Oleh:

dr. Astri

Pembimbing:
Dr. dr. Teuku Heriansyah, Sp.JP (K)-FIHA

Program Pendidikan Dokter Spesialis (PPDS) Jantung dan Pembuluh Darah

Fakultas Kedokteran Unsyiah - RSUZA Banda Aceh
2019
 Introduction
• Type 2 Diabetes Mellitus (T2DM) is significantly associated
with Cardiovascular Disease (CVD) and is a risk factor for
Heart Failure (HF)

• T2DM is also a risk factor for Chronic Kidney Disease (CKD)

and End Stage Renal Disease (ESRD). Furthermore, T2DM
medications often have deleterious side effects

• The 2008 United States Food and Drug Administration (FDA)

antidiabetic drug guidance required Cardiovascular Outcome
Trials (CVOTs) to demonstrate that new antihyperglycemic
drugs would not increase the risk for Myocardial Infarction,
Stroke, or CV death
 Introduction
• The FDA has approved four Sodium-Glucose Cotransporter 2
Inhibitors (SGLT2i) based on these guidelines: Canaglifozin
(Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance),
and Ertugliflozin (Steglatro)

• Three of those SGLT2i (Canagliflozin, Dapagliflozin,

Empagliflozin) have been studied in CVOTs. Canagliflozin has
also been studied in an additional randomized clinical trial
involving patients with diabetic kidney disease

• This study reviews the design and results of each of the four
SGLT2i trials and discuss the potential determinants for their
cardiovascular, renal and safety outcomes
Method

• This study reviews the relevant trials’ original

methodology and results papers of four SGLT2i trials,
which are:
 The EMPA-REG OUTCOME Trial
 The CANVAS Program Trial
 The DECLARE-TIMI 58 Trial
 The CREDENCE Trial
The EMPA-REG OUTCOME Trial (The Empagliflozin
Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus
Patients-Removing Excess Glucose)

• It is the first SGLT2i cardiovascular trial

• The method of this study is Randomized Double-
blind Controlled Trial
• Total participants are 7020 patients with T2DM
and CVD
• Patients are given 10 mg to 25 mg of
Empagliflozin or placebo
• It has a 3.1 years follow up period
The EMPA-REG OUTCOME Trial (The Empagliflozin
Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus
Patients-Removing Excess Glucose)

• The criteria of the patients in this study is:

• The GFR of the patients’ at least >30 mL/min/1.73 m2
(calculated using the Modification of Diet in Renal
Disease or MDRD)
The CANVAS Program Trial (The Canagliflozin Cardio
Vascular Assessment Study)

• It is the second SGLT2i cardiovascular trial

• The method of this study is a combination of
cohort and randomized double blind controlled
trial
• Total participants are 10.142 patients with T2DM
• Patients are given 100 mg to 300 mg of
Canagliflozin or placebo
• It has a 2.4years follow up period
The CANVAS Program Trial (The Canagliflozin
Cardio Vascular Assessment Study)

• The criteria of the patients in this study are:

• Patients are required to be ≥ 30 years old with
established CVD or ≥50 years with at least 2 CVD risk
factors
• Patients are required to have a GFR ≥ 30 ml/min/1.73
m2 (calculated using MDRD equation)
The DECLARE-TIMI 58 Trial(The Dapagliflozin Effect on
Cardiovascular Events)

• It is the third SGLT2i cardiovascular trial and the

most recent one
• The method of this study is a randomized double
blind controlled trial
• Total participants are 17,160 patients with T2DM
• Patients are given 10 mg of Dapagliflozin or
placebo
• It has a 4.2years follow up period
The DECLARE-TIMI 58 Trial(The
Dapagliflozin Effect on Cardiovascular Events)
• The criteria of the patients in this study are:
• Male patients are required to be ≥ 55 years old and
female patients are required to be ≥ 60 years old with
≥1 CVD risk factor
• Patients are required to have a Creatinine Cleareance
≥ 60 mg/min with no specified minimum GFR
(Creatinine Cleareance is calculated using Cockroft-
Gault equation)
The CREDENCE Trial (The Canagliflozin and Renal
Events in Diabetes with Established Nephropathy Clinical
Evaluation)

• The method of this study is a randomized double

blind controlled trial
• Total participants are 4401 patients with T2DM
and CKD
• Patients are given 100 mg of Canagliflozin or
placebo
• It has a 2.6 years follow up period
The CREDENCE Trial (The Canagliflozin and
Renal Events in Diabetes with Established
Nephropathy Clinical Evaluation)
• The criteria of the patients in this study are:
• Patients are required to have a GFR between 30 and
90 ml/min/1.73 m2 (calculated using CKD-EPI
equation)
• Patients are required to have albuminuria, defined as
UACR (Urinated Albumin Creatinine Ratio) > 300-500
mg/g
• Patients are not required to have prior CVD
Result
Table 2 Adverse events in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI
58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin
Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess
Glucose (EMPA–REG OUTCOME), and Canagliflozin and Renal Events in Diabetes with
Established Nephropathy Clinical Evaluation (CREDENCE) trials
Table 3 Risk associated with study drug compared to placebo for adverse events in the
Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin
CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome
Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA–REG
OUTCOME), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy
Clinical Evaluation (CREDENCE) trials
Discussion
• The most important finding of this review is the
absolute risks of cardiovascular events appeared
to be more related to baseline renal filtration
than the baseline CVD rate

• Out of the four SGLT2i trials, CREDENCE had the

highest cardiovascular event rates and DECLARE-
TIMI 58 had the lowest cardiovascular event rates
• Relative Risk Reductions (RRRs) varied among
the trials, but CREDENCE had the largest
cardiovascular RRRs and DECLARE-TIMI 58 had
the smallest cardiovascular RRRs

• CREDENCE had the highest composite renal event

rates and DECLARE-TIMI 58 had the lowest
composite renal event rates

• CREDENCE had the highest renal risk and

DECLARE-TIMI 58 had lowest renal risk
• Baseline renal filtration function appears to play a
major role in predicting cardiorenal outcomes,
even more so than prior CVD

• CREDENCE has been found to increase a two

fold MACE events compared to DECLARE-TIMI 58

• This means that SGLT2i decreased cardiovascular

risk depending on baseline renal filtration
function but not prior CVD status
Conclusion

• Baseline renal filtration function and degree of

albuminuria are the most significant indicators of
risk for both cardiovascular and renal events
• These two factors also anticipate the greatest
clinical benefit for SGLT2i
Critical Appraisal
 PICO Journal

Intervention Outcome
• 1876 normotensive • Normotensive
healthy athletes. • Exercise testing athletes with
HBPR and with • to evaluate the clinical
NBPR to outcome, in terms of
exercise test incident hypertension
or cardiovascular
events, in athletes
Population Comparison
presenting an
abnormally high blood
pressure response
(HBPR) to exercise.
Design of Study

• Method of Study : Randomized Double Blind

Controlled Trial
• Focus of Study : Prognostic
• Worksheet :Prognostic
Validity
Recruitement:
Apakah subjek penelitian mewakili atau representatif?
YA

• Cara perekrutan dan

penilai serta kredibelitas
penilai disebutkan
Validity
Apakah pemantauan dilakukan lama dan selesai ?

Ya, penelitian dilakukan selama 4 tahun

 Validity
Apakah kriteria outcome yang digunakan objektif dan tidak bias?

Ya

Penilai variabel adalah orang yang kredibel sehingga dapat digunakan sebagai
data yang objektif
Importance
No. Pertanyaan Jawaban
1. Seberapa besar kemungkinan Pasien DM Tipe 2 yang diberi Dapagliflozin 10
kejadian pada periode waktu mg lebih memiliki risiko penurunan kejadian
tertentu? terhadap penyakit kardiovaskular dan renal
daripada
2. Seberapa tepat perkiraan Confidence Interval 95 %
kemungkinannya?
 APPLICABILITY

NO APPLICABILITY JAWABAN
1 Apakah perlakuan tersebut tersedia, terjangkau dan Ya Tidak Tidak Jelas
akurat?
 
2 Apakah kita dapat memperkirakan prevalensi Ya Tidak Tidak Jelas
kematian pada pasien kita?
 
3 Apakah post test probability yang dihitung mengubah Ya Tidak Tidak Jelas
tatalaksana?
 
4 Apakah uji prognostik tersebut bermanfaat bagi Ya Tidak Tidak Jelas
pasien?
 
5 Apakah pasien saya mirip dengan pasien dalam Ya Tidak Tidak Jelas
penelitian?
 
Kesimpulan

• Penelitian yang dilaporkan dalam jurnal tersebut VALID

• CLINICALLY IMPORTANCY dalam penelitian tersebut
tergambar dalam jurnal, dimana probability dan accuracy
bermakna.
• Hasil penelitian yang dilaporkan dalam jurnal tersebut
bersifat APPLICABLE untuk pasien.
Terima Kasih