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`ELSEVIER
`Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase
`IV in the treatment of type 2 diabetes mellitus
`Jens Juul Holst and Carolyn F Deacon
`
`Proof-of-concept for the efficacy of a glucagon-like peptide 1
`(GLP-1)-based therapy of patients with type 2 diabetes
`was provided in 2002 by means of prolonged continuous
`subcutaneous infusion of native GLP-1. Since then, several
`long-acting analogues of GLP-1, as well as inhibitors of
`dipeptidyl peptidase IV, the enzyme that rapidly inactivates
`endogenous GLP-1, have demonstrated efficacy in long term
`clinical trials.
`
`Addresses
`Department of Medical Physiology, University of Copenhagen,
`The Panum Institute, DK-2200 Copenhagen N, Denmark
` e-mail: holst@mfi.ku.dk
`
`Current Opinion in Pharmacology 2004, 4:589–596
`
`This review comes from a themed issue on
`Endocrine and metabolic diseases
`Edited by Julia Buckingham and Brian Furman
`
`Available online 14th October 2004
`
`1471-4892/$ – see front matter
`# 2004 Elsevier Ltd. All rights reserved.
`
`DOI 10.1016/j.coph.2004.08.005
`
`Abbreviations
`ADA
`American Diabetes Association
`DPP-IV
`dipeptidyl peptidase IV
`GLP-1
`glucagon-like peptide 1
`HbA1c
`glycated haemoglobin
`SU
`sulfonylurea
`T2DM
`type 2 diabetes mellitus
`
`Introduction
`Glucagon-like peptide 1 (GLP-1) is a 30 amino acid
`peptide secreted by intestinal L-cells in response to
`meal
`ingestion. It functions as one of the incretin
`hormones; that is, the gut hormones that enhance
`nutrient-stimulated insulin secretion more than the
`nutrients themselves,
`if given intravenously [1]. In
`patients with type 2 diabetes mellitus (T2DM), the
`incretin effect is severely impaired or absent [2], and it
`is probable that this deficiency contributes to the defi-
`cient insulin secretion that characterizes T2DM [3].
`The causes of the deficient incretin effect in patients
`with T2DM have been analysed [3] and seem to com-
`prise an impaired secretion of GLP-1, an impaired
`sensitivity of
`the b-cell
`to the actions of GLP-1
`(whereas the efficacy is at least partially preserved)
`[4], and an abolished effect of glucose-dependent insu-
`linotropic polypeptide on second-phase insulin secre-
`
`tion [5]. In agreement with this, intravenous infusions of
`GLP-1 in near physiological amounts have been shown
`to almost completely normalize glucose metabolism in
`patients with T2DM [6,7]. Because of this, there is
`currently great interest in trying to develop GLP-1 as a
`new therapeutic agent for T2DM [8]. However, GLP-1
`has many more actions than merely stimulating insulin
`secretion, and all of these seem to be expedient in the
`context of diabetes therapy.
`
`Actions of GLP-1
`GLP-1 potently stimulates insulin secretion in a strictly
`glucose-dependent manner. Binding of GLP-1 to the
`GLP-1 receptor of b-cells causes activation — via a
`stimulatory G protein — of adenylate cyclase, resulting
`in the formation of cAMP. Subsequent activation of
`protein kinase A and the cAMP-regulated guanine
`nucleotide exchange factor II (also known as Epac2) leads
`to a plethora of events including altered ion channel
`activity,
`intracellular calcium handling and enhanced
`exocytosis of insulin-containing granules [1]. The clinical
`implication of the dependence on blood glucose concen-
`trations at or above normal fasting glucose levels is that
`GLP-1 is incapable of causing profound hypoglycaemia
`(except perhaps in the presence of sulfonylurea (SU)
`drugs; see below).
`
`GLP-1 stimulates all steps of insulin biosynthesis, as well
`as insulin gene transcription [9], thereby providing con-
`tinued and augmented supplies of insulin for secretion.
`Activation of PDX-1, a key regulator of islet growth and
`insulin gene transcription, might be involved [10]. In
`addition, GLP-1 upregulates genes for
`the cellular
`machinery involved in insulin secretion, such as glucoki-
`nase and glucose transporter-2 genes [10].
`
`GLP-1 has been shown to have trophic effects on b-cells
`[11]: not only does it stimulate b-cell proliferation [12,13]
`but it also enhances the differentiation of new b-cells
`from progenitor cells in the pancreatic duct epithelium
`[14]. Proliferation was also induced in aging glucose-
`intolerant rats, with a resulting improvement in glucose
`tolerance [15]. Most recently, GLP-1 has been shown to
`inhibit apoptosis of b-cells,
`including human b-cells
`[16]. Because the normal number of b-cells is main-
`tained in a balance between apoptosis and proliferation,
`this observation is of considerable interest, and also raises
`the possibility that GLP-1 could be useful in conditions
`with increased b-cell apoptosis (e.g. when cells are
`exposed to the toxic effects of hyperglycaemia and
`hyperlipidaemia).
`
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`
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`
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`590 Endocrine and metabolic diseases
`
`GLP-1 also strongly inhibits glucagon secretion. In
`patients with T2DM, there is fasting hyperglucagonemia
`as well as exaggerated glucagon responses to meal inges-
`tion [17]; therefore, it is likely that the hyperglucagone-
`mia contributes to the hyperglycemia of the patients.
`This effect could be as important as the insulinotropic
`effects.
`
`Further important effects of GLP-1 include inhibition of
`gastrointestinal secretion and motility, notably gastric
`emptying [18,19]. This effect is desirable in patients with
`diabetes because the slower gastric emptying rate reduces
`postprandial glucose excursions; the clinical importance
`of this is evident from the use of another potent gastric
`inhibitor, amylin, for diabetes treatment [20].
`
`GLP-1 also inhibits appetite and food intake. This has
`been demonstrated in both normal subjects, obese sub-
`jects and subjects with T2DM [21], and it is likely that
`GLP-1 is one of the physiological regulators of appetite
`and food intake.
`
`GLP-1 has cardiovascular actions, as it has been known
`for some time that there are GLP-1 receptors in the heart
`[22]. A physiological function for these receptors was
`indicated in recent studies in mice lacking the GLP-1
`receptor, which exhibit impaired left ventricular contrac-
`tility and diastolic functions, as well as impaired responses
`to exogenous epinephrine [23]. Recent studies in rats
`showed that GLP-1 protects the ischaemic and reper-
`fused myocardium in rats by mechanisms independent of
`insulin [24]. These findings could have important clin-
`ical implications. Thus, Nikolaidis et al. [25] studied
`patients treated with angioplasty after acute myocardial
`infarction, with postoperative left ventricular ejection
`fractions as low as 29%. In these patients, GLP-1 admin-
`istration significantly improved the ejection fraction to
`39% and improved both global and regional wall motion
`indices. Cerebral GLP-1 receptor stimulation increases
`blood pressure and heart rate and activates autonomic
`regulatory neurons in rats, leading to downstream activa-
`tion of cardiovascular responses [26]. Furthermore, it has
`been suggested that catecholaminergic neurons in the
`area postrema expressing the GLP-1 receptor may link
`peripheral GLP-1 and central autonomic control sites that
`mediate the diverse neuroendocrine and autonomic
`actions of peripheral GLP-1 [27]. It should be noted,
`however, that peripheral administration of GLP-1 in
`humans is not associated with changes in blood pressure
`or heart rate [28].
`
`intracerebroventricular
`showed that
`studies
`Recent
`administration of GLP-1 was associated with improved
`learning in rats and neuroprotective effects [29,30]. GLP-
`1 has been proposed as a new therapeutic agent for
`neurodegenerative diseases, including Alzheimer’s dis-
`ease [31].
`
`Actions of native GLP-1 in type 2 diabetes
`These actions render GLP-1 highly attractive as a ther-
`apeutic agent, but an extremely rapid enzymatic degra-
`dation of the molecule makes it unsuitable for injection
`therapy. This metabolism, which is attributable to the
`actions of the ubiquitous enzyme dipeptidyl peptidase IV
`(DPP-IV), results in a half-life for GLP-1 of only about
`two minutes [32]; furthermore, the actions on metabolism
`of single subcutaneous injections are short-lived. How-
`ever, continuous subcutaneous infusion using insulin
`pumps was employed in a study where the hormone
`was given for six weeks to probe its effects in patients
`with T2DM [28]. Patients were evaluated before, after
`one week and after six weeks of treatment. No changes
`were observed in the saline-treated group, whereas in the
`GLP-1 group fasting and average plasma glucose con-
`centrations were lowered by approximately 5 mmol/l;
`glycated haemoglobin (HbA1c; a long-term [months]
`measure of mean plasma glucose concentrations)
`decreased by 1.2%; free fatty acids were significantly
`lowered; and the patients had a gradual weight loss of
`approximately 2 kg. In addition, insulin sensitivity (as
`determined by a hyperinsulinaemic euglycaemic clamp)
`almost doubled, and insulin secretion capacity (measured
`using a 30 mmol/l glucose clamp + arginine) greatly
`improved. There was no significant difference between
`results obtained after one and six weeks of treatment, but
`there was a tendency towards further improvement in
`plasma glucose as well as insulin secretion. There were
`few side effects and no differences between saline- and
`GLP-1-treated patients in this respect. Of note, the dose
`selected was not necessarily maximal (and was not asso-
`ciated with side effects). Further studies using the same
`technique indicated that a higher infusion rate might be
`even more effective [33].
`
`The conclusion drawn was that GLP-1-based therapy has
`unusually attractive potential
`in diabetes treatment.
`Therefore, two strategies have been pursued: the devel-
`opment of DPP-IV-resistant analogues of GLP-1 and
`development of inhibitors of DPP-IV.
`
`Resistant analogues or activators of the
`GLP-1 receptor
`Exendin 4
`DPP-IV cleaves peptides at the penultimate N-terminal
`amino acid residue if this is Pro or Ala (Ala in GLP-1).
`Therefore, substitution of this residue can render the
`molecule resistant [34]. However, this only prolongs the
`half-life of the molecule from 2 min to 4–5 min, because
`renal extraction and degradation effectively clears the
`plasma of substituted, as well as unsubstituted, GLP-1
`[35]. A prolonged effect therefore requires changes that
`decrease renal elimination. Exendin 4, isolated from the
`saliva of the lizard Heloderma suspectum (also called the
`Gila monster) is such a molecule. It is 53% homologous
`to GLP-1 (but is not the GLP-1 of the Gila monster) and
`
`Current Opinion in Pharmacology 2004, 4:589–596
`
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`Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus Holst and Deacon 591
`
`is cleared from plasma at a rate of 1.8 ml/kg/min, which is
`similar in magnitude to the normal glomerular filtration
`rate [36]. Otherwise, exendin 4 appears to act in humans
`in a manner identical to that of GLP-1 [36]. The clinical
`usefulness of exendin 4 was evaluated in a proof-of-
`concept Phase II study recently reported by the Amylin
`Corporation [37]. Exendin 4 (now named AC2993 or
`Exenatide) was injected subcutaneously twice or three
`times daily for four weeks in patients already treated
`with metformin, SU or both. In all groups, there was a
`reduction in HbA1c ranging from 0.7% to 1.1%. The
`most common adverse effect was transient mild to mod-
`erate nausea. Mild hypoglycaemia was reported in about
`a third of the patients also treated with SU. This finding
`was not substantiated by measurements, but could
`reflect a partial uncoupling of the glucose dependency
`of the insulinotropic actions of GLP-1 by SU (as dis-
`cussed above) but, conversely, also illustrates the
`potency of this combination. In late 2003, the company
`completed Phase III studies with a similar design, in
`which Exenatide was given as twice-daily injections
`initially in doses of 5 mg for one month, and subse-
`quently at 5 mg or 10 mg per injection for five months.
`This approach reduced the tendency to cause initial
`nausea. Mild hypoglycemia was noted in 35% of the
`patients also treated with SU. The average drop in
`HbA1c over six months of treatment was 1% from a
`base line value >8%, and values below 7% (the currently
`recommended target) were observed in 40–46% of
`patients (at 10 mg). Antibodies against Exenatide were
`observed in approximately one-fifth of the patients, but
`this was unrelated to the clinical efficacy. Recent studies
`presented by the Amylin Corporation at the American
`Diabetes Association (ADA) in Orlando 2004 indicated
`that subcutaneous injections of a stable GLP-1 receptor
`agonist (exendin 4) twice-daily for a year to individuals
`with T2DM were associated with a gradual weight loss,
`with no signs of impaired efficacy over time. Indeed, the
`efficacy of this appetite-reducing effect was demon-
`strated convincingly not only in these clinical studies
`but also in recent studies involving lifetime administra-
`tion of exendin 4 to rats. The treated animals survived
`longer than controls, an effect that was thought to result
`from decreased food intake and hence a significantly
`lower body weight [38].
`
`It can be concluded that Exenatide provides considerable
`additional glycemic control, even in patients inade-
`quately treated with oral antidiabetic agents, and also
`causes weight loss, which can be predicted to provide
`further improvements of metabolism. However, two
`injections of exenatide per day do not provide a full
`24-hour exposure to the GLP-1 receptor agonist, which
`is considered important for the full anti-diabetic effect
`of intravenously administered GLP-1 [39]; this might
`explain a less conspicuous effect on fasting plasma
`glucose.
`
`Albumin-bound GLP-1 derivatives
`Another approach has been to bind a GLP-1 analogue
`to albumin to exploit the slow elimination kinetics of
`this molecule in the body. Three different methods
`have been employed to achieve this: NovoNordisk in
`Denmark developed an acylated derivative of GLP-1
`that binds non-covalently to albumin; the Canadian
`company, Conjuchem, created an analogue of GLP-1
`which, after injection, establishes a covalent bond with
`albumin; and the American company Human Genome
`Sciences has generated a fusion protein consisting of a
`DPP-IV-resistant GLP-1 analogue covalently bound to
`human albumin.
`
`NN2211
`The selection of the NovoNordisk compound NN2211
`for clinical development was recently described [40]. It
`consists of native GLP-1, in which a C16 acyl chain is
`attached via a glutamoyl spacer to Lys26 (Lys34 was
`substituted by Arg). The compound shows a slow release
`from the subcutaneous injection site and binds to albu-
`min, which renders the molecule resistant to DPP-IV and
`allows at least the bound fraction to escapes renal elim-
`ination. This resulted in a half-life in healthy subjects and
`patients with T2DM of 10–12 h following a single sub-
`cutaneous injection [41] and thereby adequate 24 h expo-
`sure after a single daily injection. In addition, in chronic
`treatment, the large post-injection concentration excur-
`sions caused by less long-lived analogues that might be
`associated with side effects such as nausea are likely to be
`avoided, as shown in studies in pigs [42]. The analogue
`itself is equipotent to GLP-1 at the cloned human GLP-1
`receptor. In clinical studies, NN2211 effectively reduced
`fasting, as well as meal-related (12 h post-injection) gly-
`caemia, by modifying insulin secretion, delaying gastric
`emptying and suppressing prandial glucagon secretion
`[41] and, in a one-week study, improved both a and b
`cell function and reduced hepatic glucose production
`[43]. Phase II studies involving three months of daily
`injections have recently been reported [44]. In a blinded
`design, ascending doses of NN2211 in monotherapy were
`compared with glimepiride. It was concluded that
`NN2211 improved glycaemic control significantly and
`was comparable to glimepiride. Weight was maintained
`with a tendency to decrease, and the risk of hypoglyce-
`mica was low. It is noteworthy that antibodies against
`NN2211 could not be detected. This analogue clearly
`possesses favorable pharmacokinetic properties.
`
`CJC-1131
`The Conjuchem compound CJC-1131 is composed of a
`D-Ala8-substituted GLP-1 molecule with a linker and a
`reactive moiety (maleimidoproprionic acid) attached
`to the C-terminus. After injection in vivo, this molecule
`conjugates covalently to Lys34 of the albumin molecule
`and thereby acquires the half-life of albumin. The CJC-
`1131–albumin conjugate binds to the GLP-1 receptor and
`
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`
`Current Opinion in Pharmacology 2004, 4:589–596
`
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`

`Figure 1
`
`CH2CH3
`
`S
`
`H3C
`
`H2N
`
`N
`
`C
`
`O
`Isoleucine-thiazolidide
`
`H2N
`
`O
`
`N
`
`Valine-pyrrolidide
`
`F
`
`NH2
`
`O
`
`F
`
`F
`
`MK-0431
`
`N
`,#
`
`H
`N
`
`O
`
`N
`
`N
`
`N
`
`N
`
`N
`
`F
`
`F
`
`F
`
`NH
`
`N
`
`N
`
`~~~6
`?-J-6"
`
`NVP-DPP728
`
`HO
`
`N
`
`H
`N
`
`O
`
`N
`
`LAF237
`
`Current Opinion in Pharmacology
`
`Structures of DPP-IV inhibitors.
`
`mals, the impaired glucose tolerance that normally devel-
`ops with ageing is prevented [55,56], whereas the lack of
`DPP-IV protects both Fischer rats and CD26 knockout
`mice from diet (high fat)-induced insulin resistance
`and glucose intolerance [56–58]. Again, these effects
`are believed to involve preservation of endogenous
`GLP-1 levels, because intact GLP-1 concentrations are
`elevated.
`
`Clinical studies
`After these promising preclinical studies, the first clinical
`proof-of-concept was obtained using the short-acting
`Novartis inhibitor, NVP-DPP728 [59]. When given twice
`or three times daily for four weeks in patients with
`relatively mild T2DM (mean HbA1c of 7.4%), both
`fasting and prandial glucose levels were lowered signif-
`icantly, resulting in a reduction in HbA1c of 0.5%; despite
`the fall in glycemia, fasting and post-prandial insulin
`levels were sustained. NVP-DPP728 appeared to be well
`tolerated, with only minor adverse events being reported.
`However, some of these symptoms (pruritus and naso-
`pharyngitis) seem to be drug- rather than class-specific,
`because they were not reported for another inhibitor,
`LAF237, also developed by Novartis. NVP-DPP728
`has now been dropped in favour of LAF237, which is
`longer-acting and suitable for once-daily administration.
`A clinical study with this compound was recently
`reported, showing it to have a pharmacodynamic profile
`similar to that of its predecessor [60]. The mechanism of
`
`592 Endocrine and metabolic diseases
`
`activates cAMP with a potency similar to that of GLP-1
`[45]. In recent studies in human volunteers, elimination
`half-lives ranging from 9–14 days were noted [46], and in
`studies presented at the International Diabetes Federa-
`tion Congress in 2003 the compound was reported to have
`dose-dependent effects on glycaemia and body weight
`lasting at least 48 h, and up to eight days in some patients.
`Results of Phase II clinical studies have recently (July
`2004) been announced as a press release from the com-
`pany and, although effective in reduced fasting blood
`glucose and HbA1c levels as well as body weight, the
`compound was most effective when administered once
`daily, contrasting with the reported long half-life. The
`company claims that the conjugate is not antigenic.
`
`Albugon
`Very little is known about the Albugon compound from
`Human Genome Sciences. However, it has been reported
`to retain the insulinotropic activities of GLP-1 and to
`delay gastric emptying. In glucose-intolerant mice and in
`diabetic rats, a single injection almost normalized glucose
`levels for 24 h; the half life was said to be three days in
`monkeys [47].
`
`Inhibitors of DPP-IV
`Preclinical studies
`Therapeutic use of inhibitors of the enzyme responsible
`for the inactivation of GLP-1 as anti-diabetic agents was
`first proposed in 1995 [48] on the basis of the finding that
`GLP-1 seems uniquely sensitive to cleavage by DPP IV;
`compounds of this class have now reached Phase III
`clinical trials. With a DPP-IV inhibitor (see Figure 1),
`it is possible to completely prevent the N-terminal degra-
`dation of GLP-1 that occurs in vivo, resulting in signifi-
`cant enhancement of its insulinotropic activity [49].
`Studies in Vancouver diabetic fatty rats have shown that
`chronic oral administration of the Probiodrug DPP-IV
`inhibitor isoleucine thiazolidide (P32/98) for 12 weeks
`improves glucose tolerance, insulin sensitivity and b-cell
`responsiveness [50]. The longer-acting Ferring inhibitor,
`FE 999-011, continuously inhibits plasma DPP IV activ-
`ity and not only normalises the glucose excursion after
`oral glucose administration in insulin-resistant Zucker
`obeses rats but also delays the onset of hyperglycaemia
`in Zucker diabetic fatty rats [51]. These effects were, at
`least in part, attributed to increased levels of intact GLP-
`1. Increased intact GLP-1 concentrations were also impli-
`cated in the improved islet function seen after chronic
`treatment of high-fat fed (glucose-intolerant and insulin-
`resistant) mice with valine-pyrrolidide [52]. Fischer rats,
`which have a catalytically inactive DPP-IV molecule, and
`CD26 knockout mice with a targeted disruption of the
`gene encoding DPP-IV further support the involvement
`of DPP-IV in mediating glucose tolerance. Such animals
`have improved glucose tolerance compared with their
`wild-type counterparts [53–55]. In DPP-IV-negative
`Fischer rats and DPP-IV inhibitor-treated control ani-
`
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`Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus Holst and Deacon 593
`
`action was suggested to be incretin-mediated, because
`LAF237 treatment increased both baseline and prandial
`active GLP-1 levels. As with NVP-DPP78, insulin levels
`were not increased but, interestingly, glucagon levels
`were significantly suppressed. Clinical data
`from
`longer-term studies presented at the recent ADA meeting
`in Orlando showed that 12 weeks of monotherapy with
`LAF237 was associated with sustained reductions in
`HbA1c (from a starting level of 8%, falling to 7.4% at
`the end of the study) [61]. Encouragingly, patients with
`the worst metabolic control (HbA1c ranging between 8%
`and 9.5%) showed the greatest reductions (1.2%), sug-
`gesting that DPP-IV inhibition may not be restricted only
`to those patients with mild diabetes. Furthermore,
`LAF237 was able to prevent the worsening of glycaemic
`control when given for up to 12 months in combination
`with metformin in patients otherwise inadequately con-
`trolled with metformin alone [62]. Side effects were
`mild and, importantly, hypoglycemia was not reported.
`However, in contrast to GLP-1 analogues, there was no
`change in body weight. Phase III clinical trials are cur-
`rently in progress, and filing for FDA approval is expected
`in 2006.
`
`Merck also has an inhibitor (MK-0431) in Phase III trials
`(http://www.merck.com), but so far little is known about
`this compound. Results of placebo-controlled, single-
`dose studies were presented at the ADA in Orlando.
`MK-0431 was well tolerated and caused significant reduc-
`tions in the glycaemic excursion following an oral glucose
`tolerance test, which were associated with increases in
`intact GLP-1 and insulin, and reductions in glucagon
`secretion [63].
`
`DPP-IV inhibitors are in development at GlaxoSmith-
`Kline (Phase I), Bristol-Meyer-Squibb (Phase II) and
`Probiodrug (P93/01; Phase II), with several other com-
`panies reportedly having a DPP-IV inhibitor programme.
`Single doses of P93/01 were shown to have good toler-
`ability and result in dose-related reductions in prandial
`glucose in T2DM subjects when HbA1c was above
`6% [64].
`
`The clinical studies with DPP IV inhibitors that have
`been reported so far have not been associated with any
`serious adverse side effects, but there has been under-
`standable concern that undesirable side effects could
`arise from inhibiting an enzyme with multiple substrates
`or because of non-mechanism-based actions (i.e. not
`related to the selective inhibition of DPP-IV). With
`regard to multiple substrates, although several regulatory
`peptides, neuropeptides, chemokines and cytokines
`have been identified as potential substrates from in vitro
`kinetic studies (reviewed by Lambeir et al. [65]), it is
`uncertain how many of these are endogenous substrates
`and, if so, whether DPP-IV-mediated degradation is their
`primary route of elimination. In addition to GLP-1, the
`
`other incretin hormone, glucose-dependent insulinotro-
`pic polypeptide, is an endogenous DPP-IV substrate, as
`is the neuropeptide pituitary adenylate cyclase-activat-
`ing peptide [66], but inhibition of their degradation
`would be expected to contribute to the anti-diabetic
`effects of DPP-IV inhibitors. The evidence for a phy-
`siological role for DPP-IV in degradation of many of the
`other potential substrates remains to be demonstrated.
`DPP-IV also has several other roles that could potentially
`be compromised by DPP-IV inhibition. It is present on
`the surface of T cells (where it is usually referred to as the
`T cell marker CD26) and contributes to T cell activation
`and proliferation via its interaction with other mem-
`brane-expressed molecules such as CD45, although it
`is uncertain whether the catalytic activity is required, or
`indeed whether its presence is obligatory [67]. In this
`context, a family of DPP-IV-related enzymes is now
`known to exist, which have similar catalytic activities.
`Selective inhibition of two of these enzymes (DPP 8 and
`DPP 9) was recently reported to affect T cell activation
`in vitro [68] and be associated with severe, even lethal
`side effects in preclinical species [69], whereas selective
`DPP-IV inhibition was not, suggesting that DPP 8 and
`9 could be responsible for some of the functions pre-
`viously attributed to DPP-IV. In turn, this raises the
`possibility that some of the potential or reported side
`effects of DPP IV inhibition could be attributable to
`inhibition of DPP 8 and 9, rather than DPP-IV itself. It is,
`therefore, highly relevant that rodents which lack DPP-
`IV enzymatic activity (the Fischer rat and the CD26
`knockout mouse) are completely viable and seem to
`suffer no ill effects because of the lack of DPP-IV.
`Selectivity data for the inhibitors in development have
`not been released, apart from the Merck compound,
`which is reported to have >2500-fold selectivity for
`DPP-IV relative to DPP 8 and 9 [70].
`
`Conclusions
`It seems clear from the most recent clinical results that
`both GLP-1 analogues (or GLP-1 receptor activators such
`as exendin) and DPP-IV inhibitors effectively improve
`metabolic control in patients with T2DM. Both seem to
`be effective in monotherapy and in combination with
`other antidiabetic agents. DDP-IV inhibitors are admi-
`nistered orally, whereas the analogues require parenteral
`administration. The analogues cause significant reduc-
`tions in body weight, whereas the inhibitors seem to be
`weight neutral. Clinical data obtained so far do not allow
`conclusions to be drawn on whether the protective effect
`on b-cells seen in laboratory animals can also be demon-
`strated in patients with T2DM.
`
`Acknowledgements
`
`The authors were supported by grants from The Danish Medical
`Research Council and the European Foundation for the
`Study of Diabetes.
`
`www.sciencedirect.com
`
`Current Opinion in Pharmacology 2004, 4:589–596
`
`MPI EXHIBIT 1028 PAGE 5
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`

`594 Endocrine and metabolic diseases
`
`References and recommended reading
`Papers of particular interest, published within the annual period of
`review, have been highlighted as:
` of special interest
` of outstanding interest
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