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An update on DPP-4 inhibitors in the
 management of Type 2 diabetes:
potential roles in monotherapy and
       combination therapy
              Harvey L. Katzeff
         Merck Research Laboratories
           Rahway, New Jersey, USA
Combining antihyperglycaemic agents:
              major sites of action

                                          Hyperglycaemia
   α-Glucosidase
     inhibitors                                                                Glitazones
                        Carbohydrate                             Glucose               (+)
            (–)          Absorption                              Uptake
                                               Glucose
                                              Production                        Muscle/fat
         GI tract
                                                                                             +
                  Metformin (–)                 Liver             (–)   Injected (+)
                                                                         Insulin

                                     X
                                  Glucagon
                                  Secretion                   GLP-1 analogues
                                                              DPP-4 inhibitors
                                                     –
                      ↑ Glucagon               Insulin
                                              Secretion

            Sulfonylureas                                                   Insulin
                          (+)                 Pancreas                     Secretion
             Meglitinides
DDP-4=dipeptidyl-peptidase-4; GLP-1=glucagon-like peptide-1
Inhibition of DPP-4 increases active incretin
       levels, enhancing downstream incretin actions


              Active GIP                       • Increased insulin secretion
              Active GLP-1                     • Decreased glucagon release
         DPP-4      Χ DPP-4 inhibitor

              Inactive GIP                     Glucose control improved
              Inactive GLP-1




GIP=glucose-dependent insulinotropic peptide
Sitagliptin and vildagliptin overview

      F
  F
            NH2 O

                    N       N
                                N
      F                 N
                            CF3


• DPP-4 inhibitors for the treatment of patients with Type 2
  diabetes: sitagliptin has recently been FDA approved, and
  vildagliptin is currently under FDA review
• Provide potent and highly selective inhibition of the
  DPP-4 enzyme
• No CYP or drug-drug interaction
• 30%–85% excretion via the urine
Selectivity of oral DPP-4 enzyme inhibitors


             Enzyme                  Sitagliptin IC50 (nM)             Vildagliptin IC50 (nM)
       DPP-4                                              18                         120
       DPP-8                                        48,000                          9000
       DPP-9                                     >100,000                              –
       DPP-2, DPP-7                              >100,000                        >100,000
       FAP                                       >100,000                              –
       PEP                                       >100,000                              –
       APP                                       >100,000                              –




Herman et al. ADA. 2004; Stein. ADA. 2006. Late-breaking clinical presentation
A single dose of sitagliptin increased
                                active GLP-1 and GIP over 24 hours
                                     Crossover Study in Patients With Type 2 Diabetes                                           Placebo

                                                                                                                                Sitagliptin
                                Active GLP-1                                                  Active GIP                        25 mg

                        OGTT                      OGTT                                 OGTT                   OGTT              Sitagliptin
                     2 hrs (n=55)              24 hrs (n=19)                        2 hrs (n=55)           24 hrs (n=19)        200 mg
                40                                                             90
                35                                                             80
                         2-fold increase in active GLP-1                                 2-fold increase in active GIP
                30          P<0.001 vs placebo                                 70             P<0.001 vs placebo
GLP-1 (pg/ml)




                                                                 GIP (pg/ml)
                25                                                             60
                                                                               50
                20
                                                                               40
                15
                                                                               30
                10                                                             20
                 5                                                             10
                 0                                                              0
                     0     2     4     6              24 26 28                      0   2     4     6                24 26 28
                                Hours postdose                                               Hours postdose
     Herman et al. Diabetes. 2005; Stein. ADA. 2006. Late-breaking clinical presentation
Sitagliptin increased insulin, decreased glucagon, and
                reduced glycaemic excursion after a glucose load
                             Crossover Study in Patients With Type 2 Diabetes
          40
                 Insulin                                                                                                                    Placebo
          30     Drug                Glucose                                                                                                Sitagliptin 25 mg
                 dose                  load                              22%
mcIU/ml




          20                                                                                                                                Sitagliptin 200 mg


          10                                                                             320       Glucose
                                                                                                Drug              Glucose                                 ~26%
               P<0.05 for both dose comparisons to placebo for AUC                       280    dose                load
          0
                   0           1           2          3              4



                                                                                mmol/l
                                                                                         240
          75
                 Glucagon
                                                                                         200
          70
                                                                                         160
          65
pg/ml




                                                                                               P<0.001 for both dose comparisons to placebo for AUC

          60                                                                             120
                                                                         ~12%
                                                                                                  0           1          2          3          4      5          6
          55
               P<0.05 for both dose comparisons to placebo for AUC
                                                                                                                             Time (hours)
          50
                   10     2       3       4
                    Time (hours)
Stein. ADA. 2006. Late-breaking clinical presentation
Vildagliptin increased GLP-1 and GIP and decreased
              blood glucagon hormone concentrations
                                                            35
                                                            30
                                                                  A                                             Day -1




                                Intact GLP-1
                                                            25                                                  Day 28




                                   (pmol/l)
                                                            20
         GLP-1                                              15
                                                            10
                                                             5
                                                             0

                                                            250
                                      Intact GIP (pmol/l)         B
                                                            200

                                                            150
         GIP                                                100

                                                            50

                                                             0

                                                            125

                                                                  C
                                      Glucagon (ng/l)




                                                            100

         Glucagon
                                                            75



                                                            50
                                                              6:00    9:00   12:00      15:00   18:00   21:00
                                                                                     Time
Mari et al. J Clin Endocrinol Metab. 2005
Monotherapy trials


                        • DPP-4 vs placebo
                        • DPP-4 vs metformin
                        • DPP-4 vs TZD




TZD=thiazolidinedione
Sitagliptin improved both fasting and post-meal
                                     glucose in monotherapy vs placebo

                                       Fasting Glucose                                                   Post-meal Glucose
                         189       Δ FPG* = -17.1 mg/dl (P<0.001)                            288       Δ in 2-hr PPG* = -46.7 mg/dl (P<0.001)


                         180




                                                                    Plasma glucose (mg/dl)
Plasma glucose (mg/dl)




                                                                                             252


                         171

                                                                                             216

                         162
                                                                                                                Baseline                     Baseline
                                                                                                                24 weeks                     24 weeks
                                                                                             180
                         153
                                       Placebo (n=247)
                                                                                                   Placebo (n=204)             Sitagliptin (n=201)
                                       Sitagliptin 100 mg (n=234)
                         144                                                                 144
                               0   5       10    15     20     25                                  0    60    120          0     60    120
                                        Time (weeks)                                                         Time (minutes)

      *Least-squares (LS) mean difference from placebo after 24 weeks
      Aschner et al. ADA. 2006. Abstract 1995-PO; Stein. ADA. 2006. Late-breaking clinical presentation
DPP-4 inhibitors provide progressively greater reductions
        in HbA1c with progressively higher baseline HbA1c

                                                Inclusion Criteria: 7%–10%
                                          18-Week Study                                            24-Week Study
Baseline HbA1c (%)                      <8%      8%–9%    ≥9%                                    <8%     8%–9%   ≥9%
            Mean (%)                    7.37      8.40    9.48                                   7.39     8.36   9.58
                                 0.0                                                      0.0
                                 -0.2                                                     -0.2




                                                                 Reduction in HbA1c (%)
        Reduction in HbA1c (%)




                                 -0.4   N=96                                              -0.4
                                                                                                 N=130
                                                  N=70
                                 -0.6                                                     -0.6
                                 -0.8   -0.44                                             -0.8
                                                                                                          N=62
                                                                                                 -0.57
                                 -1.0             -0.61                                   -1.0
                                                          N=27                                            -0.8
                                 -1.2                                                     -1.2
                                 -1.4                                                     -1.4                   N=37
                                 -1.6                     -1.2                            -1.6
                                 -1.8                                                     -1.8                   -1.52
 Reductions are placebo-subtracted
 Raz et al. ADA. 2006. Abstract 1996-PO; Aschner et al. ADA. 2006. Abstract 1995-PO;
 Stein. ADA. 2006. Late-breaking clinical presentation
Vildagliptin monotherapy:
                          similar response to 50 and 100 mg daily
                                           Mean HbA1c reduction from
                                         baseline at 24 weeks (7.5%–11%)
                          0.0

                          -0.1
                          -0.2
    Change in HbA1c (%)




                          -0.3
                                                                        -0.3
                          -0.4
                          -0.5
                          -0.6

                          -0.7
                          -0.8
                                   -0.78        -0.79
                          -0.9       *           *        -0.88
                                                                  Vildagliptin 50 mg QD (n=104)
                          -1.0                              †
                                                                  Vildagliptin 50 mg BID (n=90)
*P=0.006; †P=0.001 vs placebo                                     Vildagliptin 100 mg QD (n=92)
Source: Study 2301, Novartis
                                                                  Placebo (n=94)
Primary ITT (intent-to-treat) population
Vildagliptin monotherapy
                                          vs metformin
                         9.5


                         9.0                                    Vildagliptin        Metformin
        Mean HbA1c (%)




                         8.5


                         8.0


                         7.5


                         7.0


                         6.5
                               -4   0   4   8   12   16    20   24   28   32   36    40   44    48   52

                                                          Time (weeks)


Vildagliptin did not achieve non-inferiority
Dejager et al. ADA. 2006. Abstract 120-OR
Vildagliptin monotherapy
                                     vs rosiglitazone

                     9.0
                                                             Vildagliptin

                                                             Rosiglitazone
                     8.5
    Mean HbA1c (%)




                     8.0



                     7.5



                     7.0
                           -4   0   4         8       12     16        20    24
                                              Time (weeks)

Rosenstock et al. ADA. 2006. Abstract 557-P
Sitagliptin improved the β-cell response
               to glucose: monotherapy studies
    Pooled Monotherapy Studies – Subset of Patients With Frequently Sampled MTT
                                                     Model-based assessment of β-cell function
                                                     1400
                                                              Sitagliptin 100 mg QD                  Placebo
                                                                  Baseline                      Baseline
                                                     1200
                                                             End-Treatment                End-Treatment
                      Insulin secretion (pmol/min)




                                                     1000


                                                      800


                                                      600


                                                      400


                                                      200

                                                            160      180         200      220        240       260
                                                                             Glucose concentration
                                                                                    (mg/dl)
MTT=meal tolerance test
Φs=static component; describes relationship between glucose concentration and insulin secretion
Stein. ADA. 2006. Late-breaking clinical presentation
Sitagliptin improved markers of β-cell function:
                                    24-week monotherapy study

                        0.55
                                    Proinsulin/insulin ratio                                80           HOMA-β
                                                                                            75

                         0.5                                                                70

                                                                                            65
                                                                                                            P<0.001*
Ratio (pmol/l/pmol/l)




                        0.45                                          P<0.001*
                                                                                            60

                                                                                            55

                         0.4                                                                50

                                                                                            45

                        0.35                                                                40

                                                                                            35

                         0.3                                                                30
                                    Placebo               Sitagliptin 100 mg                      Placebo         Sitagliptin 100 mg

                         ∆ from baseline vs pbo=0.078                          Hatched=Baseline   ∆ from baseline vs pbo=13.2
                                                                                Solid=Week 24
                               (95% CI: -0.114, -0.023)                                                 (95% CI: 3.9, 21.9)
        *P value for change from baseline compared with placebo
        Aschner et al. ADA. 2006. Abstract 1995-PO; Stein. ADA. 2006. Late-breaking clinical presentation
Vildagliptin increases
                                                    disposition index
                                            180                        *†
                                            160
            Disposition index (AIRg X Si)



                                                    Baseline
                                            140
                                                    Week 12
                                            120     Post washout

                                            100

                                            80                                *

                                            60

                                            40

                                            20

                                             0
                                                    Placebo        Vildagliptin


*P<0.05 vs baseline; †P<0.05 vs placebo
D’Alessio et al. ADA. 2006. Abstract 454-P
Combination therapy

• Add-on therapy
  – Add-on to metformin
  – Add-on to pioglitazone
  – Add-on to insulin

• Initial combination
  – DPP-4 + metformin
  – DPP-4 + pioglitazone
Sitagliptin once daily lowered HbA1c
                        when added to metformin or pioglitazone

                    Add-on to Metformin Study                                  Add-on to Pioglitazone Study
                    Δ in HbA1c vs Pbo* = -0.65% (P<0.001)                      Δ in HbA1c vs Pbo* = -0.70% (P<0.001)
              8.2                                                        8.2

              8.0                                                        8.0

              7.8                                                        7.8
  HbA1c (%)




                                                             HbA1c (%)
              7.6                                                        7.6

              7.4                                                        7.4

              7.2          Placebo (n=224)                               7.2         Placebo (n=174)
                           Sitagliptin 100 mg (n=453)                                Sitagliptin 100 mg (n=163)
              7.0                                                        7.0
                    0       6       12        18        24                     0       6        12      18        24
                                Time (weeks)                                               Time (weeks)

*Placebo-subtracted difference in LS means
Rosenstock et al. ADA. 2006. Abstract 556-P; Karasik et al. ADA. 2006. Abstract 501-P;
Stein. ADA. 2006. Late-breaking clinical presentation
Vildagliptin added to metformin
                               improved glycaemic control
                    Vildagliptin 50 mg QD &               Vildagliptin 50 mg BID &                    Placebo &
                    metformin                             metformin                                   metformin


                                                                            11.0

             8.5


                                                                            10.0




                                                                 FPG (mM)
 HbA1c (%)




             8.0



                                                                             9.0
             7.5




             7.0                                                             8.0
                   -8   -4   0    4   8   12    16   20   24                       -8   -4   0    4   8   12    16   20   24

                                 Time (weeks)                                                    Time (weeks)


Garber et al. ADA. 2006. Abstract 121-OR
Sitagliptin added to metformin improved
                         24-hour glucose profile in Type 2 diabetes

                                                                 Placebo + metformin (n=13)
                                                                 Sitagliptin 50 mg BID + metformin (n=15)
                           Breakfast   Lunch      Dinner
                   240    Dose 1               Dose 2
                           7:30                18:30              Difference in 24-hour weighted
                   220                                            LS mean glucose: -32.8 mg/dl
                                                                  (-1.82 mmol/l), P<0.001
 Glucose (mg/dl)




                   200
                   180
                   160
                   140
                   120
                   100

                             8:00      13:00       19:00      0:00                  7:30
                             Day 1                            Day 2
                                                  Time

Stein. ADA. 2006. Late-breaking clinical presentation; adapted from Brazg et al. ADA. 2005.
Abstract 11-OR
Sitagliptin added to ongoing metformin
                               or pioglitazone: change in body weight over time

                               0.0
                                                                                   2.0
LS mean change from baseline




                               -0.2                                                1.5
      body weight (kg)




                                                                                   1.0
                               -0.4

                                                                                   0.5
                               -0.6
                                                                                    0.0

                               -0.8
                                          Placebo + metformin (n=169)              -0.5       Placebo + pioglitazone (n=174)
                                          Sitagliptin 100 mg QD + metformin                   Sitagliptin 100 mg QD + pioglitazone
                                          (n=399)                                             (n=163)
                               -1.0                                                -1.0
                                      0                   12                  24          0       6        12      18       24

                                                   Time (weeks)                                       Time (weeks)


           Karasik et al. ADA. 2006. Abstract 501-P; Rosenstock et al. ADA. 2006. Abstract 556-P
HbA1c during insulin add-on:
                             core and extension study

                 9.0               Pbo + insulin              Vildagliptin 50 mg + insulin
                                   Vildagliptin 50 mg BID + insulin


                 8.5
                                                              ∆ HbA1c -0.4 ± 0.1, P=0.001
Mean HbA1c (%)




                 8.0



                 7.5


                 7.0
                       -8   0            12              24                                  52
Fonseca et al. ADA. 2006. Poster 467-P
                                              Time (weeks)
Fonseca et al. EASD. 2006. PS 62. 0802
Sitagliptin once daily showed similar glycaemic
                 efficacy to glipizide when added
                      to metformin (52 weeks)
                            8.4                                               Glipizide (n=411)
                            8.2                                               Sitagliptin 100 mg QD
                                                                              (n=382)
                            8.0
     Mean change in HbA1c




                            7.8       Mean change from baseline (for both groups)*: 0.67%
                            7.6
                            7.4
                            7.2
                            7.0
                            6.8
                            6.6
                            6.4
                            6.2
                            6.0
                                  0       12          24           38               52
                                                    Time (weeks)
*Per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis
Stein. ADA. 2006. Late-breaking clinical presentation
Sitagliptin once daily showed better safety
                                and tolerability profile compared
                                     with glipizide (52 weeks)
                               Change in Body Weight                                  50
                                                                                           Hypoglycaemia
                      94
                               Δ between groups = -2.5 kg (P<0.001)
                                                                                      40
                      92
                                                                                             32%
   Body weight (kg)




                                                                      Incidence (%)
                                                                                      30                P<0.001

                      90
                                                                                      20

                      88
                                                                                      10
                                                                                                          4.9%

                      86                                                               0
                           0       12       24       38          52
                                        Time (weeks)                                              Week 52

                                 Glipizide (n=411)                                         Glipizide (n=584)
                                 Sitagliptin 100 mg QD (n=382)                             Sitagliptin 100 mg (n=588)

Stein. ADA. 2006. Late-breaking clinical presentation
Initial combination of vildagliptin
                                                  and pioglitazone (24 weeks)
                                                    Mean HbA1c reduction from baseline=8.7%

                                             0.0
         Change from baseline in HbA1c (%)




                                             -0.5



                                             -1.0
                                                          -1.1

                                             -1.5                     -1.4


                                             -2.0                                 -1.9
                                                                                    *
                                                               Vildagliptin 100 mg daily (n=150)
               -2.5                                           Pioglitazone 30 mg daily (n=157)
                                                              Vildagliptin 100 mg daily + pioglitazone
Intention-to-treat population                                  30 mg daily (n=146)
*P=0.001 vs pioglitazone 30 mg; low-dose combination arm is not included
Nathwani. ADA. 2006. Late-breaking clinical presentation
Metabolic effects of DPP-4 inhibitors

• Small decrease in VLDL with corresponding
  increase in HDL
  – No change in LDL
• Small decrements in blood pressure
• Small decrease in high-sensitivity C-reactive protein
• Animal models may reveal improvement in β-cell
  mass
  – Studies in humans have not yet been performed
    to validate these findings
Safety and tolerability overview
                  of DPP-4 inhibitors
•   Well tolerated in phase 1-3 trials; in completed and ongoing studies,
    >4000 patients on sitagliptin (to doses of 200 mg QD in phase 3
    studies)
•   Pre-specified pooled phase 3 analysis, including monotherapy and
    combination studies: over 1500 patients on sitagliptin and over 750
    patients on placebo
    – Summary measures of adverse experiences (AEs) were similar to
      placebo
       • Including overall clinical AEs, serious AEs, discontinuations due
         to AEs, drug-related AEs, laboratory AE summary measures
    – Small differences in incidence of specific AEs
       • Between-group difference (sitagliptin 100 mg and placebo
         group) in incidence >1% for only 1 specific AE (nasopharyngitis
         1.2% difference)
Summary
•   DPP-4 inhibitors administered for the treatment of Type 2 diabetes
    – Significant reductions in HbA1c across a range of starting
      HbA1c levels in monotherapy and combination use
    – Sustained HbA1c reduction to 1 year
    – Improvements in multiple measures of β-cell function
•   Compared with a sulfonylurea or TZD, DPP-4 inhibitors provide
    – Similar efficacy
    – Superior improvements in β-cell function, less hypoglycaemia, and
      weight loss (vs weight gain)
•   DPP-4 inhibitors are well tolerated with summary measures of AEs similar
    to placebo

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An Update On Dpp 4 Inhibitors In The Management Of Type 2 Diabetes

  • 1. An update on DPP-4 inhibitors in the management of Type 2 diabetes: potential roles in monotherapy and combination therapy Harvey L. Katzeff Merck Research Laboratories Rahway, New Jersey, USA
  • 2. Combining antihyperglycaemic agents: major sites of action Hyperglycaemia α-Glucosidase inhibitors Glitazones Carbohydrate Glucose (+) (–) Absorption Uptake Glucose Production Muscle/fat GI tract + Metformin (–) Liver (–) Injected (+) Insulin X Glucagon Secretion GLP-1 analogues DPP-4 inhibitors – ↑ Glucagon Insulin Secretion Sulfonylureas Insulin (+) Pancreas Secretion Meglitinides DDP-4=dipeptidyl-peptidase-4; GLP-1=glucagon-like peptide-1
  • 3. Inhibition of DPP-4 increases active incretin levels, enhancing downstream incretin actions Active GIP • Increased insulin secretion Active GLP-1 • Decreased glucagon release DPP-4 Χ DPP-4 inhibitor Inactive GIP Glucose control improved Inactive GLP-1 GIP=glucose-dependent insulinotropic peptide
  • 4. Sitagliptin and vildagliptin overview F F NH2 O N N N F N CF3 • DPP-4 inhibitors for the treatment of patients with Type 2 diabetes: sitagliptin has recently been FDA approved, and vildagliptin is currently under FDA review • Provide potent and highly selective inhibition of the DPP-4 enzyme • No CYP or drug-drug interaction • 30%–85% excretion via the urine
  • 5. Selectivity of oral DPP-4 enzyme inhibitors Enzyme Sitagliptin IC50 (nM) Vildagliptin IC50 (nM) DPP-4 18 120 DPP-8 48,000 9000 DPP-9 >100,000 – DPP-2, DPP-7 >100,000 >100,000 FAP >100,000 – PEP >100,000 – APP >100,000 – Herman et al. ADA. 2004; Stein. ADA. 2006. Late-breaking clinical presentation
  • 6. A single dose of sitagliptin increased active GLP-1 and GIP over 24 hours Crossover Study in Patients With Type 2 Diabetes Placebo Sitagliptin Active GLP-1 Active GIP 25 mg OGTT OGTT OGTT OGTT Sitagliptin 2 hrs (n=55) 24 hrs (n=19) 2 hrs (n=55) 24 hrs (n=19) 200 mg 40 90 35 80 2-fold increase in active GLP-1 2-fold increase in active GIP 30 P<0.001 vs placebo 70 P<0.001 vs placebo GLP-1 (pg/ml) GIP (pg/ml) 25 60 50 20 40 15 30 10 20 5 10 0 0 0 2 4 6 24 26 28 0 2 4 6 24 26 28 Hours postdose Hours postdose Herman et al. Diabetes. 2005; Stein. ADA. 2006. Late-breaking clinical presentation
  • 7. Sitagliptin increased insulin, decreased glucagon, and reduced glycaemic excursion after a glucose load Crossover Study in Patients With Type 2 Diabetes 40 Insulin Placebo 30 Drug Glucose Sitagliptin 25 mg dose load 22% mcIU/ml 20 Sitagliptin 200 mg 10 320 Glucose Drug Glucose ~26% P<0.05 for both dose comparisons to placebo for AUC 280 dose load 0 0 1 2 3 4 mmol/l 240 75 Glucagon 200 70 160 65 pg/ml P<0.001 for both dose comparisons to placebo for AUC 60 120 ~12% 0 1 2 3 4 5 6 55 P<0.05 for both dose comparisons to placebo for AUC Time (hours) 50 10 2 3 4 Time (hours) Stein. ADA. 2006. Late-breaking clinical presentation
  • 8. Vildagliptin increased GLP-1 and GIP and decreased blood glucagon hormone concentrations 35 30 A Day -1 Intact GLP-1 25 Day 28 (pmol/l) 20 GLP-1 15 10 5 0 250 Intact GIP (pmol/l) B 200 150 GIP 100 50 0 125 C Glucagon (ng/l) 100 Glucagon 75 50 6:00 9:00 12:00 15:00 18:00 21:00 Time Mari et al. J Clin Endocrinol Metab. 2005
  • 9. Monotherapy trials • DPP-4 vs placebo • DPP-4 vs metformin • DPP-4 vs TZD TZD=thiazolidinedione
  • 10. Sitagliptin improved both fasting and post-meal glucose in monotherapy vs placebo Fasting Glucose Post-meal Glucose 189 Δ FPG* = -17.1 mg/dl (P<0.001) 288 Δ in 2-hr PPG* = -46.7 mg/dl (P<0.001) 180 Plasma glucose (mg/dl) Plasma glucose (mg/dl) 252 171 216 162 Baseline Baseline 24 weeks 24 weeks 180 153 Placebo (n=247) Placebo (n=204) Sitagliptin (n=201) Sitagliptin 100 mg (n=234) 144 144 0 5 10 15 20 25 0 60 120 0 60 120 Time (weeks) Time (minutes) *Least-squares (LS) mean difference from placebo after 24 weeks Aschner et al. ADA. 2006. Abstract 1995-PO; Stein. ADA. 2006. Late-breaking clinical presentation
  • 11. DPP-4 inhibitors provide progressively greater reductions in HbA1c with progressively higher baseline HbA1c Inclusion Criteria: 7%–10% 18-Week Study 24-Week Study Baseline HbA1c (%) <8% 8%–9% ≥9% <8% 8%–9% ≥9% Mean (%) 7.37 8.40 9.48 7.39 8.36 9.58 0.0 0.0 -0.2 -0.2 Reduction in HbA1c (%) Reduction in HbA1c (%) -0.4 N=96 -0.4 N=130 N=70 -0.6 -0.6 -0.8 -0.44 -0.8 N=62 -0.57 -1.0 -0.61 -1.0 N=27 -0.8 -1.2 -1.2 -1.4 -1.4 N=37 -1.6 -1.2 -1.6 -1.8 -1.8 -1.52 Reductions are placebo-subtracted Raz et al. ADA. 2006. Abstract 1996-PO; Aschner et al. ADA. 2006. Abstract 1995-PO; Stein. ADA. 2006. Late-breaking clinical presentation
  • 12. Vildagliptin monotherapy: similar response to 50 and 100 mg daily Mean HbA1c reduction from baseline at 24 weeks (7.5%–11%) 0.0 -0.1 -0.2 Change in HbA1c (%) -0.3 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.78 -0.79 -0.9 * * -0.88 Vildagliptin 50 mg QD (n=104) -1.0 † Vildagliptin 50 mg BID (n=90) *P=0.006; †P=0.001 vs placebo Vildagliptin 100 mg QD (n=92) Source: Study 2301, Novartis Placebo (n=94) Primary ITT (intent-to-treat) population
  • 13. Vildagliptin monotherapy vs metformin 9.5 9.0 Vildagliptin Metformin Mean HbA1c (%) 8.5 8.0 7.5 7.0 6.5 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) Vildagliptin did not achieve non-inferiority Dejager et al. ADA. 2006. Abstract 120-OR
  • 14. Vildagliptin monotherapy vs rosiglitazone 9.0 Vildagliptin Rosiglitazone 8.5 Mean HbA1c (%) 8.0 7.5 7.0 -4 0 4 8 12 16 20 24 Time (weeks) Rosenstock et al. ADA. 2006. Abstract 557-P
  • 15. Sitagliptin improved the β-cell response to glucose: monotherapy studies Pooled Monotherapy Studies – Subset of Patients With Frequently Sampled MTT Model-based assessment of β-cell function 1400 Sitagliptin 100 mg QD Placebo Baseline Baseline 1200 End-Treatment End-Treatment Insulin secretion (pmol/min) 1000 800 600 400 200 160 180 200 220 240 260 Glucose concentration (mg/dl) MTT=meal tolerance test Φs=static component; describes relationship between glucose concentration and insulin secretion Stein. ADA. 2006. Late-breaking clinical presentation
  • 16. Sitagliptin improved markers of β-cell function: 24-week monotherapy study 0.55 Proinsulin/insulin ratio 80 HOMA-β 75 0.5 70 65 P<0.001* Ratio (pmol/l/pmol/l) 0.45 P<0.001* 60 55 0.4 50 45 0.35 40 35 0.3 30 Placebo Sitagliptin 100 mg Placebo Sitagliptin 100 mg ∆ from baseline vs pbo=0.078 Hatched=Baseline ∆ from baseline vs pbo=13.2 Solid=Week 24 (95% CI: -0.114, -0.023) (95% CI: 3.9, 21.9) *P value for change from baseline compared with placebo Aschner et al. ADA. 2006. Abstract 1995-PO; Stein. ADA. 2006. Late-breaking clinical presentation
  • 17. Vildagliptin increases disposition index 180 *† 160 Disposition index (AIRg X Si) Baseline 140 Week 12 120 Post washout 100 80 * 60 40 20 0 Placebo Vildagliptin *P<0.05 vs baseline; †P<0.05 vs placebo D’Alessio et al. ADA. 2006. Abstract 454-P
  • 18. Combination therapy • Add-on therapy – Add-on to metformin – Add-on to pioglitazone – Add-on to insulin • Initial combination – DPP-4 + metformin – DPP-4 + pioglitazone
  • 19. Sitagliptin once daily lowered HbA1c when added to metformin or pioglitazone Add-on to Metformin Study Add-on to Pioglitazone Study Δ in HbA1c vs Pbo* = -0.65% (P<0.001) Δ in HbA1c vs Pbo* = -0.70% (P<0.001) 8.2 8.2 8.0 8.0 7.8 7.8 HbA1c (%) HbA1c (%) 7.6 7.6 7.4 7.4 7.2 Placebo (n=224) 7.2 Placebo (n=174) Sitagliptin 100 mg (n=453) Sitagliptin 100 mg (n=163) 7.0 7.0 0 6 12 18 24 0 6 12 18 24 Time (weeks) Time (weeks) *Placebo-subtracted difference in LS means Rosenstock et al. ADA. 2006. Abstract 556-P; Karasik et al. ADA. 2006. Abstract 501-P; Stein. ADA. 2006. Late-breaking clinical presentation
  • 20. Vildagliptin added to metformin improved glycaemic control Vildagliptin 50 mg QD & Vildagliptin 50 mg BID & Placebo & metformin metformin metformin 11.0 8.5 10.0 FPG (mM) HbA1c (%) 8.0 9.0 7.5 7.0 8.0 -8 -4 0 4 8 12 16 20 24 -8 -4 0 4 8 12 16 20 24 Time (weeks) Time (weeks) Garber et al. ADA. 2006. Abstract 121-OR
  • 21. Sitagliptin added to metformin improved 24-hour glucose profile in Type 2 diabetes Placebo + metformin (n=13) Sitagliptin 50 mg BID + metformin (n=15) Breakfast Lunch Dinner 240 Dose 1 Dose 2 7:30 18:30 Difference in 24-hour weighted 220 LS mean glucose: -32.8 mg/dl (-1.82 mmol/l), P<0.001 Glucose (mg/dl) 200 180 160 140 120 100 8:00 13:00 19:00 0:00 7:30 Day 1 Day 2 Time Stein. ADA. 2006. Late-breaking clinical presentation; adapted from Brazg et al. ADA. 2005. Abstract 11-OR
  • 22. Sitagliptin added to ongoing metformin or pioglitazone: change in body weight over time 0.0 2.0 LS mean change from baseline -0.2 1.5 body weight (kg) 1.0 -0.4 0.5 -0.6 0.0 -0.8 Placebo + metformin (n=169) -0.5 Placebo + pioglitazone (n=174) Sitagliptin 100 mg QD + metformin Sitagliptin 100 mg QD + pioglitazone (n=399) (n=163) -1.0 -1.0 0 12 24 0 6 12 18 24 Time (weeks) Time (weeks) Karasik et al. ADA. 2006. Abstract 501-P; Rosenstock et al. ADA. 2006. Abstract 556-P
  • 23. HbA1c during insulin add-on: core and extension study 9.0 Pbo + insulin Vildagliptin 50 mg + insulin Vildagliptin 50 mg BID + insulin 8.5 ∆ HbA1c -0.4 ± 0.1, P=0.001 Mean HbA1c (%) 8.0 7.5 7.0 -8 0 12 24 52 Fonseca et al. ADA. 2006. Poster 467-P Time (weeks) Fonseca et al. EASD. 2006. PS 62. 0802
  • 24. Sitagliptin once daily showed similar glycaemic efficacy to glipizide when added to metformin (52 weeks) 8.4 Glipizide (n=411) 8.2 Sitagliptin 100 mg QD (n=382) 8.0 Mean change in HbA1c 7.8 Mean change from baseline (for both groups)*: 0.67% 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 0 12 24 38 52 Time (weeks) *Per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis Stein. ADA. 2006. Late-breaking clinical presentation
  • 25. Sitagliptin once daily showed better safety and tolerability profile compared with glipizide (52 weeks) Change in Body Weight 50 Hypoglycaemia 94 Δ between groups = -2.5 kg (P<0.001) 40 92 32% Body weight (kg) Incidence (%) 30 P<0.001 90 20 88 10 4.9% 86 0 0 12 24 38 52 Time (weeks) Week 52 Glipizide (n=411) Glipizide (n=584) Sitagliptin 100 mg QD (n=382) Sitagliptin 100 mg (n=588) Stein. ADA. 2006. Late-breaking clinical presentation
  • 26. Initial combination of vildagliptin and pioglitazone (24 weeks) Mean HbA1c reduction from baseline=8.7% 0.0 Change from baseline in HbA1c (%) -0.5 -1.0 -1.1 -1.5 -1.4 -2.0 -1.9 * Vildagliptin 100 mg daily (n=150) -2.5 Pioglitazone 30 mg daily (n=157) Vildagliptin 100 mg daily + pioglitazone Intention-to-treat population 30 mg daily (n=146) *P=0.001 vs pioglitazone 30 mg; low-dose combination arm is not included Nathwani. ADA. 2006. Late-breaking clinical presentation
  • 27. Metabolic effects of DPP-4 inhibitors • Small decrease in VLDL with corresponding increase in HDL – No change in LDL • Small decrements in blood pressure • Small decrease in high-sensitivity C-reactive protein • Animal models may reveal improvement in β-cell mass – Studies in humans have not yet been performed to validate these findings
  • 28. Safety and tolerability overview of DPP-4 inhibitors • Well tolerated in phase 1-3 trials; in completed and ongoing studies, >4000 patients on sitagliptin (to doses of 200 mg QD in phase 3 studies) • Pre-specified pooled phase 3 analysis, including monotherapy and combination studies: over 1500 patients on sitagliptin and over 750 patients on placebo – Summary measures of adverse experiences (AEs) were similar to placebo • Including overall clinical AEs, serious AEs, discontinuations due to AEs, drug-related AEs, laboratory AE summary measures – Small differences in incidence of specific AEs • Between-group difference (sitagliptin 100 mg and placebo group) in incidence >1% for only 1 specific AE (nasopharyngitis 1.2% difference)
  • 29. Summary • DPP-4 inhibitors administered for the treatment of Type 2 diabetes – Significant reductions in HbA1c across a range of starting HbA1c levels in monotherapy and combination use – Sustained HbA1c reduction to 1 year – Improvements in multiple measures of β-cell function • Compared with a sulfonylurea or TZD, DPP-4 inhibitors provide – Similar efficacy – Superior improvements in β-cell function, less hypoglycaemia, and weight loss (vs weight gain) • DPP-4 inhibitors are well tolerated with summary measures of AEs similar to placebo