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`© SUPPLEMENT TO JAPI JUNE 2010 • VOL 58
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`Historical Overview of Incretin Based Therapies
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`A Bhansali
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`5
`1, D Maji2, PV Rao 3, S Banerjee4, H Kumar
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`Abstract
`A set of physiological responses is activated following meal intake, providing neural and endocrine signals regulating the
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`digestion, absorption and assimilation of ingested nutrients, in which incretin plays an important role. It is believed that
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`the incretin effect is mediated mainly by two incretin hormones: gastric inhibitory polypeptide (GIP) and glucagon-like
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`peptides (GLP)-1. Shortly following release from gut L cells, GLP-1 is rapidly degraded by dipeptide peptidase-4 (DPP-4)
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`to GLP-1(9-36) or GLP-1(9-37) amide, which inactivates native GLP-1. Because of the short plasma half-life of native
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`GLP-1, about 2 minutes, long-acting derivatives should be developed to make GLP-1 treatment therapeutically relevant.
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`It has been demonstrated that DPP-4 inhibition can protect GLP-1 and GIP from degradation, resulting in enhanced
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`insulinotropic activity of infused GLP. Currently, DPP-4 inhibitors on the market are mainly sitagliptin and vildagliptin.
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`Both inhibitors have significant antidiabetic effects when given in monotherapy and can result in further improvements
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`in glycaemic control when given in combination with other antidiabetic agents such as metformin, sulfonylurea (SU) and
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`thiazolidinediones (TZDs ). Exenatide is the first GLP-1 receptor agonist that has been approved £or use as an adjunctive
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`therapy to improve glycaemic control in patients with type 2 diabetes who are not adequately controlled with metformin/
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`SU mono- or combination therapy. Liraglutide is the first once-daily human GLP-1 analogue. In July 2009, Victoza
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`(liraglutide) was approved by the European Medicines Agency (EMA) in the treatment of type 2 diabetes mellitus to
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`achieve glycaemic control. In January 2010, the U.S. Food and Drug Association (FD A) approved Victoza® as an adjunct
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`therapy to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus. It has been shown in
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`different trials that at suggested therapeutic doses of 1.2 mg and 1.8 mg, liraglutide can lower glycated haemoglobin Ale
`(HbA1c) by 1.0-1.5% points as
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`mono-or combination therapy in approximately two-thirds of subjects. GLP-1 receptor
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`agonistshowed a greater effect than the DPP-4 inhibitor in reducing postprandial glucose (PPG) concentrations, a more
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`potent effect in increasing insulin secretion and decreasing postprandial glucagon secretion, a relatively greater effect
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`in reducing caloric intake, and it decreased the rate of gastric emptying.
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`Overall, available evidence supports the use of incretin-based therapies in diabetes patients requiring effective glycaemic
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`and body weight control while minimising the risk of hypoglycaemia.
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`®
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`from gut extracts did not eliminate such effects. This finding
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`The DiscoverHormones y of Incretin
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`indicates that the insulinotropic activity of rat gut extracts can
`and Incretin Effect
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`only be partially related to GIP, and additional insulinotropic gut
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`factors may also be released following oral glucose.4 Using GIP
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`set of physiological responses is activated following meal
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`antiserum, Alam MJ et al. measured circulating GIP levels in 18
`A
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`intake, providing neural and endocrine signals regulating
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`healthy volunteers, and 13 type 2 and 9 type 1 diabetes patients
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`the digestion, absorption and assimilation of ingested nutrients,
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`following ingestion of 75 g of glucose.5 Besides the significant
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`in which incretin, mainly GIP and GLP-1 (Table 1), plays an
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`difference in blood glucose and insulin levels observed between
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`important role.1
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`healthy and diabetes patients, circulating GIP levels at all time­
`The existence of incretins was postulated in the early 20th
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`points and integrated incremental GIP over 120 minutes were
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`century when Murce administered duodenal extract in patients
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`not different among various groups. Results from this study
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`with diabetes and demonstrated reduction in glucosuria.
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`implicated that gut-derived biological active factor other than
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`However, the identity of the putative incretin factor(s) remained
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`GIP also played a significant role in the pathogenesis of the
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`elusive until the purification and characterisation of the first
`disease.
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`incretin, GIP, was discovered in 1973. GIP is a peptide of 42
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`amino acids, produced predominantly in duodenal K cells in
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`the proximal small intestine, and can inhibit acid secretion
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`in denervated gastric pouches.2 Soon after its discovery,
`GIP
`GLP-1
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`insulinotropic properties of GIP were further exposed.3 The
`Gastric inhibitory polypeptide
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`Glucagon-like peptide 1
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`predominant stimulus for GIP secretion is nutrient intake.
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`ls released from L cells in ileum Is released from K cells in
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`Circulating levels of GIP are low in the fasting state and rise
`and colon
`duodenum
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`within minutes of food ingestion.
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`Stimulates insulin response from Stimulates insulin response from
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`beta cells in a glucose-dependent beta cells in a glucose-dependent
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`An early animal experiment has shown that gut extracts
`manner
`manner
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`from rats have insulinotropic activity. However, removal of GIP
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`Inhibits gastric emptying Has minimal effects on gastric
`emptying
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`Reduces food intake and body Has no significant effects on
`weight
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`satiety or body weight
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`Inhibits glucagon secretion from Does not appear to inhibit
`alpha cells
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`glucagon secretion from alpha
`cells
`Deficient in type 2 diabetes Normal levels but decreased
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`responsiveness in type 2 diabetes
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`Table 1: GLP-1 and GIP
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`A decade later, a second peptide with incretin activity was
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`MPI EXHIBIT 1137 PAGE 1
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`© SUPPLEMENT TO JAPI , JUNE 2010 VOL. 58
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`11
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`GLP-1 Gly Thr PheThr Ser Asp Val Ser Ser TyrleuGlu
`Gly Gin Ala Ala Lys Glu Phe lie Alu Trp Leu Val Lys Gly Arg Amide (7-36)Amide
`25
`30
`3536
`Protealytic attack (DPP-4)
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`10
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`15
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`20
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`Byetta@ (Exenatide, Exendin-4, Amylin Pharmaceuticals/ Eli Lilly & Co.)
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`Liraglutide (NN2211; Novo Nordisk)
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`His€t lu Gly Thr PheThr Ser Asp Val Ser SerTyr Leu Gilt Gly Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val.GlyArg Gly
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`C Albumin
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`....... •• C-16 Free Fatty acid
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`(non-covalent binding to albumin)
`------
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`Fig. 1 : Molecular structure of native GLP-1, exenatide & Liraglutide
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`identified after cloning and characterising of the proglucagon
`Summary of Native GLP-1 Studies
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`gene. Proglucagon is a pro-hormone containing two separate
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`peptides: GLP-1 and -2.6 Only the amino acid sequence of GLP-1
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`A single-centre, randomised, parallel, double-blind, placebo­
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`controlled trial was conducted in 40 hospitalised patients who
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`(Figure 1) after residue 7 shows the similarity to glucagon and
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`were randomised to receive continuous infusions of either
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`to other biologically active members of the incretin family,
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`placebo or native GLP-1 at 4 or 8 ng/kg/min for either 16 or 24
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`particularly GIP.7 Circulating concentration of GLP-1 after a meal
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`h per day over 7 days. Results demonstrated that continuous
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`is about 10-fold lower than that of GIP. GLP-1 is rapidly degraded
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`infusion of native GLP-1 dramatically lowered both fasting
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`by DPP-4 into GLP-1(9-36) or GLP-1(9-37) amide following its
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`and postprandial glucose concentrations without any sign of
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`release from gut L cells, which are an inactive form of native
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`tachyphylaxis over 7 days.17 However in this study, it was not
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`GLP-1.8 In addition, the remaining proportion of GLP-1 or GIP
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`possible to completely normalise plasma glucose concentrations
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`will be rapidly cleared from the kidney. In circulation the plasma
`9
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`within the therapeutic window. This study demonstrated that
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`half-life (tv,) of GLP-1 is about 1-2 minutes.
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`native GLP-1 should be given continuously to obtain the most
`The effects of GLP-1 are mediated after binding to its
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`optimal glycaemic control.
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`specific plasma membrane receptors that belong to the 7 trans­
`Because of the short plasma half-life of native GLP-1, there
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`10
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`membrane-domain receptor family coupled to G-proteins.
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`is a need to develop long-acting derivatives to make GLP-1
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`GLP-1 receptors are expressed in the gastrointestinal tract,
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`treatment clinically relevant.
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`endocrine pancreas (a and [3 cells), lung, kidneys, heart and
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`several areas of the brain (hypothalamus, nucleus of the solitary
`DPP-4 Inhibitors
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`tract, area postrema).
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`DPP is an enzyme secreted from endothelial cells that rapidly
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`It is shown that GLP-1(7-36) is a more potent insulin
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`secretagogue than GIP in vitra.12 It has been shown in both
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`degrades both GIP and GLP-1. It has been demonstrated that
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`inhibiting DPP-4 activity can effectively protect GIP from
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`preclinical and human studies that, in vivo, GLP-1 can stimulate
`manner.12, 13 Otherinsulin secretion in a glucose-dependent
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`degradation, resulting in enhanced insulinotropic activity of
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`infused GIP.17 Furthermore, in the presence of the DPP-4 inhibitor
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`biological effects, which include inhibiting glucagon secretion,
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`(valine-pyrrolidide), the proportion of intact GLP-1 released
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`decelerating gastric emptying and reducing food intake with
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`from the perfused porcine ileum is increased under both basal
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`GLP-1, were also demonstrated. Furthermore, previous studies
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`18 In the light of these findings, DPP-4
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`and stimulated conditions.
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`indicated that GLP-1 promoted enhanced glucose disposal in
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`inhibitor has been proposed as a new therapy for the treatment
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`peripheral tissues. In addition, activation of the incretin receptors
`19
`of type 2 diabetes.
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`on [3 cells resulted in other longer term effects such as enhanced
`14
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`[3-cell proliferation and promoted resistance to [3-cell apoptosis.
`The main DPP-4 inhibitors on the market are sitagliptin
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`(Januvia, Merck & Co., Inc.) and vildagliptin (Galvus, Novartis
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`Interestingly, GLP-1 may also have other beneficial effects
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`AG). Both inhibitors have good oral bioavailability and a
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`that are independent from its effects on glucose metabolism.
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`relatively long duration of action. Once-daily dosing of DPP-4
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`Animal studies showed that GLP-1 protected myocardial cells
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`inhibitors can give 70-90% inhibition of plasma DPP-4 activity
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`from ischemic and reperfusion injury, prevented endothelial
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`over a 24-h period. DPP-4 inhibitors (glycated haemoglobin A
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`dysfunction, promoted endothelium in dependent artery
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`relaxation and increased diuresis and natriuresis.15 In subjects
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`] reduction by 0.7%) can be administrated as monotherapy
`[HbA
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`and result in further improvement in glycaemic control when
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`with type 2 diabetes, studies showed that GLP-1 reduced systolic
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`given in combination with other antidiabetic agents including
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`blood pressure (SBP) and deceased plasma concentrations
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`SU and TZDs.20 Ahren et al. demonstrated that after
`metformin,
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`of triglyceride and plasminogen activator inhibitor (PAI-1)
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`and brain natriuretic peptide (BNP), which are considered
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`12 weeks' oral administration with DPP-4 inhibitor, vildagliptin
`16
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`biomarkers of cardiovascular diseases.
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`in patients with type 2 diabetes, long-term glycaemic control,
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`1,
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`1,
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`11,
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`MPI EXHIBIT 1137 PAGE 2
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`12
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`© SUPPLEMENT TO JAPI JUNE 2010 • VOL 58
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`GLP-1 receptor DPP-4 inhibitors
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`Table 2: GLP-1 receptor agonist and DPP-4 inhibitors
`The most common adverse effects experienced by patients
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`who were treated with exenatide were nausea and vomiting.
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`However, incidence of gastrointestinal adverse effects was
`a onist
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`significantly reduced with step-wise dose escalation of exenatide.
`Subcutaneous Oral
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`Administration
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`Currently there are no reports of hypersensitivity reactions to
`up to 24h/d 3-6 h (meals)
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`exenatide. Yet the amino acid sequence of exenatide shares
`GLP-1/receptor
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`Pharmacological Close to physiological
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`slightly more than 50% of its identity with human native GLP-1.28
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`agonist concentration
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`This may explain why the second most reported adverse event
`Action through GLP-1 receptor GLP-1 receptor, GIP-
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`associated with exenatide therapy was antibody formation.
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`(exclusively) receptor and others
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`Approximately 40-67% of patients treated with exenatide had
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`GLP-1 receptor Pharmacological Enhancement of
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`positive anti-exenatide antibody titres at the end of the study.29
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`activation GLP-lR endogenous GLP-1 and GIP
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`30 In another open-label, single-arm, multicentre, 24-week study
`potentiation
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`in patients who were re-exposed to exenatide, an anti-exenatide
`HbA reduction -0.8-1.8% ss-0.5-1.1 %
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`antibody was developed in more than 70% of patients.31 Among
`Weight change Satiety and Weight neutral
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`those who developed an antibody, around 40% of patients did
`weight loss
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`not have HbA reduction. However, the study design limitations
`Beta-cell mass effects Robust Probable
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`(overall sample size and disparity between subgroups) and the
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`(animal experiments)
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`dissimilar diabetes treatment at study initiation do not allow for
`Adverse events Nausea and Well tolerated
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`conclusions to be drawn on the HbA findings.
`vomitin
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`•
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`1,
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`1,
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`1,
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`t½
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`21
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`significantly reduced.
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`23
`24
`•
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`25
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`Pancreatitis has been reported as a rare side effect of exenatide
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`prandial plasma glucose, as well as fasting plasma glucose were
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`therapy principally through post-marketing surveillance. A
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`summary of the first 30 cases of individuals taking exenatide
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`Previous clinical trials also indicated that a DPP-4 inhibitor
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`who developed acute pancreatitis was published in 2008.32
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`such as vildagliptin improved acute j3-cell function by
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`The authors noted that in at least 90% of these subjects, there
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`showing that oral administration with vildagliptin increased
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`were other factors that could predispose the individuals to
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`insulin response in relation to the glucose response after meal
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`pancreatitis. Analysis of pancreatitis in subjects with type 2
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`ingestion,22 and increased estimated insulin secretory rate after
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`diabetes notably suggests that their risk is increased threefold
`meal ingestion.
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`over nondiabetic subjects.33 Since only a fraction of this risk
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`could be attributed to biliary pancreatitis, it seems likely that
`It was shown in clinical trials that both vildagliptin and
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`other factors such as obesity and hypertriglyceridemia might
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`sitagliptin were tolerable and safe with an adverse events
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`contribute to the increased risk in this population.
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`profile similar to that of placebo-administered patients. Also,
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`the reported numbers of hypoglycaemia were very low during
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`A recent study compared the effects of GLP-1 receptor
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`DPP-4 treatment. Unlike GLP-1 receptor agonist or human GLP-1
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`agonist exenatide with that of DPP-4 inhibitor sitagliptin on
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`analogue, most studies with DPP-4 inhibitor reported that the
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`postprandial glucose (PPG) concentrations, insulin and glucagon
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`drug had no effect on blood pressure. Moreover, in contrast to
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`secretion, gastric emptying, and caloric intake.34 Although
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`limited by the short treatment duration (2 weeks), the study
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`the reduction in body weight seen after treatment with GLP-1
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`showed that the GLP-1 receptor agonist had a better effect than
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`analogues, DPP-4 inhibitors were body weight neutral.
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`the DPP-4 inhibitor in reducing PPG concentrations (Table 2).
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`DPP-4 inhibitors may be considered as an additional choice
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`Furthermore, exenatide was more potent in terms of increased
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`and possible alternative treatment to currently available
`insulin secretion, decreased postprandial glucagon secretion and
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`antidiabetic agents in type 2 diabetes. However, long-term safety
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`reduced caloric intake as compared with sitagliptin. Results also
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`and efficacy data are still required.
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`indicated that in contrast to exenatide, sitagliptin had no effect
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`on gastric emptying.
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`ptor agonist
`GLP-1 rece
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`Exenatide (Figure 1) has been developed by Amylin
`Human GLP-1 analogue
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`Pharmaceuticals, Inc. and Eli Lilly and Company for diabetes
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`Liraglutide (Figure 1) is a once-daily human GLP-1 analogue,
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`treatment under the name Byetta®. It is a synthetic peptide,
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`which has been developed by Novo Nordisk.
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`and originally identified in the lizard Heloderma spectum. As
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`In liraglutide, lysine at position 34 of human native GLP-1
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`a GLP-1 receptor agonist ( designating a synthetic replica of
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`is substituted by arginine, and a palmitic acid chain (C-16)
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`exendin 4), exenatide is administered twice daily.26 Exenatide
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`is attached to an e-amino group of lysine at position 26 via
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`received FDA approval as an adjunctive therapy to improve
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`glutamate spacer. Liraglutide has 97% amino acid homology with
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`glycaemic control in patients with type 2 diabetes who are
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`the human GLP-1 peptide and is produced by a recombinant
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`inadequately controlled with metformin, SU and TZD mono-or
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`DNA technology in Saccharomyces cerevisiae.
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`combination therapy.
`®
`In July 2009, Victozawas approved by EMA in the
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`
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`Clinical trials with exenatide demonstrated that exenatide
`
`
`
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`treatment of type 2 diabetes mellitus to achieve glycaemic
`
`
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`stimulated insulin secretion in a glucose-dependent manner,
`
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`control in combination with 1) metformin or SU, in patients
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`and suppressed glucagon secretion, slowed gastric emptying
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`with insufficient glycaemic control despite maximal tolerated
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`and reduced food intake in patients with type 2 diabetes. It also
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`dose of monotherapy with metformin or SU, or 2) metformin
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`showed that exenatide administration improved long-term
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`and SU or metformin and TZD in patients with insufficient
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`glycaemic control.27 Exenatide may delay or even halt the
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`glycaemic control despite dual therapy. In January 2010, the FDA
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`progression of type 2 diabetes due to its effect on �-cell mass
`®
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`and function. However, this effect has to be further evaluated
`
`
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`approved Victozaas an adjunct to diet and exercise to improve
`in long-term clinical trials.
`
`
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`
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`glycaemic control in adults with type 2 diabetes mellitus. In
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`MPI EXHIBIT 1137 PAGE 3
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`© SUPPLEMENT TO JAPI , JUNE 2010 VOL. 58
`
`13
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`Table 3 : Liraglutide vs. exenatide
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`the next 15 years.
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`Another safety concern is a possible increased risk of
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`Liraglutide Exenatide
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`pancreatitis attributable to drugs that act through the GLP-1
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`Homology with native 97%
`50%
`pathway.36 This concern arises
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`from post-marketing reports
`GLP-1
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`submitted to the FDA Adverse Event Reporting System regarding
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`Administration Injection once daily Injection twice daily
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`pancreatitis associated with the use of exenatide and sitagliptin,
`
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`Glucose-dependent insulin Yes
`Yes
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`both of which act through this pathway. In the phase 2 and phase
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`secretion and glucagon
`
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`3 trials of liraglutide, there were seven cases of pancreatitis
`Yes
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`Slows gastric emptying Little
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`
`reported among the 4257 patients treated with liraglutide, and
`Effect on HbA
`0.9-1.6%
`1-1.6%
`
`
`
`only one case in the 2381 patients in the comparator group. The
`Effect on body weight
`
`Weight loss Weight loss
`
`
`small number of events makes it difficult to draw conclusions
`Effect on FPG
`Good
`Modest
`
`
`
`about causation, but this imbalance, along with concerns about
`Effect on PPG
`Modest
`Good
`
`
`
`
`
`exenatide and sitagliptin, led the FDA to require the sponsor to
`Effect on CVD risk factors Improvement Improvement (with
`
`
`
`
`
`
`perform post-approval mechanistic studies in animals and to
`weight loss)
`
`
`conduct an epidemiologic evaluation using a large insurance­
`Common side effects Some nausea
`Nausea
`
`
`
`claims database. Prescribers and patients should be aware
`Pancreatitis Rare
`Rare
`
`
`
`that the common side effects of liraglutide include nausea and
`
`Rodent medullary thyroid Signal
`
`Little or no signal
`
`vomiting, but persistent or severe nausea and vomiting should
`cancer
`
`
`be carefully evaluated since they may be early manifestations
`
`
`
`
`
`India, Victoza® is approved for "use in type 2 diabetes". So it
`
`
`of pancreatitis and therefore warrant prompt discontinuation
`
`
`can be used in monotherapy as well as in combination with
`
`
`
`of liraglutide treatmentRecently, in a 26-week randomised,
`
`
`
`
`other antidiabetic agents. At the suggested therapeutic doses of
`
`
`
`
`
`parallel-group, multinational, open-label trial, clinical efficacy
`
`
`1.2 mg and 1.8 mg in several phase 3 trials, liraglutide lowered
`37 In this
`
`
`
`and safety of liraglutide was compared with exenatide.
`
`
`
`
`
`HbAby 1.0-1.5% in approximately two-thirds of patients when
`
`
`
`
`trial, 464 adults with type 2 diabetes, who were inadequately
`
`
`
`
`administered as monotherapy or in combination with other oral
`
`
`
`
`controlled on maximally tolerated doses of metformin, SU or
`
`
`
`antidiabetic drugs (OADs).23 The magnitude of HbAreduction
`
`
`both, were treated. Results showed that liraglutide reduced
`
`
`
`was significantly greater with liraglutide than with a number
`mean HbA
`
`
`significantly more than exenatide with a difference
`
`
`
`of currently available type 2 diabetes treatments. A significant
`
`
`
`of 0.33%. More patients achieved a HbAvalue of less than
`
`reduction in weight and a decrease in SBP were documented
`
`
`7% in the liraglutide group than exenatide (54% vs. 43%). Both
`
`across a number of the phase 3 trials.
`
`
`
`drugs resulted in similar weight loss, and were well tolerated,
`Liraglutide was generally well tolerated. The most common
`
`
`
`
`
`but nausea was less persistent and minor hypoglycaemia less
`
`
`
`
`adverse events with liraglutide treatment were related to the
`
`
`frequent with liraglutide than with exenatide (Table 3).
`
`
`
`gastrointestinal system, and the most frequently reported side
`In addition, recombinant albumin-GLP-1 fusion proteins
`
`
`
`
`
`
`effect was nausea. These adverse events were mostly mild and
`
`
`
`have been developed that mimic the full range of GLP-1 actions.
`
`
`
`
`occurred during the initial period of treatment. Development of
`
`
`
`Albiglutide is one example: it stimulates GLP-1 receptor­
`
`
`
`an anti-liraglutide antibody was rare. In addition, no neutralising
`
`
`
`
`
`dependent pathways coupled with glucose homeostasis and
`
`
`
`
`
`effect of such an antibody was observed in the clinical trials.
`
`
`
`
`
`gastrointestinal motility, improves insulin secretion and reduces
`In preclinical carcinogenicity studies, liraglutide was
`
`
`
`
`
`
`
`
`
`blood glucose.38 Little clinical information is currently available
`
`
`
`associated with a dose-dependent increase in the frequency
`
`
`
`
`regarding this drug's safety in humans. Taspoglutide is a
`
`
`
`of thyroid C-cell tumours in rats and mice.35 Calcitonin was
`
`
`
`
`matrix-free sustained-release formulation for GLP-1 now being
`
`
`
`measured in the liraglutide phase 3a trials as a marker to monitor
`
`
`converted for phase 3 studies.
`
`
`
`
`thyroid C-cell mass. There were no clinical signals of increased
`Semaglutide (NN9535) is a once-weekly human GLP-1
`
`
`
`
`
`
`
`
`C-cell tumours (i.e., medullary thyroid carcinoma) with
`
`
`
`analogue that is being developed by Novo Nordisk for the
`
`
`
`
`liraglutide in humans and non-human primates. In the controlled
`
`
`
`treatment of type 2 diabetes. Semaglutide lowers blood glucose
`
`
`
`clinical trials, increases in calcitonin levels occurred in a slightly
`
`
`
`through stimulating release of insulin and lowers body weight.
`
`
`
`
`higher percentage of the patients treated with liraglutide than in
`
`
`The phase 2 programme with more than 400 people was
`
`
`
`
`
`
`control patients; although the increases represented shifts from
`
`
`
`completed in 2009. Novo Nordisk is also developing an oral
`
`
`
`
`
`below to slightly above the assay's detection limit (0.7 ng/L),
`
`
`
`GLP-1 (NN9924) to increase the convenience of GLP-1 treatment
`36 Furthermore,
`
`
`calcitonin levels were still within normal ranges.
`
`
`
`
`of type 2 diabetes. It is more resistant to enzymatic degradation,
`
`
`
`
`data from a long-term study did not reveal any notable difference
`
`
`
`
`
`and its first phase 1 clinical trial started January 2010.
`
`
`
`
`in mean calcitonin levels between liraglutide and control groups
`In conclusion, available evidence indicates that unlike current
`
`
`
`
`
`
`
`
`
`over 2 years of follow-up. The FDA concluded that increases in
`
`antidiabetic treatments, incretin-based therapies possess great
`
`
`
`
`the incidence of carcinomas among rodents translated into a
`
`
`
`
`potential in offering effective glycaemic and weight control to
`
`
`
`
`
`low risk for humans, because statistically significant increases
`
`
`
`
`patients with type 2 diabetes. This new therapeutic modality
`
`
`
`occurred only at drug exposure levels many times those
`
`
`
`
`
`does not increase the risk of hypoglycaemia. However, more
`
`
`
`
`
`anticipated in humans, and the increase in cancers did not affect
`
`
`
`data on long-term safety and the cost-effectiveness analysis of
`
`
`
`
`
`overall survival rates. However, it is difficult to extrapolate
`
`
`such treatment are still needed.
`
`
`
`
`findings from studies in animals to humans. To further explore
`
`
`
`
`
`possible associations between medullary thyroid cancer and
`Acknowledgements
`
`
`
`
`liraglutide use, the FDA exercised its authority under the Food
`
`
`
`and Drug Administration Amendments Act to require additional
`
`The authors wish to thank Yang N, of Novo Nordisk
`
`
`
`
`
`studies in animals and the establishment of a cancer registry to
`
`
`International Operations for providing medical editorial
`
`
`
`monitor the annual incidence of medullary thyroid cancer over
`assistance.
`
`1,
`
`
`
`1,
`
`1,
`
`1,
`
`1,
`
`MPI EXHIBIT 1137 PAGE 4
`
`

`

`14
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`© SUPPLEMENT TO JAPI JUNE 2010 • VOL 58
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