Rev MJ Davies 118.07.qxp 12/11/07 11:55 Page 2
`
`REVIEW
`
`The dipeptidyl-peptidase-4 (DPP-4)
`inhibitors: a new class of oral therapy for
`patients with type 2 diabetes mellitus
`
`MA Elrishi, K Khunti, J Jarvis, MJ Davies*
`
`Introduction
`The incretins are peptide hormones
`that are released from the gut in
`response to the ingestion of food and
`enhance glucose-stimulated insulin
`secretion from the pancreas.1
`Oral glucose intake stimulates
`insulin release to a greater extent
`than does a comparable glucose chal-
`lenge delivered intravenously.2 This
`augmentation of insulin secretion
`following an oral glucose challenge is
`known as
`the
`‘incretin effect’.
`The incretin effect is mediated via
`gut hormones that cause insulin
`secretion as a response to hyper-
`glycaemia.1,3
`Glucose-dependent
`insulinotropic polypeptide (GIP) was
`the first incretin hormone isolated.4
`GIP inhibits gastric acid secretion
`and regulates fat metabolism in
`adipocytes. Glucagon-like peptide-1
`(GLP-1) was the second incretin hor-
`mone isolated.4 GIP is predominantly
`produced in jejunal K cells whereas
`GLP-1 is produced by the L cells in
`the ileum.1,5
`
`Incretins and type 2 diabetes
`It has been shown that the incretin
`effect is diminished in patients with
`type 2 diabetes mellitus (T2DM)6
`(Figure 1). T2DM patients have
`reduced circulating GLP-1 and
`GIP concentrations by as much as
`54% compared to normal subjects.7
`Studies show that GIP has lost most of
`its insulinotropic abilities in patients
`with T2DM; this implies that GLP-1 is
`
`ABSTRACT
`The observation that an oral glucose load is more effective at releasing insulin, compared
`with the same amount of glucose given intravenously, has been called the incretin effect,
`and is due to the augmentation of glucose-stimulated insulin secretion by intestinally
`derived peptides.
`Glucagon-like peptide-1 (GLP-1), in particular, has been shown to stimulate insulin
`release in a glucose-dependent manner in humans, but it is rapidly metabolised by
`dipeptidyl-peptidase-4 (DPP-4). Inhibition of DPP-4 activity enhances fasting and
`post-prandial GLP-1 which, in turn, improves glycaemic control by increasing glucose-
`dependent insulin secretion and by decreasing glucagon concentration.
`Current oral antidiabetic drugs (OADs) for type 2 diabetes are limited by adverse
`effects such as gastrointestinal problems, weight gain, oedema, or hypoglycaemia. In
`addition, there are recent concerns about rosiglitazone and cardiovascular outcomes, and
`with the thiazolidinediones in general regarding excess fracture rate in women and
`increased risk of heart failure. Thus the introduction of a new class of OADs, the DPP-4
`inhibitors, is welcome.
`This review article discusses the most clinically relevant data published on DPP-4
`inhibitors based on Medline literature searches (1966 to August 2007) and posters and
`oral presentations from the American Diabetes Association Scientific Sessions in 2006
`and 2007. We have concentrated our review on two DPP-4 inhibitors: sitagliptin (Januvia)
`and vildagliptin (Galvus). Copyright © 2007 John Wiley & Sons.
`Practical Diabetes Int 2007; 24(9): 474–482
`
`KEY WORDS
`type 2 diabetes; gliptins; dipeptidyl-peptidase-4 (DPP-4) inhibitors; glycaemic
`management; HbA1c; incretin effect; oral antidiabetic drugs (OADs)
`
`a more effective therapeutic target
`for T2DM.8 GLP-1 has a half life of
`<two minutes because it is rapidly
`inactivated by the enzyme dipeptidyl-
`peptidase. Dipeptidyl-peptidase-4 was
`first reported in 1966 as glycyl-prolyl-
`β-naphthylamidase9 and later named
`dipeptidyl peptidase (DPP-4). DPP-4
`is the archetypal member of its six
`member gene family. Four members
`of this family – DPP-4, FAB (fibroblast
`activation protein), DPP-8 and DPP-9
`– have a rare substrate specificity:
`
`hydrolysis of a prolyl bond two
`residues from the N-terminus. The
`ubiquitous DPP-4 glycoprotein has
`proved interesting in the fields of
`immunology, endocrinology, haema-
`tology and endothelial cell biology
`and has become a novel target for
`T2DM therapy.10
`
`Mechanism of action
`DPP-4 inhibitors suppress the degra-
`dation of a variety of bioactive
`peptides, including GLP-1, thereby
`
`MA Elrishi, MRCP, MMedSci/MSc,
`Specialist Registrar, Diabetes and
`Endocrinology, Leicester Royal Infirmary,
`University Hospitals of Leicester NHS
`Trust, UK
`K Khunti, MD, FRCGP, Professor of
`General Practice and Primary Health Care,
`Department of Health Sciences, University
`of Leicester, Leicester General Hospital, UK
`
`J Jarvis, MSc, BSc(Hons), RN, Nurse
`Research Fellow, Department of Diabetes
`Research, University Hospitals of Leicester
`NHS Trust, UK
`MJ Davies, FRCP, MD, Professor of
`Diabetes Medicine, Department of
`Cardiovascular Sciences, University of
`Leicester and Honorary Consultant,
`University Hospitals of Leicester, UK
`
`*Correspondence to: Professor Melanie
`Davies, FRCP, MD, Department of
`Cardiovascular Sciences, University of
`Leicester, c/o Victoria Building, Leicester
`Royal Infirmary, Leicester LE1 5WW, UK;
`e-mail: melanie.davies@uhl-tr.nhs.uk
`
`Received: 15 October 2007
`Accepted: 16 October 2007
`
`474 Pract Diab Int November/December 2007 Vol. 24 No. 9
`
`Copyright © 2007 John Wiley & Sons
`
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`

`
`Rev MJ Davies 118.07.qxp 19/11/07 14:52 Page 3
`
`REVIEW
`DPP-4 inhibitors: a new class of oral therapy for type 2 diabetes
`
`Figure 1. Incretin effect in type 2 diabetes. (Adapted from Nauck M, et al. Diabetologia 1986; 29: 46–526 by Merck
`Sharp & Dohme. Permission has been granted by MSD to reproduce this figure, © MSD)
`
`Healthy controls (n=8)
`
`Type 2 diabetes (n=14)
`
`-10 -5
`
`60
`
`120
`
`180
`
`Diminished
`incretin effect
`
`20
`
`15
`
`10
`
`5 0
`
`80
`
`60
`
`40
`
`20
`
`0
`
`(mmol/L)
`
`Venous plasma glucose
`
`IR insulin (mU/L)
`
`-10 -5
`
`60
`
`120
`
`180
`
`Normal
`incretin effect
`
`20
`
`15
`
`10
`
`5 0
`
`80
`
`60
`
`40
`
`20
`
`0
`
`(mmol/L)
`
`Venous plasma glucose
`
`IR insulin (mU/L)
`
`-10 -5
`
`120
`60
`Time (minutes)
`
`180
`
`-10 -5
`
`120
`60
`Time (minutes)
`
`180
`
`Oral glucose (50g/400ml)
`
`Isoglycaemic intravenous glucose
`
`extending their period of action,
`and work by acting as competitive
`antagonists of the DPP-4 enzyme.11
`In addition to the impact on
`GLP-1 action, they may affect other
`peptides,
`including peptide YY,
`neuropeptide Y, growth hormone
`releasing hormone and vasoactive
`intestinal polypeptide.12 In T2DM
`subjects, the continuous infusion of
`GLP-1 has been shown to decrease
`plasma glucose and HbA1c levels, and
`increase β-cell mass.13
`
`Selectivity with DPP-4
`inhibitors
`DPP-4 inhibitors have demonstrated
`efficacy in animal models, but also
`result in toxicities. Some, but not all
`DPP-4 inhibitors, have been reported
`to produce skin lesions in studies in
`monkeys.14 It has been proposed that
`the toxic effect associated with these
`inhibitors arises from the inhibition of
`DPP-8 and/or DPP-9, and not DPP-4.
`Selective inhibition of DPP-8/9-atten-
`uated T-cell activation suggests that
`these enzymes are involved in the
`immune system. A study by Lankas et
`
`al. demonstrated that a selective inhi-
`bition of DPP-8/9 was toxic, whilst a
`selective inhibition of DPP-4 was not.15
`
`Sitagliptin
`Merck
`(Januvia,
`Sitagliptin
`Pharmaceuticals) is a potent, highly
`specific DPP-4 inhibitor that is rap-
`idly absorbed orally, and inhibits
`plasma DPP-4 activity by 90%.16 It is
`the first in this new class of OADs
`to gain regulatory approval, by the
`Food and Drug Administration
`(FDA) in October 2006 and by the
`European Union in March 2007, for
`the treatment of T2DM.17,18
`In
`North America it is licensed for
`use as monotherapy and for use in
`combination with metformin or thi-
`azolidinediones (TZDs). In the
`European Union its use is recom-
`mended in combination with met-
`formin when diet and exercise plus
`metformin do not provide adequate
`glycaemic control, or for combined
`use with TZDs.18
`In single dose studies in non-dia-
`betic subjects, sitagliptin was well
`absorbed with about 80% of the
`
`administered dose excreted un-
`changed in the urine.19 Sitagliptin
`induced a two-fold increase in active
`GLP-1 following a meal; similar
`results were seen following a divided
`dosage.20
`
`Monotherapy vs placebo
`(See Table 1: summary of clinical
`trials with sitagliptin.) A trial of
`sitagliptin monotherapy decreased
`glycosylated haemoglobin (HbA1c)
`levels
`compared
`to
`placebo
`(p<0.001).21 Patients with a baseline
`HbA1c ≥9% had a greater reduction
`in placebo-subtracted HbA1c of
`about -1.50%. Sitagliptin (100mg
`and 200mg) significantly decreased
`two-hour post-prandial
`glucose
`(placebo-subtracted -2.6mmol/L and
`-3.0mmol/L, respectively; p<0.001).21
`In a trial by Raz et al., patients with
`T2DM were randomised to receive
`placebo, or sitagliptin 100mg or
`200mg. After 18 weeks, HbA1c was sig-
`nificantly reduced with sitagliptin.22
`
`Combination therapy
`See Table 1.
`
`Pract Diab Int November/December 2007 Vol. 24 No. 9
`
`Copyright © 2007 John Wiley & Sons 475
`
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`

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`Rev MJ Davies 118.07.qxp 19/11/07 14:52 Page 4
`
`REVIEW
`DPP-4 inhibitors: a new class of oral therapy for type 2 diabetes
`
`Table 1. Summary of clinical trials with sitagliptin
`
`Source
`
`No. of
`Trial
`duration subjects
`(weeks)
`
`Change
`Treatment and dose Duration Mean
`of
`baseline in HbA1c
`diabetes HbA1c
`(%)
`(years)
`(%)
`(placebo
`subtracted*)
`
`P-value Change
`in weight
`
`Aschner,
`et al.21
`
`24
`
`741
`
`Raz, et al.22
`
`18
`
`521
`
`Goldstein,
`et al.23
`
`24
`
`1091
`
`Charbonnel, 24
`et al.24
`
`701
`
`Nauck,
`et al.25
`
`52
`
`1172
`
`Hermansen, 24
`et al.26
`
`441
`
`Sitagliptin 100mg od
`Sitagliptin 200mg od
`Vs placebo
`
`Sitagliptin 100mg od
`Sitagliptin 200mg od
`Vs placebo
`
`Sitagliptin 100mg od
`Metformin 1000mg
`Metformin 2000mg
`Sitagliptin 50mg bd +
`metformin 1000mg
`Sitagliptin 50mg bd +
`metformin 2000mg
`Placebo
`
`Sitagliptin 100mg +
`metformin ≥ 1500mg
`Vs metformin +
`placebo
`
`4.4
`
`8.0
`
`4.5
`
`8.1
`
`4.5
`
`8.8%
`
`<0.001
`
`<0.001
`
`<0.001
`
`-0.79*
`-0.94*
`
`-0.60*
`-0.48*
`
`-0.83*
`-0.99*
`-1.30*
`-1.57*
`
`-2.07*
`
`–
`
`6.2
`
`8.0
`
`-0.65*
`
`<0.001
`
`-0.2kg
`-0.1kg
`-1.1kg
`
`-0.6kg
`-0.2kg
`-0.7kg
`
`0.0kg
`-0.6–1.3kg
`-0.6–1.3kg
`-0.6–1.3kg
`
`-0.6–1.3kg
`
`-0.9kg
`
`-0.6–0.7kg
`in both
`groups
`
`Metformin ≥ 1500mg 6.5
`+ sitagliptin 100mg
`Vs metformin
`≥ 1500mg +
`glipizide 5–20mg
`
`6.2
`
`7.7
`
`7.6
`
`-0.51
`
`-0.56
`
`Similar
`reduction
`
`-1.5kg
`
`+1.1kg
`
`Sitagliptin 100mg +
`glimepiride ≥ 4mg vs
`glimepiride ≥ 4mg +
`placebo
`Glimepiride ≥ 4mg +
`metformin ≥ 1500mg
`+ sitagliptin 100mg
`vs glimepiride ≥ 4mg
`+ metformin ≥ 1500mg
`+ placebo
`
`8.8
`
`8.3
`
`<0.001
`
`-0.57*
`
`-0.89*
`
`+0.8kg for
`sitagliptin
`groups
`
`-0.4kg for
`placebo
`groups
`
`Rosenstock, 24
`et al.27
`
`353
`
`6.1
`
`Pioglitazone +
`sitagliptin 100mg vs
`pioglitazone +
`placebo
`
`8.1
`
`8.0
`
`-0.7*
`
`<0.001
`
`+1.8kg
`
`+1.5kg
`
`Added to metformin
`In a randomised, double-blind,
`placebo-controlled, parallel-group
`study, patients with T2DM were ran-
`domised to six arms which included
`combination (metformin plus sita-
`gliptin) treatment, metformin alone,
`sitagliptin alone or placebo. The
`placebo-subtracted HbA1c changes are
`
`shown in Table 1. The incidence of
`hypoglycaemia was low (0.5–2.2%)
`across active treatment groups and
`was not significantly different from
`that in the placebo group (0.6%).23
`In a study in T2DM subjects treated
`with metformin ≥1500mg, addition of
`sitagliptin led to a placebo-subtracted
`reduction in HbA1c (-0.65%), fasting
`
`plasma glucose (-1.4mmol/L), and
`two-hour post-meal plasma glucose
`(-2.8mmol/L) (p<0.001 for all three
`measures).24
`
`Added to metformin and
`compared with glipizide
`Subjects who failed to reach target
`HbA1c on metformin were ran-
`
`476 Pract Diab Int November/December 2007 Vol. 24 No. 9
`
`Copyright © 2007 John Wiley & Sons
`
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`Rev MJ Davies 118.07.qxp 19/11/07 14:52 Page 5
`
`REVIEW
`DPP-4 inhibitors: a new class of oral therapy for type 2 diabetes
`
`domised to either sitagliptin 100mg
`or glipizide 5–20mg.25 Reductions
`in HbA1c levels in the two groups
`were similar at 52 weeks. A signifi-
`cantly lower rate of hypoglycaemia
`occurred in subjects treated with
`sitagliptin (5%) than in those on
`glipizide (32%) (p<0.001).
`
`Added to glimepiride alone or to
`glimepiride and metformin
`to
`The addition of
`sitagliptin
`glimepiride-treated patients as dual
`therapy, and glimepiride plus met-
`formin-treated patients as triple
`therapy, has been examined. In the
`entire cohort, patients on sitagliptin
`had a placebo-adjusted HbA1c
`reduction of -0.74% (p<0.001). The
`study also showed that sitagliptin
`decreased fasting and post-prandial
`glucose and increased homeostasis
`model assessment-β (HOMA-β), a
`marker of β-cell function, by 12%
`(p<0.05) relative to placebo. The
`addition of sitagliptin was generally
`well tolerated; however, there was a
`higher incidence of hypoglycaemia
`(12% vs 2%) and drug-related
`adverse experiences (15% vs 7%) in
`the sitagliptin group compared
`with the placebo group. In addition,
`the body weight increased with
`sitagliptin compared to placebo
`(+0.8kg vs -0.4kg; p<0.001).26
`
`Added to pioglitazone
`Rosenstock et al. conducted a 24-week
`study of sitagliptin added to pioglita-
`zone therapy. T2DM subjects on
`pioglitazone (30 or 45mg) were ran-
`domised to receive sitagliptin 100mg
`daily or placebo. The addition of
`sitagliptin produced a significant
`reduction in HbA1c compared to the
`placebo plus pioglitazone group.27
`
`Sitagliptin use in the elderly
`population
`Preliminary information on the effi-
`cacy and tolerability of sitagliptin in
`subjects with T2DM aged ≥65 years
`compared to subjects aged <65 years,
`from pooled data of four studies,
`shows that the overall incidence of
`adverse events were generally similar
`among older and younger patients.28
`
`Vildagliptin
`(Galvus, Novartis
`Vildagliptin
`International) is a potent, selective,
`
`bioavailable DPP-4 inhibitor; it is rap-
`idly absorbed orally.29 It improves gly-
`caemic control by increasing α- and β-
`cell responsiveness to glucose and
`suppressing inappropriate glucagon
`secretion.30 Vildagliptin is not yet
`approved by the FDA. However, the
`European Union granted approval
`for vildagliptin to be used in combina-
`tion with metformin, sulphonylurea
`or TZDs.31
`
`Monotherapy
`See Table 2: summary of clinical
`trials with vildagliptin.
`
`Monotherapy vs placebo
`A double-blind, randomised, multi-
`centre, placebo-controlled parallel
`study in drug naive subjects with
`T2DM looked at the efficacy and tol-
`erability of vildagliptin 50mg od,
`50mg bd or 100mg od. HbA1c
`reduced in all treatment arms.32
`
`Monotherapy vs metformin
`Schweizer et al.33 performed a 52-
`week, multicentre, randomised, dou-
`ble-blind study comparing vilda-
`gliptin 50mg bd
`to metformin
`1000mg bd in patients with T2DM.
`Both vildagliptin and metformin
`decreased HbA1c but the reduction
`was significantly greater for met-
`formin (p<0.001) The incidence of
`hypoglycaemia was 0.6% with vilda-
`gliptin vs 0.4% with metformin.
`
`Monotherapy vs rosiglitazone
`Rosenstock et al. compared vilda-
`gliptin with rosiglitazone in a 24-
`week trial of patients with T2DM.
`Both vildagliptin and rosiglitazone
`resulted in comparable reductions
`in HbA1c of more than 1% from
`baseline (p<0.001).34 Patients using
`rosiglitazone, however, had an aver-
`age increase in body weight of 1.6kg
`at the end of the study, while
`patients using vildagliptin had an
`average decrease in weight of -0.3kg
`(p<0.001).
`
`Combination therapy
`See Table 2.
`
`Added to metformin
`In a multicentre, randomised, dou-
`ble-blind, placebo-controlled trial
`vildagliptin was added to a stable dose
`of metformin; the 12-week study was
`
`Pract Diab Int November/December 2007 Vol. 24 No. 9
`
`followed by a 40-week extension. At
`12 weeks, the vildagliptin plus met-
`formin group demonstrated a
`decrease in HbA1c compared with
`the
`placebo
`plus metformin
`group (p<0.0001). Fasting plasma
`glucose was reduced by -1.2mmol/L
`(p=0.0057)
`in
`the
`vildagliptin
`group, and the mean post-prandial
`glucose was reduced by -2.2mmol/L
`(p<0.0001). At the end of 52 weeks,
`between-group differences in change
`in HbA1c, fasting plasma glucose,
`and mean post-prandial glucose
`were -1.1% (p<0.0001), -1.1mmol/L
`(p=0.0312), and -2.4mmol/L (p=
`0.0001), respectively.35 A further
`study, in which either placebo or
`vildagliptin 50mg od or 100mg od
`given in divided doses was added to
`metformin, showed significant reduc-
`tion in HbA1c (p<0.001).36
`In a study of 416 patients,
`vildagliptin 50mg od or 50mg bd was
`added to metformin and compared
`with placebo. HbA1c was reduced by
`0.7% and 1.1% in the 50mg and
`100mg vildagliptin groups, respec-
`tively, with no weight gain seen.37
`
`Added to sulphonylurea
`In another study,38 vildagliptin was
`added to sulphonylurea monother-
`apy (glimepiride). This study com-
`pared vildagliptin 50mg od and
`50mg bd vs placebo in patients con-
`tinuing glimepiride treatment (4mg
`od). Starting from a mean HbA1c of
`8.5%, vildagliptin 50mg od reduced
`HbA1c by 0.6% with twice daily
`vildagliptin giving little additional
`efficacy. Vildagliptin 50mg od
`was not associated with increased
`hypoglycaemia (1.2% vs 0.6% for
`vildagliptin and placebo, respec-
`tively) or weight gain (-0.1kg vs
`placebo 0.3kg, p=0.409).
`
`Added to insulin
`In a multicentre, 24-week, double-
`blind, randomised, placebo-controlled
`trial in 296 patients with T2DM (inad-
`equately controlled on insulin, with a
`baseline HbA1c of 8.4%), subjects were
`given 50mg of vildagliptin twice a day
`in addition to insulin (n=144). In
`those patients aged ≥65 years, the
`adjusted mean change from baseline
`to endpoint HbA1c was -0.7% in the
`vildagliptin group vs -0.1% in the
`placebo group (p<0.001).39
`
`Copyright © 2007 John Wiley & Sons 477
`
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`Rev MJ Davies 118.07.qxp 19/11/07 14:52 Page 6
`
`REVIEW
`DPP-4 inhibitors: a new class of oral therapy for type 2 diabetes
`
`Table 2. Summary of clinical trials with vildagliptin
`
`Source
`
`No. of
`Trial
`duration subjects
`(weeks)
`
`Change
`Treatment and dose Duration Mean
`of
`baseline in HbA1c
`diabetes HbA1c
`(%)
`(years)
`(%)
`(placebo
`subtracted*)
`
`P-value Change
`in weight
`
`Pi-Sunyer,
`et al.32
`
`24
`
`354
`
`Schweizer,
`et al.33
`
`52
`
`Rosenstock, 24
`et al.34
`
`Ahren,
`et al.35
`
`12
`
`780
`
`786
`
`107
`
`Bosi, et al.36
`
`24
`
`544
`
`Garber,
`et al.37
`
`24
`
`416
`
`Garber,
`et al.38
`
`24
`
`408
`
`Fonseca,
`et al.39
`
`24
`
`296
`
`1.8
`Vildagliptin 50mg od
`Vs vildagliptin 50mg bd 2.4
`Vs vildagliptin
`2.1
`100mg od
`Vs placebo
`
`2.5
`
`Vildagliptin 50mg bd vs 1
`metformin 1000mg bd
`
`Vildagliptin 50mg bd vs 2.3
`rosiglitazone 8mg od
`2.7
`
`8.4
`
`8.7
`
`8.7
`
`-0.5*
`-0.7*
`-0.8*
`
`-1.0
`-1.4
`
`-1.1
`-1.3
`
`=0.011
`<0.001
`<0.001
`
`<0.001
`
`-0.4kg
`0.0
`-0.4kg
`
`-1.4kg
`
`+0.3kg
`-1.9kg
`
`-0.3kg
`Similar
`reduction +1.6kg
`
`Vildagliptin 50mg od
`+ metformin
`
`5.6
`
`7.7
`
`-0.6* at
`12/52
`
`<0.001
`both
`
`Vs metformin +
`placebo
`
`5.5
`
`7.8
`
`-1.1* at
`52/52
`
`-0.4kg at
`12/52
`-0.2kg at
`52/52
`-0.5kg at
`12/52
`-0.2kg at
`52/52
`
`Vildagliptin 50mg od
`+ metformin ≥ 1500mg
`Vildagliptin 100mg od
`+ metformin ≥ 1500mg
`Metformin vs placebo
`
`Vildagliptin 50mg od
`+ metformin ≥ 1500mg
`vs metformin +
`placebo
`Vildagliptin 50mg bd
`+ metformin ≥ 1500mg
`vs metformin + placebo
`
`Vildagliptin 50mg od
`+ glimepiride 4mg od
`Vildagliptin 50mg bd
`+ glimepiride 4mg od
`Placebo +
`glimepiride 4mg od
`
`Vildagliptin 50mg bd
`+ unspecified insulin
`vs placebo + insulin
`
`6.2
`
`8.4
`
`-0.7*
`
`-1.1*
`
`<0.001
`
`-0.4kg
`
`<0.001
`
`+0.2kg
`
`6.2
`
`8.4
`
`-0.7
`
`<0.001
`
`-1.0kg
`
`No weight
`gain in
`either
`group
`
`7–8
`
`8.5
`
`-1.1
`
`-0.6*
`
`-0.7*
`
`<0.001
`
`-0.1kg
`
`<0.01
`
`-0.1kg
`
`+0.3kg
`
`14.5
`
`8.4
`
`-0.3*
`
`<0.01
`
`+1.3kg
`
`+0.6kg
`
`DPP-4 inhibitors’ vs other
`OADs’ effect on lipid profiles
`In a head-to-head comparison of
`vildagliptin 50mg bd with rosiglita-
`zone 8mg od over 24 weeks, the lipid
`profile improved with vildagliptin
`compared to the rosiglitazone group,
`
`as demonstrated by decreased total
`cholesterol (-14%, p<0.001), LDL
`(-16%, p<0.001), triglycerides (-9%,
`p=0.010), and VLDL (-8%, p=0.007),
`and a small increase was observed in
`HDL (+4 vs +9%, p=0.003).34
`Matikainen et al. evaluated the
`
`effects of vildagliptin on the post-
`prandial lipid profile. Vildagliptin
`therapy produced a
`significant
`reduction in triglycerides by 22%
`(p=0.037) with a favourable change
`in triglycerides compared with met-
`formin.40
`
`478 Pract Diab Int November/December 2007 Vol. 24 No. 9
`
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`
`REVIEW
`DPP-4 inhibitors: a new class of oral therapy for type 2 diabetes
`
`Table 3. Pharmacokinetic and adverse effects of sitagliptin and
`vildagliptin
`
`Pharmacokinetic
`
`Sitagliptin
`
`Vildagliptin
`
`Route
`
`Bioavailability
`
`Secretion
`
`Hepatic insufficiency
`
`Oral od
`
`87%
`
`Primarily by the kidney
`~80%.19 Sitagliptin
`exposure is increased in
`patients with impaired
`renal function44
`
`Moderate hepatic
`insufficiency had no
`statistically significant
`effect on half-life or renal
`clearance53
`
`Oral od
`
`>80%
`
`Mainly by metabolism
`and subsequent
`urinary excretion
`(22%) of metabolites
`
`Increased by 30%
`in patients with
`severe hepatic
`insufficiency54
`
`Drug interaction
`
`Low threshold
`
`Low threshold
`
`The impact of sitagliptin on
`lipid profile showed no consistent
`changes compared with glipizide,
`except for HDL-cholesterol which
`increased by 3.7% compared with a
`1.2% HDL increase in the glipizide
`group.25
`
`DPP-4 inhibitors’ effect on
`weight
`A recent meta-analysis examined data
`from 13 trials on the impact of DPP-4
`inhibitors on weight.41 There was a
`small increase in weight with DPP-4
`inhibitors compared with placebo
`(weighted mean difference, 0.5kg;
`95% CI, 0.3–0.7kg). Nauck et al. found
`sitagliptin had a favourable weight
`profile compared with glipizide (with
`a between-treatment difference of
`-2.5kg).25 However, Rosenstock et al.
`noted that the loss in body weight with
`vildagliptin was not statistically signifi-
`cant.34 In summary, DPP-4 inhibitors
`appear to be weight-neutral medica-
`tions, providing a probable advantage
`over TZDs (weighted mean differ-
`ence, -1.7kg; 95% CI, -2.2kg to -1.2kg).
`However, compared with metformin,
`as one would expect there was a
`-1.9kg (p<0.001) weight loss favouring
`metformin.33
`
`DPP-4 inhibitors and safety
`profile
`Generally no significant adverse
`effects (AEs) of DPP-4 inhibitors
`were noted in most trials. Doses up
`to 100mg daily of vildagliptin,36,42
`and 200mg of sitagliptin appear to
`be both safe and tolerable.43 DPP-4
`inhibitor-treated patients rarely
`experience hypoglycaemia unless
`used in combination with other
`OADs,
`in particular, sulphony-
`lureas; however, severe hypogly-
`caemia was reported in only two
`patients
`treated with a DPP-4
`inhibitor.41 The low rate of hypo-
`glycaemia may be due to the
`glucose-dependent
`action
`of
`both vildagliptin and sitagliptin,
`and has an important advantage
`over the sulphonylureas in particu-
`lar. Gastrointestinal side effects
`of metformin remain a major
`tolerability issue. Both the DPP-4
`inhibitors do not appear to cause
`similar side effects. A further impor-
`tant advantage of DPP-4 inhibitors is
`that they appear to be weight neu-
`
`tral21,37 or, at worse, result in very
`minimal weight gain.41 Weight neu-
`trality has the potential to increase
`patient compliance.
`Sitagliptin is excreted primarily
`by the kidney, about 80% excreted
`unchanged in urine.19 (Table 3). It
`is necessary, therefore, to check urea
`and electrolytes before starting ther-
`apy and to monitor them on a regu-
`lar basis. One study found a similar
`overall incidence of adverse effects
`when patients with renal impair-
`ment were
`treated with dose-
`adjusted sitagliptin.44 The increase
`is approximately 2.3-fold relative to
`healthy
`subjects
`for patients
`with a creatinine clearance of
`30–49ml/min and 3.8-fold with a
`creatinine clearance of <30ml/min,
`and 4.5-fold for patients on dialy-
`sis.45 Pooled analysis presented by
`Stein et al.43 summarised the tolera-
`bility and the most common AEs of
`sitagliptin in 5141 subjects. The
`overall incidence of AEs was similar
`in the sitagliptin and non-exposed
`groups; drug-related AEs were
`higher in non-exposed patients due
`to hypoglycaemia in sulphonylurea-
`treated patients (Table 4).
`Skin lesions in monkeys delayed
`the FDA approval for vildagliptin
`which was expected at the end of last
`year, and the FDA requested clinical
`trial in patients with kidney impair-
`ment.46 Reported AEs of vildagliptin
`were mild-to-moderate, with the
`
`most common AEs reported being
`headache (7.1%), abdominal pain
`(4.3%), dizziness (8.6%) and nausea
`(3.8%).42,47
`
`DPP-4 inhibitors: implications
`for the management of T2DM
`Studies have shown that, in patients
`with T2DM, this new class of drugs
`can stimulate the release of insulin,
`inhibit the release of glucagon, and
`improve glucose homeostasis. In
`clinical studies in humans, no signif-
`icant AEs have been shown. In
`contrast to other OADs, DPP-4
`inhibitors appear to be weight
`neutral, and have moderate but
`favourable effects on dyslipidaemia.
`Because of their favourable risk:ben-
`efit profile, this class may be useful
`in combination with other OADs, in
`particular metformin.
`
`Which patients might benefit
`from the DPP-4 inhibitors?
`There is strong evidence that met-
`formin should be the initial drug
`of choice in T2DM, endorsed by
`the recent consensus algorithm by
`Nathan et al.48 In North America,
`sitagliptin is licensed for use in
`T2DM patients as a monotherapy or
`in combination with either met-
`formin or TZDs. The European
`Union recommends
`its use
`in
`combination
`with metformin
`when diet and exercise plus met-
`formin do not provide adequate
`
`Copyright © 2007 John Wiley & Sons 479
`
`Pract Diab Int November/December 2007 Vol. 24 No. 9
`
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`
`REVIEW
`DPP-4 inhibitors: a new class of oral therapy for type 2 diabetes
`
`Table 4. Sitagliptin pooled adverse effects (AEs). Drug-related clinical AEs occurring at an incidence of >0.5%.
`(Adapted from Stein PP, et al. American Diabetes Association 67th Annual Scientific Sessions, Chicago, June 2007)43
`
`Sitagliptin 100mg
`crude rate n (%)
`(n=2786)
`
`Non-exposed crude
`rate n (%) (n=2355)
`
`Difference between
`sitagliptin and
`non-exposed crude
`rate (95% CI)
`
`Upper abdominal pain
`Constipation
`Diarrhoea
`Dyspepsia
`Nausea
`Fatigue
`Peripheral oedema
`Low blood glucose
`Hypoglycaemia
`Dizziness
`Headache
`
`13
`22
`35
`16
`25
`14
`10
`6
`72
`14
`31
`
`(0.5)
`(0.8)
`(1.3)
`(0.6)
`(0.9)
`(0.5)
`(0.4)
`(0.2)
`(2.6)
`(0.5)
`(1.1)
`
`9
`13
`41
`10
`25
`17
`13
`13
`176
`12
`27
`
`(0.4)
`(0.6)
`(1.7)
`(0.4)
`(1.1)
`0.7)
`(0.6)
`(0.6)
`(7.5)
`(0.5)
`(1.1)
`
`0.1
`0.2
`-0.5
`0.1
`-0.2
`-0.2
`-0.2
`-0.3
`-4.9
`0.0
`0.0
`
`(-0.3, 0.5)
`(-0.2, 0.7)
`(-1.2, 0.2)
`(-0.3, 0.6)
`(-0.7, 0.4)
`(-0.7, 0.2)
`(-0.6, 0.2)
`(-0.7, 0.0)
`(-6.1, -3.7)
`(-0.4, 0.4)
`(-0.6, 0.6)
`
`Table 5. Comparison of DPP-4 inhibitors with GLP-1 agonists (exenatide)
`
`DPP-4 inhibitors
`(sitagliptin and vildagliptin)
`
`GLP-1 agonists (exenatide)
`
`Oral route od
`
`Subcutaneous route bd
`
`Physiological fluctuations in
`hormone levels
`
`Sustained effect that may be
`prolonged
`
`Limited by endogenous secretion
`
`Not limited endogenous secretion
`
`New mechanism of action with
`possible β-cell sparing
`
`New mechanism of action with
`possible β-cell sparing
`
`Good tolerability27,36,43
`
`Tolerability is an issue mainly due
`to the nausea. Mean 41.9% (95%
`CI)41
`
`GLP-1 and GIP enhanced
`
`Only GLP-1 enhanced
`
`Weight neutral21,37 or minimal weight
`gain almost = +0.5kg41
`
`Weight loss almost = -2.0kg49
`
`Reduction in HbA1c
`almost = 0.6–0.8%21,22,51
`
`Reduction in HbA1c
`almost = -1.0%49
`
`Cost about (sitagliptin) £399/year55
`
`Cost about £818/year55
`
`glycaemic control, and for combina-
`tion with TZDs.
`The DPP-4 inhibitors provide a
`new option for T2DM therapy.
`However, there are still some ques-
`tions about the place of DPP-4
`inhibitors in treating T2DM. In the
`current climate, cardiovascular safety
`is a key factor and the effect of DPP-4
`inhibitors on cardiovascular out-
`comes has not been tested.
`
`DPP-4 inhibitors compared
`with GLP-1 analogues
`Although the actions of both exe-
`natide
`and DPP-4
`inhibitors
`(sitagliptin and vildagliptin) depend
`on the incretin effects, there are
`important differences between these
`two classes (see Table 5).
`The DPP-4 inhibitors are avail-
`able orally, they have the potential
`for once-daily administration and
`
`they do not have the gastrointestinal
`side effects of GLP-1 analogues.
`DPP-4 inhibitors are weight neutral,
`whereas GLP-1 agonists are associ-
`ated with significant weight loss.49
`
`Other DPP-4 inhibitors in
`development
`There are many other DPP-4
`inhibitors in development. For exam-
`ple, recently presented data on
`saxagliptin showed that it was safe
`and well tolerated in healthy subjects
`at a dose range of 40–400mg, and in
`T2DM the dose range was between
`2.5 and 40mg.50 Other DPP-4
`inhibitors that are being developed
`include alogliptin benzoate (SYR-
`322).51 Furthermore, a long-acting
`DPP-4 inhibitor, BI 1356, has been
`developed by Boehringer Ingelheim.
`Data from a 28-day trial showed it to
`be a potent hypoglycaemic agent pro-
`ducing a significant reduction in
`HbA1c (p<0.025).52
`
`Conclusions
`A number of studies have been
`recently published and presented on
`DPP-4 inhibitors. These studies show
`that sitagliptin and vildagliptin are
`well tolerated and efficacious in opti-
`mising glycaemic control in patients
`with T2DM, as both monotherapy or
`in combination with other OADs.
`They appear to be weight neutral and
`have a low rate of hypoglycaemia.
`The safety profile of the DPP-4
`inhibitors appears to be reassuring;
`however, clinical trials of longer dura-
`tion and in larger populations are
`
`480 Pract Diab Int November/December 2007 Vol. 24 No. 9
`
`Copyright © 2007 John Wiley & Sons
`
`Mylan EX 1014, Page 7
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`

`
`Rev MJ Davies 118.07.qxp 19/11/07 14:52 Page 9
`
`REVIEW
`DPP-4 inhibitors: a new class of oral therapy for type 2 diabetes
`
`required to examine long-term effi-
`cacy and safety.
`
`Key points
`
`Conflict of interest statement
`Professor Melanie Davies has acted as
`consultant and speaker for Novartis,
`Novo Nordisk, Sanofi-Aventis, Lilly,
`Merck Sharp & Dohme, and Servier.
`She has received grants in support of
`investigator and investigator-initiated
`trials from Novartis, Novo Nordisk,
`Sanofi-Aventis, Lilly, Pfizer, Merck
`Sharp & Dohme, and Servier.
`Professor Kamlesh Khunti has
`acted as consultant and speaker for
`Novartis, Novo Nordisk, Sanofi-
`Aventis, Lilly, and Merck Sharp &
`Dohme. He has received grants in sup-
`port of investigator and investigator-
`initiated trials from Novartis, Novo
`Nordisk, Sanofi-Aventis, Lilly, Pfizer,
`Servier, and Merck Sharp & Dohme.
`
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`Pract Diab Int November/December 2007 Vol. 24 No. 9
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`• Glucagon-like peptide has been shown to stimulate insulin release in
`humans but is rapidly metabolised by dipeptidyl-peptidase-4. DPP-4
`inhibitors enhance fasting and post-prandial levels of GLP-1 leading to
`improved glycaemic control, thus they represent a novel and unique
`potential therapy for type 2 diabetes
`• Current oral antidiabetic drugs (OADs) have a number of limitations and
`often need to be used in combination in order to optimise glucose control.
`The introduction of a new class of OADs is therefore welcome
`• The number of clinical trials with both sitagliptin and vildagliptin, both as
`monotherapy or in combination with metformin, sulphonylureas and
`pioglitazone, show additional significant reductions in HbA1c and a minimal
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`
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