oxyntomodulin and Pancreatitis

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

Glucagon-like peptide-1 receptor agonist (GLP-1RAs) labels warn about acute pancreatitis (AP) and impose upon doctors the obligation to inform patients about symptoms of AP. Here we systematically reviewed the risk of AP in randomized placebo-controlled trials (RCTs) investigating the effect of GLP-1RAs in type 2 diabetes. We performed a systematic review with meta-analysis of long-term (minimum 24 months), placebo-controlled GLP-1RA RCTs in which AP was a predefined adverse event and adjudicated by blinded and independent adjudicating committees. Three high-quality RCTs included a total of 9347 GLP-1RA-treated and 9353 placebo-treated patients with type 2 diabetes. Compared to placebo, treatment with GLP1-RA was not associated with increased risk of AP (Peto odds ratio 0.745 [95% CI, 0.47-1.17]). Trial Sequential Analysis suggested that additional evidence is needed. In conclusion, this review found no evidence that treatment with GLP-1RA increases the risk of AP in patients with type 2 diabetes.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Odds Ratio; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Risk Factors

Glucagon-like peptide 1 receptor (GLP-1R) agonists provide good glycemic control combined with low hypoglycemia risk and weight loss. Here, we summarize the recently published data for this therapy class, focusing on sustainability of action, use in combination with basal insulin, and the efficacy of longer acting agents currently in development. The safety profile of GLP-1R agonists is also examined.. GLP-1R agonists provide sustained efficacy and their combination with basal insulin is well tolerated, providing additional glycemic control and weight benefits compared with basal insulin alone. Data suggest that the convenience of longer acting agents may be at the expense of efficacy. Despite the initial concerns, most evidence indicates that GLP-1R agonists do not increase the risk of pancreatitis or thyroid cancer. However, the extremely low incidence of these events means further investigations are required before a causal link can be eliminated. Large-scale clinical trials investigating the long-term cardiovascular safety of this therapy class are ongoing and may also provide important insights into pancreatic and thyroid safety.. GLP-1R agonists offer sustained glycemic efficacy, weight loss benefits, and a low risk of hypoglycemia. The results of ongoing trials should help to clarify the safety of this therapy class.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Male; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Thyroid Neoplasms; Treatment Outcome; Venoms

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Diabetes Mellitus; Gastric Acid; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Insulin; Pancreatitis; Pepsin A; Peptide Fragments; Peptides; Proinsulin; Radioimmunoassay; Salivation; Splanchnic Circulation

Topics: Antigens; Chemical Phenomena; Chemistry; Diabetes Mellitus; Dumping Syndrome; Gastrectomy; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Intestine, Small; Obesity; Pancreatitis; Peptides; Radioimmunoassay; Vagotomy

The effects of incretin therapies on pancreatic safety are currently being evaluated. In 3 phase 3 clinical studies of once weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D), symptoms suggestive of acute pancreatitis as well as pancreatic enzymes were assessed and the risk of acute pancreatitis was evaluated. Patients who met any of the predefined criteria (clinical signs/symptoms of acute pancreatitis, confirmed amylase or lipase level ≥3 times the upper limit of normal [ULN], abdominal imaging of the pancreas) were adjudicated for acute pancreatitis by a blinded external committee. A total of 43 events in 40 patients (dulaglutide, 35/917 patients; liraglutide, 2/137 patients; insulin glargine, 2/180 patients; and placebo, 2/70 patients) were adjudicated (1 patient had events adjudicated during both placebo and dulaglutide treatment); 2 patients treated with dulaglutide had acute pancreatitis confirmed (2/917 [0.2%]; 2.651 patients/1,000 patient-years). One of these patients was diagnosed by the investigator with acute pancreatitis related to dulaglutide, but there was no typical abdominal pain. The event in the other patient occurred following an endoscopic ultrasound-guided fine needle aspiration. Transient increases in lipase ≥3×ULN were observed in 2% of patients in both the dulaglutide and liraglutide groups; the incidence in dulaglutide-treated patients was not significantly different from the incidences in liraglutide, placebo-, or insulin glargine-treated patients. Results of systematic assessments of pancreatic safety in 3 phase 3 studies for up to 52 weeks do not suggest an increased risk of acute pancreatitis in Japanese patients treated with dulaglutide.

Topics: Acute Disease; Adult; Aged; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Japan; Male; Middle Aged; Pancreas; Pancreatitis; Recombinant Fusion Proteins

The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2 diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index < 25 kg/m(2)); 3) patients with latent autoimmune diabetes in adults; 4) diabetic patients with mutations in the HNF-1alpha gene [maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min) plasma insulin response tended to be enhanced by both GIP and GLP-1, compared with glucose alone, in all five groups. In contrast, the late-phase (20-120 min) plasma insulin response to GIP was attenuated, compared with the plasma insulin response to GLP-1, in all five groups. Significantly higher glucose infusion rates were required during the late phase of the GLP-1 stimulation, compared with the GIP stimulation. In conclusion, lack of GIP amplification of the late-phase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Male; Middle Aged; Neurotransmitter Agents; Nuclear Proteins; Pancreatitis; Peptide Fragments; Phenotype; Protein Precursors; Transcription Factors

Diabetes mellitus secondary to chronic pancreatitis is characterized by a progressive destruction of the pancreas, including loss of the islet cells, leading to a form of diabetes that can mimic both type 1 and type 2 diabetes. Glucagon-like peptide 1(7-36)amide (GLP-1), an intestinally derived insulinotropic hormone, represents a potential therapeutic agent for type 2 diabetes, because exogenous GLP-1 has been shown to increase the insulin and reduce the glucagon concentrations in these patients, and thus induce lower blood glucose, but without causing hypoglycemia. Ten patients with diabetes mellitus secondary to chronic pancreatitis and five normal subjects were studied. Nine patients were treated with insulin and one patient with sulfonylurea. In the fasting state, saline or GLP-1 in doses of 0.4 or 1.2 pmol/min/kg body weight were infused intravenously for 4 hours. Blood glucose was reduced in all patients with both doses of GLP-1; plasma C-peptide increased (p<0.02), and plasma glucagon decreased (p<0.02) compared with basal levels, also in three patients with normoglycemia and high levels of presumably exogenous insulin. Similar results were obtained in the normal subjects. In conclusion, GLP-1 treatment may be considered in patients with diabetes mellitus secondary to chronic pancreatitis, provided that a certain amount of alpha- and beta-cell secretory capacity is still present.

Topics: Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Middle Aged; Pancreatitis; Peptide Fragments

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: 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

To assess the risk of acute pancreatitis during treatment with glucagon-like peptide 1 receptor agonist dulaglutide, placebo, and active comparators across phase 2/3 dulaglutide trials.. A total of 6,005 patients with type 2 diabetes participated (dulaglutide group. The exposure-adjusted incidence rate of acute pancreatitis in dulaglutide-treated patients was similar to the rates with placebo, with few reported cases during the entire program.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin Glargine; Male; Metformin; Middle Aged; Pancreatitis; Peptides; Recombinant Fusion Proteins; Sitagliptin Phosphate; Venoms

To study GIP and insulin release after a test meal in patients with chronic pancreatitis with and without secondary diabetes mellitus.. 28 patients with chronic pancreatitis were classified in groups I and II according to the presence or absence of secondary diabetes mellitus. Twelve healthy subjects were included as controls. After a test meal plasma GIP levels and serum insulin levels were determined at 0, 30, 60, 120 and 180 min.. A significant diminished GIP response was found in the groups of patients with respect to the control group. No association could be detected with severity of pancreatic insufficiency. Higher values of GIP were demonstrated at 60 and 120 min in patients without diabetes than in patients with it.. An abnormal GIP response is present in cases of chronic pancreatitis irrespective of the presence or severity of pancreatic insufficiency. This response is further affected if secondary diabetes mellitus is present.

Topics: Adult; Age Factors; Diabetes Mellitus; Digestion; Exocrine Pancreatic Insufficiency; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Pancreatitis; Peptide Fragments; Postprandial Period; Sex Factors

A disturbed intraduodenal milieu and pancreatic scarring in advanced chronic pancreatitis (CP) may lead to changes of gut and pancreatic hormones. In the present study, the gastroduodenal mucosal content of several regulatory peptides was determined in 8 patients with severe calcific CP and 8 healthy volunteers. In addition, hormone release into the bloodstream was estimated after intraduodenal acid/glucose stimulation in the control subjects and 8 CP patients each with or without secondary diabetes mellitus (DM), and in 8 patients with juvenile DM, so that disturbed gut hormone release could be attributed either to CP or DM. While VIP release into the circulation was similar in all participants, mucosal levels of VIP and substance P were significantly elevated in the duodenal bulb and descending duodenum of CP patients. The somatostatin content of gastroduodenal mucosa in CP was at least as high as in normals. Gastrin was significantly more abundant only in the duodenal bulb of CP patients, while plasma gastrin was normal. Duodenal CCK concentrations tended to be elevated in the duodenal bulb, but not significantly. The release of secretin seemed to be higher in type-1 diabetics than in CP patients. The mucosal pattern of GIP was nearly identical in CP patients and controls. Compatible with this finding, the GIP release did not show any peculiarities in CP with or without DM or in DM. Basal and stimulated plasma levels of motilin were abnormally high in CP. Pancreatic polypeptide plasma levels were normal in DM, but significantly reduced in CP, especially in CP with DM. Fasting PP and stimulated pancreatic enzyme outputs were linearly related.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Chronic Disease; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Male; Middle Aged; Motilin; Neurotensin; Pancreatic Polypeptide; Pancreatitis; Secretin; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Pancreatic and gut hormones have been measured in 39 patients with chronic pancreatitis, 16 of whom had severe pancreatic insufficiency. Patients with pancreatic insufficiency had significantly diminished fasting levels and postprandial rises of pancreatic polypeptide which were less than 20% of normal. Patients with chronic pancreatitis, with or without exocrine insufficiency, had two- to threefold higher plasma levels of motilin and enteroglucagon than controls. Plasma levels of insulin, pancreatic glucagon, gastric inhibitory polypeptide and gastrin were similar to normal in these patients. The pattern of response of these hormones to a test breakfast differs markedly from those seen in other gut disease states and may reflect pathophysiological mechanisms.

Topics: Adult; Blood Glucose; Chronic Disease; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Motilin; Pancreatic Hormones; Pancreatic Polypeptide; Pancreatitis

Pancreatic-type glucagon (PTG) has been found in the plasma of totally pancreatectomized human beings. Arginine infusion, however, caused no increase in PTG. Pancreas-resected patients had a normal response of PTG to arginine and a subnormal increase in C peptide. Gut glucagon-like immunoreactants (gut GLI) were increased in resected patients and further increased in totally pancreatectomized patients. Gut GLI showed no change during arginine stimulation.

Topics: Adult; Aged; Arginine; C-Peptide; Chronic Disease; Female; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Pancreas; Pancreatectomy; Pancreatitis; Peptides; Radioimmunoassay

Plasma insulin, pancreatic glucagon and immunoreactive glucagon-like polypeptide of intestinal origin (enteroglucagon) have been measured in 10 patients with chronic pancreatitis and 5 normal subjects. Basal levels and changes following oral glucose (50 g) and an intravenous infusion of arginine (25 g in 30 min) have been studied. In patients with chronic pancreatitis the plasma insulin response to oral glucose and intravenous arginine was reduced. Basal pancreatic glucagon was increased in the patients and increased further with oral glucose. During an arginine infusion the pancreatic glucagon showed a brisk early increase greater than that seen in the normal subjects. Basal enteroglucagon levels were significantly increased in chronic pancreatitis but response to orla glucose and arginine infusion were little different from those seen in the normal subjects.

Topics: Adult; Arginine; Chronic Disease; Female; Glucagon; Glucagon-Like Peptides; Glucose Tolerance Test; Humans; Infusions, Parenteral; Insulin; Islets of Langerhans; Male; Middle Aged; Pancreatitis