Glucagon-like Peptide-1 Receptor Agonist Therapy Research Articles

Risk of stroke and retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: An eight RCTs meta-analysis.

To explore the risk of stroke (including ischemic and hemorrhagic stroke) in type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trials(CVOT). Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetics published in full-text journal databases such as Medline (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to May 1, 2022 were searched. We assess the quality of individual studies by using the Cochrane risk of bias algorithm. RevMan 5.4.1 software was use for calculating meta- analysis. A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported statistically significant effect on total stroke risk[RR=0.83, 95%CI(0.73, 0.95), p=0.005], and its subtypes such as ischemic Stroke [RR=0.83, 95%CI(0.73, 0.95), p=0.008] from treatment with GLP-1RA versus placebo, and have no significant effect on the risk of hemorrhagic stroke[RR=0.83, 95%CI(0.57, 1.20), p=0.31] and retinopathy [RR=1.54, 95%CI(0.74, 3.23), p=0.25]. GLP-1RA significantly reduces the risk of ischemic stroke in type 2 diabetics with cardiovascular risk factors.

Abstract 11522: Impact of Chronic Glucagon-Like Peptide-1 Receptor Agonist and Sodium Glucose Cotransporter-2 Inhibitor Therapy on In-Hospital Outcomes of Patients Hospitalized With Acute Myocardial Infarction

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i) demonstrated cardiovascular and renal protection in addition to their glucose-lowering effect. Whether their benefits occur also in patients with diabetes mellitus (DM) during hospitalization with acute myocardial infarction (AMI) has not been investigated yet. Methods: We evaluated in-hospital outcomes of patients hospitalized with AMI according to their chronic use (before hospitalization) of GLP-1 RA and SGLT-2i therapy. Using administrative healthcare databases, we analyzed patients hospitalized with a primary diagnosis of AMI from 2010 to 2019 in the Lombardy region, Italy. Patients were stratified according to their DM status, then divided into three cohorts: Group 1 (non-DM patients); Group 2 (DM patients taking GLP-1 RA or SGLT-2i); and Group 3 (DM patients not taking GLP-1 RA and/or SGLT-2i). Patients were matched in a 1:1:1 ratio using a propensity score including all available variables. The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy. Results: We identified 146,800 patients hospitalized with AMI (26% of them with DM). After propensity score matching, 1,030 patients were included in each group. The primary endpoint rate in the overall population was 16% (n=502) and it significantly increased going from Group 1 to Group 3 (13%, 16%, and 20% respectively; p for trend &lt0.0001). The risk of the composite endpoint significantly increased from Group 1 to Group 3 (P for trend &lt0.0001). In comparison with Group 2, Group 3 had a significant higher risk of the composite endpoint (OR 1.40 [95% CI 1.11-1.77]). Conclusions: Our study shows that DM patients hospitalized with AMI and on chronic GLP-1 RA and/or SGLT-2i therapy have a better in-hospital clinical outcome than DM patients without them.

Initiation of the Fixed Combination IDegLira in Patients with Type 2 Diabetes on Prior Injectable Therapy: Insights from the EASY French Real-World Study.

Combining basal insulin (BI) with glucagon-like peptide-1 receptor agonist (GLP-1RA) is recognized as a relevant option to optimize glucose control in type 2 diabetes (T2D). The EASY real-world study aimed to evaluate the modalities of initiation and the effectiveness of the insulin Degludec plus Liraglutide (IDegLira) fixed-ratio combination in the French health care system. A retrospective analysis included all patients with T2D and prior injectable therapy (GLP1-RA and/or insulin) who started treatment with IDegLira from September 2016 to December 2017 in 11 French diabetes centers. Baseline characteristics, reasons for IDegLira initiation, and modes of implementation were collected from the medical records. Changes in HbA1c and body weight were determined in patients with available follow-up data (nearest 6-month visit). IDegLira was initiated in 629 patients previously treated with GLP-1RA alone (11.6%), insulin alone (31.5% including 16.5% with BI and 14.9% with multiple daily injections [MDI]) or a free combination of GLP-1RA and insulin (56.9% including 44.8% with BI and 12.1% with MDI), associated or not with oral agents. IDegLira starting dose (mean of 29 ± 11 dose steps) most often exceeded the recommended dose, and was significantly correlated with prior BI but not GLP-1RA dosage. At initiation, mean age, body mass index (BMI) and HbA1c were 60.1 ± 10.2years, 33.4 ± 6.2kg/m2 and 8.8 ± 1.7%, respectively. In 461 patients with available follow-up (median 178days), HbA1c decreased in all subgroups submitted to treatment intensification (- 1.7 ± 1.8% [p < 0.0001], - 1.2 ± 1.8% [p < 0.001] and -0.8 ± 1.8% [p = 0.0026] in patients with prior GLP-1RA, BI or MDI therapy, respectively) but also in those switching from BI and GLP-1RA free combination (- 0.2 ± 0.9%, p = 0.0419). Significant body weight gain occurred in patients previously treated with GLP-1RA alone (+ 1.5 ± 5.8kg, p = 0.0572) or combined to BI (+ 1.0 ± 3.1kg, p < 0.0001) while those on BI (- 1.4 ± 4.6kg, p = 0.0139) or MDI (- 1.4 ± 5.0kg, p = 0.0484) experienced weight loss. While providing new information on the use of IDegLira in the French healthcare system, these data confirm the effectiveness of this fixed-ratio combination in the management of T2D.

RF28 | PSUN182 Risk of Pancreatitis After Glp-1 Receptor Agonist in Individuals With Known History of Pancreatitis

Abstract Introduction Randomized clinical trials identified a small increased risk of acute pancreatitis in patients using glucagon-like peptide-1 receptor agonist (GLP1- RA) therapy. As a result, GLP-1RA therapy is generally avoided in patients with a history of acute pancreatitis. The aim of this report was to evaluate the real-world experience of GLP-1RA therapy in patients with a history of acute pancreatitis. Methods A retrospective chart review was conducted (2010-2019) using the enterprise-wide electronic health record (EHR) system. Patients with a history of acute pancreatitis and a subsequent encounter diagnosis of acute pancreatitis (ICD-9/ ICD-10 codes), after exposure to GLP-1R, were identified. Exposure to GLP-1RA was defined as a documented prescription for GLP-1RA in the EHR. Patients were followed until the date of recurrent acute pancreatitis (RAP) or censoring. Categorical and continuous variables were summarized using N (%) and mean (SD), respectively. Results A total of 161 patients were identified, 50.9% were female, 56.6% Caucasian, with mean age (years) 54 (±13) and mean BMI 35 kg/m2 (±8). Type 2 diabetes, hypertension, and obesity were present in 92.5% (N=149), 86.3% (N=139), and 73.9% (N=119), respectively. The mean duration of follow-up for all patients was 28.2 months (±24.6). The etiologies of the first documented episode of pancreatitis prior to GLP-1RA exposure were gall stones (N=49, 30.4%), alcoholism (N=21, 13%), hypertriglyceridemia (N=9, 5.6%), medication-induced N=5 (3.1%), and the remaining cases (N=77, 47.8%) were classified as idiopathic. Among these 161 patients, N=16 (9.9%) had a second episode of pancreatitis after GLP1-RA exposure. The mean duration of exposure to GLP-1RA prior to RAP was 10.8 months (±7.2). RAP was attributed to GLP 1-RA exposure N=6 (37.5%), alcohol intake N=2 (12.5%), hypertriglyceridemia N=3 (18.8%), oral hypoglycemic agent N=1 (6.2%), ampulla stenosis N=1 (6.2%), and the remaining N=3 (18.8%) were considered idiopathic. Conclusions Among 161 patients with a history of acute pancreatitis exposed to GLP-1RA, a total of 16 (9.9%) cases of RAP were identified, but only N=6 (4%) of these were determined attributable to GLP-1RA exposure. The overall rate of RAP among our cohort of GLP-1RA exposed patients (9.9%) is similar to the overall rate of RAP reported in the literature (12.7%), regardless of the underlying etiology or drug exposure.1 Acute pancreatitis related to drug exposure is a diagnosis of exclusion; thus, it is certainly possible that some of the cases in our report considered idiopathic were actually related to GLP-1RA exposure. While caution needs to be exercised, our data would support the use of GLP-1RA in patients with a history of acute pancreatitis, on an individualized basis, where the benefits are considered to outweigh the risks. References 1) Mallick et al. Differences between the outcome of recurrent acute pancreatitis and acute pancreatitis. JGH Open. 2018 Jun 6;2(4): 134-138. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:30 p.m. - 12:35 p.m.

Impact of chronic GLP-1 receptor agonist and SGLT-2 inhibitor therapy on in-hospital outcomes of patients with diabetes mellitus hospitalized with acute myocardial infarction

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i) demonstrated cardiovascular and renal protection in addition to their glucose-lowering effect. Whether their benefits occur also in patients with diabetes mellitus (DM) during hospitalisation with acute myocardial infarction (AMI) has not been investigated yet. Purpose We evaluated in-hospital outcomes of patients hospitalised with AMI according to their chronic use (before hospitalisation) of GLP-1 RA and SGLT-2i therapy. Methods Using administrative healthcare databases, we analysed patients hospitalised with a primary diagnosis of AMI from 2010 to 2019 in the Lombardy region, Italy. Patients were stratified according to their DM status, then divided into three cohorts: Group 1 (non-DM patients); Group 2 (DM patients taking GLP-1 RA or SGLT-2i); and Group 3 (DM patients not taking GLP-1 RA and/or SGLT-2i). Patients were matched in a 1:1:1 ratio using a propensity score including all available variables. The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy. Results We identified 146,800 patients hospitalised with AMI (26% of them with DM). After propensity score matching, 1,030 patients were included in each group. The primary endpoint rate in the overall population was 16% (n=502) and it significantly increased going from Group 1 to Group 3 (13%, 16%, and 20% respectively; p for trend &amp;lt;0.0001). The risk of the composite endpoint significantly increased from Group 1 to Group 3 (P for trend &amp;lt;0.0001). In comparison with Group 2, Group 3 had a significant higher risk of the composite endpoint (OR 1.40 [95% CI 1.11–1.77]). Conclusions Our study shows that DM patients hospitalised with AMI and on chronic GLP-1 RA and/or SGLT-2i therapy have a better in-hospital clinical outcome than DM patients without them. Funding Acknowledgement Type of funding sources: None.

P15.05: Safety of Once-Weekly Dulaglutide on Post-transplant Diabetes Mellitus: A Preliminary Single-Centre Experience

Introduction: Almost all immunosuppressive drugs (IS), including glucocorticoids, calcineurin and mTOR inhibitors, play a central role in the development of Post-Transplant Diabetes Mellitus (PTDM). IS potentially cause the development of a dysglycemic state, both for the direct cytotoxic action on pancreatic beta cells and for the induction of insulin resistance. PTDM is also associated with increased risk for cardiovascular disease and with worse graft and patients’ survival. Currently there are no clear recommendations on the choice of the most safe and effective anti-diabetic drug for PTDM. IS are linked with several pharmacokinetic interactions and burdened with vary degree of nephrotoxicity. Glucagon like peptide- 1 receptor agonists (GLP1RA) are largely used for the treatment of type 2 diabetes. They act stimulating endogenous insulin secretion in a glucose-dependent manner. GLP1RAs reduce blood sugar by stimulating insulin release, suppressing high glucagon levels, delaying gastric emptying, and reducing food intake. Furthermore, GLP1 has been shown to promote proliferation of beta cells in animal models. GLP1RA has proven to be safe and effective in reducing HbA1c without directly causing hypoglycemia and has shown a clear association with cardiovascular risk reduction and renal protection. Despite GLP1RA seems to act with a mechanism that perfectly contrasts the pathogenetic aspects of PTDM, in the literature clinical experience is entirely limited to case series and retrospective studies. Method: In order to assess primarily safety of GLP1RA therapy in patients with PTDM we have prospectively enrolled a sample of N = 20 patients referred to liver (N = 10), renal (N = 5), as well as heart (N = 4) and lung (N = 1) transplant at ISMETT. All patients were placed on once-weekly dulaglutide therapy. Weight, HbA1c Level, as well as complete lipid profile and liver function tests were performed at 3 months and again at 6 months. One-way Repeated measurements ANOVA was used to test significant change in collected variables over time. Results: The study was closed at 6 months follow-up visit. Mild gastrointestinal symptoms were experienced by patients at the treatment start and resolved in 2 weeks. There were no persistent side effects due to dulaglutide in our study population and all recruited patients were on dulaglutide at 6 months evaluation. Body weight, Total cholesterol, Fibrosis-4 Index, alanine aminotransferase and aspartate aminotransferase levels were all reduced at the end of the follow-up, while blood glucose as well as HbA1c were stable over time (Table 1, Figure 1). Conclusion: Dulaglutide has proven to be safe in a population of transplanted patients with PTDM. In addition, a significative reduction of metabolic parameters was found. GLP1RA could be a preferred treatment for patients with PTDM considering also the extraglycemic effects of cardiovascular and renal protection.

Effects of GLP-1 receptor agonists on arrhythmias and its subtypes in patients with type 2 diabetes: A systematic review and meta-analysis.

PurposeAn update of a systematic review and meta-analysis of the risk of arrhythmias and their subtypes in type 2 diabetic patients receiving glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trial(CVOT).MethodsRandomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetes mellitus patients published in full-text journal databases such as MEDLINE (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to March 1, 2022 were searched. We assessed the quality of individual studies by the Cochrane risk-of-bias algorithm. RevMan 5.4.1 software was use for calculating meta-analysis.ResultsA total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported no significant effect on total arrhythmia [RR=0.96, 95% CI (0.96, 1.05), p =0.36], and its subtypes such as atrial fibrillation [RR=0.96, 95% CI (0.86, 1.07), p =0.43], atrial flutter [RR= 0.82, 95% CI (0.57, 1.19), p =0.30], atrial tachycardia [RR=0.64, 95% CI (0.20, 2.01), p =0.44)], sinoatrial node dysfunction [RR=0.74, 95% CI (0.44, 1.25), p =0.26], ventricular preterm systole [RR=1.42, 95% CI (0.62, 3.26), p =0.41], second degree AV block [RR=0.96, 95% CI (0.53, 1.72), p =0.88], complete AV block [RR=0.75, 95% CI (0.49, 1.17), p =0.21], ventricular fibrillation [RR=1.00, 95% CI (0.50, 2.02), p =1.00], ventricular tachycardia [RR=1.37, 95% CI (0.91, 2.08), p =0.13] from treatment with GLP-1RA versus placebo. However, the risk of hypoglycemia was reduced by about 30% [RR=0.70, 95% CI (0.57, 0.87), p=0.001] and the risk of pneumonia by about 25% [RR=0.85, 95% CI (0.75, 0.97), p=0.01], both statistically significant differences.ConclusionIn type 2 diabetic patients, treatment with GLP-1RA has no significant effect on the risk of major arrhythmias but significantly reduces the risk of hypoglycemia and pneumonia.

Clinical Utility of Cardiovascular Risk Scores for Identification of People With Type 2 Diabetes More Likely to Benefit From Either GLP-1 Receptor Agonist or SGLT2 Inhibitor Therapy.

Differentiation of risk for major adverse cardiovascular events (MACE) from heart failure hospitalization (HHF) or kidney disease is important when selecting glucose-lowering therapy. We investigated the ability of separate MACE and HHF risk scores to 1) differentiate MACE from HHF risk; and 2) identify individuals more likely to benefit from either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter-2 inhibitors (SGLT2is). We identified three trials in type 2 diabetes that reported cardiovascular outcomes stratified by Thrombolysis In Myocardial Infarction Risk Scores for MACE and HHF. Pooled placebo-arm rates of HHF, MACE, and their ratio and estimated GLP-1RA- and SGLT2i-mediated reductions in events (MACE and HHF combined) were compared across cardiovascular risk strata in the trial populations. The HHF rate was less frequent than MACE at all risk levels but increased from 18% of the MACE rate at low-intermediate HHF risk to 61% at highest HHF risk. Similarly, with increasing MACE risk, the incidence of HHF increased from 19% of the MACE incidence in those at low MACE risk to 51% in those with the highest MACE risk. Estimated GLP-1RA- and SGLT2i-mediated reductions in cardiovascular events were similar in those at low-intermediate MACE or HHF risk but tended to favor SGLT2is at higher risk levels of both scores. A greater increase in the rate of HHF relative to MACE was observed with progressively higher cardiovascular risk, regardless of the risk score applied. Consequently, SGLT2is may offer greater overall cardiovascular protection in those at highest MACE risk, not just those at highest HHF risk.

Sodium-Glucose Cotransporter-2 Inhibitor and Glucagon-Like Peptide-1 Receptor Agonist Combination Therapy in Type 2 Diabetes: Protocol for a Kidney End Points Real-world Study (COMBi-KID Study).

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are both considered to be part of standard care in the management of glycemia in type 2 diabetes. Recent trial evidence has indicated benefits on primary kidney end points for individual drugs within each medication class. Despite the potential benefits of combining SGLT2is and GLP-1RAs for glycemia management, according to national and international guideline recommendations, there is currently limited data on kidney end points for this drug combination.ObjectiveThe aims of the study are to assess the real-world effects of combination SGLT2i and GLP-1RA therapies for diabetes management on kidney end points, glycemic control, and weight in people with type 2 diabetes who are being treated with renin-angiotensin system blockade medication.MethodsThis retrospective cohort study will use the electronic health records of people with type 2 diabetes that are registered with general practices covering over 15 million people in England and Wales and are included in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network. A propensity score–matched cohort of prevalent new users of SGLT2is and GLP-1RAs and those who have been prescribed SGLT2is and GLP-1RAs in combination will be identified. They will be matched based on drug histories, comorbidities, and demographics. A repeated-measures, multilevel, linear regression analysis will be performed to compare the mean change (from baseline) in estimated glomerular filtration rate at 12 and 24 months between those who switched to combined therapy and those continuing monotherapy with an SGLT2i or GLP-1RA. The secondary end points will be albuminuria, serum creatinine level, glycated hemoglobin level, and BMI. These will also be assessed for change at the 12- and 24-month follow-ups.ResultsThe study is due to commence in March 2022 and is expected to be complete by September 2022.ConclusionsOur study will be the first to assess the impact of combination SGLT2i and GLP-1RA therapy in type 2 diabetes on primary kidney end points from a real-world perspective.International Registered Report Identifier (IRRID)PRR1-10.2196/34206

GLP-1 Receptor Agonists in the Treatment of Patients with Type 2 Diabetes and Chronic Kidney Disease

Diabetic kidney disease (DKD) represents an important diabetes (DM) complication associated with significant impacts on morbidity, mortality, and quality of life. Recent evidence from cardiovascular and kidney outcome trials has dramatically impacted the standard of care for patients with DKD. While agents from the glucagon-like peptide-1 (GLP-1) receptor agonist class are known for their atherosclerotic cardiovascular disease (ASCVD) benefits, growing mechanistic and clinical evidence supports the benefit of GLP-1 receptor agonist therapy on progression of DKD. GLP-1 receptor activation is associated with anti-inflammatory and antifibrotic effects in the kidney, providing a plausible mechanism for kidney protection. Based on currently available clinical trial evidence, guidelines recommend the use of GLP-1 receptor agonists to mitigate ASCVD risk in patients with type 2 diabetes (T2D). Furthermore, based on secondary outcome data for kidney disease, GLP-1 receptor agonists are recommended as an option to mitigate kidney and ASCVD risk in patients with T2D and DKD who require intensification of glycemic control or for those who cannot take a sodium-glucose cotransporter-2 (SGLT2) inhibitor due to side effects or advanced stage DKD. Ongoing dedicated kidney disease outcome trials will further inform the role of GLP-1 receptor agonists in DKD management. This review discusses current considerations for GLP-1 receptor agonist use in patients with T2D and DKD.

Glucagon-like peptide-1 receptor agonist (GLP1-RA) therapy in type 2 diabetes.

Type 2 diabetes (T2D) is a national health priority. Its rising prevalence isaccompanied by a high burden of diabetes-related complications, many ofwhich are preventable. Numerous glucose-lowering medications have beendeveloped in recent years with growing evidence relating to their efficacy and safety. These advances haveincreased the complexity of prescribing decisions inT2D. This review provides clinicians with relevant evidence and practical advice concerning glucagon-like peptide-1 receptor agonists (GLP1-RAs) in T2D. The Royal Australian College of General Practitioners recommends GLP1-RAs as an option for second-line therapy in T2D. GLP1-RAs contribute to weight loss and glycated haemoglobin reduction. GLP1-RAs also reduce incidence of cardiovascular events in selected populations, and available evidence suggests renoprotective effects. Common adverse effects include gastrointestinal symptoms, especially in the weeks following treatment initiation. GLP1-RAs should be considered for people with T2D at high cardiovascular risk or where weight loss is a priority.

Comparison of the Usability, Accuracy, Preference, and Satisfaction of Three Once-Weekly Glucagon-Like Peptide 1 Receptor Agonist Pen Devices in People With Type 2 Diabetes.

This study's aim was to compare the time and accuracy of use and participants' satisfaction and preferences with pen devices for the once-weekly glucagon-like peptide 1 (GLP-1) receptor agonists dulaglutide, exenatide XR BCise, and semaglutide. In this triple crossover, open-label, simulated injection study, GLP-1 receptor agonist pen devices were compared, with time and accuracy of use and participants' satisfaction and preferences as primary outcomes. Participants had type 2 diabetes and were naive to GLP-1 receptor agonist therapy. Participants watched instructional videos for each device, demonstrated administration, and then provided feedback after each demonstration. Investigators tracked errors and omissions of demonstration steps for accuracy and time. Differences across devices were compared using univariate mixed models, adjusting for multiple comparisons. Of the 60 participants, 50% were male, a majority (65%) were Caucasian, and most (65%) had adequate health literacy. Participants rated the dulaglutide device easier to use than those of exenatide XR BCise or semaglutide (P <0.001 for each). Participants expressed greater satisfaction with the dulaglutide device compared with those of exenatide XR BCise or semaglutide (P <0.01 for each). Most participants (75%) preferred the dulaglutide device overall; however, many participants (61%) preferred the size and portability of the semaglutide device. The dulaglutide device took less time to use than the exenatide XR BCise or semaglutide devices (69 vs. 126 and 146 seconds, respectively; P <0.001 for each). Participants were less accurate when using the dulaglutide device. Most participants preferred the dulaglutide device. The dulaglutide device took the least amount of time to demonstrate; however, demonstration accuracy was lower.

Tolerability and Effectiveness of Switching to Dulaglutide in Patients With Type 2 Diabetes Inadequately Controlled With Insulin Therapy.

AimsGlucagon‐like peptide 1 (GLP-1) receptor agonists have demonstrated strong glycemic control. However, few studies have investigated the effects of switching from insulin to GLP-1 receptor agonists. We aimed to investigate, using real-world data, whether switching to dulaglutide improves glycemic control in patients with type 2 diabetes mellitus (T2D) inadequately controlled with conventional insulin treatment.Materials and methodsWe retrospectively evaluated 138 patients with T2D who were switched from insulin to dulaglutide therapy. We excluded 20 patients who dropped out during the follow-up period. The participants were divided into two groups according to whether they resumed insulin treatment at 6 months after switching to a GLP-1 receptor agonist (group I) or not (group II). A multiple logistic regression analysis was performed to evaluate the parameters associated with the risk of resuming insulin after replacement with dulaglutide.ResultsOf 118 patients initiated on the GLP-1 receptor agonist, 62 (53%) resumed insulin treatment (group I), and 53 (47%) continued with GLP-1 receptor agonists or switched to oral anti-hypoglycemic agents (group II). Older age, a higher insulin dose, and lower postprandial glucose levels while switching to the GLP-1 receptor agonist were associated with failure to switch to the GLP-1 receptor agonist from insulin.ConclusionsA considerable proportion of patients with T2D inadequately controlled with insulin treatment successfully switched to the GLP-1 receptor agonist. Younger age, a lower dose of insulin, and a higher baseline postprandial glucose level may be significant predictors of successful switching from insulin to GLP-1 receptor agonist therapy.

Real-world outcomes of addition of insulin glargine 300 U/mL (Gla-300) to glucagon-like peptide-1 receptor agonist (GLP-1RA)therapy in people with type 2 diabetes: The DELIVER-G study.

To provide real-world data on the addition of basal insulin (BI) in people with type 2 diabetes mellitus (PWD2) suboptimally controlled with glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy. However, real-world data on the addition of BI to GLP-1RA therapy are limited. We used a US electronic medical record data source (IBM® Explorys®) that includes approximately 4 million PWD2 to assess the real-world impact of adding the second-generation BI analogue insulin glargine 300 U/mL (Gla-300) to GLP-1RA therapy. Insulin-naïve PWD2 receiving GLP-1RAs who also received Gla-300 between March 1, 2015 and September 30, 2019 were identified; participants were required to have data for ≥12 months before, and ≥6 months after, addition of Gla-300. The mean (standard deviation [SD]) age of participants (N=271) was 57.9 (10.8) years. Baseline glycated haemoglobin (HbA1c) was 9.16% and was significantly reduced (-0.97 [SD 1.60]%; P< 0.0001) after addition of Gla-300; a significant increase in the proportion of PWD2 achieving HbA1c control was observed after addition of Gla-300 (HbA1c <7.0%: 4.80% vs. 22.14%, P< 0.0001; HbA1c <8.0%: 19.56% vs. 51.29%, P< 0.0001). The incidence of overall (8.49% vs. 9.59%; P= 0.513) and inpatient/emergency department (ED)-associated hypoglycaemia (0.37% vs. 0.74%; P= 1.000), as well as overall (0.33 vs. 0.46 per person per year [PPPY]; P= 0.170) and inpatient/ED-associated hypoglycaemia events (0.01 vs. 0.04 PPPY; P= 0.466) were similar before and after addition of Gla-300. In US real-world clinical practice, adding Gla-300 to GLP-1RA significantly improved glycaemic control without significantly increasing hypoglycaemia in PWD2. Further research into the effect of adding Gla-300 to GLP-1RA therapy is warranted.

The time-varying cardiovascular benefits of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes mellitus: Evidence from large multinational trials.

AimsTo evaluate the time‐varying cardio‐protective effect of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) using pooled data from eight contemporary cardiovascular outcome trials using the difference in the restricted mean survival time (ΔRMST) as the effect estimate.Material and MethodsData from eight multinational cardiovascular outcome randomized controlled trials of GLP‐1RAs for type 2 diabetes mellitus were pooled. Flexible parametric survival models were fit from published Kaplan‐Meier plots. The differences between arms in RMST (ΔRMST) were calculated at 12, 24, 36 and 48 months. ΔRMST values were pooled using an inverse variance‐weighted random‐effects model; heterogeneity was tested with Cochran's Q statistic. The endpoints studied were: three‐point major adverse cardiovascular events (MACE), all‐cause mortality, stroke, cardiovascular mortality and myocardial infarction.ResultsWe included eight large (3183‐14 752 participants, total = 60 080; median follow‐up range: 1.5 to 5.4 years) GLP‐1RA trials. Among GLP‐1RA recipients, we observed an average delay in three‐point MACE of 0.03, 0.15, 0.37 and 0.63 months at 12, 24, 36 and 48 months, respectively. At 48 months, while cardiovascular mortality was comparable in both arms (pooled ΔRMST 0.163 [−0.112, 0.437]; P = 0.24), overall survival was higher (ΔRMST = 0.261 [0.08‐0.43] months) and stroke was delayed (ΔRMST 0.22 [0.15‐0.33]) in patients receiving GLP‐1RAs.ConclusionsGlucagon‐like peptide‐1 receptor agonists may delay the occurrence of MACE by an average of 0.6 months at 48 months, with meaningfully larger gains in patients with cardiovascular disease. This metric may be easier for clinicians and patients to interpret than hazard ratios, which assume a knowledge of absolute risk in the absence of treatment.

Glucagon-like peptide-1 (GLP-1) receptor agonists and cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of double-blind, randomized, placebo-controlled clinical trials

BackgroundThe cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.MethodsPubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.ResultsWe included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).ConclusionWe concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.

Disutility of injectable therapies in obesity and type 2 diabetes mellitus: general population preferences in the UK, Canada, and China

IntroductionOnce-daily and once-weekly injectable glucagon-like peptide-1 receptor agonist therapies (GLP-1 RAs) are established in obesity and type 2 diabetes mellitus (T2DM). In T2DM, both once-daily and once-weekly insulin are expected to be available. This study elicited utilities associated with these treatment regimens from members of the general public in the UK, Canada, and China, to quantify administration-related disutility of more-frequent injectable treatment, and allow economic modelling.MethodsTwo anchor states (no pharmacological treatment), and seven treatment states (daily oral tablet and generic injectable regimens of variable frequency), with identical outcomes were tested A broadly representative sample of the general public in each country participated (excluding individuals with diabetes or pharmacologically treated obesity). An adapted Measurement and Valuation of Health protocol was administered 1:1 in web-enabled interviews by trained moderators: visual analogue scale (VAS) as a “warm-up”, and time trade-off (TTO) using a 20-year time horizon for utility elicitation.ResultsA total of 310 individuals participated. The average disutility of once-daily versus once-weekly GLP-1 RA was − 0.048 in obesity and − 0.033 in T2DM; the corresponding average disutility for insulin was − 0.064. Disutilities were substantially greater in China, relative to UK and Canada.DiscussionWithin obesity and T2DM, more-frequent treatment health states had lower utility. Scores by VAS also followed a logical order. The generated utility values are suitable for use in modelling injectable therapy regimens in obesity and T2DM, due to the use of generic descriptions and assumption of equal efficacy. Future research could examine the reasons for greater administration-related disutility in China.

Abstract #1155435: Use of Glucagon-like Peptide 1 Receptor Agonist Therapy for Inpatients with Type II Diabetes and Chronic Kidney Disease: A Retrospective Analysis

The use and overall benefit of non-insulin glucose lowering agents for hospitalized patients is unclear due to limited data. Our study aims to determine the impact and safety of GLP-1 receptor agonist therapy in hospitalized diabetes patients with chronic kidney disease.

The Efficacy of Treatment Intensification by Quadruple Oral Therapy Compared to GLP-1RA Therapy in Poorly Controlled Type 2 Diabetes Mellitus Patients: A Real-world Data Study.

We compared the glycemic efficacy of treatment intensification between quadruple oral antidiabetic drug therapy and once-weekly glucagon-like peptide-1 receptor agonist (GLP-1RA)-based triple therapy in patients with poorly controlled type 2 diabetes mellitus refractory to triple oral therapy. For 24 weeks, changes in glycosylated hemoglobin (HbA1c) from baseline were compared between the two treatment groups. Of all 96 patients, 50 patients were treated with quadruple therapy, and 46 were treated with GLP-1RA therapy. Reductions in HbA1c for 24 weeks were comparable (in both, 1.1% reduction from baseline; P=0.59). Meanwhile, lower C-peptide level was associated with a lower glucose-lowering response of GLP-1RA therapy (R=0.3, P=0.04) but not with quadruple therapy (R=-0.13, P=0.40). HbA1c reduction by GLP-1RA therapy was inferior to that by quadruple therapy in the low C-peptide subgroup (mean, -0.1% vs. -1.3%; P=0.04). Treatment intensification by switching to quadruple oral therapy showed similar glucose-lowering efficacy to weekly GLP-1RA-based triple therapy. Meanwhile, the therapeutic response was affected by C-peptide levels in the GLP-1RA therapy group but not in the quadruple therapy group.

Decreased Risk of Anxiety in Diabetic Patients Receiving Glucagon-like Peptide-1 Receptor Agonist: A Nationwide, Population-Based Cohort Study

Background: Previous findings on using Glucagon-like peptide-1 receptor agonist (GLP1-RA) as an antidepressant were conflicting, lacking large-scale studies. We used population-based data to investigate depression and anxiety risk in diabetic patients receiving the medication. Methods: From claims records of the National Health Insurance Research Database (NHIRD) of Taiwan, we identified cohorts of 10,690 GLP1-RA users and 42,766 propensity score-matched patients without GLP1-RA use from patients with diabetes mellitus (DM) diagnosed in 2011–2017, matched by age, gender, index year, occupation, urbanization, comorbidities, and medications. Incidence, hazard ratios (HR) and 95% confidence interval (CI) of depression and/or anxiety were estimated by the end of 2017. Results: The overall combined incidence of anxiety and/or depression was lower in GLP1-RA users than in non-users (6.80 versus 9.36 per 1,000 person-years), with an adjusted HR adjusted hazard ratio (aHR) of 0.8 (95% CI: 0.67–0.95) after controlling for covariates. The absolute incidence reduction was greater in anxiety (2.13 per 1,000 person-years) than in depression (0.41 per 1,000 person-years). The treatment effectiveness was significant for women. Patients taking GLP1-RA for longer than 180 days had the incidence of anxiety reduced to 2.93 per 1,000 person-years, with an aHR of 0.41 (95%CI: 0.27–0.61), compared to non-users. Dulaglutide could significantly decrease risks of both anxiety and depression. Conclusion: Patients with DM receiving GLP1-RA therapy have a greater reduction of the risk of anxiety than that of depression. Our findings strengthen previous research that advocated possible anti-depressant or anxiolytic effects of GLP1-RA and may lead to improved treatment adherence among patients with DM.