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Lixisenatide – Once-daily Glucagon-like Peptide-1 Receptor Agonist in the Management of Type 2 Diabetes Figure 1: Structure of the Glucagon-like Peptide-1 Receptor Agonists Liraglutide, Exenatide and Lixisenatide Human GLP-1 Hls Aln Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Lle Ala Trp Leu Val Lys Arg Gly Gly Liraglutide


Hls Aln Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Lle Ala Trp Leu Val Arg Arg Gly Glu


Gly C-15 fatty acid Exenatide Lixisenatide Hls Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Lle Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Hls Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Lle Glu Trp Leu Lys Asn Gly Pro Ser Ser Gly Ala Pro Pro Ser Lys Lys Lys Lys Lys Lys Gly


The amino acid sequence of three glucagon-like peptide-1 (GLP-1) receptor agonists are shown in comparison to the sequence of human GLP-1; differences with human GLP-1 are indicated by blue circles; differences between exenatide and lixisenatide are shown by purple circles. Sources: data taken from Werner, et al., 20109


and Nauck, 201132 with permission.


Figure 2: Dose-dependent Effects of Lixisenatide On Glycosylated Haemoglobin in a Phase II Clinical Trial Placebo


QD (once daily)


-0.9 -0.7 -0.5 -0.3 -0.1


-0.8 -0.6 -0.4 -0.2 0


-1 Base overall mean: HbA1C=7.55 %


HbA1C = glycosylated haemoglobin; LS = least squares. No significant differences were seen between once daily and twice daily dosing. Source: adapted from Ratner RE, et al., 201024 with permission.


The insulin secretion pattern was studied in isolated pancreas from male Zucker diabetic fatty (ZDF) rats treated with lixisenatide and compared with isolated pancreas from lean and obese ZDF rats not treated with lixisenatide.17


Biphasic insulin secretion was preserved


in the lixisenatide-treated obese ZDF rats, similar to what happened in lean controls, but was absent in older obese ZDF rats.17


In a study


using human islet cells, lixisenatide showed dose-dependent improvement of glucose-stimulated insulin secretion.18


Improvement of oral glucose tolerance with lixisenatide was shown in animal studies (obese ZDF rats, db/db mice and dogs).12,19,20 Decreased post-prandial glucose excursion following a mixed meal was seen in mongrel dogs.21 levels12,19,20


and glycosylated haemoglobin (HbA1C)19


Marked reductions in glucose were shown in


lixisenatide-treated animals compared with saline-treated animals.


In a comparison study of dogs treated with lixisenatide or liraglutide, blood glucose excursion following glucose challenge in oral glucose tolerance tests was significantly lower in dogs treated with lixisenatide. A similar effect was seen in C57BL/6J mice following a liquid meal.22


Starting at different doses, both


lixisenatide (1 µg/kg) and liraglutide (≥500 µg/kg) inhibited gastric emptying in Wistar rats.22


Lixisenatide was shown to be cardioprotective in a study on isolated Langendorff-perfused rat hearts in which the left anterior descending coronary artery was transiently occluded for 45 minutes and then reperfused for 120 minutes. There was significant reduction in the infarct size with lixisenatide compared with vehicle control.23


EUROPEAN ENDOCRINOLOGY


Table 1: Pharmacokinetics of Available Glucagon-like Peptide-1 Receptor Agonists


GLP-1 Receptor t½ Agonist


Human GLP-1 ~1–2 minutes31 Exenatide Liraglutide


~2.4 hours32 ~13 hours32


Exenatide LAR ~2 weeks36 Lixisenatide


~2.6 hours37


GLP-1 Receptor Affinity


--


~1x9 ~1x34 ~1x9 ~4x9


GLP-1 = glucagon-like peptide-1; LAR = long-acting release. Dosing


Frequency --


Twice daily33 Once daily35


Once weekly36 Once daily24


5 μg


n=107 -0.18


n=55 -0.47


p=0.0056


n=50 -0.50


p=0.0033


n=53 -0.69


p<0.0001


n=51 -0.76


p<0.0001


n=51 -0.65


p<0.0001


n=54 -0.78


p<0.0001


n=52 -0.75


p<0.0001 10 μg 20 μg 30 μg 5 μg BID (twice daily) 10 μg 20 μg 30 μg


n=53 -0.87


p<0.0001


Phase II Studies


A dose-finding study was undertaken in patients with type 2 diabetes not controlled by metformin. This was a multinational, 13-week, randomised, double-blind, parallel-group, placebo-controlled study that enrolled 542 patients inadequately controlled after at least three months of metformin therapy.24


Participants had a mean age of 56 ± 9 years with mean disease duration of 6.6 ± 5 years, mean body mass


index (BMI) of 31.9 ± 4 kg/m2, and mean baseline HbA1C of 7.5 ± 0.6 %. Participants were randomised to one of 12 groups: lixisenatide (5, 10, 20 or 30 µg) administered once or twice daily or four volume-matched placebo treatments administered twice daily. All lixisenatide groups


experienced dose-dependent reductions in HbA1C ranging from 0.47 % to 0.76 % in the once-daily regimen and from 0.65 % to 0.87 % in the twice-daily regimen compared with placebo (see Figure 2).24


Secondary efficacy endpoints were the percentage of patients achieving HbA1C of <7 % and <6.5 %, changes in body weight, fasting


13


LS mean change in HbA1C (%) at endpoint


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