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TREATMENTS

Long-Acting -Like 1 Receptor A review of their efficacy and tolerability

ALAN J. GARBER, MD, PHD administration, is defined as the differ- ence in secretory response from an oral load compared with intra- venous glucose administration (6) argeting the system has be- factors or rates of are war- (Supplementary Fig. 1). come an important therapeutic ap- ranted. At present, many available treat- There are two naturally occurring T incretin that play a role in the proach for treating . 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 (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 ) 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 ), 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 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 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 , Baylor College of Medicine, Houston, Texas. of GLP-1 receptor 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, 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 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 , 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, , ), 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 release view, we refer to “short-acting” GLP-1 re- 97% sequence identity to native GLP-1 (LAR) (Eli Lilly/), ceptor agonists as those agents having (25). The addition of a C16 fatty acid side (Roche), (GlaxoSmithKline), duration of action of ,24 h and “long- chain enables once-daily dosing of lira- and LY2189265 (Eli Lilly) (Supplementary acting” as those agents with duration of glutide by prolonging its duration of ac- Table 1). action .24 h (Table 1). tion to over 24 h. This protraction is At the time of writing, Roche had achieved through reversible binding to al- suspended the development of taspoglu- OVERVIEW OF LICENSED bumin and increased stability through tide, currently in phase 3 trials, because of GLP-1 RECEPTOR AGONISTS heptamer formation mediated by the fatty the high discontinuation rates as a result acid side chain (26). of gastrointestinal tolerability and serious Exenatide The safety and efficacy of liraglutide hypersensitivity reactions (33). Exenatide, an exendin-4 mimetic with have been well detailed in the phase 3 53% sequence identity to native GLP-1, Liraglutide Effect and Action in Diabetes LONG- VERSUS SHORT- is currently approved for the treatment of (LEAD) trials (27–32). Data from the ACTING GLP-1 RECEPTOR type 2 diabetes as monotherapy (in the LEAD trials have demonstrated that lira- AGONISTS: EFFICACY AND U.S.) (19) and in combination with met- glutide effectively improves glycemic TOLERABILITY—A number of phase formin 6 sulfonylurea (17). Because of control (up to a 1.5% decrease in A1C) 3 head-to-head trials have been conducted its half-life of 2.4 h, exenatide is recom- in individuals with type 2 diabetes, when investigating the efficacy and tolerability mended for twice-daily dosing. used as monotherapy or in combination of long- versus short-acting GLP-1 receptor Clinical trial results have demon- with one or more selected oral anti- agonists, results of which are brieflyde- strated that exenatide, when used in com- diabetic drugs. Across the trials, body scribed here. bination with selected oral antidiabetic weight was seen to decrease; the largest drugs, effectively reduces A1C by 20.4 weight loss resulted from treatment with Once-daily liraglutide versus twice-daily exenatide fi Table 1—Short- and long-acting GLP-1 receptor agonists The ef cacy and tolerability of once-daily liraglutide were compared with twice- daily exenatide in a phase 3 randomized $ Short-acting ,24 h Long-acting 24 h head-to-head trial over 26 weeks involv- Twice daily Once daily Once weekly ing 464 patients (32). Results from this trial revealed that liraglutide provided a Exenatide (launched) Liraglutide (launched) Exenatide LAR (phase 3) significantly greater reduction in mean Taspoglutide (phase 3) A1C compared with exenatide (21.12 vs. Albiglutide (phase 3) 20.79%; P , 0.0001) (Supplementary LY2189265 (phase 2) Fig. 2). As a result, a greater proportion of

S280 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 care.diabetesjournals.org Garber patients with type 2 diabetes reached the P = 0.0023), and a significantly greater samereductioninA1Cfrombaseline ADA A1C target (#7.0%) (3) with liraglu- proportion of subjects reached the A1C (22.0% at week 52) as subjects who had tide compared with exenatide (54 vs. 43%; target of #7.0% with exenatide LAR ver- been treated only by exenatide LAR. De- P = 0.0015) (32). In addition, fasting sus twice-daily exenatide (77 vs. 61%, re- creases in body weight were similar for plasma glucose significantly decreased spectively; P = 0.0039) (Supplementary both treatment groups. As seen in the ori- with liraglutide treatment (21.61 mmol/L Fig. 3). In addition, a significantly greater ginal DURATION (Diabetes Therapy Uti- with liraglutide vs. 20.60 mmol/L with ex- reduction in fasting plasma glucose was lization: Researching Changes in A1C, enatide; P , 0.0001). observed with exenatide LAR versus twice- Weight and Other Factors Through Inter- The effects on body weight were daily exenatide (22.3 vs. 21.4 mmol/L for vention with Exenatide Once Weekly) -1 similar with both liraglutide and exena- exenatide LAR and twice-daily exenatide, study, incidence of hypoglycemia was low tide (23.24 vs. 22.87 kg, respectively), respectively; P , 0.0001). and limited to patients who received exe- with a similar proportion of patients los- A progressive reduction in body natide in combination with a sulfonylurea. ing weight in both treatment groups (78% weight was observed throughout the with liraglutide vs. 76% with exenatide) study, with both treatment groups expe- LONG-ACTING GLP-1 (32). Both drugs were well tolerated, with riencing similar reductions in weight RECEPTOR AGONISTS: only mild-to-moderate side effects ob- from baseline (23.7 kg with exenatide OVERVIEW OF CLINICAL served. Nausea was reported as the most LAR vs. 23.6 kg with twice-daily exena- EFFICACY—Currently, there are no common adverse effect with both treat- tide; P = 0.89). The most common ad- data directly comparing the clinical effi- ments, although it was less frequent and verse effects seen with exenatide LAR cacy of the long-acting GLP-1 receptor less persistent with liraglutide. Further versus twice-daily exenatide were nausea agonists (liraglutide, exenatide LAR, albi- benefits of liraglutide treatment included (26.4 vs. 34.5%, respectively) and in- glutide, taspoglutide, LY2189265). This a reduced number of hypoglycemic events jection site pruritus (17.6 vs. 1.4%, re- section provides an indirect comparison and higher overall treatment satisfaction. spectively). The proportion of patients of the clinical trial results achieved with A 14-week LEAD-6 extension study reporting minor hypoglycemic events long-acting GLP-1 receptor agonists to date. was also completed, in which patients, was low in both treatment arms (0 vs. already randomized to liraglutide, stayed 1.1% of the study population for exenatide A1C on liraglutide, and those on exenatide LAR and twice-daily exenatide, respec- Data from published clinical trials using switched to once-daily liraglutide (34). tively); reports of minor hypoglycemia long-acting GLP-1 receptor agonists (lira- Individuals switching from exenatide to were increased in patients taking a sulfo- glutide, exenatide LAR, albiglutide, taspo- liraglutide achieved an additional reduc- nylurea concomitantly (14.5 vs. 15.4% of glutide, LY2189265) reveal that reductions tion in A1C of 20.3%, from 7.2% at week the study population for exenatide LAR in A1C from baseline range from 20.87 to 26 to 6.9% at week 40 (Supplementary and twice-daily exenatide, respectively). 21.9% (31,33,35–39) (Fig. 1). Results Fig. 2). Further reductions in fasting The A1C and fasting plasma glucose with exenatide LAR demonstrated that plasma glucose (20.9 mmol/L), body reductions seen in the first 30 weeks were these improvements in A1C could be weight (20.9kg),andSBP(23.8 maintained throughout an extension maintained after 2 years (mean A1C de- mmHg) were also seen after the switch study (22 weeks), where patients either crease at 2 years: 21.8%) (36). Greater to liraglutide. Patients switched from ex- switched from twice-daily exenatide to reductions in A1C were seen with liraglu- enatide to liraglutide also experienced a once-weekly exenatide LAR or continued tide compared with the DPP-4 inhibitor reduction in rates of hypoglycemia from exenatide LAR treatment (35). Individuals (mean A1C decrease: 21.50 2.6 episodes/patient-year at week 26 to switching from twice-daily exenatide to and 21.24% with 1.8 and 1.2 mg liraglu- 1.3 episodes/patient-year at week 40. exenatide LAR displayed further improve- tide, respectively, vs. 20.90% with sita- After the switch from exenatide to liraglu- ments in glycemic control, achieving the gliptin; P , 0.0001) (37). tide, 3.2% of patients experienced nausea during the extension period, compared with 1.5% of individuals who continued liraglutide treatment.

Once-weekly exenatide LAR versus twice-daily exenatide The safety and efficacy of once-weekly exenatide LAR (2 mg) versus twice-daily exenatide (10 mg) was evaluated in a phase 2/3 randomized open-label trial over 30 weeks involving 295 patients na- ive to drug therapy or on one or more oral antidiabetic drugs (24). Results from this trial revealed that exenatide LAR im- proved glycemic control significantly more than twice-daily exenatide. Re- ductioninA1Cwassignificantly greater Figure 1—Change in A1C with long-acting GLP-1 receptor agonists across the clinical trials with exenatide LAR versus twice-daily ex- (24,32,36–39,41). *P , 0.01 vs. comparator; **P , 0.001; ***P , 0.0001; ###P , 0.0001 vs. enatide (21.9 vs. 21.5%, respectively; placebo. care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S281 Long-acting GLP-1s: efficacy and tolerability

Overall, at least 50% of patients Table 2—Summary of efficacy and tolerability with long-acting GLP-1 receptor agonists reached an A1C target of ,7.0% with the long-acting GLP-1 receptor agonists Exenatide (31,33,36,37,39,40); results varied from Liraglutide LAR Taspoglutide Albiglutide LY2189265 52% after 16 weeks of treatment with al- biglutide (38) to 81% after 8 weeks of tas- Change in A1C (%) 21.1 to 21.6 21.9 21.2 20.9 21.5 poglutide treatment (39). Change in body weight (kg) 20.2 to 23.2 23.7 22.8 21.4 22.5 Change in SBP (mmHg) 22.3 to 26.7 24.7 Not reported 25.8 25.1 Weight loss Nausea (%) 7–29 26.4 52 25.8 13 Body weight has been shown to signifi- Vomiting (%) 4.4–17 10.8 22 12.9 Not reported cantly decrease in a dose-dependent man- Data are from the following references: 24, 27–32, 36–39, 41, and 43. ner with all of the long-acting GLP-1 receptor agonists; results varied from 21.4 kg after 16 weeks of treatment background (24,27,31,32). No major hy- with native GLP-1, were seen in 2.5% of with 30 mg albiglutide (38) to 23.87 kg poglycemic events were reported. albiglutide-treated patients (38). after 15 weeks of treatment with exena- Liraglutide shares 97% sequence tide LAR (2.0 mg) (40) (Fig. 2; Table 2). Gastrointestinal side effects identity with native GLP-1 and, across Gastrointestinal effects, including nausea the LEAD trials, 8.6% of patients devel- SBP and vomiting, appear to be the most fre- oped antiliraglutide antibodies (18); how- In addition to their effects on glycemic quently reported adverse effect seen with ever, there were no indications from the control and body weight, the long-acting the long-acting GLP-1 receptor agonists clinical trial data that the formation of these GLP-1 receptor agonists have been shown (Table 2). These side effects occur early on antibodies affected efficacy (27–32,42). to reduce SBP in patients with type 2 in the treatment, but tend to be transient Indeed, even after 78 weeks’ treatment diabetes, ranging from 24.7 mmHg after and rarely result in patient withdrawal with liraglutide (26 weeks in the LEAD-6 15 weeks with exenatide LAR (33) to (24,32,36–39,41). After taspoglutide trial plus a 52-week extension), only 2.6% 26.7 mmHg after 26 weeks with liraglu- treatment, for example, nausea and vom- of patients treated with liraglutide had tide (30) (Table 2). iting were usually resolved within 1 day, low-titer liraglutide antibodies, and these and subsequent taspoglutide administra- antibodies did not affect reductions in LONG-ACTING GLP-1 tions were less likely to induce nausea A1C in these patients (32). RECEPTOR AGONISTS: (39). Furthermore, a smaller proportion A larger proportion of patients de- OVERVIEW OF SAFETY AND of patients reported nausea or vomiting veloped antibodies to exenatide (after 26 TOLERABILITY after liraglutide treatment compared weeks: 113/185 patients; 61%), and this with patients treated with exenatide is likely to be due to the lower sequence Hypoglycemia (25.5% of the study population vs. 28% identity of exenatide with native GLP-1. Minor hypoglycemic events have been with twice-daily exenatide; vomiting: Patients with high-titer exenatide anti- observed at a relatively low rate after the 6.0% of the study population vs. 9.9% bodies exhibited a smaller decrease in commencement of treatment with long- with twice-daily exenatide) (32). A1C (20.5%) compared with patients acting GLP-1 receptor agonists, with be- with low-titer antibodies (21.0%). Fol- tween 0 and 14.5% of patients experiencing Antibodies lowing a switch to liraglutide after 26 this side effect (24,28,38). As reported pre- Antibody formation was very low in pa- weeks, patients previously treated with viously, the greatest proportion of patients tients treated with once-weekly GLP-1 exenatide still exhibited anti-exenatide reporting minor hypoglycemic events was receptor agonists. Antibodies to albiglu- antibodies after treatment weeks 40 when adding treatments to a sulfonylurea tide, which has 95% identity (49.7%) and 78 (17.5%). However, the per- sistence of anti-exenatide antibodies did not affect subsequent liraglutide treatment.

SUMMARY—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 treat- ment compared with twice-daily exena- tide. Furthermore, exenatide LAR provided better glycemic control than exenatide with comparable weight loss. Trials are ongoing to evaluate the efficacy of ex- enatide LAR when compared with in- sulin glargine in patients with type 2 diabetes on a metformin background with Figure 2—Change in body weight with long-acting GLP-1 receptor agonists across the clinical or without prior sulfonylurea treatment trials (24,32,36–39,41). **P , 0.001; ***P , 0.0001. (DURATION-3; NCT00641056) or used

S282 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 care.diabetesjournals.org Garber as monotherapy in drug-naive patients College of Endocrinology consensus panel emea-combined-h698en.pdf. Accessed 17 (DURATION-4; NCT00676338). on type 2 diabetes mellitus: an algorithm for May 2010 As a drug class, long-acting GLP-1 glycemic control. Endocr Pract 2009;15: 18. Novo Nordisk A/S. Victoza summary of – receptor agonists increase glycemic con- 540 559 product characteristics [Internet]. Available trol in patients with type 2 diabetes with a 5. American Diabetes Association. Standards from http://www.ema.europa.eu/humandocs/ of medical care in diabetes—2009. Di- PDFs/EPAR/victoza/H-1026-PI-en.pdf. Ac- low risk of hypoglycemia because of their abetes Care 2009;32(Suppl. 1):S13–S61 cessed 17 May 2010 glucose-dependent mechanism of action. 6. Baggio LL, Drucker DJ. Biology of in- 19. Amylin/Eli Lilly. Byetta summary of This drug class has also been demon- cretins: GLP-1 and GIP. Gastroenterology product characteristics: US [Internet]. strated to promote weight loss and reduce 2007;132:2131–2157 Available from http://www.accessdata. SBP, which could be of benefit to patients 7. Drucker DJ, Nauck MA. The incretin fda.gov/drugsatfda_docs/label/2009/ with type 2 diabetes, reducing their car- system: glucagon-like peptide-1 receptor 021773s9s11s18s22s25lbl.pdf. Accessed diovascular risk. Furthermore, although agonists and dipeptidyl peptidase-4 in- 21 May 2010 nausea is a common side effect with long- hibitors in type 2 diabetes. Lancet 2006; 20. Kendall DM, Riddle MC, Rosenstock J, – acting GLP-1 receptor agonists, it tends 368:1696 1705 et al. Effects of exenatide (exendin-4) on to be transient and, overall, long-acting 8. Nauck M, Stöckmann F, Ebert R, glycemic control over 30 weeks in patients Creutzfeldt W. Reduced incretin effect in with type 2 diabetes treated with metfor- GLP-1 receptor agonists are generally well type 2 (non-insulin-dependent) diabetes. min and a sulfonylurea. Diabetes Care tolerated. Thus, long-acting GLP-1 recep- Diabetologia 1986;29:46–52 2005;28:1083–1091 tor agonists may provide an effective ther- 9. Højberg PV, Vilsbøll T, Rabøl R, et al. Four 21. DeFronzo RA, Ratner RE, Han J, Kim DD, apeutic option for individuals with type 2 weeks of near-normalisation of blood Fineman MS, Baron AD. Effects of ex- diabetes and are well placed to meet the glucose improves the insulin response enatide (exendin-4) on glycemic control standard of care guidelines set by the ADA to glucagon-like peptide-1 and glucose- and weight over 30 weeks in metformin- in treating more than just blood glucose. dependent insulinotropic polypeptide in treated patients with type 2 diabetes. Di- patients with type 2 diabetes. Diabetologia abetes Care 2005;28:1092–1100 2009;52:199–207 22. Buse JB, Henry RR, Han J, Kim DD, Acknowledgments—Writing assistance was 10. Nauck MA, Kleine N, Orskov C, Holst JJ, Fineman MS, Baron AD; Exenatide-113 provided by Watermeadow Medical, funded Willms B, Creutzfeldt W. Normalization Clinical Study Group. Effects of exenatide by Novo Nordisk A/S. A.J.G. received re- of fasting hyperglycaemia by exogenous (exendin-4) on glycemic control over 30 search support from Novo Nordisk and glucagon-like peptide 1 (7-36 amide) in weeks in sulfonylurea-treated patients with GlaxoSmithKline; received advisory board/ type 2 (non-insulin-dependent) diabetic type 2 diabetes. Diabetes Care 2004;27: consultant/speaker honoraria from Novo patients. Diabetologia 1993;36:741–744 2628–2635 Nordisk, GlaxoSmithKline, and Roche; served 11. Zander M, Madsbad S, Madsen JL, Holst 23. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, on the speakers’ bureaus of Merck, Novo JJ. Effect of 6-week course of glucagon- Widel MH, Brodows RG; GWAA Study Nordisk, and GlaxoSmithKline; served on like peptide 1 on glycaemic control, in- Group. Exenatide versus advisory boards for GlaxoSmithKline, Roche, sulin sensitivity, and beta-cell function in in patients with suboptimally controlled Novo Nordisk, and Merck; served as a con- type 2 diabetes: a parallel-group study. type 2 diabetes: a randomized trial. Ann sultant for GlaxoSmithKline, Roche, Novo Lancet 2002;359:824–830 Intern Med 2005;143:559–569 Nordisk, and Sankyo; and attended speakers' 12. Buteau J, Foisy S, Joly E, Prentki M. 24. Drucker DJ, Buse JB, Taylor K, et al. Ex- bureaus for GlaxoSmithKline, Novo Nordisk, Glucagon-like peptide 1 induces pancre- enatide once weekly versus twice daily for Merck, and Sankyo. No other potential conflicts atic beta-cell proliferation via transacti- the treatment of type 2 diabetes: a ran- of interest relevant to this article were reported. vation of the domised, open-label, non-inferiority study. receptor. Diabetes 2003;52:124–132 Lancet 2008;372:1240–1250 13. Farilla L, Hui H, Bertolotto C, et al. 25. Russell-Jones D. Molecular, pharmaco- References Glucagon-like peptide-1 promotes islet logical and clinical aspects of liraglutide, a 1. Kahn SE, Haffner SM, Heise MA, et al. cell growth and inhibits apoptosis in Zucker once-daily human GLP-1 analogue. Mol Glycemic durability of , met- diabetic rats. Endocrinology 2002;143: Cell Endocrinol 2009;297:137–140 formin, or glyburide monotherapy. N Engl J 4397–4408 26. Steensgaard DB, Thomsen JK, Olsen HB, Med 2006;355:2427–2443 14. Vilsbøll T, Agersø H, Krarup T, Holst JJ. Knudsen LB. The molecular basis for the 2. UK Prospective Diabetes Study (UKPDS) Similar elimination rates of glucagon-like delayed absorption of the once-daily hu- Group. Intensive blood-glucose control peptide-1 in obese type 2 diabetic patients man GLP-1 analogue, liraglutide. Diabetes with sulphonylureas or insulin compared and healthy subjects. J Clin Endocrinol 2008;57(Suppl. 1):A164 with conventional treatment and risk of Metab 2003;88:220–224 27. Marre M, Shaw J, Brändle M, et al. Lir- complications in patients with type 2 di- 15. Larsen J, Hylleberg B, Ng K, Damsbo P. aglutide,1a once-daily human GLP-1 abetes (UKPDS 33). Lancet 1998;352: Glucagon-like peptide-1 infusion must analogue, added to a sulphonylurea 837–853 be maintained for 24 h/day to obtain ac- over 26 weeks produces greater im- 3. Nathan DM, Buse JB, Davidson MB, et al. ceptable glycemia in type 2 diabetic patients provements in glycemic and weight Medical management of hyperglycaemia who are poorly controlled on sulphonyl- control compared with adding rosigli- in type 2 diabetes mellitus: a consensus urea treatment. Diabetes Care 2001;24: tazone or placebo in subjects with type 2 algorithm for the initiation and adjust- 1416–1421 diabetes (LEAD-1 SU). Diabet Med 2009; ment of therapy: a consensus statement 16. Richter B, Bandeira-Echtler E, Bergerhoff K, 26:268–278 from the American Diabetes Association Lerch CL. Dipeptidyl peptidase-4 (DPP-4) 28. Nauck M, Frid A, Hermansen K, et al. and the European Association for the inhibitors for type 2 diabetes mellitus. Co- Efficacy and safety comparison of lir- Study of Diabetes. Diabetologia 2009;52: chrane Database Syst Rev 2008:CD006739 aglutide, , and placebo, all in 17–30 17. Amylin/Eli Lilly. Byetta summary of combination with metformin, in type 2 4. Rodbard HW, Jellinger PS, Davidson JA, product characteristics: Europe [Inter- diabetes: the LEAD (liraglutide effect and et al. Statement by an American Associa- net]. Available from http://www.ema. action in diabetes)-2 study. Diabetes Care tion of Clinical Endocrinologists/American europa.eu/humandocs/PDFs/EPAR/byetta/ 2009;32:84–90 care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S283 Long-acting GLP-1s: efficacy and tolerability

29. Garber A, Henry R, Ratner R, et al. Lir- twice-daily exenatide further improves with type 2 diabetes inadequately con- aglutide versus glimepiride monotherapy glycemic control in patients with type 2 trolled with metformin alone: a double- for type 2 diabetes (LEAD-3 Mono): a ran- diabetes using oral agents. Diabetes Care blind placebo-controlled study. Diabetes domised, 52-week, phase III, double-blind, 2010;33:1300–1303 Care 2009;32:1237–1243 parallel-treatment trial. Lancet 2009;373: 35. Buse JB, Drucker DJ, Taylor KL, et al. 40.KimD,MacConellL,ZhuangD,etal. 473–481 DURATION-1: exenatide once weekly Effects of once-weekly dosing of a long- 30. ZinmanB,GerichJ, BuseJB,etal.Efficacy provides sustained glycemic control and acting release formulation of exenatide on and safety of the human glucagon-like weight loss over 52 weeks. Diabetes Care glucose control and body weight in sub- peptide-1 analog liraglutide in combina- 2010;33:1255–1261 jects with type 2 diabetes. Diabetes Care tion with metformin and thiazolidine- 36. Trautmann M, Wilhelm K, Taylor K, Kim T, 2007;30:1487–1493 dione in patients with type 2 diabetes Zhuang D, Porter L. Exenatide once-weekly 41. Umpierrez G, Blevins T, Rosenstock J, (LEAD-4 Met+TZD). Diabetes Care 2009; treatment elicits sustained glycaemic ChengC,BastyrE,AndersonJ.Theeffect 32:1224–1230 control and weight loss over 2 years. Di- of LY2189265 (GLP-1 analogue) once 31. Russell-Jones D, Vaag A, Schmitz O, et al. abetologia 2009;52(Suppl. 1):S286 weekly on HbA1c and function in Liraglutide vs insulin glargine and placebo 37. Pratley RE, Nauck M, Bailey T, et al. Lir- uncontrolled type 2 diabetes mellitus: the in combination with metformin and sul- aglutide versus sitagliptin for patients EGO study analysis. Diabetologia 2009; fonylurea therapy in type 2 diabetes mel- with type 2 diabetes who did not have 52(Suppl. 1):S59 litus (LEAD-5 met+SU): a randomised adequate glycaemic control with metfor- 42. Garber A, Marre M, Nauck M, et al. The controlled trial. Diabetologia 2009;52: min: a 26-week, randomised, parallel- efficacy of liraglutide is not impacted in 2046–2055 group, open-label trial. Lancet 2010;375: subjects positive for anti-liraglutide anti- 32. Buse JB, Rosenstock J, Sesti G, et al. Lir- 1447–1456 bodies: a pooled analysis [article online]. aglutide once a day versus exenatide twice 38. Rosenstock J, Reusch J, Bush M, Yang F, Available from http://www.comtecmed. a day for type 2 diabetes: a 26-week Stewart M; Albiglutide Study Group. Po- com/codhy/2010/orals.aspx#o8. Accessed randomised, parallel-group, multinational, tential of albiglutide, a long-acting GLP-1 26 May 2010 open-label trial (LEAD-6). Lancet 2009;374: receptor agonist, in type 2 diabetes: a 43. Bergenstal R, Wysham C, Yan P, Macconell 39–47 randomized controlled trial exploring L, Malloy J, Porter L. DURATION-2: ex- 33. Fiercebiotech. Roche faces long delay for weekly, biweekly, and monthly dosing. enatide once weekly demonstrated su- diabetes drug taspoglutide [Internet]. Avail- Diabetes Care 2009;32:1880–1886 perior glycaemic control and weight able from http://www.fiercebiotech.com/ 39. Nauck MA, Ratner RE, Kapitza C, Berria R, reduction compared to sitagliptin or pio- story/roche-faces-long-delay-diabetes- Boldrin M, Balena R. Treatment with glitazone after 26 weeks of treatment. drug-taspoglutide/2010-06-18. Accessed the human once-weekly glucagon-like Abstract 6-LB presented at the Ameri- 26 November 2010 peptide-1 analog taspoglutide in combi- can Diabetes Association 2009 Scientific 34. Buse JB, Sesti G, Schmidt WE, et al. nation with metformin improves glycemic Sessions, 5–9 June 2009, New Orleans, Switching to once-daily liraglutide from control and lowers body weight in patients Louisiana

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