Glucagon-like Peptide 1 Receptor Agonists: A Novel Treatment for Type 2 Diabetes

Carbohydrate metabolism is mediated by multiple glucoregulatory hormones, including the incretin hormones (gut hormones), also known as incretins. Incretins are secreted in response to the presence of ingested nutrients. The “incretin effect” refers to the observation that insulin secretion in response to ingested glucose is greater than insulin secretion that occurs following isoglycemic intravenous glucose infusion.[1,2] In healthy human subjects, the incretin hormone glucagon-like peptide 1 (GLP-1) has been shown to stimulate insulin secretion, suppress glucagon secretion, and delay gastric emptying.[3] Mimicking the glucose-dependent, insulin-stimulating action of native GLP-1 forms the basis for the GLP-1 receptor agonists, a potential future treatment for type 2 diabetes.

GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)

Both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion in animals and humans and help achieve glucose homeostasis after a meal. GIP is released by intestinal K-cells, in the duodenum and proximal jejunum; GLP-1 is synthesized by the L-cells, located primarily in the ileum and colon.3 It has been shown in humans with type 2 diabetes that meal-stimulated GLP-1 secretion is greatly reduced, even though sensitivity to its activity still remains.[4,5] GIP is known to regulate fat metabolism,3 among other actions, but it is not yet a candidate for clinical development because people with type 2 diabetes lose sensitivity to the effects of GIP.

One reason that GLP-1 receptor agonists are a promising drug class is that their strong insulinotropic effect is glucose-dependent, and they are thus unlikely to cause profound hypoglycemia; also, they do not cause weight gain, and instead seem to be associated with gradual weight loss.3 Recent evidence suggests that GLP-1 also may be cardioprotective and vasoactive, since it protects ischemic and reperfused myocardia in animals[6] and positively influences vascular endothelium among people with type 2 diabetes and stable coronary artery disease.[7]

Mechanism of action of GLP-1

GLP-1 has been shown to have multiple physiologic activities in the central nervous system and gastrointestinal system that could lower A1C. Some of the multiple effects of GLP-1 are shown in Table 1.

Table 1. Mechanisms of GLP-1-regulated glucose homeostasis[3]

In preclinical studies, researchers examined the physiological importance of GLP-1 via interruption of the action of GLP-1 and found that it regulates many pathways essential to glucose metabolism and weight regulation.3 For example, genetically altered (knockout) mice lacking the receptors for GIP and GLP-1 demonstrate glucose intolerance,[8] which indicates that these incretin hormones are active in glucose uptake. The acute and chronic glucose-lowering effects of GLP-1 observed in nondiabetic animals also were demonstrated in multiple animal models of diabetes.[3] For example, it was found that when native GLP-1 is infused for 48 hours in rats, glucose was lowered,[9] and the effect extends beyond the infusion time, exhibiting a memory effect for sustained improvement in glycemic control.[3]

Clinical studies with native GLP-1

Infusion of native human GLP-1 (7-36) amide into healthy human subjects has been shown to stimulate insulin secretion, reduce glucagon secretion, and significantly enhance glucose release during glucose loading.[10] Using continuous infusions of native GLP-1, reductions in weight and food consumption were demonstrated in lean and overweight human subjects.[11] Since continuous infusion is not clinically feasible for treating people with diabetes and native GLP-1 is rapidly degraded in vivo by the enzyme dipeptidyl peptidase-IV (DPP-IV), degradation-resistant compounds are being developed and tested for their ability to achieve similar effects with a longer duration of action that could prolong GLP-1 signaling.

Clinical studies with GLP-1 receptor agonists

A number of GLP-1 receptor agonists are currently in development or newly approved for the treatment of type 2 diabetes. The GLP-1 receptor agonist exenatide is a synthetic version of exendin-4, which was originally isolated from the salivary gland secretions of a Gila monster lizard species. It shares 53% of the amino acids with mammalian GLP-1.[12] Liraglutide (NN2211) is a long-acting GLP-receptor analog designed for once-daily injection;[13] CJC-1134 is a modified analog of exendin-4 conjugated to recombinant human albumin that is in early stage clinical trials.[14,15]AVE0010 (formerly known as ZP-10) has completed phase 2a clinical trials.[16]  LY548806 is a GLP-1 derivative designed to avoid rapid proteolysis by DPP-IV.[17] Other GLP-receptor agonists entering into or in early stage currently in clinical development include GSK716155 (albumin-glucagon-like peptide-1, GLP-1, formerly known as Albugon), R1583 (BIM 51077), and GLP1-I.N.T.

Exenatide

Three pivotal studies led to the FDA approval of exenatide in April 2005. All 3 of the clinical studies (termed the AMIGO studies) were conducted in subjects with type 2 diabetes whose hyperglycemia was not adequately controlled by their present therapies. Exenatide was added to therapy with sulfonylurea[18], metformin[19], and sulfonylurea and metformin used in combination.[20] Results of these 3 studies are described below.

Exenatide plus sulfonylurea

A study among 377 subjects at 101 sites in the US evaluated exenatide’s ability to improve glycemic control in patients failing therapy with a sulfonylurea (SU).¹⁸ At the end of the study, among evaluable subjects with baseline A1C >7%, the following percentages achieved an A1C of 7%: 41% (10 mcg exenatide), 33% (5 mcg exenatide), and 9% (placebo; P<.001). Fasting plasma glucose concentrations decreased in the 10 µg arm compared with placebo (P<.05). At the end of the study, subjects taking exenatide had dose-dependent progressive weight loss that did not appear to plateau by the end of the study. In the 10 µg exenatide arm, the loss was –1.6 ±0.3 kg from baseline (P<.05 vs placebo). The most frequent adverse events were generally mild to moderate gastrointestinal effects, particularly nausea that was mild to moderate and appeared in the first few weeks of therapy. No instances of severe hypoglycemia occurred. However, mild-to-moderate hypoglycemia did occur more frequently among patients treated with exenatide and SU, relative to patients treated only with SU. However, no increase in hypoglycemia was observed in a similarly designed study on metformin-treated patients. One possible explanation for the hypoglycemia observed in this study was due to the increased susceptibility to hypoglycemia that frequently occurs among SU-treated patients at lower ambient glycemic levels.

Exenatide plus metformin

This study involved 243 evaluable patients with type 2 diabetes who were taking metformin at maximally effective doses.¹⁹ After 30 weeks, 46% (10 mcg bid), 32% (5 mcg bid), and 13% (placebo) of the exenatide subjects achieved an A1C <7% (P<.01). Subjects on exenatide also showed dose-dependent weight loss by the end of the study (P<.05 compared with placebo). Markers of β-cell function were improved in the exenatide groups compared with the placebo group (P<.01).

Exenatide plus metformin and sulfonylurea

A similar study involving 733 patients evaluated exenatide added to maximum doses of metformin and an SU.²⁰ An A1C of <7% was achieved by 30% (10 mcg group), 24% (5 mcg group), and 7% (placebo group, P<.001). At week 30 exenatide patients had significant weight loss from baseline vs placebo (P<.01).

Liraglutide

The long-acting GLP-1 analog liraglutide has been tested in patients with type 2 diabetes in a number of studies and has been shown to be effective over a variety of durations. In one study, treatment with liraglutide improved glycemic control and decreased endogenous glucose release, and improved islet cell function after 1 week of treatment.[21] Similarly, 8 weeks of treatment with liraglutide also was associated with improvements in glycemic control.[22] A 12-week study was conducted among 193 subjects with type 2 diabetes using various doses of liraglutide added to therapy of metformin and SUs.[23] The primary endpoint was A1C after 12 weeks. A1C decreased in all but the lowest liraglutide dosage group. In the 0.75 mg liraglutide group, A1C decreased by 0.75% (P<.0001) and fasting glucose decreased by 1.8 mmol/L (P = .0003) compared with placebo. Improvement in glycemic control was evident after 1 week. Body weight decreased by 1.2 kg in the 0.45 mg liraglutide group (P = .0184) compared with placebo, but no weight loss was observed among patients treated with higher doses of liraglutide. No safety issues were raised. Observed adverse events were mild and transient.

Another study of liraglutide evaluated the dose-response relationship of liraglutide on body weight and glycemic control in patients with type 2 diabetes previously treated with oral antidiabetic drug monotherapy.[24] After 4 weeks of treatment with metformin, 210 subjects were randomized to receive one of 5 doses of liraglutide (0.045-0.75 mg) once a day or to continue on metformin 1000 mg twice daily for 12 weeks. Improvements in glycemic control and weight were comparable among the 6 treatment groups. Mean A1C changes from baseline for the 0.045, 0.225, 0.45, 0.6, 0.75 mg liraglutide groups and the metformin group were +1.28%, +0.86%, +0.22%, +0.16%, +0.30%, and +0.09%, respectively. Thus, A1C levels were comparable among the 3 highest-dose liraglutide groups and the metformin groups, whereas the lowest 2 liraglutide doses did not maintain the fasting plasma glucose values achieved by metformin. A weight change of -0.05-1.9% was observed among the 6 treatment groups. No major hypoglycemic episodes were reported.

CJC-1134

CJC-1134 is a modified exendin-4 analogue that is linked to recombinant human albumin. Recent phase 1/2 trial data indicate that this agent is well tolerated at doses of 310, 620, 1250, and 2500 μg in patients with A1C levels between 6.5% and 11%. Specifically, no nausea, vomiting, or injection site reactions were observed.¹⁴ With the 5000-μg dose, symptoms linked to an overstimulation of the GLP-1 receptors were observed. At the 1250-mcg dose, glucose levels declined significantly. The average glucose decline from baseline after the first week was 19% (ranging from 15-24% with average on day 7 of 20%), resulting in an average glucose value for the week of 9.8 mmol/L. With treatment, glucose levels were significantly different from baseline levels (P = .0007) and those of placebo (P = .045). In addition, an extended glucose-lowering effect was observed for more than 2 weeks, and weight reduction was observed with doses that showed a glucose-lowering effect. Studies to evaluate the administration of this drug with 1 month of dosing are underway.

AVE0010 (Formerly ZP10)

AVE0010 is a GLP-1 receptor agonist that incorporates a Structure Inducing Probe peptide modification technology. AVE0010 has shown efficacy and safety in a phase 2 clinical trial.¹⁶ A total of 64 patients with well-controlled diabetes were treated for 4 weeks with AVE0010 once or twice daily or with placebo as an add-on therapy to antidiabetic treatment. Upon once- or twice-daily administration, AVE0010 showed a statistically significant reduction in postprandial blood glucose compared with placebo. The efficacy tended to be dose-dependent with both treatment regimens. The safety analysis indicated that AVE0010 was safe and well tolerated, with nausea and vomiting comparable between treatment and placebo groups.

LY548806

LY548806 is a GLP-1 derivative designed to avoid rapid proteolysis by DPP-IV and the tendency to aggregate in solution.[17] It may be useful as an intravenous agent in acute care settings due to its predictable pharmacokinetics. The safety and tolerability of LY548806 were evaluated in a study of 36 patients with type 2 diabetes who underwent dose escalation in placebo-controlled, single-blind studies. In part A, 18 subjects underwent 6-hour IV infusions of placebo or LY548806 (1.5-40 µg/hour), with 2 active doses and 1 placebo dose per patient. In part B, 18 subjects were given IV infusions of LY548806 at 10 µg/hour, 18 µg/hour, or 19.8 µg/hour for 24 hours. The drug was safe and appeared to be well tolerated, and no episodes of hypoglycemia were observed. However, nausea and vomiting increased at higher doses.[17]

Conclusion

GLP-1 receptor agonists belong to an exciting, emerging therapeutic class, and they represent a novel approach to the treatment of type 2 diabetes. Because of the progressive nature of type 2 diabetes, the majority of patients will eventually need multiple agents to control their disease.[25] This novel class represents another treatment option that has the potential to help patients with type 2 diabetes meet their glycemic goals potentially with fewer side effects than conventional oral antidiabetic agents.

References

1. Elrick H, Stimmler L, Hlad CJ, Arai Y. Plasma insulin responses to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076-1082.
2. Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia.1985;28:565-573.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940.
4. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia.1986;29:46-52.
5. Vilsboll T, Krarup T, Deacon CF, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609–613.
6. Bose A, Mocanu MM, Mensah KN, et al. GLP-1 protects ischemic. and reperfused myocardium via PI3 kinase and p42/p44 MAPK signalling pathways. Diabetes. 2004;53(suppl 2):A1.
7. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol. 2004;287:E1209-E1215.
8. Miyawaki K, Yamada Y, Yano H, et al. Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA.1999;96:14843–14847.
9. Wang Y, Perfetti R, Greig NH, et al. Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest. 1997;99:2883-2889.
10. Kreymann B, Ghatei MA, Williams G, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987;2:1300-1304.
11. Verdich C, Flint A, Gutzwiller, JP, et al. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libidum energy intake in humans. J Clin Endocrinol Metab. 2001;86:4382-4389.
12. Nielsen LL. Young AA, Parkes DG.Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regulatory Peptides. 2004;117:77-88.
13. Harder H, Nielsen L, Thi TD, Astrup A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care. 2004;27:1915-1921.
14. Phase I/II Preliminary Results of PC-DAC™: Exendin-4 trial for type 2 diabetes demonstrate excellent tolerability and positive efficacy. Conjuchem.com. Available at: http://www.glucagon.com/CJC1134PresRelease04-26-2006.pdf Accessed June 5, 2006.
15. PC-DAC™:Exendin-4 (CJC-1134-PC).Conjuchem.com. Available at:http://conjuchem.hyphenhealth.com/products/PCDACExendin4.shtml Accessed June 5, 2006.
16.   Sanofi-Aventis finalize phase IIa clinical study with GLP-1 agonist for type 2 diabetes licensed from Zealand Pharma.. Zealand Pharma. Available at: http://www.lsp.nl/news/pdf/03032005_zealand.pdf. Accessed June 5, 2006.
17. Jackson K, Mace K, Sykes A, et al. Pharmacodynamic and pharmacokinetic properties of LY 548806. American Diabetes Association 65th Scientific Sessions. June 10-14, 2005. San Diego, Calif. Abstract 562.
18. Buse J, Henry RR, Han J, Kim DD, Fineman MS, Baron AD for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 Diabetes. Diabetes Care. 2004;27:2628-2635.
19. DeFronzo R, Ratner R, Han J, Kim D, Fineman M, Baron A. Effects of exenatide (synthetic exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
20. Kendall DM, Riddle MC, Dongliang Z, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-1091.
21. Degn KB, Juhl CB, Sturis J, et al. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004;53:1187-1194.
22. Harder H, Thi TDT, Neilsen L, Astrup A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care. 2004;27:1915-1921.
23. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR; NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004;27:1335-1342.
24. Feinglos MN, Saad MF, Pi-Sunyer FX, An B, Santiago O. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med. 2005;22:1016-1023.
25. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;28:2005-2012.