1

CHANGING PARADIGMS : THE ROLES OF SGLT2-INHIBITOR

(Focus on Dapagliflozin, Provided with Clinical Trial Results)

2017
04-1112-B
Prof. Dr. dr. Askandar Tjokroprawiro Sp.PD, K-EMD, FINASIM
SURABAYA DIABETES AND NUTRITION CENTRE - Dr. SOETOMO TEACHING HOSPITAL
FACULTY OF MEDICINE AIRLANGGA UNIVERSITY, SURABAYA

SYMPOSIUM LUNCH-2A

THE 63rd QUADRUPLE JOINT SYMPOSIUM

Surabaya Metabolic Syndrome Update – 13 (SUMETSU-13)
Metabolic Cardiovascular Disease Surabaya Update – 13 (MECARSU-13)
Surabaya Obesity Update – 10 (SOBU-10)
Surabaya Diabetes Update – 27 (SDU-27)
Surabaya (JW Marriott Hotel), 18-19 February 2017
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 MAP OF ORAL ANTI DIABETES (OAD) IN DAILY PRACTICE 2

(Summarized : Tjokroprawiro 1996-2017)

1 SUs : Gliquidone, Glipizide, Gliclazide, Glibenclamide, Glimepiride
I INSULIN SECRETAGOGUES 2 NON-SUs (Metaglinides : Nateglinide, Repaglinide) 3 DPP-4 Inhibitors
4 GLIMIN (new tetrahydrotriazine-containing class) : IMEGLIMIN (1500 mg twice/day) : Insulin,  Muscle glucose uptake,  HGP
5 GPR40 Agonist (TAK-875) : 50-200 mg once/day. The long-chain FAs amplify glucose-stimulated insulin secretion,  GLP-1
6 GPR119 Agonist 7 GPR120 Agonist 8 GPR142 Agonist : Insulinotropic and -cell Proliferation (ADA 2015)

II INSULIN SENSITIZERS (Rosi-*), Pio-, Neto-, Dar-glitazone)

1 THIAZOLIDINEDIONES (TZDs) = Glitazone Class : Pioglitazone
2 NON-TZDs : *) Withdrawn
a Glitazar Class (Mura-*), Raga-, Ima-, Tesa-, Saroglitazar**) : MRITS **) A Novel dual PPAR / agonist approved in India for Tx Diabetic Hyper TG
b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain)
3 BIGUANIDE : METFORMIN, METFORMIN XR (Glucophage XR), 3-Guanidinopropionic-Acid 4 DLBS-3233 (Inlacin®)
5 Dopamine-2 Agonists (Bromocriptine) : Activates Dopaminergic Receptors ( Insulin Sensitivity & No Hypoglycemia, ?CVD Events)
6 DPP-4 Inhibitors 7 Methazolamide (ALT and Weight Loss) 8 Berberine (Chinese Herb) ***) : Insulin Sensitizer and Incretin Enhancer

III INTESTINAL ENZYME INHIBITORS 1 -Glucosidase Inhibitor (AGI): Acarbose

2 -Amylase Inhibitor (AMI): Tendamistase
IV INCRETIN-ENHANCERS DPP-4 INHIBITORS Sita-, Vilda-, Saxa-, Lina- , Alo-, Dena-, Duto-, Melo-,
(Gliptin – Class) (13) Teneli-, Omari-, Gosogliptin, SYR-322, TA-666
* Glyxambi® (empaglifozin + linagliptin)
V FIXED DOSE COMBINATION (FDC) TYPES Xigduo XR (dapa + met XR) Invokamet® (cana + met)
Glucophage XR, Glucovance®, Amaryl-M®, Janumet® , Galvusmet®, Kombiglyze®XR, Trajenta®Duo , Actosmet®
VI OTHER SPECIFIC (OS) TYPES 1 Sodium GLucose co Transporter-2 (SGLT2)-Inhibitors (17) Gliflozin Class:
Dapagliflozin (Farxiga® 10 mg, FDA-2014), Canagliflozin (Invokana® 100mg, 300mg, FDA-filed), Empaglifozin (Jardiance® 10mg, 25mg, Phase-III),
Ipragliflozin: ASP1941, (Ph-III), Tofogliflozin : CSG412 (Ph-III), Luseogliflozin TS-071 (Ph-II), Ertugliflozin: PF-04971729 (Ph-II), Sergliflozin (?),
Remogliflozin (?), BI 44847 (Ph-II), LX-4211 (Ph-II), ISIS 388626 (Ph-I), YM-543, BI 10773, KGT-1681, AVE-2268, SAR7266 2 Glucokinase Activator (GKA):
MTBL1, MK-0941. 3 Oxphos-Blocker 4 FBPase – Inhibitor 5 INCB13739 (11HSD1–inhibitor) 6 Berberine ***) : Rhizomacoptidis
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 THE KIDNEYS FILTER AND REABSORB 180 g OF GLUCOSE 3

PER DAY IN THE NEPHRONS BY ACTIVE TRANSPORT

(Brown 2000, Wright 2001, Lee et al 2007, Provided 2015-2017)

180 g GLUCOSE
FILTERED GLOMERULUS PROXIMAL TUBULE DISTAL TUBULE COLLECTING DUCT
EACH DAY
S1 S2
180 g RENAL GLUCOSE
FILTRATION SGLT1
SGLT2 S3
90%

180 g RENAL GLUCOSE

RGR
REABSORPTION
Loop
of Minimal
Henle Glucose
UP TO ~90% OF GLUCOSE ~10% OF GLUCOSE
IS REABSORBED IS REABSORBED Excretion
FROM THE S1/S2 SEGMENTS FROM THE S3 SEGMENT
UGE
RGR : Renal Glucose Reabsorption UGE : Urinary Glucose Excretion
POORLY CONTROLLED T2DM : RGR FORXIGA :  RGR ,  UGE ,  BLOOD GLUCOSE
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 4

FORXIGA -FPG Showed Significant Efficacy from the First Week of Treatment
(Bailey et al 2010)

FPG 1 Week
0.2
1.26 mg/dL Metformin + Metformin +
FORXIGA 5 FORXIGA 10
0
Metformin +
Placebo
-0.2

-0.4

-0.6

-0.8 -12.1 mg/dL

p<0.0001
-1 -16.6 mg/dL
p<0.0001
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 FORXIFA-HbA1c: REDUCTION MORE THAN 1.5% 5
(Katz et al 2014)

FORXIGA Add on to Add on to Add on to

Placebo Metformin SU Pio
0.0
-0.2
Adjusted mean change from baseline

-0.4
-0.6 -0.5 -0.5 -0.5
HbA1c at 24 weeks (%)

-0.8
-1.0
-1.2
-1.4 -1.3
-1.6 -1.5 -1.57
-1.8
-2.0
-2.2 HbA1c
-2.4
-2.6 (24 weeks)

Baseline HbA1c 9.4% 9.7% 9.4% 9.3% 9.7% 9.6%

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 FORXIFA-HbA1c: ADDITIONAL BENEFITS WEIGHT LOSS >3 kg : at 24-208 WEEKS 6
(Bailey et al 2010)

24-wk add-on 24-wk add-on 48-wk add-on 208-wk add-on

to Met to Glim to Pio to Met
Adjusted  from baseline weight (kg)

2.99

0.73

-0.72 -0.69
-0.9


-2.26

-2.9  p <0.001 vs. comparator 
-3.65
Forxiga 10 Placebo Forxiga 10 Placebo Forxiga 10 Placebo Forxiga 10 Placebo
Baseline
86.3kg 87.7kg 80.6kg 80.9kg 80.6kg 80.9kg 80.6kg 80.9kg
Weight

FORXIGA Consistent reductions in Body Weight in patients as add on therapy at 24-208 weeks
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 7

FORXIGA -FAT MASS: DEMONSTRATED A SIGNIFICANT REDUCTION IN FAT MASS

RATHER THAN LEAN TISSUE OR FLUID LOSS SUSTAINED UP TO 102 WEEKS
(Bolinder et al 2012)

Placebo + Forxiga 10 mg + Placebo + Forxiga 10 mg +

Metformin Metformin Metformin Metformin
(n=86) (n=83) (n=71) (n=66)
0.0
-0.65
Change in body composition (kg)

-0.5 -1.46
-0.40 -2.16 -2.80
-1.0
-0.90
-1.5
-1.00
-2.0
-2.5 P < 0.0001 P < 0.0001 -1.30
95% Cl – 2.84 to -1.31 95% Cl – 2.51 to -0.96
-3.0
-3.5
Fat Mass
-4.0
Lean Tissue Mass
-4.5
-5.0 24 Weeks 102 Weeks

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 FORXIGA IS NOT INDICATED FOR THE MANAGEMENT OF OBESITY 8
WEIGHT CHANGE WAS A SECONDARY ENDPOINT IN CLINICAL TRIALS
(Bolinder et al 2012, 2014)

MR Substudy: VAT and SAT at Week 24

VAT Volume (cm3) SAT Volume (cm3)
Placebo Forxiga 10 mg Placebo Forxiga 10 mg
+ Metformin + Metformin + Metformin + Metformin
0

-50
Mean change from baseline (cm3)

-39.2
-100
-121.4
-150 VAT SAT
-200
P = 0.0084 P = 0.0084
-250

-300
-297.5 -306.4
-350
VAT : Visceral Adipose Tissue SAT : Subcutaneous Adipose Tissue
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 IN A PRESPECIFIED POOLED ANALYSIS OF 13 PLACEBO-CONTROLLED STUDIES, 9
FORXIGA 10 mg REDUCED SBP AND DBP VERSUS PLACEBO AT WEEK 24.
Similiar reduction were observed up to 104 weeks
(Forxiga Indonesia 2015)

SYSTOLIC BLOOD PRESSURE : SBP DIASTOLIC BLOOD PRESSURE : DBP

FORXIGA 10 mg Control Groups FORXIGA 10 mg Control Groups

0.0
-0.5
-0.5 mmHg -0.5 mmHg
Blood Pressure (mmHg)

-1.0 (n=2,295) DBP (n=2,295)

Mean change in

-1.5
SBP
-2.0
-2.5 -1.8 mmHg
(n=2,360)
-3.0
-3.5
-4.0 -3.7 mmHg
-4.5 (n=2,360)

-5.0

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HbA1c-Over 4 Years : FORXIGA AS ADD-ON TO METFORMIN VERSUS SU 10
(Comparable HbA1c Reductions over 4 Years)
(Del Prato et al 2015)

Glipizide + Metformin
+0.20%
0.4 (Mean Baseline HbA1c 7.74%)
Adjusted mean Change from

(95% Cl, 0.05

to 0.36)
0.2
Baseline HbA1c (%)

0.30%
0.0 difference

-0.2 -0.10%
(95% Cl, -0.25
to 0.05)
-0.4 FORXIGA 10 mg + Metformin
(Mean Baseline HbA1c 7.69%)
-0.6

-0.8
Rescue Therapy NOT Available Rescue Therapy Available
-1.0
0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208
Study Week

At 52 Week Primary Endpoint FORXIGA was non-inferior to glipizide:

Both resulted in HbA1c reductions of -0.52%

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 RENAL-FUNCTION: IN FORXIGA-TREATED PATIENTS, RENAL 11

FUNCTION REMAINED STABLE OVER TIME UP TO WEEK-208

(Del Prato et al 2015)

DAPA + MET GLIP + MET

N N 406 408
Mean Baseline eGFR 89.6 90.5
140
eGFR mL/min/1.73m2

120

100

80

60

40

20

0
BL 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 206
Sample Size (including data after rescue), n Week
DAPA + MET 406 383 359 366 355 340 332 319 314 268 242 234 202 190 185 180 173 163 163 158
GUP + MET 408 377 353 360 355 344 331 310 303 248 224 209 187 180 172 167 154 150 148 140
p value not obtain from citation source

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 12
FORXIGA-CV EFFECTS : META-ANALYSIS DATA: THE RESULTS
SUGGEST THE POTENTIAL FOR A BENEFICIAL CV EFFECTS
(Bailey et al 2010)

Kaplan-Meier Estimate for Primary Endopoint (MACE + UA),

all Phase IIb and III pool
6 a MACE+UA Control
Proportion of Patients (%)

4
DAPA
3
FORXIGA vs Control
2 HR=0.787 (95% Cl, 0.579 to 1.070)
Event Rates: 1.46% versus 2.15%
1 per 100 Patients Year

0
0 100 200 300 400 500 600 700 800 900 1000 11001200 1300 14001500
Days
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 DAPA vs SAXA : Efficacy Outcomes 13
(Adjusted Change from Baseline at 24 Weeks)
(Rosenstock et al 2016)
Both Dapagliflozin and Saxagliptin demonstrated efficacy at 24 Weeks; however, dapagliflozin significantly
reduced HbA1c (Figure A on this slide), FPG, and 2h-PPG (Figures C and D on next slide) to a greater extent
than saxagliptin
A B
BL, % (SD) 9.03 (1.05) 8.87 (1.17) BL, kg (SD) 87.98 (18.69) 86.25 (18.61)
n 143 151 n 145 152
SAXA+MET DAPA+MET SAXA+MET DAPA+MET
0.0 1.0 0.0

from baseline in body weight (kg)

Adjusted mean (95% Cl) change

Adjusted mean (95% Cl) change

0.5
from baseline in HbA1c (%)

0.0
SAXA
-0.5 -0.5
DAPA SAXA
-1.0 DAPA
-1.5
-1.0 -2.0
−0.88
-2.5
-3.0
HbA1c
−1.20 BW −2.39
-1.5 -3.5 −2.39 (−3.08, −1.71) kg
−0.32 (−0.54%, −0.10%)
p=0.0040 p<0.0001
A. HbA1c; B. body weight. n is the number of randomized patients with non-missing baseline and Week 24 LOCF values.
BL, baseline; CI, confidence interval; DAPA, dapagliflozin; FPG, fasting plasma glucose; MET, metformin; 2h-PPG, 2-hour
postprandial glucose; SAXA, saxagliptin.
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 DAPA vs SAXA : Efficacy Outcomes 14
(Adjusted Change from Baseline at 24 Weeks)
(Rosenstock et al 2016)
Both Dapagliflozin and Saxagliptin demonstrated efficacy at 24 Weeks; however, dapagliflozin significantly
reduced HbA1c (Figure A on this slide), FPG, and 2h-PPG (Figures C and D on next slide) to a greater extent
than saxagliptin
C D
BL, mg/dL (SD) 191.6 (45.35) 185.0 (47.61) BL, mg/dL (SD) 255.6 (64.25) 247.0 (56.30)
n 142 148 n 147 144
SAXA+MET DAPA+MET SAXA+MET DAPA+MET
0.0 1.0

from baseline in 2h-PPG (mg/dL)

Adjusted mean (95% Cl) change

Adjusted mean (95% Cl) change

from baseline in FPG (mg/dL)

-5.0 SAXA -10.0

-10.0 -20.0 SAXA
-15.0 DAPA -30.0
-20.0
−14.0
-40.0 DAPA
-25.0 -50.0 −35.6
-30.0 -60.0
-35.0 -70.0
-40.0 FPG −31.7 -80.0
2h-PPG −70.4
−17.7 (−25.6, −9.8) mg/dL
p<0.0001 −34.9 (−44.7, −25.1) mg/dL
p<0.0001
C. FPG; D. 2h-PPG; n is the number of randomized patients with non-missing baseline and Week 24 LOCF values.
BL, baseline; CI, confidence interval; DAPA, dapagliflozin; FPG, fasting plasma glucose; MET, metformin; 2h-PPG,
ASK-SDNC 2-hour postprandial glucose; SAXA, saxagliptin.
 The Selected 10 Publications on Dapagliflozin in 2015 15

(Summarized : Tjokroprawiro 2016-2017)

1 Cefalu et al 2015 : in T2DM plus CVD + Loop Diuretics

Safety and Efficacy of Dapagliflozin in Px with T2DM and CARDIOVASCULAR DISEASE
RECEIVING LOOP DIURETICS

2 Hansen et al 2015 :  20% Insulin Dose in T1DM

A 20% reduction in Insulin Dose upon Initiation of Dapa Therapy in Px with T1DM
Seems Appropriate to Avoid an Increased risk of Hypoglycemia
3 Heerspink et al 2015 :  Albuminuria in T2DM with Hy + RAS Blockers
Dapa REDUCED ALBUMINURIA in Px with T2DM and Hypertension Using Renin-
Angiotensin System Blockade Therapy (at week 4, and this Effect was Sustained over 12
Weeks, Independent of Changes in HbA1c, SBP, and eGFR)
4 Katz et al 2015 :  Insulin Resistance,  Insulin Sensitivity
• In T2DM Pxs with CVD, Dapa was Associated with a Greater DECREASE in INSULIN
RESISTANCE compared with Placebo over 24 Weeks of Treatment
• Dapa Improved Insulin Sensitivity Independently of Glycemic Control in Pxs with T2DM,
suggesting an Additional Health Benefit with Potential Implications on Disease Progression
5 Kosiborod et al 2015 :  HbA1c,  BW in T2DM + HF
Treatment (Efficacy and Safety) with Dapa 10 mg Produced Clinically Meaningful Reductions
in HbA1c and Body Weight versus Placebo in Px with T2DM and HEART FAILURE (HF)

ASK-SDNC Continued
 The Selected 10 Publications on Dapagliflozin in 2015 16

(Summarized : Tjokroprawiro 2016-2017)

6 Matthaei et al 2015 : In T2DM Inadequately Controlled with Met+SU

Efficacy and Safety of Dapagliflozin in Px with T2DM Inadequately Controlled
on Metformin plus SUs According to Background SU
7 Moran et al 2015 :  HbA1c,  BW,  SBP
Treatment (Monotherapy and Combination Therapy) with Dapa 5 and 10 mg/d
Significantly Reduced HbA1c, BW, and SBP compared with Placebo,
Irrespective of Baseline HbA1c
8 Rohwedder et al 2015 SAXA + DAPA :  Genitourinary Infections
Dual TREATMENT WITH SAXAGLIPTIN + DAPAGLIFLOZIN provides a
similar Increase in urinary glucose excretion with FEWER GENITOURINARY
INFECTIONS Compared with Dapagliflozin
9 Tang et al 2015 : DAPA + Insulin = Complementary Approach (T1DM & T2DM)
The co-administration of Dapa with Insulin could Potentially Provide a
Complementary Approach to Glycemic control in T1DM and T2DM Patients
10 Yang et al 2015 : Well Tolerated and Renal Safety in Asian
Dapa was Generally Well Tolerated and not Associated with Impaired Renal
Function in Asian patients with T2DM (RENAL SAFETY)
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 THE 12 (Twelve) FINDINGS WITH CLINICAL BENEFITS OF FORXIGA in 2016-2017 17
(Summarized & Illustrated : Tjokroprawiro 2015-2017)

Rosenstock et al Hayashi et al 2017 Ekhlom et al 2016

2016 Dapa (12 Weeks) :  sdLDL-C,  1 ( -Cell Function, greatest :
10 saxa + dapa, and plac. + dapa)
HDL2-C,  LDL-C,  BW,  SBP, 
DAPA, MET >< SAXA+MET TG,  Liver Transaminases, Apn
Better : FPG, 2hPPG,
A1C, SBP, and BW 11 Gorgojo-Martinez et al
Wu et al 2016 2 2016
Dapa + GLP1RAs :  A1C and
SGLT2is protect : MACE, CV 9 Further Weight Loss
Death, HF, Death from any
Cause
12 Publications Juani et al 2016
Sonesson et al 2016 on FORXIGA 3 Dapa in Ramadan :
Dapa in T2DM (208 Weeks) : 8  hypoglycemia
No  Major Adverse CV Events 2016 : 10 Journals
Scheerer et al 2016 2017 : 2 Journals Kohan et al 2016
Dapa (3-6 Months) in T2DM: 7 Dapa in Normal or Mildly
4
 A1C, BW, SBP Impaired Renal Function
(102 Ws) : No Renal Toxicity
Rosenstock et al 12
2016 Araki et al 2017 Li et al 2016
Dapa: Greater Glycemic 6
(T2DM, DEASY trial, 1 Year, add-on to 5 Dapa in T2DM : Improved
Efficacy than Saxa, plus Insulin) : Efficacy and Safety, Insulin- Glycemic Variations,
 BW Sparing Effect,  A1C,  BW  Oxidative Stress
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 THE 55 ANALYZED PATIENTS (n-55) : 3 MONTH ADD-ON THERAPY WITH FORXIGA 18
(Tjokroprawiro, Hermawan, Murtiwi, Zaky, Dana, Ganjar, Decsa, Danial, Rosyid 2016)
THE ANALYZED PATIENT’S DATA INFORMATION (n-55)
 VARIATION OF TREATMENT BEFORE FORXIGA
(Total Number of DM Patients : 85. The Analyzed Pts : 55)
1. Forxiga Only =0 5. Forxiga + 3 OADs = 11
2. Forxiga + Detemir = 2 6. Forxiga + Detemir + 1 OAD =5
3. Forxiga + 1 OAD =4 7. Forxiga + Detemir + 2 OADs = 22
4. Forxiga + 2 OADs = 11
 FORXIGA DOSE : 10 mg/Day before Breakfast or Lunch
 NUMBER OF PATIENTS : 55
 GENDER FOR ALL (55 Patients : 30 Males, 25 Females)
 AGE 46-79 years (Mean 62.68 + SD 8.46)
 ADD-ON THERAPY WITH FORXIGA : 3 MONTH-STUDY PERIOD
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 RESULTS – Add-on Therapy with Forxiga : 3 Month-Study Period 19
(Tjokroprawiro, Hermawan, Murtiwi, Zaky, Dana, Ganjar, Decsa, Danial, Rosyid 2016)

PARAMETER n BEFORE AFTER CHANGE p

1 FPG (mg/dL) 55 188.76 + 69.15 144.80 + 51.31 −43.96 < 0.001
2 1hPPG (mg/dL) 55 291.15 + 78.50 238.62 + 60.64 −52.53 < 0.001
3 A1C (%) 55 9. 61+ 2.05 8.11 + 1.19 - 1.50 < 0.001

4 SBP (mmHg) 55 130.73 + 16.90 124.18 + 9.75 - 6.55 < 0.001

5 DBP (mmHg) 55 82.09 + 10.97 80.73 + 6.34 - 1.36 < 0.001
6 BW Change (Kg) 55 71.19 + 12.26 69.00 + 10.20 −1.96 0.005
7 FASTING INSULIN
55 On Going - - -
(Normal : 2.6 – 24.9 uU/mL)

8 HOMA-B 55 On Going - - -
(Normal : 70-150%)
9 HOMA-R 55 On Going - - -
(Normal : < 2.0)

FPG : Fasting Plasma Glucose, 1hPPG : 1 hour Prandial Plasma Glucose,

SBP : Systolic Blood Pressure, DBP : Diastolic Blood Pressure
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 Bar Diagram – Surabaya Add-on Therapy with Forxiga : 3 Month-Study Period-2016 20
(Tjokroprawiro, Hermawan, Murtiwi, Zaky, Dana, Ganjar, Decsa, Danial, Rosyid 2016)

n-55
−52.53
55 (p < 0.001)
n-55
50 −43.96
45 (p < 0.001)

40

35
30

25
20
15 n-55
n-55 −6.55 n-55
10 n-55
−1.50 (p < 0.001) −1.36 −1.96
5 (p < 0.001) (p < 0.001) (p=0.005)
0 Decrease in Decrease in Decrease Decrease Decrease Decrease
FPG mg/dL 1hPPG in A1C In SBP In DBP in BW
mg/dL % mmHg mmHg Kg
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 21

THE 6 BENEFITS OF 3 MONTH ADD-ON THERAPY WITH FORXIGA SURABAYA 2016

(Tjokroprawiro, Hermawan, Murtiwi, Zaky, Dana, Ganjar, Decsa, Danial, Rosyid 2016)

1 SIGNIFICANT  FPG : -43.96 mg/dL (p <0.001)

1.
2 SIGNIFICANT  1hPPG : -52.53 mg/dL (p<0.001)
2.
3 SIGNIFICANT  A1C (%) : -1.50% (p<0.001)
3.
4 SIGNIFICANT  SBP : -6.55 mmHg (p<0.001)
4.
5 SIGNIFICANT  DBP : -1.36 mmHg (p<0.001)
5.
6 SIGNIFICANT  Body Weight (BW) : -1.96 kg (p=0.005)
6.
Such Findings May Support the Metabolic Cardiovascular Effects of Forxiga ??
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 22
BASED ON ADD-ON THERAPY WITH FORXIGA FOR 3 MONTHS, SURABAYA-2016
(Tjokroprawiro, Hermawan, Murtiwi, Zaky, Dana, Ganjar, Decsa, Danial, Rosyid 2016)

 BW : −1.36 kg  FPG :−43.96 mg/dL

6 1
(p<0.001) (p<0.001)

THE 6 BENEFITS OF
 DBP : -1,36 mmHg 3 MONTH ADD-ON
p<0.001)
5 THERAPY WITH 2  1hPPG:−15.77 mg/dL
(p<0.001)
FOXIGRA
SURABAYA-2016

 SBP : −6.55 mmHg

4 3  A1C (%): −1.50%
(p=0.005)
(p<0.001)

FORXIGA : An OAD with CV Properties

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 POTENTIAL CLINICAL BENEFITS OF SGLT2-INHIBITOR 23
Cefalu et al 2015, Efstathiou et al 2015, Hatanaka et al 2015, Katz et al 2015, Wang et al 2015, Juani et al 2016,
Li et al 2016, Sonesson et al 2016, Hayashi et al 2017, Araki et al 2017, Illustrated : Tjokroprawiro 2016-2017

SIXTEEN (16) POTENTIAL BENEFITS OF SGLT2-INHIBITOR

1 INSULIN-INDEPENDENT
LOWERING GLUCOSE
2 CALORIE LOSS DUE TO
GLUCOSE EXCRETION
3  FPG
4  PPG
5  A1C
6  SBP
7  VAT
8  BW
9  AT INFLAMMATION,
 ARTERIAL STIFFNESS
Data on File 2014
10 CELL
 CELLFUNCTION
FUNCTION
11  ROS
12  INSULIN SENSITIVITY
KIDNEY:  LIPID,
13 KIDNEY: LIPID,
 INFLAMMATION,
INFLAMMATION,  DN
DN
14 CV EFFICACY & SAFETY
15  sdLDL,  HDL2-C, lb LDL-C,
 LDL-C,  TG,  Liver ALT,  Apn
16 Low risk of Hypoglycaemia in
Ramadan Month
ADA-Scientific Session, Boston 5-9 June 2015

 FPG : Fasting Plasma Glucose  AT : Adipose Tissue

 PPG : Prandial Plasma Glucose  BW : Body Weight
DIRECT EXCRETION OF GLUCOSE
 DN : Diabetic Nephropathy  VAT : Visceral Adipose Tissue
AND ITS ASSOCIATED CALORIES
 BP : Blood Pressure  ADA : American Diabetes Association
Glucuresis  IR : Insulin Resistance  IS : Insulin Sensivity
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologic
andMetabolicDrugsAdvisoryCommittee/UCM264314.pdf?utm_campaign=Google2&utm_source=fdaSear
ch&utm_medium=website&utm_term=Dapagliflozin&utm_content=14
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Several items on LDL-C, sd LDL-C, lb LDL-C
(Summarized : Tjokroprawiro 2017)

A
A. Chol-rich lb LDL-C
LDL-C : B. Chol-poor sd LDL-C
B
Dapa : A  LDL-C (lb LDL-C = large bouyant LDL-C)

1 DAPA effects : Increased HDL2-C and Increased sdLDL-C : due to Hyper

TG,  BW,  Insulin Sensitivity (IS),  Insulin Resistance (IR)
2 Possible Mechanism for Increased LDL-C:
a. Suppresed Conversion from Chol-rich lb LDL-C to Chol-poor sd LDL-C
(lb LDL-C = large bouyant LDL-C)
b. Impared LDL-C Catabolism by  LDL receptors
c.  LDL-C production by  LPL-activity (due to increased IS)
3 Conclusion
Dapa : -  sdLDL-C,  HDL2-C,
-  LDL-C,  BW,  SBP,  TG,  Liver Transaminases, Apn
-  Chol-rich lb LDL-C (result in )
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