Treatment intensification in patients with inadequate glycemic control on basal insulin: rationale and clinical evidence for the use of short‐acting and other glucagon‐like peptide‐1 receptor agonists (original) (raw)
Related papers
An Update in Incretin-Based Therapy: A Focus on Glucagon-Like Peptide-1 Receptor Agonists
Diabetes Technology & Therapeutics, 2012
The glucagon-like peptide-1 receptor agonists, exenatide and liraglutide, offer a unique mechanism in the treatment of type 2 diabetes mellitus (T2DM) as part of the incretin system. Their mechanism of action is to increase insulin secretion, decrease glucagon release, reduce food intake, and slow gastric emptying. They target postprandial blood glucose values and have some effect on fasting levels as well. In addition, they promote weight loss and may help to preserve b-cell function, both major problems in T2DM patients. Changes in hemoglobin A1c are similar to those produced by other T2DM agents, including thiazolidinediones, low-dose metformin, and sulfonylureas, and better than those caused by a-reductase inhibitors and dipeptidyl peptidase-4 inhibitors. These agents have been safely studied in combination with metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin therapy. Overall, data are limited for head-to-head comparisons, but it appears that liraglutide may have better efficacy and tolerability compared with exenatide; however, more studies are needed. They are overall well tolerated, with the main adverse events being similar to those with metformin (gastrointestinal intolerances that are transient and dose dependent). However, patients must be monitored for pancreatitis as a rare but possible side effect. For T2DM patients willing to use an injectable agent, exenatide and liraglutide offer another therapeutic option to control hyperglycemia with the potential for weight loss and may be combined with other agents safely.
European Journal of Endocrinology, 2008
Type 2 diabetes mellitus is associated with progressive decreases in pancreatic b-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet aand b-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve b-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.
Therapeutics and Clinical Risk Management
Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Although the short duration of action of GLP-1 renders it unsuited to therapeutic use, 2 long-acting GLP-1 receptor agonists, exenatide and liraglutide, represent a significant advance in treatment. In controlled trials, both produce short-term glucose-lowering effects, with the reduction in hemoglobin A(1c) of up to 1.3%. These responses are often superior to those observed with additional oral agents. However, unlike sulfonylureas, thiazolidinediones, or insulin, all of which lead to significant weight gain, GLP-1 receptor agonists uniquely result in long-term weight loss of around 5 kg, and higher doses may enhance this further. Reduction in blood pressure of 2-7 mm Hg also has been observed. Both drugs produce transient mild gastrointestinal side effects; although mild hypoglycemia can occur...
Exenatide, a GLP-1 agonist in the treatment of Type 2 diabetes
Expert Review of Endocrinology & Metabolism, 2012
Incretin-based therapies represent a new and innovative treatment modality in the management of Type 2 diabetes. Their therapeutic actions address many of the key metabolic defects in the pathophysiology of diabetes. Incretin hormones augment insulin secretion in a glucosedependent manner. They have a low risk of inducing hypoglycemia, unlike many other antidiabetic medications. They also have the beneficial effect of being associated with early satiety, decreased caloric intake and weight loss. Exenatide was the first incretin-based therapy to be licensed for use and has now been developed in a once-weekly preparation. We review the evidence base for the use of exenatide and discuss the implications for the management of diabetes.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well established as effective treatments for patients with type 2 diabetes. GLP-1 RAs augment insulin secretion and suppress gluca-gon release via the stimulation of GLP-1 receptors. Although all GLP-1 RAs share the same underlying mechanism of action, they differ in terms of formulations, administration, injection devices and dosages. With six GLP-1 RAs currently available in Europe (namely, immediate release exenatide, lixisenatide, liraglutide; prolonged-release exenatide, dulaglutide and semaglutide), each with its own characteristics and administration requirements, physicians caring for patients in their routine practice face the challenge of being cognizant of all this information so they are able to select the agent that is most suitable for their patient and use it in an efficient and optimal way. The objective of this review is to bring together practical information on the use of these GLP-1 RAs that reflects their approved use.
The Journal of family practice, 2018
Editorial support was provided by Gregory Scott, PharmD, RPh. The author was responsible for all content and editorial decisions. SUPPORT This article is sponsored by Primary Care Education Consortium and supported by funding from Sanofi US. like peptide-1 receptor agonist (GLP-1RA) took an average 4.3 years and happened in 31% of eligible patients. 7 In patients treated with basal insulin, markers indicating the need to consider additional therapy include (1) an elevated A1c and persistent postprandial hyperglycemia despite a normal or near-normal fasting plasma glucose (FPG) concentration; (2) a total daily dose of basal insulin >0.5 units/kg; (3) severe, nocturnal, or frequent symptomatic hypoglycemia; and (4) persistent difference between bedtime and before-breakfast blood glucose >55 mg/dL. 8,9 An even lower total daily dose of basal insulin as a marker for dose intensification has been suggested by a post hoc analysis of 3 insulin glargine titration studies of at least 24 weeks' duration (N=458). 10 The analysis found that reduction in the FPG begins to slow at ~0.3 units/kg, leveling at ~0.5 units/kg. These findings are a concern and emphasize the importance of staying ahead of this progressive disease through timely, individualized treatment intensification. Recommendations for intensifying glycemic control over time vary between the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE), although both recommend using a patient-centric approach to treatment and intensifying every 2 to 3 months. 8,11 The 2018 ADA/ EASD guideline recommends a sequential approach to treatment, generally beginning with metformin monotherapy. 8 If the A1c target is not achieved after 3 months of metformin monotherapy, and adherence is assured, treatment should be intensified based on patient factors, including cardiovascular risk. Options include sodium-glucose cotransporter-2 inhibitors (SGLT-2is), GLP-1RAs, dipeptidyl peptidase-4 inhibitors (DPP-4is), thiazolidinediones (TZDs), sulfonylureas, and basal insulin. For patients with A1c ≥10%, blood glucose ≥300 mg/dL, or markedly symptomatic, combination injectable therapy (basal insulin in combination with a GLP-1RA or prandial insulin) should be considered. In contrast, the 2018 AACE/ACE guideline stratifies therapy based on A1c (<7.5%, 7.5%-9%, >9%). 11 The AACE/ ACE guideline recommends the following hierarchy of usage S49
Diabetes care, 2014
Mealtime insulin is commonly added to manage hyperglycemia in type 2 diabetes when basal insulin is insufficient. However, this complex regimen is associated with weight gain and hypoglycemia. This study compared the efficacy and safety of exenatide twice daily or mealtime insulin lispro in patients inadequately controlled by insulin glargine and metformin despite up-titration. In this 30-week, open-label, multicenter, randomized, noninferiority trial with 12 weeks prior insulin optimization, 627 patients with insufficient postoptimization glycated hemoglobin A1c (HbA1c) were randomized to exenatide (10-20 µg/day) or thrice-daily mealtime lispro titrated to premeal glucose of 5.6-6.0 mmol/L, both added to insulin glargine (mean 61 units/day at randomization) and metformin (mean 2,000 mg/day). Randomization HbA1c and fasting glucose (FG) were 8.3% (67 mmol/mol) and 7.1 mmol/L for exenatide and 8.2% (66 mmol/mol) and 7.1 mmol/L for lispro. At 30 weeks postrandomization, mean HbA1c cha...
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 2012
The prevalence of obesity and diabetes continues to rise in the US. Glucagon-like peptide-1 receptor agonist (GLP-1RA) is an effective treatment option for type 2 diabetes mellitus (T2DM) that promotes weight loss. Common and effective treatment options added to metformin therapy (basal insulin, sulfonylureas, and pioglitazone) contribute to weight gain, which makes the addition of GLP-1RAs advantageous. Exenatide was the first agent in this class and has recently been approved for use in combination with insulin glargine by the US Food and Drug Administration and the European Medicines Agency. Until recently, there was a lack of data examining basal insulin combined with these agents. The main purpose of this article is to review the prospective interventional data on the safety and efficacy of GLP-1RAs (exenatide, liraglutide, albiglutide, lixisenatide) combined with basal insulin therapy in nonpregnant adults with T2DM. Databases searched were PubMed, Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews (inception to January 2012). Abstracts presented at relevant diabetes and endocrine meetings from 2009 to 2011 were also reviewed, as were reference lists of identified publications. A total of five studies met the criteria and were included in the review. Data from these studies demonstrated that this combination therapy offers advantages for the treatment of diabetes, such as additional lowering of A1c without major risk for hypoglycemia, lower basal insulin requirements, decreased postprandial glucose levels (with or without fasting plasma glucose decreases), and weight loss, or at the very least, less weight gain. However, the gastrointestinal side effects and high cost of these agents may limit their use. This review demonstrates that adding a GLP-1RA to an existing basal insulin regimen is a reasonable treatment strategy in nonpregnant adult patients with T2DM.