Dipeptidyl Peptidase Research Articles

Superior benefits of sodium-glucose co-transporter-2 inhibitors compared with dipeptidyl peptidase-4 inhibitors for diabetic kidney disease: A cohort study.

To compare cardiorenal outcomes of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) in a national diabetic kidney disease (DKD) population. A cohort study was conducted using Taiwan's National Health Insurance Research Database and Laboratory Databases. Propensity score-matched prevalent new users of SGLT-2is (n = 1524) and DPP-4is (n = 6005) during 2017-2018 were selected from adults with DKD and an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2. Composite renal outcomes included sustained eGFR decrease, renal failure and renal mortality. Composite cardiovascular (CV) outcomes included acute myocardial infarction, stroke, hospitalization for heart failure and CV death. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with DPP-4i users, SGLT-2i users had a reduced risk of composite renal endpoint (HR: 0.16; CI: 0.12-0.24), consistently for a prolonged time to 50% or higher eGFR decrease (HR 0.17; CI: 0.11-0.27), renal failure (HR: 0.14; CI: 0.08-0.23) and decreased renal death (HR: 0.10; CI: 0.01-0.70). SGLT-2i users had a better composite CV outcome than DPP-4i users (HR: 0.74; CI: 0.64-0.85), and lower risks of stroke (HR: 0.76; CI: 0.62-0.92) and hospitalization for heart failure (HR: 0.68; CI: 0.55-0.84). Findings were consistent in analyses stratified by concomitant antidiabetic agents or intervals between DKD diagnosis and study drug initiation. This study shows the superior cardiorenal benefits of SGLT-2is compared with DPP-4is in the DKD population, regardless of concomitant antidiabetic agents or time from DKD onset to study drug initiation. SGLT-2is should be prioritized in adult patients with DKD.

Potent and Protease Resistant Azapeptide Agonists of the GLP‐1 and GIP Receptors

AbstractThe gut‐derived peptide hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) play important physiological roles including glucose homeostasis and appetite suppression. Stabilized agonists of the GLP‐1 receptor (GLP‐1R) and dual agonists of GLP‐1R and GIP receptor (GIPR) for the management of type 2 diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase‐4 (DPP4), that catalyzes rapid removal of the two N‐terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide makes them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza‐amino acids, that are bioisosteric replacements for α‐amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza‐amino acid can populate the same conformational space that GLP‐1 adopts when bound to the GLP‐1R. The insertion of an aza‐amino acid at the second position from the N‐terminus in semaglutide and in a dual agonist of GLP‐1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variation that may influence downstream signaling.

The effect of antidiabetic drugs on bone metabolism: a concise review.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, which derives from either insufficient insulin production [type 1 diabetes mellitus (T1DM)] or both impaired insulin sensitivity along with inadequate insulin production [type 2 diabetes mellitus (T2DM)] and affects millions of people worldwide. In addition to the adverse effects of DM on classical target organs and tissues, skeletal health can also be adversely affected. There is considerable evidence linking DM with osteoporosis. The fracture risk in patients with DM differs upon the type of diabetes, and it appears to be related to the type of anti-diabetic treatment. Antidiabetic drugs may have various effects on bone health. Most of them have neutral or even favorable effects on bone metabolism with the exception of thiazolidinediones (TZDs). Some studies suggest that TZDs may have negative impact on bone health by decreasing bone formation and increasing the fracture risk. There are also limited studies linking the use of canagliflozin, a Sodium-glucose contransporter-2 inhibitor (SGLT2i), with increased fracture risk. On the other hand, therapies that are based on incretin effect, like Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonizts (GLP-1RAs) might have positive effects on bone health by promoting bone formation. Herein we review the impact of antidiabetic drugs on bone health, highlighting the potential benefits and risks associated with these medications in an attempt to contribute to the development of personalized treatment strategies for individuals with DM.

Clinical implications and pharmacological considerations of glycemic variability in patients with type 2 diabetes mellitus

Glycemic variability (GV), independently of glycemic control, has emerged as a prognostic marker in patients with type 2 diabetes mellitus (DM). In this study, we assessed the prognostic value of long-term GV for predicting major adverse cardiovascular events (MACE) in our local population. We also assessed its prognostic value for diabetic microvascular complications (DMC) and its relationships with antidiabetic medications. This was a retrospective cohort study that recruited 680 patients with type 2 DM across 2015–2017. MACE were defined as: the composite of; total death, myocardial infarction (MI), stroke, hospitalization due to heart failure, and revascularization. GV was calculated for two glycemic control markers: glycated hemoglobin (G-Hb) and fasting blood sugar (FBS); via three metrics- standard deviation (SD), coefficient of variation (CV), and variability independent from the mean (VIM). Cox proportional hazard models and Kruskal-Wallis tests were used in the statistical analysis. 105 events classified as MACE were identified in 86 patients and 104 DMC in 98 patients in an average follow-up period of 78.43 months. Long-term GV was found to be an independent predictor of MACE, particularly for FBS-CV but not a predictor of DMC. FBS-CV ≥ 17.51% as compared with < 17.51% was a significant and independent predictor of MACE, with HR 1.589 (95% CI; 1.022, 2.472) (P = 0.040). DMC were predicted mainly by the duration of type 2 DM, and by the glycemic control; similarly represented by G-Hb and FBS. Patients on metformin, and dipeptidyl peptidase (DPP) 4 inhibitors, had the lowest GV, as compared with patients whose treatments included insulin/sulphonylureas (P < 0.001). In our population, long-term GV predicted MACE: with FBS-CV superior to the “gold standard” glycemic control marker G-Hb. Further, GV may be explained, partially at least, by the choice of antidiabetic medications: this finding might contribute to the cardiovascular protection attributed to one class rather than another.

Bioactive compounds and in vitro biological properties of Arthrospira platensis and Athrospira maxima: a comparative study

Cyanobacteria, especially Arthrospira, are valuable resources of nutrients and natural pigments with many beneficial health-related properties. This study optimized the extraction conditions of Arthrospira to achieve high phenolic contents and antioxidant activities. Under optimized extraction conditions, the bioactive compounds (phenolics and pigment components), antioxidant activities, and inhibitions of the key enzymes relevant to some non-communicable diseases were compared between Arthrospira platensis and Arthrospira maxima. Optimized extraction conditions were determined as 2 h shaking time, 50 °C extraction temperature, and 1% (w/v) solid-to-liquid ratio, giving effective phenolic and phycocyanin contents using aqueous extraction, while 80% (v/v) aqueous ethanolic extraction provided high total chlorophyll content. Most antioxidant activities were higher using 80% (v/v) aqueous ethanolic extracts. Both Arthrospira species inhibited the key enzymes involved in controlling non-communicable diseases including hyperlipidemia (lipase), diabetes (α-amylase, α-glucosidase, and dipeptidyl peptidase-IV), Alzheimer’s disease (acetylcholinesterase, butyrylcholinesterase and β-secretase), and hypertension (angiotensin-converting enzyme). High inhibitory activities were detected against β-secretase (BACE-1), the enzyme responsible for β-amyloid plaque formation in the brain that acts as a significant hallmark of Alzheimer’s disease. Arthrospira extract and donepezil (Alzheimer’s disease drug) synergistically inhibited BACE-1, suggesting the potential of Arthrospira extracts as effective BACE-1 inhibitors. Interestingly, A. maxima exhibited higher bioactive compound contents, antioxidant activities, and key enzyme inhibitions than A. platensis, indicating high potential for future food and medicinal applications.

Effects of Exercise on Hormones in Women with Polycystic Ovary Syndrome

Numerous reproductive-aged women are impacted by polycystic ovary syndrome (PCOS), an endocrine-gynecology condition. While a risk factor for polycystic ovarian syndrome (PCOS) has been identified, much about the disease's origins and pathophysiology is still up in the air. We searched PubMed and ClinicalTrials.gov extensively for results pertaining to the utilisation of repurposed pharmaceuticals in order to acquire information about the causes and treatments of polycystic ovarian syndrome (PCOS) for this study. We looked at everything that could be causing polycystic ovary syndrome. In addition, the data for both the most commonly prescribed PCOS medications and those that have been repurposed are summarised in the tables. Insulin resistance, inflammation, environmental toxicants, epigenetics, oxidative stress, hyperandrogenism, stress, and nutrition were all part of the internal components that were reviewed. Altering one's way of life and making use of complementary and alternative medicine is often the first line of defence against illness for many people. There is some evidence that certain medications and supplements may be effective in treating polycystic ovarian syndrome (PCOS). These chemicals include mucolytic medicines, thiazolidinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, 3-hydroxy-3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, and glucose-like peptide-1 receptor agonists.

Association of serum and salivary dipeptidyl peptidase-4 (DPP-4) with oral cancerous and precancerous lesions; an observational diagnostic accuracy study

BackgroundEnhancing the prognosis and treatment outcomes of oral cancer relies heavily on its early detection. This study aims to establish a connection between serum and salivary dipeptidyl peptidase-4 (DPP-4) levels and oral squamous cell carcinoma (OSCC), comparing them with oral potentially malignant lesions (OPMLs) and control subjects and validating salivary DPP-4 as a diagnostic marker for the early detection of oral cancer.MethodologyForty-five systemically healthy individuals were categorized into three groups: Group I consisted of 15 patients diagnosed with OSCC, Group II comprised 15 patients with OPMLs (including leukoplakia and oral lichen planus), and Group III included 15 participants without any oral mucosal lesions. Serum and whole unstimulated salivary samples were collected from all participants to assess DPP-4 levels using an enzyme-linked immunosorbent assay (ELISA) kit. Receiver operating characteristic (ROC) analysis was conducted to determine the area under the curve (AUC), sensitivity, specificity, and diagnostic accuracy of DPP-4.ResultsBoth serum and salivary DPP-4 levels were highest in the healthy group, followed by OPMLs, and lowest in the OSCC group, with statistically significant differences observed. ROC analysis demonstrated excellent diagnostic accuracy of salivary DPP-4 in distinguishing OSCC from healthy individuals, OPMLs from healthy individuals, and OSCC from OPMLs, with accuracies of 100%, 100%, and 96.67%, respectively. Salivary DPP-4 levels also exhibited a statistically significant correlation with OSCC grades.ConclusionsDPP-4 appears to play a protective, anti-oncogenic role in maintaining oral tissue health. The remarkable diagnostic accuracy of both serum and salivary DPP-4 in discriminating between OSCC, OPMLs, and healthy controls suggests its potential utility as a well-established marker for early oral cancer diagnosis. Salivary DPP-4, being non-invasive, could serve as a convenient chair-side diagnostic tool for the early detection of OSCC.Clinical trial registrationThe study was retrospectively registered on clinicaltrial.gov with NCT06087042, date of registration (first posted date): 17/10/2023

Targeting Hypoglycemic Natural Products from the Cloud Forest Plants Using Chemotaxonomic Computer-Assisted Selection.

The cloud forest (CF), a hugely biodiverse ecosystem, is a hotspot of unexplored plants with potential for discovering pharmacologically active compounds. Without sufficient ethnopharmacological information, developing strategies for rationally selecting plants for experimental studies is crucial. With this goal, a CF metabolites library was created, and a ligand-based virtual screening was conducted to identify molecules with potential hypoglycemic activity. From the most promising botanical families, plants were collected, methanolic extracts were prepared, and hypoglycemic activity was evaluated through in vitro enzyme inhibition assays on α-amylase, α-glucosidase, and dipeptidyl peptidase IV (DPP-IV). Metabolomic analyses were performed to identify the dominant metabolites in the species with the best inhibitory activity profile, and their affinity for the molecular targets was evaluated using ensemble molecular docking. This strategy led to the identification of twelve plants (in four botanical families) with hypoglycemic activity. Sida rhombifolia (Malvaceae) stood out for its DPP-IV selective inhibition versus S. glabra. A comparison of chemical profiles led to the annotation of twenty-seven metabolites over-accumulated in S. rhombifolia compared to S. glabra, among which acanthoside D and cis-tiliroside were noteworthy for their potential selective inhibition due to their specific intermolecular interactions with relevant amino acids of DPP-IV. The workflow used in this study presents a novel targeting strategy for identifying novel bioactive natural sources, which can complement the conventional selection criteria used in Natural Product Chemistry.

Pulmonary outcomes of incretin-based therapies in COPD patients receiving single-inhaler triple therapy

IntroductionPatients with chronic obstructive pulmonary disease (COPD) on triple therapy often face exacerbations and comorbidities. Emerging evidence suggests that glucagon-like peptide-1 (GLP-1) analogs may reduce the risk of exacerbation in patients with COPD and type 2 diabetes mellitus (T2DM). This study investigates the impact of GLP-1 analogs on pulmonary outcomes in patients with COPD on single-inhaler triple therapy (SITT) and T2DM.MethodsWe conducted a retrospective cohort study using the TriNetX database and analysed adult patients with COPD and T2DM who received SITT between April 2005 and July 2023. Patients were categorized into GLP-1 analog and dipeptidyl peptidase-4 inhibitors (DPP4i) cohorts. The primary efficacy outcome was COPD exacerbation and the secondary efficacy outcomes were pneumonia, acute respiratory distress syndrome, intubation, oxygen dependence, and all-cause mortality. The secondary outcomes were serious gastrointestinal adverse events.ResultsWe included 6898 patients, with 4184 receiving GLP-1 analogs and 2714 receiving DPP4i. After matching, 1751 GLP-1 analog users were matched with 1751 DPP4i users. GLP-1 analog users had an 18% lower risk of COPD exacerbation (hazard ratio [HR], 0.82 [95% CI: 0.71–0.94]), a 28% reduced risk of pneumonia (HR, 0.72 [95% CI: 0.61–0.85]), a 34% reduced risk of oxygen dependence (HR, 0.66 [95% CI: 0.47–0.91]), and a 40% decreased risk of all-cause mortality (HR, 0.60 [95% CI: 0.47–0.77]). No significant serious gastrointestinal adverse events were observed.ConclusionGLP-1 analogs may be associated with reduced COPD exacerbations, pulmonary comorbidities, and mortality in patients with COPD receiving SITT and T2DM, with no significant serious gastrointestinal safety concerns.

Physicochemical, Antioxidant, Organoleptic, and Anti-Diabetic Properties of Innovative Beef Burgers Enriched with Juices of Açaí (Euterpe oleracea Mart.) and Sea Buckthorn (Hippophae rhamnoides L.) Berries

Background: The aim of this study was to evaluate the selected quality parameters of innovative beef burgers produced with the addition of açaí and/or sea buckthorn berry juices. Methods: Five variants of innovative burgers were obtained, differing in the proportion of juices in the recipe. The pH of meat stuffing, thermal losses, production yield, color (CIE L*a*b*), content of polyphenolic compounds, degree of oxidation of the lipid fraction (TBARS), and antioxidant activity against ABTS radicals were determined. Anti-diabetic activity was measured as the ability to inhibit α-glucosidase and dipeptidyl peptidase−4 activity. A sensory evaluation was also performed. Results: Beef burgers formulated with açaí and sea buckthorn juices had up to five times higher total polyphenol content than burgers without added juices. The addition of the juices increased antioxidant activity against ABTS radicals (from 42 to 440 µmol/L/100 g) and effectively inhibited oxidation of the lipid fraction of the beef burgers. Recipe modifications resulted in changes in the color parameters of the beef burgers and had a positive effect on the sensory quality attributes evaluated. Beef burgers containing 0.5 g of açaí juice and 1.0 g of sea buckthorn juice were rated the best in terms of acceptability of appearance, aroma, color, juiciness, and tenderness. The addition of açaí and sea buckthorn juice did not increase the inhibitory activity against α-glucosidase and dipeptidyl peptidase-IV of the innovative beef burgers. Conclusions: The proposed recipe modification may be an effective way to fortify beef burgers with phytochemicals with antioxidant properties while maintaining their sensory properties.

Hyperkalemia and maintenance of renin-angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors.

Post-hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i). Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014-2021). The outcomes were incident hyperkalaemia (potassium>5.0 mmol/L), mild hyperkalemia (potassium>5-≤5.5mmol/L) and moderate to severe hyperkalemia (potassium>5.5mmol/L). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs). 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one third of participants in each arm discontinued treatment within a year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64-0.93), including both mild (0.76; 0.62-0.93) and moderate/severe (0.53; 0.40-0.69) hyperkalemia events. Of 19.116 participants that used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83-1.14). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy.

Kidney Outcomes with GLP-1RAs, SGLT2 Inhibitors, DPP-4 Inhibitors, and Sulfonylureas in Type 2 Diabetes and Moderate Cardiovascular Risk

Background: Chronic kidney disease (CKD) is a serious diabetes-related complication. While guidelines recommend use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists to mitigate cardiorenal risk in high-risk patients, the benefit of early initiation of these agents relative to other commonly prescribed glucose-lowering agents in patients at lower baseline cardiovascular disease (CVD) risk remains less clear. Methods: This retrospective observational study emulated an idealized target trial using claims data from OptumLabs® Data Warehouse to test the comparative association of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or sulfonylurea on a primary kidney composite outcome of incident CKD stages 3-5, kidney failure, or need for kidney replacement therapy (KRT) in patients with type 2 diabetes (T2D) and moderate CVD risk. A secondary composite outcome included all components of the primary composite outcome plus death. Results: A total of 364,714 adults ≥21 years of age initiating treatment with a DPP-4 inhibitor (N=78,843), GLP-1 receptor agonist (N=42,049), SGLT2 inhibitor (N=45,466), or sulfonylurea (N=198,356) were identified. Relative to DPP-4 inhibitor, SGLT2 inhibitor (HR: 0.71; 95% CI: 0.67-0.74; P˂0.001) and GLP-1 receptor agonist (HR: 0.87; 95% CI: 0.83-0.92; P˂0.001) treatment was superior for the primary composite outcome. Similarly, SGLT2 inhibitor (HR: 0.69; CI: 0.66-0.73) and GLP-1 receptor agonist (HR: 0.86; CI: 0.82-0.91) treatment was associated with risk reductions for the primary outcome relative to sulfonylurea treatment. When comparing SGLT2 inhibitor to GLP-1 receptor agonist therapy, SGLT2 inhibitors were superior for the primary composite outcome (HR: 0.81; 95% CI: 0.75-0.76; P˂0.001). Similar findings were observed for the secondary composite outcome across all comparisons. Conclusions: SGLT2 inhibitors and GLP-1 receptor agonists were superior to DPP-4 inhibitors and sulfonylurea for preventing kidney complications in a T2D population with moderate baseline CVD risk.

Male Sprague Dawley Rats with Type 2 Diabetes Mellitus and Obesity on Body Weight, Body Mass Index, and Fat Content as Affected by Alkaloid Fraction of Litsea Glutinosa Leaves (AFLG)

There were 463 million people living with diabetes around the world, and it is expected to increase by 48% in 2045. Dipeptidyl Peptidase 4 (DPP4) inhibitor is asecond-line anti-diabetic drug, that frequently causes weight gain for long term treatment. Alkaloid fraction of L. glutinosa leaves (AFLG) is able to inhibit DPP4 activity in diabetic rats. Therefore, this study aimed to evaluate the effect of AFLG on body weight (BW), BMI, and fat percentage in male rats with model type 2 diabetes mellitus (T2DM) and obesity. Male Sprague Dawley rats, which weighed 200-250 g, were used in this experimental study. Twelve rats were fed with a high-fat diet for 30 days and then were intraperitoneally injected with 230 and 65 mg/kg BW nicotinamide and streptozotocin, respectively. Those rats were randomly divided into 4 groups, control (C) and three treatment (T1-T3) groups, which were orally given 20, 40, and 80 mg/kg BW/day AFLG for 28 days. Collected data were analyzed using a paired t-test, the one-way ANOVA test. Significant differences in BW in T2 and T3 (p = 0.001), Rohrer index in T2 (p = 0.001) and fat content in C (p = 0.013) were observed between before and after treatments. The average of BW, Lee, Rohrer, and TM indexes and fat content in treatment groups did not significantly differ from the C group after 28 days of treatment (p &gt; 0.005). In conclusion, Alkaloid fraction of L. glutinosa leaves does not influence body weight, nutrition status, or fat content of male rats’ models of T2DM and obesity.

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

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

8139 Examining the Association of GLP1-RA or DPP4i with Bullous Skin Diseases in Veterans

Abstract Disclosure: S. Saad-Omer: None. M. Kinaan: None. N. Sami: None. I. Mansi: None. Introduction: Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are Autoimmune Blistering Disorders (AIBDs). GLP-1 Receptor Agonists (GLP1-RA) and Dipeptidyl peptidase 4 inhibitors (DPP4i) have been noted in various case reports and case control studies to be linked with certain AIBDs; however, their overall role in these diseases is not completely understood, despite the exponential increase in use of these medications. This study aims to be the first study to investigate the association of DPP-4 inhibitors and GLP-1 agonists with incidence of AIBD, PV, and BP in a large cohort of American veterans. Methods: This retrospective cohort study of veterans enrolled in the Veterans Health Administration (VHA) used Corporate Data Warehouse (CDW). We extracted data of patients from fiscal years (FY) 2006 to end of FY 2021 who filled either GLP1-RA or DPP4i prescriptions. CDW is a comprehensive data source that encompasses vital status, demographic data, inpatient and outpatient diagnoses and procedure codes, vital signs, laboratory data, and pharmacy fill data. The study groups included: 1) GLP1-RA group: patients who initiated GLP1-RA; and 2) DPP4i group: patients who initiated DPP4i. Our primary outcome was the incidence of AIBDs. We compared baseline characteristics of patients who experienced the outcome and those who did not among GLP1-RA or DDP4i users. We, thereafter, examined factors associated with incidence of AIBD, PV, and BP among GLP1-RA users and DPP4i users. Results: The initial cohort of GLP1-RA or DPP4i users comprised a total of 415,895 patients, from which we excluded 397 (0.095%) patients with prior bullous skin diseases before starting GLP1-RA or DPP4i medications. Overall, a total of 154 patients developed PV/BP disease after initiation of either DPP4i or GLP1-RA. Of these 154 patients, 123 of these patients were on DPP4i and 31 of these patients were on GLP1-RA. The mean age (SD) of PV/BP patients was 72 (11) years compared to an average age of 66 (10) years in patients who did not develop PV/BP. Patients were also found to be predominately white (77.9%). Factors associated with increased risk of BP were use of DPP4i (Odds Ratio [OR] 1.90, 95% confidence interval [95% CI: 1.14-3.47, p=&amp;lt;0.01), and older age (OR: 1.07, 95%CI: 1.04-1.09, p&amp;lt;0.01). Use of GLP1-RA or DPP4i was not associated with PV incidence. (OR: 1.31, 95% CI: 0.65-2.62, p=&amp;lt;0.45). Conclusion: In conclusion, our study supports existing literature that DPP4i use is associated with an increased risk of developing BP. Our data does not find association with GLP-1 agonists nor DPP4 inhibitors in increasing the risk of PV. 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

8707 Are We Adequately Prescribing Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i) Or Glucagon-Like Peptide 1 Receptor Agonist (GLP-1 RA) In Patients With Type 2 Diabetes Mellitus (T2DM) And Established Atherosclerotic Cardiovascular Disease (ASCVD) Or Chronic Kidney Disease (CKD) In An Outpatient Setting: A Community Center Experience

Abstract Disclosure: R.K. Maan: None. A. Sawhney: None. A. Hayat: None. S. Kc: None. A. Madan: None. S. K c: None. L. Williams: None. A. Zweben: None. A. Rana: None. Introduction: The American Diabetes Association (ADA) recommends prescribing Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i) or Glucagon-Like Peptide 1 Receptor Agonist (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and established Atherosclerotic Cardiovascular Disease (ASCVD) or Chronic Kidney Disease (CKD) for its cardiovascular benefits. Methods: Our retrospective study analyzed data from 511 T2DM patients who visited the outpatient clinic between 7/1/22 to 6/30/23. Using Microsoft Excel, we assessed adherence to ADA guidelines by collecting data for SGLT2i, GLP-1 RA and statin prescriptions, urine microalbumin creatinine ratio measurements, and appropriate management of albuminuria. The study also investigated patients on dipeptidyl peptidase-4 inhibitors (DPP-4i) who were eligible for SGLT2i or GLP-1 RA. Results: Out of the 511 patients, 478 were eligible for SGLT2i or GLP-1 RA, and only 60% were prescribed these medications. Out of 479 patients eligible for statin prescription, only 85% were on it. Albuminuria was appropriately managed in 76% of eligible patients with Angiotensin-Converting Enzyme Inhibitors (ACEI) or Angiotensin II Receptor Blockers (ARBs). Additionally, 8 out of 11 patients on DPP-4i were eligible for SGLT2i or GLP-1 RA. Conclusion: We concluded that 60% of the patients eligible for SGLT2i or GLP-1 RA were prescribed the medication in our outpatient settings. The barriers identified were issues with insurance prior authorization and knowledge gaps. We aim to improve adherence to guidelines through multifaceted education strategies combined with audits and feedback.

7265 Characterization of Treatment Intensified (Add-on To Metformin) Adults With Type 2 Diabetes Mellitus In Thailand: A cross sectional real-world study (CONVERGE)

Abstract Disclosure: C. Sriphrapradang: Research Investigator; Self; Novo Nordisk. Speaker; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly &amp; Company, Novo Nordisk. R. Chinthammit: Employee; Self; 2.Novo Nordisk Pharma Thailand Ltd. G. Nayak: Employee; Self; Novo Nordisk Pharma Thailand Ltd. Background: Globally, 1 in 3 people with type 2 diabetes (T2D) have established cardiovascular disease (CVD), but only 2 in 10 receive antidiabetic agents (ADA) (members of glucagon-like peptide-1 receptor agonist [GLP-1RAs] and sodium-glucose co-transporter-2 inhibitors [SGLT-2is]) with proven CV benefits. Guidelines recommend a holistic approach to managing glycemic control and CVD risk. Understanding clinical characteristics and medication patterns in people with T2D in a local setting could help address the unmet needs in T2D management. Objective: The CONVERGE (Cardiovascular Outcomes and Value in the Real World with GLP-1RAs) study in three Asian countries (India, Pakistan, Thailand) involves two phases. Phase 1 characterizes eligible adults with T2D intensified on metformin (add-on to metformin) regarding demographics, clinical parameters, and medication patterns. Here we report findings from Thailand. Methods: Due to healthcare differences, a mosaic approach was used for the retrospective cross-sectional data collection based on medical record reviews. For Thailand, electronic medical record (EMR) data of eligible adults (≥18 years old) with T2D from December 12, 2008 (on or post-market approval of GLP-1RAs [start of medical record]) to December 31, 2017. Data were collected at start of medical record and at 6 or 12 months prior to baseline based on variable type. Results: Due to descriptive nature of the study, no formal sample size calculation was performed. Data from 1,000 adults were collected in reverse chronological order as the EMR held a larger pool of eligible patients. At baseline, the mean (SD) age was 60 (12) years, HbA1c was 8.0%, and the median (IQR) T2D duration was 1.0 (0.2-2.4) years. Metformin (81%), sulfonylureas (45%), and dipeptidyl peptidase-4 inhibitors (39%) were frequently prescribed. Among the subgroups, patients taking SGLT-2is had a longer T2D duration, those on GLP-1RA had a higher body mass index, and those in the insulin group had a higher HbA1c. Overall, 86% received ≥1 ADAs, with most (80%) patients from the GLP-1RA subgroup received 3/≥4 ADAs before baseline compared to other subgroups. Overall, 90% received ≥1 CVD medication, while most (70%) patients in the GLP-1RA subgroup received 3/≥4 CVD medications than other subgroups. Metformin (81%) and lipid-lowering agents (78%) were the most prescribed ADA and CVD medications, respectively. The utilization of ADAs with CV benefits was low (GLP-1RA, 1.5%; SGLT-2is, 6%). Conclusion: These results indicate low ADA utilization with CV benefits, which may be attributed to the study period when no CV benefit data was available for GLP-1RA/SGLT-2is and to partial implementation of reimbursement policy. As more evidence becomes available on positive CV outcomes, future studies are required to estimate the ADA usage with CV benefits in Thailand. Presentation: 6/1/2024

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