DIABETES TREATMENTS Long-Acting Glucagon-Like Peptide 1 Receptor Agonists A review of their efficacy and tolerability ALAN J. GARBER, MD, PHD administration, is defined as the differ- ence in insulin secretory response from an oral glucose load compared with intra- venous glucose administration (6) argeting the incretin system has be- factors or rates of hypoglycemia are war- (Supplementary Fig. 1). come an important therapeutic ap- ranted. At present, many available treat- There are two naturally occurring T incretin hormones that play a role in the proach for treating type 2 diabetes. ments for type 2 diabetes fail to maintain Two drug classes have been developed: glycemic control in the longer term be- maintenance of glycemic control: glucose- glucagon-like peptide (GLP)-1 receptor cause of gradual disease progression as dependent insulinotropic polypeptide agonists and dipeptidyl peptidase 4 b-cell function declines. Where sulfony- and GLP-1, both of which have a short (DPP-4) inhibitors. Clinical data have lureas or thiazolidinediones (common half-life because of their rapid inactivation revealed that these therapies improve gly- oral antidiabetic drugs) are used, the risk by DPP-4 (7). In patients with type 2 di- cemic control while reducing body weight of hypoglycemia and weight gain can in- abetes, the incretin effect is reduced or, in (GLP-1 receptor agonists, specifically) and crease (1,2). The development of new some cases, absent (8). In particular, the systolic blood pressure (SBP) in patients therapies for the treatment of type 2 dia- insulinoptropic action of glucose-depen- with type 2 diabetes. Furthermore, in- betes that, in addition to maintaining gly- dent insulinotropic polypeptide is lost in cidence of hypoglycemia is relatively low cemic control, could reduce body weight patients with type 2 diabetes. However, it with these treatments (except when used and hypoglycemia risk (3,4), may help has been shown that, after administration in combination with a sulfonylurea) be- with patient management. Indeed, guide- of pharmacological levels of GLP-1, the in- cause of their glucose-dependent mecha- lines have been developed that support sulin secretory function can be restored in nism of action. There are currently two the consensus that blood pressure, weight this population (9), and thus GLP-1 has GLP-1 receptor agonists available (exena- reduction, and avoidance of hypoglycemic become an important target for research tide and liraglutide), with several more events should be targeted in type 2 dia- into new therapies for type 2 diabetes. currently being developed. This review betes management alongside glycemic tar- GLP-1 has multiple physiological ef- considers the efficacy and safety of both gets. For example, the American Diabetes fects that make it an attractive candidate the short- and long-acting GLP-1 receptor Association (ADA) defines multiple goals for type 2 diabetes therapy. It increases agonists. Head-to-head clinical trial data of therapy that include A1C ,7.0% and insulin secretion while inhibiting gluca- suggest that long-acting GLP-1 receptor SBP ,130 mmHg and no weight gain gon release, but only when glucose levels agonists produce superior glycemic con- (or, in the case of obese subjects, weight are elevated (6,10), thus offering the po- trol when compared with their short- loss) (5). In particular, incretin-based tential to lower plasma glucose while re- acting counterparts. Furthermore, these therapies (GLP-1 receptor agonists, spe- ducing the likelihood of hypoglycemia. long-acting GLP-1 receptor agonists were cifically) can help meet these new tar- Furthermore, gastric emptying is delayed generally well tolerated, with transient gets by offering weight reduction, (10) and food intake is decreased after nausea being the most frequently reported blood pressure reduction, and reduced GLP-1 administration. Indeed, in a 6- adverse effect. hypoglycemia in addition to glycemic week study investigating continuous Careful consideration should be given control. GLP-1 infusion, patients with type 2 di- to the selection of therapies for managing abetes achieved a significant weight loss type 2 diabetes. In particular, antidiabetic WHAT IS GLP-1?—The incretin of 1.9 kg and a reduction in appetite from agents that offer improved glycemic con- effect, responsible for 50–70% of total baseline compared with patients receiving trol without increasing cardiovascular risk insulin secretion after oral glucose placebo, where there was no significant ccccccccccccccccccccccccccccccccccccccccccccccccc change in weight or appetite (11). Preclini- cal studies reveal other potential benefits From the Molecular and Cellular Biology Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, Texas. of GLP-1 receptor agonist treatment in Corresponding author: Alan J. Garber, [email protected]. individuals with type 2 diabetes, which This publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in include the promotion of b-cell prolifera- Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were tion (12) and reduced b-cell apoptosis made possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol- Myers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-La (13). These preclinical results indicate Roche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pfizer. that GLP-1 could be beneficial in treating DOI: 10.2337/dc11-s231 patients with type 2 diabetes. However, The article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/ because native GLP-1 is rapidly inactivated dc11-s231/-/DC1. © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly and degraded by the enzyme DPP-4 and cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ has a very short half-life of 1.5 min (14), to licenses/by-nc-nd/3.0/ for details. achieve the clinical potential for native care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S279 Long-acting GLP-1s: efficacy and tolerability GLP-1, patients would require 24-h ad- to 21.5% in patients with type 2 diabetes liraglutide in combination with metfor- ministration of native GLP-1 (15). Be- inadequately controlled on metformin min 6 sulfonylurea (23.24 kg with 1.8 cause this is impractical as a therapeutic with or without a sulfonylurea (20–24). mg liraglutide). Reductions in SBP were option for type 2 diabetes, it was neces- Across these studies, body weight was also observed across the trials (mean de- sary to develop longer-acting derivatives seen to decrease in a dose-dependent crease 22.1 to 26.7 mmHg) (27–32). of GLP-1. manner; treatment with 10 mg exenatide, Liraglutide was generally well toler- as an add-on to metformin, resulted in the ated, with only transient nausea experi- DEVELOPMENT OF DPP-4– greatest weight loss (22.8 kg) in patients enced toward the beginning of the RESISTANT GLP-1 RECEPTOR previously treated with metformin alone studies. The rate of minor hypoglycemia AGONISTS—Two classes of incretin- (21). Exenatide was generally well toler- was very low in these trials (incidence based therapy have been developed to ated, with mild-to-moderate gastrointesti- ranged from 0.03 to 0.6 events/patient/ overcome the clinical limitations of na- nal effects being the most common year with the different treatment groups tive GLP-1: GLP-1 receptor agonists (e.g., adverse effect (20–23). The number of pa- [excluding those using liraglutide in com- liraglutide and exenatide), which exhibit tients experiencing nausea peaked during bination with a sulfonylurea]). However, increased resistance to DPP-4 degradation the initial weeks of treatment (0–8 weeks) as seen in the exenatide trials, frequency and thus provide pharmacological levels but decreased thereafter. Rates of hypogly- of hypoglycemia increased slightly when of GLP-1, and DPP-4 inhibitors (e.g., sita- cemia were relatively low in these studies, liraglutide was used in combination with gliptin, vildagliptin, saxagliptin), which although frequency of hypoglycemia was a sulfonylurea (incidence of major hypo- reduce endogenous GLP-1 degradation, increased when exenatide was used in glycemia: 0.056 events/patient/year; minor thereby providing physiological levels of combination with a sulfonylurea (20). In- hypoglycemia: 1.2 events/patient/year with GLP-1. In this review, we focus on the deed, the summary of product character- 1.8 mg liraglutide in combination with GLP-1 receptor agonist class of incretin- istics for exenatide states that when metformin and a sulfonylurea). based therapies. The efficacy and tolera- exenatide is used in combination with a bility of the DPP-4 inhibitors have been sulfonylurea, consideration should be OVERVIEW OF GLP-1 reviewed elsewhere (16). Two GLP-1 recep- given to reducing the sulfonylurea dose RECEPTOR AGONISTS IN tor agonists are licensed at present in Eu- to reduce the risk of hypoglycemia (17). DEVELOPMENT—In addition to lir- rope, the U.S., and Japan: exenatide (Byetta, aglutide and exenatide, there are several Eli Lilly) (17) and liraglutide (Victoza, Novo Liraglutide once-weekly GLP-1 receptor agonists in Nordisk) (18). For the purposes of this re- Liraglutide is a GLP-1 analog that shares development: exenatide long-acting