SGLT2 Research Articles

Impact of SGLT2-Inhibitor Therapy on Survival in Patients with Transthyretin Amyloid Cardiomyopathy: Analysis of a Prospective Registry Study.

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) represent a high-risk heart failure population with continued unmet therapeutic needs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction, and first evidence regarding their safety and effectiveness in patients with ATTR-CM is arising. This study investigates the association between SGLT2i therapy and clinical outcomes in these patients. Methods: This is an analysis of a prospective registry conducted at a referral centre for hypertrophic cardiomyopathies including 116 patients with confirmed ATTR-CM. Fifty-one patients (44%) were treated with SGLT2i while 65 patients (56%) remained SGLT2i-naïve. Results: During a median follow-up of 2.6 (1.7-3.7) years, 38 patients (33%) died, of whom 11 patients (9%) received SGLT2i treatment and 27 patients (23%) were treatment-naïve. SGLT2i therapy was significantly associated with lower mortality (HR 0.457, 95%CI 0.227-0.922, p = 0.029). This association persisted after adjusting for age and sex (HR 0.479, 95%CI 0.235-0.977, p = 0.043) and after additional adjustment for eGFR, NT-proBNP, LVEF, and concomitant therapy with tafamidis (HR 0.328, 95%CI 0.141-0.760, p = 0.009). However, when potential immortal time bias was considered, this association lost statistical significance (HR 1.075, 95%CI 0.524-2.206, p = 0.843). No significant associations between SGLT2i therapy and worsening heart-failure hospitalization or cardiovascular mortality were observed. Conclusions: In crude analysis, SGLT2i therapy associates with better survival in patients with ATTR-CM. However, after adjustment for immortal time, this association becomes statistically insignificant. Hence, to draw final conclusions on the effectiveness of SGLT2i therapy in these patients, a randomized controlled trial is warranted.

Heterogeneous afferent arteriolopathy: a key concept for understanding blood pressure-dependent renal damage.

Hypertension, aging, and other factors are associated with arteriosclerosis and arteriolosclerosis, primary morphological features of nephrosclerosis. Although such pathological changes are not invariably linked with renal decline but are prevalent across chronic kidney disease (CKD), understanding kidney damage progression is more pragmatic than precisely diagnosing nephrosclerosis itself. Hyalinosis and medial thickening of the afferent arteriole, along with intimal thickening of small arteries, can disrupt the autoregulatory system, jeopardizing glomerular perfusion pressure given systemic blood pressure (BP) fluctuations. Consequently, such vascular lesions cause glomerular damage by inducing glomerular hypertension and ischemia at the single nephron level. Thus, the interaction between systemic BP and afferent arteriolopathy markedly influences BP-dependent renal damage progression in nephrosclerosis. Both dilated and narrowed types of afferent arteriolopathy coexist throughout the kidney, with varying proportions among patients. Therefore, optimizing antihypertensive therapy to target either glomerular hypertension or ischemia is imperative. In recent years, clinical trials have indicated that combining renin-angiotensin system inhibitors (RASis) and sodium-glucose transporter 2 inhibitors (SGLT2is) is superior to using RASis alone in slowing renal function decline, despite comparable reductions in albuminuria. The superior efficacy of SGLT2is may arise from their beneficial effects on both glomerular hypertension and renal ischemia. A comprehensive understanding of the interaction between systemic BP and heterogeneous afferent arteriolopathy is pivotal for optimizing therapy and mitigating renal decline in patients with CKD of any etiology. Therefore, in this comprehensive review, we explore the role of afferent arteriolopathy in BP-dependent renal damage.

Acetazolamide Therapy and Kidney Function in Persons with Nonalbuminuric Diabetes Mellitus Type 1.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower the risk of kidney failure in persons with type 2 diabetes. The presumed mechanism of action is through greater delivery of sodium to the distal tubule, activation of tubuloglomerular feedback which lowers glomerular filtration rate (GFR) and intra-glomerular pressure. SGLT2is are not approved for use in persons with type 1 diabetes due to the risk of diabetic ketoacidosis. Acetazolamide, a proximal tubule diuretic, delivers more sodium to the distal nephron, and may activate tubuloglomerular feedback in a similar way to SGLT2is without a higher risk of diabetic ketoacidosis. The kidney effects and safety of acetazolamide in persons with type 1 diabetes have not been well studied. Methods: We conducted a dose-escalation trial to determine the effects of 3 dosages of oral acetazolamide (62.5mg, 125mg, and 250mg, all twice-daily) in 12 persons with type 1 diabetes. Participants were treated for 2 weeks followed by a 2-week washout before exposure to the next dosage level. Blood and urine chemistries, as well as iohexol measured GFR, were assessed before and after each treatment interval. We aimed to identify a dose that maximized measured GFR reductions while minimizing adverse effects. Results: The mean age was 46±17 years, 100% were White, and 75% were female. The mean measured GFR was 89±18ml/min/1.73m2 at baseline. Acetazolamide reduced measured GFR by 15% (95% CI 9, 21), 14% (95% CI 7, 21), and 15% (95% CI 10, 21) after 2 weeks at the 62.5mg, 125mg, and 250mg twice-daily dosage levels respectively. The measured GFR reduction was fully reversed after each 2-week washout. Serum bicarbonate was reduced by 2.3, 4.2 and 4.4 mEq/L with escalating doses, and no episodes of hypokalemia (< 3.5 mEq/L) were observed. Conclusions: Among persons with type 1 diabetes and preserved kidney function, acetazolamide caused an acute, reversible reduction in measured GFR without effects on glucose metabolism.

Individualized treatment of diabetes mellitus in older adults.

The population of older adults with diabetes mellitus is growing but heterogeneous. Because geriatric syndromes, comorbidity or multimorbidity, the complexity of glucose dynamics, and socioeconomic conditions are associated with the risk of severe hypoglycemia and mortality, these factors should be considered in individualized diabetes treatment. Because cognitive impairment and frailty have similar etiologies and risk factors, a common strategy can be implemented to address them through optimal glycemic control, management of vascular risk factors, diet, exercise, social participation, and support. To prevent frailty or sarcopenia, optimal energy intake, adequate protein and vitamin intake, and resistance or multi-component exercise are recommended. For hypoglycemic drug therapy, it is important to reduce hypoglycemia, to use sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, taking into account the benefits for cardiovascular disease and the risk of adverse effects, and to simplify treatment to address poor adherence. Glycemic control goals for older adults with diabetes should be set according to three categories, based on cognitive function and activities of daily living, using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items. This categorization can be used to determine treatment strategies for diabetes when combined with the Comprehensive Geriatric Assessment (CGA). Based on the CGA, frailty prevention, treatment simplification, and social participation or services should be implemented for patients in Category II and above. Measures against hypoglycemia and for the prevention of cardiovascular disease and chronic kidney disease should also be promoted. Treatment based on categorization and CGA by multidisciplinary professionals would be an individualized treatment for older adults with diabetes. Geriatr Gerontol Int 2024; ••: ••-••.

The effect of empagliflozin (sodium-glucose cotransporter-2 inhibitor) on osteoporosis and glycemic parameters in patients with type 2 diabetes: a quasi-experimental study.

Diabetic osteoporosis (DOP) is a metabolic disease that occurs in patients with diabetes due to insufficient insulin secretion. This condition can lead to sensory neuropathy, nephropathy, retinopathy, and hypoglycemic events, which can increase the risk of fractures. This study aimed to assess the effectiveness of Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, in treating diabetic osteoporosis (DOP) and preventing fractures. This quasi-experimental study enrolled 100 patients with diabetic osteoporosis from February 2023 to February 2024. Participants were randomly assigned to an intervention group (n = 50) and a control group (n = 50). The intervention group received Empagliflozin in combination with symptomatic treatment, while the control group received only symptomatic treatment. The treatment duration was six months. Fasting blood glucose (FBG), 2-hour postprandial blood glucose (2h PG), glycosylated hemoglobin A1c (Hb A1c), bone mineral density (BMD), serum phosphorus and calcium concentration were measured after the intervention and the incidence of fracture was followed up for 12 months. The data were analyzed using SPSS 23. Descriptive statistics (mean, standard deviation, and percentage) and analytical methods (t test, Chi square) were also used to analyze the data. After six months of treatment, the intervention group exhibited significantly lower levels of FBG (P < 0.001), 2h-PG (P = 0.001), and HbA1c (P < 0.001) than the control group. Additionally, bone mineral density, serum phosphorus, and calcium levels were significantly higher in the intervention group (P < 0.001). After a 12-months follow-up, the incidence of fractures in the intervention group was 2%, while it was 16.33% in the control group (P < 0.05). Empagliflozin, when combined with symptomatic treatment, demonstrates a positive clinical effect in patients with diabetic osteoporosis. The treatment effectively improves blood glucose metabolism, bone mineral density, and phosphorus and calcium metabolism, ultimately leading to a significant reduction in the incidence of fracture.

Blood Pressure Reduction and Changes in Antihypertensive Medication Use Among Patients With Hypertension Who Initiated Sodium-Glucose Cotransporter-2 Inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated a blood pressure (BP) reduction benefit despite other indications for use. We evaluated BP changes and antihypertensive medication use pre- and post-SGLT2i initiation among 12 960 patients with treated hypertension and among subgroups with apparent treatment-resistant hypertension (aTRH) and/or proteinuria. Post-SGLT2i initiation, the mean (SD) systolic blood pressure (SBP) was reduced from 133.9 (16.4) to 128.6 (15.5) mmHg and the mean diastolic blood pressure (DBP) was reduced from 70.8 (11.8) to 68.3 (11.3) mmHg among all patients. The mean SBP/DBP reduction was 5.3/2.5, 6.2/2.8, and 6.1/2.9mmHg among all patients, patients with aTRH, and patients with proteinuria, respectively. Achieved BP < 130/80mmHg increased by 12.5%, 16.9%, and 11.1% for all patients, patients with aTRH, and patients with proteinuria, respectively. Discontinuation of ≥ 1 antihypertensive medication within 12 months of SGLT2i initiation occurred in 33.4% overall, 47.6% of patients with aTRH, and 38.7% of patients with proteinuria.

The effects of sodium-glucose cotransporter 2 inhibitors on the 'forgotten' right ventricle.

With the progress in diagnosis, treatment and imaging techniques, there is a growing recognition that impaired right ventricular (RV) function profoundly affects the prognosis of patients with heart failure (HF), irrespective of their left ventricular ejection fraction (LVEF). In addition, right HF (RHF) is a common complication associated with various diseases, including congenital heart disease, myocardial infarction (MI), pulmonary arterial hypertension (PAH) and dilated cardiomyopathy (DCM), and it can manifest at any time after left ventricular assist devices (LVADs). The sodium-glucose cotransporter 2 (SGLT2) inhibition by gliflozins has emerged as a cornerstone medicine for managing type 2 diabetes mellitus (T2DM) and HF, with an increasing focus on its potential to enhance RV function. In this review, we aim to present an updated perspective on the pleiotropic effects of gliflozins on the right ventricle and offer insights into the underlying mechanisms. We can ascertain their advantageous impact on the right ventricle by discussing the evidence obtained in animal models and monumental clinical trials. In light of the pathophysiological changes in RHF, we attempt to elucidate crucial mechanisms regarding their beneficial effects, including alleviation of RV overload, reduction of hyperinsulinaemia and inflammatory responses, regulation of nutrient signalling pathways and cellular energy metabolism, inhibition of oxidative stress and myocardial fibrosis, and maintenance of ion balance. Finally, this drug class's potential application and benefits in various clinical settings are described, along with a prospective outlook on future clinical practice and research directions.

8722 Sodium-Glucose Cotransporter 2 Inhibitors And The Risk Of Kidney Cancer Among Patients With Type 2 Diabetes: A Population-Based Cohort Study

Abstract Disclosure: M. Lee: None. H. Kim: None. R. Kim: None. Y. Yang: None. S. Lee: None. E. Kang: None. There is an important need to develop clinical strategies to reduce the risk of incident kidney cancer, especially in patients with type 2 diabetes (T2D) and concomitant chronic kidney disease. Here, we investigated kidney cancer risk associated with sodium-glucose cotransporter 2 (SGLT2) inhibitor use in patients with T2D, using a nationwide cohort of the Korean National Health Insurance claims and health examination database. After 1:1 propensity score matching, 83,531 SGLT2 inhibitor users and 83,531 non-users on other oral glucose-lowering drugs were selected from 814,685 cancer-free participants, aged 20 to 79 years, who started oral glucose-lowering drugs for T2D from 2014 to 2018. During 559,738 person-years of follow-up, 143 (25.5 per 100,000 person-years) new kidney cancer events occurred. SGLT2 inhibitor use was associated with a 37% reduced risk of kidney cancer compared with other oral glucose-lowering drug use (18.1 vs. 29.9 per 100,000 person-years; hazard ratio [HR], 0.63; 95% CI, 0.43 to 0.92). The reduced kidney cancer risk by SGLT2 inhibitor use was consistent even after additional adjustment for all variables composing the propensity scores (HR, 0.64; 95% CI, 0.43 to 0.93) and regardless of age, sex, BMI, comorbidities, or diabetic complications including nephropathy (all p &amp;gt; 0.1 for interaction). SGLT2 inhibitor use may be a preferable option for patients with T2D at high risk of kidney cancer. Presentation: 6/3/2024

7578 SGLT2 Inhibitor Is Associated With A Decreased Risk Of Cerebrovascular Events And Dementia Compared To Thiazolidinedione In Subjects With Type 2 Diabetes

Abstract Disclosure: H. Park: None. S. Park: None. H. Kim: None. D. Byun: None. Subjects with type 2 diabetes (T2D) are at higher risk of developing cerebrovascular disease, cognitive decline, and dementia. Hyperinsulinemia and insulin resistance in the brain have been linked to amyloid beta metabolism, raising the risk of Alzheimer's dementia. Recently, several clinical studies have shown potential beneficial effects of sodium glucose co-transporter-2 (SGLT2) inhibitors, and thiazolidinediones, in the risk of cerebrovascular events and dementia in T2D. This study was aimed to investigate the comparative efficacy of SGLT2 inhibitors and thiazolidinediones in modifying the risk of cerebrovascular events, dementia, and Alzheimer's dementia. Using the common data model, we analyzed patients from December 31, 2011 to December 30, 2022 from 15 hospitals in South Korea. Clinical outcomes between SGLT2 inhibitors and thiazolidinediones were compared using hazard ratios (HRs), with large-scale propensity score matching and a random-effects model applied. Our analyses showed that subjects on SGLT2 inhibitors had a significantly reduced rate of cerebrovascular events (HR 0.2787, 95% CI 0.1882-0.4127, p&amp;lt;0.00001), dementia (HR 0.5395, 95% CI 0.3824-0.7614, p=0.0004), and Alzheimer's dementia (HR 0.586, 95% CI 0.4634-0.7411, p&amp;lt;0.00001), compared to those on thiazolidinediones. In summary, these results suggest that SGLT2 inhibitor administration is associated with a lower risk of cerebrovascular events, dementia, and Alzheimer's dementia compared to thiazolidinedione in subjects with T2D. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms. Presentation: 6/3/2024

8418 Association of GLP-1 Receptor Agonists and SGLT-2 Inhibitors with Major Adverse Cardiovascular Events and Serious Liver Events among Patients with Type 2 Diabetes and MASLD

Abstract Disclosure: A. Kutz: None. D.J. Wexler: None. J. Liu: None. J.M. Paik: None. E. Patorno: None. Introduction and study question Little is known about the cardiovascular (CV) and hepatic effectiveness of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter 2 inhibitors (SGLT-2i) in people with type 2 diabetes (T2D) and known metabolic dysfunction-associated steatotic liver disease (MASLD) in clinical practice. We assessed the comparative CV and hepatic effectiveness and the safety of GLP-1 RA and SGLT-2i in people with T2D and prevalent MASLD. Methodology Using pooled data from Medicare fee-for-service (2013–2020) and a large U.S. health insurance database (2013-June 2022), we conducted two propensity-score fine stratification weighted cohort studies including adults with T2D and a diagnosis of MASLD who initiated GLP-1RA, SGLT-2i, or dipeptidyl peptidase 4 inhibitors (DPP-4i, reference). Using Cox proportional hazards models, we assessed the primary CV effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, or all-cause mortality. The primary hepatic effectiveness outcome was a composite of serious liver events (hospitalization for ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, bleeding esophageal varices, hepatic encephalopathy, or liver transplantation). The safety outcome was a composite of severe adverse events (lower limb amputation, non-vertebral fracture, emergency admission for hypoglycemia, or hospitalization for acute kidney injury, diabetic ketoacidosis [DKA], severe genital or urinary tract infection, acute pancreatitis, or biliary event). Major results Compared with DPP-4i (n=17,084 initiators), the hazard ratio (HR) for the primary CV outcome associated with GLP-1 RA (n=13,666 initiators) was 0.67 (95% CI, 0.56 to 0.81), corresponding to an incidence rate difference (IRD) per 1,000 person-years of -21.6 (95% CI, -26.7 to -16.6). The HR for the primary hepatic outcome was 0.47 (95% CI, 0.25 to 0.90), the IRD -2.1 (95% CI -3.4 to -0.9). Similar CV benefits were observed for SGLT-2i (n=11,108) vs DPP-4i (n=16,979), with a HR for the primary CV outcome of 0.82 (95% CI 0.70–0.96) and an IRD of -11.0 (95% CI -16.2 to -5.8). For the primary hepatic outcome, the HR was 0.81 (95% CI 0.45 to 1.44) and the IRD -1.1 (95% CI -2.4 to 0.3). Severe adverse events were not more frequent with GLP-1RA or SGLT-2i compared with DPP-4i. Interpretation and conclusion Among people with T2D and MASLD, the use of GLP-1 RA or SGLT-2i was associated with fewer CV events, vs DPP-4i, while GLP-1 RA also reduced serious liver events. Compared with DPP-4i, GLP-1RA or SGLT-2i were not associated with higher safety adverse event rates. Presentation: 6/2/2024

8647 Reversal Of Left Atrial Dilation In Heart Failure With Preserved Ejection Fraction (HFpEF) Treated With A GLP-1 Receptor Agonist And A Mineralocorticoid Receptor Antagonist

Abstract Disclosure: M. Marino: None. L.S. Phillips: Advisory Board Member; Self; Diasyst, Inc.. Research Investigator; Self; Abbvie, Research Support, Jansen Pharmaceuticals, Research Support, Novo Nordisk, Research Support, Abbott Laboratories, Research Support, GlaxoSmithKline, Research Support, Sanofi-Aventis, Research Support, Pfizer, Inc.. Background: HFpEF is a major public health problem, since contributors include age, hypertension, hyperglycemia, and inactivity - and the US population is aging, hypertension and hyperglycemia are often inadequately treated, and inactivity is common. Moreover, management is difficult, since few medications have improved outcomes, and there is little long-term experience with sodium-glucose co-transporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and mineralocorticoid receptor antagonists. Clinical Case: In October 2010, a 69-year-old male with a history of lung adenocarcinoma with left lower lobe segmentectomy, prostate cancer post prostatectomy, and well-managed hypertension and hyperglycemia experienced severe shortness of breath while running on a track as part of his routine exercise. A left heart catheterization was performed to determine if the symptoms reflected inadequate perfusion, revealing only 30% stenosis in the left anterior descending coronary artery, ruling out coronary disease as the primary etiology. However, the left ventricular end diastolic pressure (LVEDP) was elevated (25 mmHg vs. normal &amp;lt;12), indicating heart failure. A transthoracic echocardiogram (TTE) in December 2010 revealed a normal left ventricular ejection fraction (EF 65%), a severely dilated left atrium [left atrial volume index (LAVI) 57 mL/m2 vs. normal &amp;lt;34], and diastolic dysfunction [flow velocity across the mitral valve (E/A ratio 1.61 and E/e’ 7.26). The patient was given pioglitazone 30mg daily before and nebivolol 2.5mg BID after the TTE, but in March 2011, a TTE showed an EF of 57% with persistent left atrial dilation (LAVI 50 mL/m2). A dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin 100mg daily) was begun August 2011, changed to liraglutide 1.8mg daily in December 2011, and eplerenone 75mg daily was begun February 2012. In June 2012, the LAVI was markedly improved (39 mL/m2). The nebivolol was switched to irbesartan 225mg daily in August 2012, and canagliflozin 300mg daily was added September 2013. A repeat TTE in March 2014 found an EF of 60%, and showed that the LAVI had returned to normal (34 mL/m2). During this period, mean blood pressure was 111/67 mmHg, LDL cholesterol 57 mg/dL, and HbA1c 5.4%, indicating that inadequate risk factor management was unlikely to be contributing to the diastolic dysfunction. Presently, the patient takes semaglutide, pioglitazone, telmisartan, empagliflozin, and eplerenone, continues to exercise vigorously, and a recent TTE showed an EF of 62% with mild left atrial dilation (LAVI 36.6). Conclusion: Left atrial dilation was improved after addition of a GLP-1 receptor agonist and a mineralocorticoid receptor antagonist, prior to use of an SGLT-2 inhibitor. Future investigations are needed to further understand the cardiovascular utility of these medications - beyond glycemic control and electrolyte balance. Presentation: 6/3/2024

8075 Euglycemic Diabetic Ketoacidosis Associated With Cocaine Use

Abstract Disclosure: N.N. Solanki: None. A.N. Kiani: None. M. Feldman: None. Euglycemic diabetic ketoacidosis (EDKA) is characterized by increased anion gap metabolic acidosis, ketonemia or ketonuria, and normal blood glucose levels (&amp;lt;200 mg/dL). Due to the absence of hyperglycemia, it commonly presents as a diagnostic and therapeutic dilemma. EDKA is commonly associated with decreased caloric intake, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, recent use of insulin, heavy alcohol consumption, chronic liver disease, glycogen storage disorders, and drug-induced intoxication. Cocaine use is a lesser-known etiology for EDKA. We present a case of a 64-year-old female with a history of type 2 diabetes mellitus who presented with complaints of decreased oral intake for two days secondary to nausea and vomiting and productive cough for one week, along with cocaine use. Despite an extensive history of diabetes and no recent SGLT-2 inhibitor use, her labs were consistent with euglycemic DKA. Her imaging and further investigations revealed respiratory syncytial virus pneumonia. The patient was initially managed for starvation ketoacidosis with fluid resuscitation with no improvement in acidosis and later treated with DKA protocol with rapid correction of her anion gap metabolic acidosis. This case highlights the challenges associated with diagnosing and treating EDKA. Early initiation of DKA protocol should be considered in diabetic patients presenting with euglycemia with high anion gap metabolic acidosis with a clinical picture of starvation and cocaine use. Presentation: 6/3/2024

7800 Real World Incidence Of Urinary Tract Infections (UTI) &amp; Genital Tract Infections (GTI) With SGLT2 Inhibitors Alone Or In Combination With DPP4 Inhibitors In Patients With T2D In India

Abstract Disclosure: A. Gupta: None. N. Singh: None. S. Phatak: None. A.N. Singh: None. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with urinary and genital tract infections (UTI and GTI), as they increase glucose availability in these areas, fostering bacterial growth. A study found a 26% lower occurrence of UTI and GTI in patients using a combination of Dipeptidyl Peptidase-4 inhibitors (DPP4i) and SGLT2i compared to those on SGLT2i alone. (1) The present study assessed whether patients receiving SGLT2i were at increased risk of significant UTIs &amp; GTIs compared with those using a combination of SGLT2i &amp; DPP-4i. A cross-sectional, multicenter, real-world study was conducted that enrolled patients with Type 2 Diabetes Mellitus (T2D) from 15th June to 30th September 2023 across 42 sites in India. The recorded data encompassed demographic information, glycemic parameters, medication use &amp; information on hygiene practices. The sample considered for this analysis is those on SGLT2i &amp; with or without DPPi. [Note – all patients are on other OHAs besides SGLT2i or DPP4i]. Of 10,179 patients, 2,123 were on only SGLT2i (Group A), and 8,052 were on SGLT2i and DPP4i (Group B). Group A showed a significantly higher incidence of UTI (9.09% vs. 6.11%) and GTI (6.64% vs. 5.2%). Elderly patients, especially those aged 60-69 and &amp;gt;70, exhibited higher UTI and GTI rates in Group A. In both genders, the incidence of UTI was higher in Group A (7.93%-males &amp; 10.53%-females) than in Group B (5.41%-males &amp; 7.11%-females). Amongst males, the incidence of GTI was significantly higher in Group A (5.63%) than in Group B (4.12%). In females, no significant difference was noted. Two models were developed to assess the impact of SGLT2i and insulin usage on UTI and GTI likelihood. Propensity score matching addressed confounding variables like age, gender, BMI, and comorbidities. Subsequently, logistic regression analysis focused solely on medication variables. The odds of developing UTI were calculated for various medication possibilities. As against ‘No SGLT2i’, Group A has 2.24 (CI 1.69-2.96) times higher odds of UTI, while Group B has 1.45 (CI 1.15-1.72) times. or GTI, Group A shows 3.18 (CI 2.23-4.53) times higher odds, and Group B has 2.48 (CI 1.90-3.25) times, as against ‘No SGLT2i’. In summary, DPP-4 &amp; SGLT2 inhibitors combination therapy decreases the incidence of UTI &amp; GTI linked to SGLT2i. Reference: (1) Fadini et al. DPP4i moderate the risk of GTI &amp; UTI associated with SGLT2i. Diab Obes Metab. 2018 Mar;20(3):740-744. Presentation: 6/2/2024

8527 The Role Of SGLT2 Inhibitors In Outcomes After LVAD Implantation

Abstract Disclosure: L. Carafone: None. S. McNitt: None. I. Goldenberg: None. J. Alexis: None. Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are important medications in the treatment of diabetes mellitus, however they offer several additional benefits, including improved heart failure outcomes in patients with and without diabetes. The role of SGLT2i in heart failure outcomes for patients who receive left ventricular assist device (LVAD) implantation is not known. Right heart failure, in particular, is a frequent complication and major contributor to morbidity and mortality after LVAD implantation. SGLT2i have been increasingly used in patients who undergo LVAD implantation, however it is unknown whether right heart failure events post-LVAD implantation are meaningfully impacted by SGLT2i use. Objective: The purpose of this study was to evaluate the role of SGLT2i in outcomes after LVAD implantation. The primary endpoint was the onset of a first right heart failure (RHF) event following LVAD implantation. Secondary endpoints included recurrent RHF, first and recurrent hospitalization for RHF, and all-cause mortality. Methods: The study population comprised all consecutive patients who received a HeartMate 3 LVAD implantation at the medical center from 9/25/2015 through 9/1/2023 who are included in the institution’s LVAD Database. Both patients who received and did not receive a SGLT2i were included. A time-dependent model was used to evaluate treatment with SGLT2i as a time-dependent variable. Multivariable propensity score matching was used in the analysis of outcomes. Results: A total of 399 patients were analyzed, which included 175 patients who received SGLT2i and 224 patients who did not receive SGLT2i. Cox proportional hazards regression, employing propensity score stratification, demonstrated SGLT2i use was not associated with a statistical significant effect in the primary endpoint of a first occurrence of RHF event (HR = 1.41, 95% CI = 0.77-2.61, p = 0.268). Similarly, SGLT2i use was not associated with secondary outcomes, including recurrent RHF (HR = 1.28, 95% CI = 0.76-2.16, p = 0.360), first or recurrent hospitalization for RHF (HR = 0.38, 95% CI = 0.11-1.33, p = 0.131 and HR = 0.63, 95% CI = 0.27-1.46, p = 0.285, respectively), and all-cause mortality (HR = 0.90, 95% CI = 0.44-1.83, p = 0.771). Presence or absence of diabetes diagnosis did not significantly impact outcomes. Conclusions: The observational data in this study suggest no incremental benefit of SGLT2i for right heart failure or mortality outcomes after LVAD implantation, however large-scale prospective studies are needed to evaluate the role of SGLT2i in this setting. Further elucidating the role of these medications in LVAD outcomes will be critical in clinical decision-making regarding use of SGLT2i in this population. Presentation: 6/1/2024

8243 Euglycemic Diabetic Ketoacidosis Unveiled: Delayed Presentation and Complications of SGLT-2 Inhibitor Therapy in a Multimorbid Patient - A Case Report

Abstract Disclosure: T. Amin: None. A.K. Bala: None. M.A. Jones: None. M.S. Akula: None. K. Chalasani: None. M. Patel: None. J. Cheng: None. Introduction: Normal serum glucose levels (&amp;lt;200 mg/dL) in euglycemic diabetic ketoacidosis (EDKA) can complicate the typical clinical presentation of diabetic ketoacidosis (DKA), posing a diagnostic challenge. SGLT-2 inhibitors, a class of antihyperglycemic drugs, have been rarely but significantly associated with EDKA. These inhibitors enhance renal glucose clearance by preventing glucose reabsorption via sodium-glucose cotransport. The increased renal clearance may contribute to the euglycemic picture, potentially leading to an underestimation of required insulin dosage, thereby precipitating ketoacidosis in EDKA. Although the mechanisms of EDKA are not fully understood, the association with SGLT-2 inhibitors is becoming increasingly evident. Case A 53-year-old male with a medical history of type 2 Diabetes Mellitus, coronary artery disease, chronic kidney disease, hyperlipidemia, was admitted to the trauma bay after a fall. Medications included empagliflozin, metformin, aspirin, amlodipine, spironolactone, and carvedilol. Upon presentation, he had a brief loss of consciousness, complained of headache and chest pain, and was found to have an epidural hematoma with regional brain compression on the CT head. Admission labs showed a blood glucose level of 172, an unremarkable anion gap, and normal renal and liver function tests. Due to traumatic brain injury, he was admitted to the ICU for neurological monitoring. Despite remaining neurologically stable, he developed hypoxia, necessitating intubation. After successful extubation, he exhibited worsening metabolic acidosis on the fourth day, with an elevated anion gap of 22 and a blood glucose level of 174. Arterial blood gas analysis revealed a pH of 7.3 (and elevated beta-hydroxybutyrate (&amp;gt;4), while lactic acid levels remained normal. Urine analysis showed elevated blood glucose (&amp;gt;1000) and ketones (&amp;gt;40). Home medications, metformin, and empagliflozin were appropriately withheld, but euglycemic DKA attributed to empagliflozin was diagnosed. Treatment included intravenous fluid resuscitation and insulin infusion, leading to resolution of acidosis and improved mentation within 24 hours. Conclusion: EDKA is a diagnosis of exclusion often overlooked in ICU patients due to diverse causes of high-anion gap metabolic acidosis. Typical cases occur while the patient is using the drug, often associated with triggers like illness, alcohol use, surgery, or starvation. SGLT2 inhibitors, such as empagliflozin, with a half-life of 12.4 hours, are expected to clear the bloodstream in about 48 hours, yet this case suggests an association with EDKA both during use and after drug cessation. This delayed presentation highlights additional risk considerations associated with SGLT2 inhibitors, guiding future clinical diagnoses of EDKA even several days post discontinuation. Presentation: 6/3/2024

6741 Serum Urate-Lowering Effects Of Sodium-Glucose Transport Protein 2 Inhibitors Compared To Dipeptidyl Peptidase-4 Inhibitors In Gout Patients With Type 2 Diabetes Mellitus: A Population-Based Cohort Study

Abstract Disclosure: R.K. Shariff: None. C. Chung: None. P. Huang: None. S. Mon: None. K. Ma: None. Background/Purpose: Effective management of gout in patients requiring long-term urate-lowering therapy involves maintaining serum rate levels within specific ranges. Hyperuricemia and gout have been associated with an increased risk of Type 2 Diabetes Mellitus (T2DM), with a reported prevalence of 16% in gout patients. Pharmacological approaches to glycemic control, including Sodium-glucose Transport Protein 2 Inhibitors inhibitor (SGLT2i) and Dipeptidyl Peptidase-4 Inhibitors (DPP-4i), have showed potential serum urate lowering effects. However, a direct comparison of these effects in patients with gout and concomitant T2DM is lacking. This study aims to evaluate the serum urate-lowering effects of SGLT2i compared to DPP-4i in this patient population. Methods: This was a population-based cohort study of patients with gout diagnosed following the 2015 Gout classification criteria in the American College of Rheumatology/European League Against Rheumatism collaborative initiative and T2DM diagnosed following the American Diabetes Association criteria, respectively. Subjects treated between 2008 and 2023 at 92 United States hospitals were screened. Propensity score matching was used to balance the baseline differences in age of gout onset, sex, comorbidities, and past medical history between the two groups. The primary predictor variable was the use of therapies of SGLT2i and DPP-4i. The primary outcome of interest was the serum urate more than 6 mg/dL during the follow-up period. Kaplan-Meier analysis and log-rank tests were utilized to compare if the numbers of serum urate were higher than 6 mg/dL in both arms. A Cox proportional hazards model was utilized to estimate the association between the use of SGLT2i versus DPP-4i and the numbers of serum urate higher than 6 mg/dL. Inclusion criteria include patients with gout and concomitant T2DM, age over 18, and must have serum uric acid level data available. Results: Of the 11,495 gout patients, including 3,593 users of SGLT2i users, were propensity score-matched to 3593 DPP-4i users. Among gout patients with T2DM on SGLT2i, 598 experienced serum urate levels exceeding than 6 mg/dL, while in the DPP-4i group, 920 patients had serum urate higher than 6 mg/dL. The use of SGLT2i was associated with significantly lower odds of serum uric acid exceeding 6 mg/dl compared to DPP-4i. (OR: 0.580 [0.517-0.651]). Conclusion: Our study suggests that SGLT2i may offer a more effective means of managing serum uric acid levels in gout patients with concomitant T2DM compared to DPP-4i. Clinical trials are required to validate the findings. For clinical practice, the dosage for SGLT2i to cause the urate-lowering effect needs to be investigated. With further studies and clinical trials, the rationale of choosing SGLT2i over DPP-4i may be incorporated into the management of T2DM in gout patients with T2DM. Presentation: 6/1/2024

6527 Genetic variants may influence the glycemic response to sodium-glucose cotransporter-2 inhibitors in the Mass General Brigham Biobank

Abstract Disclosure: J.H. Li: None. A. Barry: None. A. Huerta-Chagoya: None. L. Szczerbinski: None. J.M. Mercader: None. J.C. Florez: Consulting Fee; Self; AstraZeneca. Grant Recipient; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Merck. A. Leong: None. Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are increasingly prescribed for the treatment of type 2 diabetes, but there is interindividual variability in glycemic response. We investigated whether two genetic variants, rs33954001, a missense variant (p.His615Gln) in SLC5A1 encoding SGLT1, and rs8050500 near SLC5A2 encoding SGLT2, previously associated with glycemic traits in genome-wide association studies, had any influence on short-term glycated hemoglobin (HbA1c) lowering in patients on SGLT2i treatment. Methods: We identified 1,961 ancestrally diverse, genotyped individuals with documented exposure to a SGLT2i in the Mass General Brigham Biobank, a hospital-based biobank linked with patient medical records. Of these, 736 individuals had a baseline HbA1c ≥ 6% within 6 months of the index appearance of an SGLT2i and a follow-up HbA1c measured 6-12 months after. Genotyping was performed on the Illumina Multi-Ethnic Genotyping Array and the Illumina Global Screening Array. Variants were imputed with the TOPMed reference panel. Using linear regression models, we evaluated the additive effect of the genetic variants on HbA1c reduction, defined as baseline HbA1c minus follow-up HbA1c, adjusted for age, sex, 10 genetic ancestry principal components to account for population stratification, the number of concomitant glucose-lowering drug classes, and three covariates accounting for potential genotyping batch effects. To determine whether genetic effects varied by pretreatment glycemic control, we tested for a genotype × baseline HbA1c interaction and performed stratified analysis by baseline HbA1c (≥ 8% vs. &amp;lt; 8%). Results: The mean age of participants was 63.7 years and 41% were female. The baseline HbA1c was 8.0 ± 1.9%. The mean HbA1c reduction was 0.6% over a mean follow-up time of 8.7 ± 1.6 months. None of the variants were associated with HbA1c reduction (p &amp;gt; 0.05) in the whole dataset. However, in stratified analyses, among those with baseline HbA1c ≥ 8% (n = 382), we observed that carriers of the G allele at rs33954001 had a 0.5% greater HbA1c reduction (p = 0.048) compared to those with CC genotype. Further adjustment for baseline renal function did not modify results. In the Genotype-Tissue Expression (GTEx) portal, the G allele was associated with higher SLC5A1 expression in nerve (p = 1 × 10-8), esophageal mucosa (p = 4 × 10-5) and stomach (p = 9 × 10-5), but not kidney. In the Translational human pancreatic Islet Genotype tissue-Expression Resource (TIGER), the G allele was associated with SLC5A1 expression in pancreatic islets (p = 2 × 10-6). Conclusion: Genetic variation in SLC5A1 may partly explain heterogeneity in SGLT2i treatment effects among people with sub-optimally controlled diabetes, possibly due to differences in SLC5A1 tissue-specific expression. These findings require validation in large hospital-based biobanks or dedicated clinical trials. Presentation: 6/2/2024

7890 Combination of Dorzagliatin and Canagliflozin Improves β-cell Function and Alleviates Hepatic Steatosis in db/db Mice

Abstract Disclosure: Z. Zhang: None. S. Chen: None. S. Ji: None. Q. Zhao: None. J. Qiao: None. M. Liu: None. Introduction: Early combination of anti-hyperglycemic medications with different targets is an optimal choice for patients with type 2 diabetes (T2D) who do not achieve targeted HbA1c with monotherapy. Dorzagliatin is a novel dual-acting glucokinase activator that has been shown to be effective in both drug-naive and metformin-treated patients with T2D. However, the effect of combination of dorzagliatin and sodium-glucose cotransporter-2 inhibitor (SGLT2i) remains unknown. Methods: Ten-week-old db/db mice were treated daily with either dorzagliatin (30mg/kg of body weight) alone, or canagliflozin (30mg/kg of body weight) alone, or dorzagliatin plus canagliflozin, or vehicle only by gavage for 6 weeks. Body weight and fasting blood glucose were monitored weekly. Plasma insulin, triglyceride, and cholesterol were measured every two weeks. The morphology of islets and liver was evaluated by chemical staining and immunofluorescence. Results: The 6-week treatment of dorzagliatin had no significant effect on fasting blood glucose and fasting plasma insulin but reduced body weight in db/db mice compared to those treated with vehicle. It also caused a significant decrease of islet size and β-cell number. Surprisingly, dorzagliatin alleviated hepatic steatosis but did not affect serum lipid levels. The combination of dorzagliatin and canagliflozin lowed fasting blood glucose and improved glucose tolerance without affecting bodyweight, and the anti-diabetic effect was stronger than the canagliflozin-only treatment group. Combination treatment group also showed an increased islet size and β-cell number, and alleviated liver steatosis compared with vehicle group. Conclusion: The combination of dorzagliatin and canagliflozin had better antidiabetic effects than single-agent administration, providing clinical guidance for the combination therapy of dorzagliatin and SGLT2i in the treatment of type 2 diabetes. Presentation: 6/2/2024

12442 Effectiveness Of An Electronic Decision Support Algorithm To Optimize Recommendation Of SGLT2i And GLP-1RA In Patients With Type 2 Diabetes Upon Discharge From Internal Medicine Wards

Abstract Disclosure: E. Jaffe: None. I. Ayalon-Dangur: Grant Recipient; Self; Boehringer Ingelheim. A. Grossman: None. H. Hendel: None. Y. Oved: None. A. Shaked: None. I. Shimon: None. B. Basharim: None. M. Abo Molhem: None. R. McNeil: None. R. Abuhasira: None. T. Shitrit: None. L. Azulay Gitter: None. R. El Saleh: None. T. Shochat: None. N. Eliakim-Raz: None. Background: Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality. Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with T2DM with or at high risk for cardiovascular disease to reduce mortality. Despite the established benefit, many studies found low treatment rates with these medications in eligible patients. The aim of our study is to examine the effectiveness of a clinical decision support (CDS) algorithm that was developed in our institution, in improving the recommendation rate of SGLT2i and GLP-1RA upon discharge from hospitalization in internal medicine wards. Methods: Our algorithm was developed to automatically recommend SGLT2i and GLP-1RA for T2DM patients based on current guidelines. Data was collected from electronic medical records of all T2DM patients ≥18 years old who were eligible for SGLT2i or GLP-1RA and hospitalized for any reason in one of five internal medicine wards in Beilinson Hospital. The primary outcome was to evaluate the rate of physician recommendation of SGLT2i or GLP-1RA at hospital discharge for eligible patients pre-algorithm implementation (January 2021-December 2021) versus post-algorithm implementation (April 2023-September 2023). Results: A total of 1318 patients were included in the pre-algorithm group and 970 were included in the post-algorithm group. Median age was 75 and 73 years in the pre- and post-algorithm groups, respectively. In the pre-algorithm group, 62% were males vs 60% in the post-algorithm group. Median length of hospitalization was three days and four days in the pre- and post-algorithm groups, respectively. The rate of SGLT2i and GLP-1RA recommendation for eligible patients was 8.50% (112 of 1318 patients) in the pre-algorithm group and 22.68% (220 of 970 patients) in the post-algorithm group. The odds ratio of the recommendation rate in the post vs pre-algorithm group was 3.151, 95% confidence interval 2.467– 4.025, p&amp;lt;0.0001. Conclusion: The results of this study demonstrate the benefit of an algorithm as part of a CDS system to improve recommendation rates of SGLT2i and GLP-1RA for eligible patients upon discharge from hospitalization. Future studies should assess the impact of the algorithm on prescription rates, patient adherence, and long-term outcomes. Presentation: 6/2/2024

7490 Comparative Clinical Analysis of DPP-4 inhibitors and SGLT2 inhibitors; Switch Study in Real-World Setting

Abstract Disclosure: H. Choe: None. M. Kwak: None. J. Lee: None. Y. Choi: None. E. Hong: None. Objective: Dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) represent two distinct pharmacological pathways in the management of type 2 diabetes, both aiming to improve glycemic control without risk of hypoglycemia. Metabolic implications and glycemic control associated with the interchange between SGLT2i and DPP-4i are scarce. This study aimed to evaluate the effect of switching between SGLT2i and DPP4i on various clinical parameters in Korean patients with type 2 diabetes. Methods: We conducted a retrospective cohort study at Hallym University Dongtan Sacred Heart Hospital, using clinical data warehouse. Baseline measurements and follow-up data at 3 months were collected for parameters including hemoglobin A1c (HbA1c), blood pressure, lipid profile, liver enzymes, renal function, and other metabolic markers. Results: Between 2015 and 2023, 104 participants switched from SGLT2 inhibitors to DPP4 inhibitors, while 321 switched in the opposite direction. Initially, those who switched from SGLT2 inhibitors to DPP4 inhibitors presented with lower baseline HbA1c levels (7.22 ± 0.73% versus 7.42 ± 0.76%, P = 0.017) and higher estimated glomerular filtration rates (eGFR) (95.2 ± 23.1 versus 85.9 ± 23.7 mL/min/1.73m², P = 0.001) compared to those who switched from DPP4 inhibitors to SGLT2 inhibitors. At three months of follow-up, the SGLT2 inhibitors to DPP4 inhibitors group exhibited a more significant reduction in HbA1c (adjusted β 0.22, 95% CI 0.03 to 0.40, P = 0.023), especially in patients with reduced eGFR (&amp;lt;60 mL/min/1.73 m²) (β 1.2, 95% CI 0.30 to 2.11, P = 0.013; P for interaction = 0.005). On the other hand, the DPP4 inhibitors to SGLT2 inhibitors group showed a greater decrease in fasting glucose levels (β -9.73, 95% CI -17.6 to -1.86, P = 0.016), along with more pronounced reductions in liver enzymes AST (β -4.15, 95% CI -6.49 to -1.81, P &amp;lt; 0.001) and ALT (β -6.42, 95% CI -9.58 to -3.27, P &amp;lt; 0.001), and a significant increase in hematocrit (β 3.31, 95% CI 2.36 to 4.26, P &amp;lt; 0.001) compared to the initial group. Conclusions: The study concludes that in Korean patients with type 2 diabetes, switching from SGLT2 inhibitors to DPP4 inhibitors is associated with a greater reduction in HbA1c, particularly in those with reduced renal function. Conversely, switching from DPP4 inhibitors to SGLT2 inhibitors results in more substantial improvements in fasting glucose and liver enzyme levels, suggesting differential benefits depending on the direction of the medication switch. Presentation: 6/3/2024