oxyntomodulin and Diabetic-Retinopathy

Semaglutide is a recently approved glucagon-like peptide-1 receptor agonist used to treat patients with type 2 diabetes mellitus (T2DM). The SUSTAIN 6 trial found a significantly higher rate of retinopathy complications in the semaglutide-treated group compared with the placebo group.. This study aimed to evaluate the association between semaglutide and the risk of retinopathy in patients with T2DM.. Electronic databases were systematically searched up to April 2021 to identify randomized controlled trials that reported diabetic retinopathy (DR) events in semaglutide-treated and control groups. A meta-analysis was conducted using Review Manager 5.4 software to calculate the risk ratio (RR) and 95% confidence intervals (CIs).. A total of 23 randomized trials involving 22,096 patients with T2DM were included. There were 730 incident DR cases-463 in the semaglutide group and 267 in the control group. Overall, semaglutide was not associated with increased DR risk compared with controls when all trials were combined (RR 1.14, 95% CI 0.98-1.33). Subgroup analysis showed that semaglutide was associated with an increased risk of DR compared with placebo (RR 1.24, 95% CI 1.03-1.50). Moreover, patient age ≥ 60 years and diabetes duration ≥ 10 years were also factors for increased risk of DR when using semaglutide (RR 1.27, 95% CI 1.02-1.59; RR 1.28, 95% CI 1.04-1.58, respectively).. Semaglutide was not associated with an increased risk of DR; however, caution regarding DR risk is needed for older patients or those with long diabetes duration when taking semaglutide.

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Middle Aged; Randomized Controlled Trials as Topic

The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

Topics: Acute Kidney Injury; Animals; Blood Glucose; Body Weight; Cardiovascular System; Cholelithiasis; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Gallbladder; Gastrointestinal Tract; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin; Nausea; Pancreas; Pancreatic Neoplasms; Pancreatitis; Patient Safety; Peptides; Thyroid Neoplasms; Time Factors

Semaglutide once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection has been approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM). Areas Covered: The safety and efficacy of the semaglutide once-weekly injection are reviewed using results from preliminary pharmacology studies and later-phase randomized control trials (RCTs) and meta-analyses. Semaglutide once-weekly is compared to placebo and active comparators for T2DM in the SUSTAIN clinical trial series, with outcomes of: glycemic control, weight loss, major adverse cardiovascular events, and adverse effects. Risk for diabetic retinopathy complications (DRCs) is reviewed in detail, due to significantly higher risk for DRCs seen in SUSTAIN 6. SUSTAIN 6 is the first instance of a GLP-1 RA demonstrating significantly increased risk for DRCs. Semaglutide's current regulatory approvals, practice considerations, and cost-effectiveness compared to similar therapies are also considered. Expert Commentary: Semaglutide demonstrates high glycemic efficacy and favorable safety profile, and reduces the risk for cardiovascular events. Mild to moderate gastrointestinal events and retinopathy complications were more common with semaglutide compared to placebo, though serious adverse events were similar to controls and infrequent. Improved clinical efficacy should be carefully weighed against the risk for GI and retinopathy complications.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic

Glucagon-like peptide 1 receptor (GLP-1R) agonists are increasingly being used as treatment for type 2 diabetes. Since the U.S. Food and Drug Administration published recommendations about the cardiovascular safety of new antidiabetes therapies for treating type 2 diabetes in 2008, the results of two outstanding clinical trials using GLP-1R agonists addressing this issue (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation [LEADER] and Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6]) have been published. Both studies found beneficial effects in terms of reducing the rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, their results regarding the progression of diabetic retinopathy (DR) were neutral with liraglutide (LEADER) or worse when compared with placebo in the case of semaglutide (SUSTAIN-6). These results are surprising because of the beneficial effects of GLP-1R analogs reported in experimental models of DR. In this Perspective, an overview of the mechanisms by which GLP-1R activation exerts its effects in preventing or arresting experimental DR is given. In addition, we consider the possible reasons for the negative results regarding the progression of DR in the SUSTAIN-6 study, as well as the gaps that still need to be covered to further clarify this important issue in the management of type 2 diabetes.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Disease Progression; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Molecular Targeted Therapy; Myocardial Infarction; Stroke; Treatment Outcome

To evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme.. The SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon-like peptide-1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2-year, pre-approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at-risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage-points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC.. There was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre-existing DR and poor glycaemic control at baseline, and who were treated with insulin.. Early worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Japan; Male; Middle Aged; Risk Factors

Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.. We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.. At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.. In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Kaplan-Meier Estimate; Male; Middle Aged

Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively.. Adverse events (AEs) from 16 randomized placebo- or active-controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480).. In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide.. The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Gastrointestinal Diseases; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Pancreatitis

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Glucagon-Like Peptides; Humans; Hypoglycemic Agents

To investigate the protective efficacies and potent mechanisms of combination therapy with semaglutide and rosiglitazone (RSG) on the high-glucose incubated human ARPE-19 cells and diabetic retinopathy (DR) model rats.. The CCK-8 methods were used to evaluate the protective effects of semaglutide and RSG alone or combination on the cell viability of high-glucose treated ARPE-19 cells. After the DR rat model was established, the effects of combined treatment on general indexes, retinal morphological changes, retinal Müller cells as well as PI3K/Akt/MTOR related factors of DR model rats were investigated.. The CCK-8 assay showed obviously enhanced protective efficacies of combination therapy with semaglutide and RSG on the ARPE-19 with oxidative stress induced by high-glucose with combination index all below 1.5 demonstrating obvious synergistic effects. Combined incubation could also effectively decrease the expression of inflammatory factors, including TNF-α, IL-1β, IL-6, and the increase of ROS content in ARPE cell culture supernatant induced by high-glucose. Combined use of the antioxidant, PI3K/Akt and mTOR inhibitors, we further demonstrated that combined incubation of semaglutide and RSG could effectively by reduce high glucose-induced inflammatory injury inhibiting ROS/PI3K/Akt/mTOR signaling. Furthermore, chronic combination treatment effectively improved the histopathological characteristics and down-regulated the GFAP expression in Müller cells as well as PI3K/Akt/MTOR signaling pathway-related factors in retina which was better than any monomer treatment group.. Combined semaglutide with RSG exhibited synergistically protective efficacies on retinal cells by decreasing the GFAP expression, inhibiting oxidative stress and PI3K/Akt/MTOR signaling-transduction in DR model rats.

Topics: Animals; Antioxidants; Cell Line; Cell Survival; Diabetic Retinopathy; Disease Models, Animal; Drug Therapy, Combination; Ependymoglial Cells; Glial Fibrillary Acidic Protein; Glucagon-Like Peptides; Humans; Inflammation; Male; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Rosiglitazone; Signal Transduction; TOR Serine-Threonine Kinases

Topics: Adverse Drug Reaction Reporting Systems; Diabetic Retinopathy; Drug-Related Side Effects and Adverse Reactions; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; United States; United States Food and Drug Administration

Topics: Acute Kidney Injury; Administration, Oral; Carcinoma, Neuroendocrine; Constipation; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dyspepsia; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Nausea; Pancreatitis; Thyroid Neoplasms; Vomiting

Topics: Adult; Arcuate Nucleus of Hypothalamus; Binge-Eating Disorder; Craniopharyngioma; Diabetes Insipidus; Diabetes Mellitus; Diabetic Retinopathy; Disorders of Excessive Somnolence; Drug Therapy, Combination; Female; Glucagon-Like Peptides; Hormone Replacement Therapy; Humans; Hypoglycemic Agents; Hypophysectomy; Hypopituitarism; Immunoglobulin Fc Fragments; Obesity; Pituitary Neoplasms; Postoperative Complications; Recombinant Fusion Proteins; Reoperation