR criteria for Black patients with HFrEF (EF&lt; 40%) and CKD for initiation of dapagliflozin with/without race inclusion in computing eGFR. Methods: Retrospective single-center analysis of Black patients with HFrEF (EF&lt;40%) hospitalized with a diagnosis of acute heart failure. Patients on any modality of dialysis were excluded. The serum creatinine value on discharge was used to compute eGFR using both MDRD and CKD-EPI formulae with and without the race coefficient. Eligibility eGFR value for initiation dapagliflozin for HFrEF was set at &gt;25cc/min/1.73m 2 , and the eGFR range of interest for initiation in CKD was set at the 25-75cc/min/1.73m 2 range. Results: A total of 396 Black patients were included in the analysis of which 62% were men. The mean age was 64±15 years and 37% had CKD stage 3-5. The proportion of patients eligible for initiation of dapagliflozin (eGFR&gt;25cc/min/1.73m 2 ) for HFrEF did not change significantly (93% with race vs 91% without race p=0.431 for MDRD and 92% vs 90% p=0.450 for CKD-EPI). On the other hand, the proportions for patients eligible by CKD eGFR range of 25 to 75 cc/min/1.73m 2 significantly increased with eGFR estimated without the race coefficient. This was true for both the MDRD and CKD-EPI equations (see Figure 1). Conclusions: The proportion of eligible patients for SGLT2i therapy (HFrEF and CKD) significantly increased when eGFR was computed without the race coefficient, driven by an increased CKD stage 3 range re-classification. Race coefficient removal in computation of eGFR did not adversely impact eligibility for SGLT2i when used for HFrEF.

Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial.

Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes. Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term. The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58-0.94] and 0.70 [0.37-1.30], respectively), expanded MACEs (0.77 [0.62-0.96] and 0.87 [0.51-1.48]), renal composite (0.70 [0.59-0.83] and 0.52 [0.33-0.83]), and MACEs or death (0.74 [0.59-0.93] and 0.65 [0.36-1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use. The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298.

Initiation of SGLT2 Inhibitors and the Risk of Lower Extremity Minor and Major Amputation in Patients with Type 2 Diabetes and Peripheral Arterial Disease: A Health Claims Data Analysis

To assess the association between long term risk of hospitalisation for heart failure (HHF) and lower extremity minor and major amputation (LEA) in patients initiating sodium glucose cotransporter 2 inhibitors (SGLT2i) suffering from type 2 diabetes and peripheral arterial disease (PAD). Outcomes were compared with patients without PAD and evaluated separately for the time periods before and after the official warning of the European Medicines Agency (EMA) in early 2017. This study used BARMER German health claims data including all patients suffering from type 2 diabetes initiating SGLT2i therapy between 1 January 2013 and 31 December 2019 with follow up until the end of 2020. New users of glucagon like peptide 1 receptor agonists (GLP1-RAs) were used as active comparators. Inverse probability weighting with truncated stabilised weights was used to adjust for confounding, and five year risks of HHF and LEA were estimated using Cox regression. Periods before and after the EMA warning were analysed separately and stratified by presence of concomitant PAD. In total, 44 284 (13.6% PAD) and 56 878 (16.3% PAD) patients initiated SGLT2i or GLP1-RA, respectively. Before the EMA warning, initiation of SGLT2i was associated with a lower risk of HHF in patients with PAD (hazard ratio, HR, 0.85, 95% confidence interval, CI, 0.73 - 0.99) and a higher risk of LEA in patients without PAD (HR 1.79, 95% CI 1.04 - 2.92). After the EMA warning, the efficacy and safety endpoints were no longer statistically different between groups. The results from this large nationwide real world study highlight that PAD patients exhibit generally high amputation risks. This study refutes the idea that the presence of PAD explains the excess LEA risk associated with initiation of SGLT2i. The fact that differentials among study groups diminished after the EMA warning in early 2017 emphasises that regulatory surveillance measures worked in everyday clinical practice.

Effect of Treatment With Sodium-Glucose Cotransporter 2 Inhibitor on the Initiation of Continuous Positive Airway Pressure Therapy in Type 2 Diabetic Patients With Obstructive Sleep Apnea Syndrome.

BackgroundObese patients with type 2 diabetes mellitus often develop obstructive sleep apnea syndrome (OSAS). In this study, continuous positive airway pressure (CPAP) was initiated in Japanese patients with type 2 diabetes mellitus who developed OSAS during treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the effect of the SGLT2 inhibitor therapy on the patients was investigated.MethodsThe study was conducted in outpatients with type 2 diabetes mellitus with serum hemoglobin A1c (HbA1c) values of ≥ 6.5% who developed OSAS. The patients were divided into two groups according to whether they were receiving treatment with an SGLT2 inhibitor or with other oral hypoglycemic agents: the SGLT2 inhibitor group (n = 9) and non-SGLT2 inhibitor group (n = 7). The patients in the former group were under treatment with one of the following three SGLT2 inhibitors: luseogliflozin (2.5 mg/day), dapagliflozin (5 mg/day) and empagliflozin (10 mg/day). The patients took the drugs once daily, before or after breakfast. The patients were initiated on CPAP therapy for OSAS, and their weight, body mass index (BMI), serum HbA1c level, lipid profile, liver function parameters, serum uric acid, and apnea-hypopnea index (AHI) measured before the initiation of CPAP therapy (baseline) were compared with the values measured 3 months after the start of CPAP therapy.ResultsThe AHI decreased significantly after 3 months of CPAP therapy, as compared to that at the baseline, in both the SGLT2 inhibitor and non-SGLT2 inhibitor groups. There was no significant change in the serum HbA1c value after 3 months of CPAP therapy as compared to that at the baseline in either group. The body weight and BMI increased significantly after 3 months of CPAP therapy in the SGLT2 inhibitor group, but not in the non-SGLT2 inhibitor group.ConclusionThe body weight and BMI increased significantly after 3 months of CPAP therapy initiated for OSAS in the type 2 diabetic patients who were receiving SGLT2 inhibitor therapy. Thus, when CPAP therapy is adopted for an obese diabetic patient with OSAS, it should be borne in mind that the body weight may increase if the patient is receiving SGLT2 inhibitor treatment.

Finerenone in Predominantly Advanced CKD and Type 2 Diabetes With or Without Sodium-Glucose Cotransporter-2 Inhibitor Therapy

IntroductionFIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) investigated the nonsteroidal, selective mineralocorticoid receptor (MR) antagonist finerenone in patients with CKD and type 2 diabetes (T2D). This analysis explores the impact of use of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) on the treatment effect of finerenone.MethodsPatients (N = 5674) with T2D, urine albumin-to-creatinine ratio (UACR) of 30 to 5000 mg/g and estimated glomerular filtration rate (eGFR) of 25 to <75 ml/min per 1.73 m2 receiving optimized renin-angiotensin system (RAS) blockade were randomized to finerenone or placebo. Endpoints were change in UACR and a composite kidney outcome (time to kidney failure, sustained decrease in eGFR ≥40% from baseline, or renal death) and key secondary cardiovascular outcomes (time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) (ClinicalTrials.gov, NCT02540993).ResultsOf 5674 patients, 259 (4.6%) received an SGLT-2i at baseline. Reduction in UACR with finerenone was found with or without use of SGLT-2i at baseline, with ratio of least-squares means of 0.69 (95% CI = 0.66–0.71) and 0.75 (95% CI -= 0.62–0.90), respectively (Pinteraction = 0.31). Finerenone also significantly reduced the kidney and key secondary cardiovascular outcomes versus placebo; there was no clear difference in the results by SGLT-2i use at baseline (Pinteraction = 0.21 and 0.46, respectively) or at any time during the trial. Safety was balanced with or without SGLT-2i use at baseline, with fewer hyperkalemia events with finerenone in the SGLT-2i group (8.1% vs. 18.7% without).ConclusionUACR improvement was observed with finerenone in patients with CKD and T2D already receiving SGLT-2is at baseline, and benefits on kidney and cardiovascular outcomes appear consistent irrespective of use of SGLT-2i.

Improving management of heart failure with reduced ejection fraction with sglt2i's by exploring practical considerations: an online education intervention

Abstract Background Heart Failure (HF) is a leading and increasing cause of morbidity and mortality worldwide. In the last 20 years, a strong emphasis has been placed on improving survival and quality of life in patients with HF. However, despite substantial therapeutic advances, morbidity, mortality, and hospitalization rates remain high. Purpose To determine if an online continuing professional development (CPD) intervention could improve knowledge and confidence of cardiologists and primary care physicians related to: reviewing the latest data and practical considerations of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of patients with heart failure with reduced ejection fraction (HFrEF), including implications for patient care. Methods Cardiologists and primary care physicians electively participated in a 30-minute, video-based, 3-faculty expert panel educational discussion reviewing the latest data and practical considerations of SGLT2 inhibitors in the management of patients with HFrEF. The effects of education were assessed using a repeated pairs, pre-assessment/post-assessment study design. For all questions combined, a McNemar's test assessed differences from pre- to post-assessment. P-values &amp;lt;0.05 are statistically significant. Cohen's d was used to estimate the magnitude of effect of education on the overall outcomes (knowledge/competence) range of &amp;lt;0.20 (modest), 0.20–0.49 (small), 0.50–0.79 (moderate), and &amp;gt;0.80 (large). The activity launched on December 23, 2020 and data were collected through to March 06, 2021. Results Overall significant improvements were seen after education for both cardiologists (N=186; P&amp;lt;0.001; moderate educational effect, d=0.57) and primary care physicians (N=140; P&amp;lt;0.001; small educational effect, d=0.40). Pre-assessment, the average correct response rate was 47% for cardiologists and 37% for primary care physicians, while post-assessment average correct response rates increased to 63% and 50%, respectively. Significant improvements were observed in cardiologists' and primary care physicians' knowledge related to the dissemination of the latest clinical data of novel therapies and appropriate patient selection for the treatment of HFrEF with an SGLT2 inhibitor (Table 1). As a result of the education, 70% of cardiologists and 77% of primary care physicians had a measurable improvement in confidence in their ability to appropriately select patients with HFrEF who could benefit from initiation of SGLT2 inhibitor therapy. Conclusion The statistically significant improvements observed in this intervention demonstrate the benefits of using a video-based panel discussion with synchronized slides to increase knowledge and confidence of cardiologists and primary care physicians on SGLT2i's latest clinical data and practical considerations. The outcomes suggest that this type of intervention could positively impact the quality of life and clinical outcomes of patients with HFrEF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim &amp; Lilly Table 1

Improving management of heart failure with reduced ejection fraction with sglt2i's using the latest clinical data: an online education intervention

Abstract Background Heart Failure (HF) is a leading and increasing cause of morbidity and mortality worldwide. In the last 20 years, a strong emphasis has been placed on improving survival and quality of life in patients with HF. However, despite substantial therapeutic advances, morbidity, mortality, and hospitalization rates remain high. Purpose To determine if an online continuing professional development (CPD) intervention could improve knowledge and confidence of cardiologists and primary care physicians related to: reviewing the latest clinical data on the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of patients with heart failure with reduced ejection fraction (HFrEF) and exploring the safety profile of SGLT2 inhibitors in HFrEF patients. Methods Cardiologists and primary care physicians electively participated in a 30-minute, video-based activity comprising of 4 mini lectures with synchronized slides by expert faculty on the review of clinical data on the use of SGLT2 inhibitors in the management of patients with HFrEF and exploring the safety profile of SGLT2 inhibitors in HFrEF patients. The effects of education were assessed using a repeated pair, pre-assessment/post-assessment study design. For all questions combined, a chi-square test assessed differences from pre- to post-assessment. P-values &amp;lt;0.05 are statistically significant. Cramer's V was used to assess level of educational effect using the range of &amp;lt;0.06 (modest), 0.06–0.15 (noticeable), 0.16–0.26 (considerable), and &amp;gt;0.26 (extensive). The activity launched on November 2, 2020 and data were collected through to December 22, 2020. Results Overall significant improvements were seen after education for both cardiologists (N=124; P&amp;lt;0.001; noticeable educational effect, V=0.129) and primary care physicians (N=207; P&amp;lt;0.0001; noticeable educational effect, V=0.113). Pre-assessment, the average correct response rate was 40% for cardiologists and 32% for primary care physicians, while post-assessment average correct response rates increased to 53% and 43%, respectively. Significant improvements were observed in cardiologists' and primary care physicians' knowledge related to the dissemination of the latest clinical data of novel therapies and the mechanistic effects of SGLT2 inhibitors in patients with HFrEF (Table 1). As a result of the education, 24% of cardiologists and 30% of primary care physicians had a measurable improvement in confidence in their ability to appropriately select patients with HFrEF who could benefit from initiation of SGLT2 inhibitor therapy. Conclusion The statistically significant improvements observed in this intervention demonstrate the benefits of using a video-based mini lectures with synchronized slides to increase knowledge and confidence of cardiologists and primary care physicians on SGLT2i's and how these therapies could positively impact the quality of life and clinical outcomes of patients with HFrEF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim &amp; Lilly Table 1

IDENTIFYING BARRIERS TO SGLT2 INHIBITOR USE IN ELIGIBLE PATIENTS WITH HEART FAILURE: A REAL-WORLD EXPERIENCE FROM A SINGLE CENTRE

<h3>BACKGROUND</h3> 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, the Canadian Cardiovascular Society (CCS) has recently published a guideline update strongly recommending 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. Canadian real-world data investigating the use of SGLT2 inhibitors and perceived barriers to their initiation in eligible heart failure patients are currently lacking. <h3>METHODS AND RESULTS</h3> 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 Mar 31, 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, 258 of 384 (67%) patients screened were eligible for SGLT2 inhibitor therapy. Among eligible patients, average age was 63.1 years (SD +/- 13.7); 197 patients were male (76.4%) and 61 female (23.6%); 14 (5.4%) were NYHA class 1, 200 (77.5%) were NYHA class 2, 42 (16.3%) were NYHA class 3 and 2 (0.8%) were NYHA class 4. In total 104/258 eligible patients were prescribed SGLT2 inhibitors (40.3%). The most common reasons for not prescribing SGLT2 inhibitor therapy included: up-titration or initiation of other medications/defer to future visit in 97 patients (63.0%), patient preference or refusal in 13 patients (8.4%) and inability to afford the cost of medication in 11 patients (7.1%). <h3>CONCLUSION</h3> A substantial proportion (67%) 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.

Real-world barriers and safety of initiating sodium-glucose co-transporter 2 inhibitor treatment immediately following an acute cardiac event in people with diabetes

In this real-world study, the main barriers for not initiating SGLT2 inhibitor therapy early after an acute cardiac event are prescribing criteria around glycated haemoglobin and renal function. Initiation of SGLT2 inhibitors near to, or at, hospital discharge following the cardiac event was not associated with 30-day diabetic ketoacidosis readmissions.

Sodium-Glucose Cotransporter-2 Inhibitors Versus Glucagon-like Peptide-1 Receptor Agonists and the Risk for Cardiovascular Outcomes in Routine Care Patients With Diabetes Across Categories of Cardiovascular Disease.

Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in placebo-controlled trials of patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). To evaluate whether SGLT2 inhibitors and GLP-1 RAs are associated with differential cardiovascular benefit among T2D patients with and without CVD. Population-based cohort study. Medicare and 2 U.S. commercial claims data sets (April 2013 to December 2017). 1:1 propensity score-matched adult T2D patients with and without CVD (52901 and 133139 matched pairs) initiating SGLT2 inhibitor versus GLP-1 RA therapy. Primary outcomes were myocardial infarction (MI) or stroke hospitalization and hospitalization for heart failure (HHF). Pooled hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, with 95% CIs, controlling for 138 preexposure covariates. The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with a slightly lower risk for MI or stroke in patients with CVD (HR, 0.90 [95% CI, 0.82 to 0.98]; RD, -2.47 [CI, -4.45 to -0.50]) but similar risk in those without CVD (HR, 1.07 [CI, 0.97 to 1.18]; RD, 0.38 [CI, -0.30 to 1.07]). The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with reductions in HHF risk regardless of baseline CVD in patients with CVD (HR, 0.71 [CI, 0.64 to 0.79]; RD, -4.97 [CI, -6.55 to -3.39]) and in those without CVD (HR, 0.69 [CI, 0.56 to 0.85]; RD, -0.58 [CI, -0.91 to -0.25]). Treatment selection was not randomized. Use of SGLT2 inhibitors versus GLP-1 RAs was associated with consistent reductions in HHF risk among T2D patients with and without CVD, although the absolute benefit was greater in patients with CVD. There were no large differences in risk for MI or stroke among T2D patients with and without CVD. Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.