A NEW APPROACH IN THE

PREVENTION OF
CARDIOVASCULAR DISEASE IN
TYPE-2 DIABETES PATIENTS
HARSINEN SANUSI
DIVISI ENDOKRINOLOGI DAN METABOLIK DEPARTEMEN ILMU
PENYAKIT DALAM FKUH RS DR WAHIDIN SUDIROHUSODO MAKASSAR

PKB IX Minggu 29 September 2019 jam 10.45-11.30

ThePathogenesis of type 2 diabetes:
 OMINOUS OCTET 2008

DeFronzo RA. Diabetes. 2009;58:773-795.

 TREATMENT OF TYPE 2
DIABETES MELLITUS
• ORAL ANTI DIABETICS (OAD)
• Sulfonylureas
• Metformin
• Alpha Glucosidase inhibitors
• Thiozilidindione

• DPP4 inhibitors
• SGLT-2 inhibitors
• PARENTRAL ANTIDIABETICS
• Insulin
• Glucagon like peptide (GLP)-1
SGLT2 INHIBITORS (GLIFLOZINS)

• DAPAGLIFLOZIN FORXIGA ®
• CANAGLIFLOZIN 2017 FDA WARNING
• EMPAGLIFLOZIN
• IPRAGLIFLOZIN
• TOFOGLIFLOZIN
• REMOGLIFLOZIN
• SERGIGLIFLOZIN
PERSPECTIVES ON SGLT2 INHIBITION
•Potential Advantages
• HbA1c Reduction
• Insulin Independence
•Weight loss (75g urine glucose = 300kcal/day) 2- to 3-kg weight loss
•Low risk of hypoglycemia
•SBP reductions
•Complement action of other anti diabetic agent
•Can be used regardless duration of Diabetes
SYSTOLIC BLOOD PRESSURE
• Significant reduction of 2 to 3 mm Hg in systolic blood
pressure :
- Fluid loss
- Reduced renin angiotensin activity (RAA) system as a
result of tubular glomerular feedback
- Improved vascular function
- Alterations in hormonal signalling
 Algoritme Pengobatan DMT2 ASVD, HF
9 atau CKD
2 01
S D PILIHAN PERTAMA METFORMIN +PPH +
A1C TINGGI

E A
A- ASVD HF & CKD

AD PREDOMINATE PREDOMINATE

SGLT-2-I GLP-1 RA SGLT2-I GLP-1 RA

A1c diatas target
KOMBINASI SGLT-2 + GLP-1RA A1c diatas target

DPP-4 I, BASAL DPP-4 I, BASAL INSULIN, SU

INSULIN, TZD, SU HINDARI TZD
SGLT2I FIT IN THE TREATMENT ALGORITHM
• Monotherapy
• Add on SU, MET, PIO
• Add on to insulin in T2DM
• Double or triple Combo therapy
• Add on IGT /IFG
• A1C >10 %
RECENT META-ANALYSIS DATA SUGGEST NET
PROTECTION AGAINST CARDIOVASCULAR EVENTS
WITH SGLT2 INHIBITORS (WU et al)
SGLT2 Control Relative SGLT2 Control Relative
inhibitor (n/N) risk inhibitor (n/N) risk
(n/N) (95% CI) (n/N) (95% CI)

MACE
Canagliflozin 104/6396 2/3403
62/3403 1.02 (0.74–1.42) Non-fatal stroke
Canagliflozin 47/6396 16/3327 1.53 (0.87–2.69)
Dapagliflozin 73/5936 62/3403 0.67 (0.48–0.94)
Empagliflozin 50/4687 60/2333 1.24 (0.93–1.67)
Empagliflozin 490/4687 282/2333 0.86 (0.75–0.99)
(I2=0%) 1.30 (1.00–1.68)
Ipragliflozin 7/628 10/368 0.41 (0.16–1.07) Unstable angina
(12 =43%) 0.84 (0.75–0.95) Canagliflozin 26/6396 18/3327 0.75 (0.41–1.37)

MACE plus Empagliflozin 133/4687 66/2333 1.00 (0.75–1.34)

(I2=0%) 0.95 (0.73–1.23)
Canagliflozin 130/6395 71/3327 0.95 (0.72–1.27)
Heart failure*
Dapagliflozin 97/5936 81/3403 0.69 (0.51–0.95)
Empagliflozin 126/4687 95/2333 0.65 (0.50–0.85)
Empagliflozin 621/7082 359/3547 0.87 (0.77–0.98) (I2=0%) 0.65 (0.50–0.85)
(12 =24%) 0.85 (0.77–0.95) All-cause death
Cardiovascular death Canagliflozin 49/6177 37/3262 0.70 (0.46–1.07)
Dapagliflozin 37/5936 24/3403 0.88 (0.53–1.48)
Canagliflozin 21/6396 16/3327 0.68 (0.36–1.31)
Empagliflozin 278/7082 201/3647 0.69 (0.58–0.82)
Empagliflozin 172/4687 137/2333 0.62 (0.50–0.78)
(I2=0%) 0.71 (0.61–0.83)
(12 =0%) 0.63 (0.51–0.77)
Non-fatal MI
Canagliflozn 45/6396 27/3327 0.87 (0.54–1.39)
Empagliflozin 213/4687 121/2333 0.88 (070–1.09)
(12 =0%) 0.88 (0.72–1.07)

0.5 1.0 1.5 2.0 2.5 0.5 1.0 1.5 2.0 2.5
Relative risk Relative risk
Favours SGLT2 inhibitor Favours control Favours SGLT2 inhibitor Favours control

CI, confidence interval; MACE, major adverse cardiovascular event; MI, myocardial infarction; SGLT2, sodium–glucose co-transporter 2
Wu JH, et al. Lancet Diabetes Endocrinol 2016;4:411–9
RECENT META ANALYSIS WITH DAPAGLIFLOZIN
(Sonesson et al)
21 Phase IIb/III trials, n=9339 (DAPA n=5936; Control n=3403)

DAPA
Meta Analysis* Favors DAPA
HR vs Control
DAPA  ●  Control (95% CI)
n/N Event rate/ Event rate/
DAPA 100 p-y Control 100 p-y
0.79
MACE plus UA 95/5699 1.46 81/3240 2.15
(0.58, 1.1)
0.77
MACE 72/5418 1.15 62/3101 1.69
(0.54, 1.1)
0.70
CV death 20/3825 0.37 18/2200 0.59
(0.36, 1.36)
0.57
MI 30/5244 0.48 33/3014 0.91
(0.34, 0.95)
1.00
Stroke 25/4227 0.45 18/2412 0.57
(0.54, 1.86)
Hospitalization 0.36
10/2576 0.15 16/1780 0.41
for heart failure (0.16, 0.84)
0.07 0.70 2.0 7.00

*All Phase 2b and 3 Pool, ST + LT -30MU; Stratified by study; Only trials with at least one positively adjudicated event included in analysis; Cox Proportional
Hazards model.
n= number of patients with an event; N= number of patients in treatment group; CV=cardiovascular; DAPA=dapagliflozin; HR=hazard ratio; CI=confidence interval;
MACE=Major Adverse Cardiovascular Event; UA=unstable angina; MI=myocardial infarction.

Sonesson C et al. Cardiovasc Diabetol. 2016;15:37.

 TREATING PATIENTS WITH T2D MEANS CONTROLLING HBA 1C AND PREVENTING MICRO- AND MACRO-VASCULAR MORBID
EVENTS

Microvascular
disease >50%
(kidney, nerves,
eyes) develop microvascular disease
within 10 years1
Patients
with T2D 54%
MI increased risk of MI (median 5.5 years)
are at compared to those without T2D2
increased
risk of: 72%
Stroke increased risk of stroke (median 5.5 years)
compared to those without T2D2

33%
Heart failure increased risk of hospitalization for heart failure
(at 4 years) compared to those without T2D3
CV, cardiovascular; HbA1c, glycated haemoglobin; MI, myocardial infarction; T2D, type 2 diabetes.
1. Litwak L, et al. Diabetol Metab Syndr. 2013;5:57. 2. Shah AD, et al. Lancet Diabetes Endocrinol. 2015;3:105-113. 3. Cavender MA, et al. Circulation. 2015;132:923-931.
 CARDIOVASCULAR OUTCOME TRIAL
(CVOT)
• Empagliflozin was shown to reduce the primary composite endpoint of
CV death, myocardial infarction (MI) or stroke, as well as CV mortality,
total mortality, hospitalization for heart failure (HF) and several renal
outcomes (EMPA-REG, EMPRISE)
• Canagliflozin Cardiovascular Assessment Study(CANVAS) programme
also demonstrated a reduction in the composite primary CV endpoint with
canagliflozin

•Dapaglflozin
 DECLARE-TIMI 58 TRIAL
(DAPAGLIFLOZIN EFFECT ON CARDIOVASCULAR
EVENTS)

A randomized trial designed to establish the

CV safety and potential CV benefit
 DECLARE-TIMI 58 is the largest, broadest and longest SGLT-2i
CVOT looking at clinically relevant CV & renal endpoints in T2D
Composite endpoint of
T2D, ≥40 years plus:

Primary Endpoints
Placebo CV death, MI, stroke (MACE)
 Multiple (≥2) risk factors* OR

Double-blind
 Established CV disease

1:1
N=17,160
Composite endpoint of
Largest number of T2D patients Hospitalization for heart failure or
with a broad range of CV risk Dapagliflozin (10 mg per day)
CV death

 Add on to background CV and GLD per treating physician Secondary Endpoints

 Follow-up visits every 6 months; phone contact every 3 months • Renal composite endpoint
 Event-driven duration, with median follow-up of 4.2 years#
• All-cause mortality

DECLARE provides a comprehensive assessment of the impact of dapagliflozin on common and clinically
important diabetes-related CV events
*≥55-year-old males and ≥60-year-old females plus at least one of the following: dyslipidemia, hypertension, or current smoking.
#
median follow-up times: CANVAS – 2.4yrs; EMPA-REG OUTCOME – 3.1yrs

Forxiga is not indicated for CV and Renal outcomes.

CV, cardiovascular; CVOT, CV outcomes trial; GLD, glucose-lowering drug; MACE, major adverse cardiac event; MI, myocardial infarction; T2D, type 2 diabetes
1. Raz I, et al. Diabetes Obes Metab 2018;20:1102–1110; 2. Wiviott SD, et al. Am Heart J 2018;200:83–89; 3. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018; 4. Zinman B, et al.
N Engl J Med 2015;373:2117–2128; 5. Neal B, et al. N Engl J Med 2017;377:644–657
 DECLARE has the largest proportion and numbers of T2D patients
at low CV risk among the SGLT-2i CV outcomes studies to date
In the T2D patient population, most patients do not have established CV disease 1

EMPA-REG OUTCOME2
(N=7,020)
>99% eCVD
Placebo event rate
N=6,964 43.9/1000 pt-yrs

CANVAS3
(N=10,142)
~65.6% eCVD ~34.4% MRF Placebo event rate
N=6,656 N=3,486 31.5/1000 pt-yrs

DECLARE4,5
(N=17,160)
~40.6% eCVD ~59.4% MRF Placebo event rate
N=6,974 N=10,186 24.2/1000 pt-yrs

Forxiga is not indicated for CV and Renal outcomes.

CV, cardiovascular; eCVD, established CV disease; SGLT-2i, sodium glucose co-transporter 2 inhibitor; T2D, type 2 diabetes
1. Einarson TR, et al. Cardiovasc Diabetol 2018;17:83; 2. Zinman B, et al. N Engl J Med 2015;373:2117–2128; 3. Neal B, et al. N Engl J Med 2017;377:644–657;
4. Raz I, et al. Diabetes Obes Metab 2018;20:1102–1110 5. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018
 DECLARE showed that dapagliflozin is CV safe for this broad
T2D population earlier in the CV risk continuum
The DECLARE trial includes more T2D patients earlier on the CV risk continuum

Patient risk factor criteria in each SGLT2i CV outcomes trial

Pt with T2D Pt with T2D Pt with T2D

+ eCVD (41%) + eCVD (66%) + eCVD (99%)
Or Or
≥2 CV risk ≥3 CV risk
factors (59%) factors (34%)

Forxiga is not indicated for CV and Renal outcomes.

CV, cardiovascular; eCVD, established CV disease; SGLT-2i, sodium glucose co-transporter 2 inhibitor; T2D, type 2 diabetes
1. Wiviott SD, et al. Am Heart J 2018;200:83–89; 2. Neal B, et al. N Engl J Med 2017;377:644–657; 3. Zinman B, et al. N Engl J Med 2015;373:2117–2128
Cardiovascular Risk Factors
HbA1c Weight
LSM Difference 0.42% (95% CI 0.40- LSM Difference 1.8 kg (95% CI 1.7-2.0)
0.45)

All P-values (except BL) <0.001 All P-values (except BL) <0.001
 Cardiovascular Risk Factors
SBP
LSM Difference 2.7 mmHg (95% CI 2.4-3.0)
DBP
LSM Difference 0.7mmHg (95% CI 0.6-0.9)

All P-values (except BL) <0.001 All P-values (except BL) <0.001
 What does DECLARE tell us about dapagliflozin’s CV benefits in a
broad, predominantly lower CV risk population of T2D patients?

Microvascular
disease

MI
T2D

Stroke
?
Heart failure

CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes.

 DECLARE defines the changing landscape of T2D
management with Dapagliflozin
• Using dapagliflozin early in T2D will not only control
the HbA1c but also prevent progression CV events and
renal disease
• Preventing hHF or renal disease progression with
dapagliflozin before their disease develops presents
to reduce morbidity and mortality among T2D patients.

Forxiga is not indicated for CV and Renal outcomes.

CV, cardiovascular; CVOT, CV outcome trial; GLP-1A, glucagon-like peptide-1 agonist; HbA1c, glycated haemoglobin; hHF, hospitalized heart failure; SGLT-2, sodium-glucose co-transporter 2; SU,
sulphonylurea; T2D, type 2 diabetes
1. Zinman B, et al. N Engl J Med 2015;373:2117–2128; 2. Neal B, et al. N Engl J Med 2017;377:644–657 3. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018
Primary Endpoint: Composite of hHF or CV Death

HR 95% CI p-value
6 Placebo (496 Events)
0.83 (0.73, 0.95) 0.005
Cumulative Incidence (%)
DAPA 10 mg (417 Events)

Risk Reduction
2 17%

0 180 360 540 720 900 1080 1260 1440

Days
N at risk
DAPA 10 mg 8582 8517 8415 8322 8224 8110 7970 7497 5445
Placebo 8578 8485 8387 8259 8127 8003 7880 7367 5362

Forxiga is not indicated for CV and Renal outcomes.

N at risk is the number of patients at risk at the beginning of the period.
CV, cardiovascular; DAPA, dapagliflozin; hHF, hospitalization for heart failure.
Wiviott SD et al. Online ahead of print. New Engl J Med. 2018.
 Primary Endpoint:
Composite of hHF or CV death and the Individual Components
Number of events

DAPA 10 mg Placebo
(N=8582) (N=8578) HR (95%CI) p-value

Composite of hHF/CV death 417 496 0.83 (0.73, 0.95) 0.005

Hospitalization for HF 212 286 0.73 (0.61, 0.88)

CV death 245 249 0.98 (0.82, 1.17)

0.6 0.7 0.8 0.9 1.0 1.1 1.2

Forxiga is not indicated for CV and Renal outcomes.

Favors
DAPA
Favors
Placebo
RR 27%
Two-sided p-value is shown for the primary efficacy composite outcome of CV death or hHF.27%
CV, cardiovascular; DAPA, dapagliflozin; HF, heart failure; hHF, hospitalization for heart failure.
Wiviott SD et al. Online ahead of print. New Engl J Med. 2018.
 While SGLT-2i’s reduce MACE in T2D patients with eCVD only,
SGLT-2i’s prevent hHF in patients earlier in the CV risk continuum
MACE Hazard ratio (95% CI) hHF Hazard ratio (95% CI)
Established CV Disease Established CV Disease
0.90 (0.79, 1.02) 0.78 (0.63, 0.97)
DECLARE DECLARE

0.82 (0.71, 0.94) 0.68 (0.51, 0.90)

CANVAS CANVAS

0.86 (0.74, 0.99) 0.65 (0.50, 0.85)

EMPA-REG EMPA-REG

Multiple Risk Factors Multiple Risk Factors

0.64 (0.46, 0.89)
1.01 (0.86, 1.20)
DECLARE DECLARE

0.64 (0.35, 1.15)

CANVAS 0.98 (0.74, 1.30) CANVAS

Favors Favors Favors Favors

SGLT2i Placebo SGLT2i Placebo
Forxiga is not indicated for CV and Renal outcomes.

CV, cardiovascular; eCVD, established CV disease; hHF, hospitalized heart failure; MACE, major cardiovascular disease; SGLT-2i, SGLT co-transporter 2 inhibitor; T2D, type 2 diabetes
1. Zinman B, et al. N Engl J Med 2015;373:2117–2128; 2. Neal B, et al. N Engl J Med 2017;377:644–657 3. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018
 However, dapagliflozin prevents hHF consistently across a broad
range of T2D patients regardless of history of eCVD or HF
hHF: history of eCVD hHF: history of HF

Hazard ratio (95% CI) Hazard ratio (95% CI)

Established CV Disease (eCVD) Prior HF*

hHF 0.78 (0.63, 0.97) hHF 0.73 (0.55, 0.96)

Multiple Risk Factors (No eCVD) No Prior HF*

hHF 0.64 (0.46, 0.88) hHF 0.73 (0.58, 0.92)

0 0.5 1 1.5 0 0.5 1 1.5

Favors Favors Favors Favors

Dapagliflozin Placebo Dapagliflozin Placebo
Forxiga is not indicated for CV and Renal outcomes.
*10% of patients in DECLARE had prior HF
CV, cardiovascular; eCVD, established CV disease; HF, heart failure; hHF, hospitalized heart failure; SGLT-2i, SGLT co-transporter 2 inhibitor; T2D, type 2 diabetes
1. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018
 Does dapagliflozin do anything more for microvascular disease
besides HbA1c control?

Microvascular HbA1c control

disease Dapagliflozin demonstrated
 A1c lowering data
 Durability of A1c reductions

MI

more?
T2D
Stroke

Heart failure

HbA1c or A1c, glycated hemoglobin; MI, myocardial infarction; T2D, type 2 diabetes.
 Learning from all SGLT2 CVOTs….
These data with
dapagliflozin from
DECLARE- TIMI 58
extend the benefit of
SGLT2i to a broader
population of patients
for primary and
secondary prevention

Forxiga is not indicated for CV and Renal outcomes.

Pump, Pipes and Filter: do SGLT2 inhibitors have it all covered?

Verma S, Jüni P, Mazer CD, The Lancet 2018, in press
 THE DECLARE – TIMI 58 TRIAL
• Conclusion: Dapagliflozin is safe
• Dapagliflozin does not increase and may reduce the
occurrence of major CV events
• Dapagliflozin is the largest study to address this
question with an SGLT-2 inhibitor in both patients with
T2DM and both established CV disease and those
without CV disease, but with multiple risk factors.
KEY SAFETY EVENTS
Dapagliflozin Placebo (%) Between Group Comparison
(%)
Treatment emergent SAE 34.1 36.2 P<0.001
Treatment emergent AE leading to drug D/C 8.1 6.9 P=0.01
Major Hypoglycemia 0.7 1.0 P=0.02
Diabetic Ketoacidosis* (DKA) 0.3 0.1 P=0.02
Amputation 1.4 1.3 NS
Fracture 5.3 5.1 NS
Symptoms of volume depletion 2.5 2.4 NS
Genital infection (SAE, DAE) 0.9 0.1 P<0.001
Urinary tract infection (SAE, DAE) 1.5 1.6 NS
Fournier’s Gangrene 0.0 0.1 NS
Malignancy event* 5.6 5.7 NS
Cancer of Bladder* 0.3 0.5 P=0.02
Hepatic event* 1.0 1.0 NS

*CEC Adjudicated
 SUMMARY
DAPAGLIFLOZIN (FORXIGA)
• DAPA of significantly reduce HbA1c, total body weight, BP
• DAPA well tolerated, if monotherapy or ad on with
MET,SU,PIO or insulin combination
• DAPA was safe and generally well-tolerated
• DAPA reduced CVD/HHF
• MACE  Reduction in CVD/HHF was consistent
TERIMAKASIH ATAS
PERHATIANNYA
EFFECT ON CVD/HHF
IN KEY SUBGROUPS

CVD/HH MACE
F

CONFIDENTIAL