REVIEWS
`
`Incretin-based therapies for type 2
`diabetes mellitus
`
`Julie A. Lovshin and Daniel J. Drucker
`
`Abstract | Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4
`inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose
`metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they
`either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like
`peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective
`drug classes to be based on incretins, has fostered the development of multiple new agents that are
`currently in late stages of clinical development or awaiting approval. This Review highlights our current
`understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging
`clinical profile of new agents.
`
`Lovshin, J. A. & Drucker, D. J. Nat. Rev. Endocrinol. 5, 262–269 (2009); doi:10.1038/nrendo.2009.48
`
`Introduction
`The observation that the incretin hormone glucagon-like
`peptide 1 (GLP-1) stimulates insulin release in response
`to an enteric glucose load in humans1 was followed by
`major advances in our understanding of how GLP-1 regu-
`lates glucose metabolism.2,3 In addition, GLP-1—unlike
`the other incretin hormone, glucose-dependent insulino-
`tropic polypeptide (GIP)—retains its glucose-regulatory
`actions in patients with diabetes mellitus. These findings
`led to the discovery and generation of structurally dis-
`tinct GLP-1 receptor (GLP-1R) agonists, which mimic
`the actions of GLP-1 in vivo in humans.2–4 Furthermore,
`characterization of the essential role of dipeptidyl pep-
`tidase 4 (DPP-4) in the inactivation of bioactive GLP-1
`and GIP5,6 promoted the development of orally available
`DPP-4 inhibitors, administration of which stabilizes
`both incretin hormones at physiologically active levels.
`Herein, we review the data from clinical trials that have
`assessed GLP-1R agonists and DPP-4 inhibitors (Table 1)
`and highlight emerging incretin-based therapies that are
`in the late stages of clinical testing.
`
`Incretin action and incretin mimetics
`Biologically active GLP-17–36 amide is derived from
` pro glucagon through post-translational processing. Pro-
`glucagon is generated throughout the small and large
`intestines in specialized intestinal L-cells, the majority of
`
`Competing interests
`D. J. Drucker has declared associations with the following
`companies: Amylin Pharmaceuticals, Arena Pharmaceuticals,
`Arisaph Pharmaceuticals, Conjuchem, Eli Lilly, Emisphere
`Technologies, GlaxoSmithKline, Glenmark Pharmaceuticals,
`Hoffman LaRoche, Isis Pharmaceuticals, Mannkind, Merck
`Research Laboratories, Metabolex, Novartis Pharmaceuticals,
`Novo Nordisk, Phenomix, Takeda and Transition Pharmaceuticals.
`See the article online for full details of the relationships.
`J. A. Lovshin declared no competing interests.
`
`which are located in the distal part of the small intestine
`and in the colon. GLP-1 is secreted at low basal rates in the
`fasting state, and its secretion is increased following nutri-
`ent ingestion. GLP-1 exerts its actions through binding to
`GLP-1R, a heptahelical trans membrane surface receptor
`that is expressed on pancreatic β cells. GLP-1R signaling
`increases the β cells’ sensitivity to glucose, directly pro-
`tects rodent and human pancreatic β cells from apoptotic
`cell death, and triggers proliferative pathways that lead
`to expansion of the β-cell mass in animal experiments.
`GLP-1 also suppresses glucagon secretion from pancre-
`atic α cells, which reduces hepatic glucose production
`and delays transit of nutrients from the stomach to the
` duo denum via inhibition of gastric emptying.7
`Additional, extrapancreatic functions of GLP-1
`include its actions on the hypothalamus to promote
`satiety, which results in body weight loss during chronic
`GLP-1 adminis tration. Although GIP also exerts potent
`incretin-like effects on β cells in healthy individuals,
`the actions of GIP are impaired in patients with dia-
`betes mellitus, which limits the possibilities of its clinical
`use.8 Moreover, sustained GIP administration promotes
`expansion of the adipocyte mass and insulin resistance
`in diabetic rodents, whereas the effect of GIP on human
`adipocyte biology is uncertain. New evidence suggests
`that the insulinotropic actions of GIP may be partially
`restored in patients with diabetes mellitus in whom
`hyperglycemia has been corrected as a result of insulin
`administration.9 Hence, the therapeutic role, if any, of
`GIP in the treatment of patients with diabetes mellitus
`requires further clarification.
`Continuous, subcutaneous administration of native
`GLP-1 to patients with type 2 diabetes mellitus (T2DM)
`lowers fasting and postprandial levels of glucose and
`HbA1c effectively, and also results in weight loss.10
`
`Department of
`Medicine, Samuel
`Lunenfeld Research
`Institute,
`Mt Sinai Hospital,
`University of Toronto,
`Toronto, Canada
`(JA Lovshin,
`DJ Drucker).
`
`Correspondence:
`DJ Drucker,
`Mt Sinai Hospital,
`Samuel Lunenfeld
`Research Institute,
`60 Murray Street,
`Mail Box 39, Toronto,
`ON M5T 3L9, Canada
`d.drucker@utoronto.ca
`
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`However, the expense and inconvenience of con tinuous
`GLP-1 delivery, together with the rapid enzymatic
`inactiva tion of native GLP-1 peptide (the plasma half-life
`of native GLP-1 is shorter than 2min in vivo) necessitated
`the development of alternative therapeutic approaches.
`Two different drug classes have emerged, both of which
`potentiate the actions of incretin hormones: peptide-
`based, degradation-resistant GLP-1R agonists, which
`have to be administered by subcutaneous injection; and
`orally administered DPP-4 inhibitors, which suppress
`the enzymatic inactivation of GLP-1 and GIP.4 Although
`both forms of incretin-based therapy exert their glucose-
` regulatory effects largely through potentiation of the
`actions of GLP-1, several key features distinguish
`the mecha nisms of action of these agents. Whereas both
`therapies act on pancreatic islets to stimulate insulin
`secretion and inhibit glucagon secretion, GLP-1R ago-
`nists also inhibit gastric emptying and promote satiety,
`which leads to weight loss, as shown in clinical studies
`(Figure 1). By contrast, DPP-4 inhibitors also stabilize
`the level of bioactive GIP, which raises the possibility that
`these agents lower glucose levels in part through GIP-
`mediated stimulation of insulin secretion (Figure 2).9
`Following the successful clinical introduction of the first
`GLP-1R agonist (exenatide) and the first DPP-4 inhibi-
`tor (sitagliptin), multiple DPP-4 inhibitors and GLP-1R
`agonists have reached the final stages of clinical develop-
`ment. In this Review, we discuss each class separately,
`with an emphasis on emerging new therapeutic agents.
`
`GLP-1R agonists
`Exenatide
`The first GLP-1R agonist to be approved for human clini-
`cal use was exenatide, a synthetic form of the naturally
`occurring Heloderma suspectum peptide exendin 4. This
`peptide exhibits about 50% amino acid identity with
`human GLP-1 and is a potent agonist of human GLP-1R.
`As exendin 4 contains a glycine residue at position 2,
`it is resistant to degradation by DPP-4 and thus has an
`increased circulating half-life in vivo. Three pivotal,
`phase III clinical trials, each of 30 weeks duration,
`examined the efficacy of twice-daily injections of 5 g
`or 10 g exenatide in individuals who had T2DM that
`was inadequately controlled with a sulfonylurea and/or
`metformin.11–13 Substantial changes were demonstrated
`in HbA1c levels (an increase of 0.86% with exenatide plus
`a sulfonylurea; decreases of 0.78% with exenatide plus
`metformin and of 0.8% with exenatide plus a sulfonyl-
`urea and metformin), in association with modest reduc-
`tions in body weight from baseline values (of 1.6 kg,
`2.8 kg and 1.6 kg, respectively) after 30 weeks of therapy
`with 10 g exenatide twice daily. Exenatide lowered both
`fasting and postprandial glucose concentrations, and was
`generally well tolerated; mild nausea and vomiting were
`the most common adverse effects. Nausea tended to dis-
`sipate over time in the majority of treated individuals.
`Consistent with the glucose-dependent mechanisms
`of GLP-1 action, exenatide therapy in the absence of
`
`REVIEWS
`
`Key points
`■
`■
`
`Incretins exert antidiabetic actions in a glucose-dependent manner
`Glucagon-like peptide 1 receptor (GLP-1R) agonists, but not dipeptidyl
`peptidase-4 (DPP-4) inhibitors, inhibit gastric emptying and might cause
`weight loss
`DPP-4 inhibitors can be administered orally and are well tolerated
`GLP-1R agonists must be administered by subcutaneous injection
`and commonly cause nausea
`
`■
`■
`
`Table 1 | Incretin-based therapies
`
`Agent
`
`Dose
`
`Status
`
`Exenatide
`
`Liraglutide
`
`GLP-1R agonists (subcutaneous injection)
`5–10 g twice daily
`1.2–1.8mg once daily
`5–30 g once or twice daily
`2 mg once weekly
`
`AVA0010
`
`Exenatide QW
`
`Taspoglutide
`
`20–30mg once weekly
`
`Albiglutide
`
`30–50mg once weekly
`
`CJC-1134-PC
`
`1.5–3mg once or twice weekly
`
`NN9535
`
`LY2189265
`
`LY2428757
`
`0.1–1.6mg once weekly
`
`0.25–3mg once weekly
`
`0.5–17.6mg once weekly
`
`DPP-4 inhibitors (oral)
`
`Sitagliptin
`
`Vildagliptin
`
`Alogliptin
`
`Saxagliptin
`
`Linagliptin
`
`Dutogliptin
`
`25–100mg once daily
`
`50mg twice daily
`
`12.5–25mg once daily
`
`5–10mg once daily
`
`2.5–5mg once daily
`
`200–400mg once daily
`
`A
`
`F
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`A
`
`A
`
`F
`
`F
`
`I
`
`I
`
`Abbreviations: QW, once weekly; A, approved; F, filed for regulatory
`approval; I, being investigated.
`
`concomitant sulfonylurea use was not associated with
`any notable frequency of reports of hypoglycemia.
`The results of these trials led to the approval of
`exenatide by the FDA in April 2005 and by the European
`Medicines Agency in November 2006 as adjunctive treat-
`ment in combination with metformin, sulfonyl urea, or
`both, in patients with T2DM. A subsequent study exam-
`ined the efficacy of exenatide therapy in combination
`with thiazolidinediones (pioglitazone and rosiglita zone).
`About 71% of the participants completed the 16-week
`study, and those who were treated with exenatide
`achieved substantial reductions from baseline values in
`fasting blood glucose (about 1.69 mmol/l), HbA1c levels
`(0.98%) and weight loss (1.5 kg).14 On the basis of these
`results, exenatide was approved for use in combination
`with a thiazolidinedione, with or without metformin.
`The efficacy of exenatide has been assessed in head-
`to-head comparison trials with insulin glargine in
`combination with metformin or a sulfonylurea. In an
`open-label study, similar improvements in blood glucose
`
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`REVIEWS
`
`CNS
` Body weight
` Appetite
`
`Heart
`Blood vessels
` Blood pressure
`
`Stomach
` Gastric emptying
`
`Pancreatic
`islet cells
` Glucagon secretion
` Insulin secretion
` β-cell survival
` Glucose sensitivity
`
`Figure 1 | GLP-1 receptor agonists exert diverse actions on distinct target tissues,
`which lead to reduction of blood glucose level and body weight in humans.
`Abbreviations: CNS, central nervous system; GLP-1, glucagon-like peptide 1.
`
`control (reductions of 1.1% in HbA1c after 26 weeks of
`therapy) were achieved in the two treatment groups.
`In contrast with insulin therapy, which generally led
`patients to gain weight, exenatide treatment resulted in
`weight loss (+1.8 kg versus –2.3 kg, respectively). Rates
`of hypo glycemia were comparable in the two groups, but
`the incidence of gastro intestinal malaise and drop-out
`rates were higher with exenatide therapy.15 Qualitatively
`similar results were obtained in a 52-week, open-label
`study: in patients who were already receiving metformin
`and a sulfonylurea, treatment with twice-daily, biphasic
`insulin aspart was markedly better tolerated than twice-
`daily exenatide.16 The insulin-treated patients had
`less nausea and a lower drop-out rate. However, only
`exenatide-treated patients lost weight (which led to an
`approximate 5.4 kg diff erence between the groups).16
`Taken together, these studies suggest that exenatide
`represents a reasonable alternative to the initiation of
`insulin therapy in patients whose diabetic symptoms are
`suboptimally controlled with oral hypoglycemic agents,
`particularly for those who are concerned about their
`potential weight gain.
`In a relatively small study, 69 patients with in adequate
`glycemic control were randomly assigned either
`exenatide (n = 36) or insulin glargine (n = 33) for 1 year.
`Both therapies produced similar improvements in gly-
`cemic control (0.7–0.8% reduction in HbA1c). Although
` arginine-stimulated and glucose-stimulated insulin secre-
`tion improved to a greater extent in exenatide-treated
`patients than in insulin-treated patients, repeat analy-
`ses that were carried out 4 weeks after discontinu ation
`of either exenatide or insulin revealed no significant,
`sustained differences in multiple parameters of β-cell
`
`function.17 Thus, the available data do not yet support the
`hypothesis that therapy with GLP-1R agonists produces
`durable improvements in β-cell function.
`
`Liraglutide
`The success of exenatide has accelerated the development
`of new GLP-1R agonists with pharmacokinetic properties
`optimized for once-daily or once-weekly administration.
`Liraglutide (Novo Nordisk, Bagsvaerd, Denmark) is a
`modified form of human GLP-1 (hGLP-17–37) that con-
`tains a Ser34Arg amino-acid substitution and has a C16
`palmitoyl fatty-acid side-chain at Lys26. These modifica-
`tions facilitate binding of liraglutide to serum albumin,
`self-oligomerization, and resistance to DPP-4-mediated
`inactivation, which result in a prolonged half-life of this
`molecule in vivo. Plasma levels of liraglutide remain stable
`for up to 13 h after a single subcutaneous injection. Dose-
`ranging, phase II studies demonstrated that liraglutide
`mimics all of the expected actions of GLP-1 in humans:
`its administration results in 24 h glucose control, low rates
`of hypoglycemia, and weight loss in most individuals.
`Nausea and diarrhea are the most commonly reported
`adverse events.18
`Once-daily administration of low doses of liraglutide
`(0.1–0.9 mg daily) in a cohort of Japanese patients with
`T2DM was well tolerated and reduced HbA1c levels, by
`up to 1.85%, without major episodes of hypoglycemia;
`no change in body weight was observed after 14 weeks
`of therapy.19 Several phase III clinical trials have investi-
`gated the efficacy of liraglutide (either as monotherapy or
`in combination with other drugs) versus that of other oral
`hypoglycemic agents, exenatide, or insulin. The results of
`these clinical trials suggest that liraglutide was at least as
`efficacious in lowering HbA1c as comparator treatments
`and was usually associated with weight loss of several
`kilograms. Additive therapy with liraglutide (1.2 mg or
`1.8 mg) given to patients whose diabetic symptoms were
`inadequately controlled with metformin and rosiglita-
`zone resulted in a mean HbA1c reduction of 1.5%, from
`a baseline value of 8.6%, in association with weight loss
`of about 2 kg and a reduction in systolic blood pressure.20
`Nausea, vomiting and diarrhea were the most common
`adverse events and the principal reasons for withdrawal
`from the study in liraglutide-treated patients.
`A 52-week study compared glimepiride mono therapy
`with liraglutide monotherapy (1.2 mg or 1.8 mg daily)
`in patients with T2DM. Liraglutide was more effective
`than glimepiride for reducing HbA1c level (by 0.84%
`and 1.14% versus 0.5%, respectively). Moreover, patients
`treated with liraglutide lost weight and exhibited a
`reduction in blood pressure, whereas those treated with
`glimepiride gained weight.21 The efficacy of liraglutide
`versus rosiglitazone therapy has also been assessed in
`patients who failed to achieve optimal glycemic control
`on glimepiride. Liraglutide, at doses of 1.2 or 1.8 mg daily,
`was more effective than rosiglitazone in producing addi-
`tional reductions in fasting plasma glucose and HbA1c
`levels over 26 weeks. Moreover, patients who received
`
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`liraglutide did not gain weight, in contrast to those in the
`rosiglitazone group, in whom an average weight gain of
`2.1 kg was reported.22
`The efficacy of additive glimepiride 4 mg once daily
`was compared with that of a range of liraglutide doses,
`0.6–1.8 mg daily, for 26 weeks in patients whose dia-
`betic symptoms were not adequately controlled with
`metformin therapy.23 Liraglutide was as effective as
`glimepiride in reducing HbA1c levels (mean reduc-
`tions of approximately 1%). Fewer episodes of minor
`hypo glycemia, a slight reduction (2–3 mmHg) in blood
`pressure, an increase in heart rate and more nausea
`were seen in liraglutide-treated patients compared with
` glimepiride-treated patients. Notably, body weight
`decreased in liraglutide -treated indivi duals but increased
`in those treated with glimepiride , whereas control of
`postprandial glycemic excursions and reductions in the
`proinsulin:insulin ratio were similar in the two groups.23
`Similarly, liraglutide produced a greater reduction in
`HbA1c level and body weight than insulin glargine on
`a background therapy of metformin and glimepiride.
`Glycemic targets (HbA1c ≤6.5% and <7%) were achieved by
`more patients in the liraglutide group (37.1% and 53.1%,
`respectively) than in the insulin glargine group (23.6%
`and 45.8%, respectively).24 Moreover, patients treated
`with liraglu tide had a reduction in waist circumference
`and lost about 1.8 kg in weight, whereas insulin glargine
`treatment was associated with weight gain of 1.6 kg.
`Liraglutide therapy improved the proinsulin:C-peptide
`ratio and reduced systolic blood pressure; however, some
`patients in the liraglutide group experienced episodes of
`major hypoglycemia (n = 5), whereas no such episodes
`occurred in the insulin glargine group.24
`Of particular interest, liraglutide 1.8 mg daily caused
`a greater reduction in fasting glucose and HbA1c levels
`than exenatide 10 g twice daily (1.1% versus 0.8%,
`respectively) over 30 weeks in an open-label study,
`whereas reductions in body weight and blood pres-
`sure were similar in the two groups).25 The incidence of
`minor hypo glycemia was lower among liraglutide-treated
`patients than in those treated with exenatide. Patients who
`were treated with exenatide for 30 weeks and switched
`to liraglutide for the next 14 weeks exhibited a further
`reduction of about 0.3% in their HbA1c level. A New
`Drug Application was filed for liraglutide in the US in
`May 2008. Liraglutide is also being investigated for the
`treatment of obesity in nondiabetic individuals at doses
`of up to 3 mg daily.
`
`Modified forms of exenatide
`AVE0010 (Sanofi-Aventis, Paris, France) is a modified
`exendin 4 molecule with additional lysine residues at
`the carboxy terminal. A phase IIb, dose-ranging study
`of AVE0010 was carried out in 542 patients who had
`T2DM that was inadequately controlled with metformin
`alone.26 Patients were treated for 13 weeks with escalat-
`ing doses of AVE0010 (5 g, 10 g, 20 g, or 30 g) once
`or twice daily, or placebo. Reductions were observed in
`
`Active GLP-1 and GIP
`
`Pancreatic
`islet cell
`
`DPP-4 inhibition
`
`REVIEWS
`
`Insulin
`
`Glucagon
`
`Post-prandial
`glucose
`
`Fasting glucose
`
`DPP-4 inhibitor
`
`DPP-4
`
`DPP-4 cleaves
`intact GLP-1 and GIP
`
`GLP-1 + GIP receptor
`
`GLP-17–36 amide
`GLP-19–36 amide
`GIP1–42
`GIP3–42 (inactive)
`Figure 2 | Mechanism of action of DPP-4 inhibitors. These agents prevent the
`enzymatic inactivation of GLP-1 and GIP. The binding of active GLP-1 and GIP to
`incretin receptors of the pancreatic β cell potentiates insulin secretion and inhibits
`glucagon secretion. Abbreviations: DPP-4, dipeptidyl peptidase 4; GIP,
`glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1.
`
`HbA1c levels from baseline with once daily (0.28–0.57%)
`and twice daily (0.47–0.69%) AVE0010, associated with
`decre ments in body weight. AVE0010 is now being
`studied in phase III clinical trials.
`A long-acting, once-weekly formulation of exenatide
`was evaluated at two doses, 0.8 mg and 2 mg, in patients
`with diabetes mellitus who were treated with diet and
`exercise and/or metformin for 15 weeks. Both cohorts
`exhibited marked reductions in their HbA1c level (of 1.4%
`and 1.7% from baseline, respectively), however, only those
`treated with 2 mg exenatide lost weight.27 Subsequently,
`a clinical trial compared the efficacy of 10 g exenatide
`twice daily with that of 2 mg exenatide once weekly in
`300 patients who were either not treated with oral hypo-
`glycemic agents or who were receiving one or two oral
`hypo glycemic agents for 30 weeks.27 Remarkable reduc-
`tions were seen in HbA1c level in both groups, with more
`substantial reductions in HbA1c observed with once-
`weekly exenatide than with twice-daily exenatide (1.9%
`versus 1.5%, respectively). More patients treated with
`once-weekly exenatide achieved target levels of HbA1c
`<7% than those who received twice-daily exenatide (77%
`versus 61%, respectively). Reductions in body weight
`were similar in both treatment groups (3.6–3.9 kg). Once-
`weekly exenatide was associated with a greater reduction
`in plasma glucagon levels and fasting plasma glucose levels
`than was twice-daily exenatide (decreases of 2.3 mmol/l
`versus 1.4 mmol/l, respectively), however, twice-daily
`exenatide was a more potent suppressor of post prandial
`glycemic excursions. Nausea and vomiting were the
`most commonly reported adverse effects with both
`formulations, and were less frequently reported with
`once-weekly exenatide than with twice-daily exenatide.
`By contrast, injection-site reactions and antiexenatide
`antibodies were more common in individuals treated with
`once-weekly exenatide, and the subset of participants in
`
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`REVIEWS
`
`this group with the highest antibody titers exhibited a
`modest reduction in efficacy.28
`
`Albiglutide
`Albiglutide (GlaxoSmithKline, Brentford, London, UK) is
`a long-acting, recombinant GLP-1R agonist, which con-
`sists of two tandem-linked copies of a modified human
`GLP-1 sequence within the large human serum albumin
`molecule; this structure enables sustained action and
`once-weekly administration. Despite the relatively large
`size of albiglutide, preclinical studies in rodents demon-
`strate that it activates the GLP-1R and reproduces a
`broad spectrum of GLP-1 actions, including inhibition of
`gastric emptying and perception of satiety following acute
`administration.29 Moreover, chronic albiglutide adminis-
`tration prevents weight gain in mice fed a high-fat diet.30
`Analysis of the pharmacokinetic properties of albiglutide
`was carried out in patients with T2DM who received a
`range of albiglutide doses from 9–64 mg. Albiglutide
`reduced both fasting and postprandial glucose levels, and
`had a circulating half-life of 6–7 days.31 This agent entered
`phase III clinical studies in the first quarter of 2009.
`
`Taspoglutide
`Taspoglutide (Roche, Basel, Switzerland; Ipsen, Paris,
`France) is a GLP-1-based molecule that contains amino-
`isobutyric acid substitutions at positions 8 and 35, which
`confer resistance to degradation by DPP-4. A zinc-based
`formulation of taspoglutide is suitable for once-weekly
`administration. Pharmacokinetic and pharmacodynamic
`studies in 48 individuals who had T2DM that was sub-
`optimally controlled with metformin demonstrated that
`plasma levels of taspoglutide were sustained for 14 days
`and were associated with reductions in the 24 h blood-
`glucose area under the curve, and with progressive weight
`loss of 0.9 kg, compared to placebo. A randomized,
` placebo-controlled, phase II clinical trial has investigated
`the efficacy and safety of either weekly or biweekly taspo-
`glutide administration in 306 patients who had T2DM
`that was inadequately treated with metformin.32 Both
`taspoglutide regimens reduced HbA1c levels after 8 weeks
`of therapy: 79% of those who received 10 mg taspoglutide
`per week and 81% of those who received 20 mg per week
`achieved HbA1c levels <7%, and dose-dependent reduc-
`tions were observed in body weight in both groups.
`Taspoglutide therapy was associated with transient
`nausea and vomiting, and some patients developed anti-
`peptide antibodies. A second phase II study examined
`taspoglutide dosing regimens in 133 metformin-treated
`patients who were randomly allocated placebo or 20 mg
`taspoglutide once weekly for 4 weeks, followed by a
`second 4-week treatment period with 20 mg, 30 mg or
`40 mg once weekly. All patients experienced improve-
`ments in glucose control, with nausea as the most com-
`monly reported adverse event.33 Withdrawal from the
`study was more common in patients who received the two
`highest doses of taspoglutide. This drug is currently being
`evaluated in phase III clinical studies.
`
`Other long-acting GLP-1R agonists
`Additional long-acting GLP-1R agonists in clinical trials
`include CJC1134 (ConjuChem, Montreal, Canada),
`a protein that contains an exendin 4 peptide moiety
`covalently linked to human serum albumin through a
`chemical linkage, which proved to exert a broad range
`of GLP-1-receptor-dependent glucose-regulatory actions
`in preclinical studies.34 Similarly, multiple once-weekly
`GLP-1 therapies are under active clinical investigation in
`phase I–II studies (NN9535, LY2199265, and a pegylated
`GLP-1 molecule, LY2428757; see Table 1), but few data are
`available on the structure or efficacy of these molecules.
`
`Adverse effects of GLP-1R agonists
`Nausea and vomiting are the principal adverse events
`that are observed following GLP-1R agonist adminis-
`tration; their incidence seems to be related to both the
`absolute maximal drug concentration and the time taken
`to reach this concentration. Although nausea and vomit-
`ing are usually mild, transient, and diminish over time in
`most individuals, some patients will not be able to toler-
`ate or continue GLP-1-based therapy owing to persistent
`gastrointestinal discomfort.
`Structurally distinct GLP-1R agonists, such as exenatide,
`are associated with induction of antiexenatide anti bodies;
`up to 50% of patients who are treated with exenatide twice
`daily develop such antibodies, and a slightly greater pro-
`portion of patients develop them following treatment
`with once-weekly exenatide.28 Although the presence
`of antiexenatide antibodies does not seem to be a major
`determinant of thera peutic effective ness for the majority
`of patients who receive twice-daily treatment, a small
`subset of individuals who have high titers of antibodies
`(>1:625) may experience diminished thera peutic efficacy.
`Similarly, in comparison with patients without high titers
`of antiexenatide antibodies, patients with high antibody
`titers who were treated with once-weekly exenatide had
`a relatively small, but still highly remarkable (1.4%)
`reduction in HbA1c after 30 weeks of therapy.28 Much less
`information is available about antibody titers and their
`relationship to therapeutic outcomes following therapy
`with liraglutide or other emerging GLP-1R agonists.
`Pancreatitis has been reported in patients who were
`treated with exenatide in postmarketing surveillance35
`and in several participants of the liraglutide clinical trial
`program.21 As pancreatitis can be associated with sub-
`stantial morbidity and death, considerable apprehension
`has developed in relation to the potential relationship
`between therapy with a GLP-1R agonist and the new
`onset of or potential exacerbation of pancreatitis. Few
`clinical epidemiological data are available that allow
`ascertainment of an accurate incidence of pancreatitis
`among those with diabetes mellitus who are treated with
`exenatide as compared with those who receive other
`antidiabetic therapies. Similarly, although exendin 4 and
`GLP-1 have been shown to potentiate amylase release
`from pancreatic fragments in preclinical studies,36 no
` evidence from animal experiments has suggested that
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`© 2009 Macmillan Publishers Limited. All rights reservedMPI EXHIBIT 1012 PAGE 5
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1012, p. 5 of 8
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`

`REVIEWS
`
`GLP-1 or exendin 4 alone cause or exacerbate pancre-
`atitis. As many patients who are treated with GLP-1R
`agonists experience transient abdominal discomfort due
`to inhibition of gastric emptying, which is also a charac-
`teristic symptom of pancreatitis, the diagnosis of pancre-
`atitis might be difficult in such patients. Understanding
`the potential relationship between GLP-1R agonist
`therapy and pancreatic inflammation is of considerable
`clinical importance, as at least 6 deaths have occurred
`among those who were treated at some point with
`exenatide and have later developed pancreatitis.
`
`DPP-4 inhibitors
`Sitagliptin and vildagliptin
`DPP-4 inhibitors, sometimes called ‘incretin enhancers’,
`exert their glucose-regulatory actions through prolonga-
`tion of the actions of GLP-1 and, to a lesser extent, GIP.37
`Sitagliptin was approved for use in the US in October 2006
`and in other countries thereafter, and vildagliptin was sub-
`sequently approved for use in Europe and other countries
`but not in the US. DPP-4 inhibitors may be administered
`orally, once daily (sitagliptin) or twice daily (vildagliptin),
`they do not influence body weight, and are well toler-
`ated. In the US, sitagliptin has been approved for use as
`monotherapy or in combination with metformin, or a
`sulfonyl urea, or a thiazolidinedione.38–43 Perhaps the most
`compelling indication for the use of DPP-4 inhibitors is
`in combination with metformin for patients with early
`T2DM who are assigned their first combination therapy,
`because a substantial proportion of such patients who
`were treated with both metformin and sitagliptin achieved
`target levels of HbA1c.41 Similar clinical trial results have
`been observed with vildagliptin.44–46 All DPP-4 inhibitors
`(sitagliptin, vildagliptin and other agents in late stages of
`clinical testing) are selective for DPP-4, but exert differen-
`tial affinity for DPP-4-related enzymes when tested with
`recombinant enzymes in vitro. Moreover, these agents
`might have active or inactive metabolites, and the drugs
`and their metabolites display unique pharmacokinetic
`properties and might cause molecule-specific adverse
`events.47 For example, the dose of sitagliptin must be
`reduced to 50 mg or 25 mg in individuals with moderate
`to severe impairment of renal function,48 whereas vilda-
`gliptin must be given in divided doses of 50 mg twice daily
`because 100 mg given in a single daily dose is associated
`with elevated levels of transaminases. Moreover, vilda-
`gliptin is converted to a metabolite that is cleared by the
`kidney; the biological importance of this metabolite, if
`any, remains uncertain.
`
`Alogliptin and saxagliptin
`Alogliptin (Takeda, Osaka, Japan) is a quinazolinone-
`based DPP-4 inhibitor that has been investigated in
`phase III clinical trials as monotherapy or in combina-
`tion with other oral antidiabetic agents (metformin,
`sulfonylurea, or thiazolidinedione). Alogliptin has been
`evaluated as monotherapy for 26 weeks in patients with
`poorly controlled diabetes mellitus at doses of 12.5 mg or
`
`25 mg daily, which achieved reductions in HbA1c levels
`of 0.56% and 0.59%, respectively, and seemed to be well
`tolerated.49 Alogliptin, used at doses of 12.5 mg and
`25 mg once daily, also lowered patients’ blood glucose
`levels when it was added to existing therapy in patients
`who had responded inadequately to metformin alone.50
`Patients experienced a 0.6% reduction in HbA1c level
`and a 1 mmol/l reduction in fasting glucose level after
`26 weeks of adding alogliptin to metformin therapy.
`Notably, alogliptin, as well as vildagliptin, have been
`successfully