Glucagon-like Peptide-1 Receptor Agonists In Type Research Articles

Cardiovascular, Kidney and Safety Outcomes with GLP-1 Receptor Agonists Alone and in Combination with SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors both improve cardiovascular and kidney outcomes in persons with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. Methods: We searched MEDLINE and Embase databases from inception until July 12, 2024 for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events ([MACE] nonfatal myocardial infarction, stroke or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50 % reduction in estimated glomerular filtration rate (eGFR ), kidney failure or death due to kidney failure, and annualized rate of decline in eGFR (eGFR slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on PROSPERO (CRD42024565765). Results: We identified three trials with 1,743/17,072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of MACE by 21% (HR 0.79, 95% CI 0.71-0.87), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR 0.77, 95% CI 0.54-1.09 and HR 0.79, 95% CI 0.71-0.87, respectively; P-heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR 0.58, 95% CI 0.36-0.93 and HR 0.73, 95% CI 0.63-0.85; P-heterogeneity=0.26). Effects on the composite kidney outcome (RR 0.79, 95% CI 0.66-0.95 ) and eGFR slope (0.78 mL/min/1.73m2/year, 95% CI 0.57-0.98) also did not vary according to SGLT2 inhibitor use (P-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P-heterogeneity=0.29 and 0.50, respectively). Conclusions: In persons with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.

Mechanistic Pathways and Clinical Implications of GLP-1 Receptor Agonists in Type 1 Diabetes Management.

GLP-1 receptor agonists, which were initially intended to treat type 2 diabetes patients, have demonstrated promise as an adjuvant therapy for type 1 diabetes (T1D). These medications can manage T1D by improving β-cell function, reducing glucose fluctuation, and providing cardioprotective effects. Recent research suggests that boosting cell proliferation and lowering apoptosis can help maintain the bulk of β-cells. Furthermore, GLP-1 receptor agonists have potent anti-inflammatory characteristics, improving immunological control and lowering systemic inflammation, both of which are critical for reducing autoimmune damage in T1D. Beyond glucose control, these agonists have neuroprotective qualities and aid in weight management. Combining these medications with insulin could significantly change how T1D is managed. The clinical data and biological mechanisms discussed in this review support the potential use of GLP-1 receptor agonists in T1D.

Race and ethnicity and pharmacy dispensing of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) improve cardiorenal outcomes in patients with type 2 diabetes. Equitable use of SGLT2i and GLP-1 RA has the potential to reduce racial and ethnic health disparities. We evaluated trends in pharmacy dispensing of SGLT2i and GLP-1 RA by race and ethnicity. Retrospective cohort study of patients (≥18 years) with type 2 diabetes using 2014-2022 electronic health record data from six US care delivery systems. Entry was at earliest pharmacy dispensing of any type 2 diabetes medication. We used multivariable logistic regression to evaluate the association between pharmacy dispensing of SGLT2i and GLP1-RA and race and ethnicity. Our cohort included 687,165 patients (median 6 years of dispensing data; median 60 years; 0.3% American Indian/Alaska Native (AI/AN), 16.6% Asian, 10.5% Black, 1.4% Hawaiian or Pacific Islander (HPI), 31.1% Hispanic, 3.8% Other, and 36.3% White). SGLT2i was lower for AI/AN (OR 0.80, 95% confidence interval 0.68-0.94), Black (0.89, 0.86-0.92) and Hispanic (0.87, 0.85-0.89) compared to White patients. GLP-1 RA was lower for AI/AN (0.78, 0.63-0.97), Asian (0.50, 0.48-0.53), Black (0.86, 0.83-0.90), HPI (0.52, 0.46-0.57), Hispanic (0.69, 0.66-0.71), and Other (0.78, 0.73-0.83) compared to White patients. Dispensing of SGLT2is, and GLP-1 RAs was lower in minority group patients. There is a need to evaluate approaches to increase use of these cardiorenal protective drugs in patients from racial and ethnic minority groups with type 2 diabetes to reduce adverse cardiorenal outcomes and improve health equity. Patient-Centered Outcomes Research Institute and National Institutes of Health.

SGLT-2 inhibitors and GLP-1 receptor agonists for Type 2 diabetes.

SGLT-2 inhibitors and GLP-1 receptor agonists for Type 2 diabetes.

Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Aims/hypothesisA precision medicine approach in type 2 diabetes could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the recently developed Bayesian causal forest (BCF) method to develop and validate an individualised treatment selection algorithm for two major type 2 diabetes drug classes, sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA).MethodsWe designed a predictive algorithm using BCF to estimate individual-level conditional average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA, based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England (Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2252 people with type 2 diabetes from Scotland (SCI-Diabetes [Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were replicated in clinical trial data (HARMONY programme: liraglutide [n=389] and albiglutide [n=1682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on glycaemic response on weight change, tolerability and longer-term risk of new-onset microvascular complications, macrovascular complications and adverse kidney events.ResultsModel development identified marked heterogeneity in glycaemic response, with 4787 (17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>0.3%) with SGLT2i over GLP1-RA and 5551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1-RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an independent Scottish dataset identified clear differences in glycaemic outcomes between those predicted to benefit from each therapy. Sex, with women markedly more responsive to GLP1-RA, was identified as a major treatment effect modifier in both the UK observational datasets and in clinical trial data: HARMONY-7 liraglutide (GLP1-RA): 4.4 mmol/mol (95% credible interval [95% CrI] 2.2, 6.3) (0.4% [95% CrI 0.2, 0.6]) greater response in women than men. Targeting the two therapies based on predicted glycaemic response was also associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications.Conclusions/interpretationPrecision medicine approaches can facilitate effective individualised treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical features for treatment selection could support low-cost deployment in many countries.Graphical

Safety and Efficacy of GLP-1 Receptor Agonists in Type 2 Diabetes Mellitus with Advanced and End-Stage Kidney Disease: A Systematic Review and Meta-Analysis.

Background and Objectives: Limited evidence exists regarding the safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes mellitus (T2DM) patients with advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD). Thus, we conducted a systematic review and meta-analysis to assess the safety and efficacy of GLP-1RAs in T2DM patients with advanced CKD and ESKD. Materials and Methods: We performed a systematic literature search in MEDLINE, EMBASE, and Cochrane database until 25 October 2023. Included were clinical trials and cohort studies reporting outcomes of GLP-1RAs in adult patients with T2DM and advanced CKD. Outcome measures encompassed mortality, cardiovascular parameters, blood glucose, and weight. Safety was assessed for adverse events. The differences in effects were expressed as odds ratios with 95% confidence intervals (CIs) for dichotomous outcomes and the weighted mean difference or standardized mean difference (SMD) with 95% confidence intervals for continuous outcomes. The Risk of Bias In Non-randomized Studies-of Interventions (ROBIN-I) tool was used in cohort and non-randomized controlled studies, and the Cochrane Risk of Bias (RoB 2) tool was used in randomized controlled trials (RCTs). The review protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42023398452) and received no external funding. Results: Eight studies (five trials and three cohort studies) consisting of 27,639 patients were included in this meta-analysis. No difference was observed in one-year mortality. However, GLP-1RAs significantly reduced cardiothoracic ratio (SMD of -1.2%; 95% CI -2.0, -0.4) and pro-BNP (SMD -335.9 pmol/L; 95% CI -438.9, -232.8). There was no significant decrease in systolic blood pressure. Moreover, GLP-1RAs significantly reduced mean blood glucose (SMD -1.1 mg/dL; 95% CI -1.8, -0.3) and increased weight loss (SMD -2.2 kg; 95% CI -2.9, -1.5). In terms of safety, GLP-1RAs were associated with a 3.8- and 35.7-time higher risk of nausea and vomiting, respectively, but were not significantly associated with a higher risk of hypoglycemia. Conclusions: Despite the limited number of studies in each analysis, our study provides evidence supporting the safety and efficacy of GLP-1RAs among T2DM patients with advanced CKD and ESKD. While gastrointestinal side effects may occur, GLP-1RAs demonstrate significant improvements in blood glucose control, weight reduction, and potential benefit in cardiovascular outcomes.

Designing and computational analyzing of chimeric long-lasting GLP-1 receptor agonists for type 2 diabetes

Glucagon-like peptide-1 (GLP-1) is an intestinally derived incretin that plays a vital role in engineering the biological circuit involved in treating type 2 diabetes. Exceedingly short half-life (1–2 min) of GLP-1 limits its therapeutic applicability, and the implication of its new variants is under question. Since albumin-binding DARPin as a mimetic molecule has been reported to increase the serum half-life of therapeutic compounds, the interaction of new variants of GLP-1 in fusion with DARPin needs to be examined against the GLP-1 receptor. This study was aimed to design stable and functional fusion proteins consisting of new protease-resistant GLP-1 mutants (mGLP1) genetically fused to DARPin as a critical step toward developing long-acting GLP-1 receptor agonists. The stability and solubility of the engineered fusion proteins were analyzed, and their secondary and tertiary structures were predicted and satisfactorily validated. Molecular dynamics simulation studies revealed that the predicted structures of engineered fusion proteins remained stable throughout the simulation. The relative binding affinity of the engineered fusion proteins' complex with human serum albumin and the GLP-1 receptor individually was assessed using molecular docking analyses. It revealed a higher affinity compared to the interaction of the individual GLP-1 and HSA-binding DARPin with the GLP-1 receptor and human serum albumin, respectively. The present study suggests that engineered fusion proteins can be used as a potential molecule in the treatment of type 2 diabetes, and this study provides insight into further experimental use of mimetic complexes as alternative molecules to be evaluated as new bio-breaks in the engineering of biological circuits in the treatment of type 2 diabetes.

Sodium-glucose cotransporter-2 inhibitors compared with glucagon-like-peptide-1 receptor agonists and out-of-hospital cardiac arrest in type 2 diabetes: a nationwide nested case-control study.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have beneficial direct effects on the myocardium by impacting cardiac ion channels and exchangers that control cardiac electrophysiology. We investigated the relationship between SGLT-2is in comparison to glucagon-like peptide-1 receptor agonists (GLP-1as) and out-of-hospital cardiac arrest (OHCA) in individuals with type 2 diabetes. Using data from Danish registries, we conducted a nationwide nested case-control study in a cohort of individuals with type 2 diabetes between 2013 and 2019. Cases were defined as OHCA victims from presumed cardiac causes and each case was randomly matched with five controls without OHCA based on age, sex, and index-date (OHCA date). Conditional logistic regression models were used to estimate the adjusted odds ratios (ORs) with 95% confidence interval (95% CI) of OHCA comparing SGLT-2i use with GLP-1as (reference). The study population consisted of 3 618 OHCA cases and 18 090 matched controls. SGLT-2i was used by 91 cases and 593 controls, and was associated with reduced odds of OHCA compared with use of GLP-1a after controlling for the relevant confounders (adjusted OR 0.76 [95% CI:0.58-0.99]). The adjusted OR of OHCA associated with SGLT-2i use did not vary significantly by sex (p-value interaction: 0.461), pre-existing cardiac disease (p-value interaction: 0.762), heart failure (p-value interaction: 0.891), diabetes duration (p-value interaction: 0.101) and chronic kidney disease (p-value interaction: 0.894). Use of SGLT-2i is associated with a reduced risk of OHCA compared with use of GLP-1a in type 2 diabetes.

Government declares 'national shortage' of GLP-1 receptor agonists for type 2 diabetes until 2024

Government declares 'national shortage' of GLP-1 receptor agonists for type 2 diabetes until 2024

Patient-perceived benefits and risks of off-label use of SGLT2 inhibitors and GLP-1 receptor agonists in type 1 diabetes: a structured qualitative assessment.

Patients with type 1 diabetes mellitus (T1DM) may have suboptimal glucose control and are interested in the use of adjuvant therapies. To determine, from the patients' perspective, the reasons for initiation of glucagon-like peptide 1 receptor agonist (GLP-1RA) and/or sodium glucose cotransporter 2 inhibitor (SGLT2i) in treating T1DM; perceived benefits/side effects, reasons for discontinuation, and willingness to reinitiate therapy. Retrospective chart review with structured telephone interviews. We identified patients with T1DM treated with a GLP-1RA and/or SGLT2i for >3 months at University of Texas Southwestern Medical Center (Dallas, TX, USA) and Poznan University (Poznan, Poland). We conducted structured telephone interviews regarding their experiences. We interviewed 68 participants treated with GLP-1RA and 82 with SGLT2i. Treatment was initiated for improving glycemic control (as reported by 61.8% versus 81.7% of GLP-1RA and SGLT2i users, respectively), weight loss/appetite suppression (51.4% versus 23.2%) and to reduce insulin requirement (13.2% versus 11%). Most participants (86.8% of GLP-1RA and 89.0% of SGLT2i users) reported ⩾1 benefit attributed to therapy. Reported benefits were improved glycemic control (reported by 58.8% versus 82.9% of GLP-1RA and SGLT2i users, respectively), weight loss/appetite suppression (63.2% versus 30.5%), and reduced insulin requirement (27.9% versus 34.1%). More GLP-1RA users reported side effects versus SGLT2i users (63.2% versus 36.6%); 22.6% discontinued GLP-1RA due to side effects versus 11.0% SGLT2i users. Diabetic ketoacidosis (DKA) was reported by 4.9% of SGLT2i users, but none in GLP-1RA users. Of those who discontinued medication, 60.7% of GLP-1RA versus 56.0% of SGLT2i prior users were willing to reinitiate treatment. Patients with T1DM report initiating adjuvant treatment with GLP-1RA and/or SGLT2i to improve glycemic control and lose weight; most patients reported perceived benefits from these therapies. Side effects (including DKA) are reported more commonly in real life than in clinical trials. Given patient interest in these medications, further studies should evaluate the long-term risk-benefits ratio in larger cohorts.

Parameters influencing renal response to SGLT2 inhibitors and GLP1 receptor agonists in type 2 diabetes patients with preserved renal function: a comparative, prospective study.

SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1-RA) protect the kidney in type 2 diabetes (T2DM) subjects. The role of patient's phenotype years before starting the treatment in determining the kidney response to these drugs has never been evaluated. Clinical and biochemical parameters were collected in 92 T2DM patients with preserved kidney function from year -4 (T-4) to year +3 (T+3) from the introduction of semaglutide or empagliflozin (T0). Glomerular filtration rate (eGFR) slopes were evaluated to identify eGFR changes (ΔGFR) and predictors of treatment response. Urinary markers of kidney impairment were measured at T0, including KIM-1, TNFR1 and L-FABP. Characteristics of patients on semaglutide (n = 46) or empagliflozin (n = 37) were similar at T-4 and T0. ΔGFR from T0 to T+3 was -5.5 [-10.0; -0.7] vs -2.6 [-102.4] ml/min/1.73m2 for GLP1-RA and SGLT2i, respectively (p = ns). Compared with patients with a slower eGFR decline, those with ΔGFR > 5ml/min/1.73m2 from T0 to T+3 (49%) or ΔGFR > 10ml/min/1.73m2 from T-4 to T+3 (25%) had similar characteristics and urinary markers at T-4 and T0. The latter group showed greater eGFR decline from T-3 to T0, which tended to be delayed more by SGLT2i than GLP1-RA (p = 0.09). In our cohort, subjects with T2DM and preserved renal function show similar eGFR response to treatment with GLP1-RA or SGLT2i. Baseline urinary biomarkers or prior phenotyping do not predict treatment response. An early eGFR decline identifies patients prone to lose more eGFR over time, who may benefit more from SGLT2i treatment.

PSUN270 Magnified Risk of Pancreatitis by GLP-1: A Case of Necrotizing Pancreatitis in a Patient on Dulaglutide with Baseline Elevated Triglycerides

Abstract Introduction Glucagon-like peptide 1 receptor agonists (GLP-1 RA), used in the treatment of diabetes mellitus, have been associated with pancreatitis in both animal studies and clinical trials. Furthermore, GLP-1 RA are associated with increased levels of serum lipase and amylase, possibly indicating resultant pancreatic inflammation.1 While there is debate on the actual degree of risk of pancreatitis in patients on GLP-1 RA, there may be individuals who are at higher risk due to baseline comorbidities that may have their risk of pancreatitis further potentiated by treatment with GLP-1 RA. We present a case in which a patient with baseline moderately elevated triglycerides on long term GLP-1 RA develops necrotizing pancreatitis after minimal alcohol intake. Case A 46-year-old man with type 2 diabetes mellitus, hyperlipidemia, and depression presented with one day history of severe right upper quadrant abdominal pain, nausea, and non-bloody, non-bilious vomiting. He also endorsed subjective fevers and chills, shortness of breath, chest pain, and constipation. He reported that he had drank one bottle of sparkling wine the day prior but denied drinking regularly. Labs and imaging were consistent with acute necrotizing pancreatitis with elevated lipase (502 U/L), elevated triglycerides (TG) (3,480 mg/dL), and CT abdomen/pelvis showing focal hypoattenuation/edema of the pancreatic head with surrounding fat stranding. Subsequent MRI abdomen showed evolving necrotic pancreatitis with focal area of nonenhancement in the pancreatic head. He denied any history of gallstones, recent trauma, diarrhea, weight loss, or prior pancreatitis. Review of his medications was notable for dulaglutide for management of his diabetes. He also had a history of consistently elevated TG to the mid-300s mg/dL as far back as 3 years ago. Patient was ultimately managed conservatively with intravenous fluids with resolution of symptoms and downtrend of lipase and triglycerides. He was discharged on fenofibrate and icosapent ethyl for further triglyceride control. Discussion While several META analyses have not shown significant association between GLP-1 RA and pancreatitis, there still is a proportion of patients who have developed pancreatitis on GLP-1 RA.2 Our patient had baseline elevated triglycerides, but they were below the typical threshold for treatment. With minimal alcohol consumption, he still developed pancreatitis. We suspect that his risk for pancreatitis was magnified by his GLP-1 RA. We believe that in patients such as ours who have baseline independent risk factors for pancreatitis, GLP-1 RA should be carefully considered before initiation. 1. Trujillo J. Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes. J Clin Pharm Ther. 2020;45 Suppl 1(Suppl 1): 43-60. doi: 10.1111/jcpt.13225 2. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials. Diabetes Res Clin Pract. 2014;103(2): 269-275. doi: 10.1016/j.diabres.2014.01.010 Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Perceptions and Preferences Toward GLP-1 Receptor Agonists in Type 2 Diabetes Management in Saudi Arabia: A Cross-sectional, Two-arm Study

Perceptions and Preferences Toward GLP-1 Receptor Agonists in Type 2 Diabetes Management in Saudi Arabia: A Cross-sectional, Two-arm Study

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

745-P: Short-Acting Exenatide Added Three Times Daily to Insulin Therapy Improves Insulin Sensitivity in Type 1 Diabetes

Average life expectancy in type 1 diabetes is reduced by more than a decade due to cardiovascular (CV) disease. Reduced insulin sensitivity as assessed by low values of estimated glucose disposal rate (eGDR) has been observed to correlate with increased risk of CV events. How short-acting glucagon-like peptide 1 receptor agonists (GLP-1RA) influence eGDR in type 1 diabetes remains unknown. We analyzed eGDR post-hoc in a phase 2, double-blind, randomized (1:1) , clinical trial (NCT03017352) that evaluated the short-acting GLP-1RA exenatide μg added three times daily to insulin therapy as compared with placebo over 26 weeks of treatment in 1individuals with type 1 diabetes (76/32 men/women, age 50 (14) years (mean (standard deviation)) , diabetes duration 21 (12) years, BMI 28 (4) kg/m2, glycated hemoglobin A1c 8.2 (0.7) % / 66 (7) mmol/mol) . Exenatide significantly increased eGDR by 0.36 mg/kg/min (95 % confidence interval 0.03; 0.69, P = 0.032) (Table 1) as compared with placebo after 26 weeks’ treatment. Short-acting exenatide apparently improved insulin sensitivity in patients with long-standing type 1 diabetes and inadequate glycemic control, alluding to potential CV benefits of this GLP-1RA in type 1 diabetes. Disclosure N.Johansen: Employee; Novo Nordisk A/S. T.F.Dejgaard: Advisory Panel; Novo Nordisk, Research Support; Novo Nordisk, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. A.Lund: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. Funding Partly funded by AstraZeneca

504-P: Success of Aligned Clinician–Patient Education Improves Clinicians’ Ability to Use GLP-1 RAs in Practice and Patients’ Understanding of GLP-1 RAs

We sought to determine if online aligned education for clinicians and patients could improve understanding and use of GLP-1 RAs for T2D. For clinicians, a live-streamed virtual symposium was held as part of the 2021 Metabolic and Endocrine Disease Summit (MEDS) summer (July) and fall (October) meetings, followed by an enduring available in August, 2021. Pre/post questions were used to assess changes in knowledge, confidence and practice. For patients, the online text, integrated visuals and patient video activity, which launched in June 2021, used a pre/post knowledge question and post-activity intent to change and confidence questions to assess impact. Absolute improvements were calculated for all questions, data collected through November 1, 2021. Clinician Activity Learners: 581 (Summer) and 364 (Fall) . Demographics: 47%-56% were nurse practitioners, 22% physician assistants, and 9%-12% physicians. Knowledge changes: 13%-16% increase in recognizing GLP-1 RAs with CV benefits/indications, 6%-7% increase in identifying weight loss as a benefit of GLP-1 RAs, 12%-23% increase in selecting patient education to help mitigate side effects. After the education, 80%-86% reported confidence in starting a patient with CVD/obesity on a GLP-1 RA. Enduring Learners: 1,662 clinicians (as of November 1, 2021) . Patient Activity: 11,029 learners have participated in the patient/caregiver activity, “Understanding the Use of GLP-1 Receptor Agonists for Type 2 Diabetes.” Knowledge changes: 22% increase in recognizing how GLP-1 RAs work (39% pre to 61% post) . Intent-to-act: 70% plan to talk to their HCP about if taking a GLP-1 RA can help manage their T2D better. Confidence changes: 78% reported increased confidence in talking to my HCP about GLP-1 RAs for T2D. These outcomes are a strong indicator that aligned clinician and patient activities are successful at improving both clinicians’ and patients’ understanding and use of GLP-1 RAs for T2D. Disclosure A.Larkin: None. A.Le: None. Funding Independent Educational Grant from Novo Nordisk.

Global use of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. Results from DISCOVER

BackgroundDespite strong evidence of benefit, uptake of newer glucose-lowering medications that reduce cardiovascular risk has been low. We sought to examine global trends and predictors of use of SGLT2i and GLP-1 RA in patients with type 2 diabetes.MethodsDISCOVER is a global, prospective, observational study of patients with diabetes enrolled from 2014–16 at initiation of second-line glucose-lowering therapy and followed for 3 years. We used hierarchical logistic regression to examine factors associated with use of either an SGLT2i or GLP-1 RA at last follow-up and to assess country-level variability.ResultsAmong 14,576 patients from 37 countries, 1579 (10.8%) were started on an SGLT2i (1275; 8.7%) or GLP-1 RA (318; 2.2%) at enrollment, increasing to 16.1% at end of follow-up, with large variability across countries (range 0–62.7%). Use was highest in patients treated by cardiologists (26.1%) versus primary care physicians (10.4%), endocrinologists (16.9%), and other specialists (22.0%; p < 0.001). Coronary artery disease (OR 1.29, 95% CI 1.08–1.54) was associated with greater use of SGLT2i or GLP-1 RA while peripheral artery disease (OR 0.73, 95% CI 0.54–1.00) and chronic kidney disease (OR 0.73, 95% CI 0.58–0.94) were associated with lower use (OR 0.73, 95% CI 0.54–1.00). The country-level median odds ratio was 3.48, indicating a very large amount of variability in the use of SGLT2i or GLP-1 RA independent of patient demographic and clinical factors.ConclusionsGlobal use of glucose-lowering medications with established cardiovascular benefits has increased over time but remains suboptimal, particularly in sub-groups most likely to benefit. Substantial country-level variability exists independent of patient factors, suggesting structural barriers may limit more widespread use of these medications.

Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study.

BackgroundsGlucagon-like peptide-1 receptor agonist (GLP-1 RA) is probably one of more effective antidiabetic agents in treatment of type 2 diabetes mellitus (T2D). However, the heterogenicity in responses to GLP-1 RA may be potentially related to gut microbiota, although no human evidence has been published. This pilot study aims to identify microbial signatures associated with glycemic responses to GLP-1 RA.Materials and MethodsMicrobial compositions of 52 patients with T2D receiving GLP-1 RA were determined by 16S rRNA amplicon sequencing. Bacterial biodiversity was compared between responders versus non-responders. Pearson’s correlation and random forest tree algorithm were used to identify microbial features of glycemic responses in T2D patients and multivariable linear regression models were used to validate clinical relevance.ResultsBeta diversity significantly differed between GLP-1 RA responders (n = 34) and non-responders (n = 18) (ADONIS, P = 0.004). The top 17 features associated with glycohemoglobin reduction had a 0.96 diagnostic ability, based on area under the ROC curve: Bacteroides dorei and Roseburia inulinivorans, the two microbes having immunomodulation effects, along with Lachnoclostridium sp. and Butyricicoccus sp., were positively correlated with glycemic reduction; Prevotella copri, the microbe related to insulin resistance, together with Ruminococcaceae sp., Bacteroidales sp., Eubacterium coprostanoligenes sp., Dialister succinatiphilus, Alistipes obesi, Mitsuokella spp., Butyricimonas virosa, Moryella sp., and Lactobacillus mucosae had negative correlation. Furthermore, Bacteroides dorei, Lachnoclostridium sp. and Mitsuokella multacida were significant after adjusting for baseline glycohemoglobin and C-peptide concentrations, two clinical confounders.ConclusionsUnique gut microbial signatures are associated with glycemic responses to GLP-RA treatment and reflect degrees of dysbiosis in T2D patients.

The potential of GLP-1 receptor agonists in type 2 diabetes and chronic kidney disease: from randomised trials to clinical practice.

Chronic kidney disease (CKD) affects around 10% of the global population and is most often caused by diabetes. Diabetes with CKD (diabetic kidney disease, DKD) is a progressive condition that may cause kidney failure and which contributes significantly to the excess morbidity and mortality in these patients. DKD is treated with direct disease-targeting therapies like blockers of the renin–angiotensin system, sodium–glucose cotransporter-2 (SGLT-2) inhibitors and non-steroidal mineralocorticoid receptor antagonists as well as indirect therapies impacting hyperglycaemia, dyslipidaemia, obesity and hypertension, which all together reduce disease progression. While no glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are currently indicated to improve kidney outcomes, accumulating evidence from cardiovascular outcomes trials (CVOTs) corroborates a kidney-protective effect in people with T2D and CKD, and GLP-1 RAs are now mentioned in international treatment guidelines for type 2 diabetes (T2D) with CKD. GLP-1 RAs are indicated to improve glycaemia in people with T2D; certain GLP-1 RAs are also approved for weight management and to reduce cardiovascular risk in T2D. Ongoing pivotal trials are assessing additional indications, including T2D with CKD. In this article, we review and discuss kidney outcomes from a multitude of completed clinical trials as well as real-world evidence and ongoing clinical trials.

A Novel Anti-Inflammatory Renoprotective Effect of GLP-1 Receptor Agonists in Type 1 Diabetes: Shifting Macrophage Polarization

A Novel Anti-Inflammatory Renoprotective Effect of GLP-1 Receptor Agonists in Type 1 Diabetes: Shifting Macrophage Polarization