Reductions in SBP were also observed across the trials (mean decrease −2.1 to −6.7 mmHg) (27–32). How they work: GLP-1 is a hormone produced in the small intestine that stimulates insulin secretion and inhibits glucagon secretion, thereby lowering blood sugar. Their effect on insulin and glucagon levels has recently been studied but is not fully explained. The most common adverse effects seen with exenatide LAR versus twice-daily exenatide were nausea (26.4 vs. 34.5%, respectively) and injection site pruritus (17.6 vs. 1.4%, respectively). Summary of efficacy and tolerability with long-acting GLP-1 receptor agonists. While some recent studies have not found that these drugs can cause either pancreatitis or cancer,[5] a 2017 study found that recent prescription of incretins was associated with an increased risk of pancreatic cancer over non-insulin anti diabetic drugs (NIADs). This drug article relating to the gastrointestinal system is a stub. Our Drug Interaction Checker provides rapid access to tens of thousands of interactions between brand and generic drugs, over-the-counter drugs, and supplements. Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. Thus, long-acting GLP-1 receptor agonists may provide an effective therapeutic option for individuals with type 2 diabetes and are well placed to meet the standard of care guidelines set by the ADA in treating more than just blood glucose. SGLT-2 inhibitors block reabsorption of glucose in the kidneys, leading to excretion of glucose in urine. 2). In addition, fasting plasma glucose significantly decreased with liraglutide treatment (−1.61 mmol/L with liraglutide vs. −0.60 mmol/L with exenatide; P < 0.0001). Clinical data have revealed that these therapies improve glycemic control while reducing body weight (GLP-1 receptor agonists, specifically) and systolic blood pressure (SBP) in patients with type 2 diabetes. As seen in the original DURATION (Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly) -1 study, incidence of hypoglycemia was low and limited to patients who received exenatide in combination with a sulfonylurea. Reduction in A1C was significantly greater with exenatide LAR versus twice-daily exenatide (−1.9 vs. −1.5%, respectively; P = 0.0023), and a significantly greater proportion of subjects reached the A1C target of ≤7.0% with exenatide LAR versus twice-daily exenatide (77 vs. 61%, respectively; P = 0.0039) (Supplementary Fig. SGLT-2 inhibitors are a new class of drugs for Type 2 diabetes with novel mechanism of action. The fungal bisanthroquinone skyrin, isolated from Talaromyces wortmannin, inhibits glucagon -stimulated cAMP formation and glucose output from rat and human hepatocytes. Victoza summary of product characteristics [Internet]. This section provides an indirect comparison of the clinical trial results achieved with long-acting GLP-1 receptor agonists to date. Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists or incretin mimetics, are agonists of the GLP-1 receptor. At the time of writing, Roche had suspended the development of taspoglutide, currently in phase 3 trials, because of the high discontinuation rates as a result of gastrointestinal tolerability and serious hypersensitivity reactions (33). Skyrin does not appear to interfere with glucagon receptor binding in CHO cells or hepatocytes. Data from the LEAD trials have demonstrated that liraglutide effectively improves glycemic control (up to a 1.5% decrease in A1C) in individuals with type 2 diabetes, when used as monotherapy or in combination with one or more selected oral antidiabetic drugs. Furthermore, a smaller proportion of patients reported nausea or vomiting after liraglutide treatment compared with patients treated with exenatide (25.5% of the study population vs. 28% with twice-daily exenatide; vomiting: 6.0% of the study population vs. 9.9% with twice-daily exenatide) (32). Results with exenatide LAR demonstrated that these improvements in A1C could be maintained after 2 years (mean A1C decrease at 2 years: −1.8%) (36). Another class of medications associated with weight loss and improved blood sugar control is the sodium glucose cotransporter 2 (SGLT-2) inhibitors. [6], As of 2017 it was unclear if they affect a person's risk of death. Change in A1C with long-acting GLP-1 receptor agonists across the clinical trials (24,32,36–39,41). Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. The sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of glucose-lowering drugs which act by inhibiting the reabsorption of filtered glucose from the kidneys. Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists or incretin mimetics, are agonists of the GLP-1 receptor. "Glucagon-like Peptide-1 Analogs Other Than Exenatide", "The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca2+ signalling in steatotic hepatocytes", "Standards of medical care in diabetes—2012", "Incretin Meds Like Januvia and Victoza Again Linked to Pancreatic Cancer", "Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis", "Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes", "FDA Approves New Treatment for Type 2 Diabetes", "FDA approves Adlyxin to treat type 2 diabetes", "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide", "FDA Approves Weekly Injectable Diabetes Drug: Dulaglutide", Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes. In particular, incretin-based therapies (GLP-1 receptor agonists, specifically) can help meet these new targets by offering weight reduction, blood pressure reduction, and reduced hypoglycemia in addition to glycemic control. Glucagon prompts gluconeogenesis and glucose efflux from the liver. Indeed, guidelines have been developed that support the consensus that blood pressure, weight reduction, and avoidance of hypoglycemic events should be targeted in type 2 diabetes management alongside glycemic targets. [8], These agents work by activating the GLP-1R, rather than inhibiting the breakdown of GLP-1 as do DPP-4 inhibitors, and are generally considered more potent.[14]. As a result, a greater proportion of patients with type 2 diabetes reached the ADA A1C target (≤7.0%) (3) with liraglutide compared with exenatide (54 vs. 43%; P = 0.0015) (32). Check mild interactions to serious contraindications for up to 30 drugs, herbals, and supplements at a time. Insulin binding to its receptor promotes glucose disposal in peripheral tissues and suppresses hepatic glucose output. Results from this trial revealed that liraglutide provided a significantly greater reduction in mean A1C compared with exenatide (−1.12 vs. −0.79%; P < 0.0001) (Supplementary Fig. Greater reductions in A1C were seen with liraglutide compared with the DPP-4 inhibitor sitagliptin (mean A1C decrease: −1.50 and −1.24% with 1.8 and 1.2 mg liraglutide, respectively, vs. −0.90% with sitagliptin; P < 0.0001) (37). The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization … These side effects occur early on in the treatment, but tend to be transient and rarely result in patient withdrawal (24,32,36–39,41). Available from, Bergenstal R, Wysham C, Yan P, Macconell L, Malloy J, Porter L. DURATION-2: exenatide once weekly demonstrated superior glycaemic control and weight reduction compared to sitagliptin or pioglitazone after 26 weeks of treatment. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a group of drugs used to treat type 2 diabetes. Drug Drug Description; Glucagon: A form of recombinant glucagon used to treat hypoglycemia in diabetes mellitus and as a part of gastrointestinal imaging procedures. Furthermore, exenatide LAR provided better glycemic control than exenatide with comparable weight loss. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. A number of phase 3 head-to-head trials have been conducted investigating the efficacy and tolerability of long- versus short-acting GLP-1 receptor agonists, results of which are briefly described here. Indeed, in a 6-week study investigating continuous GLP-1 infusion, patients with type 2 diabetes achieved a significant weight loss of 1.9 kg and a reduction in appetite from baseline compared with patients receiving placebo, where there was no significant change in weight or appetite (11). Indeed, the summary of product characteristics for exenatide states that when exenatide is used in combination with a sulfonylurea, consideration should be given to reducing the sulfonylurea dose to reduce the risk of hypoglycemia (17). 17 Furthermore, pasireotide has been shown to reduce glucagon secretion from pancreatic α‐cells. DPP-4 inhibitors, also known as gliptins, are a class of drug which help to stimulate the production of insulin and reduce the production of glucagon, particularly during digestion. Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. Individuals switching from twice-daily exenatide to exenatide LAR displayed further improvements in glycemic control, achieving the same reduction in A1C from baseline (−2.0% at week 52) as subjects who had been treated only by exenatide LAR. Writing assistance was provided by Watermeadow Medical, funded by Novo Nordisk A/S. Exenatide, an exendin-4 mimetic with 53% sequence identity to native GLP-1, is currently approved for the treatment of type 2 diabetes as monotherapy (in the U.S.) (19) and in combination with metformin ± sulfonylurea (17). Because this is impractical as a therapeutic option for type 2 diabetes, it was necessary to develop longer-acting derivatives of GLP-1. Two drug classes have been developed: glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors. Following a switch to liraglutide after 26 weeks, patients previously treated with exenatide still exhibited anti-exenatide antibodies after treatment weeks 40 (49.7%) and 78 (17.5%). Short- and long-acting GLP-1 receptor agonists. **P < 0.001; ***P < 0.0001. The rate of minor hypoglycemia was very low in these trials (incidence ranged from 0.03 to 0.6 events/patient/year with the different treatment groups [excluding those using liraglutide in combination with a sulfonylurea]). Overall, at least 50% of patients reached an A1C target of <7.0% with the long-acting GLP-1 receptor agonists (31,33,36,37,39,40); results varied from 52% after 16 weeks of treatment with albiglutide (38) to 81% after 8 weeks of taspoglutide treatment (39). GLP-1 has multiple physiological effects that make it an attractive candidate for type 2 diabetes therapy. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. Byetta summary of product characteristics: US [Internet]. © 2021 by the American Diabetes Association. The results achieved with long-acting GLP-1 receptor agonists appear to be superior to those achieved with short-acting GLP-1 receptor agonists, with greater improvements in glycemic control after once-daily liraglutide treatment compared with twice-daily exenatide. Available from, Amylin/Eli Lilly. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. [7] A JAMA article meta-analysis in 2018 (covering studies concerning GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors) showed GLP-1 agonists were associated with lower stroke risk than controls. Further benefits of liraglutide treatment included a reduced number of hypoglycemic events and higher overall treatment satisfaction. In particular, antidiabetic agents that offer improved glycemic control without increasing cardiovascular risk factors or rates of hypoglycemia are warranted. Furthermore, incidence of hypoglycemia is relatively low with these treatments (except when used in combination with a sulfonylurea) because of their glucose-dependent mechanism of action. In this review, we focus on the GLP-1 receptor agonist class of incretin-based therapies. The incretin effect, responsible for 50–70% of total insulin secretion after oral glucose administration, is defined as the difference in insulin secretory response from an oral glucose load compared with intravenous glucose administration (6) (Supplementary Fig. GlucaGen se presenta en un vial con glucagón, polvo blanco y estéril, con una jeringa desechable que contiene el disolvente. Clinical trial results have demonstrated that exenatide, when used in combination with selected oral antidiabetic drugs, effectively reduces A1C by −0.4 to −1.5% in patients with type 2 diabetes inadequately controlled on metformin with or without a sulfonylurea (20–24). As reported previously, the greatest proportion of patients reporting minor hypoglycemic events was when adding treatments to a sulfonylurea background (24,27,31,32). Abstract 6-LB presented at the American Diabetes Association 2009 Scientific Sessions, 5–9 June 2009, New Orleans, Louisiana, Sign In to Email Alerts with your Email Address. Careful consideration should be given to the selection of therapies for managing type 2 diabetes. 2). Change in body weight with long-acting GLP-1 receptor agonists across the clinical trials (24,32,36–39,41). Glucagon is available under the following different brand names: Glucagen, Glucagon Emergency Kit, and GlucaGen HypoKit. The glucagon receptor is a central target in novel and anticipated type 2 diabetes therapies, and hemodynamic consequences of glucagon signaling have therefore become increasingly important. The efficacy and tolerability of the DPP-4 inhibitors have been reviewed elsewhere (16). The addition of a C16 fatty acid side chain enables once-daily dosing of liraglutide by prolonging its duration of action to over 24 h. This protraction is achieved through reversible binding to albumin and increased stability through heptamer formation mediated by the fatty acid side chain (26). For the purposes of this review, we refer to “short-acting” GLP-1 receptor agonists as those agents having duration of action of <24 h and “long-acting” as those agents with duration of action >24 h (Table 1). Drug images are also included. In addition, a significantly greater reduction in fasting plasma glucose was observed with exenatide LAR versus twice-daily exenatide (−2.3 vs. −1.4 mmol/L for exenatide LAR and twice-daily exenatide, respectively; P < 0.0001). El polvo está compactado. Liraglutide shares 97% sequence identity with native GLP-1 and, across the LEAD trials, 8.6% of patients developed antiliraglutide antibodies (18); however, there were no indications from the clinical trial data that the formation of these antibodies affected efficacy (27–32,42). 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diabetes, Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes, Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients, Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor, Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats, Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects, Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on 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