Putu Moda Arsana

Malang, 2018
 Decreased incretin effect /
increase glucose absorption Acarbose
SU
Islet β cell
Glinide
GLP-1 Agonist
Increased lipolysis
DPP IV I and reduced
glucose uptake TZD
Impaired
Islet  cell insulin
secretion
SGLT-2 I
Increased Hyperglycemia
glucagon
secretion Increased glucose
reabsorption
Decrease glucose
uptake
Increased hepatic
Metformin glucose Metformin
production TZD
Neurotransmitter
Bromocriptin
dysfunction
 In Normal Person, The kidneys filter and reabsorb 180 g
of glucose per day in the nephrons by active transport

180 g glucose
Proximal Distal Collecting
filtered Glomerulus
each day tubule tubule duct
S1 S2

Glucose
filtration
SGLT1
SGLT2 10%
S3

90%

Glucose
reabsorption Loop
of
Henle Minimal
Up to ~90% of glucose ~10% of glucose glucose
is reabsorbed is reabsorbed excretion
from the S1/S2 segments from the S3 segment

Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys

Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Brown GK. J Inherit Metab Dis 2000;23:237–246.

MED/026/Jul 14 – Jul 15/ZM 4

 In Diabetics, Kidney Continued glucose reabsorption even at high
glucose levels induces sustained hyperglycaemia in diabetics 1,2

Paradoxically, SGLT2 reabsorbs glucose through an insulin-independent pathway,

even in the presence of hyperglycaemia

Filtered glucose
No excretion
3 Excretion
threshold Excreted glucose
Rate of glucose filtration /
reabsorption / excretion

Reabsorbed glucose (diabetes)

(mmol/min)

Reabsorbed glucose (normal)

Saturation
threshold
1

0
0 8.3 13.3 25 mmol/L Plasma glucose
0 149.6 239.6 450.5 mg/dL
Adapted from Chao EC, et al. Nat Rev Drug Discov 2010;9:551-559; Marsenic O. Am J Kidney Dis 2009;53:875-883; Nairs S, et al. J Clin Endocrinol Metab
2010;95:34-42.
MED/026/Jul 14 – Jul 15/ZM 5
 The Importance role of SGLT-2 inhibition in
Diabetics

Glomerulus Proximal tubule Distal tubule Collecting duct

S1

Glucose
filtration SGLT1 S3
SGLT2

Reduced glucose SGLT2 inhibitor

reabsorption
Increased
glucose
Loop of Henle excretion

Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Han S. Diabetes
2008;57:1723–1729.
MED/026/Jul 14 – Jul 15/ZM 6
RCT’s Study

RWS/E
 Fase Hasil
Fase I ✓ OK
Fase II ✓ OK
Fase III ✓ OK
Fase IV ✓ OK
 Efek Dapagliflosin pada Uji Klinik Fase
III (RCT)

What effects do SGLT2

inhibitors have on HbA1c, FPG
and PPG reduction?

MED/026/Jul 14 – Jul 15/ZM

 Consistent decreases in HbA1c from baseline
at week 24 across all dapagliflozin studies
Mono Add-on Add-on Add-on Add-on Dapa
therapy1 to Met2 to Glim3 to Pio4 to Ins5 + Met XR6
Base 7.92 8.06 8.11 8.37 8.53 9.05
line
HbA1c

-0.13
adjusted  from baseline HbA1c

-0.23
Primary endpoint for 24-week

-0.3 -0.3
-0.42

-0.84 -0.82
-0.89 -0.9
(%)

-0.97

* * * *
*
-1.44

-1.98

*p <0.001 compared with *

placebo
1Ferrannini E, et al. Diabetes Care 2010;33:2217-24. 2Bailey CJ, et al. Lancet 2010;375:2223-33. 3Strojek K, et al. Diabetes Obes Metab 2011;13:928-38.
4Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 0986-P. 5Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21-A22. Abstract
0078-OR. 6Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
MED/026/Jul 14 – Jul 15/ZM 10
 Consistent decreases in fasting plasma glucose (FPG) at
week 24 across dapagliflozin studies

Monotherapy1 Add-on to Met2 Add-on to Ins3 Add-on to Pio4

mmol/L mg/dL

0.28 3.3
FPG adjusted mean change from baseline

0.00

0.28
-4.1
-5.94 -6
0.56

0.83

1.11

1.39 -21.7
-23.4
1.67
-28.8
-30
1.94

1Ferrannini E, et al. Diabetes Care 2010;33:2217–2224; 2Bailey CJ, et al. Lancet 2010;375:2223–2233; 3Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21–A22 [Abstract
0078-OR]; 6Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract 0986-P];

MED/026/Jul 14 – Jul 15/ZM 11

 Reduction in postprandial glucose (PPG) with
dapagliflozin in patients with type 2 diabetes
Mean change in PPG levels (12 weeks) Mean change in PPG levels (24 weeks)
Time (min) Time (min)
0 30 60 90 120 150 180 0 30 60 90 120 150 180
0 0

PPG levels (mg/dL)

PPG levels (mg/dL)
Mean change in

Mean change
-20 -20
Placebo Placebo
2.5 mg/d 5 mg/d
-40 5 mg/d -40 10 mg/d
10 mg/d
-60 -60

-90 -90 Add-on to

Monotherapy (12 weeks) pioglitazone (24
(Phase 2) and 48 weeks)
Dapagliflozin mg/d Dapagliflozin mg/d
Placebo 2.5 5 10 Placebo 2.5 5 10
in 2-h PPG levels (mg/dL)

in 2-h PPG levels (mg/dL)

Adjusted mean change

0 0

Adjusted mean change

-10 -10

-20 -20

-30 -30

-40 -40
-50 -50 48
24 weeks
weeks
Add-on to glimepiride (24 and 48 weeks)
Salsali A, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June [Poster 1104-P].

MED/026/Jul 14 – Jul 15/ZM 12

 What effects do SGLT2 inhibitors
have on Beta cells function and
Insulin sensitivity?

MED/026/Jul 14 – Jul 15/ZM

 Insulin Secretion and Beta-cell Function Were
Significantly Improved With Dapagliflozin
• To examine the glucotoxicity hypothesis, dapagliflozin was used to lower the plasma glucose concentration.
The effect of this intervention on beta-cell function was examined using a euglycemic hyperinsulinemic
clamp
Insulin Secretion and Beta-cell Function
(measured As Δc-pep0–120/ΔG0–120 ÷ IR after 2 Weeks)
0.30 *
0.25

Δc-pep0–120/ΔG0–120 ÷ 1/TGD
0.05 * 0.20
Δc-pep0–120/ΔG0–120

0.04 0.15

0.03 0.10

0.02 0.05

0.01 0
Dapa Placebo Dapa Placebo Dapa Placebo Dapa Placebo
Baseline Treatment Baseline Treatment
Insulin Secretion Beta cell Function
*, P < .05 vs baseline and vs placebo

MED/026/Jul 14 – Jul 15/ZM Merovci A, et al. J Clin Endocrinol Metab 100: 1927–1932, 2015
 Beta-cell Glucose Sensitivity Significantly
Increased With Dapagliflozin

Beta-cell glucose sensitivity measured with the Mari model

750
P<0.01
Insulin Secretory Rate

Dapa
(pmol/min*mM)

500

Baseline
250

0
10 15 20 25

Plasma Glucose Concentration (mM)

Merovci A, et al. J Clin Endocrinol Metab 100: 1927–1932, 2015

MED/026/Jul 14 – Jul 15/ZM

 What effects do SGLT2
inhibitors have on body weight?

MED/026/Jul 14 – Jul 15/ZM

 Consistent reductions in body weight with
dapagliflozin
24-wk 24-wk add-on 52-wk add-on 24-wk add-on 24 wk-add-on 24-wk add-on 24-wk Dapa
Monotherapy to Met2 to Met3 to Glim4 to Ins5 to Pio6 + Met XR7
Baseline 90.2kg 88kg 85.9kg 81.1kg 93.8kg 86.3kg 81.1kg
Weight

1.64
1.44
24- and 52-week adjusted 
from baseline weight (kg)

0.02

-0.14

-0.89
-0.72
*
-1.36
-1.67

-2.19 -2.26 *
-3.16
-2.86
-3.22
*
NS * -3.33

* *
*p <0.001 vs. comparator
NS: not significant

1Ferrannini E, et al. Diabetes Care 2010;33:2217–2224; 2Bailey CJ, et al. Lancet 2010;375:2223–2233; 3Nauck MA, et al. Diabetes Care 2011;34:2015-2022;
4Strojek K, et al. Diabetes Obes Metab 2011;13:928-938 5Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21–A22 [Abstract 0078-OR]; 6Rosenstock J, et al. 71st ADA
Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract 0986-P]; 7Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.

MED/026/Jul 14 – Jul 15/ZM 17

 Dapagliflozin reduces total body weight
and fat mass at week 24
DXA: dual X-ray absorptiometry

Langkilde A.M, Study D1690C00012. Internal Presentation January, 2011.

MED/026/Jul 14 – Jul 15/ZM 18

 What effects do SGLT2
inhibitors have on blood
pressure?

MED/026/Jul 14 – Jul 15/ZM

 Blood pressure reductions consistently observed
with dapagliflozin in phase III studies
Mean changes in systolic blood pressure (mmHg)
Monotherapy Add-on to Add-on to Add-on Add-on 48 week add-on
AM only1 Met vs. SU2 Met3 to SU4 to TZD5 to insulin6

2
Week 24 or 48 mean change from baseline mmHg

-1

-2

-3

-4

-5

-6

1Ferrannini E, et al. Diabetes Care 2010;33:2217-2224; 2Nauck MA, et al. Diabetes Care 2011;34:2015-22; 3Bailey CJ, et al. Lancet 2010;375:2223-33;
4Strojek K, et al. Diabetes Obes Metab 2011;13:928-38; 5Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 0986-P];
6Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21-A22 [Abstract 0078-OR].

MED/026/Jul 14 – Jul 15/ZM 20

 What adverse events should we
look out for with SGLT2
inhibitors?

MED/026/Jul 14 – Jul 15/ZM

 Risk of urinary tract infections
% Patients

DAPA Placebo
10 mg
N=1193 N=1393

Total 4.3 3.7

n=598 n=677
Female
7.7 6.6

n=595 n=716
Male
0.8 1.0

Note: these data are based on a pre-specified pooled analysis of 12 placebo-

controlled dapagliflozin registration studies
MED/026/Jul 14 – Jul 15/ZM Forxiga PI, November 2012; FDA Committee Meeting; Dapagliflozin: Available at:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM264314.pdf
 Risk of genital infections

DAPA vs. placebo CANA vs. placebo

(2.5 mg-10 mg)* (50 mg-300 mg)

Overall incidence (%) 4.8 vs. 0.9 3.0–8.0 vs. 2.0

Incidence in women (%) 5.8–8.4 vs. 1.5 13.0–25 vs. 3.0

Note: Dapagliflozin and canagliflozin have not been studied in a head-to-head trial
* these data are based on a pre-specified pooled analysis of 12 placebo-controlled dapagliflozin
registration studies
• With both SGLT2 inhibitors, increased incidence of genital infections was dose-
independent
• Vulvovaginal mycotic infection and vaginal infections most common genital infections with
dapagliflozin
• Vulvovaginal mycotic infection and vulvovaginal candidiasis most common genital
infections with canagliflozin
• With both SGLT2 inhibitors, most infections were mild to moderate in intensity and
resolved with standard anti-fungal therapy
Forxiga PI, November 2012; Rosenstock et. al. Diabetes Care, 2012; Published online ahead of print: DOI: 10.2337/dc11-1926.
FDA Committee Meeting; Dapagliflozin: Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM264314.pdf

MED/026/Jul 14 – Jul 15/ZM

 Pertanyaan:
Apakah pada kondisi sesungguhnya Dapagliflosin tetap
memberikan efek klinis yang menguntungkan serta efek
samping yang minimal?

Uji Klinik Fase IV

(Real World Study)
Real World Evidence:

CVD-REAL
Truven MarketScan Claims & Encounters and linked Medicare

National full-population registries

National full-population registries All cause death

hHF
National full-population registries

Clinical Practice Research Datalink (CPRD) and

The Health Improvement Network (THIN)

Diabetes Patienten Verlaufsdokumentation (DPV) initiative

hHF – Hospitalisation for heart failure

Kosiborod M, et al. CIRCULATION 2017 [ePub ahead of print] doi. 10.1161/CIRCULATIONAHA.117.029190
 P-value for SGLT-2 inhibitor vs other glucose-
Heterogeneity p-value: 0.169
lowering drug: <0.001

Data are on treatment, unadjusted

Kosiborod M, et al. CIRCULATION 2017 [ePub ahead of print] doi. 10.1161/CIRCULATIONAHA.117.029190

 P-value for SGLT-2 inhibitor vs other glucose-lowering drug: <0.001 Heterogeneity P-value: 0.089

Data are on treatment, unadjusted. This data analysis did not include Germany as data for all-cause
death were not available form the DPV database.

Kosiborod M, et al. CIRCULATION 2017 [ePub ahead of print] doi. 10.1161/CIRCULATIONAHA.117.029190

* Diagnosis of AMI, unstable angina, stroke, HF, transient ischemic attack, coronary revascularization, or occlusive
PAD prior to index drug initiation.

Oral (377-OR) presentation at the 77th scientific sessions of the ADA; June 9 – 13th, 2017; San Diego, USA.
 Norhammar A, Bodegard J, Nystrom, T, Nathanson D, Gulseth HL, Thuresson M, Fenici P,
Eriksson JW and Birkeland K

Poster (P3008) presented at European Society of Cardiology - Heart Failure meeting; April
29 – May 2, 2017; Paris, France.
 Dapagliflozin DPP-4 inhibitor Weighted average estimates
(n=8,582) (n=25,746) (n=34,328)

No of events Rate/100 P-Y No of events Rate/100 P-Y Hazard ratio 95% CI P-value

Hospitalization for heart

77 0.95 375 1.47 0.63 0.50–0.81 <0.001
failure

MACE 83 1.83 372 2.57 0.71 0.56–0.90 0.004

Non-fatal myocardial
40 0.88 170 1.17 0.75 0.53–1.06 0.102
infarction

Non-fatal stroke 37 0.81 147 1.01 0.80 0.56–1.15 0.222

CV mortality 18 0.39 77 0.53 0.74 0.44–1.23 0.241

All-cause death 106 1.04 468 1.44 0.73 0.59–0.91 0.004

Poster (P3008) presented at European Society of Cardiology - Heart Failure meeting; April 29 – May 2, 2017; Paris, France.
 Australia – National Diabetes Services Scheme (NDSS)*

Canada – Manitoba Population Health Research Data Repository

Israel – The Maccabi Health Management Organization

Japan – Medical Data Vision

Singapore – SingHealth Diabetes Registry

South Korea – National Health Insurance Service (NHIS)

*Included in the ACD analysis only

ITT, unadjusted analysis P-value for SGLT2i vs. oGLD: p<0.001

Heterogeneity p-value: p<0.001

ITT, unadjusted analysis P-value for SGLT2i vs. oGLD: p=0.001
Heterogeneity p-value: p<0.001
ITT, unadjusted analysis P-value for SGLT2i vs. oGLD: p<0.001
Heterogeneity p-value: p<0.001
ITT, unadjusted analysis P-value for SGLT2i vs. oGLD: p<0.001
Heterogeneity p-value: p=0.787
ITT, unadjusted analysis
P-value for SGLT2i vs. oGLD: p<0.001
Heterogeneity p-value: p=0.029
ITT, adjusted analysis
 Dapagliflozin: RCT Vs RWE
 Dapagliflozin delivers comparable reductions in HbA1c, weight and blood pressure* in real-world clinical practice to
that seen in randomised clinical trials. Real world data below is from observational studies obtained from patients’
electronic records.

Clinical trial data†‡1,2 Real-world data§¶**3–5

As add-on to various agents including metformin over 6–12
As add-on to metformin at 24 weeks, dapagliflozin months, dapagliflozin was associated with a reduction in
delivers: HbA1c, weight and SBP:

HbA1c HbA1c
Add-on to MET:
–0.84%1 –0.80 to –1.16%3–5

Weight Weight
Add-on to MET:
–2.9 kg1 –2.5 to –4.6 kg3,5

SBP SBP
Add-on to MET:
–5.1 mmHg1 –2.3 mmHg3

*Dapagliflozin is not indicated for the management of weight loss or blood pressure, and any changes were secondary endpoints in
clinical trials.
Study details are available in slide notes. MET, metformin; SBP, systolic blood pressure.
1. Bailey CJ, et al. Lancet 2010;375:2223–33; 2. Wilding JPH, et al. Ann Intern Med 2012;156:405–15; 3. Scheerer M, et al. Diabetologie und Stoffwechsel 2015;10:98; 4. Scheerer M, et al.
Diabetologie und Stoffwechsel 2015;10:99; 5. Wilding JPH, et al. Poster presented at the 51st European Association for the Study of Diabetes, Stockholm, Sweden. 14–18 September 2015;
Abstract A-15-209.

MED/026/Jul 14 – Jul 15/ZM

 Thank You

MED/026/Jul 14 – Jul 15/ZM 41