Glucagon-like Peptide-1 Receptor Agonist Therapy Research Articles

Navigating Glucagon-Like Peptide Receptor Agonist Reinitiation Amid Access Barriers: An Adverse Drug Event Case Report.

Background: The expanding roles and popularity of glucagon-like peptide-1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has created access barriers to medication use. We sought to describe an adverse drug event which occurred after reinitiation of a GLP-1 receptor agonist following a prolonged lapse in therapy due to poor medication access. Case Summary: Once-weekly injectable semaglutide was prescribed to an outpatient 33-year-old male for chronic weight management. After a delayed initiation due to global shortage, semaglutide was initiated and titrated over five months before a seven week lapse in therapy due to prior authorization interruption. Despite the extended treatment gap, the patient was directed to reinitiate semaglutide at the target dose rather than starting dose, which was followed by recurrent, symptomatic nausea and vomiting requiring medical intervention. Practice Implications: A prolonged lapse in GLP-1 receptor agonist therapy, typically defined as missing three or more doses of a once-weekly injectable, warrants consideration of reinitiation at a reduced dose, personalized to the patient's prior gastrointestinal tolerability, efficacy goals, and therapy lapse duration. Therapy lapses with GLP-1 receptor agonists may be prevented by utilizing a multi-modal approach including extended dosing intervals, intermediate doses, agent interchange, efficient prior authorization communication, and cautious initiation of GLP-1 recent agonists while supply cannot meet demand.

Initiating GLP-1 Therapy in Combination with FreeStyle Libre Provides Greater Benefit Compared to GLP-1 Therapy Alone.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy provides glycemic benefits to individuals with type 2 diabetes (T2D). However, the effects of GLP-1 RA therapy in combination with FreeStyle Libre systems (FSL) are unknown. This study aimed to compare changes in HbA1c between people acquiring GLP-1 with FSL (GLP-1+FSL) vs. GLP-1 without FSL (GLP-1). This real-world study utilized Optum's de-identified Market Clarity Data, a linked electronic health records (EHR)-claims database and included adults with T2D and HbA1c ≥8% who acquired their first GLP-1 RA medication between 2018-2022. GLP-1+FSL subjects acquired their first FSL within ±30 days of their first GLP-1 acquisition. Cohorts were matched 1:5 on baseline insulin therapy, age, sex, baseline HbA1c and GLP-1 type. Paired changes in HbA1c were compared between unmatched and matched groups at six months. The study included 24,724 adults in the unmatched cohort (GLP-1+FSL, n=478; GLP-1, n=24,246). The matched cohort included 478 GLP-1+FSL users and 2,390 GLP-1 users: mean age 53.5±11.8 and 53.5 ±11.3 years, HbA1c 10.25±1.68% and 10.22±1.69%, respectively. HbA1c reduction was greater in the GLP-1+FSL group compared to the GLP-1 group in the unmatched cohort (-2.43% vs. -1.73%, difference 0.70%, p<0.001, respectively) and in the matched cohort (-2.43% vs. -2.06%, difference 0.37%, p<0.001). GLP-1+FSL vs. GLP-1 treatment was associated with greater HbA1c reduction in the intensive insulin (-2.32% vs. -1.50%), non-intensive insulin (-2.50% vs. 1.74%), and noninsulin group (-2.46% vs. -1.78%), as well as in patients using semaglutide (2.73% vs. 1.92%) and dulaglutide (2.45% vs. 1.71%) GLP-1 RA, all p<0.001. Adults with sub-optimally controlled T2D, initiating GLP-1 RA with FreeStyle Libre, had greater improvement in HbA1c compared to those treated with GLP-1 RA only. These results suggest an additional glycemic benefit of FSL when used with a GLP-1 RA in T2D treatment.

Reduced Efficacy of Glucagon-Like Peptide-1 Receptor Agonists Therapy in People With Type 1 Diabetes and Genetic Forms of Obesity.

Once weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) have been shown to improve glycemic outcomes and cause significant weight loss. However, 9% to 27% of individuals have little or no response to these drugs. In this article, we investigated the efficacy of GLP-1 RA therapy among adults with type 1 diabetes and obesity likely related to genetic mutations compared with obesity likely unrelated to genetic mutations. In this retrospective study, we compared body weight and glycated hemoglobin (HbA1c) change with the use of GLP-1 RA therapy (including a dual agonist, Tirzepatide) over six months among adults with type 1 diabetes and obesity likely (n = 11, median age 39.5 years with a median BMI of 43.0 kg/m2) versus unlikely related to genetic mutation(s) (n = 15, median age 45.8 years with a median BMI of 38.7 kg/m2). Six months of GLP-1 RA treatment resulted in a numerically lower reduction of weight (-5.75 ± 9.46 kg vs -8.65 ± 9.36 kg, P = .44) and HbA1c (-0.28 ± 0.96% vs -0.43 ± 0.57%, P = .64) among individuals with obesity likely versus unlikely related to a genetic mutation(s), respectively. Fewer individuals with genetic obesity met goal weight loss ≥5% or HbA1c decrease ≥0.4% than did individuals with obesity unlikely related to a genetic cause (36.4% vs 80.0%, P = .04). The weight loss and glycemic lowering effects of GLP-1 RA therapy may be decreased in people with type 1 diabetes and obesity likely related to genetic causes. Further research is needed to understand GLP-1 RA mechanisms via energy regulating genes.

Risk of diabetic retinopathy and diabetic macular oedema with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in type 2 diabetes: a real-world data study from a global federated database.

A protective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin. This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan-Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA1c, BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed. SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208). Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated retinal imaging are required to determine the causal relationship with these therapies.

Existing and emerging GLP-1 receptor agonist therapy: Ramifications for diabetic retinopathy screening.

GLP-1 receptor agonist treatment revolutionised the management of type 2 diabetes mellitus with significant enhancement of cardiovascular risk reduction. They have been instrumental in effectively managing the glycaemic control of this at-risk patient group. This class of drugs are associated with rapid improvement in glucose levels and consequently, transient early worsening of pre-existing diabetic retinopathy (DR) which is well-recognised, but this paradox is less commonly perceived in routine clinical practice. The recent shortage of supply has resulted in an enforced hiatus to prescribing all existing GLP-1 receptor agonists, which is expected to last all through 2024. This becomes even more pertinent as their DR could have progressed due to worsening HbA1c as a result of the unforeseen interruption to GLP-1 receptor agonist treatment. Therefore, when these medications are recommenced in a few months' time, all prescribers need to be aware of these patients' most up-to-date DR status and liaise with their affiliated screening service.

GLP-1 Receptor Agonists Promote Weight Loss Among People with HIV.

Weight gain and associated metabolic complications are increasingly prevalent among people with HIV (PWH). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin-based therapies for diabetes and weight management that have been shown to result in substantial weight loss; however, studies of their effects in PWH are limited. A retrospective single-center cohort study was conducted among PWH who were taking GLP-1RAs at UC San Diego Owen Clinic between 2/1/2021 to 2/1/2023. Baseline clinical data were collected and changes in weight, body mass index (BMI), and hemoglobin A1C (A1C) before starting GLP-1RAs compared to the most recent clinic visit were calculated (with a minimum of 3 months follow-up time required). Logistic regression was performed to identify variables associated with >5% of total body weight loss. A total of 225 patients received on average 13 months of GLP-1RA therapy, with 85 (37.8%) achieving the maximum GLP-1RA dose. GLP-1RA therapy resulted, on average, in a loss of 5.4 kg, decrease in BMI by 1.8 kg/m2, and decrease in A1C by 0.6%. In the multivariable analysis, higher baseline BMI [OR 1.10 (1.03-1.16)], treatment duration of GLP-1RA therapy greater than 6 months [OR 3.12 (1.49-6.49], and use of tirzepatide [OR 5.46 (1.44-20.76)] were significantly more likely to be associated with >5% weight loss. Use of GLP-1RAs led to declines in weight, BMI, and hemoglobin A1C among PWH and offers an additional strategy to address weight gain and diabetes.

Adjuvant Glucose-Like Peptide 1 Receptor Agonist Therapy for Suboptimal Weight Loss After Bariatric Surgery: a Systematic Review.

Addressing suboptimal weight loss post-bariatric surgery poses a challenge. While glucagon-like peptide 1 receptor agonists (GLP1-RA) show promise in managing obesity, their role as an adjuvant treatment after bariatric surgery remains uncertain. We conducted a systematic literature review focused on the efficacy and safety of GLP1-RA in bariatric surgery patients with insufficient weight loss or distant weight regain. Our literature search identified 1167 articles, with 10 (involving 594 patients) meeting inclusion/exclusion criteria for detailed review. GLP1-RA therapy resulted in 5 to 17% weight loss over 6 to 12 months, with 10-50% experiencing non-severe side effects like nausea. Overall, GLP1-RA emerges as an effective adjuvant therapy for patients experiencing inadequate weight loss or regain after bariatric surgery, offering a viable alternative to revision surgery.

Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study

Background & AimsIn phase 2 studies, efruxifermin, an Fc–FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis (NASH), now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. MethodsCohort D was a double-blind, placebo-controlled phase 2b study in adults with T2D and MASH with fibrosis (F1–F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. ResultsAdults (N=31) with T2D and MASH fibrosis (F1–F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (N=21) or placebo (N=10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well tolerated. The most frequent efruxifermin-related adverse events were mild–moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P<.0001 vs placebo) compared to a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA–mediated weight loss. ConclusionsThe tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. Clinicaltrials.gov no. NCT05039450

GLP-1RA Essentials in Gastroenterology: Side Effect Management, Precautions for Endoscopy and Applications for Gastrointestinal Disease Treatment

Amidst the obesity and type II diabetes mellitus (T2DM) epidemics, glucagon-like peptide-1 receptor agonists (GLP-1RAs) stand out as a promising therapeutic ally, achieving notable success in glycemic control and weight management. While GLP-1RAs’ positive clinical outcomes are commendable, they introduce significant gastrointestinal (GI) challenges, emphasizing the pivotal role of gastroenterologists in understanding and managing these implications. Physicians should be vigilant of potential complications if endoscopy is indicated and considered. A protocol coined “The Three E’s: Education, Escalation, and Effective Management” is essential as the first defense against GLP-1RA-induced dyspepsia, necessitating routine GI consultations. Awareness and intervention of potential aspiration due to GLP-1RA-induced gastroparesis are vital in clinical management. Furthermore, the evolving recognition of GLP-1RAs’ beneficial effects on non-alcoholic steatohepatitis (NASH) suggests gastroenterologists will increasingly prescribe them. Thus, a comprehensive understanding of pharmacological properties and potential GI complications, including the undetermined cancer risk landscape, becomes paramount. This review accentuates the nuances of GLP-1RA therapy from a gastroenterological lens, juxtaposing the therapeutic potential, manageable side effects, and circumstantial challenges, ensuring that GI specialists remain at the forefront of holistic care in obesity and T2DM management.

Restoration of blood vessel regeneration in the era of combination SGLT2i and GLP-1RA therapy for diabetes and obesity.

Ischaemic cardiovascular diseases, including peripheral and coronary artery disease, myocardial infarction, and stroke, remain major comorbidities for individuals with type 2 diabetes (T2D) and obesity. During cardiometabolic chronic disease (CMCD), hyperglycaemia and excess adiposity elevate oxidative stress and promote endothelial damage, alongside an imbalance in circulating pro-vascular progenitor cells that mediate vascular repair. Individuals with CMCD demonstrate pro-vascular 'regenerative cell exhaustion' (RCE) characterized by excess pro-inflammatory granulocyte precursor mobilization into the circulation, monocyte polarization towards pro-inflammatory vs. anti-inflammatory phenotype, and decreased pro-vascular progenitor cell content, impairing the capacity for vessel repair. Remarkably, targeted treatment with the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin in subjects with T2D and coronary artery disease, and gastric bypass surgery in subjects with severe obesity, has been shown to partially reverse these RCE phenotypes. SGLT2is and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the management of individuals with T2D and comorbid obesity. In addition to glucose-lowering action, both drug classes have been shown to induce weight loss and reduce mortality and adverse cardiovascular outcomes in landmark clinical trials. Furthermore, both drug families also act to reduce systemic oxidative stress through altered activity of overlapping oxidase and antioxidant pathways, providing a putative mechanism to augment circulating pro-vascular progenitor cell content. As SGLT2i and GLP-1RA combination therapies are emerging as a novel therapeutic opportunity for individuals with poorly controlled hyperglycaemia, potential additive effects in the reduction of oxidative stress may also enhance vascular repair and further reduce the ischaemic cardiovascular comorbidities associated with T2D and obesity.

Outcomes of SGLT-2i and GLP-1RA Therapy Among Patients With Type 2 Diabetes and Varying NAFLD Status

Nonalcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor, but whether sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with reduced cardiovascular risk in patients with type 2 diabetes (T2D) and concomitant NAFLD remains uncertain. To investigate the outcomes of SGLT-2i and GLP-1RA therapy among patients with T2D varied by the presence or absence of NAFLD. This retrospective, population-based, nationwide cohort study used an active-comparator new-user design. Two distinct new-user active-comparator cohorts of patients aged 40 years and older who initiated SGLT-2i or GLP-1RA were propensity score matched to patients who initiated dipeptidyl peptidase-4 inhibitors (DPP-4i). The study was conducted in South Korea from January 2013 to December 2020, and data analysis was conducted from October 2022 to March 2023. The main outcomes were (1) major adverse cardiovascular events (MACE), a composite end point of hospitalization for myocardial infarction, hospitalization for stroke, and cardiovascular death, and (2) hospitalization for heart failure (HHF). Cox proportional hazards models were used to estimate hazard ratios (HRs). The Wald test was applied to assess heterogeneity by NAFLD. After 1:1 propensity score matching, 140 438 patients were retrieved in the first cohort (SGLT-2i vs DPP-4i; mean [SD] age, 57.5 [10.3] years; 79 633 [56.7%] male) and 34 886 patients were identified in the second cohort (GLP-1RA vs DPP-4i; mean [SD] age, 59.5 [10.5] years; 17 894 [51.3%] male). Compared with DPP-4i, SGLT-2i therapy was associated with a lower risk of MACE (HR, 0.78 [95% CI, 0.71-0.85]) and HHF (HR, 0.62 [95% CI, 0.48-0.81]). GLP-1RA therapy was associated with a decreased risk of MACE (HR, 0.49 [95% CI, 0.39-0.62]) but had statistically nonsignificant findings regarding HHF (HR, 0.64 [95% CI, 0.39-1.07]). Stratified analysis by NAFLD status yielded consistent results for SGLT-2i (MACE with NAFLD: HR, 0.73 [95% CI, 0.62-0.86]; without NAFLD: HR, 0.81 [95% CI, 0.72-0.91]; HHF with NAFLD: HR, 0.76 [95% CI, 0.49-1.17]; without NAFLD: HR, 0.56 [95% CI, 0.40-0.78]) and for GLP-1RA (MACE with NAFLD: HR, 0.49 [95% CI, 0.32-0.77]; without NAFLD: HR, 0.49 [95% CI, 0.37-0.65]; HHF with NAFLD: HR, 0.82 [95% CI, 0.38-1.76]; without NAFLD: HR, 0.54 [95% CI, 0.27-1.06]). In this population-based cohort study, SGLT-2i therapy was associated with a decreased risk of MACE and HHF, while GLP-1RA therapy was associated with a decreased risk of MACE among patients with T2D, irrespective of baseline NAFLD status.

The effects of incretin mimetics on the level of the microbial metabolite trimethylamine-N-oxide, a marker of cardiovascular risk in type 2 diabetic patients

Background. The purpose was to investigate the effect of therapy with glucagon-like peptide-1 receptor agonists (GLP-1ra) on the serum concentration of trimethylamine-N-­oxide (TMAO), an intestinal microbiome metabolite, in patients with type 2 diabetes mellitus (T2DM) in relation to clinical and laboratory indicators and parameters of body composition. Materials and methods. Thirty-three T2DM patients (17 women and 16 men) were examined aged 31 to 72 years who had unsatisfactory control of carbohydrate metabolism (HbA1c &gt; 7.4 %) against the background of previous glucose-lowering therapy (metformin, sulfonylurea derivatives, insulin, gliflozin) and were administered GLP-1ra. Before the start of treatment and after 6 months of therapy, parameters of anthropometry, body composition were measured (using the bioelectrical impedance analysis with the Tanita analyzer); blood glucose and glycated hemoglobin, TMAO concentration, blood lipids were assessed. Results. Patients diagnosed with Т2DM had HbA1c &gt; 7.4 %; 91 % had general obesity (body mass index 34.7 ± 6.6 kg/m2), 100 % had abdominal obesity (waist circumference 118.00 ± 11.24 cm, Med ± SD). In 72 % of cases, there was a history of cardiovascular complications (myocardial infarction, stroke, coronary and peripheral atherosclerosis, arterial stenosis). Under the influence of a 6-month administration of GLP1ra, there was a decrease in the degree of total and abdominal obesity, a significant drop in the percentage of fat and the level of visceral fat, which was accompanied by an increase in hydration, a reduction in triglyceridemia and the concentration of very-low-density lipoprotein cholesterol (VLDL-C). A significant decrease in the level of TMAO microbial metabolite in the blood serum was recorded, which may reflect the antiatherogenic effect of GLP1ra, associated with the control of cholesterol and bile acid metabolism, the stimulation of VLDL-C receptors, and the effect on the secretion of insulin, glucagon, ghrelin, leptin, incretins. Conclusions. A study on the clinical effects of the incretin mimetic (GLP-1ra) in patients with T2DM confirmed its positive impact on glucose metabolism and blood lipids. At the same time, during GLP-1ra therapy, an improvement of some compositional and lipid indicators (visceral fat, triglycerides, VLDL-C) was recorded with a simultaneous decrease in the concentration of TMAO toxic metabolite.

Study of the influence of GLP-1 receptor agonists on the metabolic activity of the intestinal microbiota in patients with type 2 DM

The aim: to investigate the peculiarities of the metabolic activity of the intestinal microbiota in patients with type 2 diabetes under the influence of glucagon-like peptide-1 receptor agonist therapy. Materials and methods: 21 patients with type 2 diabetes mellitus were included in the study, the average age was 57.2±8.53 years (M±SD), the HbA1c level was 8.29±0.88 % (M±SD). Patients were prescribed raGLP-1 at the maximum tolerated dose for 6 months. Before and after the course of treatment, indicators of body composition were determined by the bioelectrical impedance method (TANITA BC-545N analyzer, Japan), characteristics of carbohydrate metabolism and the lipid spectrum of blood serum, as well as the concentration of GLP-1, trimethylamine-N-oxide (TMAO) by the immunoenzymatic method, of short-chain fatty acids (SCFA) by the method of chromatographic research. Results. After 6 months of therapy with liraglutide against the background of a statistically significant decrease in fasting blood glucose and HbA1c levels (p&lt;0.05), a decrease in body mass index and waist circumference (p&lt;0.05), a decrease in the content of visceral (p&lt;0.05 ) and total fat (p&lt;0.05) in patients with type 2 diabetes, there was a decrease in the concentration of TMAO in blood serum (p&lt;0.05) and an increase in the concentration of SCFA: acetic, propionic (p&lt;0.05) in the coprofiltrate and a tendency to increase in the level of butyric acids. Data analysis also established an increase in the concentration of endogenous GLP-1 in the blood (p&lt;0.05). Conclusions. The detected changes in microbial metabolites may indicate a positive effect of raGLP-1 on the composition of the intestinal microbiota and its metabolic activity in patients with T2DM, which in turn contributes to the improvement of endogenous secretion of incretins

Practical Applications of a Nausea and Vomiting Model in the Clinical Development of Additional Doses of Dulaglutide.

Dulaglutide 3.0 and 4.5 mg weekly doses were approved for additional glycemic control in adult patients with type 2 diabetes inadequately controlled with metformin and 0.75 or 1.5 mg weekly doses of dulaglutide. Effects such as nausea and vomiting are commonly reported with dulaglutide and other glucagon-like peptide-1 receptor agonist therapies. Based on a pharmacokinetic/pharmacodynamic model-informed approach, a stepwise dose-escalation scheme with 4-week intervals between dose increments was suggested to mitigate gastrointestinal events for dulaglutide. These gastrointestinal events are dose dependent and attenuate over time with repeated dosing. A Markov chain Monte Carlo pharmacokinetic/pharmacodynamic joint model was developed using AWARD-11 data (N = 1842) to optimize dulaglutide dose escalation to 3.0 and 4.5 mg to mitigate gastrointestinal events. Model simulations evaluated probabilities of nausea and vomiting events for various dosing scenarios in patients needing higher doses for additional glycemic control. The model indicated that patients may dose escalate from 1.5 to 3.0 mg, then 4.5 mg weekly after at least 4 weeks on each dose. No clinically meaningful differences in nausea or vomiting events were expected when patients escalated to 3.0 or 4.5 mg following initiation at 0.75 or 1.5 mg dulaglutide. Based on the findings of this model, a minimum 4-week duration at each dose before escalation was appropriate to reduce gastrointestinal events of dulaglutide, consistent with observed gastrointestinal events data from the AWARD-11 study and supporting the currently recommended dose-escalation regimen of dulaglutide doses of 3.0 and 4.5mg for additional glycemic control.

FRI639 Effect Of Early Initiation Of GLP-1 RAs On Weight Reduction Among People With Type 2 Diabetes

Abstract Disclosure: C. Chinthammit: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. R. Mody: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. D. Liu: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. B.D. Benneyworth: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. C. Vallarino: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. Early initiation of glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy is associated with improved glycemic outcomes among people with type 2 diabetes (T2D). However, there is limited real-world evidence suggesting a similar impact on weight reduction. This study examined the relationship between timing of initiation of a GLP-1 RA and magnitude of weight reduction. This retrospective cohort study used data from the Optum® de-identified Market Clarity database from April 1, 2014, to March 31, 2020. Adults with T2D who initiated GLP-1 RA treatment during the index period, April 1, 2016 - March 31, 2019, were included. Date of first prescription was defined as index date. Patients were required to have continuous enrollment ≥2 years pre-index and 1-year post-index; have ≥1 weight and BMI values during the 6-month baseline and 1-year post-index periods; baseline BMI ≥25 kg/m2, and ≥1 pre-index oral antihyperglycemic drug (OAD) claim. Timing of GLP-1 RA initiation was proxied by the number of classes of OADs (1 OAD, 2 OADs, 3+ OADs) prescribed in the pre-index period, with fewer OADs indicating initiation of GLP-1 RA earlier in disease progression. Outcomes included weight change from baseline to 6 and 12 months of follow-up and proportion of patients achieving ≥5% weight reduction after GLP-1 RA initiation. In order to control for confounding, multivariable analyses (MVA) used weights based on propensity scores to examine the relationship between timing of GLP-1 RA initiation and post-index weight outcomes. Of the 4,194 patients evaluated, 1,317 (31.4%), 1,480 (35.3%), and 1,397 (33.3%) were classified into the 1 OAD, 2 OAD, and 3+ OAD cohorts, respectively. Baseline characteristics were fairly uniform across the three cohorts, but the 1 OAD cohort had more females (59.5%) than 2 OAD (51.1%) and 3+ OAD (44.7%), and a higher mean baseline BMI (1 OAD: 38.7 kg/m2; 2 OAD: 37.4 kg/m2; 3+ OAD: 36.4 kg/m2; p&amp;lt;0.0001). The 1 OAD cohort experienced a larger magnitude of weight reduction from baseline to 6 months (-3.0 kg) and 12 months (-3.1 kg) of follow-up vs 2 OAD (-2.4 kg and -2.7 kg) and 3+ OAD (-2.3 kg and -2.4 kg). The 1 OAD cohort had the largest proportion of patients who achieved ≥5% weight reduction at 6 months (24.9%) and 12 months of follow-up (25.5%) vs 2 OAD (19.7% and 22.1%) and 3+ OAD (21.4% and 20.6%). MVA showed that earlier GLP-1 RA initiation (1 OAD) was associated with greater weight reduction at 6 months (p=0.008) and 12 months (p=0.012) of follow-up compared to later initiation (3+ OAD). No significant differences in weight change were observed between the 2 OAD and 3+ OAD cohorts. This study showed that earlier initiators (1 OAD) of a GLP-1 RA experienced a larger magnitude of weight reduction than later initiators (3+ OADs). The research underscores the importance of further exploring the potential impact of early T2D treatment on weight reduction. Presentation: Friday, June 16, 2023

S1349 Glucagon-Like Peptide-1 Receptor Agonist and Pioglitazone Therapy Have Superior Mortality and Liver Outcomes for Patients With Type 2 Diabetes and a Diagnosis or at Risk for Undiagnosed Non-alcoholic Fatty Liver Disease

S1349 Glucagon-Like Peptide-1 Receptor Agonist and Pioglitazone Therapy Have Superior Mortality and Liver Outcomes for Patients With Type 2 Diabetes and a Diagnosis or at Risk for Undiagnosed Non-alcoholic Fatty Liver Disease

Efficacy and safety of glucagon-like peptide-1 receptor agonists therapy initiation in patients with type 2 diabetes hospitalized with coronavirus infection

BACKGROUND. The search for new effective methods of treatment and prevention of COVID-19 in patients with type 2 diabetes mellitus (T2DM) remains an urgent task for the healthcare system.AIM. To evaluate the efficacy and safety of initiating of glucagon-like peptide-1 receptor agonists (GLP-1RA) therapy in T2DM patients hospitalized with COVID-19.MATERIALS AND METHODS. The inclusion criteria were history of T2DM, BMI&gt; 27 kg/m2, confirmed diagnosis of COVID-19. The intervention group of 53 patients started dulaglutide therapy (1,5 mg once weekly) during the first 24 hours of admission, the control group consisted of 50 patients, who proceeded with glucose-lowering therapy. We evaluated the effect of therapy on carbohydrate metabolism, laboratory and clinical parameters, the outcome of COVID-19 and the safety of therapy (hypoglycemic events, side effects).RESULTS. There were no differences found in the degree of decrease in the level of glycemia in the compared groups: fasting plasma glucose (FPG) on day 7 of hospitalization– 8,2 [6,0;9,8] mmol/L vs 8,1 [6,5;9,8] mmol/L (p=0,935), mean daily glycemia (MDG) — 9,7 [8,3;11,8] mmol/L vs 11,1 [8,7;12,8] mmol/L (p=0,182). Therapy of dulaglutide had a positive effect on inflammatory markers: CRP (15,8 vs 24,4 mg/l, p=0,035), LDH (261,6 vs 326,1 U/l, p=0,016) and the level of lymphocytes (1,2 vs 0,9 x 10*9/L, p=0,049) and on clinical parameters: saturation, the need for oxygen therapy and the risk of severe course according to the NEWS2 scale. The death rate in the group receiving GLP-1RA is 3,5 times lower compared to the control group (5,7% vs 20,0%, p=0,038). The initiation of dulaglutide therapy in patients with T2DM hospitalized with COVID-19 reduced the chance of death and transfer to mechanical ventilation by 4,2 times compared to the control group (OR = 0,24, 95% CI: 0,062–0,931). GLP-1RA therapy in patients with COVID-19 and T2DM is safe in terms of hypoglycemic events and side effects.CONCLUSIONS. The initiation of GLP-1RA therapy leads to a decrease in FPG and MDG, comparable with the control group. The start of GLP-1RA therapy in hospitalized patients with COVID-19 and T2DM reduces the chance of death, favorably affecting on laboratory and clinical parameters.

Do GLP-1 Analogs Have a Place in the Treatment of PCOS? New Insights and Promising Therapies.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age. This condition is characterized by hyperandrogenism and either oligo- or anovulation. PCOS patients often present comorbidities such as obesity, insulin resistance, impaired glucose metabolism, dyslipidemia, hypertension, metabolic syndrome, and an increased risk of diabetes. Given the profound implications of metabolic impairment in PCOS, the accurate diagnosis and management of these facets are imperative. The first-line approach to treatment involves lifestyle modifications, including dietary adjustments and exercise aimed at achieving weight loss, a strategy consistently emphasized across the literature. Supplementation with probiotics, vitamin D, and L-carnitine have also provided additional benefits to patients. In select cases, pharmacological interventions are needed for optimal therapeutic results. The most common medications used in PCOS include metformin, thiazolidinediones, inositols, and two classes of antidiabetic agents: dipeptidyl peptidase-IV (DPP-IV) inhibitors, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new addition to the therapeutic arsenal for the metabolic management of PCOS. GLP-1 receptor agonists cause insulin release in a glucose-dependent manner, yielding clinical benefits such as heightened satiety, reduced appetite, and appetite regulation. GLP-1RAs have demonstrated efficacy in reducing glycated hemoglobin levels and promoting weight loss while ameliorating hyperlipidemia. Prior to initiating GLP-1RA therapy, patients should undergo screening for contraindications, including history of pancreatitis, diabetic retinopathy, or thyroid cancer. The effects of treatment should be monitored using laboratory testing and body weight measurements. Effective communication between clinician and patient should be maintained with regular check-in for a period of 6 to 12 months.

Comparison of the efficacy and safety of hypoglycemic treatments in patients with non-alcoholic fatty liver disease and type-2 diabetes: a systematic review and Bayesian network analysis.

The association between non-alcoholic fatty liver disease (NAFLD) and metabolic disorders, especially type-2 diabetes (T2DM), has been proven to be bidirectional. Hypoglycemic agents may be promising treatments for those disorders. However, there is currently no approved hypoglycemic therapy for NAFLD. In this review, we aimed to compare the efficacy and safety of twelve different hypoglycemic treatments in patients with NAFLD and T2DM. We systematically screened randomized controlled trials (RCTs) published from March 2013 to March 2023 by searching PubMed, Embase, Medline, and Web of Science without any language restriction. We registered this project on the PROSPERO website: https://www.crd.york.ac.uk/PROSPERO/ (ID: CRD42023429701). All subsequent analyses were performed under the registered protocol. The mean difference (MD) and 95% confidence interval (95% CI) were adapted to evaluate the effect size of the treatment. The surface under the cumulative sorting curve (SUCRA) was used to rank the efficacy of the included treatments. We included 19 trials involving 1212 patients in total. Insulin plus glucagon-like peptide-1 receptor agonist (GLP1RA) combination therapy was probably the most effective treatment for reducing weight and body mass index (BMI) (SUCRA: 0.93 and 1.00). Thiazolidinediones (TZD) were probably the most effective treatment for reducing glycosylatedhemoglobin (HbA1c) and γ-glutamyltranspeptidase (γ-GGT) levels (SUCRA: 0.78 and 0.97). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) had the highest probability of presenting good therapeutic efficacy in reducing triglyceride (TG) levels (SUCRA: 0.72). The most common adverse reactions were gastrointestinal disorders, mainly after the administration of GLP1RA, and mild hypoglycemia, which was closely related to the use of insulin. GLP1RA plus insulin combination therapy, GLP1RA, SGLT2i, and TZD may be the most effective therapeutic methods for patients with NAFLD and T2DM.

SGLT2i and GLP-1 RA therapy in type 1 diabetes and reno-vascular outcomes: a real-world study

Aims/hypothesisInsulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1 diabetes. Little work has previously been undertaken to evaluate safety with long-term efficacy and cardio-renal benefits of such therapies. We sought to investigate the real-world impact of sodium–glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in individuals with type 1 diabetes in relation to effect on blood glucose levels, adverse events and cardio-renal outcomes.MethodsWe performed a retrospective cohort study of all patients aged 18 or over with type 1 diabetes on the TriNetX platform, a global collaborative network providing access to real-time, anonymised medical records. We included patients who had been treated with an SGLT2i or GLP-1 RA for at least 6 months and analysed the efficacy, safety and cardio-renal outcomes 5 years after initiation of therapy.ResultsWe identified 196,691 individuals with type 1 diabetes, 13% of whom were treated with adjunctive glucose-lowering therapy in addition to insulin. Included in the core analysis were 1822 patients treated with a GLP-1 RA and 992 individuals treated with an SGLT2i. Both agents provided clinically meaningful reductions in HbA1c (−2.6 mmol/mol [−0.2%] with SGLT2i and −5.4 mmol/mol [−0.5%] with GLP-1 RA). The SGLT2i treated cohort showed preservation of eGFR over a 5-year period compared with the GLP-1 RA treated cohort (+3.5 ml/min per 1.73 m2 vs −7.2 ml/min per 1.73 m2, respectively), including patients with established chronic kidney disease (CKD). The SGLT2i treated cohort experienced higher rates of diabetic ketoacidosis (DKA) (RR 2.08 [95% CI 1.05, 4.12] p=0.0309) and urinary tract infection/pyelonephritis (RR 2.27 [95% CI 1.12, 4.55] p=0.019) compared with the GLP-1 RA treated cohort. However, the SGLT2i treated cohort were less likely to develop heart failure (RR 0.44 [95% CI 0.23, 0.83] p=0.0092), CKD (RR 0.49 [95% CI 0.28, 0.86] p=0.0118) and be hospitalised for any cause (RR 0.59 [95% CI 0.46, 0.76] p≤0.0001) when compared with the GLP-1 RA treated cohort.Conclusions/interpretationBoth SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in type 1 diabetes. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA and urinary tract infection compared with GLP-1 RA therapy. Long-term evaluation of the efficacy and safety of these adjunctive therapies is required to guide their use in individuals with type 1 diabetes.Graphical