exenatide and Drug-Related-Side-Effects-and-Adverse-Reactions

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

Topics: Diabetes Mellitus; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Venoms

We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.

Topics: Adverse Drug Reaction Reporting Systems; Aripiprazole; Chemical and Drug Induced Liver Injury; Data Mining; Databases, Factual; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Exenatide; Humans; Hypercalcemia; Ketolides; Pancreatitis; Peptides; Rhabdomyolysis; Rosuvastatin Calcium; Suicide; Teriparatide; Time Factors; United States; United States Food and Drug Administration; Varenicline; Venoms

In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry.. From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m(2), n = 22,015), and metabolic control (HbA(1c) ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21-26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27-40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9-1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0-1.5% with DPP-4 inhibitors.. In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials.

Topics: Adamantane; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Italy; Male; Metformin; Middle Aged; Monitoring, Physiologic; Nitriles; Peptides; Pyrazines; Pyrrolidines; Registries; Sex Factors; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Drugs are designed for therapy, but medication-related adverse events are common, and risk/benefit analysis is critical for determining clinical use. Rosiglitazone, an efficacious antidiabetic drug, is associated with increased myocardial infarctions (MIs), thus limiting its usage. Because diabetic patients are often prescribed multiple drugs, we searched for usage of a second drug ("drug B") in the Food and Drug Administration's Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone ("drug A")-associated MI. In FAERS, rosiglitazone usage is associated with increased occurrence of MI, but its combination with exenatide significantly reduces rosiglitazone-associated MI. Clinical data from the Mount Sinai Data Warehouse support the observations from FAERS. Analysis for confounding factors using logistic regression showed that they were not responsible for the observed effect. Using cell biological networks, we predicted that the mitigating effect of exenatide on rosiglitazone-associated MI could occur through clotting regulation. Data we obtained from the db/db mouse model agreed with the network prediction. To determine whether polypharmacology could generally be a basis for adverse event mitigation, we analyzed the FAERS database for other drug combinations wherein drug B reduced serious adverse events reported with drug A usage such as anaphylactic shock and suicidality. This analysis revealed 19,133 combinations that could be further studied. We conclude that this type of crowdsourced approach of using databases like FAERS can help to identify drugs that could potentially be repurposed for mitigation of serious adverse events.

Topics: Adverse Drug Reaction Reporting Systems; Animals; Blood Coagulation; Confounding Factors, Epidemiologic; Databases as Topic; Diabetes Mellitus, Experimental; Drug Combinations; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Exenatide; Heart Function Tests; Humans; Mice; Myocardial Infarction; Peptides; Plasminogen Activator Inhibitor 1; Rosiglitazone; Systems Biology; Thiazolidinediones; Thrombelastography; Ultrasonography; United States; United States Food and Drug Administration; Venoms

Topics: Amyloid; Analgesics; Anticonvulsants; Antiparkinson Agents; Diabetes Mellitus, Type 2; Diphtheria-Tetanus-Pertussis Vaccine; Drug Approval; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Exenatide; gamma-Aminobutyric Acid; Heart Failure; Humans; Hydralazine; Hypoglycemic Agents; Indenes; Indoles; Islet Amyloid Polypeptide; Isosorbide Dinitrate; Patient Education as Topic; Patient Selection; Peptides; Pregabalin; Sleep Wake Disorders; United States; United States Food and Drug Administration; Venoms

Topics: Acamprosate; Adenine Nucleotides; Alcohol Deterrents; Amyloid; Analgesics, Non-Narcotic; Anti-HIV Agents; Antifungal Agents; Antineoplastic Agents; Aptamers, Nucleotide; Arabinonucleosides; Azabicyclo Compounds; Benzofurans; Clofarabine; Drug Approval; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Exenatide; Fibroblast Growth Factor 7; Guanine; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Lipopeptides; Lipoproteins; Macular Degeneration; Micafungin; omega-Conotoxins; Patient Education as Topic; Peptides; Peptides, Cyclic; Piperazines; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Stomatitis; Taurine; Tetrahydroisoquinolines; Urinary Incontinence; Venoms