GLP1 Receptor Agonists

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Exenatide (synthetic exendin-4)

Exenatide (synthetic exendin-4) was isolated from the salivary gland of the gila monster, a lizard found in the deserts of Arizona [117]. Due to an ~50% amino acid homology with native human GLP-1 (Figs. 1 and 4), this peptide acts as a potent agonist at the mammalian GLP-1 receptor, but is not substrate to proteolytic cleavage by DPP-4 [117]. This leads to a circulating plasma half-life of 2-4 h, with exenatide levels being raised for ~6 h after a single subcutaneous injection [118].

The clinical effects of exenatide in the treatment of type 2 diabetes have been examined in phase 3 trials (Fig. 5). In these studies, exenatide (5 or 10 p,g s.c. twice daily) was added to an existing therapy with metformin [119], sulfonylureas [120], a combination of both [121], or thiazolidinediones [122]. HbA1c-reductions achieved after exenatide treatment over 30 weeks ranged from 0.8% to 1.0%, with HbA1c-levels at baseline ranging between 8.2% and 8.6%. In addition, body weight was reduced by ~1-3 kg after 30 weeks (baseline weight: ~100 kg), and patients continuing in an open-label extension study for 80 weeks exhibited a total weight loss averaging ~4.5 kg [123]. The latter effect is remarkable in that all other insulinotropic drugs (sulfonylureas and glinides) as well as insulin itself typically cause weight gain during long-term administration [1].

In an open-label comparison of exenatide with insulin glargine in diabetic patients suboptimally controlled with metformin and sulfonylurea, both treatment regimens led to a reduction in HbA1c levels by ~1.1% after 26 weeks (baseline: 8.2%)



helle qprrpLey^i amide

C-1G free fatty acid


C-1G free fatty acid


Fig. 4. Peptide and chemical structure, respectively, of the incretin mimetics exenatide and liraglutide and the DPP-4 inhibitors sitagliptin ((2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8fl)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine) and vildagliptin (1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine). (Modified from Drucker and Nauck 2006 [145]).

Table 2. Comparison of the incretin mimetics exenatide, exenatide LAR and liraglutide.


Exenatide LARa



s.c. injection

s.c. injection

s.c. injection

Half-life (h)


>1 weekb


Frequency of injections

Twice daily

Once weekly

once daily

Dose per injection

5-10 |g

Up to 2 mgc

Up to 2 mg

DPP-4 substrate?




insulin secretiond




Glucagon secretiond



Fasting glucose



Postprandial glucose excursions



Weight reduction




Gastric empting









Yes («50%)

Yes («25%)

Yes («10%)

Antibody production

Yes («45%)

Probably yes


aLAR = long-acting release preparation (biodegradable polymeric microspheres). bEstimate, since no pharmacokinetic characteristics have been published.

cSince liraglutide strongly binds albumin, only 1-2% are non-albumin bound, free liraglutide able to interact with GLP-1 receptors.

dThe influence on insulin and glucagon secretion is glucose-dependent.

eThe active ingredient of exenatide LAR is identical to unretarded exenatide; no studies have reported the action profile of exenatide LAR with respect to insulin and glucagon secretion. fOnly if combined with other agents which can cause hypoglycemic episodes (e.g., sulfonylureas).

Incretin Mimetics DPP-4 Inhibitors

Exenatide Liraglutide Sitagliptin Vildagliptin

H Exenatide Sitagliptin

Exenatide LAR ^■Vildagliptin Placebo Metformin

Insulin glargine ^■Sulfonylurea ^■Insulin Glitazone

^m Liraglutide

Fig. 5. Results from clinical tiials of using incretin mimetics like exenatide injected subcutaneously twice daily, a long-acting release form of exenatide injected sub-cutaneously once weekly (¡eft panels) and liraglutide injected once daily (second column of panels) and DPP-4 inhibitors like sitagliptin (third column of panels) and vildagliptin (rightpanels) on HbAlc (upperpanels) and body weight (lowerpanels). Background colors indicate concomitant antidiabetic treatment (pink: metformin, light green: sulfonylurea; orange: thiazolidinediones; gray: combinations of oral antidiabetic agents). Columns and bars represent mean change from baseline ± SEM. If no comparator is shown, the results are placebo-corrected. Asterisks indicate significant differences to placebo or the respective comparator. Doses are indicated in the top panels; duration of trials is presented in the lower panels. Results are from the following studies: exenatide [119,121,122,124,125,185,237]; exenatide LAR [135]; liraglutide [130-133,238]; sitagliptin [148,170,239-243]); vildagliptin [153,155,156,244-247]. (Extensively modified from Drucker and Nauck 2006 [145]).

[124]. However, while fasting glucose concentrations were reduced to a greater extent with insulin glargine, exenatide treatment elicited greater reductions in postprandial glycemia. The most striking differences between both treatment regimens were observed in body weight. Thus, patients treated with insulin glargine experienced a weight gain of 1.8 kg, whereas patients on exenatide lost on average 2.3 kg over the treatment period [124]. Similar findings have been reported for the comparison of exenatide and premixed insulin aspart, both injected subcutaneously twice daily [125] (Fig. 5).

In April 2005, exenatide (trade name, Byetta) was approved by the FDA for the treatment of type 2 diabetic patients who have not achieved adequate glycemic control on maximally tolerated doses of metformin and/or a sulfonylurea. In Europe, exenatide was approved in November 2006.


Liraglutide (NN2211; Arg34, Lys26-[N-e (y-Glu[N-a-hexadecanoyl])]-GLP-1[7-37]) is a GLP-1 derivative developed by Novo Nordisk, which is currently undergoing phase 3 clinical trials. The plasma half-life of this compound has been extended to ~10-14 h through an amino acid substitution (Arg34^Lys) and the attachment of a glutamic acid and a 16-C-free fatty acid addition to Lys26 [126-128]. The acyl moiety induces non-covalent binding to albumin with ~1-2% of Liraglutide circulating as the non-albumin bound, "free" peptide [129]. These modified pharmacokinetic properties make the compound suitable for once-daily s.c. administration. In clinical studies in patients with type 2 diabetes, liraglutide reduced HbA1c levels by up to 1.75% [130]. Liraglutide induced a moderate weight loss during chronic administration [131-133], similar to the effects of native GLP-1 and exenatide.

Long-acting GLP-1 Receptor Agonists

As a single subcutaneous injection of exenatide does not produce effective glucose control for more than 6-8 h, there is considerable interest in the development of longer-acting GLP-1 receptor agonists, which require less frequent parenteral administration. Exenatide LAR ("long-acting release") is a poly-lactide-glycolide microsphere suspension containing 3% exendin-4 peptide, which exhibits sustained dose-dependent glycemic control in diabetic fatty Zucker rats for up to 28 days following a single subcutaneous injection

[134]. Preliminary experience with exenatide LAR in 45 subjects with type 2 diabetes mellitus indicates a much greater reduction in fasting glucose concentrations and HbA1c following once-weekly administrations of exenatide LAR for 15 weeks

[135]. However, long-term experience with exe-natide LAR in larger numbers of patients has not yet been reported. Exenatide LAR is currently being examined in a Phase 3 trial head to head against twice-daily exenatide.

Properties of exenatide, exenatide LAR, and liraglutide are compared systematically in Table 2.

Additional strategies for development of long-acting GLP-1 receptor agonists include the use of chemical linkers to form covalent bonds between GLP-1 (CJC-1131) or exendin-4 (CJC-1134) (ConjuChem Inc.) [136]. Similarly, recombinant albumin-GLP-1 proteins (e.g., "albugon") have been developed, which mimic the full spectrum of GLP-1 actions in preclinical studies [137]. Although these drugs are expected to exhibit a prolonged pharmaco-kinetic profile suitable for once-weekly dosing in diabetic patients, only limited clinical information is available about the efficacy and safety of these albumin-based drugs in human subjects.

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