DAPAGLIFLOZIN IN PATIENTS

WITH CHRONIC KIDNEY

DISEASE

Fatimah AlGreeshah 220011161

Amjad Alabdulhadi 220022104
Aysha Alamoudi 220012956
Maryam Alolyan 220010705
Fatima Alessa 220009565
 OVERVIEW
Article presentation:
● Introduction
● Methods
● Results
●Conclusion
Critical appraisal, evaluate the following:
● The title and abstract
● The journal
● The study investigators
● Methodology (randomization; type of blinding)
● Internal and external validity (i.e., risk of
sampling, selection, performance, compliance
bias)
● Statistical analyses
 01
INTRODUCTION
 STUDY RATIONAL:

Patients with chronic kidney disease have a high risk of adverse renal and
cardiovascular outcomes. The effect of Dapagliflozin is unknown in
patients with chronic kidney disease, with or without type 2 diabetes.
The aim of study to ensure and assess that Dapagliflozin and Prevention of
Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial to estimate
the longterm efficacy and safety of the SGLT2 inhibitor (Dapagliflozin) in
patients with chronic kidney disease, with or without type 2 diabetes.
Source of funding:

Funded by AstraZeneca.

May
 02
METHODS
Source of funding:

Randomized
March
Parallel design

Double-blinded
May
Placebo controlled

Multicenter clinical trial

 Source of funding:

Conducted at 386 sites in 21 countries:

China March Mexico
United Kingdom Germany
Denmark United States
Sweden Japan
Ukraine Peru
Vietnam Philippines
Argentina May Poland
Brazil Russia
Canada Spain
Hungary India
Korea
 Source of funding:

March
From February 2, 2017, till June 12, 2020.
Treatment duration is 33 months.

May
Source of funding:

March
There is run – in period .

May
 Source of funding:

March
All the participants signed written informed consent
prior to any trial specific procedure commenced and
approved by IRB.

May
 Source of funding:

Inclusion criteria:

1. Provision of signed informed consent beforeMarch

beginning any study specific procedures.

2. Both gender, Female or male aged ≥18 years at the time of consent.

3. At visit 1 :eGFR 25 and ≤75 mL/min/1.73m² (CKD-EPI Formula).

May
4. At visit 1 :UACR ≥200 and ≤5000 mg/g.

5. Stable, if not medically contraindicated , for the patient maximum tolerated labelled
daily dose, treatment with angiotensin converting enzyme (ACE) inhibitor or angiotensin
receptor blocker (ARB) for at least 4 weeks prior to visit 1.
 Source of funding:

Exclusion criteria:

1.Polycystic kidney disease (autosomal dominantMarch

or recessive), lupus nephritis, or vasculitis
associated with anti-neutrophil cytoplasmic antibody (ANCA).

2. Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary

or secondary kidney disease by 6 months before enrolment.
May
3. History of organ transplantation.

4. Receiving therapy with a sodium glucose co-transporter 2 (SGLT2) inhibitor by 8 weeks before
enrolment or previous intolerance of an SGLT2 inhibitor .
 Source of funding:

Exclusion criteria:
March
5. Type 1 diabetes (T1D).

6. New York Heart Association (NYHA) class IV Congestive Heart Failure at the time of enrolment .

7. MI, unstable angina, stroke or transient ischemic

Mayattack (TIA) by 12 weeks before enrolment .

8. Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery

bypass grafting [CABG]) or valvular repair/replacement by 12 weeks before enrolment or is
planned to receive any of these procedures after randomization.
Source of funding:

March
Dapagliflozin per oral 10mg once daily
Placebo once daily

May
 Source of funding:

Participants were randomly assigned to have dapagliflozin (10 mg once daily) or

March fixed randomization schedule, by
matching placebo, in order with the sequestered,
using of balanced blocks to estimate an approximate 1:1 ratio of the two
interventions ( size of blocks was unclear )

Randomization was stratified Cox proportional-hazards model in order of the

May
diagnosis of type 2 diabetes (yes or no) and the urinary albumin-to-creatinine ratio
(≤1000 or >1000). Investigators applied an interactive voice response or Web
response system to assess trial group assignments.
Stratified randomization method & balanced blockes

Drop-out 0.2%
Drop-out 0.5%
 Source of funding:

Primary outcome:
Decreased in the estimated glomerular
Marchfiltration rate (GFR) of at least
50% ( ratio )
End stage kidney disease (nominal)
Death caused by renal causes (nominal)
Death caused by cardiovascular causes
May(nominal)
Estimated GFR of < 15 ml/min/1.73m^2 (ratio)
Dialysis for long term (nominal)
Renal transplantation (nominal)
 Source of funding:

Secondary outcome:
Composite of decreased estimated March
GFR of > or = 50% , end stage kidney
disease, or death from kidney causes (nominal)
Composite of death from cardiovascular causes or hospitalizations for
heart failure (nominal)
Death from any causes (nominal) May
 Source of funding:

Both primary & secondary composite outcomes, assessed in a time-to-event analysis.

Both used two sided alpha level of 0.05, whichMarch
means type 1 error is low because the
alpha level sets at 0.05 and it’s acceptable.
Both conducte p value < 0.001.
Primary endpoint analysis was based on intention to treat population (ITT).
May
 Source of funding:

There is no required sample size (unclear)

Power of analysis: 90% March
beta = 10%
Which means type 2 error is low, because the power sets at 90% and the beta
is 10% and it’s acceptable.
May
 03
RESULTS
Were there any significant differences among study
groups at baseline that could influence study
results?
Baseline Characteristics were well balanced between
groups A and B

Were any important baseline comparisons of

factors that might affect the study finding
overlooked?
Yes
Primary composite outcome were statically significant because p value
is lower than 0.001.
Secondary outcomes were statically significant in the first outcome
because p value is lower than 0.001 however the other outcomes are
greater which is statistically insignificant.
Between the Dapagliflozin and placebo groups, the overall frequencies of
adverse events and serious adverse events were comparable (Table 2).
Both were not experienced diabetic ketoacidosis.
Those without type 2 diabetes did not experience severe hypoglycemia or
diabetic ketoacidosis.
In the placebo group, there was one verified case of Fournier's gangrene; in
the dapagliflozin group, there were none.
 Source of funding:

.
1. Trial was stopped on the basis of a recommendation from the independent data monitoring
committee. This may have decreased the power of
Marchsome secondary outcomes. The strong
internal and external validity of the treatment effect suggests that this limitation is unlikely to
have had a major effect, on the findings.

2. Like in other trials of SGLT2 inhibitors, there was an initial dip in the estimated GFR,
May This dip in the estimated GFR reflects
followed by a stabilization of kidney function decline.
favorable hemodynamic alterations in the glomerulus. The authors did not collect estimated
GFR values following the end of the trial and are unable to as certain whether the initial
dip in the estimated GFR is reversible even though after the discontinuation of dapagliflozin.
 04
CONCLUSION
 Source of funding:

The study accept alternative hypothesis, met March

with the objective of the study . Among
patients with chronic kidney disease, regardless of the exist or absence of diabetes, the
risk of a composite of a sustained decreasing in the estimated GFR of at least 50%, end
stage kidney disease, or death from kidney or cardiovascular causes was significantly
much more lower with dapagliflozin than with placebo.
May
CRITICAL APPRAISAL
 Source of funding:

.
DAPAGLIFLOZIN IN PATIENTS WITH CHRONIC KIDNEY DISEASE
The title is Unbiased, it didn’t mention anyMarch
results, concise and has no abbreviations.
The title is informative, it mentions population, intervention (PICO).

————————————
May
Abstract provides a clear overview of the purpose, method, results, and conclusion of
the study.
Abstract mentions everything that present in the paper.
 Source of funding:

.
JOURNAL NAME: THE NEW ENGLAND
JOURNAL OF MEDICINE (NEJM)

its peer reviewed journal ( double blinded )

It has editorial board.

JIF 91.245
.
 Source of funding:

Potential conflict of interest:

the study is funded by Astrazeneca and Dapagliflozin (Farxiga) is manufactured

in Astrazeneca as well.
there are two authors and member in DAPA-CKD who work in Astrazeneca at
the same time. so, there is a potential conflict of interest.
 Potential conflict of interest:

.
 type of bias risk of bias Judgement

Sample bias High majority of the study : male

majority of the study : T2DM
.

generation randomized sequence

Selection bias Low
computer software program

Performance bias Low Double blind

Attrition bias Low Dropout rate close to each other

Compliance bias Unclear Authors didn’t mention about adherence

Reporting bias high many missed informations

 Source of funding:

They used Multicenter so high external and March

internal validity
All the factors like study design , method, statistical analysis was appropriate so high
internal validity.
All the factors like types of patients enrolled, how they selected, study settings and
timing of the study was inappropriate so low May external validity.
sampling bias can affect on external validity
 Source of funding:

Price : 159 SR
 Source of funding:

Title: The dapagliflozin and prevention of adverse outcomes in chronic kidney

disease (DAPA-CKD) trial: baseline characteristics

abstract:

year of publication: 2020

Describe the conclusion: Participants with a wide range of significant kidney

diseases receiving renin angiotensin system blocking therapy have been enrolled
in the DAPA-CKD trial. The trial will examine the efficacy and safety of
dapagliflozin in participants with CKD Stages 2–4 and elevated albuminuria, with
and without type 2 diabetes (T2D) .