incretins and Vomiting

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a new class of drugs used in the treatment of type 2 diabetes mellitus (T2DM). Gastrointestinal (GI) adverse events (AEs) are the most frequently reported treatment-related AEs for GLP-1 RAs. We aim to evaluate the effect of GLP-1 RAs on the incidence of GI AEs of T2DM.. The overview of the GI events of GLP-1 RAs has been performed on relevant publications through the literature search, such as MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov The manufacturer was contacted regarding unpublished data. We analyzed direct and indirect comparisons of different treatments using Bayesian network meta-analysis.. Taspoglutide 30 mg once weekly (TAS30QW) and lixisenatide 30 μg twice daily (LIX30BID) were ranked the top two drugs in terms of GI AEs versus placebo. The odds ratios of nausea and vomiting for TAS30QW were 11.8 (95% confidence interval [CI], 2.89, 46.9) and 51.7 (95% CI, 7.07, 415), respectively, and that of diarrhea was 4.93 (95% CI, 1.75, 14.7) for LIX30BID.. Our study found all GLP-1 RA dose regimens significantly increased the incidence of GI AEs, compared with placebo or conventional treatment. The occurrence of GI AEs was different with diverse dose regimens of GLP-1 RAs. TAS30QW had the maximum probability to occur nausea and vomiting, whereas LIX30BID had the maximum probability to cause development of diarrhea versus other treatments.

Topics: Diabetes Mellitus, Type 2; Diarrhea; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Middle Aged; Nausea; Peptides; Receptors, Glucagon; Vomiting

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer.

Topics: Animals; Antibody Formation; Blood Pressure; Carcinoma, Medullary; Cardiotonic Agents; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Gastrointestinal Motility; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Lipids; Meta-Analysis as Topic; Nausea; Pancreatitis; Receptors, Glucagon; Rodentia; Species Specificity; Thyroid Neoplasms; Vomiting

Although several classes of pharmacotherapy are available for type 2 diabetes, glycaemic control is often hampered by medication-related adverse effects and contraindications such as renal impairment. Glucagon-like peptide-1 (GLP-1) receptor agonists provide a new pharmacotherapeutic option based on the multiple glucose-lowering effects of the human hormone GLP-1. This mechanism of action not only provides therapeutic efficacy but also suggests that GLP-1 receptor agonists have distinct safety and tolerability concerns compared with other diabetes therapies. Stimulation of pancreatic insulin secretion by GLP-1 receptor agonists is glucose dependent, conferring a lesser risk of hypoglycaemia than that seen with sulfonylureas. Individual GLP-1 receptor agonists differ in their metabolism and excretion profiles, affecting the choice of agent for patients with renal impairment. As with other protein-based therapies, GLP-1 receptor agonists may induce the formation of antibodies that may attenuate therapeutic efficacy and affect safety. Conclusions on cardiovascular safety must await outcomes studies, but at present no signal of harm has been reported, and preclinical data and effects on risk markers suggest a potential for benefit. Current data on thyroid medullary cancer in humans and pancreatic malignancy in rodents do not suggest that there is any reason to restrict the clinical use of GLP-1 analogues in most people with diabetes. It is currently difficult to ascertain the possible contributory role of GLP-1 receptor agonists in increasing the risk of pancreatitis, and vigilance for signs and symptoms is prudent. Primary tolerability issues include transient gastrointestinal symptoms, common with GLP-1 receptor agonists, which can be reduced through dose titration.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Incretins; Liraglutide; Nausea; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Thyroid Gland; Venoms; Vomiting

Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.. To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.. Review of Phase III clinical trials based on Medline search published up to April 2008.. The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.. Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.

Topics: Adamantane; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nausea; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Vomiting

A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).. LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.. LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.. Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

Topics: Adult; Animals; Appetite; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diarrhea; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Male; Mice; Mice, Inbred C57BL; Middle Aged; Receptors, Gastrointestinal Hormone; Vomiting

Gastrointestinal (GI) adverse events (AEs) are the most frequently reported treatment-related AEs associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of type 2 diabetes mellitus. The GI safety of albiglutide, a once-weekly GLP-1RA, was assessed using data from five phase III studies. In a pooled analysis of four placebo-controlled trials, the most common GI AEs were diarrhoea (albiglutide, 14.5% vs. placebo, 11.5%) and nausea (albiglutide, 11.9% vs. placebo, 10.3%), with most patients experiencing 1-2 events. The majority were mild or moderate in intensity and their median duration was 3-4 days. Vomiting occurred in 4.9% of patients in the albiglutide vs. 2.6% in the placebo group. For both albiglutide and placebo, serious GI AEs (2.0% vs. 1.5%) and withdrawals attributable to GI AEs (1.7% vs. 1.5%) were low. In a 32-week trial of albiglutide 50 mg weekly versus liraglutide 1.8 mg daily, nausea occurred in 9.9% of patients in the albiglutide group vs. 29.2% in the liraglutide group. Vomiting occurred in 5.0% in the albiglutide vs. 9.3% in the liraglutide group. In conclusion, albiglutide has an acceptable GI tolerability profile, with nausea and vomiting rates slightly higher than those for placebo but lower than those for liraglutide.

Topics: Abdominal Pain; Clinical Trials, Phase III as Topic; Constipation; Diabetes Mellitus, Type 2; Diarrhea; Gastroesophageal Reflux; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Humans; Incretins; Nausea; Severity of Illness Index; Vomiting

Topics: Acute Disease; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incidence; Incretins; Nausea; Pancreatitis; Receptors, Glucagon; Treatment Outcome; United States; Vomiting

Topics: Anti-Obesity Agents; Female; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Male; Nausea; Obesity; Treatment Outcome; Vomiting; Weight Loss