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					Journal Club (EMB)
   C1 Tsang Ming Lam
      Warning!!
• The following
  presentation may
  cause severe
 drowsiness, confusion
 and dissatisfaction
       What to do if…
• DM patients with frequent hypoglycemia
  but suboptimal control
• Hypoglycemia may cause serious
  consequences:
• Elderly frequent fall, drivers, work in
  heights
• Hypoglycemia prone to occur if meal/
  working time irregular
• Patient usually c/o increase in
  appetite and may have weight gain
  after start of sulfonylurea/
  glitazones
       New class of drug
•   Acts on incretin axis
•   Shown to cause fewer hypoglycemia
•   Neutral in weight gain
•   Approved by DFA in 2007
•   Approved and available in HK in 2008
• Efficacy and safety of the dipeptidyl
  peptidase-4 inhibitor, sitagliptin, compared
  with the sulfonylurea, glipizide, in patients
  with type 2 diabetes inadequately
  controlled on metformin alone: a
  randomized, double-blind, non-inferiority
  trial
• M. A. Nauck et al, Diabetes, Obesity and
  Metabolism 2007 Vol 9, 194-205
     Non-inferiority trial
•   Standard Tx=A
•   New Tx=B
•   If efficacy of B likely >A
•   Then a well designed superiority trial,
    i.e double blind randomised control
    trial would be enough to show the
    result
• What if B similar to A
• If you design a RCT like a superiority
  trial, showing B~A
• Can it statistically prove B~A???
           Problems
• 1. Margin setting
• B/A > δ
• How small is δ so B is considered to
  similar to A
• Is this difference non significant?
• Who to decide
• When is the end point
• Sometimes Tx effect may change in
  time
• Concept on durability
    2. Assay sensitivity

• i.e. ability of the study to
  demonstrate difference
• A poorly designed/ done trial may
  also show no difference between A
  and B
• Poor study:
• poor compliance, poor diagnostic
  criteria, excessive variability of
  measurements, and biased end-point
  assessment
   3. Intention to Treat

• If subject of B stopped tx or
  switched to A
• Then the difference of outcome
  must be less than it should be
• It worked only if B is likely> A as
  shown by previous non RCT trials
• But there bound to be discontinued/
  excluded patients from B
• So, 2 groups of patient analysed
  separately
• Per protocol population
• All patient treated population
• If results shown in both group, likely B~A
• But the pre-protocol population may
  then be biased
• Need to assess reason for
  discontinuation
          4. Blinding

• Double blinded
• Investigator could still be biased
• Showing both group similar results
    Ways to prove Assay
        sensitivity
• Well designed and conducted
• Randomized
• Placebo in both arms
• If both arms showed effect similar
  to previous studies
• i.e. reproducible effect likely valid
  study
          Introduction
• Metformin
• the most commonly used OHA
• excessive hepatic glucose output and
  insulin resistance
• β-cell function deteriorate over time
• glycaemic control fail to maintain control
       Sulfonylureas
• insulin secretagogues
• the most common next therapeutic
  step
• strictly glucose dependent
• associated with hypoglycaemia
• weight gain
          Sitagliptin
• a dipeptidyl peptidase-4 (DPP-4)
  inhibitor
• enhancement of the incretin axis
             Incretin
• glucagon-like peptide-1 (GLP-1) and
  glucose-dependent insulinotropic peptide
  (GIP)
• augment glucose-induced insulin secretion
  after meals
• GLP-1 suppresses glucagon release, delays
  gastric emptying and increases satiety
• effects that disappear when glucose levels
  approach normal concentrations
Insulin release    Decrease glucagon release,
                   delay gastric emptying,
                   increase satiety

                                Meal
         GIP      GLP-1


                   DPP-4

                                 Degraded
   Sitagliptin
             Previous trials
•   Single doses of sitagliptin:
•   active GLP-1 and GIP levels
•   enhance insulin secretion
•   suppress glucagon release

• sitagliptin added to ongoing metformin monotherapy:
• Improved blood glucose and measures of β-cell function
• neutral effect on body weight
• low risk of hypoglycaemia and GI adverse experiences.
• sitagliptin added to ongoing
  metformin monotherapy:
• improved fasting and postprandial
  glycaemic control and β-cell function
• neutral effect on body weight
• low risk of hypoglycaemia and GI
  adverse experiences
            This Study
• 52-week study

• type 2 diabetes with inadequate glycaemic
  control on metformin monotherapy

• compare the glycaemic efficacy and safety
  of the addition of sitagliptin with glipizide
Patient selection criteria
•   Included:
•   Men and women (age 18–78 years)
•   type 2 diabetes
•   not currently on an OHA
•   taking any OHA in monotherapy
•   taking metformin in combination with
    another OHA
• excluded if
• history of type 1 diabetes
• insulin use within 8 weeks of screening
• renal function impairment inconsistent
  with the use of metformin
• FG (bld/ h’stix) at or just prior to
  randomization >15.0 mmol/l (270 mg/dl)
• Other treatments prohibited

• Other medication allowed if in stable
  dose, e.g. anti HT/ lipid/ T4/ OTC
        Study design
• multinational, randomized, parallel-
  group, non-inferiority study with an
  active-controlled, double-blind
  treatment period
• Active controlled study: known active Tx
  vs test Tx
• separate, independent group of patients in
  a control group is called a parallel-group
  study
• gives both the test treatment and the
  control to the same patients is called a
  within-patient control study.
• on metformin ≥1500 mg/day and had
  an HbA1c≥ 6.5 and ≤10%
• entered a 2-week placebo run-in
  period
• Then randomised
• 1:1 100mg satigliptin/ 5mg glipizide
  qd
• On diet, MF< 1.5g qd, another OHA+/- MF
•  metformin monotherapy treatment
  titration and dose-stable period of at
  least 8 weeks
• If HbA1c≥6.5 and ≤10%
• entered a 2-week single-blind placebo
  run-in period
• Randomised
• glipizide uptitrated according to
  protocol-specified criteria to 20
  mg/day
• Pre meal FG> 6.1 increase
• Review Q 3 weeks till 18th week
• unless at risk for hypoglycaemia
• Decrease if recurrent hypo
   Efficacy assessments
• HbA1c, FPG, insulin, proinsulin and lipid
  parameters
• β-cell function: HOMA-β, proinsulin/insulin
  ratio
• changes in insulin resistance: HOMA-
  insulin resistance (HOMA-IR) and
  quantitative insulin sensitivity check index
  (QUICKI)
• Durability: comparing the rate of rise
  in HbA1c from Week 24 to Week 52.
    Safety assessments
• adverse experiences, physical
  examinations, vital signs, ECGs and body
  weight
• adverse experiences, its intensity and
  relationship to study drug
• blood chemistry, haematology and
  urinalysis
• Hypoglycaemia: symptoms and h’stix
  record
 discontinued for lack of
         efficacy
• Week 0-6: on 10mg of glipizide/glipizide placebo
  for at least 2 weeks, FPG > 14.4 mmol/l (270
  mg/dl)
• Week 6-12: on maximal dose (20mg), FPG > 13.3
  mmol/l (240 mg/dl)
• Week 12-8: on maximal dose, FPG > 12.2 mmol/l
  (220 mg/dl)
• Week 18 – 30: FPG > 11.1 mmol/l (220 mg/dl)
• Week 30-52: HbA1c > 8.0%.
    Statistical analyses
• primary efficacy analysis: HbA1c
  change from baseline at Week 52
  using a per-protocol (PP) approach
        The PP population
•   completed all 52 weeks of treatment
•   no reasons for exclusion:
•   no baseline data
•   no treatment data at Week 52
•   No major protocol violations (e.g. drug
    compliance <75%, change in metformin
    dose, addition of non-study OHA,
    incorrect double-blind study medication)
• Non-inferior if the upper boundary of the
  two-sided 95% confidence interval (CI)
  for the mean difference between
  sitagliptin and glipizide was less than the
  margin, δ= 0.3%.
• The difference was assessed by testing
  the difference in the least squares (LS)
  mean change (or mean per cent change)
  from baseline at Week 52
• Least square is an statistical analysis
  method to calculate result
• Like regression analysis
• This study: change in A1c
   Don’t border to
understand it yourself
• Additional efficacy analyses were
  based on APT population
• missing values in the APT analysis
  were handled by the last observation
  carried forward approach
• durability of HbA1c lowering: evaluating the
  coefficient of durability (COD), defined as the
  rate of rise in HbA1c from Week 24-52
• proportion of patients achieving HbA1c < 7 or
  <6.5% was compared using a logistic regression
  analysis
• Subgroup analyses for the primary efficacy
  endpoint by baseline HbA1c categories (<7, 7% to
  <8, 8% to <9, ≥9%).
• Safety and tolerability : review
  adverse experiences, laboratory
  safety parameters, body weight, vital
  signs and ECG data from the APT
  population
• Compliance was assessed by tablet
  count.
                Results
• Patient disposition and characteristics:

• 1172 randomized patients, 793 in PP analysis
  (sitagliptin, n = 382 and glipizide, n = 411)
• 379 patients excluded from the PP analysis, 96%
  as missing treatment data at Week 52
• More patients in the sitagliptin group
  discontinued treatment, mainly for lack of
  efficacy
• baseline HbA1c higher: 8.6 vs. 7.5%,
  respectively
• slightly older: 57 vs. 55 years
• slightly more body weight: 93 vs. 90
  kg
Fig 1
•   The mean dose of glipizide was 10.3 mg/day in the PP population
•   ~58% reached a final dose of at least 10 mg/day (22% reached a
    final dose of 20 mg/day)

•   10% of patients were not taking glipizide at study end

•   APT population, the mean dose of glipizide was 10.6 mg/day

•   the mean duration of exposure to study drug was slightly greater
    in the sitagliptin group [297.1 days (42.4 weeks)] than in the
    glipizide group [287.5 days (41.1 weeks)]

•   The mean (s.d.) compliance rates were 98.6% (3.8) and 98.3% (3.6)
• well balanced for baseline demographics
  and efficacy variables for all randomized
  patients and PP population
• average duration of known diabetes of 5.8
  years
• 70% on an OHA monotherapy at screening
• mean HbA1c of 7.5% (range = 5.8–10.1%;
  73% of patients with an HbA1c < 8.0%)
• mean FPG of 8.8 mmol/l (158 mg/dl)
Baseline demographics and efficacy endpoint
      data for all randomized patients
           Efficacy
• In the PP population, HbA1c change
  from baseline at Week 52 was
  −0.67% in both groups
• upper limit of the two-sided 95% CI
  for the between-group LS mean
  difference (0.08%) was less than
  0.3%
• In the APT population, HbA1c
  change : −0.51% (95% CI: −0.60,
  −0.43) with sitagliptin and −0.56%
  (−0.64, −0.47) with glipizide
• between-group difference in LS mean
  change from baseline (95% CI) =
  0.04% (−0.04, 0.13)
• Glipizide: greater initial HbA1c lowering,
  maximum at Week 24
• Sitagliptin: smaller rise in HbA1c from
  Week 24 to Week 54
• COD (95% CI): 0.008%/week (0.005, 0.010)
  vs. 0.011%/week (0.008, 0.013
• between-group difference in COD (95% CI)
  =−0.003 (−0.005, −0.001)].
• In PP population, % of patients with an
  HbA1c < 7% at Week 52 A (63%; n/N =
  240/382) B (59%; 242/411)
• difference in proportion (95% CI) = 3.9%
  (−2.8, 10.7)]
• In both groups, 29% of the patients
  reached an HbA1c < 6.5%
• difference in proportion (95% CI) =−0.1%
  (−6.4, 6.2)
• In APT population, 52 and 51% of
  patients had an HbA1c < 7%
• difference in proportion (95% CI) =
  0.9% (−4.9, 6.7)
• 24 and 25% had an HbA1c < 6.5%
• difference in proportion (95% CI)
  =−0.7% (−5.7, 4.3)
• increase in treatment effects with
  increasing baseline HbA1c

• PP population: greatest in
  HbA1c≥9.0% [−1.68% , −1.76 %]

• APT population: [−0.94%, −1.31]
         FG, insulin, insulin
          resistance, lipid
• PP population, maximal FG effect at Week 24
  followed by a rise through Week 52 for both Tx
• The LS mean FPG change not different between
  groups
• sitagliptin group: smaller increase from baseline in
  fasting insulin
• sitagliptin group: decrease from baseline in
  fasting proinsulin and the proinsulin/insulin ratio
• glipizide group: increase from baseline in these
  two endpoints
• sitagliptin group: smaller increase in HOMA-β

• No meaningful changes in HOMA-IR

• QUICKI was significantly increased from baseline
  with sitagliptin relative to glipizide

• No between-group differences for any measured
  lipid parameter, except for HDL-C

• % change [3.7% , 1.2%]
   Safety and tolerability
• no meaningful differences in overall adverse experiences

• adverse experiences higher with glipizide than with
  sitagliptin (30.3 vs. 14.5)
• higher incidence of hypoglycaemia observed with glipizide
  treatment

• two serious adverse experiences considered related to
  study drug in the glipizide group (myocardial infarction and
  spontaneous abortion)

• none in the sitagliptin group
• adverse experiences by body systems
  was comparable between the groups

• most of these events mild in intensity,
  not related to study drug, and
  resolved while patients continued in
  the study
                hypoglycemia
•   Glipizide: 187 (32.0%) patients, 657 episodes
•   Sitagliptin: 29 (4.9%) , 50 episodes

•   598 episodes in the glipizide group, h’stix obtained, 435 (73%)
    were <3.9 mmol/l
•   Sitagliptin gp, 43 episodes obtained, and 31 (72%) <3.9 mmol/l

•   Eight patients (1.4%) on glipizide had a hypoglycaemic episode that
    required non-medical assistance compared with one patient (0.2%)
    on sitagliptin

•   seven patients (1.2%) in the glipizide group had an episode that
    required medical assistance compared with one patient (0.2%) in
    the sitagliptin group.
               BW
• body weight significantly reduced
  with sitagliptin [−1.5 kg, 1.1kg]
• waist circumference: [−1.4 cm , 0.7
  cm]
• no clinically differences in change in
  measured chemistry and haematology
  analytes
• No meaningful differences were
  observed in vital signs or in ECG data.
          Discussion
• Met primary end point
• Although more sitagliptin-treated
  patients discontinued treatment
  because of lack of efficacy, PP and
  APT population showed similar result
• A similar proportion of patients in
  each group attained the HbA1c
  targets of <7 and <6.5%
• similar reductions in HbA1c from
  baseline
• FPG was also reduced to a similar
  extent
• maximal efficacy in HbA1c and FPG
  was observed at 24 to 30 weeks
• subsequent increases in both groups
• Initial reduction slightly greater with
  glipizide (<0.2% difference)
• afterwards the rate of rise in the
  glipizide group was greater
• Possible explanations:
• less compliance to diet and exercise
  over the course of the treatment
  period
• the natural history of the disease
  with progressive loss of β-cell
  function
• a decrease in efficacy of study drug
  or of metformin
• HOMA-β increased significantly in the glipizide group than
  in the sitagliptin group
• As expected as sulfonylurea agents directly stimulate
  insulin secretion
• The fasting proinsulin/insulin ratio is a measure of β-cell
  dysfunction
• the ratio increased in glipizide gp; reduced in sitagliptin gp
• may reflect the effects of glipizide on the β-cell, through
  ongoing β-cell stimulation, and/or progressive β-cell
  deterioration

•   The improvement in the ratio with sitagliptin suggests it
    may have a beneficial effect on β-cell function
• treatments were generally well tolerated
• substantially higher rate of drug-related
  adverse experiences with glipizide mainly
  because of the increased incidence of
  hypoglycaemia
• the overall adverse experience profiles
  were similar between groups
• No meaningful differences were observed
  in the results of laboratory safety
  assessments
            Conclusion
• the addition of sitagliptin compared with
  the addition of glipizide
• similar HbA1c-lowering efficacy in 1 yr
• both treatments were generally well
  tolerated
• sitagliptin had a considerably lower risk of
  hypoglycaemia and produced weight loss
• This study was funded by Merck & Co.,
  Whitehouse Station, NJ, USA

• Michael Nauck has received honoraria from Merck
  & Co. for memberships on the advisory boards and
  for speaking on subjects related to sitagliptin,
  DPP-4 inhibitors and incretins, in general
• He has also received honoraria from Bristol-
  Myers-Squibb, GlaxoSmithKline, Merck
  (Darmstadt), Novartis, Probiodrug and Roche for
  consultations and speaking on topics closely
  related to sitagliptin and DPP-4 inhibitors
• G. M., D. S., L. T. and P. S. are employees of
  Merck Research Laboratories
• Merck & Co., is one of the largest
  pharmaceutical companies in the
  world
• sitagliptin is one of their products
       Supplementary
        Information
• Sitagliptin showed to be effective as
  a monotherapy, in combination with
  metformin, glitazones
• But causes more hypogylcemia in
  combination with sulfonylurea
• Once daily dose only
• Safe but dose adjustment required in
  renal insufficiency
• Cost– 3.6 US/ tab in US in 2007
     What I’ve learned
• Incertin axis
• Sitagliptin
• Its mechanism, use, benefit over
  sulfonylurea
• Non inferiority trial
• Ways to prove Assay sensitivity
• Thank you

				
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posted:7/23/2011
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