Glucagon-like Peptide-1 Receptor Agonist Therapy Research Articles

Updated evidence on cardiovascular and renal effects of GLP-1 receptor agonists and combination therapy with SGLT2 inhibitors and finerenone: a narrative review and perspectives.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a reliable hypoglycaemic and weight-loss effect that can intervene in obesity, which is the basis of type 2 diabetes pathology. GLP-1RA therapy has shown potential benefits in reducing the risk of major adverse cardiovascular events and improving kidney outcomes in patients with diabetes at high risk for cardiovascular disease. More recent evidence is expanding their benefits to heart failure with preserved ejection fraction and clinically important renal outcomes in patients with and without diabetes. Some sub-analyses of large clinical trials suggest that GLP-1RA and sodium-glucose cotransporter 2 inhibitor combination therapy may provide more significant reductions in heart failure hospitalization and renal composite events than each alone. Moreover, the addition of finerenone to this combination therapy could potentially provide stronger cardiorenal protective benefits. Further studies are needed to assess the potential cardiovascular and renal benefits of combination therapy and to determine suitable patient population for the therapy.

Safety and Effectiveness of Glucagon-like Peptide-1 Receptor Agonists in Inflammatory Bowel Disease

INTRODUCTION: The safety and effectiveness of glucagon-like peptide (GLP) 1 receptor agonists (GLP1-RA) in inflammatory bowel disease (IBD) patients are poorly understood. METHODS: IBD patients treated with GLP1-RA were retrospectively identified for outcomes of adverse events, weight change, and clinical, endoscopic, and biomarker response. RESULTS: Among a total of 120 IBD patients, GI side effects being the most common (11.5%). Semaglutide showed the most significant weight reduction. CRP levels decreased after one year (p=0.005). No differences were observed in IBD-related hospitalizations or endoscopic scores. DISCUSSION: GLP1-RA therapy appears safe and effective, with an associated CRP reduction, in IBD patients.

Abstract 4129733: Glucagon-like Peptide 1 Receptor Agonists Effect on Low-Density Lipoprotein Cholesterol and Total Cholesterol Levels Independent of Weight Reduction: A Meta-analysis and Meta-regression of Placebo-controlled Randomized Controlled Trials

Background: The impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on lipid components is unclear. The objective of this study was to measure the lipid-lowering effect of GLP-1RAs. Methods: A thorough database search was performed to identify placebo-controlled randomized controlled trials (RCTs) on GLP-1RA therapy through January 2023. From these trials, data was extracted and a robust statistical analysis was performed using a random effects model to determine outcomes with weighted mean difference (MD) in milligrams per deciliter (mg/dL) and 95% confidence intervals (CIs). The primary outcome was the mean difference in low-density lipoprotein cholesterol (LDL-C). Secondary outcomes were mean differences in total cholesterol (TC), triglycerides, high-density lipoprotein-C (HLD-C), and very low-density lipoprotein-C (VLDL-C). To account for covariates, subgroup analyses and meta-regression were performed. Results: A total of 33 studies were included in the final meta-analysis carried out between 2008 and 2023, which were conducted in 26 countries. Of the 5,918 participants, the study population comprised 2,603 (44%) males and 3,315 (56%) females, aged between 33.7 and 65.9 years. GLP-1RAs significantly reduced LDL-C compared to placebo (MD -2.93, 95% CI (-5.01, -0.85), P=0.01). Treatment effect was consistent regardless of duration of treatment;12 weeks or less MD: -5.39, 95% CI (-10.36, -0.42), P=0.03 vs >12 weeks MD: -2.39, 95% CI (-4.70, -0.007), P=0.04, P interaction 0.28). In our analysis, GLP-1RA reduced TC by ~7 mg/dl. There was no significant reduction in triglycerides (MD = -7.19, 95% CI (- 15.01, 0.62], P=0.07) and VLDL-C ~4 mg/dl (MD = -3.99, 95%, CI (-8.73, 0.75), P=0.10). Furthermore, GLP-1RA did not increase HDL-C (MD = -0.12, 95% CI (-0.73, 0.49], P=0.69. Regression analysis determined that weight loss did not affect the treatment effect on LDL-C (tau2=28.38, I2=99.83, R2=0.0, p=0.67), and total cholesterol (tau2=93.6, I2=99.86, R2=0.0, p=0.92). Conclusion: Patients on GLP-1RA experienced modest LDL-C and TC lowering compared to placebo. GLP-1RA did not decrease triglycerides and VLDL-C. GLP-1RA did not increase HDL-C.

Abstract 4135846: Cardiovascular Effectiveness of Glucagon-like Peptide-1 Receptor Agonists and Empagliflozin Combination Therapy in Adults with Type 2 Diabetes

Introduction/Background: Both empagliflozin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated cardiovascular (CV) benefits in clinical trials. However, few trials examined the combination of both therapies and evidence is scarce on whether the addition of empagliflozin to GLP-1RA has further CV benefits. Aim/Goal: We evaluated the risk of CV outcomes in patients with type 2 diabetes (T2D) initiating baseline GLP-1RA therapy that added empagliflozin compared to those that added sulfonylureas (SU). Methods: Using Medicare, Optum, and Marketscan data (2014-22), we identified patients with T2D aged ≥18 years initiating GLP-1RA that subsequently added either empagliflozin or SU. Follow-up began on the date of additional therapy and continued until discontinuation of either drug, a gap in insurance coverage, death, or study end. After propensity score standardized mortality ratio weighting adjusting for 98 covariates, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years evaluating a composite of myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), or all-cause death in the overall population and in patients with history of CV disease. Results: We identified 27,962 patients initiating GLP-1RA + empagliflozin vs 25,137 patients initiating GLP-1RA + SU. After weighting, relative to patients initiating GLP-1RA + SU, those initiating GLP-1RA + empagliflozin had lower risks of MI-stroke [HR 0.70 (0.55, 0.90); RD: -4.3 (-6.6, -2.0)], HHF in the primary hospital discharge position [HR: 0.59 (0.43, 0.81); RD: -3.9 (-5.8, -2.1)]; HHF in any discharge positions [HR: 0.84 (0.72, 0.98); RD: -7.6 (-11.6, -3.6)], and all-cause death [HR: 0.83 (0.62, 1.11); RD: -1.3 (-3.2, 0.56)]. Findings were similar but with larger RDs in patients with baseline CV disease ( Table ). Conclusion: In US clinical practice, patients with T2D initiating GLP-1RA that added empagliflozin had lower risks of MI-stroke, HHF, and death compared to adding SU, which suggests an additive CV benefit when combining GLP-1RA and empagliflozin therapies.

Consensus Report on Glucagon-Like Peptide-1 Receptor Agonists as Adjunctive Treatment for Individuals With Type 1 Diabetes Using an Automated Insulin Delivery System.

With increasing prevalence of obesity and cardiovascular diseases, there is a growing interest in the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as an adjunct therapy in type 1 diabetes (T1D). The GLP-1RAs are currently not approved by the US Food and Drug Administration for the treatment of T1D in the absence of randomized controlled trials documenting efficacy and safety of these agents in this population. The Diabetes Technology Society convened a series of three consensus meetings of clinicians and researchers with expertise in diabetes technology, GLP-1RA therapy, and T1D management. The project was aimed at synthesizing current literature and providing conclusions on the use of GLP-1RA therapy as an adjunct to automated insulin delivery (AID) systems in adults with T1D. The expert panel members met virtually three times on January 17, 2024, and April 24, 2024, and August 14, 2024, to discuss topics ranging from physiology and outcomes of GLP-1RAs in T1D to limitations of current sensors, algorithms, and insulin for AID systems. The panelists also identified research gaps and future directions for research. The panelists voted to in favor of 31 recommendations. This report presents the consensus opinions of the participants that, in adults with T1D using AID systems, GLP-1RAs have the potential to (1) provide effective adjunct therapy and (2) improve glycemic and metabolic outcomes without increasing the risk of severe hypoglycemia or diabetic ketoacidosis.

Temporal changes in mediation effects on cardiovascular and microvascular outcomes with glucagon-like peptide-1 receptor agonist therapy: a post-hoc analysis of the LEADER trial.

Temporal changes in mediation effects on cardiovascular and microvascular outcomes with glucagon-like peptide-1 receptor agonist therapy: a post-hoc analysis of the LEADER trial.

Adequate sleep duration accentuates the effect of glucagon-like peptide-1 receptor variant on HbA1c: A gene-environment interaction study

BackgroundBoth glucagon-like peptide-1 receptor (GLP1R) agonists and lifestyle modifications are widely adopted in managing glycemia. However, the joint effects of GLP1R agonists with lifestyle on glycemic traits have not been evaluated. MethodsThis gene-environment study tested the interaction between GLP1R-rs10305492 variant, consistent with the effect of GLP1R agonist therapies, and four lifestyle factors (diet, physical activity, sleep duration, and chronotype) for glucose and glycated hemoglobin (HbA1c) levels among 263,846 UK Biobank participants. Linear regression models were conducted to evaluate the effects of the rs10305492 and lifestyle factors on glucose and HbA1c levels. ResultsGLP1R-rs10305492-AA/AG genotype combined a healthy diet, regular physical activity, adequate sleep duration, or morning chronotype were associated with lower glucose and HbA1c levels (all P for trend < 0.001). A synergistic effect was found between rs10305492 and sleep duration on HbA1c, suggesting a recommended adequate sleep duration (7–8 h/day) may amplify the HbA1c lowering effect of GLP1R agonists. Joint effects of the rs10305492 and adequate sleep were associated with a 26 % reduced risk of hyperglycemia (>7.8 mmol/L) risk and a 22 % lower of high HbA1c (>39 mmol/mol or 5.7 %). ConclusionsCombining GLP1R agonists with adequate sleep may provide additional benefits for glycemic control in clinical practice.

Effect of GLP-1 receptor agonist therapy on endometrial cancer

Effect of GLP-1 receptor agonist therapy on endometrial cancer

Neuroprotective effects of GLP-1 receptor agonists in neurodegenerative Disorders: A Large-Scale Propensity-Matched cohort study

BackgroundGLP-1 receptor agonists, traditionally used for treating type 2 diabetes mellitus and obesity, have demonstrated anti-inflammatory properties. However, their potential neuroprotective effects in neurodegenerative disorders remain unclear. ObjectiveTo evaluate the impact of GLP-1 receptor agonists on the risk of developing various neurodegenerative conditions in obese patients. MethodsThis comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients across 73 healthcare organizations in 17 countries. Propensity score matching was performed, resulting in 102,935 patients in each cohort. We compared the risk of developing neurodegenerative disorders between obese patients receiving GLP-1 receptor agonist therapy and those who were not. ResultsObese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Alzheimer’s disease (RR = 0.627, 95 %CI = 0.481–0.817), Lewy body dementia (RR = 0.590, 95 %CI = 0.462–0.753), and vascular dementia (RR = 0.438, 95 %CI = 0.327–0.588). The risk reduction for Parkinson’s disease was not statistically significant overall (RR = 0.784, 95 %CI = 0.580–1.058) but was significant for semaglutide users (RR = 0.574, 95 %CI = 0.369–0.893). Semaglutide consistently showed the most pronounced protective effects across all disorders. Additionally, a significant reduction in all-cause mortality was observed (HR = 0.525, 95 %CI = 0.493–0.558). ConclusionThis study provides evidence that the effects of GLP-1 receptor agonists may extend beyond their known metabolic and cardioprotective benefits to include neuroprotection, associated with a decreased risk of developing various neurodegenerative disorders. These findings suggest the potential for expanding the therapeutic applications of GLP-1 receptor agonists to improve neurocognitive outcomes. Further research is warranted to elucidate the mechanisms underlying these neuroprotective effects and to explore their clinical applications in neurodegenerative disease prevention and treatment.

The Effect of Glucagon-like-Peptide-1 Receptor Agonists on Diabetic Retinopathy Progression, Central Subfield Thickness, and Response to Intravitreal Injections.

Objectives: To examine the effects of glucagon-like-peptide-1 receptor agonists (GLP1-RAs) on diabetic retinopathy (DR) progression, visual acuity (VA), central subfield thickness (CST), and response to intravitreal injections (IVIs) in the Hadassah ophthalmological cohort. Methods: Of 4500 Hadassah patients with DR, 146 had a documented first course of GLP1-RA treatment lasting at least a year along with ophthalmological follow-up. Of these, 35 underwent at least two optical coherence tomography (OCT) exams with a one-year interval. These 35 GLP1-RA-naïve patients were compared to a control group of 31 patients with DR who did not receive GLP1-RA treatment. We compared demographics, medical records, ocular data, and OCT characteristics between the two study groups. Results: At baseline, patients who received GLP1-RA treatment had a significantly higher prevalence of retinal detachment and vitreous hemorrhage, as well as a higher (though not statistically significant) prevalence of cardiovascular comorbidities compared to the control group. At the end of the follow-up period, the GLP1-RA group had a higher prevalence of DR progression compared to controls (3/19 vs. 0/20, respectively; p = 0.106, Fisher's exact test), but also showed a better response to IVIs (27/35 vs. 17/31, respectively; unadjusted OR: 2.78, p = 0.058; 95% CI: [0.963, 8.020], Pearson's chi-square test). However, vitreous hemorrhage and hyperreflective retinal foci were confounding factors (adjusted IVI response OR: 1.76, p = 0.229, 95% CI: [0.553, 5.650], logistic regression). No significant differences were observed between the two groups in terms of change in visual acuity (-0.135 vs. -0.063 logMAR, respectively; p = 0.664, Student's t-test) or CST (-13.49 vs. -30.13 μm; p = 0.464, Student's t-test). Conclusions: This study presents preliminary findings showing no significant differences in DR progression, visual acuity, and CST between patients treated with GLP1-RA and control patients. Moreover, GLP1-RA therapy was not significantly associated with improved IVI response, with ocular parameters acting as confounding factors.

Safety and Efficacy of Sodium-Glucose Transport Protein 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in Diabetic Kidney Transplant Recipients: Synthesis of Evidence.

Background: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of novel antidiabetics, namely, sodium-glucose transport protein 2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP1-RA), in diabetic kidney transplant recipients. Methods: Medline, Scopus, Web of Science, CENTRAL, and Clinicaltrials.gov were systematically searched from inception until 25 August 2024. Pooled estimates were obtained by applying random-effects models. Results: Overall, 18 studies (17 observational studies and one randomized controlled trial) were included. GLP1-RA were administered to 270 and SGLT2-i to 1003 patients. After GLP1-RA therapy, patients presented significantly lower glycated hemoglobin [mean difference (MD): -0.61%; 95% confidence interval (CI): -0.99; -0.23] and body weight (MD: -3.32 kg; 95% CI: -5.04; -1.59) but a similar estimated glomerular filtration rate (eGFR) and systolic blood pressure. After SGLT2-i therapy, patients had significantly lower glycated hemoglobin (MD: -0.40%, 95% CI: -0.57; -0.23) and body weight (MD: -2.21 kg, 95% CI: -2.74; -1.67), while no difference was noted in eGFR or systolic blood pressure. Preliminary data have shown an association between SGLT2-i use and a reduced risk of cardiovascular events, graft loss, and mortality. Evidence regarding the association between GLP1-RA and SGLT2-i and proteinuria was mixed. No significant effects on calcineurin inhibitor levels were observed. The risk of urinary tract infections was similar among patients treated with SGLT2-i or placebo (odds ratio: 0.84, 95% CI: 0.43; 1.64). Conclusions: Observational data suggest that GLP1-RA and SGLT2-i administration in diabetic kidney transplant recipients may be associated with better glycemic control and reduced body weight, presenting an acceptable safety profile.

Surgical or medical treatment of obesity-associated type 2 diabetes-an increasing clinical conundrum

In this editorial, we comment on the article by He et al , specifically in relation to the efficacy of bariatric surgery vs glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy in the management of type 2 diabetes (T2D) associated with obesity. Bariatric surgery has now also been shown to be safe and effective in pre-teens and teenagers with obesity and T2D, but information on newer GLP-1RAs in these groups is predictably limited. In older individuals (age &gt; 65 years), both bariatric surgery and GLP-1RA therapy improve cardiovascular outcomes. Bariatric surgery is not infrequently associated with post-operative postprandial hypoglycemia, which is not the case with GLP-1RAs and, paradoxically, there is evidence that GLP-1RAs may reduce both the frequency and severity of postprandial hypoglycemia. Comparative trials of the long-term efficacy of bariatric surgery and GLP-1RAs are indicated.

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.

8088 Connecting the Dots: Semaglutide, Constipation, and Diverticulitis - A case report

Abstract Disclosure: K. Tiwari: None. F. Sajid: None. J.G. Karam: None. Introduction: Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus and weight management. Common side effects, primarily gastrointestinal (&amp;gt;10%), include nausea, vomiting, diarrhea, and constipation. Here, we present a case of acute sigmoid diverticulitis with an adjacent abscess in a patient who was recently initiated on GLP-1 receptor agonist therapy. Case presentation: A 76-year-old female with a medical history of type 2 diabetes mellitus on metformin and empagliflozin, hypertension, chronic kidney disease stage 3A, obesity (BMI: 43), and no known history of diverticulosis was started on semaglutide for additional glycemic, renal, and weight loss benefits, given suboptimal control of her obstructive sleep apnea, blood pressure, and knee arthritis. She received semaglutide subcutaneously at a dose of 0.25 mg weekly for 4 weeks, followed by an increased dosage of 0.5 mg for one week. However, she experienced a slight worsening of underlying constipation as a side effect. On the sixth week of therapy, she started having progressive lower abdominal pain with nausea, chills, and diarrhea, for which she presented to the Emergency Department. She was found to have leukocytosis, and a Computed Tomography (CT) of the abdomen/pelvis revealed peri-colonic fat stranding in the mid-ascending colon, wall thickening in the distal sigmoid colon, and a low-density fluid collection abutting the sigmoid/descending colonic wall, indicative of diverticulitis with a small abscess. She was admitted to the hospital for six days and was treated conservatively with Intravenous (IV) antibiotics, and her diet was slowly advanced as tolerated. Semaglutide was discontinued, and the patient was discharged home with outpatient endocrinology and gastrointestinal follow-up. A post-discharge colonoscopy showed diffuse diverticulosis. Conclusion: Constipation and old age are common risk factors for diverticulitis. While GLP1-1 receptor analogs have proven significant and multiple benefits, more knowledge about associated gastrointestinal complications resulting from slower food transit in the gastrointestinal tract is emerging. Older patients with underlying constipation and/or diverticulosis should particularly be monitored and treated for worsening constipation to avoid complications such as acute diverticulitis. Vigilance and awareness in recognizing and managing this potential complication are crucial with the wider indications and use of GLP-1 receptor analogs. Presentation: 6/3/2024

8679 Case: The Sexual, Physical and Psychological Effects of Post-Finasteride Syndrome

Abstract Disclosure: E.M. Lonergan: None. S.M. Maher: None. I. Yaseen: None. D.B. O'Shea: None. Post-finasteride syndrome (PFS) is an increasingly recognised disorder with a myriad of physical and neuropsychiatric symptoms persisting for greater than three months in a small proportion of patients treated with Finasteride. We present the case of a 45-year-old male who was taking oral Finasteride for hair loss. He first presented to endocrinology services having stopped Finasteride after twenty years reporting new onset reduced libido, penile shrinkage, fatigue, new food intolerances and agitated depression which was the predominant symptom in this case. He described the emergence of gynaecomastia, which was evident on examination, as well as muscle atrophy. Biochemistry was unremarkable including testosterone 24.6 nmol/L (8.6-29.0), oestradiol 100 pmol/L (50 – 159), LH 7.1 IU/L (1.7-8.6), FSH 16.8 IU/L (1.5-12.4), urinary free cortisol 177 nmol/24h (12-486) and urinary steroid profile. The patient was offered a trial of IM testosterone for 3 months followed by a course of hCG which he declined after discussing with patients online via a PFS patient forum citing anecdotal pseudo immune downregulation in this cohort. GLP-1 receptor agonist therapy was considered as a second-line treatment option. The patient expressed a preference for hydrocortisone treatment after conducting online research which has not been commenced due to a lack of evidence. The inhibition of 5-alpha-reductase in Finasteride-treated patients has been documented to cause reversible sexual dysfunction. However, with increasing case reports of PFS, it was included in the list of Rare and Genetic Diseases of the NIH in 2015. The syndrome encompasses symptoms and signs seen in our case, as well as erectile dysfunction, decreased ejaculatory volume, infertility, Peyronie’s disease, testicular pain, dry skin, memory problems and insomnia. Suicidal ideation was included in the product label as per FDA mandate in 2022. The literature is largely inconclusive regarding the underlying aetiology, duration, and severity of the disorder. A large retrospective study revealed 0.8% of patients developed sexual dysfunction with persistence in 33% of these cases after drug suspension, the main independent risk factor being drug treatment for longer than 7 months. Neuropsychiatric symptoms are likely related to the presence of 5-alpha-reductase isoforms in the brain with resulting alterations in CSF and plasma neuroactive steroid levels and metabolites. Evidence-based treatment options for PFS are limited. PFS is a rare but debilitating syndrome to which a subset of patients appears to be predisposed, but of which the pathophysiology is poorly understood. Further studies in this regard, as well as an exploration of effective treatment options are required. Presentation: 6/1/2024

6923 Case Report: Long Standing Type 2 Diabetes with TOFI Phenotype Successfully Weaned Off One Hundred Units of Basal-Bolus Insulin Therapy With Glucagon-Like Peptide 1 Receptor Agonist Therapy

Abstract Disclosure: Y.C. Kon: None. A 60-year-old Indian male was diagnosed with type 2 diabetes in 1997. In July 2017, his fasting blood glucose level (FBGL) was 10.3 mM, paired C-peptide 719 pM, eGFR measured as more than 60 ml/min. Since Sep 2017, he had been compliant on the same stable regimen of sc insulatard 20 units om and 20 units at 10 pm, sc actrapid 20 units t.i.d premeal, PO metformin 850 mg t.i.d and PO dapagliflozin 10 mg om. In the past, he had suffered myocardial infarction, with left ventricular ejection fraction 35%, and had left anterior descending coronary artery stenting. In 2017, he had automatic cardioverter defibrillator implanted for primary arrhythmia prevention. His cardiac medications included bisoprolol fumarate 5 mg om, losartan 25 mg om, spironolactone 25 mg om, aspirin 100 mg om and high intensity statin therapy. Since 2020, his HbA1c had measured 8% to 9% with FBGL at 6 mM to 11 mM. Hence he was referred by his cardiologist in Oct 2022 to optimize glycaemic control. Once every few months, he experienced hypoglycaemic symptoms with corresponding low capillary blood glucose (CBG) of 3 mM, reversed with glucose intake. On physical examination, he weighed 81.6 kg, BMI was 25.4 kg/m2, BP 110/67 mmHg, pulse rate 69/min regular, waist circumference 106 cm. There was no acanthosis nigricans. He did not appear Cushingoid nor acromegalic. As he had “thin outside, fat inside (TOFI)” type 2 diabetes phenotype, he was started on sc liraglutide 1.8 mg om. His actrapid dose was halved to 10 units premeal, and insulatard dose halved to 10 units bid. His dapagliflozin was switched to subsidised empagliflozin 25 mg om. Subsequently, his premeal CBG measured 4 to 7 mM, bedtime CBG 4-6 mM, with occasional minor hypoglycaemic episodes with CBG at 3-4 mM. In July 2023, HbA1c measured 6.3%, FBGL was 5.5 mM and paired C-peptide measured as 554 pM. Basal insulatard was discontinued and he was switched from liraglutide to sc dulaglutide 1.5 mg once weekly. In Oct 2023, his FBGL was 5.2 mM and HbA1c had improved markedly to 5.7%. His weight had reduced from 81.6 kg to 70.0 kg, BMI decreased from 25.4 kg/m2 to 22.9 kg/m2 and waist circumference reduced from 106 cm to 97 cm. As he continued to experience occasional minor hypoglycemic episodes, actrapid insulin was discontinued. On his current therapy of sc dulaglutide 1.5 mg once weekly, PO empagliflozin 25 mg om, PO metformin 850 mg tid, and PO acarbose 50 mg t.i.d, his fasting CBG measured 6.7-7.7 mM, premeal CBG 6.4 to 10.1 mM, off all insulins and without further episodes hypoglycaemia. Conclusion: Patients with long standing “TOFI” type 2 diabetes and robust C-peptide may be trialled on GLP1-receptor agonist therapy to wean off high daily doses of insulin, thus avoiding hypoglycaemia, achieving weight and abdominal fat loss, whilst maintaining glycaemic control. This is especially important in patients with established coronary artery disease. Presentation: 6/3/2024

S863 Impact of Duration of GLP-1 Receptor Agonist Therapy in Endoscopic Outcomes

S863 Impact of Duration of GLP-1 Receptor Agonist Therapy in Endoscopic Outcomes

Effects of glucagon-like peptide-1 receptor agonists on glycated haemoglobin and continuous glucose monitoring metrics as adjunctive therapy to insulin in adults with type 1 diabetes: A meta-analysis of randomized controlled trials.

To conduct a meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) metrics as an adjunct to insulin therapy in adults with type 1 diabetes mellitus (T1D). A systematic literature search was conducted through Medline (via PubMed), Cochrane Library, and Google Scholar up to 27 May 2024. Dual-independent study selection, data extraction, and quality assessment were performed. Results were summarized using random-effects meta-analysis. Six RCTs were identified, involving a total of 378 individuals with T1D. The use of GLP-1RAs in addition to standard insulin therapy was associated with a significant reduction in HbA1c (mean difference [MD] -0.21%, 95% confidence interval [CI] -0.36 to -0.06; p = 0.007) and a similar time in range (TIR) compared to placebo (MD -0.22%, 95% CI -2.39 to 1.95; p = 0.84). GLP-1RA therapy resulted in a significantly higher time below range (MD 1.13%, 95% CI 0.50 to 1.76; p < 0.001) and a lower time above range compared with placebo (MD -1.83%, 95% CI -2.51 to -1.15; p < 0.001). Nonsignificant differences were noted for the secondary outcomes, including the mean amplitude of glucose excursion, continuous overall net glycaemic action for 60 min, mean daily glucose, coefficient of variation, and mean standard deviation of weekly glucose levels. Our findings suggest that, in individuals with T1D, add-on therapy with GLP-1RAs does not confer significant benefits in terms of CGM metrics and is associated with a longer time below the target glycaemic range.

A post-hoc pooled analysis to evaluate efficacy and safety of insulin glargine 300 U/mL in insulin-naïve people with type 2 diabetes with/without prior use of glucagon-like peptide-1 receptor agonist therapy

AimsTo evaluate treatment advancement with insulin glargine 300 U/mL (Gla-300), with or without prior glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in type 2 diabetes (T2D). MethodsEfficacy and safety outcomes of insulin-naïve patients intensifying with Gla-300, with/without prior GLP-1 RA therapy, were evaluated in three analyses (N = 3562): a pooled analysis of seven interventional studies, a subanalysis comparing participants who stopped GLP-1 RA therapy and initiated Gla-300 with those who received add-on Gla-300, and an expanded analysis including two observational studies. ResultsGlycaemic outcomes, including HbA1c improvement and fasting plasma glucose, were similar between groups with/without prior GLP-1 RA use. HbA1c least squares mean change from baseline was − 1.7 % and − 1.6 % with and without prior GLP-1 RA, respectively. Glycaemic outcomes were similar between participants who stopped GLP-1 RA therapy when initiating Gla-300 and those who received add-on Gla-300, although more participants receiving add-on Gla-300 achieved HbA1c targets. The expanded analysis yielded similar results. Incidence of hypoglycaemia was low with no clinically relevant weight changes in all analyses. ConclusionsTreatment advancement with Gla-300 in patients with T2D, with/without prior GLP-1 RA therapy, improved glycaemic outcomes with no relevant impact on weight, while maintaining a low hypoglycaemia risk.

GLP-1 Receptor Agonist Therapy in Cystic Fibrosis-Related Diabetes: A Case Report.

GLP-1 Receptor Agonist Therapy in Cystic Fibrosis-Related Diabetes: A Case Report.