JOURNAL READING

dr. Ganang K Ahimsa

Pembimbing dr. Vina Yanti, SpPD-KEMD
JUDUL JURNAL
BACKGROUND
Heart Failure (HF) & Diabetes
mellitus
• Diabetes mellitus (DM) is
Associated with increased risk
for cardiovascular disease
(CVD), including heart failure
(HF).
• Indeed, CVD are major cause of
morbidity and mortility in
T2DM patients.
DPP IV inhibitor
• Animal studies strongly suggest
that treatment of T2DM with
DPP-4i is protective for HF.
• Early clinical studies produced
conflicting data
• Cardiovascular outcome of
DPP-4i have not been well
established because of the
relatively shrt duration of
prescription, particularly for HF
risk
OBJECTIVE OF STUDY

Goal of
Hypothesis the
present
study

DPP4i could significantly

lower future HF risk Evaluate the risk of HF and
compared with sulfonylurea cardiovascular outcome of
treatment in patients with DPP-4i compared with
and without pre-existing sulfonylurea
cardiovascular disease
METHODS

Design 1 Cohort Retrospective Observational Study

South korean; data from 1st january 2009 to 31th December

Setting 2 2015

761,349 patients were enrolled in this study with data taken

Subject 3 from Korean health insurance review and Assesment service
database

From 2009 to 2005, 2,806,740 patients

with T2DM (ICD 10th , code E11) who
were ever prescribed SU or DPP-4i were Study inclusion criteria and outcome were defined
analyzed using longitudinal patient data
from korean health insurance review by the diagnosis of T2DM and HF based on the ICD-
database that included patient 10-CM code of E.11 and I50.XX, respectively.
demographic, diagnoses, drug
prescription, and procedures
METHODS
Inclusion Criteria

T2DM patients aged > 19 years old who were newly prescribed sulfonylurea or DPP-4i from 2009 to 2015

Exclusion criteria
Patients who prescribed both SU and DPP-4i

Patients with more than 1 year of wash-out period (verifying first-prescription of each drug and securing wash-out period)

More than 1 diagnosis of type 2 DM during the baseline period

Type 1 DM diagnosis during the baseline period

PCOS diagnosis during the baseline period

Gestational diabetes mellitus diagnosis during the baseline period

Hospitalization for heart failure diagnosis during 60 days before index date
MethodS

Statistical Analysis

Propensity score-matched cohort  reduced bias due to confounding variable

Cox proportional hazards models  compare outcome for sulfonylurea versus

DPP-4i

6
 Propensity score
matching method was Propensity score
used to minimize the matching were performed
differences and various 3x with 1:1 ratio to
biases between two balance covariates across
the two study groups.
study groups on study
outcomes.

The difference The value of absolute of

between matched SMD ≤ 0.1 indicates a
negligible difference in
pairs was estimated potential confounders
using standardized between the two study
mean difference (SMD) groups.

STATISTICAL ANALYSIS
 Risk of Cardiovascular
outcomes was Subgroup analysis
obtained by using was performed to Statistical
survival analysis determine whether significance was
(Kaplan–Meier method
for univariate analysis each DPP4i group defined at a P
and Cox proportional continued to have value < 0.05.
hazards regression for a lower risk of HF
multivariate analysis)

STATISTICAL ANALYSIS
The SMD was 0,30 %
Baseline
in total matched characteristics
patients between
group
 T2DM prescribed DPP-4i or SU
N = 761,349

SU n=
DPP4i n=407,685
353,664
After propensity matching
DPP4i n = 255691

Sitagliptin Linagliptin Saxagliptin

Vildagliptin=36616
n=109176 n=66986 n=13632
 The hazard ratio of the
occurrence of HF in DPP4i group
vs SU is 0.78 (95% CI 0.69-0.87 ;
p<0.001)
 Cox’s model was performed
after propensity score
matching in order to assessed
all of the cardiovascular
outcomes between DPP-4i
group with Su group.

• The HR for hospitalization for MI and Stroke for DPP-4i

compared with SU were 0.76 (95% CI 0.67-0.87) and 0.63
(95% CI 0.60-0.67) respectively.
SUBGROUP ANALYSIS

Each DPP-4i group showed

lower HRs for Hospitalization
of HF than SU group
(sitagliptin HR 0.76;95% CI
0.67-0.86;p<0.001) ,
(Linagliptin HR 0.74 p=0.007) ,
(Vildagliptin HR 0.82 ; p=0.15),
( saxagliptin HR 0.93 ; p=0.79)
SUBGROUP ANALYSIS

• The HR for hospitalization for MI and

Stroke for sitagliptin compared with
SU were 0.65 (p<0.001) and 0.66
(p<0.001) respectively.
• The HR of hospitalization for stroke for
linagliptin compared with SU were
0.71 (p<0.001)
• The HR of hospitalization for stroke for
vildagliptin compared with SU were
0.66 (p<0.001)
• The HR of hospitalization for stroke for
saxagliptin compared with SU were
0.66 (p=0.005)
 Slide 16
DPP- 4 inhibitors and GLP1 Agonist
Mechanism of Action
Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin (DPP IV-Inhibitor)
Exenatide, Liraglutide (GLP 1 Agonist )
Increases and prolongs GLP-1
GLP-1 and GIP are and GIP effects on β-cells
key in regulating DPP-4 β-cells
both postprandial Food intake inhibitor Glucose-dependent
and long-term
glucose homeostasis
by augmenting
insulin secretion
glucose-dependent
pancreatic insulin
Stomach
DPP-4 Pancreas
secretion, Improve Incretin
suppressing Activity and Correct the
glucagon release, Insulin:Glucagon Ratio
slowing gastric
GI tract
Incretins
emptying, (GLP-1, GIP)
enhancing satiety, Increases and prolongs
and modulating the
so-called “gut-brain
α-cells GLP-1 effect on α-cells
axis” Intestine Glucose-dependent
* GIP does not inhibit glucagon secretion by α-cells
DPP-4: dipetidyl peptidase-4; GI: gastrointestinal; GIP:glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide
Drucker DJ et al. Nature 2006;368:1696–705. Idris I, et al. Diabetes Obes Metab 2007;9:153–65. Barnett A. Int J Clin Pract 2006;60:1454–70. Gallwitz B, et
glucagon secretion
al. Diabetes Obes Metab 2010;12:1–11.
 TECOS and EXAMINE studies of
randomised controlled trial showed
sitagliptin and alogliptin didn’t increase
risk of hospitalization for HF, respectively.

Recent large scale clinical trial ofSAVOR-

TIMI53 showed patients treated with
saxagliptin over 2 years had a 27%
increased risk of HF

Conflicting data
Study limitation

It was retrospective observational study -> using

propensity score matching to reduce bias -> the SMD
was 0.30%

This study did not analyze the association between

drug prescription and mortality because Korean Helath
insurance review and Assesment service database does
not contain mortality data for the patients
Critical appraisal
Does the Study address a clear question?

Are the results of the study valid?

What are the results?

Can I apply this valid, important evidence about

prognosis to my patient?
Does the Study address a clear question?
Patients : Diabetes
Yes
Disease/Condition : Use of DPP4-i

Outcome : Occurence of HF Hospitalization

The goal of the present study was to evaluate the risk of HF

associated with use of DPP4i in a nationwide retrospective
cohort study of diabetic patients in South Korean.
Are the results of the study valid?
• Was the defined representative sample of patients assembled at a
common (usually early) point in the course of their disease?
• Yes
Are the results of the study valid?
• Was patient follow-up sufficiently long and complete?
• Yes
Are the results of the study valid?
• Were outcome criteria either objective or applied in a
‘blind’ fashion?
• Yes
The study outcome was defined by the diagnosis of
HF based on the ICD-10-CM code of I50.xx, in either
an in-patientor outpatient department at least once.
Are the results of the study valid?
• If subgroups with different prognoses are identified, did
adjustment for important prognostic factors take place?
• Yes

Risk of study outcomes over time for the

DPP-4 inhibitor group compared with
Subgroup analysis was performed to
non-DPP-4 inhibitor group (reference)
determine whether the DPP4i group
was obtained by using survival analysis
continued to have a lower risk of HF and
(Kaplan–Meier method for univariate
other cardiovascular outcome in
analysis and Cox proportional hazards
subgroups.
regression for multivariate analysis) after
propensity score matching.
What are the results?
• How likely are the outcomes over time?
What are the results?
• How precise are the prognostic estimates?
TERIMA KASIH