Acp Sglt2 Slidecast 220

Please Take A Moment to Complete the Pre-Program Clinical
Performance and Knowledge Gap Assessment Survey
New Therapeutic Paradigms

and the Evidence Basis
Kidney-Mediated Glucose
Homeostasis in Type 2
Diabetes
Focus on the Glycemic and Cardiometabolic
Effects Mediated by SGLT2 Inhibition and Their
Potential for Achieving Individualized ADA Target
Goals
in T2D
VIVIAN
A. FONSECA, MD, FRCP- Program Chair
Professor of Medicine and Pharmacology | Tullis Tulane Alumni
Chair in Diabetes | Chief, Section of Endocrinology | Tulane
University Health Sciences Center | Past President, Science and
Medicine | American Diabetes Association
Welcome and Program

Overview
CME-certified symposium
jointly sponsored by the
University of Massachusetts
Medical School and
CMEducation Resources, LLC
Commercial Support: This
CME activity is supported by
an educational grant from
AstraZeneca
Distinguished Faculty
VIVIAN A. FONSECA, MD,
FRCP Program Chair
Professor of Medicine and
Pharmacology | Tullis Tulane
Alumni Chair in Diabetes |
Chief, Section of
Endocrinology | Tulane
University Health Sciences
Center | Past President,
Science and Medicine
American Diabetes
Association
CHARLES F. SHAEFER JR.,
MD, FACP
Assistant Clinical Professor of
GEORGE BAKRIS, MD
Professor of Medicine | Director,
Hypertension Center | University
of Chicago Medical Center |
Chicago, Illinois
MUHAMMAD ABDUL-GHANI,
MD, PHD
Assistant Professor | Diabetes
Division | School of Medicine |
UTHSCSA Graduate School of
Biomedical Sciences | San
Antonio, Texas
COI Disclosures
Faculty Member
Relationship
Vivian Fonseca, MD Research Support (to

Tulane):
Honoraria for Consulting

and Lectures:
Charles F. Shaefer,
MD, FACP
Consultant:
Speakers Bureau:
Muhammad Abdul- Consultant:

Ghani, MD, PhD
Speakers Bureau:
Grant/Research Support:
George Bakris, MD Consultant:
Grant/Research:
Corporation/Manufacturer
Grants from Eli Lilly, Abbott, Reata,

Asahi
Glaxo Smith Kline, Takeda, Novo

Nordisk,
sanofi-aventis, Eli Lilly, Pamlabs,
Astra-Zeneca, Abbott, Bristol-Myers
Squibb, Merck,
Boehringer Ingelheim
Sanofi-aventis, BMS-AZ,
Sanofi-Aventis, Amylin, BI/Lilly, BMSAZ, Novartis
N/A
N/A
N/A
AbbVie, Takeda, Medtronic, Relypsa,
BI, BMS, Janssen, Bayer
Takeda
An Evidence-to-Strategy Update for

Type 2 Diabetes
The Challenges of Achieving ADA

Glycemic Target Goals and Optimizing
Cardiometabolic Status in Patients
with T2D
Unmet Therapeutic Needs on the Landscape of Oral
Antidiabetic Drugs: What are the New Frontiers and
Paradigms?
VIVIAN A. FONSECA, MD, FRCP
Program Chair
Professor of Medicine and Pharmacology | Tullis Tulane

Alumni Chair in Diabetes | Chief, Section of
Endocrinology | Tulane University Health Sciences
Center | Immediate Past President, Science and
Evolving Frontiers of Antidiabetic

Therapy
Fact #1: We still need better control of
HbA1c levels
Fact #2: This is an unmet therapeutic need
Fact #3: There are new oral antidiabetic
drugs worthy of our attention, analysis, and

consideration
CV Mortality Increases with Increasing

A1C Level
Relative Risk of
CV Mortality
EPIC-Norfolk: 4662 Patients Followed for 4 Years
A1C (%)
EPIC = European Prospective Investigation of Cancer and Nutrition
P<0.001 age-adjusted death rates for linear trend
Reproduced with permission from the BMJ Publishing Group. Khaw K-T, et al. BMJ.
2001;322:1-6.
Impact of Intensive Glycemic

Therapy
Summary of Major Clinical Trials
Initial
trial
Long-term follow-up
Study
Microvascula
r
CVD
Mortality
UKPDS1,2
DCCT/EDIC3.4
Action to Control
Cardiovascular Risk in
Diabetes (ACCORD)5
ADVANCE6
Veterans Affairs
Diabetes Trial (VADT)7
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
3
The Diabetes Control and Complications Trial Research Group.
N Engl J Med. 1993;329;977-986. 4Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.
5
Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. 6Patel A, et al. N Engl J Med. 2008;358:2560-2572.
7
Duckworth W, et al. N Engl J Med. 2009;360:129-139.
1
2
Meta-Analysis of Intensive
Glucose Control Trials
Pooled analysis of the UKPDS, ACCORD, ADVANCE, and VADT trials yielded a
16% overall reduction in nonfatal MI. The absolute overall risk reduction was
9 events per 1000 patients over 5 years of treatment.
Events/Total (n/n)
Event Intensive
Conventional
Nonfatal MI611/14,662598/13,140
Fatal MI 540/14,662
437/13,140
Nonfatal
stroke423/14,662
Relative Risk
Risk Difference
(95% CI)
CI)
0.84 (0.75-0.94)
9 (16 to 3)
0.94 (0.75-1.18)
3 (10 to 4)
0.98 (0.82-1.17)
3 (7 to 2)
362/13,140
0.87 (0.63-1.20)
Fatal stroke88/14,662 76/13,140
PAD
409/9534
0.91 (0.79-1.03)
433/8017
0.5
1.0
2.0
n = 27,802
Relative Risk (95% CI)
(95%
0 (2 to 1)
3 (5 to 1)
In the overall analysis, intensive glucose control had no significant

effect on either:
CV mortality (relative risk 0.97 [95% CI, 0.76-1.24])
or
all-cause mortality (relative risk 0.98 [95% CI, 0.84-1.15])
PAD: peripheral arterial disease
TN, et al. Ann Intern Med. E-pub ahead of print.
ACCORD Eye: Microvascular Relative

Risk Reduction With Intensive Therapy
ACCORD Eye Glycemia Arm
Duration of
follow-up
4 years
Mean Int: 8.21.0%
Mean Std: 8.31.0%
Baseline A1C
A1C at 1 year
Retinopathy
a
Median Int: 6.4%a

Median Std: 7.5%a
Rate of progression of diabetic
retinopathy:
Intensive: 7.3%
Standard: 10.4%
(P=0.003)
Significant between-group difference was maintained throughout the study
ACCORD=Action to Control Cardiovascular Risk in Diabetes
ACCORD Study Group and ACCORD Eye Study Group. N Engl J Med.
Long-term Effects of Intensive Glucose

in Newly Diagnosed T2DM Patients
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
HR (95%CI)
Intensive (metformin) vs. Conventional glucose control
HR (95%CI)
Holman RR, et al. N Engl J Med 2008;358:254559.
HR (95%CI)
Legacy of Bad Metabolic Memory

Before entering VADT intensive
treatment arm
After entering VADT intensive

treatment arm
Generation
Generation of
of a
a
bad
bad glycemic
glycemic
legacy
legacy
9.5
9.0
Drives
Drives risk
risk of
of
complications
complications
Modelling the
prior history of
patients
recruited in
VADT illustrates
the drawbacks
of late
intervention
8.5
HbA1c (%)
8.0
7.5
7.0
6.5
6.0
1
10 11 12 13 14 15 16 17
Time since diagnosis

(years)
Solid line: changes
in HbA1c in response to intensive treatment in VADT
Upper broken line: theoretical reconstruction of prior diabetes progression based on

UKPDS
Lower broken line: the ideal time course of glycemic control
Del Prato S, et al. Int J Clin Pract 2010;64:295304.
Complications are Irreversible

ACCORD BP and lipid normalization also
did not result in event reduction
LOOK AHEAD no benefit of lifestyle
change and weight loss!
Above interventions were started too late
Therefore early intervention is better
BUT When is disease reversible ? At
diagnosis?
CV events prevented
Benefit of Different Interventions

per
200 Diabetic Patients Treated for 5
Per 1 mmol/l lowerPer 0.9% lower
Per 4 mmHg lower
Years
LDL-C
HbA1c
SBP
Sattar N; Diabetologia 2013
Primary Risk Factors for CVD

Treatment Goals
Hyperglyce
mia
FPG / preprandial glucose

PPG
A1c
Hypertensio
n
Blood pressure
LDL
Dyslipidemi
a
HDL
Triglycerides
90130 mg/dL
<180 mg/dL
<7%, or lowest possible without
unacceptable hypoglycemia
(individiualized)
<140/80 mmHg, or further lowering

if tolerated by patients
<100 mg/dL, patients with diabetes

<70 mg/dL, very highrisk patients with
diabetes and CVD
>40 mg/dL, men; >50 mg/dL, women
<150 mg/dL
American Diabetes Association, Diabetes Care 2013
Despite Important Advances in

Therapy
Glycemic Control is Not Optimal
Challenges:
Too many patients! Burden or prevention

opportunity?
Failure to attain and sustain optimal long-term

glycemic control
Hypoglycemia risk
Inadequate postprandial glucose control
Unpredictable glucose fluctuations
Weight gain
Excess CVD
Ominous OCTET
Decreased
Incretin Effect
Decreased Insulin
Secretion
Increased
Lipolysis
Isleta cell
HYPERGLYCEMIA
Increased
Glucagon
SecretionIncreased
Hepatic Glucose
Production
Increased
Glucose
Reabsorption
Decreased Glucose
Uptake
Neurotransmitter
Dysfunction
Fronzo R et al. Diabetes. 2009;58:773-795.
Antihyperglycaemic Therapy in T2DM - ADA

Guidelines 2012
Healthy eating, weight control, increased physical activity
Initial drug
monotherapy
Efficacy (
HbA1c)
Hypoglycaemia
Weight
Side
Two-drug
effects...
combinations
Costs
..
Efficacy ( HbA1c)
..
Hypoglycaemia
..
Weight
.
Side
effects..
Costs
More complex
insulin
strategies
Metformin
High
Low risk
Neutral / loss
GI/lacticacidosis
low
If individualised HbA1c target not reached, proceed to two-drug combination
Metformin +
Metformin +
Metformin +
Metformin +
SU
TZD
DPP4i
GLP1-RA
Metformin +
Insulin
High
Moderate risk
Gain
Hypoglycemia
Low
High
Intermediate
Intermediate
Intermediate
Low risk
Low risk
Low risk
Low risk
Gain
Loss
Loss
Loss
Edema, HF,
GI
GI
GI
fract
High
High
High
High
If individualised HbA1c target not reached, proceed to three-drug combination
SU+
TZD
or DPP4i
or GLP1-RA
or Insulin
TZD+
SU
or DPP4i
or GLP1-RA
or Insulin
DPP4i+
SU
or TZD
or Insulin
GLP1-RA+
SU
or TZD
or Insulin
Insulin+
TZD
or DPP4i
or GLP1-RA
If combination therapy that includes basal insulin did not achieve HbA1c target after 3-6
months, proceed to a more complex insulin strategy usually in combination with one or two
non-insulin agents
Insulin (multiple daily doses)

Inzucchi SE, et al. Diabetes Care & Diabetologia, 19 April 2012 [Epub ahead of print].

Type 2 Diabetes
So
what do we do now?
Should
we rethink
treatment strategies with
new targets?
ANSWER:
YES
Novel Drugs & Targets in

Development for Diabetes
11-hydroxysteroid
dehydrogenase (HSD)-1
inhibitors
Protein tyrosine
phosphatase 1B inhibitors
Acetyl CoA carboxylase-1
and -2 inhibitors
G-protein coupled
receptor (GPR)-40 & -119
agonists
Protein tyrosine
phosphatase (PTB)-1b
inhibitors
Carnitine
palmitoyltransferase
(CPT)-1 inhibitors
Acetyl CoA carboxylase
(ACC)-1 & -2 inhibitors
zucchi SE & McGuire DK. Circulation. 2008;117(4):574-584.
Bromocriptine
Long-acting GLP-1
receptor agonists
DPP IV inhibitors
Ranolazine
Dual PPAR/ agonists
Pan PPAR// agonists
Sodium-GLucose
coTransporter (SGLT) 1
and 2 antagonists
Salicylate derivatives
Glucagon receptor
antagonists
Fructose 1,6
bisphosphatase inhibitors
FDA
Not
approved for treatment
of diabetes
Glucokinase
activators
Focus of This Evenings

Symposium
The unmet need for safe and
effective oral agents that help meet
ADA target goals and have optimal
cardiometabolic risk profiles
The kidney plays a central role in the
pathogenesis of T2D and glucose
homeostasis
The emerging clinical role for SGLT2
inhibition as a foundation therapy for

Type 2 Diabetes
Novel Kidney-Based
Mechanisms and Strategies
for Glycemic Regulation in
Health and Disease
George L. Bakris, MD, FASH, FASN
Professor of Medicine
Director, ASH Comprehensive Hypertension Center
University of Chicago Medicine
Chicago, IL
Physiology of
Glucose Handling
by the Kidney
The Kidneys Play an Important Role

in the Handling of Glucose
Total glucose stored in body
Glucose utilization
~450 g
~250 g/day
Brain
~125 g/day
Rest of the body
~125 g/day
Glucose in Western diet
~180 g/day
Glucose production (gluconeogenesis

+ glycogenolysis)
~170 g/day
Renal glucose filtration and

reabsorption
Wright EM, et al. J Intern Med. 2007.
~140-180
g/day
The Kidney Handles Glucose By

Three Key Mechanisms1,2
Bowmans
capsule
Proximal
convoluted
tubule
Distal
convoluted
tubule
Glomerulus
1 Cortex
Collecting
duct
2 Medulla
Loop of Henle
To ureter
1.
1. Glucose
GlucoseProduction
Production
Renal Cortex: Gluconeogenesis
Main energy source: oxidation of
FFAs
Contributes ~20%25% of total
body glucose released in the fasting
state
2. Glucose Utilization
Renal Medulla
Obligate consumer of glucose,
insulin-independent
10% of total glucose uptake in the
body, fasted state
FFA=free fatty acid.

1. Gerich JE. Diabet Med. 2010;27(2):136-142.
2. Tortora GJ et al. In: Tortora GJ, Derrickson B, eds. Hoboken, NJ: John Wiley & Sons, Inc; 2009:977-1061.
Glomerular Filtration
180 L/24 h
25000 mEq Na+/24
h
Afferent Efferent
Filtration
Artery
125 mL of filtrate formed/min

(180 L/24 h)
Urine output 1.5 L/24 h
25000 mEq of Na+ Filtered
Urine Na+ excretion

100 mEq/L
Tubular system
140-180 g glucose filtered/24

Reabsorption
h
Urine glucose excretion

=0
Secretion
1.5 L/24h volume

100 mEq Na+/24
h
0 g/24h Glucose
Mount DB, Yu ASL. In: Brenner BM, ed. Brenner and Rectors The Kidney. 8th ed. Philadelphia, PA: Elsevier Saunders;
Because reabsorption occurs
2007:Chapter 5. Abdul-Ghani M, DeFronzo R. Endocr Pract. 2008;14:782-790.
(mg/min)
Rate of glucose
fltration/reabsorption/excretion
Renal Glucose Handling

600
Filtered
400
Tmax
Excreted
Reabsorbed
200
Tm
Threshold
0
0
200
400
600
Plasma glucose (mg/dL)
800
matic representation of the typical titration curve for renal glucose reabsorption in man.
ted from Silverman M, Turner RJ. Handbook of Physiology.
ndhager EE, ed. Oxford University Press; 1992:2017-2038.
Threshold,
TmGlucose,
represents
the
maximal
resorptive
capacity
of the
proximal
tubule
Active (SGLT2) and Passive (GLUT2)

Glucose Transport in a Renal Proximal
Tubule Cell
Tubular lumen
Interstitium
Na+
K+Na+/K+
ATPase
Pump
Na+
SGLT2
Glucose
Glucose
GLUT2
Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42.
Sodium-Glucose
Cotransporters
SGLT1
SGLT2
Site
Mostly intestine with

some in kidney
Almost exclusively
kidney
Sugar
specificity
Glucose or galactose
Glucose
High
Low
KM=0.4 Mm
Km=2 Mm
Low
High
Dietary glucose
absorption
Renal glucose
Affinity for
glucose
Capacity for
glucose
transport
Lee YJ. et al. Kidney Int Suppl. 2007;72:S27-S35.
Renal Glucose Reabsorption
S1 segment
of
proximal
tubule
Glucos
e
SGLT2
~90
% ~10
Reabsorption %
Distal S2/S3
segment of
proximal tubule
S
G
L
T
1
Collecting
duct
NO
GLUCOSE
Chao EC, Henry RR. Nat Rev Drug Discov. 2010;9(7):551-559.

Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Drug Discov.
Pathophysiology of
T2DM
Increased Excretion Threshold and Increased

Glucose Reabsorption Exacerbates
Hyperglycemia in Type 2 Diabetes
600
Subjects With T2D

Healthy Subjects
Healthy Subjects
Filtered
Rate of Glucose Filtration/

Reabsorption/Excretion
(mg/min)
500
400
Reabsorbed
300
Excreted
200
Tm
100
0
0
Normal
Threshold
70 110140
Increased
Threshold
1803
400
Plasma glucose (mg/dL)

T2D=type 2 diabetes; Tm=tubular maximum; UGE=urinary glucose excretion.
1. Bays H. Curr Med Res Opin. 2009;25(3):671-681. Diagram adapted with permission.
2. DeFronzo RA et al. Diabetes Care. 2013;1-8 [Epub ahead of print].
3. Abdul-Ghani M et al. Curr Diab Rep. 2012 Jun;12(3):230-8. Diagram adapted with permission.
600
Renal and Hepatic Glucose Release After

Glucose Ingestion in Patients With Diabetes
molkg-1min-1
Renal Glucose Release
Increased baseline
gluconeogenesis
Insulin resistance
with decreased
suppression of
gluconeogenesis
6
3
0
12
molkg-1min-1
Hepatic Glucose Release
8
4
Increased free fatty

acids in DM
stimulates
gluconeogenesis in
kidney
& liver (n = 10)
With
diabetes
Without diabetes (n = 10)
0
-60
90
180
Minutes
270
Meyer C, et al. Am J Physiol Endocrinol Metab. 2004;287:E1049E1056.
Altered Renal Glucose Control in

Diabetes
Gluconeogenesis is increased in
postprandial and postabsorptive states
in patients with T2D
Renal contribution to hyperglycemia

3-fold increase relative to patients
without diabetes
Glucose reabsorption
Increased SGLT2 expression and

activity in renal epithelial cells from
patients with diabetes vs
Marsenic O. Am J Kidney Dis. 2009;53:875-883.
normoglycemic individuals
Bakris GL, et al. Kidney Int. 2009;75:1272-1277.
Rahmoune H, et al. Diabetes. 2005;54:3427-3434.
Renal SGLT2 Levels

Are Increased in Type 2 Diabetes
Normalized Glucose
Transporter Protein Levels
*
2
NGT
* P < .05 between groups.
T2D
Rahmoune H, et al. Diabetes. 2005;54:34273434.
Rationale for SGLT2 Inhibition in

Diabetes Functional Disorders
Familial renal glucosuria
Due to SGLT2 gene mutations

Rare kidney disorder
Benign
No corresponding kidney complications
Urinary glucose excretion of 1-170 g/d
Absence of glucose reabsorption indicated by higher
urinary glucose excretion
Intestinal glucose-galactose malabsorption

Due to SGLT1 gene mutations
Severe diarrhea
Suggests major role for SGLT1 in intestinal
reabsorption
Corrected by removing glucose, galactose, lactose
Wright EM.
J Intern
Med.
from
the
diet
Rationale for Renal Sodium-Glucose

Cotransporter 2 (SGLT2) Inhibitors
SGLT2 is a low-affinity, high capacity

glucose transporter located in the proximal
tubule and is responsible for 90% of glucose
reabsorption
Mutations in SGLT2 transporter linked to

hereditary renal glycosuria, a benign
condition in humans
Selective SGLT2 inhibitors could reduce

blood glucose levels due to increased renal
excretion of glucose
Selective SGLT2 inhibition, therefore, would

urine
loss of
the calories from
Brookscause
AM, Thacker SM.
Ann Pharmacother
2009;43:1286
Phlorizin: The Prototype SGLT

Inhibitor
HO
HO
OH
OH
HO
HO
HO
HO
O
O
OH
OH
O
O
O
O
OH
OH
HO
HO
First described in the mid-19th

century
Isolated from the root bark of the

apple tree
Utilized in the exploration of SGLT

renkranz JR. Diabetes
Metab Res Rev. 2005.
function
Treatment of Diabetic Rats With

Phlorizin Normalizes Plasma Glucose
Levels
130
120
110
100
90
Group
Group
Group
Group
Group
300
*
Fed glucose (mg/dL)
Fasting glucose (mg/dL)
250
200
150
100
*P<.001
*P<.001 versus
versus groups
groups 1,
1, 3,
3, and
an
I (N=14) sham-operated controls
II (N=19) partial (90%) pancreatectomy
III (N=10) 90% pancreatectomy + phlorizin
IV (N=7) sham-operated + phlorizin
V (N=4) 90% pancreatectomy/phlorizin discontinue phlorizin
ossetti L, et al. J Clin Invest. 1987.
Mechanism of Action
Increase the removal of glucose via SGLT2 inhibitors

Glomerulus
Early
Proximal Convoluted
Tubule
Distal
Glucose in
urine
Decreased glucose
reabsorption into
systemic circulation
Glucose
SGLT2
SGLT2
Rothenberg PL, et al. Poster presented at: 46th Annual Meetinginhibitor
of the
European Association for the Study of Diabetes; September 20-24, 2010;
SGLT-1
Urinary Glucose Excretion (g/day)
SGLT2 Inhibitors Lower Renal

Threshold for Glucose Excretion (RTG)
125
T2DM +
100
SGLT2
inhibitio
n
75
Health
y
180
mg/dL
RTG
T2DM
240
mg/dL
RTG
RTG
50
SGLT2
inhibition
25
0
0
50
100
150
200
250
300
Plasma Glucose (mg/dL)
T2DM=Type 2 Diabetes Mellitus

Adapted with permission from Abdul-Ghani MA,
DeFronzo RA.
bdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008; Nair S, Wilding JP. J Clin Endocrinol Metab
SGLT2 Inhibitors
Dapagliflozin
(approved)
Canagliflozin
(approved)
Empagliflozin
Ipragliflozin
(BI 10773)a
(ASP1941)a
These agents have not been approved by the FDA, but they are
in Phase 3
clinical trials.
a
Conclusions
The kidney contributes to

gluconeogenesis and hyperglycemia in
type 2 diabetes.
SGLT2 inhibitors act by a novel

mechanism and may be useful in
patients who have not achieved goal
HbA1c levels.
Recent research reports that SGLT2

inhibitors lower HbA1c levels and also
have the benefit of weight reduction in
patients with T2DM.

Type 2 Diabetes
Safety and Efficacy Of SGLT2

Inhibitors in T2DM
Rationale for Use and Evidence
from Landmark Clinical Studies
Muhammad Abdul-Ghani, MD, PhD
Associate Professor of Medicine
Diabetes Division
UTHSCSA, San Antonio, TX
SGLT2 Action Is Independent of

Insulin Secretion and Insulin Action
Impaired Beta
Cell Function
Increased
Hepatic Glucose
Production
Insulin
Resistance
90 mg%
Plasma
Glucose
Glucosuria
Decrement in HbA1c (%)
0
DAP
A
2.5
mg/d
DAP
A
5
mg/d
DAP DAPA
50
A
mg/d
10
mg/d
PLA
C
-0.5
-1
List J et al, Diabetes Care 32:650-657, 2009
MET
1500
mg/
dl
Glucosuria (gram/24 h)
Effect Of Dapagliflozin On HbA1c
75
60
45
30
15
0
2.5
5 10 20 50
Dapagliflozin (mg)
SGLT2 Inhibitors are

Effective in Combination
with All Anti-Diabetic
Agents Including Insulin
Decrease In HbA1c (%)
SGLT2 Inhibitors in Combination with

Other Antidiabetic Treatment
0.0
Cana
Dapa
Empa
-0.2
-0.4
-0.6
-0.8
-1.0
Abdul-Ghani, Am J Med 2014 (in press)
Drug Naive
Metformin
SU
Pioglitazone
Insulin
Effect of Dapagliflozin Addition to Insulintreated T2DM Patients (n=71)

A1C (%)
9.0
Body Weight (kg)
0
8.5
Placebo
DAPA-10mg
8.0
Placebo
-2
DAPA-20mg
-3
7.5
7.0
-1
DAPA-20mg
-4
-5
8 10 12
Weeks
Wilding et al, Diabetes Care 32:1656-62, 2009
DAPA-10mg
1 2
10 12
SGLT2 Inhibitors are

Effective in All Stages of
the Disease
Dapagliflozin is Equally Effective in T2DM

Patients with Early and Late Stage
Disease
Early
Late
102
44
Age (years)
55
57
Weight (kg)
86.6
104*
Duration
(years)
1.0
11.1*
FPG (mg/dl)
140
162*
A1c(%)
7.6
8.4*
Number
Zhang et al, Diab Ob Metab 12:510-516, 2010
*p<0.05-0.01
Dapagliflozin (12 Weeks) Reduces A1c

Similarly in T2DM Patients with Early and
Late Stage Disease
Dapagliflozin 10mg
Dapagliflozin 20mg
DECREMENT IN A1c (%)
-0.2
-0.4
E
A
R
L
Y
L
A
T
E
E
A
R
L
Y
-0.6
-0.8
Weight loss and UgluV

were similar in early
and late stage T2DM
Zhang et al, Diab Ob Metab 12:510-516, 2010
L
A
T
E
The Amount of
Glucosuria is Smaller
than Expected from
SGLT2 Inhibition
Renal Handling Of Glucose
(180 L/day) (950 mg/L) = 170

g/day
S1
~90%
(150
Grams
)
SGLT
2
S3
~10
%
S
G
L
T
1
NO
GLUCOSE
(180 L/day) (~950 mg/L) =

~170 g/day
SGLT
2 S1
S3
S
G
L
T
1
~150 g/d,
50%
Occupancy
~20g/d,
20%
Occupanc
y
NO
GLUCOSE
(180 L/day) (~950 mg/L) = 170

g/day
SGLT 2
S1
0
g/d
~120g/d,
100%
S3
S
G
L
T
1
~50
g/d
Relationship Between UGE and

Plasma Glucose Concentration
Fraction of GFL Excreted
1.0
0.8
0.6
0.4
0.2
0.0
0
100
200
300
400
500
Plasma Glucose Concentration (mg/dL)

Abdul-Ghani M A et al. Diabetes 2013;62:3324-3328
Impact of Baseline HbA1c on

Dapagliflozin Efficacy
8.0
HbA1c (%)
FPG (mg/dl)
Dapa (mg)
Change in HbA1c (%)
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
Diabetes Care 33:2217-24, 2010
10.8
162
165
231
10
241
10

Decrease in HbA1c (%)
HbA1c
Range
HbA1c
<8%
>9%
8-9
0.0
-0.4
-0.8
-1.2
-1.6
Baseline
7.37
8.43
9.54
24 weeks
6.73
7.23
7.76
Ji et.al. Clin Therap 36:84-100, 2014
Durability of HbA1c
Decrease by SGLT2
Inhibitors
Effect of Dapagliflozin Addition on A1c in Inadequately

Controlled T2DM (A1c=8.6%) on Insulin Therapy (74-80
units/day) +OADs
0-
Placebo
(n=193)
-0.4 -0.6 -
DAPA-2.5mg (n=202)
-0.8 -
DAPA-5mg (n=221)
Wilding et al, Ann Int Med 156:405-15, 2012
Weeks
8 12 16 20 24
DAPA-10mg (n=194)
32
40
48
-
-1.2 -
-1.0 -
Change in A1c (95% CI)
-0.2 -
Dapagliflozin Versus Glipizide in Inadequately

Controlled T2DM ON Metformin One Other OAD
Baseline A1c
=7.7%
0-
Dapagliflozin
(n=400)
-0.52%
-0.4 -0.6 -
-0.52%
Nauck et al, Diabetes Care 34:2015-22, 2011
Weeks
34
42
26
18
Maintenance
-
12
Titration
-1.0
-0.8Glipizide
(n=401)
Change in HbA1c (%)
-0.2 -
52
Metabolic Effects of
SGLT2 Inhibitors
Subject Population
Subject
Population
Dapagliflozi
n
Placebo
12
male
Male
Age (years)
48 4
54 4
BMI (kg/m2)
31.4 1.9
33.2 0.4
HbA1c (%)
8.7 0.3
8.6 0.2
FPG (mg/dl)
161 9
165 10
Total Chol (mg/dl)
156 10
169 15
Triglyceride
(mg/dl)
164 34
171 56
Number
Sex
Effect of Dapagliflozin Treatment on Whole Body

Insulin Sensitivity and Beta Cell Function
p<0.05
C- Peptide/G Rd
mg/kg min
20
Before
After
Total Body TGD
P = 0.03
15
3.1
10
5
0
1.7
Before
Beta Cell
Function
After
Effect of Dapagliflozin on
Endogenous Glucose Production
Drug
Ingestion
2.8 -
Dapagliflozin
Dapagliflozin
2.4 2.0 -
Day 2
Day
3
Day
1
Day
0
1.2
Placebo
1.6 -
Placebo
EGP (mg/kg min)
3.2
Day
14
Impact of the Increase in HGP in

Response to Glucosuria on Blood
Glucose
bHGP
Glucosuria
FPG
(g/24h)
(mg/dl)
(mg/kg.m
in)
Day 1 (Before)
12
151
2.16
Day 3 (After)
92
126
2.53
-25
+45
g/24 h
Impact on Blood
Glucose
-80
g/24h
The Combination of
SGLT2 Inhibitors plus
GLP-I Analogues has the
Potential to Cause
Synergistic Decrease in
HBA1C
Effect of Background Therapy on

Canagliflozin Efficacy
Background
Therapy
DPP-IV
Inhibitor
GLP-1
Analogue
PLAC CANA
PLAC CANA
Change in HbA1c (%)
0.25
0.00
-0.25
-0.50
-0.75
-1.00
Meininger et al. Diabetologia 56 (supl 1) S373, 2013
Summary of Glycemic Actions

of SGLT2 Inhibitors
SGLT2 inhibitors lower HbA1c independent of

insulin secretion and action
Effective in all stages of the disease

Can be combined will all other therapies
The efficacy of SGLT2 inhibitors increases

with the increase in baseline HbA1c
SGLT2 inhibition stimulates a compensatory

increase in HGP
Potential combination with GLP-1 analogues
SGLT2 Inhibition Exerts

Many Non-Glycemic
Metabolic Benefits
Effect of Dapagliflozin versus

Glipizide
on Body Weight
Baseline Weight =88.4 vs
87.6kg
+1.44kg
2-
Glipizide
0Dapagliflozin
-1 -2 -
-3.22 kg
Nauck et al, Diabetes Care 34:2015-22, 2011
26
Weeks
34
42
18
P<0.0001
-
12
Maintenance
-
Titration
-
-4 -
-3 -
hange in Body Weight (kg)
1-
52
Placebo +
Metformin
N=91, n=79
Dapagliflozin 10 mg+
Metformin
N=89, n=82
Change in adipose tissue volume (cm3)
Change in body mass composition (kg)
Effect of Dapagliflozin on Body Fat

Mass
J Clin Endocrinol Metab, March 2012, 97 (3):1020-1031
Dapagliflozin 10 mg+
Placebo +
Metformin
Metformin
N=42, n=37 N=37, n=30
Effect of Dapagliflozin on Blood Pressure

In Metformin-Treated T2DM Patients
DAPA
10 mg
DAPA
5 mg
DAPA
2.5 mg
DAPA
10 mg
-0.1
0
-1
-2
-2.1
-3
-3
-4
-4
-4.3
-5
-5.1
Bailey CJ et al, Lancet 375:2223-33, 2010
-5
Diastolic BP
-2
DAPA
5 mg
-1
-0.2
DAPA
2.5 mg
Systolic BP
PLAC
PLAC
Effect of Dapagliflozin on Plasma Lipids

and
Uric Acid Concentration
Baseline
Dapagliflozin
200
48
110
6.0 5.9
195
5.5 -
104
100 - 100
44.2
44 -
190 5.0 -
42.3
183
90
LDL CHOL
(mg/dl)
40
HDL CHOL
(mg/dl)
Bailey et al, Lancet 375:2223-33,2010
180
Triglycerides
(mg/dl)
4.5
Uric Acid
5.0
Lipid Profile in Phase III Trials
Dapagliflozi Dapagliflozi
n
5 mg n 10 mg
Effect
Placebo
Number
1393
1145
1193
T. Cholesterol
-0.4%
+1.1%*
+1.4%*
HDL
+3.8%
+6.5%*
+5.5%*
LDL
-1.9%
+0.6%
+2.7%*
Triglycerides
-0.7%
-3.2%*
-5.4%*
FFA
-5.7%
-0.5%
1.2%
Hardy et.al. Diabetologia 56:S379, 2013
SGLT 2 Inhibition: Meeting Unmet

Needs in Diabetes Care
Reduces
HbA1c
Lowers TRIG
Increases HDL
Promotes
Weight Loss
Reduces
Blood
Pressure
Complements
Action of Other
Antidiabetic
Agents
Improves
Glycemic
Control
and CVRFs
Reversal of
Glucotoxicity
No
Hypoglycemia
Summary of Ongoing CV Outcomes

Trials
with SGLT2 Inhibitors
Name
NCT01032629
NCT01131676
NCT01730534
Treatment Patients
Canagliflozi T2DM and
n and
high CV
placebo
risk
Empagliflozi T2DM and
n and
high CV
placebo
risk
Dapagliflozi T2DM and
n and
high CV
placebo
risk
Number
Completion
4400
2018
7000
2015
22200
2019
Safety Issues
Hemodynamic Side Effects
Dapagliflozin on Hemodynamic
Placebo
Age (y)
HbA1c (%)
GFR (ml/min)
SBP (mmHg)
GFR (%)
Plasma Volume
(%)
RBC mass (%)
Dapaglifloz
Placebo
in
HCTZ
58
7.5
101
-0.7
-2.9
54
7.7
101
-3.3
-10.8
55
7.4
102
-6.6
-3.4
+5.2
+2.8
-7.3
+1.2
-6.5
+6.6
Heerspink et.al. Diabetes, Obesity and Metabolism 15: 853862, 2013
Incidence of Infections in
Phase III Trials of Canagliflozin
Infections
Any UTI
Symptomatic
UTI
Upper UTI
Serious UTI
Mycotic
Infections
Females
Male
Usiskin et.al. Diabetologia 56:S380, 2013
Placebo
100 mg 300 mg
5.9
4.3
2.6
3.8
3.2
0.1
0.1
0.2
0.1
3.2
10.4
11.4
0.6
4.2
3.7
Dapagliflozin Has No Effect on Bone

Markers

Type 2 Diabetes
A Practical Roadmap for

Individualizing and Optimizing Use of
SGLT2 Inhibitors
in Clinical Practice
Charles F. Shaefer, Jr., MD, FACP
Senior Partner
University Medical Group Primary Care
University Health Systems
Assistant Clinical Professor of Medicine
Medical College of Georgia at Georgia Regents
University
Augusta, Georgia
Ominous Octet
eFronzo RA. Diabetes. 2009;58:773-795.
Survival as a Function of A1C in Patients

with
Type 2 Diabetes: A Retrospective Cohort
Study*
Oral Agents
Currie CJ, et al. Lancet. 2010;6(375):481-9.
Insulin +/- Oral Agents
*28,000 patients 50 years and older
Challenges in Type 2 Diabetes
Large number of patients
Diabetes affects 25.8 million people (8.3 % of the US population)

DIAGNOSED- 18.8 million people
UNDIAGNOSED- 7.0 million people
PREDIABETES 79 million people
Progressive worsening of insulin secretory deficit

requiring increased number of antihyperglycemic
medications over time
Risk for hypoglycemia with some therapies
Risk for weight gain with some therapies
Difficulty controlling postprandial glucose and glucose
fluctuations
Preventing and managing complications and comorbidities
2010.
National
Diabetes Fact
Sheet. US Department
of Health and optimal
Human Services.
Difficulty
attaining
and sustaining
long-term
u, WT. Am J Med. 2012;343(1):21-26.
glycemic control
% Patients
With HbA1c
<7%
Many Patients With T2DM

Are Not Reaching HbA1c <7%
N=1334.
Data from NHANES: National Health and Nutrition Examination Survey.
Unmet Needs With Conventional

Antihyperglycemic Therapies
Many therapies are associated with weight

gain
Insulin and non incretin oral insulin
secretagogue therapies are associated with
significant risk for hypoglycemia
Other AEs with some therapies include GI side
effects and edema
Many therapies fail to adequately control
postprandial hyperglycemia
Therapies often fail to maintain long-term
glycemic control
Blonde L. Am J Manag Care. 2007;13:S36-S40.

Blonde L, et al. J Manag Care Pharm. 2006;12(suppl):S2-S12.
How Do SGLT2 Inhibitors Potentially

Meet These Needs?
Associated with weight reduction generally
Have no inherent propensity to cause

hypoglycemia (unless used with
secretagogues or insulin)
Very few side effects
Control postprandial hyperglycemia
Seem to offer long-term glycemic durability
Unmet Needs
Type 2 DM Control is Not Durable
12
15
18
21
24
27
30
Time (months)
omgarden, ZT. Diabtes Care. 2007;30(1):174-180.
33
36
39
42
45
Rationale for SGLT2 Inhibitors
SGLT2 is a low-affinity, high capacity glucose

transporter located in the proximal tubule and is
responsible for 90% of glucose reabsorption
Mutation in SGLT2 transporter linked to hereditary
renal glycosuria, a relatively benign condition in
humans
Selective SGLT2 inhibitors have a novel & unique
mechanism of action reducing blood glucose levels
by increasing renal excretion of glucose
Decreased glycemia will decrease glucose toxicity
leading to further improvements in glucose control
Selective SGLT2 inhibition, would also cause urine
loss of the calories from glucose, potentially
leading to weight loss
ks AM, Thacker SM. Ann Pharmacother. 2009;42(7):1286-1293.
What Shapes Clinical Consideration of

SGLT2 Inhibitors?
Efficacy
Durability
Collateral benefits
Weight reduction
Blood pressure reduction
Side effects
Patients renal status
Meta-analysis for HbA1c Change from

Baseline, 10mg Dapagliflozin versus
Placebo
Clar C et al. BMJ Open 2012;2:e001007

2012 by British Medical Journal Publishing Group

Placebo


Placebo


Placebo

Canagliflozin
Metformin + Canagliflozin Dose-Ranging Study
Mean Baseline
A1C (%)
7.71
8.01 7.81
7.57
7.70
7.71
7.62
osenstock J, et al. Abstract 77-OR. ADA 2010.
*P.001 vs. placebo calculated using LS mean
Changes from Baseline in A1C

in Phase 3 Dapagliflozin Studies
Placebo
Dapa 2.5mg
Dapa 5mg
Dapa 10mg
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet.
Collateral Benefits
Weight reduction
BP reduction
FBS reduction
Canagliflozin
SGLT2 Inhibition for Type 2 Diabetes:
Metformin + Canagliflozin Dose-Ranging Study
Mean Baseline
Weight (kg)
85.5 87.5
87.7
87.7
87.8
86.3
87
*
*
*
*
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
*
*
*P.001 vs. placebo calculated using LS mean
Changes from Baseline in Body Weight

in Phase 3 Dapagliflozin Studies
Placebo
Dapa 2.5mg
Dapa 5mg
Dapa 10mg

Baseline,
10mg Dapagliflozin versus Placebo

Meta-analysis for Weight Change from

Baseline,
10mg Dapagliflozin versus Placebo

Dapagliflozin as Add-on to Metformin

2 Year Extension Study
from BL
(SE)
A1c, %
FPG, mg/dl
Body weight, kg
% Pts with 1
hypoglycemic
event
Placebo
DAPA
2.5mg
DAPA 5mg
0.2 (0.11)
-0.48 (-.1)
-0.58 (0.1)
-0.78 (0.09)
-10.4 (3.6)
-19.3 (3.2)
-26.5 (2.8)
-24.5 (2.7)
-0.7 (0.5)
-2.2 (0.5)
-3.4 (0.4)
-2.8 (0.4)
5.8
3.6
5.1
5.2
Events suggestive of urinary tract infection

Dapagliflozin 2.5 mg: 8.0%, 5 mg: 8.8%, 10 mg: 13.3%
Placebo: 8.0%
Events suggestive of urinary tract infection

Dapagliflozin 2.5 mg: 11.7%, 5 mg: 14.6%, 10 mg: 12.6%
Placebo: 5.1%
DAPA
10mg
Events primarily mild or moderate in intensity and responded to standard treatment
Bailey CJ et al. Abstract 988-P. ADA 2011.
Blood Pressure Reduction
Changes from Baseline in Fasting Plasma

Glucose in Phase 3 Dapagliflozin Studies
5
0
-5 mg/dL
-10
-15
-20
-25
-30
Side Effects
Genital
mycotic infections
Urinary
tract infections
Bladder
cancer
Genital Mycotic Infections

Dapagliflozin
Genital
Mycotic
Infections
(GMI)
Placebo
Dapa 5 mg
Dapa 10 mg
0.9%
5.7%
4.8%
10.0%
23.1%
25%
Patients without
prior GMI
0.8%
5.9%
5.0%
Discontinuation
due to GMI
0.0%
0.2%
Genital mycotic
infection overall
Patients with
prior GMI
Farxiga Package Insert, accessed March 2014
Genital Mycotic Infections (GMI)

Canagliflozin
Genital Mycotic
Infections (GMI)
Placebo
Canagliflo Canagliflo
zin 100
zin 300
mg
mg
Female
GMI
Vulvovaginal Pruritis
3.2%
0.0%
10.4%
1.6%
11.4%
3.0%
Male
GMI
0.6%
4.2%
3.7%
Invokana Package Insert, accessed March 2014
Bladder Cancer Risk

Risk
Placebo
Number exposed
% incidence
Any exposure to
drug
Number exposed
% incidence
Exposure to drug >
12 months
Number exposed
incidence
Dapagliflozin
Canaglifloz
in
3156
0.03%
5478
.16%
4 cases
Farxiga and Invokana Package Inserts, accessed March
How Does Renal Status

Impact SGLT2 Inhibitor
Use?
Snapshot of DKD in the United States
DKD affects 20%-40% of patients with

diabetes
Diabetes accounts for 44% of new cases of

kidney failure
Leading cause of ESRD

48,374 people with diabetes began treatment for
ESRD
202,290 people with ESRD due to diabetes living
on chronic dialysis or have undergone a kidney
transplant
29% (or $33.6 billion) of excess medical

expenditures associated with diabetes care
ADA. Diabetes Care. 2008;31:596-615; National Institute of Diabetes and Digestive and Kidney
due
to
renal
Diseases.
National
Diabetes
Statistics,
2011. disease in 2007
113 was
DKD = diabetic kidney disease

ESRD = end stage renal disease
http://diabetes.niddk.nih.gov/dm/pubs/statistics/DM_Statistics.pdf. Accessed February 4, 2013.
Impact of GFR and FBS on Glucose

Clearance by SGLT2 Inhibitors
Indications for Usage of

SGLT2 Inhibitors Based on GFR
Glomerular Filtration Rates
Glomerular
Filtration
Rates
< 30
ml/min
<45 ml/min
45-60
ml/min
60
ml/min
Canagliflozin
No
No
100 mg only
100 or 300
mg
Dapagliflozin
No
No
No
5 or 10 mg
Farxiga and Invokana Package Inserts, accessed March 2014
Summary: Focus on Clinical Implications

Regarding SGLT2 Inhibitor Use
Who are best candidates for SGLT2

Inhibitor therapy?
What role do cardiometabolic

considerations play in selection of SGLT2
Inhibitors for therapy?
How do SGLT2 inhibitors fit into the overall

spectrum of diabetes care?
Who Are the Best Candidates?
Where renal status is good (usually early

on in therapy)
Where weight reduction would be

desirable
Where avoiding hypoglycemia is desirable
Where few side effects are desirable
Where A1C reductions of up to 1% may be

needed
Where basal insulin has not achieved A1C

goal and up to about 1% A1C reduction is
How Do CV Risks and Cardiometabolic Factors

Shape the Decision to Use SGLT2 Inhibitors?
Obesity is a risk factor
Hypertension is a risk factor
About 5 mm Hg reduction in SBP
Elevation in A1C is a risk factor
2.36 kg weight reduction seen over 2

years
About 1% reduction in A1C (relates to

about 16% reduction in MI risk in UKPDS)
Elevation in lipids are a risk factor
May increase LDL 4 8 mg/dl

Reason for this unknown
How Do SGLT2 Inhibitors Fit Into the

Spectrum of Diabetes Therapy?
Clearly well suited as initial monotherapy,

dual combination therapy or add on to
metformin therapy
Cardiovascular Outcome Trials are in

progress and should report out in the next
few years
Adds on well to insulin (even some studies

with T1D)
Only limitation is decreased effectiveness

with decreasing GFR ( < 60 ml/min)
Monotherapy Study
Summary and Conclusions

In treatment-nave patient with newlydiagnosed Type 2 DM, dapagliflozin
monotherapy resulted in:
Clinically meaningful decreased in A1C and fasting
plasma glucose with a near absence of
hypoglycemia
Favorable effects on weight and blood pressure
In the exploratory evening dose cohort,

changes from baseline in A1C, fasting plasma
glucose, and body weight at week 24 were
similar to those seen in the main patient
cohort
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.
In the high A1C (QAM) exploratory cohort,
Monotherapy Study
Increased incidence of urinary tract and

genital infections with dapagliflozin
treatment:
Events suggestive of urinary tract infection were
4%, 4.6%, 12.5%, and 5.7% for placebo,
dapagliflozin 2.5mg, 5mg, and 10mg groups,
respectively
Events suggestive of genital infections were
1.3%, 7.7%, 7.8%, and 12.9% for placebo,
dapagliflozin 2.5mg, 5mg, and 10mg groups,
respectively
Hypoglycemic events occurred in 2.7%,

rannini E, et al. Diabetes Care. 2010;33(10):2217-2224.
1.5%, 0%, and 2.9% in patients in
Dapagliflozin as Add-on Therapy

Add-on to metformin in patients inadequately

controlled with metformin alone
Favorable safety parameters and
tolerability
Improved glycemic control
Lowers weight
Not associated with risk for hypoglycemia
Adverse events occurred in similar
proportions
Bailey CJ, et al. Lancet.

Add-on to glimepiride in patients poorly

controlled sulfonylurea therapy
Significantly improved mean A1C
Reduced weight
Well-tolerated
Adverse events were similar across all

treatment groups
Strojek K, et al. Abstract 870. EASD 2010

Add-on to insulin in patients poorly controlled

with insulin
Sustained effectiveness and stable tolerability
Less likely to D.C or require insulin up-titration due
to poor glycemic control versus placebo
Increased frequency of weight loss and reduced
frequency of peripheral edema over time
Adverse events and discontinuations were balanced
across groups
Actively solicited signs and symptoms suggestive of
urinary tract (UTI) and genital infections (GI) were
higher with dapagliflozin vs. placebo
Wilding JPH, et al. Abstract 78-OR.
Take-Home Messages
SGLT2 inhibitors are a new class that are

independent of insulin activity for effect.
They are among the most potent oral

agents for T2D.
Outside of possible GMIs, this class has very

few side effects.
This class may have possible benefits for

CV protection by means of weight
reduction, lowering of blood pressure, and
other as yet unknown mechanisms.
New Frontiers and Emerging

Paradigms
From Science, Data, and

Evidence to Optimal Practice in
the Real World
Case Study Simulations Using an
Audience Response System (ARS)
Clinical Decision Tree Analysis Focused on
Evidence-Based Deployment of SGLT2 Inhibitors
in Patients with T2D
Case Study 1
47-year-old African American male presented

for better BP control and had a 6 year history
of Type 2 Diabetes. His family history is
positive for diabetes and hypertension in both
parents. He denies smoking or drinking and
has no allergies
PMH unremarkable other than above
ROS: positive for polyuria and nocturia and
fatigue.
Current meds: metformin 1000mg BID,
HCTZ 25mg/d, simvastatin 20 mg/d, ASA 81
mg/d
Physical Exam: BMI-32; BP 158/98 mmHg,
Case Study 1
Labs
Sodium-138, potassium-3.5 mEq/L, BUN 31,

creatinine-1.4 mg/dl (eGFR-63 ml/min), HCO328mEq/L, glucose -292 mg/dl, HbA1c-9.6%- CBC,
Hb-15.2 g/L, UAC-212 mg/d. Other labs were
normal
Plan: Stopped HCTZ and started on

chlorthalidone 25 mg/day and azilsartan 80
mg/day for BP. We checked a fasting cholesterol.
3-weeks later returned BP 136/82 mmHg, HR 76,

fasting sugar was 251 mg/dl and LDL cholesterol
was 108 mg/dl
Case Study 1 Question 1

Which of the following would you add to
metformin to maximally improve glycemic
control and aid in alleviating co-morbid
conditions?
1) Sulfonylurea
2) DPP4 inhibitor
3) SGLT2 inhibitor
4) GLP-1 agonist
Please Enter Your Response On Your Keypad
Case Study 1
Physician added exenatide extendedrelease (Bydureon) 2 mg. once-weekly

injection
3-weeks later returned with BP 136/82

mmHg, HR 76, fasting sugar was 218
mg/dl and LDL cholesterol was 108 mg/dl.

What would be your next step to maximally
improve glycemic control and aid in
alleviating co-morbid conditions?
1) Sulfonylurea
2) DPP4 antagonist
3) SGLT2 inhibitor
4) Basal insulin
Case Study 1
Plan: The patient was started on the SGLT2

inhibitor, dapagliflozin 5 mg/day and
simvastatin was increased to 40 mg at
bedtime.
Patient returned in 3 weeks and BP was

130/78 mmHg, lost 4 lbs, fasting glucose147 mg/dl

What would be your next step to maximally
improve glycemic control and aid in
alleviating co-morbid conditions?
1) Start insulin
2) Add sulfonlyurea
3) Increase dose of dapagliflozin to 10 mg po
daily
4) Add a DPP-4 inhibitor
Case Study 1
We increased dose of SGLT2 inhibitor
dapagliflozin to 10 mg daily and told him
to return in 2 months for repeat labs at 2
months.
Fasting glucose was 103 mg/dl, HbA1c was
7% and BP was 128/78 mmHg HR-74 and
had lost another 4 lbs.
Case Study 2
A 45-year-old male patient with a history
of polydipsia and polyuria
BMI=34.3 and BP=146/98
Lab tests:
FPG =356 mg/dl

HbA1c= 14.1%
Trig=452
HDL= 32
LDL=98

What would you start this patient on?
1) Lifestyle modification only
2) Life style plus metformin
3) SGLT2 inhibitor
4) Basal insulin
Antihyperglycemic Therapy in Type 2 Diabetes: ADA

Recommendations.

The patient was referred for intensive lifestyle
modification and was started on metformin 1000 mg
daily, and lorcaserin 10 mg twice daily. He returned in
4 weeks with a 3% weight loss and HbA1c level was
9.9%. At this point you would:
1) Add dapagliflozin 10 mg once daily and

discontinue lorcaserin
2) Add dapagliflozin 10 mg once daily and
continue lorcaserin
3) Begin a basal insulin and continue
lorcaserin
4) BeginPlease
a GLP-1
agonist
discontinue
Enter Your
Responseand
On Your
Keypad

8.0
HbA1c (%)
FPG (mg/dl)
Dapa (mg)
Change in HbA1c (%)
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
Diabetes Care 33:2217-24, 2010
10.8
162
165
231
10
241
10
Effect of Dapagliflozin With and Without

Metformin on HbA1c in Subjects With
New Onset T2DM
Dapagliflo
Metformin Dapa+Met
zin
Number
196
195
185
Initial A1c (%)
9.14
9.14
9.21
A1c at 24 W (%)
7.96
7.79
7.13
A1c (%)
-1.19
-1.35
-2.05
% A1c <7.0%
22.5
34.5
52.4
10.33
10.18
10.29
A1c at 24 W
8.65
8.4
7.3
A1c (%)
-1.67
-1.82
-3.01
Initial A1c>9.0%
Initial A1c
Int J Clin Pract, May 2012, 66. 5, 446-456
FPG Concentration

The patient returned 8 weeks later with a 6%
weight loss, and a HbA1c of 8.4%. At this
point you would:
1)Add basal insulin and continue lorcaserin
2)Add GLP-1 agonist and continue lorcaserin
3)Increase metformin dose to 2000 mg/day
and
continue lorcaserin.
4)Continue lorcaserin and leave antidiabetic
therapy unchanged.
Enter Your Response On Your Keypad
5)Add Please
DPP-4
inhibitor and continue lorcaseri
Case Study 3
A 56 year-old woman with T2DM
BMI=32.1, HbA1c = 8.8%
Treated with metformin 2000 mg/d,
actos 30 mg/d, and glargine 52 U/d
FPG=125 mg/dl

How would you treat this patient who is
not achieving ADA target goal on a
regimen of metformin and basal insulin
1)Initiate a short acting insulin
2) Start an SGLT2 inhibitor
3) Start a DPP-IV inhibitor
4) Start a GLP-1 analogue
Effect of Dapagliflozin Addition to Insulintreated T2DM Patients (n=71)

A1C (%)
9.0
Body Weight (kg)
0
8.5
Placebo
DAPA-10mg
8.0
Placebo
-2
DAPA-20mg
-3
7.5
7.0
-1
DAPA-20mg
-4
-5
8 10 12
Weeks
Wilding et al, Diabetes Care 32:1656-62, 2009
DAPA-10mg
1 2
10 12
Effect of Dapagliflozin Addition on A1c in Inadequately

Controlled T2DM (A1c=8.6%) on Insulin Therapy (74-80
units/day) +OADs
0-
Placebo
(n=193)
-0.4 -0.6 -
DAPA-2.5mg (n=202)
-0.8 -
DAPA-5mg (n=221)
Wilding et al, Ann Int Med 156:405-15, 2012
Weeks
8 12 16 20 24
DAPA-10mg (n=194)
32
40
48
-
-1.2 -
-1.0 -
Change in A1c (95% CI)
-0.2 -
Exenatide versus Insulin Lispro in

Subjects Treated with Basal Insulin
EXENATIDE
LISPRO
P-Value
Number
316
321
HbA1c (%)
8.2
8.2
NS
HbA1c
Body Weight
(kg)
-1.1
-1.1
NS
-2.5
+2.1
<0.002
Hypoglycemia
(event/year)
0.6
3.3
<0.01
GI Side effects
(%)
32%
8%
<0.02
Case Study 4
45 year old female presents with a 5 year

history of T2D, hypertension, mild
obesity and hyperlipidemia.
She has been treated with maximum

dose metformin daily (1000 mg BID) from
diagnosis and within 1 year her A1C fell
from 8.6% to 7.0%
However, in the next year the A1C went

up to 7.8% and she was treated with
glipizide 10 mg BID. She feels shaky
from time to time and often nibbles to
avoid that sensation. Her A1C is 7.3%.

The main problem with her current
therapy is that:
1)Her A1C is not under 7%
2)She has not optimized her SU therapy
yet
3)She is having mild hypoglycemia
4)She needs a GLP-1 RA added to lower
glucose and decrease her weight
7%
DiabetesCare,Diabetologia.19April2012[Epubaheadofprint]
(Adaptedwithpermissionfrom:IsmailBeigiF,etal.AnnInternMed2011;154:554)

She works as a school bus driver
and has a major concern about
adding an injection. Which option
best suits her needs?
1) Increase her SU to lower A1C
2) Add a TZD
4) Add an SGLT2 inhibitor

Which of the following is not of
major concern in planning her
therapy?
1)Frequency of dose administration
2)Likelihood of causing pancreatitis
3)Hypoglycemia risk
4)Potential for weight gain
Case Study 4
Dose frequency has been shown to impact

adherence
The FDA and EMA have issued statements

that there is not available data to
implicate therapies in pancreatitis risk
Hypoglycemia has been associated with

poor patient response and definite
worsening of CV events
Many antidiabetes therapies are

associated with expected weight gain
Case Study 4
Her current A1C = 7.3%

Current medications are
Metformin 1000 mg BID

Glipizide 10 mg BID
Lisinopril 20 mg QD
Simvastatin 20 mg QD
Her vital signs are

Height 64 inches
Weight = 179 lb
BP = 135/82
TC = 139
HDL = 33
LDL = 96
TG = 123

What would you do next for this
patient?
2) Add an SGLT2 Inhibitor
3) Add basal analog insulin
4) Add a TZD
Case Study 4
A DPP-4 inhibitor should get her to

A1C goal, but will not help with her
weight
Basal insulin is a reasonable choice

but she has shown resistance to
injections and will have a very hard
time getting a CDL on insulin
A TZD will increase her weight and

may contribute to a worsened
fracture risk
An SGLT2 inhibitor should reduce

weight and SBP as well as lowering

Prior to starting an SGLT2 Inhibitor
there are 2 features of her history you
want to explore. What are they?
1)Her eGFR
2)Prior history of kidney disease
3)Her history of prior GMIs
4)Her history of liver disease
5)1 and 3
6)2 and 4
Important Concerns Before

Starting An SGLT2 Inhibitor
Absolute contraindication to SGLT2

Inhibitor use
Effectiveness decreases dramatically with

decreasing eGFR
Functioning nephrons required for glucose
release
Dapagliflozin requires eGFR 60 ml/min for
use
Canagliflozin contraindicated < 30 ml/min,
discouraged < 45 ml/min, low dose only eGFR
45-60 ml/min and high dose only if eGFR > 60
ml/min
Relative increase for most common

side effect of SGLT2 use
Females prior Hx GMI

Regarding hypoglycemic risk,
adding an SGLT2 inhibitor will not
augment risk
1)True
2)False
Hypoglycemia and SGLT2 Use
Hypoglycemic risk is essentially

non-existent if not on a
secreatagogue or insulin
Use of a secreatagogue or insulin

in the presence of an SGLT2
Inhibitor will increase the
likelihood of hypoglycemia by
augmenting the risk of the SU or
insulin

You decide to do which of the
following?
1)Increase the SU to maximum
dose
2)Add dapagliflozin 5 mg daily
3)Add dapagliflozin 10 mg daily
4)Add saxagliptin 2.5 mg daily
Case Study 4
Increasing the SU is not a good choice

as she is already showing signs of mild
hypoglycemia
Dapagliflozin should be started at 5

mg daily and increased to 10 mg daily
if additional efficacy is ultimately
needed
Low dose saxagliptin has been studied

and shown beneficial in end stage
renal disease and dialysis patients
( A1C reduction 0.8% with no increase
in hypoglycemia), but it will not give
Case Study 4
Her SU is dropped due to

hypoglycemia
Dapagliflozin is added at 5 mg
QD
Her metformin is continued
Her A1c is now 6.7% and she has

lost 4 lb
Her BP is 128/80
Her lipids remain unchanged

Type 2 Diabetes
Translating Scientific and Clinical

Advances in Renal-Mediated Glucose
Regulation and SGLT2 Inhibition to the
Front Lines of Diabetes Care
The Role of SGLT2 Inhibition for
Individualizing and Optimizing Multimodal
Care in T2D
VIVIAN A. FONSECA, MD, FRCP
Program Chair
Professor of Medicine and Pharmacology | Tullis Tulane
Alumni Chair in Diabetes | Chief, Section of
Endocrinology | Tulane University Health Sciences
Center | Immediate Past President, Science and
The Emerging Role of the Kidney in Diabetes

Treatment: SGLT 2 Inhibitors Address Unmet
Needs
Good efficacy in lowering A1C
Equivalent to metformin or sulfonylurea
No increased risk of hypoglycemia
Weight loss
Once daily dosing, irrespective of meals
Oral
Effective in the full spectrum of patients
Independent of background therapy

Independent of duration of diabetes
Safety/tolerability on par with other

approved agents
Perspectives on SGLT2 Inhibition

Potential Advantages
Concerns
Once daily administration

Decreases FPG, PPG, A1c
Weight loss (60g urine glucose
= 240 kcal/day= lb/week)
No/ Low risk of hypoglycemia
Modest blood pressure
lowering
Effect independent of insulin
secretion or insulin resistance
Use complementary with other
T2D Rx- ?T1D,? Pre-diabetes
Potential for use in Type 1
Diabetes
Bacterial urinary tract

infections
Fungal genital infections
May not be as effective in
patients with renal impairment
Transient initial period of
dehydration, polyuria, thirst
No known long-term effects on
kidney and on CV outcomes
Added cost to diabetes therapy
Clinical Studies
with SGLT2 Inhibitors
Where Do They Fit in the
Treatment Algorithm?
SGLT2 Inhibitors: Where Do They Fit

in the Treatment Algorithm?
Monotherapy
Add-on to: MET, SU, PIO, DPP4i
Triple therapy with MET, DPP4i, PIO
Add-on to insulin in T2DM
Add-on to insulin in T1DM
IGT/IFG
A1c > 10.0%
Add on to GLP-1 analogue
A Road Map for Clinical Success
Your Questions from

Todays Symposium

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Please Take A Moment to Complete the Pre-Program Clinical

Performance and Knowledge Gap Assessment Survey

New Therapeutic Paradigms

Welcome and Program

Vivian Fonseca, MD Research Support (to

Honoraria for Consulting

Muhammad Abdul- Consultant:

Grants from Eli Lilly, Abbott, Reata,

Glaxo Smith Kline, Takeda, Novo

An Evidence-to-Strategy Update for

The Challenges of Achieving ADA

Professor of Medicine and Pharmacology | Tullis Tulane

Evolving Frontiers of Antidiabetic

drugs worthy of our attention, analysis, and

CV Mortality Increases with Increasing

EPIC-Norfolk: 4662 Patients Followed for 4 Years

Impact of Intensive Glycemic

In the overall analysis, intensive glucose control had no significant

ACCORD Eye: Microvascular Relative

Median Int: 6.4%a

Significant between-group difference was maintained throughout the study

ACCORD=Action to Control Cardiovascular Risk in Diabetes

Long-term Effects of Intensive Glucose

Intensive (metformin) vs. Conventional glucose control

Holman RR, et al. N Engl J Med 2008;358:254559.

Legacy of Bad Metabolic Memory

After entering VADT intensive

Time since diagnosis

Upper broken line: theoretical reconstruction of prior diabetes progression based on

Lower broken line: the ideal time course of glycemic control

Del Prato S, et al. Int J Clin Pract 2010;64:295304.

Complications are Irreversible

Benefit of Different Interventions

Sattar N; Diabetologia 2013

Primary Risk Factors for CVD

FPG / preprandial glucose

<140/80 mmHg, or further lowering

<100 mg/dL, patients with diabetes

American Diabetes Association, Diabetes Care 2013

Despite Important Advances in

Too many patients! Burden or prevention

Failure to attain and sustain optimal long-term

Inadequate postprandial glucose control

Unpredictable glucose fluctuations

Fronzo R et al. Diabetes. 2009;58:773-795.

Antihyperglycaemic Therapy in T2DM - ADA

Insulin (multiple daily doses)

An Evidence-to-Strategy Update for

Novel Drugs & Targets in

Focus of This Evenings

An Evidence-to-Strategy Update for

The Kidneys Play an Important Role

Rest of the body

Glucose in Western diet

Glucose production (gluconeogenesis

Renal glucose filtration and

The Kidney Handles Glucose By

FFA=free fatty acid.

125 mL of filtrate formed/min

Urine output 1.5 L/24 h

25000 mEq of Na+ Filtered

Urine Na+ excretion

140-180 g glucose filtered/24

Urine glucose excretion