REVIEW ARTICLES
`
`Glucagon-like peptide-1 and diabetes treatment
`
`Tina Vilsbøll, Kristine J. Hare, Jonatan O. Bagger and Filip K. Knop
`Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen,
`Hellerup, Denmark (t.vilsboll@dadlnet.dk)
`
`Abstract
`
`Type 2 diabetes is characterized by insulin resis-
`tance, impaired glucose-induced insulin secre-
`tion and inappropriately regulated glucagon
`secretion, which in combination eventually result
`in hyperglycemia and in the longer term in
`microvascular and macrovascular complications
`affecting multiple organ systems. Traditional
`treatment modalities — even multidrug
`approaches — for type 2 diabetes are often
`unsatisfactory at achieving glycemic goals as the
`disease progresses due to a steady, relentless
`decline in pancreatic β-cell function. Further-
`more, current treatment modalities are often
`limited by inconvenient dosing regimens, safety
`and tolerability issues, the latter including hypo-
`glycemia, body weight gain, edema and gastro-
`intestinal side effects.
`The incretin hormones glucagon-like peptide
`(GLP)-1 and glucose-dependent insulinotropic
`polypeptide (GIP) are intestinal hormones that
`augment insulin secretion in response to the
`ingestion of nutrients. The actions of GLP-1 and
`GIP, which also include trophic effects on the β-
`cells, have attracted a lot of interest. GLP-1 also
`inhibits glucagon secretion and suppresses food
`intake and appetite. Recently, an entirely new
`therapeutic modality for the treatment of type 2
`diabetes based on the effect of GLP-1 was intro-
`duced onto the market.
`Incretin-based therapies fall into two groups:
`(1) GLP-1 receptor agonists, i.e. injectable pep-
`tide preparations with actions similar to the nat-
`ural incretin hormone GLP-1; and (2) the
`incretin enhancers, which are orally available
`agents that inhibit the degradation of the
`incretin hormones and thereby increase their
`plasma concentrations and biological actions.
`This review outlines the scientific basis for the
`development of GLP-1 receptor agonists and
`incretin enhancers, assesses the clinical experi-
`ence gathered so far and discusses future expec-
`tations for incretin-based therapy.
`
`Key words:
`Incretin hormones, dipeptidyl peptidase-4 (DPP-4),
`glucagon-like peptide-1 (GLP-1), glucose-dependent
`insulinotropic polypeptide (GIP), incretin mimetics,
`GLP-1 receptor agonists, type 2 diabetes
`
`Incretin hormones: secretion, effect and
`degradation
`
`The ‘incretin effect’ refers to the amplification of
`glucose-stimulated insulin secretion elicited by
`hormones secreted from the gastrointestinal
`tract. In the strictest sense, it is quantified by
`comparing insulin responses to oral and intra-
`venous glucose administration where the intra-
`venous infusion is adjusted so as to result in the
`same (isoglycemic) plasma glucose concentra-
`tions as the oral stimulus [1, 2]. In healthy sub-
`jects, oral administration causes a two- to
`threefold larger insulin response compared with
`the isoglycemic intravenous stimulus.
`
`The incretin hormones GLP-1 and GIP are
`intestinal hormones that augment
`insulin secretion in response to the
`ingestion of nutrients
`
`This discrepancy in insulin secretion between
`the two stimuli is due to the actions of incretin
`hormones, glucagon-like peptide (GLP)-1 and
`glucose-dependent insulinotropic polypeptide
`(GIP). GLP-1 is a 30-amino acid polypeptide
`produced in the endocrine L-cells of the intesti-
`nal epithelium as a product of glucagon gene
`expression. The GLP-1 moiety is liberated from
`proglucagon by the action of prohormone
`convertase 1/3 (PC1/3). This is in contrast to
`proglucagon processing in the pancreatic
`α-cells, where prohormone convertase 2 cleaves
`out glucagon but leaves the GLP-1 molecule
`embedded in a large inactive fragment [3].
`The L-cells are found throughout the intestinal
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`Review articles
`
`tract, but their density is highest in the ileum
`and parts of the colon.
`GIP is produced in the endocrine K-cells,
`which are more frequent in the proximal small
`intestine [3]. As in the L-cells, PC1/3 is respon-
`sible for the processing of proGIP in endocrine
`K-cells. After the secretion of GIP and GLP-1,
`both hormones are degraded by the enzyme
`dipeptidyl peptidase-4 (DPP-4). This enzyme
`cleaves off the two N-terminal amino acids of
`the incretin hormones, which abolishes their
`insulinotropic activity.
`GLP-1 has an apparent half-life of 1–2 min
`[4], whereas GIP is degraded more slowly, with a
`half-life of 7 min [5]. The truncated metabolites
`are eliminated through the kidneys. The intact
`and active forms of GLP-1 and GIP elicit signifi-
`cant insulin responses at plasma glucose levels
`above 4 mM. At higher levels (e.g. in the post-
`prandial state) this insulinotropic power
`increases dramatically [6]. These insulinotropic
`actions are exerted by activation of specific
`GLP-1 and GIP receptors, respectively, on the
`pancreatic β-cells and consist of potentiation of
`glucose-induced insulin secretion [7]. At lower
`plasma glucose concentrations (4 mM and
`below) both hormones lose their insulinotropic
`activity completely. Therefore the incretin hor-
`mones seem to play a very important role in the
`regulation of, particularly, postprandial glucose
`clearance from the bloodstream.
`
`GLP-1 has an apparent half-life of 1–2
`min, whereas GIP is degraded more
`slowly, with a half-life of 7 min
`
`The incretin hormones have several additional
`actions besides being ‘incretins’. In addition to
`its insulinotropic action, GLP-1 enhances
`insulin biosynthesis and insulin gene expression,
`it has trophic and protective effects on the β-
`cells (stimulating β-cell growth, proliferation and
`neogenesis, and reducing β-cell apoptosis) [8].
`Furthermore, GLP-1 strongly inhibits glucagon
`secretion, which, combined with its effect on
`insulin secretion, results in an inhibition of
`hepatic glucose production that contributes to
`the glucose-lowering effect of the hormone [9].
`GLP-1 also functions as an inhibitor of upper
`gastrointestinal motility and secretion (reducing
`postprandial glucose excursions) [10], suppress-
`ing appetite and food intake. Chronic adminis-
`tration of GLP-1 has been shown to lead to
`weight loss [11]. Finally, GLP-1 appears to have
`beneficial actions on the cardiovascular system:
`
`enhancing myocardial performance in experi-
`mental and clinical cardiac insufficiency, reduc-
`ing infarct size in experimental myocardial
`infarction and improving endothelial dysfunction
`in patients with type 2 diabetes [3]. GIP appears
`to have similar actions to GLP-1 on the β-cells,
`but its effects with regard to glucagon secretion
`remain relatively unclear.
`
`Incretin hormones and type 2 diabetes
`mellitus
`
`When patients with type 2 diabetes are subjected
`to isoglycemic oral and intravenous glucose chal-
`lenges, the amplification of insulin secretion dur-
`ing the oral stimulus is markedly reduced unlike
`in healthy subjects [12]. Considering the power
`of the incretin effect to maintain postprandial
`glucose levels in healthy subjects, there can be
`little doubt that the attenuated incretin effect in
`type 2 diabetes contributes to the glucose intol-
`erance of these patients.
`When trying to explain why the incretin effect
`is lost, one may ask whether there is something
`wrong with the secretion or actions of GIP and
`GLP-1. Mixed-meal stimulation tests have
`revealed that postprandial GIP secretion is near
`normal or slightly impaired, whereas particularly
`the late phase of the GLP-1 response is signifi-
`cantly reduced in patients with type 2 diabetes
`[13]. Furthermore, in early studies of the actions
`of the two peptides, it was clearly demonstrated
`that the insulinotropic effect of GLP-1 was
`retained, whereas that of GIP was almost com-
`pletely lost [14].
`Subsequent studies of the effects of GLP-1 on
`glucose-stimulated insulin secretion (β-cell
`responsiveness to glucose) revealed that it was
`possible to completely normalize the glucose
`responsiveness with GLP-1, but also that the
`potency of GLP-1 in this respect was reduced in
`type 2 diabetic patients [15]. Further clamp
`studies revealed that particularly the late-phase
`insulin response to GIP was completely lost in
`type 2 diabetes [16]. Thus the loss of incretin
`effect in type 2 diabetes seems to be due to an
`impaired secretion of GLP-1 in particular and,
`perhaps more importantly, a loss of the
`insulinotropic effect of GIP and reduced
`insulinotropic potency of GLP-1. However, since
`the insulinotropic effect of high doses of GLP-1 is
`preserved, it should be possible to restore incretin
`action in patients with type 2 diabetes with supra-
`physiological doses of GLP-1.
`
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`GLP-1 receptor agonists
`
`It is fairly easy to stabilize the GLP-1 molecule
`against DPP-4: a substitution of alanine in posi-
`tion 2 with, for example, valine is sufficient and
`does not change the biological activity of the
`peptide [17]. However, the stabilized molecule
`is still eliminated extremely rapidly in the
`kidneys (with a half-life of 4–5 min), which
`leaves such analogues unsuitable for prolonged
`drug exposure.
`However, exendin-4, a peptide with about
`50% sequence homology to GLP-1, which was
`isolated from the saliva of the Gila monster
`(Heloderma suspectum) during a search for bio-
`logically active peptides, turned out to be a full
`agonist for the GLP-1 receptor, to be stable
`against DPP-4, and to be eliminated through the
`kidneys exclusively by glomerular filtration [18].
`After subcutaneous injection of exenatide (a syn-
`thetic replica of exendin-4) in the dose selected
`for clinical use (10 µg), the plasma concentration
`is elevated into the insulinotropic range for
`about 5–6 h. Exenatide is therefore administered
`twice daily [19]. Exenatide has been developed
`by Amylin and Eli Lilly for the treatment of type
`2 diabetes under the trade name Byetta®.
`Another GLP-1 receptor agonist under clinical
`development is liraglutide (Novo Nordisk),
`which is based on the structure of human GLP-
`1 (97% homology with the native peptide) but
`modified to include an amino acid substitution
`and an attachment of a C16 acyl chain [20],
`enabling the molecule to bind to albumin, thus
`preventing renal elimination and degradation by
`DPP-4. Following subcutaneous administration,
`liraglutide is slowly absorbed into the blood-
`stream and has a plasma half-life of approxi-
`mately 11–13 h [21], making it suitable for
`once-daily injection. Clinically, the molecule has
`similar actions to continuously infused GLP-1
`and appears to have a similar clinical potential to
`that of exendin-4 [22].
`Clinical studies using exenatide have demon-
`strated sustained beneficial effects on HbA1c,
`body weight and β-cell function in patients with
`type 2 diabetes. Controlled studies comparing
`exenatide and placebo injections as add-on ther-
`apy to already instituted antidiabetic treatment
`have revealed a statistically significant decline in
`HbA1c of approximately 1% from baseline (base-
`line HbA1c 8.2%) [23] and significant weight
`loss in favour of exenatide. The weight loss was
`progressive, dose-dependent and with no appar-
`ent plateau by week 30 (−2.3 kg); however, it
`appeared to plateau after 2–3 years of treatment
`(with a weight loss of 5.3 kg) in completers par-
`
`Review articles
`
`ticipating in an open-label extension of the trials
`[24, 25]. Side effects were primarily dose-depen-
`dent nausea and vomiting, occurring in as many
`as 57% and 17% of participants, respectively,
`although nausea was generally mild to moderate
`and declined with time.
`The clinical efficacy of exenatide in patients
`with type 2 diabetes over a period of 6 months
`has been evaluated by extractions of data from a
`primary care electronic medical record database
`[26]. In this study, weight loss among the 1785
`patients was >3 kg (baseline weight 121 kg) and
`as many as 70% of the patients lost weight. Low-
`ering of HbA1c ranged from 0.7% to 0.9%
`regardless of weight loss. It was concluded that
`the effectiveness of exenatide in a primary care
`setting is similar to that observed in controlled
`clinical trials.
`Exenatide given as twice-daily injections may
`not provide complete 24-h coverage, especially
`after midday meals, and overnight plasma con-
`centrations seem inadequate to obtain optimal
`glycemic control. Therefore a long-acting release
`(LAR) formulation of exenatide for subcuta-
`neous injection in patients with type 2 diabetes
`has recently been developed. Data from a phase-
`II trial (n = 295) in which exenatide LAR 2.0
`mg once weekly was compared with exenatide
`10 µg twice daily for 30 weeks were recently
`published [27]. These data showed significant
`reductions in HbA1c (1.9% and 1.5%, respec-
`tively) and body weight (average decrease of 4 kg
`in both groups). The trial was extended for 22
`weeks with all subjects being switched to
`exenatide LAR in the extension period. A sus-
`tained effect of exenatide LAR was seen after 52
`weeks with improvements in both HbA1c (−2%)
`and fasting plasma glucose (−2.6 mmol/l). Three
`out of four patients achieved an HbA1c of 7.0%
`or below. The change in body weight was −4 kg
`by week 52 compared with baseline. Exenatide
`LAR was well tolerated. The most common side
`effect, nausea, was predominantly mild and
`transient during the study; during the 22-week
`follow-up the incidence of nausea was 7% [28].
`Exenatide LAR is currently in phase-III clinical
`development and is expected to reach the market
`in 2010 (Table I).
`The next GLP-1 receptor agonist for the treat-
`ment of type 2 diabetes to reach the market is
`expected to be liraglutide. Published data have
`demonstrated that liraglutide as monotherapy
`(1.9 mg once daily) is capable of decreasing
`fasting plasma glucose levels by 3.4 mmol/l on
`average in patients with type 2 diabetes when
`compared with placebo [22]. In the same study,
`a decrease in HbA1c of up to 1.7% (baseline
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`Review articles
`
`Table I: The GLP-1 receptor agonists currently on the market or in clinical development.
`
`Company
`
`Compound
`
`Status of development
`
`Formulation
`
`Eli Lilly/Amylin
`
`Byetta® (exenatide)
`
`Launched
`
`Novo Nordisk
`
`Liraglutide
`
`Filed USA/EU May 2008
`
`Eli Lilly/Amylin
`
`Exenatide LAR
`
`Phase III Expected 2010
`
`Sanofi-Aventis
`
`AVE0010(ZP10)
`
`Phase III Expected 2011
`
`Roche/Ipsen
`
`Taspoglutide (R1583)
`
`Phase IIb–III Expected 2011
`
`GlaxoSmithKline
`
`Syncria® (albiglutide)
`
`Phase IIb
`
`ConjuChem
`
`Eli Lilly
`
`Sanofi-Aventis
`
`Novo Nordisk
`
`CJC-1134
`
`LY2405319
`
`AVE0010(ZP10)
`
`NN9535
`
`Phase II
`
`Phase II
`
`Phase II
`
`Phase II
`
`Twice daily
`
`Once daily
`
`Once weekly
`
`Once daily
`
`Once weekly
`
`Once weekly
`
`Once weekly
`
`Once weekly
`
`Once weekly
`
`Once weekly
`
`HbA1c 8.0%) was observed, and almost 50% of
`the patients managed to reach the HbA1c goal of
`<7%. In the highest liraglutide dose group
`(1.9 mg/day) the change from baseline in body
`weight was −3 kg (−1.2 kg compared with
`placebo). As for exenatide, transient and mild
`nausea was reported in the liraglutide-treated
`subjects (liraglutide 10%, placebo 3%). Data
`from a number of phase-III trials with liraglutide
`were presented at the 2008 annual scientific
`meetings of the American Diabetes Association
`(ADA) and the European Association for the
`Study of Diabetes (EASD). These trials, called
`the LEAD (Liraglutide Effect and Action in Dia-
`betes) trials, demonstrated that liraglutide given
`as a once-daily injection, as monotherapy and in
`combination with a range of antidiabetic drugs,
`is associated with significant improvements in
`HbA1c (sustained reductions of up to 1.6%),
`fasting plasma glucose, postprandial glucose and
`β-cell function [29, 30]. Furthermore, in trials of
`up to 1 year liraglutide showed maintained
`weight reduction (up to 4 kg in subjects with a
`high BMI) [29], minimal risk of hypoglycemia,
`reductions of up to 3.6 mmHg in systolic blood
`pressure [31], low and transient incidence of
`nausea and negligible antibody formation.
`
`Many GLP-1 receptor agonists that
`are in their late clinical development
`are anticipated to have optimized
`pharmacokinetic profiles, fewer
`gastrointestinal side effects and
`are expected to reach the market
`from 2010 onwards
`
`Very recently, liraglutide was compared with
`exenatide twice daily (for 26 weeks) and signifi-
`
`cant differences in glycemic control were
`observed (HbA1c −1.1% and −0.8%, respec-
`tively), a tendency towards a more pronounced
`weight loss with liraglutide (−3 kg vs. −2 kg)
`and less nausea in favour of liraglutide (Blonde
`L et al. Can J Diabetes 2008; 32 suppl: A107).
`Applications for liraglutide as a new drug were
`filed with the authorities in both the United
`States and the European Union in May 2008.
`Regarding adverse events of GLP-1 receptor
`agonists, attention has recently been drawn
`towards a few cases of acute pancreatitis in
`patients treated with exenatide. These cases have
`been reviewed by the US Food and Drug
`Administration during post-marketing. A very
`few cases of acute pancreatitis have also been
`diagnosed during treatment with liraglutide in
`the LEAD programme. However, it is not clear
`whether the incidence of acute pancreatitis in
`patients with type 2 diabetes treated with GLP-1
`receptor agonists is higher than in a type 2 dia-
`betic population not treated with GLP-1 recep-
`tor agonists, and, so far, the reports are few and
`seem to be correlated to other causes of pancre-
`atitis (hypertriglyceridemia, alcohol abuse, gall
`bladder stones/operation).
`Many GLP-1 receptor agonists that are in
`their late clinical development are anticipated to
`have optimized pharmacokinetic profiles and
`presumably fewer gastrointestinal side effects.
`Many of these are expected to reach the market
`from 2010 onwards (Table I).
`
`DPP-4 inhibitors
`
`The extremely rapid and extensive degradation
`of GLP-1 by DPP-4 has given rise to the
`proposal that inhibitors of the enzyme could
`be used as a therapy for patients with type 2
`
`4
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`Table II: The leading DPP-4 inhibitors — all orally available — in clinical development or on the market.
`
`Review articles
`
`Compound
`
`Status of development
`
`Januvia® (sitagliptin, MK-0431)
`
`Launched 2006
`
`Galvus® (vildagliptin, LAF-237)
`
`Launched 2008
`
`Filed USA 2008
`
`Filed USA/EU 2008
`
`Phase III
`
`Phase IIb
`
`Phase IIb
`
`Phase II
`
`Phase II
`
`Phase II
`
`Phase II
`
`Phase II
`
`Phase II
`
`Company
`
`Merck
`
`Novartis
`
`Takeda
`
`Alogliptin (SYR-322)
`
`Bristol-Myers Squibb
`
`Onglyza™ (saxagliptin)
`
`Boehringer-Ingelheim
`
`BI-1356
`
`Glenmark
`
`Phenomix
`
`Melogliptin (GRC 8200)
`
`Dutogliptin (PHX1149)
`
`Mitsubishi Tanabe Pharma
`
`Mitsubishi Tanabe Pharma
`
`TA-6666
`
`MP-513
`
`Amgen/Servier
`
`AMG 222/ALS 2-0426
`
`Pfizer
`
`Takeda
`
`Abbott Laboratories
`
`PF 00734200
`
`SYR-472
`
`ABT-279
`
`diabetes by protecting and thereby enhancing
`the circulating levels of endogenous GLP-1 [32].
`Early experiments documented that administra-
`tion of an inhibitor of DPP-4 to pigs completely
`protected both endogenous and exogenous
`GLP-1 and, furthermore, greatly enhanced
`insulin responses to glucose [33]. In a subse-
`quent study, DPP-4 inhibition was demonstrated
`also to protect GIP from degradation, again
`resulting in enhanced insulinotropic activity of
`infused GIP [34]. The idea was quickly accepted
`by the pharmaceutical industry and numerous
`companies embarked on the development of
`DPP-4 inhibitors for clinical use in the treat-
`ment of type 2 diabetes (Table II).
`
`The rapid and extensive degradation of
`GLP-1 by DPP-4 suggests that inhibitors
`of the enzyme could be used as a
`therapy for type 2 diabetes by
`enhancing the circulating levels of
`endogenous GLP-1, resulting in
`enhanced insulinotropic activity of
`infused GIP
`
`The first DPP-4 inhibitor to reach the market
`in 2007 was sitagliptin (Merck) [35]. Vildagliptin
`(Novartis) [36] was launched in the European
`Union in spring 2008. Both inhibitors have
`good oral bioavailability and a relatively
`long duration of action, such that once-daily
`(sitagliptin) or twice-daily (vildagliptin) dosing
`gives 70–90% inhibition of plasma DPP-4 activ-
`ity over a 24-h period [37], which is sufficient to
`fully protect the endogenous incretin hormones
`from degradation. Sitagliptin and vildagliptin
`
`have significant antidiabetic effects when given
`in monotherapy and result in further improve-
`ments in glycemic control when given in combi-
`nation with other antidiabetic agents including
`metformin, sulfonylurea and thiazolidinediones
`[37]. More than 25 studies have been published,
`comparing treatment with sitagliptin and
`vildagliptin with placebo, and in a few studies
`with other oral agents [23]. Most studies have
`been of a relatively short duration (<30 weeks)
`and the observed reductions in HbA1c approxi-
`mated 0.6–0.8% compared with placebo during
`the first 6 months of treatment [23].
`In a recent study sitagliptin was given for 26
`weeks in combination with various doses of
`metformin after a washout of previous medica-
`tion. The combination of the highest doses (100
`mg sitagliptin + 2000 mg metformin) resulted
`in large reductions in HbA1c with 66% of the
`patients reaching values below 7%, considered
`a therapeutic target by the ADA [38]. Data
`from the same subjects completing a 2-year
`extension trial demonstrated a sustained effect
`on glycemic control and were recently presented
`at the annual meeting of the EASD [39]. The
`combination with metformin is of particular
`interest, because recent studies have indicated
`that metformin may increase GLP-1 biosynthe-
`sis and secretion, so that a larger increase in the
`concentration of active GLP-1 may be obtained
`with the combination compared with either
`agent alone [40]. If the combination treatment
`can be demonstrated to prevent deterioration
`of β-cell function with time better than the
`currently recommended initial treatment
`(metformin) it may be recommended as an
`initial treatment for newly diagnosed patients
`with type 2 diabetes.
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`
`DPP-4 inhibition may also be combined with
`insulin treatment. Vildagliptin (50 mg b.i.d.)
`added to insulin treatment (80 U/day) reduced
`HbA1c levels by 0.5% (baseline 8.5%) vs. a
`reduction of 0.2% with placebo, and, despite
`the improvement in glycemic control, signifi-
`cantly fewer hypoglycemic events occurred
`in the patients who received the combination
`therapy [41].
`The safety profiles of the DPP-4 inhibitors
`were recently reviewed by scientists from the
`Cochrane Institute, who concluded that both
`vildagliptin and sitagliptin were well tolerated
`[42]. As opposed to the GLP-1 agonists, the
`inhibitors do not cause weight reduction but
`appear to be weight neutral. This is in itself of
`interest, since the significant reduction in blood
`glucose they provide per se would be expected to
`result in weight gain. The simplest explanation
`for the lack of effect on body weight is the fact
`that the effect of the endogenous concentrations
`of intact GLP-1 obtained with the inhibitors is
`limited compared with the effect that can be
`obtained with the GLP-1 agonists. Several
`DPP-4 inhibitors are currently undergoing clini-
`cal development and many of these are expected
`to reach the market within the next few years
`(Table II).
`
`Conclusion
`
`As the treatment efficacy of GLP-1 receptor
`agonists and incretin enhancers has been firmly
`established in respect to lowering HbA1c and
`improving β-cell function during treatment,
`these treatment modalities are expected to be
`incorporated as standard treatments and be
`included in the recommendations for the treat-
`ment of type 2 diabetes in the coming years.
`Incretin-based approaches are pleiotropic and,
`unlike existing therapies, target both α- and
`β-cell dysfunction. Studies indicate that incretin-
`based therapies — perhaps especially because of
`their trophic effects on the pancreatic β-cells —
`may halt the progression of disease that
`inevitably seems to accompany conventional
`treatment. So far this has not been established in
`clinical trials, but animal studies show that
`administration of GLP-1 receptor agonists or
`DPP-4 inhibitors is associated with β-cell prolif-
`eration and β-cell protection. If the β-cell-
`preserving potential of these drug classes can be
`demonstrated in humans, incretin-based thera-
`pies may be able to address one of the under-
`lying causes of progression of type 2 diabetes —
`the gradual loss of β-cell function and mass.
`
`Within the next year many new GLP-1 receptor
`agonists and DPP-4 inhibitors will be intro-
`duced to the market.
`
`Animal studies show that administration
`of GLP-1 receptor agonists or DPP-4
`inhibitors is associated with (cid:2)-cell
`proliferation and (cid:2)-cell protection
`
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`6
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`International Diabetes Monitor
`
`Volume 21, Number 1, 2009
`
`MPI EXHIBIT 1040 PAGE 6
`
`MPI EXHIBIT 1040 PAGE 6
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1040, p. 6 of 7
`
`

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