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New Directions in the Treatment of type 2 Diabetes

: From Clinical data to Local Experience


ID 350355/ OCT 2017

[Speaker name]

Dapagliflozin is not indicated for the management of obesity.1 Weight change was a secondary endpoint in clinical trials.1,2
1. FORXIGA®. Summary of product characteristics, 2015; 2. Bailey CJ, et al. Lancet 2010;375:2223–33.
Type 2 diabetes and glucose balance through renal sodium-
glucose cotransporters (SGLTs)

• Epidemiology of diabetes
• Current treatment and multiple challenges of type 2 diabetes
• The importance of reducing HbA1c, weight, blood pressure, and lipids
• The need for a pathway that acts independently of insulin in type 2 diabetes
• The role of the renal SGLT pathway in glucose balance
• Efficacy of Dapagliflozin
• Tolerability of Dapagliflozin
• Additional Benefit of Dapagliflozin
(Weight Reduction, VAT reduction, BP reduction & β cell preservation)
• Local clinical experience of Dapagliflozin
• Summary
1. Epidemiology and Economic
Burden of Type 2 Diabetes
Diabetes—a growing global epidemic
Diabetes* worldwide prevalence, 2011: ~360 million1
2030 prevalence estimates : >550 million1

Of all cases
of diabetes,
90% are type 2
diabetes2

2030 prevalence1:
South East Asia: 121 million
Indonesia: 7,2 → 11,8 million

•All cases of diabetes, including type 1 and type 2 diabetes, and impaired glucose tolerance (IGT), in patients aged 20-79 years.
1. International Diabetes Federation. IDF Diabetes Atlas, 5th ed. Brussels, Belgium: International Diabetes Federation, 2011.

Diabetes* worldwide prevalence estimates, 2030: >550 million1


Type 2 diabetes—CVD is a leading cause of death

Emerging Risk Factors Collaboration.


N Engl J Med. 2011;364(9):829-841.
Type 2 diabetes—controlling multiple
parameters is essential

Incremental reductions sustained


over time in HbA1c and other
parameters can benefit the
physical health of patients with
type 2 diabetes1-5

1. Stratton IM, et al. BMJ. 2000;321:405-412. 2. Pi-Sunyer FX. Postgrad Med. 2009;121(5):94-107. 3. Williamson DF, et al. Diabetes Care. 2000;23(10):1499-1504. 4.
Patel A. Lancet. 2007;370(9590):829-840. 5. Pyǒrälä K, et al. Diabetes Care. 1997;20(4):614-620.
Type 2 diabetes—guidelines recommend managing
multiple parameters1-5

Although the EASD and ADA Guidelines each set forth specific HbA1C target goals, an ADA/EASD Joint Position
Statement on management of hyperglycemia (2012) recommends that treatment targets be individualized. 6
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; ESC=Task Force on Diabetes and Cardiovascular Diseases of the European
Society of Cardiology; AACE=American Association of Clinical Endocrinologists; CDA=Canadian Diabetes Association; WHO=World Health Organization.

1. Guidelines for the prevention, management and care of diabetes mellitus. Cairo, Egypt, World Health Organization, 2006. 2. The Task Force on Diabetes and
Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28:88-136.
3. American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S4-S10. 4. Handelsman Y, et al. American Association of Clinical Endocrinologists Medical Guidelines
for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2):1-53. 5. Canadian Diabetes Association Clinical Practice
Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201. 6. Inzucchi SE, et al. ADA/EASD Position Statement. Diabetes Care. 2012;35:1-16.
Type 2 diabetes—lowering HbA1c, blood pressure,
and lipids may reduce mortality

Schernthaner G. Wien Med Wochenschr. 2010;160(1-2):8-19.


The need for a pathway that acts
independently of insulin in
type 2 diabetes
An insulin-independent pathway—renal SGLT21,2

1. Rajesh R, et al. Int J Pharma Sci Res. 2010;1(2):139-147. 2. Marsenic O. Am J Kidney Dis. 2009;53(5):875‐883.
Normal glucose homeostasis1,2
Net balance ~0 g/day
Glucose input ~250 g/day: Glucose uptake ~250 g/day:

• Dietary intake ~180 g/day • Brain ~125 g/day


• Glucose production ~70 g/day • Rest of the body ~125 g/day
• Gluconeogenesis
• Glycogenolysis
+ The kidney filters The kidney reabsorbs

circulating glucose and recirculates
glucose

Glucose filtered Glucose reabsorbed


~180 g/day ~180 g/day

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18;


2. Gerich, JE. Diabetes Obes Metab 2000;2:345–50.
Glucose handling in Type 2 diabetes1,2

Glucose input >280 g/day: Glucose uptake >250 g/day:

• Dietary intake >180 g/day • Brain ~125 g/day


• Glucose production ~100 g/day • Rest of the body >125 g/day
• Gluconeogenesis*
• Glycogenolysis
+ Increased reabsorption

Average blood glucose
concentration 150 mg/dL and recirculation of
Kidney filters all glucose
circulating glucose

Glucose filtered Above the renal threshold for


~270 g/day glucose (~200 mg/dL), glucose is
excreted in the urine (glucosuria)

*Elevated glucose production in patients with Type 2 diabetes attributed to


hepatic and renal gluconeogenesis.2
1. Gerich JE. Diabet Med 2010;27:136–42;
2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:782–90.
In normal renal glucose handling, 90% of glucose is
reabsorbed by SGLT21–4

Majority of glucose
is reabsorbed by
SGLT2 (90%)

Proximal tubule

Remaining
glucose is
SGLT2
Glucose reabsorbed by
Glucose filtration SGLT1 (10%)
Minimal to
no glucose
excretion

SGLT, sodium-glucose co-transporter 2.


Adapted from: 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21;
4. Marsenic O. Am J Kidney Dis 2009;53:875–83.
Dapagliflozin inhibits SGLT2 and removes excess
glucose in the urine independently of insulin
SGLT2
Reduced glucose
reabsorption
Dapagliflozin

Proximal tubule

Increased urinary
Increased urinary
excretion
excretion of excess
of excess
SGLT2
Glucose glucose
glucose (~70 g/day,
(~70 g/day,
Glucose filtration corresponding
corresponding toto
280kcal/day*
280 kcal/day*)1)
FORXIGA

• By inhibiting SGLT2, Dapagliflozin removes glucose and associated calories


• Dapagliflozin is >1400-times more selective for SGLT2 versus SGLT1

*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes.
FORXIGA®. Summary of product characteristics, 2015.
Dapagliflozin improves β-cell function & insulin sensitivity at
2 weeks1 by lowering plasma glucose
Insulin Secretation β-cell function

P<0.005 vs baseline
P<0.005 vs baseline

• The primary action of dapagliflozin is on the kidney and the drug has
no known direct action on the β-cell
• Dapagliflozin demonstrate Improve treatment β -cell function in
T2DM by correcting hyperglycemia, ie, reversal of glucotoxicity.

1. Aurora Merovci, et al. J Clin Endocrinol Metab, May 2015, 100(5):1927–1932


Consistent Decreases in Fasting Plasma Glucose
(FPG) at 24 weeks1,2,3
Add On to Metformin1 Add On to Sulfonilurea2 Add On to TZD3
FPG Adjusted mean Changed from Baseline

10 mg Placebo 10 mg Placebo 10 mg Placebo


0

-5 -1.8 mg/dl
-5.4 mg/dl
-5.4 mg/dl
-10
p< 0.0001 p< 0.0001 p< 0.0001

-15

-20

-25 -23.4 mg/dl

-30
-28.8 mg/dl -28.8 mg/dl

-35

1. Bailey CJ, et al. Lancet 2010;375:2223-33;


2. Strojek K, et al. Diabetes Obes Metab 2011;13:928-38;
3. Rosenstock J, et al. Diabetes Care, Volume 35, July 2012
Consistent Decreases Post Prandial Glucose (PPG) after
2 hours at 24 weeks1,2

Add-on Add on +
to Pio1 SU2
308 321.3

5 mg 10 mg Pbo

n=139

n=141 n=140

Forx 5 P=0.0007 vs plac Both P<0.0001 vs plac


Forx 10 P<0.0001 vs plac

1. Rosenstock J, et al. Diabetes Care, Volume 35, July 2012


2. Strojek et.al. Diabetes, Obesity and Metabolism 13: 928–938, 2011.
Consistent reductions in HbA1c in patients with
baseline HbA1c ≥9%
FORXIGA
Placebo
Add on to Add on to Add on to
metformin1 SU1 Met XR2

-1.44

(24 weeks)
-1.98
9.05%

NR, not reported.


1. Katz A, et al. Diabetes 2014;63(Suppl. 1):A284. 2. Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR
Dapagliflozin Consistent reductions in HbA1c in patients
as add on therapy at 24 weeks

Add-on to metformin1 Add-on to a SU2 Add-on to Pio3


0.5 0.5 0.5
Mean change in HbA1c(%)

0.0 0.0 0.0

–0.13
–0.30
-0.5 -0.5
–0.42
-0.5

–0.84* –0.82*
-1.0 -1.0 -1.0 –0.97*

P< 0.0001 P< 0.0001 P< 0.0001


CI 95% -98 to 0.70) CI 95% -0.88 to -0.51) CI 95% -33.1 to 3.0)
-1.5 -1.5 -1.5

Baseline HbA1c: 8.06% Baseline HbA1c: 8.07% Baseline HbA1c: 8.53%

*Statistically significant vs placebo using Dunnett’s correction. SU, sulphonylurea.


1. Bailey CJ, et al. Lancet 2010;375:2223–33; Dapagliflozin (10
2. Strojek K, et al. Diabetes Obes Metab 2011;13:928–38; 4. Wilding JPH, et al. Ann Intern Med 2012;156:405–15. mg)
3. Rosenstock J, et al. Diabetes Care, Volume 35, July 2012 Placebo
.
19
Dapagliflozin vs SU:
Comparable HbA1c reductions over 4 years1
At 52 week primary endpoint Dapagliflozin was non-inferior to glipizide: Both resulted in HbA1c reductions of –
0.52%2

Dapagliflozin is notmean
Data are adjusted indicated for the
change management
from baseline derived from 3aWeight
of obesity. change
longitudinal was a measures
repeated secondary mixed
endpoint in clinical trials.3,4
model.
A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety of
Dapagliflozin
10 mg + metformin (1500–2000 mg/day) versus glipizide + metformin (1500–2000 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone.1
*The risk of hypoglycaemia with dapagliflozin is dependent on the type of background therapy used.3
1. Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 21–25 June 2013. Abstract 62-LB; 2. Nauck MA, et al. Diabetes Care
2011;34:2015–22. 3. FORXIGA®. Summary of product characteristics, 2015; 4. Bailey CJ, et al. Lancet 2010;375:2223–33.
FORXIGA: Safety and tolerability from a wide-ranging
clinical programme
• The safety of Dapagliflozin 10 mg was assessed in a pooled analysis of 13 placebo-controlled studies
in >2300 patients
Adverse reactions in placebo-controlled studies of Dapagliflozin (24-week data regardless of glycaemic rescue)
Very common Common* Uncommon†
System organ class
(1/10) (1/100 to <1/10) (1/1000 to <1/100)
Infections and infestations Vulvovaginitis, balanitis and Fungal infection
related genital infections‡
UTIs§
Metabolism and nutrition disorders Hypoglycaemia (when Volume depletion||
used with a SU or insulin) Thirst
Nervous system disorders Dizziness
GI disorders Constipation
Dry mouth
Musculoskeletal and connective Back pain
tissue disorders
Renal and urinary disorders Dysuria Nocturia
Polyuria¶ Renal impairment
Reproductive system and breast Vulvovaginal pruritus
disorders Pruritus genital
Investigations Haematocrit increased** Blood creatinine increased
Creatinine renal clearance Blood urea increased
decreased Weight decreased
Dyslipidaemia††

Footnotes are available in the slide notes.


GI, gastrointestinal; SU, sulphonylurea; UTI, urinary tract infection.
FORXIGA®. Summary of product characteristics, 2015.
FORXIGA: Renal function guidance
• The efficacy of all SGLT2 inhibitors is dependent on renal function1–4

Dapagliflozin is not recommended


Dapagliflozin can be used in…1
for use in…1

…patients with moderate-to-severe


…patients with normal or mildly impaired
renal impairment (CrCl <60 mL/min or
renal function (eGFR ≥60 mL/min/1.73 m2)
eGFR <60 mL/min/1.73 m2)

The monitoring of renal function is recommended as part of HOLISTIC Diabetes


Management1
• Prior to initiation of SGLT2 inhibitor and at least yearly thereafter as part of Diabetes
Management
• Prior to initiation of concomitant medicinal products that may reduce renal function and
periodically thereafter
• For renal function approaching moderate renal impairment, at least two to four times
per year. If renal function falls below CrCl <60 mL/min or eGFR <60 mL/min/1.73 m2,
Dapagliflozin treatment should be discontinued

CrCL, creatinine clearance.


1. FORXIGA®. Summary of product characteristics 2014; 2. Canagliflozin. Summary of product characteristics 2013; 3. Empagliflozin. Summary of product characteristics 2014;
4. Gilbert RE. Kidney Int 2013; Epub ahead of print.
Kidney function in consideration Due to MOA of
Dapagliflozin in Kidney
• In patients Dapagliflozin renal function remained stable over time until 102 weeks1
• Side effects associated with increased creatinine reported 3.2% of patients Dapagliflozin vs 1.8%
placebo1
• Dapagliflozin (creatinine are reversible and are rarely associated with clinically significant changes vs
baseline) 1
Mean change in eGFR from baseline

Dapagliflozin 10 mg
Placebo
(mL/min/1.73 m2)

Number of patients
Dapaglifloz 2026 1697 1655 1777 1600 1663 712 692 656 627
in
Placebo 1955 1629 1570 1671 1513 1558 605 585 551 521

*Adverse drug reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular
filtration rate).
eGFR, estimated glomerular filtration rate; LT, long-term; MDRD, modification of diet in renal disease; MoA, mechanism of action; ST, short-term.
1. EMDAC background document.
Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf Last accessed
September 2014;
Dapagliflozin as add-on to metformin versus SU:
Lower risk of hypoglycaemia at 4 years

100
90
80 ~10X
Patients with ≥1 episode

lower
of hypoglycaemia (%)

incidence
70
60
51.5%
(n=408)
50
40
30
20 5.4%
10 (n=406)
0
Dapagliflozin 10 mg Glipizide
+ metformin + metformin

208 weeks

P value is not obtain from citation source

Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 21–25 June 2013. Abstract 62-LB.
CV events was lower in Dapagliflozin compared to
placebo Based on meta-analysis study
• A meta-analysis of CV events among 21 Phase IIb/III trials, showed no increase in the primary CV composite endpoint
of CV death, stroke, MI and hospitalisation for unstable angina with FORXIGA1,2

Control

FORXIGA

CV events were adjudicated by an independent committee.


CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; UA, unstable angina.
1. EMDAC background document. Available at:
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. Last accessed September 2014;
2. FORXIGA®. Summary of product characteristics, 2014. P value is not obtain from citation source
Clinical considerations when prescribing FORXIGA
• Dapagliflozin is not recommended in:
• Patients aged ≥75 years
• Patients receiving loop diuretics
• Dapagliflozin is also not recommended for initiation of therapy in patients who are
volume depleted
• Temporary interruption of Dapagliflozin is recommended for patients who develop
volume depletion until the depletion is corrected
• Caution should be exercised in patients for whom a FORXIGA-induced drop
in blood pressure could pose a risk
• A lower dose of an insulin secretagogue may be required to reduce the risk of
hypoglycaemia when used in combination with FORXIGA

FORXIGA®. Summary of product characteristics, 2015.


Additional Benefit of Dapagliflozin
(Weight Reduction, BP reduction & Waist Circumference)
Dapagliflozin Consistent reductions in Body Weight in
patients as add on therapy at 24 weeks
24-wk add-on 24-wk Dapa 24-wk add-on 24-wk add-on
to Met1 + Met XR4 to Glim2 to Pio3
24-week adjusted  from baseline weight (kg)

1.64

-0.72
-0.89
-1.14 *
-1.36

-2.26 *
-2.86
* * *p <0.001 vs. comparator
-3.33

Forx 10 Placebo Forx 10 Placebo Forx 10 Placebo Forx 10 Placebo


Baseline
Weight 88kg 81.1kg 81.1kg 86.3kg

1BaileyCJ, et al. Lancet 2010;375:2223–2233;; 2Strojek K, et al. Diabetes Obes Metab 2011;13:928-938; 3Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego,
24–28 June, 2011 [Abstract 0986-P]; 4Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
FORXIGA: Additional benefit of weight loss sustained over
time1

Glipizide + metformin
(n=401)
2.0 Mean baseline weight 87.6 kg
1.5 +1.36 kg
Adjusted mean change from

1.0 (95% Cl,


0.88 to 1.84 kg;
0.5
baseline weight (kg)

n=211)
0.0
-0.5
-1.0 –5.06 kg difference
(95% Cl, –5.73 to –4.4 kg)
-1.5
-2.0 Dapagliflozin 10 mg + metformin
-2.5 (n=400)
-3.0
Mean baseline weight 88.4 kg –3.70 kg
(95% Cl,
-3.5 –4.16 to –3.24 kg;
n=234)
-4.0
0 6 12 18 26 34 42 52 65 78 91 104
Study week

Data are adjusted mean change from baseline and 95% CI derived from a repeated measures mixed model.
1. Nauck MA, et al. Diabetes Care 2011;34:2015–22;
Reduction in total body weight with Dapagliflozin is
principally due to reduction in fat mass1,2
• Dapagliflozin demonstrated a significant reduction in fat mass rather than lean tissue or
fluid loss sustained up to 102 weeks2

P<0.0001 P<0.0001
95% CI -2.84 to -1.31 95% CI -2.51 to -0.96

1 2

Dapagliflozin is not indicated for the management of obesity.2 Weight change was a secondary endpoint in clinical trials.2,3
*Data are adjusted mean change from baseline derived from a longitudinal repeated-measure mixed model and include data after rescue therapy.
1. Bolinder J, et al. Diabetes Obes Metab 2012;16:159–69; 2. Bailey et al. BMC Medicine 2013, 11:43.
FORXIGA: Reduction in blood pressure
• In a prespecified pooled analysis of 12 placebo-controlled studies, Dapagliflozin 10 mg
reduced systolic and diastolic blood pressure versus placebo at Week 241
Systolic blood pressure Diastolic blood pressure
Dapagliflozin 10 mg Control groups Dapagliflozin 10 mg Control groups
0.0
-0.5
–0.5 mmHg
blood pressure (mmHg)

-1.0 –0.9 mmHg (n=1096)


Mean change in

-1.5 (n=1096)

-2.0
-2.5 –2.1 mmHg
(n=949)
-3.0
-3.5
-4.0
-4.5
–4.4 mmHg
-5.0 (n=949)
Baseline blood pressure2 126 mmHg 129 mmHg 77 mmHg 79 mmHg

Dapagliflozin is not indicated for the management of high blood pressure. Mean seated systolic and diastolic blood pressure were based on a placebo-controlled, pooled analysis from the 24-week, short-term,
double-blind treatment period, including data after rescue. N is the number of subjects with non-missing baseline and Week 24 (last observation carried forward) values in the randomised full analysis set.
Change in blood pressure was primarily assessed as safety or exploratory efficacy endpoints in the Phase III clinical programme; therefore, the background antihypertensive medications were not controlled.
1. FORXIGA®. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012; 2. BMS/AZ data on file.
P value is not obtain from citation source
Local clinical experience of Dapagliflozin
Dapagliflozin – Clinical Experience
• Clinical experience from our center: > 100 pts with T2DM
• Data available from 42 patients since Nov 2015 – May 2016 from our center
• Baseline results:
• Patients came at admission with baseline HbA1c 5.6-12.7% and body
weight 51-134 Kgs
• All patients received Dapaglifozin as add on therapy
• Efficacy
• HbA1c reduction range 0.1-1.5% in > 1 month of treatment
• Weight reduction range 1-4 Kgs in > 1 month of treatment
• Safety
• No UTI cases reported by patients
• No other adverse events found so far (DKA, hypoglycemia, etc)
Summary
FORXIGA: For your patients who are uncontrolled on
metformin with sufficient renal function

Dapagliflozin as add on to
metformin delivers significant
and sustained reductions in:1,2
 PPG, FPG & HbA1c,
Wth ADDITIONAL Benefit
As Dapagliflozin has an Insulin Independent
Reduction1 : Pathway it may also be used to complement
other medications across the spectrum of
 Weight
disease3
 Blood pressure
 Waist Circumference

Early disease Advanced disease

Dapagliflozin is not indicated for the management of obesity or high blood pressure.1 Weight change was a secondary endpoint in clinical trials.1,2
1. FORXIGA®. Summary of product characteristics, 2014; 2. Bailey CJ, et al. Lancet 2010;375:2223–33; 3. Jabbour SA, et al. Diabetes Care 2014;37:740–50;
Summary
FORXIGA…
• Has insulin-independent pathway, by removing excess glucose and calories
with urine4
• Provide a significant reduction in PPG, FPG, HbA1C and sustained when
used as add-on to metformin, sulfonylureas and TZDs1,5
• significant and sustained weight loss and blood pressure1
• Dapagliflozin Provide added benefit of significantly reduce total body weight,
blood pressure1, waist circumference and body fat mass compared to
placebo when used as add-on therapy1,2
• Dapagliflozin well tolerated1,3

Dapagliflozin is not indicated for the management of obesity or high blood pressure.1 Weight change was a secondary endpoint in clinical trials.1,5
*This information is an estimate derived from the use of information under licence from the following IMS Health information service: NPA Market Dynamics for period February – April 2014. IMS
expressly reserves the rights of copying, distribution and republication.
1. FORXIGA®. Summary of product characteristics, 2014; 2. Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 21–25 June 2013.
Abstract 62-LB; 3. Data on file (Cegedim Strategic Data, Longitudinal Patient Databases, October 2014); 4. Marsenic O. Am J Kidney Dis 2009;53:875–83; 5. Bailey CJ, et al. Lancet
2010;375:2223–33.