ca sitagliptin vs glipizide 1.1

8/12/2019 CA Sitagliptin vs Glipizide 1.1

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Critical Appraisal PresentationPresenter:Teoh Mok Oii

Muhd Ikmal Mohd Yunus


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Type 2 diabetes is increasing worldwide and it isexpected by the year 2030 at least 400 million peoplewill suffer from this metabolic disease.

Risk factors: overweight (BMI>23 kg/m2),

dyslipidaemia (HDL 1.7mmol/L),hypertension, cardiovascular diseases, family history.

Dipeptidyl-peptidase-IV inhibitors (DPP-4) improveglycaemia control in glucose-dependent mannervia

enhancement of incretin axis.

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


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Physiological effects: insulin secretion (after meals)glucagon secretionsatiety

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


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Population Type II diabetes patients who aged 18-78 years old on thefollowing regimen : (metformin + another OHA, any OHAmonotherapy) 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 baselinePrimary safety outcome: Hypoglycaemia incidence duringtreatment

YES


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This double-blinded study was comparing the relativeefficacy & safety of Sitagliptin vs Glipizide in patient with

T2DM inadequately controlled on metformin alone

Therefore RCT is the right research method since clinicalquestion is regarding a therapy

A non-inferiority design was chosen as a standardapproach to assess similarity of a new agent to a

standard therapy

YES


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Participants were stratified randomized in a 1:1 ratio to theintervention 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 ofscreening

HbA1c level (6.5 x 10) Renal function impairment

Fasting plasma glucose >15mmol/L


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Baseline demographic were similar between the two groups (duration of

known diabetes, mean HbA1c and FPG level, % use of OHA at screening)


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YES

This was a multinational, randomized, parallelgroup, non-inferiority study with an active-controlled, double-blindtreatment period.

Thus the research outcome was protected fromplacebo effect or observers bias


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Directly entered a 2-week placeborun-in period

Patients on metformin 1500 mg/daywith HbA1c >6.5 & 6.5 and


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Randomization

Following this 2-week period, eligible patients had baseline measurements andthen were randomized in a 1 : 1 ratio to the addition of sitagliptin 100 mg oncedaily or glipizide (at an initial dose of 5 mg/day)

Uptitration

After the starting dose of 5 mg/day, glipizide was uptitrated according toprotocol-specified criteriato a potential maximum dose of 20 mg/day.

In 3 week intervals during the first 18 weeks of treatment, glipizide wasuptitrated 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 atany time


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Of the total 1172 participants, 793 were included in the per-protocol analysis (sitagliptin= 382 and glipizide=411) and 379were 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.


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YES


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All patient were followed up & data collected during baseline& various time during study

After an overnight fast, blood was collected for theassessment of

1. HbA1c2. Fasting Plasma Glucose (FPG)3. Insulin & Pro -Insulin4. Lipid parameters including TC, LDL-C, TGs, HDL-C and

non- HDL-C5.

Homeostasis model assessment-b cell function (HOMA-b) and the pro-insulin/insulin ratiowere used to assessaspects of b-cell function.

6. HOMA-insulin resistance (HOMA-IR) & quantitativeinsulin sensitivity check index (QUICKI)were calculated toassess changes in insulin resistance.

YES


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Safety Assessments

Data on adverse experiences, physical examinations, vitalsigns, ECGs & body weight were collected throughoutthe study.

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

Laboratory safety evaluations included blood chemistry,haematology and urinalysis.

Patients having hypoglycaemia symptoms wereinstructed to obtain a fingerstick glucoserecordthe

value in log bookcontactstudy site.


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Patients were discontinued for lack of efficacy based onprogressively stricter glycaemic criteria:

Period Dose FPG/HbA1cRandomization-Week 6

2 tablets (5-mg tablets) ofglipizide/glipizide placebo for atleast 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 atleast 2 weeks

FPG > 13.3 mmol/l

(240 mg/dl)

Week 12 - Week 18 Patients on maximal dose ofglipizide/glipizide placebo for atleast 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%


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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


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

Sitagliptin 100mg QID, n=588

Per Protocol, n=382

Glipizide, n=584Per Protocol, n=411

Treatment groups were generally well balanced forbaseline demographics

Efficacy variables for all randomized patients

YES


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Studies Safety and Efficacy of Treatment withSitagliptin or Glipizide in Patients

with Type 2 Diabetes InadequatelyControlled 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

HbA1creduction

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)

ConfidenceLimit Ratio(CLR)

-0.64/-0.45 = 1.42 -0.75/-0.59 = 1.27

Hypoglycaemiaincidence

Sitagliptin = 31 (5.3%)Glipizide = 199 (34.1%)

Sitagliptin = 29 (4.9%)Glipizide = 187 (32%)

Weightchanges

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


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By comparing the primary efficacy and adverse outcome, thestatistical results obtained from these two studies dont

differ much.

This implies sitagliptin is non-inferior to the standardantidiabetes medication (glipizide) plus it has lesshypoglycaemia incidence and weight gain.

YES


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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


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Limitations

1. High number of withdrawal, mostly due to lack of efficacy

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

Conflict of interestAuthor Michael Nauck:

1. Honoraria from Merck & Co. for memberships on the advisoryboards and for speaking on subjects related to sitagliptin, DPP-4inhibitors and incretins, in general.

2. Honoraria from Bristol-Myers-Squibb, GlaxoSmithKline, Merck(Darmstadt), Novartis, Probiodrug and Roche for consultationsand speaking on topics closely related to sitagliptin and DPP-4

inhibitors. G. M., D. S., L. T. and P. S. are employees of MerckResearch Laboratories.


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1. The addition of sitagliptin compared with theaddition of glipizide provided similar HbA1c-lowering efficacyafter 52 weeks of treatment

in patients with type 2 diabetes withinadequate glycaemic control on metforminmonotherapy.

2. Although both treatments were generally welltolerated, sitagliptin had a considerably lowerrisk of hypoglycaemia relative to glipizide andproduced weight loss compared with weightgain with glipizide.


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OHABrand name Dosage Form & Strength Cost Range

Sulfonylureas

Glipizide

Gliclazide

Glibenclamide

Gilbenclamide+Metformin

-DiamicronDiamacron MRDaonilGlucovance

-80mg30mg,60mg5mg2.5mg/500mg,5mg/500mg

-35$ /100s(gen)

5-40-50$/84(gen)30-40$/100s(gen)

DPP-4 inhibitors

Sitagliptin

Sitagliptin+Metformin

Januvia

Janumet25mg,50mg,100mg50mg/500mg50mg/850mg50mg/1000mg

140-160$ /56s100-120$ /60s

VildagliptinVildagliptin+Metformin

Saxagliptin

Rinagliptin

GalvusGalvusMet

-

Tradjenta

50mg50mg/500mg50mg/850mg50mg/1000mg

2.5mg,5mg

5mg

100$ / 56s120$ / 60s


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ca sitagliptin vs glipizide 1.1

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