Critical Appraisal Presentation

Presenter:
Teoh Mok Oii
Muhd Ikmal Mohd Yunus
Type 2 diabetes is increasing worldwide and it is
expected by the year 2030 at least 400 million people
will suffer from this metabolic disease.

Risk factors: overweight (BMI>23 kg/m2),
dyslipidaemia (HDL <0.9 mmol/L or TG >1.7mmol/L),
hypertension, cardiovascular diseases, family history.

Dipeptidyl-peptidase-IV inhibitors (DPP-4) improve
glycaemia control in glucose-dependent manner via
enhancement of incretin axis.

MOA: Inhibit enzymatic degradation of glucagon-like
peptide-1 (GLP-1) and gastric inhibitory polypeptide
(GIP)

Physiological effects: insulin secretion (after meals)
glucagon secretion
satiety

Advantage over other OHA
Neutral body weight
Low risk of hypoglycaemia and gastrointestinal adverse
experiences

Sitagliptin
range of HbA1c lowering (0.5-0.8%)
Combination with other OHA such as metformin,
thiazolinedione and sulphonlyurea
Max dose: 100mg od


Population Type II diabetes patients who aged 18-78 years old on the
following regimen : (metformin + another OHA, any OHA
monotherapy) with HbA1c level (6.5 x 10)
Intervention Sitagliptin 100mg once daily (52 weeks of treatment)
Comparison 1. Glipizide 5mg/ day (can uptitrated to a maximum of 20mg/day) +
Metformin ( 1500mg/ day)

2. Sitagliptin 100 mg qd + Metformin ( 1500mg/ day)
Outcome Primary efficacy outcome: HbA1c change from baseline
Primary safety outcome: Hypoglycaemia incidence during
treatment
YES
This double-blinded study was comparing the relative
efficacy & safety of Sitagliptin vs Glipizide in patient with
T2DM inadequately controlled on metformin alone

Therefore RCT is the right research method since clinical
question is regarding a therapy

A non-inferiority design was chosen as a standard
approach to assess similarity of a new agent to a
standard therapy


YES
Participants were stratified randomized in a 1:1 ratio to the
intervention and control group .
Inclusion and exclusion criteria were clearly defined








YES
Inclusion criteria Exclusion criteria
Age (18-78 years) Type I diabetes
Type II diabetes
Any OHA monotherapy
On metformin + another OHA
Insulin use within three weeks of
screening
HbA1c level (6.5 x 10) Renal function impairment
Fasting plasma glucose >15
mmol/L
Baseline demographic were similar between the two groups (duration of
known diabetes, mean HbA1c and FPG level, % use of OHA at screening)
YES
This was a multinational, randomized, parallel
group, non-inferiority study with an active-
controlled, double-blind treatment period.

Thus the research outcome was protected from
placebo effect or observers bias
Directly entered a 2-week placebo
run-in period
Patients on metformin 1500 mg/day
with HbA1c >6.5 & <10%
HbA1c >6.5 and <10% after the
metformin dose-stable period-
entered a 2-week single-blind
placebo run-in period
Entered metformin monotherapy
treatment titration & dose-stable
period of at least 8 weeks
Patients not on OHA
Patients on OHA other than metformin dose 1500
mg/day
Patients on metformin in combination with another OHA
ELIGIBLE TO BE
RANDOMIZED
Randomization
Following this 2-week period, eligible patients had baseline measurements and
then were randomized in a 1 : 1 ratio to the addition of sitagliptin 100 mg once
daily or glipizide (at an initial dose of 5 mg/day)
Uptitration
After the starting dose of 5 mg/day, glipizide was uptitrated according to
protocol-specified criteria to a potential maximum dose of 20 mg/day.
In 3 week intervals during the first 18 weeks of treatment, glipizide was
uptitrated if premeal fingerstick glucose values were >6.1 mmol/l (110 mg/dl).
Withhold/
Downtitration
Uptitration withheld if patient at high risk of hypoglycaemia.
Glipizide could be downtitrated to prevent recurrent hypoglycaemic events at
any time
Of the total 1172 participants, 793 were included in the per-
protocol analysis (sitagliptin= 382 and glipizide=411) and 379
were excluded.

Withdrawal rate: Sitagliptin(34.35%), glipizide (29.45%)-
high withdrawal rate >20% (may cause data losing)

The efficacy outcome was analysed using both per-protocol
(PP) method as well as intention to treat (ITT) analysis.
YES
All patient were followed up & data collected during baseline
& various time during study
After an overnight fast, blood was collected for the
assessment of
1. HbA1c
2. Fasting Plasma Glucose (FPG)
3. Insulin & Pro -Insulin
4. Lipid parameters including TC, LDL-C, TGs, HDL-C and
non- HDL-C
5. Homeostasis model assessment-b cell function (HOMA-
b) and the pro-insulin/insulin ratio were used to assess
aspects of b-cell function.
6. HOMA-insulin resistance (HOMA-IR) & quantitative
insulin sensitivity check index (QUICKI) were calculated to
assess changes in insulin resistance.

YES
Safety Assessments

Data on adverse experiences, physical examinations, vital
signs, ECGs & body weight were collected throughout
the study.

All adverse experiences were rated by the study site
investigators for intensity and relationship to study drug.

Laboratory safety evaluations included blood chemistry,
haematology and urinalysis.

Patients having hypoglycaemia symptoms were
instructed to obtain a fingerstick glucose record the
value in log bookcontact study site.
Patients were discontinued for lack of efficacy based on
progressively stricter glycaemic criteria:

Period Dose FPG/HbA1c
Randomization-
Week 6
2 tablets (5-mg tablets) of
glipizide/glipizide placebo for at
least 2 weeks
FPG > 14.4 mmol/l
(270 mg/dl)

Week 6 - Week 12 Maximal dose (four 5-mg tablets)
of glipizide/glipizide placebo for at
least 2 weeks
FPG > 13.3 mmol/l
(240 mg/dl)

Week 12 - Week 18 Patients on maximal dose of
glipizide/glipizide placebo for at
least 2 weeks
FPG >12.2 mmol/l
(220 mg/dl)

Week 18 - Week 30 - FPG>11.1 mmol/l
(220 mg/dl)

Week 30 to Week 52 - HbA1c > 8.0%








The study was conducted with two sided 95% confidence
interval and non-inferiority margin (d)= 0.3

Alpha value was set to =0.05

Sample size in each arm >500 participants

X However, power of statistical study and beta value are not
stated (standard B-value= 0.2 and power of study = 80%)




Cant Tell
Total participant (APT), n=1172
Per Protocol (PP), n=793

Sitagliptin 100mg QID, n=588
Per Protocol, n=382

Glipizide, n=584
Per Protocol, n=411

Treatment groups were generally well balanced for
baseline demographics
Efficacy variables for all randomized patients
YES

Studies
Safety and Efficacy of Treatment with
Sitagliptin or Glipizide in Patients
with Type 2 Diabetes Inadequately
Controlled on Metformin: A 2-year
Study
Seck et al 2010
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
Nauck et al 2007
Mean
HbA1c
reduction
Sitagliptin+metformin = -0.54% (-
0.45, -0.64)
Glipizide+metformin = -0.51% (-
0.42, -0.60)
Sitagliptin+metformin = -0.67% (-
0.59, -0.75)
Glipizide+ metformin = -0.67% (-
0.59, -0.75)
Confidence
Limit Ratio
(CLR)
-0.64/-0.45 = 1.42 -0.75/-0.59 = 1.27
Hypoglycae
mia
incidence
Sitagliptin = 31 (5.3%)
Glipizide = 199 (34.1%)
Sitagliptin = 29 (4.9%)
Glipizide = 187 (32%)
Weight
changes
Sitagliptin = -1.6kg ( -2.3, -1.0)
Glipizide = 0.7kg (0, 1.3kg)
Group difference = 2.3kg
Sitagliptin = -1.5kg (-2.0, -0.9)
Glipizide = 1.1kg (0.5, 1.6)
Group difference = 2.5kg
By comparing the primary efficacy and adverse outcome, the
statistical results obtained from these two studies dont
differ much.

This implies sitagliptin is non-inferior to the standard
antidiabetes medication (glipizide) plus it has less
hypoglycaemia incidence and weight gain.
YES


YES
A proportion of Asian population involved in this
study ,n=99 as the study was multinational in
nature

All characteristics studied suits local clinical
settings
Limitations
1. High number of withdrawal, mostly due to lack of efficacy

Research funded by Merck & Co., Whitehouse Station, NJ, USA

Conflict of interest
Author Michael Nauck:
1. 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.
2. 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.
1. The addition of sitagliptin compared with the
addition of glipizide provided similar HbA1c-
lowering efficacy after 52 weeks of treatment
in patients with type 2 diabetes with
inadequate glycaemic control on metformin
monotherapy.
2. Although both treatments were generally well
tolerated, sitagliptin had a considerably lower
risk of hypoglycaemia relative to glipizide and
produced weight loss compared with weight
gain with glipizide.
OHA

Brand name
Dosage Form & Strength Cost Range
Sulfonylureas
Glipizide
Gliclazide

Glibenclamide
Gilbenclamide+Metformin
-
Diamicron
Diamacron MR
Daonil
Glucovance
-
80mg
30mg,60mg
5mg
2.5mg/500mg,5mg/500mg
-
35$ /100s(gen)

5-40-50$/84(gen)
30-40$/100s(gen)
DPP-4 inhibitors
Sitagliptin
Sitagliptin+Metformin

Januvia
Janumet
25mg,50mg,100mg
50mg/500mg
50mg/850mg
50mg/1000mg
140-160$ /56s
100-120$ /60s

Vildagliptin
Vildagliptin+Metformin




Saxagliptin
Rinagliptin
Galvus
GalvusMet




-
Tradjenta
50mg
50mg/500mg
50mg/850mg
50mg/1000mg

2.5mg,5mg
5mg
100$ / 56s
120$ / 60s