Safety Of Glucagon-like Peptide-1 Receptor Agonists Research Articles

Pharmacological management of pediatric metabolic dysfunction-associated steatotic liver disease.

Pediatric obesity, characterized by a body mass index (BMI) at or above the 95th percentile for age, affects a substantial number of children and adolescents worldwide. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, represents a prominent hepatic manifestation of obesity and metabolic syndrome, emerging as the most prevalent hepatic disorder among pediatric patients and a significant contributor to liver transplantation in adults. The escalating prevalence of pediatric MASLD mirrors the alarming rise in childhood obesity rates over recent decades. While lifestyle modifications focusing on dietary changes and increased physical activity constitute the cornerstone of MASLD management, achieving and maintaining significant weight reduction remains challenging. Moreover, disease progression often persists despite standard-of-care interventions, warranting exploration into alternative therapeutic strategies. Pharmacological interventions, particularly, glucagon-like peptide-1 receptor agonists (GLP-1RA), have shown promise in addressing pediatric obesity and its associated comorbidities, including MASLD. Recent studies have demonstrated the efficacy of GLP-1RA in inducing weight loss and improving liver enzyme levels, suggesting a potential role in halting disease progression, and reducing the risk of major adverse liver outcomes. This review provides a comprehensive overview of the current pharmacotherapy landscape for pediatric MASLD, with a focus on novel agents such as GLP-1RA. Furthermore, the manuscript proposes a practical algorithm to assist in integrating GLP-1RA into the clinical management of pediatric patients with obesity and MASLD. Despite promising results, further research is warranted to elucidate the long-term efficacy and safety of GLP-1RA in pediatric populations.

Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.

Comparison of societal guidance on perioperative management of glucagon-like peptide-1 receptor agonists: implications for clinical practice and future investigations.

The use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) by patients undergoing surgery and procedures requiring anesthesia has become a topic of significant concern for perioperative providers because of the potential increased risk of aspiration resulting from the medication's effect of delaying gastric emptying. There is currently a lack of high-quality data regarding the safety of GLP-1 RAs in patients undergoing surgery, which has led to variations in practice. We performed an internet search of society-endorsed statements and guidelines related to perioperative management of GLP-1 RAs, focusing on the top 20 countries with the largest anesthesiology societies determined by membership data from the World Federation of Societies of Anesthesiologists. We excluded articles and websites that were not in English. Our search revealed endorsed statements from fourteen major anesthesiology, endocrinology, and gastroenterology societies. There was considerable variation between societies in the recommendations and guidance for withholding these medications before surgery, the duration of withholding, assessment of the need for avoiding deep sedation or general anesthesia, use of rapid sequence intubation, need for prolonged fasting periods and clear fluid before a nil per os period, recognition of signs and symptoms for aspiration risk, the management of glucose in the perioperative period, and the use of point-of-care ultrasound for risk assessment. Society-endorsed statements and guidelines provide varying recommendations on the perioperative management of GLP-1 RAs. The insights gained from this comparative analysis may help guide clinical practice, develop institutional practice guidelines, and direct future research efforts.

Real-world effectiveness of GLP-1 receptor agonist-based treatment strategies on "time in range" in patients with type 2 diabetes.

Background: Diabetes affects millions of people worldwide annually, and several methods, including medications, are used for its management; glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of medications. The efficacy and safety of GLP-1RAs in treating type 2 diabetes mellitus (T2DM) have been assessed and have been shown to significantly improve time in range (TIR) in several clinical trials. However, presently, there is a lack of real-world evidence on the efficacy of GLP-1RAs in improving TIR. To address this, we investigated the effect of GLP-1RA-based treatment strategies on TIR among patients with T2DM in real-world clinical practice. Methods: This multicenter, retrospective, real-world study included patients with T2DM who had previously used a continuous glucose monitoring (CGM) system and received treatment with GLP-1RAs or oral antidiabetic drugs (OADs). Patients who received OADs served as controls and were matched in a 1:1 ratio to their GLP-1RA counterparts by propensity score matching. The primary endpoint was the TIR after 3-6 months of treatment. Results: According to propensity score matching, 202 patients were equally divided between the GLP-1RA and OAD groups. After 3-6 months of treatment, the TIR values for the GLP-1RA and OAD groups were 76.0% and 65.7%, respectively (p < 0.001). The GLP-1RA group displayed significantly lower time above range (TAR) and mean glucose values than the OAD group (p < 0.001). Subgroup analysis revealed that, compared with the administration of liraglutide, the administration of semaglutide and polyethylene glycol loxenatide (PEG-Loxe) significantly improved TIR over 3-6 months of treatment (p < 0.05). Conclusion: These real-world findings indicate that GLP-1RA-based treatment strategies could be superior to oral treatment strategies for improving TIR among patients with T2DM and that once-weekly GLP-1RA may be more effective than a once-daily GLP-1RA. Clinical trial registration: http://www.chinadrugtrials.org.cn/index.html, identifier number ChiCTR2300073697.

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 of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy

Increasing use of second-line noninsulin antidiabetic medication (ADM) in pregnant individuals with type 2 diabetes (T2D) may result in fetal exposure, but their teratogenic risk is unknown. To evaluate periconceptional use of second-line noninsulin ADMs and whether it is associated with increased risk of major congenital malformations (MCMs) in the infant. This observational population-based cohort study used data from 4 Nordic countries (2009-2020), the US MarketScan Database (2012-2021), and the Israeli Maccabi Health Services database (2009-2020). Pregnant women with T2D were identified and their live-born infants were followed until up to 1 year after birth. Periconceptional exposure was defined as 1 or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, or insulin (active comparator) from 90 days before pregnancy to end of first trimester. Relative risks (RRs) and 95% CIs for MCMs were estimated using log-binomial regression models, adjusting for key confounders in each cohort and meta-analyzed. Periconceptional exposure to second-line noninsulin ADMs differed between countries (32, 295, and 73 per 100 000 pregnancies in the Nordics, US, and Israel, respectively), and increased over the study period, especially in the US. The standardized prevalence of MCMs was 3.7% in all infants (n = 3 514 865), 5.3% in the infants born to women with T2D (n = 51 826), and among infants exposed to sulfonylureas was 9.7% (n = 1362); DPP-4 inhibitors, 6.1% (n = 687); GLP-1 receptor agonists, 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); and insulin, 7.8% (n = 5078). Compared with insulin, adjusted RRs for MCMs were 1.18 (95% CI, 0.94-1.48), 0.83 (95% CI, 0.64-1.06), 0.95 (95% CI, 0.72-1.26), and 0.98 (95% CI, 0.65-1.46) for infants exposed to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, respectively. Use of second-line noninsulin ADMs is rapidly increasing for treatment of T2D and other indications, resulting in an increasing number of exposed pregnancies. Although some estimates were imprecise, results did not indicate a large increased risk of MCMs above the risk conferred by maternal T2D requiring second-line treatment. Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.

Abstract 12095: Efficacy, Safety, and Cardio-Protective Effect of GLP-1 Receptor Agonists Among Patients With Diabetes Mellitus: A Meta-Analysis and Meta-Regression

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promising results in reducing the incidence of major adverse cardiovascular events (MACE) in patients with Diabetes Mellitus (DM). However, the reports of previous trials show inconsistent reports for other endpoints like myocardial infarction, stroke, and cancer. Objective: We sought to evaluate the efficacy and safety of GLP-1 receptor agonists among DM patients by including recently published trials evaluating cardiovascular outcomes. Methods: We performed a systematic literature search using PubMed, Embase, and Scopus for relevant articles from inception until 10th March 2022. Primary clinical outcomes were the incidence of MACE. The secondary efficacy outcomes were cardiovascular mortality (CVM), all-cause mortality (ACM), myocardial infarction (MI), stroke, and heart failure hospitalization (HFH). Results: A total of 8 randomized controlled trials with xx (518,105 GLP-1 RA vs. 6,817,729 placebo) patients were included in the analysis. The mean age of the patients with GLP-1 RA and the placebo group was 70.0 and 69.2 years. The mean follow-up duration was xx years. Pooled analysis shows that GLP-1 receptor agonists were associated with significant 14% reduction in MACE [HR 0.86, 95% CI (0.80-0.93), p&lt;0.01], 17% reduction in stroke [HR 0.83, 95% CI (0.76-0.92), p&lt;0.01], 10% reduction in MI [HR 0.90, 95% CI (0.83-0.99), p=0.02], 13% reduction in CVM [HR 0.87, 95% CI (0.81-0.94), p&lt;0.01), 12% reduction in ACM [HR 0.88, 95% CI (0.83-0.93), p&lt;0.01] and 9% reduction in HFH [HR 0.91, 95% CI (0.84-0.99), p=0.04] compared to that of placebo. Among safety outcomes, the risk of thyroid cancer was significantly higher in GLP-1 RA [OR 2.33, 95% CI (1.08-5.03), p=0.03) compared to placebo. Conclusions: GLP-1 receptor agonists significantly reduced MACE, MI, ACM, CVM, HFH, and stroke. However, the risk of thyroid cancer significantly increased in GLP-1 RA patients.

#6653 USE OF GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS IN KIDNEY TRANSPLANT PATIENTS: A MULTI-CENTER STUDY

Abstract Background and Aims Diabetes mellitus (DM) is a frequent complication in kidney transplant (KT) patients, leading to a higher cardiovascular mortality and graft loss. The use of therapies such as Glucagon-like peptide-1 receptor agonist (GLP-1RA) could have benefits in KT, although the experience reported so far is limited. The aim of our study is to describe the effectiveness and safety of GLP-1RA in KT patients. Method Retrospective cohort study of KT with DM who started GLP-1RA in three Spanish hospitals (Puerta del Mar University Hospital, Jerez de la Frontera University Hospital and Puerto Real University Hospital) from February 2016 to July 2022. All patients had a minimum follow-up of 6 months after starting the treatment. Clinical and demographic variables were analyzed. We collected GLP-1RA type and dose. Glomerular filtration rate (eGFR), proteinuria, and weight were collected at the start of treatment and after 6 and 12 months. We analyze glycemic control, blood pressure and lipid profile. Acute rejections (AR), de novo donor-specific antibodies (DSA) and adverse effects were documented. Parametric and non-parametric tests were performed according to the normality of the sample. Results In this period, 102 KT with DM were treated with GLP-1RA from 19/02/2016 to 22/07/2022. At the time of the prescription mean body mass index was 35.8 kg/m2 and the mean weight was 95 kg. Forty-two (44%) had developed post-transplant diabetes mellitus (PTDM). The mean age was 62 years and 56% were men. Mean baseline estimated glomerular filtration rate (eGFR) was 47.2 ml min/1.73 m2 and the time post-KT was 47 months. The GLP-1RA mostly prescribed was semaglutide (66.7%). Fifty-five (55%) patients reached the maximum recommended dose of the drug. The maintenance immunosuppressive therapy used was steroids (94.7%), tacrolimus (97.4%), mycophenolate (94.7%) and everolimus (2.6%). Eighty-four KT recipients had a minimum follow-up of 6 months and sixty-four were followed for 12 months. We observed stability in eGFR and a reduction in proteinuria (−19.1 mg/g at 6 months, p = .000 and −46.6 mg/g at 12 months, p = .000) during all the follow-up. Additionally, we found a significant reduction in systolic blood pressure (−7.5 mmHg at 6 months, p = .013 and −7,3 mmHg at 12 months, p = .004) despite the number of patients receiving angiotensin receptor blockers, angiotensin-converting enzyme and other antihypertensive therapies. Besides, their doses did not change during the period of the study. In our cohort, body weight significantly reduced (−3.6 Kg at 6 months, p = .000 and −3.6 Kg at 12 months, p = .000). Furthermore, HbA1c decreased (−1.2 mmol/L at 6 months, p = .000 and −1.5 mmol/L at 12 months, p = .000). Notably, insulin dose was also reduced (−2.2 UI/day at 6 months, p = 0.048) but the number of patients with sodium-glucose cotransporter 2 inhibitors increased at 12 months (p = 0.031). Finally, we observed a reduction in total cholesterol (−11.5 mg/dL at 6 months, p = .001 and −15.6 mg/dL at 12 months p = .000) and LDL-c (−9.2 mg/dL at 6 months, p = 0.002 and −16.8 mg/dL at 12 months, p = .000) during the follow-up. However, patients receiving statins and steroids and the dose remained unchanged. Fifteen patients (14.7%) suffered from side effects, mainly nausea and vomiting, and ten patients (9.8%) discontinued the treatment for this reason. No changes in the mycophenolate formulation were made. One patient discontinued the treatment due to the diagnosis of pancreatic cancer 8 months after starting the drug. We did not find differences in the levels or in the dose of tacrolimus. Neither AR episodes nor de novo DSAs development were notified. Conclusion This is the first multicenter study that reports the effectiveness and safety of GLP-1RA in KT patients. Our results support that it can be an option for the management of DM in these patients. Its use is safe and it does not seem to alter tacrolimus trough levels, to induce AR episodes or de novo DSAs development.

Beneficial outcomes of glucagon like peptide-1 agonist therapy in a patient with Bardet Biedl syndrome and kidney transplant

Abstract Introduction Bardet Biedl syndrome (BBS) is a rare hereditary disorder characterized by early-onset obesity, metabolic syndrome, type 2 diabetes, hypogonadism, polydactyly and renal failure. There is lack of data on the use of glucagon-like peptide-1 receptor agonist (GLP-1RA) for management of patients with BBS and kidney transplant. Herein, we report our findings on body weight, graft kidney function and metabolic parameters in a patient with BBS and kidney transplant. Clinical Case A 35-year-old man with BBS was referred to our clinic for morbid obesity, diabetes and dyslipidemia. He also had retinitis pigmentosa, acanthosis nigricans, hypertension and hypogonadotropic hypogonadism, but no polydactyly. Due to polycystic kidney disease, the patient underwent cadaveric kidney transplantation ten years ago. He quickly gained weight after starting glucocorticoids following the kidney transplant. Current medical treatment consisted of metformin 1000 mg BID, testosterone 250 mg injection every three weeks, amlodipine 5 mg daily, mycophenolate mofetil 500 mg BID, and cyclosporin 25 mg BID. His body mass index (BMI) was 45 kg/m2, body fat percentage was 41%, waist and hip circumferences were 120 and 125 cm, respectively. On laboratory examination, his fasting plasma glucose and glycated hemoglobin (HbA1c) levels were 140 mg/dL and 7.8%, respectively. A low-density lipoprotein level of 178 mg/dL, a high-density lipoprotein level of 45 mg/dL, and a triglyceride level of 200 mg/dL were found in the lipid profile. His serum creatinine and estimated glomerular filtration rate (eGFR) were 1.9 mg/dL and 66.3 mL/min/1.73 m2, respectively. The initial treatment strategy was lifestyle changes and dietary management which did not result in significant weight loss after 6 months. Following a thorough discussion on medical treatment options with the patient, exenatide was started considering obesity, diabetes and patient preference for affordability. Initial dose of 5 mcg BID was gradually titrated up to 10 mcg BID, with frequent monitoring of his kidney function tests. Over a 6-month period, exenatide treatment resulted in significant weight loss, with a reduction in BMI to 40 kg/m2, body fat percentage to 35%, waist and hip circumferences to 114 and 120 cm, respectively. HbA1c decreased from 7.8% to 6.2%, and eGFR increased from 66.3% to 84.2%. His hypertension, dyslipidemia, and urinary protein: creatinine ratio also significantly improved. He has maintained his weight and glycemic control during further follow up of 10 months. Conclusion Weight management in BBS could be challenging, and kidney transplantation may make it even more difficult. Here we show that GLP-1RA use results in significant weight loss along with improvements in glycemic control, metabolic parameters, and renal function in a patient with BBS and kidney transplant. More data are needed to confirm long term efficacy and safety of GLP-1RA in these patients.

Clinical and Safety Outcomes With GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 1 Diabetes: A Real-World Study.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are used off-label in the management of type 1 diabetes mellitus (T1DM) in real-world practice as adjuvant therapies to insulin. There are few real-world data regarding efficacy and safety of this practice. This work aimed to determine the efficacy and safety of GLP-1RAs and sodium-glucose SGLT2is in the management of T1DM in real-world practice. A retrospective chart review was performed of all instances of GLP-1RA and/or SGLT2i use greater than 90 days in adult patients with T1DM at a single academic center. We report the clinical and safety outcomes over the duration of use. We identified 104 patients with T1DM who ever used a GLP-1RA (76 patients) or SGLT2i (39 patients) for more than 90 days. After 1 year of therapy, GLP-1RA users had statistically significant reductions in weight (90.5 kg to 85.4 kg; P < .001), glycated hemoglobin A1c (HbA1c) (7.7% to 7.3%; P = .007), and total daily dose of insulin (61.8 units to 41.9 units; P < .001). SGLT2i users had statistically significant reductions in HbA1c (7.9% to 7.3%; P < .001) and basal insulin (31.3 units to 25.6 units; P = .003). GLP-1RA users compared to SGLT2i users had greater reduction in weight (P = .027) while HbA1c reduction was comparable between the groups. Over a mean total duration of use of 29.5 months/patient for both groups, more SGLT2i users experienced diabetic ketoacidosis (DKA) (12.8% vs 3.9%). Therapy was discontinued because of adverse events 26.9% of the time for GLP-1RA users vs 27.7% for SGLT2i users. GLP-1RA and SGLT2i use in T1DM is associated with clinically relevant benefits. DKA remains a clinical concern with SGLT2i use, requiring careful patient selection and monitoring, with the risk to benefit ratio of treatment evaluated at an individual level.

Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

The prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is increasing and there is an urgent need for new treatment strategy to prevent progression of hepatic steatosis and fibrosis. We have performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of hepatic steatosis and fibrosis in patients with T2DM and NAFLD. The PubMed, Web of Science, Scopus, Embase and Cochrane Central Register of Controlled Trials databases were searched for articles that met the eligibility criteria to explore the efficacy and safety of GLP-1RAs in patients with T2DM and NAFLD. We assessed pooled data using a random/fixed-effects model according to the I2 and p-values. Eight trials that included a total of 468 participants were eligible for inclusion in the review. For primary outcomes, administration of GLP-1RAs significantly decreased the content of intrahepatic adipose (IHA)[p=0.007, weight mean difference (WMD) -3.01, 95% confidence interval (CI) -4.75, -1.28], subcutaneous adipose tissue (SAT) (p<0.00001,WMD -28.53,95%CI -68.09,-26.31), and visceral adipose tissue (VAT) (p<0.0001,WMD -29.05,95%CI -42.90,-15.9). For secondary outcomes, GLP-1RAs produced a significant decrease in levels of alanine aminotransferase(ALT)(p=0.02, WMD -3.82, 95%CI -7.04, -0.60), aspartate aminotransferase (AST) (p=0.03, WMD -2.4, 95%CI -4.55,-0.25, I2 = 49%), body weight (p<0.00001,WMD -3.48,95%CI -4.58,-2.37), body mass index (p<0.00001,WMD -1.07,95%CI -1.35,-0.78), circumference waist (p=0.0002,WMD -3.87, 95%CI -5.88, -1.86) fasting blood glucose (p=0.02, WMD -0.35, 95%CI -0.06, -0.05), HbA1c (p<0.00001,WMD -0.39,95%CI -0.56,-0.22), HoMA-IR(p=0.005, WMD-1.51, 95%CI-0.87,-0.16), total cholesterol (p=0.0008, WMD -0.31, 95%CI -0.48, 0.13) and triglycerides (p=0.0008, WMD -0.27, 95%CI -0.43,-0.11) in comparison with the control regimens. The main adverse events associated with GLP-1RAs included mild-to-moderate gastrointestinal discomfort and nonsense hypoglycemia that resolved within a few weeks. GLP-1RAs were an effective treatment that improved intrahepatic visceral and subcutaneous adipose tissue, inflammatory markers, the anthropometric profiles and some metabolic indices in patients with T2DM and NAFLD, GLP-1RAs could be considered for use in these if there are no contraindications. Further studies are needed to understand the direct and indirect effects of GLP-1RAs on NAFLD and the potential mechanism via which they prevent its progression.Systematic Review Registration: PROSPERO, identifier CRD42021265806.

GLP-1 receptor agonists for Parkinson's disease.

Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the off-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no effect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists.

GLP-1 receptor agonists in diabetes for stroke prevention: a systematic review and meta-analysis.

Randomized controlled clinical trials (RCT) have demonstrated varied efficacy of glucagon-like peptide-1 receptor (GLP-1R) agonists for cardiovascular outcomes. We sought to evaluate the efficacy and safety of GLP-1R agonists among patients with Type 2 diabetes mellitus (DM) for stroke prevention. We conducted a systematic review and meta-analysis of RCTs reporting the following outcomes among patients with Type 2 DM treated with GLP-1R agonists (vs. placebo): nonfatal or fatal strokes, all-cause or cardiovascular mortality, myocardial infarction (MI) and major adverse cardiovascular events (MACE). The protocol of our systematic review and meta-analysis was registered to the PROSPERO database. We pooled odds ratios (OR) using random-effect models, and assessed the heterogeneity using Cochran Q and I2 statistics. We identified 8 RCTs, comprising 56,251 patients. In comparison to placebo, GLP-1R agonists reduced nonfatal strokes (OR 0.84; 95% CI 0.76-0.94, p = 0.002; I2 = 0%) and all strokes (OR 0.84; 95% CI 0.75-0.93, p = 0.001; I2 = 0%) by 16%. Overall, GLP-1R agonists reduced MACE by 13% (OR 0.87; 95% CI 0.81-0.94, p = 0.0003; I2 = 42%), cardiovascular mortality by 12% (OR 0.88; 95% CI 0.81-0.95; p = 0.002; I2 = 0%) and all-cause mortality by 12% (OR 0.88; 95% CI 0.82-0.95, p = 0.0007; I2 = 15%). Additional analyses demonstrated that GLP-1R agonists reduced the risk of incident MACE (OR 0.86; 95% CI 0.80-0.92; p < 0.0001; I2 = 0%) among patients with prior history of MI or nonfatal strokes. Among patients with type 2 DM,GLP-1R agonists are beneficial for primary stroke, MACE, and cardiovascular mortality prevention. Further RCTs are needed to evaluate their role for secondary stroke prevention.

Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials.

Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD. In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85-1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80-0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79-0.98), all-cause mortality (HR 0.89, 95% CI 0.81-0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76-0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86-0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82-1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83-1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo. Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

Risk of Malignant Neoplasia with Glucagon-Like Peptide-1 Receptor Agonist Treatment in Patients with Type 2 Diabetes: A Meta-Analysis.

Background Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia. Methods We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia. Results Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94–1.15; p = 0.46), liraglutide (OR 1.08, 95% CI 0.91–1.27; p = 0.38), exenatide (OR 1.00, 95% CI 0.86–1.16; p = 1.00), semaglutide (OR 0.89, 95% CI 0.35–2.22; p = 0.80), or albiglutide (OR 1.07, 95% CI 0.23–4.88; p = 0.93). A subanalysis of trials lasting longer than 3 years also showed no increase in the neoplasia risk with GLP-1 receptor agonist use (OR 1.03, 95% CI 0.92–1.15; p = 0.60). Between-trial statistical heterogeneity was low for all comparisons. Conclusion GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs. Findings from cardiovascular outcome trials showed cardiovascular safety of GLP-1 receptor agonists, but results for cardiovascular efficacy were varied. We aimed to examine overall cardiovascular efficacy for lixisenatide, liraglutide, semaglutide, and extended-release exenatide. In this systematic review and meta-analysis, we analysed data from eligible trials that assessed the safety and efficacy of GLP-1 receptor agonists compared with placebo in adult patients (aged 18 years or older) with type 2 diabetes and had a primary outcome including, but not limited to, cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. We searched PubMed and MEDLINE without language restrictions up to Sept 18, 2017, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) for cardiovascular efficacy outcomes and odds ratios for key safety outcomes. Of 12 articles identified in our search and screened for eligibility, four trials of cardiovascular outcomes of GLP-1 receptor agonists were identified: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended-release exenatide). Compared with placebo, GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke; HR 0·90, 95% CI 0·82-0·99; p=0·033), a 13% RRR in cardiovascular mortality (0·87, 0·79-0·96; p=0·007), and a 12% relative risk reduction in all-cause mortality (0·88, 0·81-0·95; p=0·002), with low-to-moderate between-trial statistical heterogeneity. No significant effect of GLP-1 receptor agonists was identified on fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure. Overall, no significant differences were seen in severe hypoglycaemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer reported between GLP-1 receptor agonist treatment and placebo. Our findings show cardiovascular safety across all GLP-1 receptor agonist cardiovascular outcome trials and suggest that drugs in this class can reduce three-point major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality risk, albeit to varying degrees for individual drugs, without significant safety concerns. GLP-1 receptor agonists have a favourable risk-benefit balance overall, which should allow the choice of drug to be individualised to each patient's needs. Amylin Pharmaceuticals (AstraZeneca).

The cardiovascular effects of glucagon-like peptide-1 receptor agonists: a trial sequential analysis of randomized controlled trials

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antidiabetic drugs. Their wider use for the treatment of patients with type 2 diabetes mellitus has led to concerns about its cardiovascular effects. However, the robustness of data leading to those concerns is unclear. The purpose of this study is to systematically assess the robustness of the available evidence on the adverse cardiovascular effects of GLP-1 receptor agonists in patients with type 2 diabetes. The Cochrane library, MEDLINE, EMBASE and www.clinicaltrials.gov were searched from inception through to 25 January 2013. Randomized controlled trials (RCTs) were selected if they compared GLP-1 receptor agonists with placebo or other drugs with a duration ≥12weeks. Mantel-Haenszel odds ratio (MH-OR) of cardiovascular events with 95% confidence interval (CI) was estimated using a random effects model. Trial sequential analysis based on required information size with an assumption of plausible reductions in relative risk in the low-bias trials, 5% risk of a type I error and 20% risk of a type II error was used to explore the robustness of available evidence. Fifty-eight trials were included in the analysis (10466 patients receiving GLP-1 receptor agonists and 7138 patients receiving comparators, respectively). Overall, the OR for cardiovascular events with GLP-1 receptor agonists was 0·52 (95% CI: 0·27-0·99) compared with placebo and 0·84 (95% CI: 0·52-1·36) with active controls. Trial sequential analyses showed that the actual accumulated sample size was only 11% (7445 of 65212) and 13% (10157 of 79198) of the required information size for placebo-controlled trials and active-controlled trials, respectively. These results indicate that there is still insufficient evidence on cardiovascular events. GLP-1 receptor agonists do not seem to show any increased risk of cardiovascular events However, the available data from RCTs remain insufficient to confirm an absence of detrimental effect. More long-term trials and population-based studies are required to provide the necessary reassurance on the cardiovascular safety of GLP-1 receptor agonists.

The Safety of Incretin-Based Therapies—Review of the Scientific Evidence

Antidiabetic therapies based on potentiation of incretin action are now widely used; however, understanding of their long-term safety remains incomplete. We searched articles in PubMed for data assessing the safety of incretin-based therapies. Three major areas of interest are reviewed: incretin action in the cardiovascular system, pancreatitis, and cancer. Incretin therapies reduce weight gain, minimize hypoglycemia, decrease inflammation, and are cardioprotective in preclinical studies. However, data permitting conclusions about whether incretin therapies modify the development of cardiovascular events in humans are not available. Case reports link incretin therapies to pancreatitis, but retrospective case control studies do not associate pancreatitis with glucagon-like peptide-1 receptor (GLP-1R) agonists or dipeptidyl peptidase-4 inhibitors. Preclinical studies of pancreatitis have yielded conflicting results, and mechanisms linking incretin receptor activation to pancreatic inflammation have not yet been forthcoming. GLP-1R activation promotes C-cell hyperplasia and medullary thyroid cancer in rodents; however, long-term clinical studies of sufficient size and duration to permit conclusions regarding cancer and incretin therapeutics have not yet been completed. The available data on incretin action and incidence of cardiovascular events, pancreatitis, or cancer are not yet sufficient or robust enough to permit firm conclusions regarding associations with incretin-based therapies in humans with diabetes. The forthcoming results of long-term cardiovascular safety studies should provide more conclusive information about the safety of GLP-1R agonists and dipeptidyl peptidase-4 inhibitors in diabetic patients.