new therapeutic glycemia treatment for type 2 diabetes · dpp-4 inhibitors glp-1 receptor agonists...
TRANSCRIPT
New Therapeutic Glycemia Treatment for Type 2 Diabetes
DISCLOSURE
Stewart B. Harris MD MPH FCFP FACPM
Professor
Ian McWhinney Chair For Studies in Family Medicine
CDA Chair in Diabetes Management
• Relationships with commercial interests:
• Consulting and advisory board honoraria from: AstraZeneca, Janssen, Lilly, Novo Nordisk, Medtronic, Merck, Sanofi
• Lecture honoraria from: AstraZeneca, Janssen, Lilly, Novo Nordisk, Medtronic, Merck, Sanofi
• Funds given to his institution for research or educational initiatives by: Abbott, AstraZeneca, CIHR, JDRF, The Lawson Foundation, Novo Nordisk and Sanofi
DISCLOSURE OF COMMERCIAL SUPPORT
• Potential for conflict(s) of interest: • Dr. Harris has received an honorarium from Jansen Inc. and AstaZenica
whose product(s) are being discussed in this program.
• Janssen Inc. and AstraZenica may benefit from the future sales of a product that will be discussed in this program: Canagliflozin, Dapaglifozin
MITIGATING POTENTIAL BIAS
• Only published data will be presented in this program and
recommendations will be based on the CDA Clinical
Guidelines
• The speaker will clearly identify when recommendations for
off-label use are suggested
CFPC CoI Templates: Slide 3
LEARNING OBJECTIVES
• Describe the mechanism for the reabsorption of glucose in
the kidneys;
• Describe the SGLT2 inhibitors (sodium/glucose
cotransporter 2), their mode of action and pharmacodynamic
effects;
• Discuss the potential role of SGLT2 inhibitors in the
treatment of type 2 diabetes.
5
6
Krentz AJ, Bailey CJ. Drugs 2005; 65:385-411.
Insulin Secretagogues
Biguanides
Alpha-glucosidase Inhibitors
Thiazolidinediones
DPP-4 Inhibitors and GLP-1 Agonists
Liver Adipose
Tissues Muscles Pancreas
Intestine
SGLT2 Inhibitors
Delay the absorption of glucose from
starch and sucrose
Reduce hepatic gluconeogenesis Sulfonylureas and
meglitinides stimulate
insulin secretion
Improve insulin resistance Increase insulin secretion, inhibit glucagon secretion
Kidneys
Reduce the reabsorption of glucose by the kidneys :
glucosuria
Antihyperglycemic Medications
Patient States Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other
Agent States BG-lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other
CDA Guidelines – Match Patient & Agent Characteristics
How to Choose the Best Second-line Agent After Metformin for an Individual Patient in Your Clinic?
CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013; 37(suppl 1):S1-S212.
Class
Relative A1C Lowering
Hypo-glycemia
Weight
Other therapeutic considerations
Cost
-glucosidase inhibitor (acarbose)
Rare Neutral
to Improved postprandial control, GI side-effects
$$
Incretin agents: DPP-4 inhibitors GLP-1 receptor agonists
to
Rare
Rare
N to
GI side-effects
$$$
$$$$
Insulin Yes No dose ceiling, flexible regimens $-$$$$
Insulin secretagogue: Meglitinide Sulfonylurea
Yes* Yes
*Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide
$$ $
Thiazolidinediones Rare
CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect
$$
Weight loss agent (orlistat)
None GI side effects $$$
Add an Agent Best Suited to the Individual (Agents Listed in Alphabetical Order)
Adapted from: CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013; 37(suppl 1):S1-S212.
Class
Relative A1C Lowering
Hypo-glycemia
Weight
Other therapeutic considerations
Cost
-glucosidase inhibitor (acarbose)
Rare
Neutral to
Improved postprandial control, GI side-effects
$$
Incretin agents: DPP-4 inhibitors GLP-1 receptor agonists
to
Rare
Rare
N to
GI side-effects
$$$
$$$$
Insulin Yes No dose ceiling, flexible regimens $-$$$$
Insulin secretagogue: Meglitinide Sulfonylurea
Yes* Yes
*Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide
$$ $
Thiazolidinediones Rare CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect
$$
Weight loss agent (orlistat)
None GI side effects $$$
Adapted from: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(suppl 1):S1-S212.
Class
Relative A1C Lowering
Hypo-glycemia
Weight
Other therapeutic considerations
Cost
SGLT2 inhibitors Rare to
Genital mycotic infections Urinary tract infections Reduced efficacy with eGFR < 60 Volume-related side-effects
$$$
Add an Agent Best Suited to the Individual (Agents Listed in Alphabetical Order)
Network Meta-analysis (add-on to metformin)
Added Therapy
Change
in A1C
(%)
Change in
Weight
(kg)
Hypoglycemia
Odds Ratio
vs placebo
Sulfonylureas -0.82 2.17 8.86
Meglitinides -0.71 1.40 10.51
Thiazolidinediones -0.82 2.46 0.45
Alpha-glucosidase Inhibitors -0.66 -1.01 0.40
DPP-4 Inhibitors -0.69 0.23 1.13
GLP-1 Receptor Agonists -1.02 -1.66 0.92
Basal Insulin -0.88 1.38 4.77
Liu, Sung-Chen et al. Diab Obes & Metab 14:810-820, 2012.
Antihyperglycemic Medications
ROLE OF KIDNEYS IN GLUCOSE REGULATION
Glucose Homeostasis in the Body
Glucose input: ≈ 250 g/day Glucose uptake : ≈ 250 g/day
• Dietary intake: ≈ 180 g/day
• Glucose production: ≈ 70 g/day
– Gluconeogenesis
– Glycogenolysis
• Brain : ≈ 125 g/day
• Rest of the body : ≈ 125 g/day
Net : approximately 0 g/day
Glucose
reabsorbed
by the kidneys:
≈ 180 g/day
Glucose
filtered
by the kidneys:
≈ 180 g/day
+ -
MENU
Wright EM et al. J Intern Med. 2007;261:32‐43; 2. MarsenicO. Am J Kidney Dis. 2009;53:875‐83
Dromedary:
Conserving water The kidneys:
Conserving glucose
MENU
Glucose conservation
RENAL GLUCOSE HANDLING IN THE NON-DIABETIC
Adapted from: 1. Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9:551-559.
2. DeFronzo RA, et al. Diab Obes Metab 2012;14:5-14. 3. Washburn WN. J Med Chem 2009;52:1785-1794.
4. Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006.
Healthy patient (normal kidney function & glucose tolerance)
Urinary
excretion
Glucose
Excess
glucose
Glomerulus
Renal
proximal
tubule
Glucose
reabsorption
15
MECHANISM OF ACTION OF SGLT2 INHIBITORS SGLT2 = SODIUM/GLUCOSE CO-TRANSPORTER 2
At normal glucose levels, the amount of glucose filtered by the
glomerulus increases with glycemia, and is entirely reabsorbed
from the proximal tubule by SGLT2 transporters: no glucosuria
SGLT=sodium-dependent glucose transporter; GLUT=facilitative glucose transporter.
Abdul-Ghani MA, DeFronzo, RA. Endocr Pract. 2008;14(6):782-790.
Bays H. Curr Med Res Opin. 2009;25(3):671-681. Reprinted with permission.
Mechanism of
action A1c Weight Hypos BP Side Effects Summary
Mechanism:
Induces glucosuria
Glycemia (mmol/L)
15 0 10
Filtered
Reabsorbed
Excreted
RTG
5
No glucosuria
Glomerulus
Renal Proximal Tubule
Glucose reabsorption
by SGLT2
14
14
Beyond a given glycemia, called the renal threshold for glucose
(RTG), this reabsorption mechanism becomes saturated, and glucose
appears in the urine: glucosuria. This is a defense mechanism against
hyperglycemia.
Glucosuria
SGLT2 inhibition reduces the glucose reabsortion capacity of the renal
tubule, leading to a decrease in the RTG and the appearance of
glucosuria at normal or mildly elevated blood glucose levels.
MECHANISM OF ACTION OF SGLT2 INHIBITORS
SGLT=Sodium/GLucose co-Transporter; GLUT=GLUcose Transporter. Abdul-Ghani MA, DeFronzo, RA. Endocr Pract. 2008;14(6):782-790. Bays H. Curr Med Res Opin. 2009;25(3):671-681.
Proximal
tubule
S1
Glomerulus
Distal
tubule
Loop of
Henle
Collecting
Duct
Glucose
filtration
Glucose
Reabsorption
S3
SGLT2 and GLUT2
High capacity (10 nmol/mg/min)
Low affinity (Km=2mM)
(ex: BULLDOZER)
SGLT1 and GLUT1
Low capacity (2 nmol/mg/min)
High affinity
(Km=0.4mM)
(ex: BROOM)
~10% ~90%
No/minimal glucose
excretion
MENU
0
25
50
75
100
125
150
Nair S & Wilding J. J Clin Endocrinol Metab. 2010;95:34-42.
Polidori D, et al. American Diabetes Association Meeting, June 25-29, 2010, Orlando, Florida; Abstract 2186-PO
Healthy RTG
~10 mmol/L
0 2 4 6 8 10 12 14
Glucose Excretion (g/day)
Plasma glucose (mmol/L)
16
Above the RTG , glucosuria occurs
Under the RTG , no or minimal glucosuria occurs
Adaptation in patients
with diabetes
Under treatment with SGLT2 inhibitors
Effects of SGLT2 Inhibitors on RTG
MENU
SGLT2 INHIBITORS
Mechanism:
Induces glucosuria A1c Weight Hypos BP Side Effects Summary
Agent Manufacturer Status
Canagliflozin Janssen Inc.
Approved in Canada,
United States, Australia,
Europe, Mexico,
Guatamala and the United
Arab Emirates
Dapagliflozin AstraZeneca Approved in Canada,
Europe Australia and
United States
Empagliflozin Boehringer Ingelheim/Eli Lilly Approved in Europe,
US and Australia
Ertugliflozin Merck/Pfizer
Ipragliflozin Astellas/Kotobuki Approved in Japan
Luseogliflozin Taisho
Tofogliflozin Chugai/ Roche
Mechanism:
Induces glucosuria A1C Weight Hypos BP Side Effects Conclusion
(-1.17)
(-0.66)
(-0.70)
(-0.78)
(-0.54)
(-0.64) (-0.83) (-0.69)
(-0.93)
(-0.60)
(-0.77) (-0.55)
(-0.61) (-0.73)
(-0.60)
(-0.62)
Reduces A1c:
0.5 to 1.2%
A1C DECREASES BY 0.6 TO 1.1% (0.5 TO 1.2% PLACEBO-CORRECTED)
Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin
EFFECTS OF SGLT-2 INHIBITORS ON A1C LEVELS
18
1. CANA: Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013
2. DAPA: Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm
3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.
Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo
*These are not head to head trials
%
-0.66
–1.00
-0.75
-0.50
–0.25
0
SITA
100
Ch
an
ge
in
A1
c (
%)
A1C: SGLT2 Inhibitors vs DPP-4 Inhibitors
-1.03**
-0.66
SITA
100
Roden M et al. ADA Annual Meeting, 2013; 1085-P. Lavalle Gonzalez FJ et al. ADA Annual Meeting, 2013; 238-OR.
Schernthaner G et al. Diabetes Care 2013.
MONOTHERAPY 24 weeks
A1c 7.9%
-0.66
-0.78
EMPA
10
EMPA
25
+MET +SU 52 weeks
A1c 8.1%
CANA
300
Placebo
+ MET 52 weeks
A1c 7.9%
SITA
100
-0.73
-0.88**
CANA
300
CANA
100
-0.73
0.08
**p<0.05 vs sitagliptin
MENU
CAN WE COMBINE
DAPA WITH DPP4I?
DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND
S: switched to nearest MET XR (1500-2000 mg/d) at the beginning of the 4-week lead -in.
BL, baseline; BMI, body mass index; BW, body weight; DAPA, dapagliflozin; FPG, fasting plama glucose; MET, metformin; MET XR, metformin
extended release; PBO, placebo; PPG, post-prandial glucose; SAXA, saxatliptin; T2DM, type 2 diabetes mellitus.
Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007
Primary end point: Change in A1C from BL at week 24
Prespecified secondary end points: Changes at week 24 from BL in 2h-PPG, FPG, and BW, and proportion of patients
achieving A1C<7.0% after 24 weeks.
Key Eligibility Criteria • T2DM and ≥18 years • A1C ≥8.0% to ≤12.0% • BMI ≤45 kg/m2
• C-peptide ≥1.0 ng/mL • Stable MET therapy
≥1500 mg/day for ≥8 weeks prior to screening
SAXA 5 mg + DAPA 10 mg + MET XR
R
1:1:1
4-week lead-in
24-week active-controlled, double-blind treatment
S
n=179
n=179
n=176
DAPA 10 mg + MET XR + PBO
SAXA 5 mg + MET XR + PBO
ADJUSTED MEAN CHANGE IN A1C AT 24 WEEKS FROM
BASELINE
aNumber of randomized patients with non-missing baseline values and week 24 values. Data are mean±SE. DAPA, dapagliflozin; MET, metformin; SAXA, saxagliptin. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007
-1.47%
-0.88%
-1.20%
Ad
juste
d M
ean
( 9
5%
CI)
Cha
nge
Fro
m
ba
se
line in A
1C
, %
DAPA+MET SAXA+MET SAXA+DAPA+MET
Baseline, %
na
8.93
158
9.03
143
8.87
151
-0.59% (-0.81%, -0.37%)
P<0.0001 -0.27% (-0.48%, -0.05%)
P=0.0166
DAPA+SAXA VS DAPA VS SAXA ON MET
BACKGROUND STUDY DESIGN
S: switched to nearest MET XR (1500-2000 mg/d) at the beginning of the 4-week lead -in.
BL, baseline; BMI, body mass index; BW, body weight; DAPA, dapagliflozin; FPG, fasting plama glucose; MET, metformin; MET XR, metformin
extended release; PBO, placebo; PPG, post-prandial glucose; SAXA, saxatliptin; T2DM, type 2 diabetes mellitus.
Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007
Primary end point: Change in A1C from BL at week 24
Prespecified secondary end points: Changes at week 24 from BL in 2h-PPG, FPG, and BW, and proportion of patients
achieving A1C<7.0% after 24 weeks.
Key Eligibility Criteria • T2DM and ≥18 years • A1C ≥8.0% to ≤12.0% • BMI ≤45 kg/m2
• C-peptide ≥1.0 ng/mL • Stable MET therapy
≥1500 mg/day for ≥8 weeks prior to screening
SAXA 5 mg + DAPA 10 mg + MET XR
R
1:1:1
4-week lead-in
24-week active-controlled, double-blind treatment
S
n=179
n=179
n=176
DAPA 10 mg + MET XR + PBO
SAXA 5 mg + MET XR + PBO
DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND ADJUSTED
MEAN CHANGE IN A1C AT 24 WEEKS FROM BASELINE
aNumber of randomized patients with non-missing baseline values and week 24 values. Data are mean±SE. DAPA, dapagliflozin; MET, metformin; SAXA, saxagliptin. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007
-1.47%
-0.88%
-1.20%
Ad
juste
d M
ean
( 9
5%
CI)
Cha
nge
Fro
m
ba
se
line in A
1C
, %
DAPA+MET SAXA+MET SAXA+DAPA+MET
Baseline, %
na
8.93
158
9.03
143
8.87
151
-0.59% (-0.81%, -0.37%)
P<0.0001 -0.27% (-0.48%, -0.05%)
P=0.0166
DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND ADJUSTED
MEAN PROPORTION OF PATIENTS ACHIEVING A1C <7.0% AT WEEK 24
aNumber of responders (x)/number of patients with non-missing baseline values and week 24 values (LOCF). Data are mean±SD. DAPA, dapagliflozin; MET, metformin; SAXA, saxagliptin. Rosenstock J et al. Diabetes Care. 2014 Oct 28. pii: DC_141142. NCT01606007
41%
18% 22%
Ad
juste
d M
ean
( 9
5%
CI)
Pro
po
rtio
n o
f
Pa
tio
ns w
ith
A1
C <
7.0
% a
t w
ee
k 2
4, %
DAPA+MET SAXA+MET SAXA+DAPA+MET
X/na 74/177 29/175 40/173
23% (14.7%, 31.5%) 19% (10.1%, 28.1%)
DAPA+SAXA VS DAPA VS SAXA ON MET BACKGROUND PROGRESSIVELY
GREATER REDUCTIONS IN A1C WITH PROGRESSIVELY HIGHER BASELINE
A1C
aNumber of randomized patients with non-missing baseline values and Week 24 value.
Adapted from Rosenstock J, et al. Diabetes Care. Published online October 28, 2014.
.
Adjusted Mean Change From Baseline in A1C Stratified by Baseline A1C Subgroup
-0.8
-1.17
-2.03
-0.69
-0.51
-1.32
-0.45
-0.84
-1.87
-2.5
-2
-1.5
-1
-0.5
0
A1
C c
han
ge f
rom
bas
elin
e (%
)
SAXA+DAPA+MET SAXA+MET DAPA+MET
<8%
Baseline mean
≥8% to <9%
Baseline mean
≥9%
Baseline mean
Baseline, %
na
7.50
37
7.61
29
7.41
37
8.44
56
8.54
51
8.49
52
10.02
65
9.90
63
9.95
62
ADD ON TO INSULIN
- LONG TERM DATA
CHANGE IN HBA1C
*Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration DAPA, dapagliflozin; INS, insulin; PBO, placebo; ST, short-term; LT, long-term
Study Week 52 65 78 91 104 0 4 8 12 16 20 24 32 40 48
-1.3
-1.2
-1.1
-1.0
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0.0
Ch
ange
in M
ean
Hb
A1
c (%
)*
PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
193 183 173 169 167 164 166 163 159 157 122 116 114 109 107 202 198 190 187 185 181 179 175 176 172 147 142 140 136 132 211 201 195 191 187 187 185 184 180 173 150 143 133 131 128 193 188 184 183 179 176 173 175 173 164 148 145 144 140 139
Sample size per time point PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
ST period LT period 1 LT period 2
J.P.H. Wilding, V. Woo, et al.: Diabetes, Obesity and Metabolism 16: 124–136, 2014.
At week 24, DAPA 2.5 mg, 5 mg and 10 mg significantly reduced BW from BL compared with PBO (P<0.001 for each group); differences were maintained to 104 weeks
CHANGE IN BODY WEIGHT
*Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration DAPA, dapagliflozin; INS, insulin; PBO, placebo; ST, short-term; LT, long-term
Study Week 193 185 175 170 170 165 168 164 158 157 122 118 114 110 107 202 198 191 188 188 182 180 176 176 174 147 142 140 136 132 211 201 196 193 190 188 187 184 181 174 150 143 134 132 128 193 190 186 183 180 178 177 176 174 166 148 146 144 142 141
Sample size per time point PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
52 65 78 91 104 0 4 8 12 16 20 24 32 40 48 -3.0
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Ch
ange
in M
ean
To
tal B
od
y W
eigh
t (k
g)*
PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
ST period LT period 1 LT period 2
-2.5
J.P.H. Wilding, V. Woo, et al.: Diabetes, Obesity and Metabolism 16: 124–136, 2014.
At week 24, DAPA 2.5 mg, 5 mg and 10 mg significantly reduced BW from BL compared with PBO (P<0.001 for each group); differences were maintained to 104 weeks
CHANGE IN INSULIN DOSE OVER TIME
*Data are adjusted mean change from baseline ± 95% CI derived from a mixed model and include data after insulin up-titration DAPA, dapagliflozin; INS, insulin; PBO, placebo; ST, short-term; LT, long-term
Study Week
191 185 176 171 170 165 168 164 158 157 121 118 114 110 104 200 197 189 187 186 181 180 174 176 173 144 142 140 136 130 209 202 194 194 190 188 187 183 181 172 147 142 134 132 128 194 189 185 183 180 178 177 175 173 166 145 146 144 142 140
Sample size per time point
PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
52 65 78 91 104 0 4 8 12 16 20 24 32 40 48 -8
-6
-4
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
Ch
ange
in M
ean
Dai
ly In
sulin
Do
se (
U)*
PBO + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
ST period LT period 1 LT period 2
J.P.H. Wilding, V. Woo, et al.: Diabetes, Obesity and Metabolism 16: 124–136, 2014.
EFFECTS OF SGLT-2 INHIBITORS ON BODY WEIGHT
Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin
(-3.2)
( -1.0)
(-2.2)
(-2.9)
(-2.0)
(-2.95)
Mechanism:
Induces glucosuria
Reduces A1c:
0.7 to 1.2 BW Hypos BP Side Effects Conclusion
(-1.8)
(-1.6)
(-1.9) (-2.0)
(-3.7)
( -1.6)
(-1.8)
(-2.3)
(-1.7)
(-2.7)
Reduces Wt:
1.0 to 3.7 Kg
BW DECREASES BY 0.1 TO 3.9 KG (1.0 TO 3.7 KG PLACEBO-CORRECTED)
31
1. CANA: Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013
2. DAPA: Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm
3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.
-4
-3
-2
-1
0
1
2
Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo
*
*These are not head to head trials
We
igh
t- k
g
-0.6 -1.11
-0.74
-2.22
- 5
- 4
- 3
- 2
- 1
0
1
2
3
Placebo + Met. n = 79
DAPA. + Met. n = 82
Variation at week 24
Toubro S et al.EASD Annual Meeting, 2012. Abstract 762.
Bolinder J et al. J Clin Endocrinol Metab. 97; 2012.
1.06
-0.89 -1.12
1.02
-2.89 -2.51
-5
-4
-3
-2
-1
0
1
2
3
CANA. 100 mg n = 71
Glimepiride n = 68
CANA. 300 mg n = 69
Fat mass Lean mass
Dapagliflozin Variation at week 52
Va
ria
tio
n v
ersu
s b
aseli
ne
(k
g)
Body Composition Studies with SGLT-2 Inhibitor Treatment (DEXA measurements)
MENU
Canagliflozin
Va
ria
tio
n v
ersu
s b
aseli
ne
(k
g)
Cefalu et al., ADA Annual Meeting, 2013. Abstract 65-LB
Body Weight: SGLT-2 Inhibitors vs SU (104 weeks)
MENU
Canagliflozin vs Glimepiride
0
10
20
30
40
50
Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin
Mechanism:
Induces glucosuria
Reduces A1c:
0.7 to 1.2
Reduces Wt:
1.0 to 3.7 Kg Hypos BP Side Effects Conclusion ↓Risk
hypos
LOW RISK OF HYPOGLYCEMIA EFFECTS OF SGLT-2 INHIBITORS ON HYPOGLYCEMIA
50
40
30
20
10
0
1. CANA: Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013
2. DAPA: Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm
Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Placebo
*These are not head to head trials
Pe
rce
nta
ge o
f H
ypo
s
EFFECTS OF SGLT-2 INHIBITORS ON BLOOD PRESSURE
-7
-6
-5
-4
-3
-2
-1
0
1
2
Monotherapy + Metformin + SU + Met + SU + Pio ± SU + Insulin
Mechanism:
Induces glucosuria
Reduces A1c:
0.7 to 1.2
Reduces Wt:
1.0 to 3.7 Kg
↓Risk
hypos BP Side Effects Conclusion
Reduces BP:
1.7 to 6.6
BP DECREASES BY 2.4 TO 6.9 MMHG (1.7 TO 6.6 PLACEBO-CORRECTED)
35
1. CANA: Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013
2. DAPA: Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm
3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.
Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo
*These are not head to head trials
mm
Hg
(-5.4)
(-2.9) (-3.4)
( -6.6)
( -5.8)
( -4.8) ( -1.8) ( -3.7)
( -1.7)
( -2.1)
( -3.5)
( -4.8) ( -4.7)
( -5.5)
( -2.5)
(-4.4)
EFFECTS OF SGLT-2 INHIBITORS ON INFECTIONS
0
5
10
15
20 Men Women Men Women
Mechanism:
Induces glucosuria
Reduces A1c:
0.7 to 1.2
Reduces BW:
1.0 to 3.7 Kg
↓Risk
hypos
Reduces BP:
1.7 to 6.6 Side Effects Conclusion
URINARY TRACT INFECTIONS GENITAL MYCOTIC INFECTIONS
Side Effects:
Genital mycotic
INCREASE IN GENITAL MYCOTIC INFECTIONS; UTI?
1. CANA: Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013
2. DAPA: Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm
3. EMPA: ADA Annual Meeting 2013: Roden M et al 1085-P; Haring H et al: 1092-P; Kovacs C et al: 1120-P and Rosenstock J et al 1102P.
.
Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Empagliflozin 25 mg/d Placebo
0
5
10
15
20
*These are not head to head trials
Pe
rce
nta
ge
Pe
rce
nta
ge
Nyirjesky P et al. ADA Annual Meeting 2013. Abstract 1069-P.
TIME TO FIRST FEMALE GENITAL MYCOTIC INFECTION
The highest rate of occurrence was observed during the first 4 months of treatment, followed by an
attenuation in the rate of increase. Less than 1% withdrawal for this reason.
MENU
All non-CANA CANA 100 mg CANA 300 mg
All non-CANA CANA 100 mg CANA 300 mg
URINARY TRACT INFECTION WITH CANA
Time to First UTI AE
):
30
DAPAGLIFLOZIN POOLED DATA (12 TRIALS): GENITAL MYCOTIC INFECTIONS
• More in women than
men
• All events were mild
to moderate in intensity
• Rarely led to
discontinuation (0.2%)
• Most events responded
to the initial course of
standard therapy and
rarely re-occurred Pe
rce
nta
ge o
f su
bje
cts
wit
h c
linic
al
dia
gno
sis
of
gen
ital
infe
ctio
n
Men Women Total
0.9
5.7
4.8
1.5
8.4
6.9
0.3
2.8 2.7
Johnsson KM, et al. J Diabetes Complications 2013; 27(5):479-84.
0
8
6
4
2
10
DAPA 5 mg
DAPA 10 mg
Placebo
Higher rates of GMI in dapagliflozin treatment groups than placebo
Men Women Total
DAPA 5 mg
DAPA 10 mg
Placebo
• More in women than men
• All events were mild to
moderate in intensity
• Rarely led to treatment
discontinuation (0.3%)
• Most events responded
to the initial course of
standard therapy and
rarely re-occurred
DAPAGLIFLOZIN POOLED DATA (12 TRIALS): UTI’S
5.7
4.3
6.6
9.6
7.7
1.0
1.6
0.8
Johnsson KM, et al. J Diabetes Complications 2013; 27(5):473-8.
Pe
rce
nta
ge o
f su
bje
cts
wit
h
clin
ical
dia
gno
sis
of
UTI
0
8
6
4
2
12
10
3.7
Rates of clinically diagnosed UTI higher in the dapa groups than placebo Upper UTI were rare and balanced between groups
Events of interest:
Hypotension
Postural Hypotension
Dehydration
Syncope
Reduced urinary output
Cana 100
Cana 300
Other
Pa
tien
ts (
%)
SIDE EFFECTS OF SGLT2 INHIBITORS
IN RELATION TO CIRCULATING VOLUME
Canagliflozin pooled data
MENU
4
6
8
10
12
VOLUME DEPLETION
Mechanism:
Induces glucosuria
Reduces A1c:
0.5 to 1.2%
Reduces weight:
1.0 to 3.7 Kg
Rare
Hypos
Reduces BP:
1.7 to 6.6 Side Effects Summary
Cana 100
Cana 300
Other
< 75 years
≥ 75 years
2
0
2.6%
4.9%
8.7%
3.1% 2.2% 1.4%
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf.
Accessed January 23, 2013
RISK FACTORS FOR VOLUME DEPLETION SYMPTOMS
Cana 100
Pa
tien
ts (
%)
4.7
1.3
0
2
4
6
8
10
Events of interest:
Hypotension
Postural hypotension
Dehydration
Syncope
Decreased urinary output
Patients on loop diuretics
Cana 100
Cana 300
All non-CANA
Pa
tien
ts (
%)
3.2
8.8
4.7
0
2
4
6
8
10
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs /EndocrinologicandMetabolicDrugs
AdvisoryCommittee/UCM336236.pdf. Consulted January 23, 2013. FDA Advisory Committee, July 19 2011 : http://www.fda.gov.
Canagliflozin pooled data
Dapagliflozin pooled data
Canagliflozin pooled data
Cana 300
Others Cana 100
Cana 300
Cana 100
Cana 300
Others Others
Dapa 10
Placebo
< 60mL/min 60 to < 90 mL/min ≥ 90 mL/min 8.1
2.5 2.4
2.9
1.5 2.4
1.2
1.8
9.7
MENU
Population at risk
> 75 yo
Patients with low baseline eGFR
-6
-4
-3
-2
-1
0
-5
-7
eG
FR (
mL/m
in/1
.73 m
2):
M
ean C
hange ±
SE
CANA 100 mg
BL: 89.7 mL/min/1.73 m2
CANA 300 mg
BL: 91.4 mL/min/1.73 m2
Glimepiride
BL: 89.5 mL/min/1.73 m2
43
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs
/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013
Baseline 4 12 26 36 44 52 weeks
EFFECTS of SGLT-2 INHIBITORS on eGFR
The eGFR decreases slightly, then increases slowly towards baseline
MENU
-1.7 ml/min/1.73m2
-3.0 ml/min/1.73m2
-5.1 ml/min/1.73m2
The eGFR decreases slightly, then increases slowly towards baseline
in presence of moderate renal failure
Yale JF et al. ADA Annual Meeting 2013. Abstract 1075-P.
EFFECTS of SGLT2 Inhibitors on eGFR
in presence of moderate renal failure
MENU
Yale JF et al. ADA Annual Meeting 2013. Abstract 1075-P.
Placebo
Empagliflozin
MENU
EFFECTS of SGLT2 Inhibitors on eGFR
in presence of moderate renal failure
The eGFR decreases slightly, then increases slowly towards baseline
In presence of moderate renal failure
-0.03
-0.44
-0.8
-0.6
-0.4
0.2
0.0
-0.2
Baseline mean A1C (%)
Baseline mean eGFR
(mL/min/1.73m2)
8.0
39.4
CANA 300 mg Placebo
Canagliflozin
eGFR 30 to <50 (N=269)
-0.32
-0.44
Cha
nge
fro
m B
ase
line
(± 9
5%
CI)
A1
C (%
)
Dapagliflozin
eGFR 30 to 59 (N=252)
8.4
44.6
DAPA 10 mg Placebo
Empagliflozin
eGFR 30 to <60 (N=374)
8.0
≈ 43
0.05
-0.37
EMPA 25 mg Placebo
Yale JF et al. Diabetes Obesity & Metabolism 2013;15:463-473. Kohan D et al. J Am Soc Nephrol 2011;22:232A:TH-PO524.
Barnett A et al. ADA Annual Meeting 2013. Abstract 1104-P.
-0.40* -0.11
(-0.40,0.45)
-0.42*
(-0.56,-0.28)
EFFECTS of SGLT2 INHIBITORS on A1c LEVELS in CKD
In moderate renal failure, the A1c reduction is halved
MENU
* p <0.001; †p <0.05.
CANA MONOTHERAPY: CHANGE IN FASTING PLASMA
LIPIDS AT WEEK 26 47
LDL-C†
*p=NS vs. PBO; †Statistical comparison for CANA 100 and 300 mg vs. PBO not performed (not pre-specified); ‡Unit of mg/mg for LDL-C/HDL-C; §p<0.001 vs. PBO; |p<0.01 vs. PBO. CANA: canagliflozin; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; LS: least squares; SE: standard error; PBO: placebo; NS: not significant; mITT: modified intent-to-treat; LOCF: last observation carried forward. 1. Stenlöf et al. 72nd ADA Scientific Sessions; 2012 June 9. [Oral number 081-OR (study 3005)].
HDL-C Triglycerides* LDL-C/HDL-C† Non–HDL-C†
Baseline (mmol/L)‡
LS Mean Change (mmol/L)‡
2.22 1.95 1.97 3.12 3.05 2.87 1.14 1.20 1.17 0.08 0.07 0.07
0.07 -0.16 -0.18 -0.07 -0.003 0.12 0.04 0.11 0.11 -0.005 -0.005 -0.003 -0.05 -0.05 0.04
4.14 3.94 3.75
DAPA Controls
Number of first events
Event Rate
Number of first events
Event Rate
Patients with
an event 48 1.13 % 30 1.66 %
CV Deaths 8 0.19 % 4 0.22 %
MI 18 0.42 % 18 1.00 %
CVA 11 0.26 % 5 0.28 %
Unstable
angina 11 0.26 % 3 0.17 %
0
1
2
3
4
0 100 200 300 400 500 600 700
Pe
rce
nta
ge
of
Pa
tie
nts
Time (days)
DAPA. vs Controls
Relative Risk: 0.674
98 % CI : 0.385 – 1.178
Controls
Langkilde A el al. American Heart Association Meeting, 2011; abstract 8947.
Number of patients
DAPA. 4 097 3 826 2 767 2 350 1 532 1 368 1 062 585
Controls 1 850 1 696 1 197 1 004 622 538 415 233
Dapagliflozin: Cardiovascular Risk
Phase 2/3 Studies
MENU
CANAGLIFLOZIN : MACE-PLUS
Note : Includes all studies with data base lock prior to January 31, 2012; mTTT analysis set; events within 30 days of last dose
Pro
babil
ity o
f a M
AC
E-p
lus
Even
t
0.04
0.03
0.02
0.01
0.00
0 6 12 18 26 39
All phase 2/3 studies, including CANVAS Kaplan-Meyer estimate
0.05
1 985
4 065
65 78 91 104
All non-CANA.
All CANA.
3 327 3 282 3 161 2 991
6 305 6 224 6 000 5 715
2 848
5 539
2 650
5 227 931
1 935
508
1 039
213
462
42
91
Number of subjects at risk
HR = 0.91 (95% CI : 0.68 – 1.22)
HR = 1.00 (0.72 – 1.39) – CANVAS
HR = 0.65 (0.35 – 1.21) – Other trials All non-CANA.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs
/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Consulted January 23, 2013.
Study Week
52
All CANA.
MENU
Therapies # Population Endpoints End Date
CANVAS Canagliflozin/ Placebo
4,330 CVD or high-risk for CVD
Noninferiority:
CV death, NF MI or NF stroke
June 2018
DECLARE Dapagliflozin/Placebo
17,150 CVD or high-risk for CVD
Noninferiority safety, superiority efficacy:
CV death, NF MI or NF stroke
April 2019
EMPA-REG Outcome
Empagliflozin/ Placebo
7,034 CVD
Noninferiority (test for superiority if noninferiority met)
CV death, NF MI or NF stroke
April 2015
Ertugliflozin CVOT
Ertugliflozin/ Placebo
3,900 CVD
Noninferiority:
CV death, NF MI or NF stroke
April 2021
ONGOING CARDIOVASCULAR OUTCOME
TRIALS: SGLT2 INHIBITORS
Adapted from: www.Clinicaltrials.gov
Dapagliflozin
FORXIGA
Start at
5 mg od
Canagliflozin
INVOKANA
Start at
100 mg od
How To Prescribe Available SGLT2 Inhibitors in Canada?
Increase to 10 mg od if required
May be increased to 300 mg od if tolerated and
additional glycemic control required
INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014.
Monotherapy DUAL THERAPY TRIPLE THERAPY Combination with any INSULIN regimen
SGLT2 Inhibitors
Metformin contraindicated or intolerable
Add-on to MET
Add-on to SU
Add-on to MET + SU
Add-on to MET +
PIO
Dapagliflozin
Canagliflozin
Approved Indications for SGLT2 Inhibitor Therapies in Canada
INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014.
eGFR
SGLT2 Inhibitors > 60 45-60 < 45
Dapagliflozin Contraindicated
Canagliflozin Do not initiate;
can continue only at 100 mg
Contraindicated
CKD Approved Indications for SGLT2 Inhibitor Therapies in Canada
INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014.
Caution for hyperkalemia – At-risk patients include moderate renal
impairment on meds (e.g., K+ sparing diuretics, ACE inhibitors, ARBs)
HEALTH CANADA CAUTIONS
ASSOCIATED WITH SGLT2 INHIBITORS Canagliflozin
Not recommended for use in
volume depletion or with loop
diuretics
Increased risk of volume-related
AEs in:
• Elderly
• Low SBP
• Moderate renal impairment
• ACE-inhibitors, ARBs, or loop diuretics
• Low SBP
Dapagliflozin
No caution for hyperkalemia
Not recommended for use in volume depletion Increased risk of volume-related AEs in: – Elderly – Low SBP – Known CVD – Antihypertensive therapies, particularly
loop diuretic
*SGLT2s are not recommended for use in volume depletion. INVOKANA Product Monograph. Janssen Inc., November 2014. FORXIGA Product Monograph. AstraZeneca. December 2014.
CAUTIONS FOR VOLUME DEPLETION*
-Elderly -Low BP or low baseline volume status
-Antihypertensives, particularly loop diuretics e.g. Furosemide
• SGLT2 inhibitors induce glucosuria, resulting in a loss of glucose in the urine.
• A1c is reduced by 0.5 to 1.2 %
• Body weight is reduced by 1.0 to 3.7 kg
• SGLT2 inhibitors rarely induce hypoglycemia, except when added to insulin or insulin secretagogues.
• Blood pressure is reduced by 1.7 to 6.6 mm Hg
• The following side effects can be observed: genital mycotic infections and side effects related to volume depletion.
SUMMARY:
Mechanism:
Induces glucosuria
Reduces A1c:
0.5 to 1.2%
Reduces weight:
1.0 to 3.7 Kg
Rare
Hypos
Reduces BP:
1.7 to 6.6 Side Effects Summary
Thank you
LONGER TERM
DATA
DAPA 10 MG RESULTS IN DURABLE IMPROVEMENTS IN HBA1C OVER
2 YEARS
BL, baseline; DAPA, dapagliflozin; HbA1c, hemoglobin A1c; MET, metformin.
0.3
0.0
-0.3
-0.6
-0.9
-1.2
0 8 16 24 37 50 63 76 89 102
Hb
A1
C (
%)
adju
sted
mea
n c
han
ge f
rom
BL
Study week
(N=135) DAPA 10 mg + MET (BL HnA1c 7.9%)
(N=137) PBO + MET (BL HnA1c 8.1%)
Study 1: Add-on to metformin
Dapa vs. SU
(N=400) DAPA 10 mg + MET (BL HnA1c 7.7%)
(N=401) GLIP + MET (BL HbA1c 7.7%)
0 6 12 18 26 34 42 52 65 78 91 104
0.2
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
Study week
Hb
A1C
(%
) ad
just
ed m
ean
ch
ange
fro
m B
L
0 8 12 24 32 40 48 52 65 78 91 104
Hb
A1C
(%
) ad
just
ed m
ean
ch
ange
fro
m B
L
Study week
(N=194) DAPA 10 mg + INS (BL HbA1c 8.6%)
(N=193) PBO + INS (BL HbA1c 8.5%)
0.2
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
Add-on to Insulin
Study 2: Add-on to metformin (N=89) DAPA 10 mg + MET (BL HbA1c 7.19%)
(N=91) PBO + MET (BL HbA1c 7.2%)
0 8 24 37 50 63 76 89 102
Study week
0.4
0.2
0.0
-0.2
-0.4
-0.6
-0.8 Hb
A1
C (
%)
adju
sted
mea
n c
han
ge f
rom
BL
DAPA 10 MG RESULTS IN DURABLE IMPROVEMENTS IN BODY
WEIGHT OVER 2 YEARS
BL, baseline; DAPA, dapagliflozin; GLIP, glipizide; INS, insulin; MET, metformin; PBO, placebo.
(N=400) DAPA 10 mg + MET (BL body weight 88.4 kg)
(N=401) GLIP + MET (BL body weight 87.6 kg)
0 6 12 18 26 34 42 52 65 78 91 104
3.0
2.0
1.0
0.0
-1.0
-2.0
-3.0
-4.0
-5.0
Study week
0 8 12 24 32 40 48 52 65 78 91 104
Tota
l bo
dy
wei
ght
(kg)
ad
just
ed m
ean
ch
ange
fro
m B
L
3.0
2.6
2.2
1.8
1.4
1.0
0.8
0.4
0.0
-0.4
-0.8
-1.2
-1.6
-2.0
-2.4
(N=194) DAPA 10 mg + INS (BL body weight 94.5 kg)
(N=193) PBO + INS (BL body weight 94.6 kg)
Study week
2.0
1.6
1.0
0.4
-0.2
-0.8
-1.4
-2.0
-2.6
-3.2
-3.8
0 8 16 24 37 50 63 76 89 102
Study week
0 4 8 16 2437 50 63 76 89 102
Study week
2.0
0.0
-2.0
-4.0
-6.0
Tota
l bo
dy
wei
ght
(kg)
ad
just
ed m
ean
ch
ange
fro
m B
L
Tota
l bo
dy
wei
ght
(kg)
ad
just
ed m
ean
ch
ange
fro
m B
L
(N=135) DAPA 10 mg + MET (BL body weight 86.2 kg)
(N=137) PBO + MET (BL body weight 87.7 kg)
(N=135) DAPA 10 mg + MET (BL body weight 92.1 kg)
(N=137) PBO + MET (BL body weight 90.0 kg)
Study 2: Add-on to metformin Study 1: Add-on to metformin To
tal b
od
y w
eigh
t (k
g) a
dju
sted
mea
n c
han
ge f
rom
BL
Dapa vs. SU Add-on to Insulin
Del Prato et al., 2013. ADA 2013, Chicago USA. Abstract 62-LB
Mean baseline A1C=7.7%
ADJUSTED MEAN CHANGE FROM BASELINE IN
HBA1C UP TO WEEK 208
0.4
0.2
0.0
-0.2
-0.4
-0.6
-0.8
-1.0 0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208
Recue therapy NOT available Recue therapy available
Study week
Dapagliflozin + Metformin Gilpizide+ Metformin
Ch
ange
in H
bA
1c
(%)*
Sample size (excluding data after rescue) DAPA + MET 400 321 233 139 105 79 GLP + MET 401 315 208 129 102 71
Week 208 values
0.20% (95% CI: 1.05, 0.36)
-0.10% (95% CI: -0.25, 0.05)
Dif. -0.30% (95% CI: -0.51, -0.09)
SUSTAINED BODY WEIGHT REDUCTION OF ADD-ON DAPAGLIFLOZIN
VS. ADD-ON GLIPIZIDE IN PATIENTS ON METFORMIN (208 WKS)
Baseline weight DAPA + MET: 88.4 kg GLIP + MET : 87.6 kg
Between-group difference at 104 weeks:
−5.06 kg (95% CI; −5.73, −4.4)
Between-group difference at 208 weeks:
−4.38 kg (95% CI; −5.31, -3.46)
GLI + MET (n = 401)
DAPA + MET (n = 400)
Del Prato et al., 2013. ADA 2013, Chicago USA. Abstract 62-LB
Between-group difference at 52 weeks:
−4.65 kg (95% CI; −5.14, −4.14), p<0.0001
0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208
3
2
1
0
-1
-2
-3
-4
-5
Ch
ange
in w
eigh
t (k
g)*
Sample size (excluding data after rescue), a DAOA + MET 400 323 234 159 GLP + MET 401 315 211 140
Study week
BLOOD PRESSURE REDUCTIONS WITH DAPAGLIFLOZIN WERE
SUSTAINED OVER 208 WEEKS
Del Prato et al., 2013. ADA 2013, Chicago USA. Abstract 62-LB
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-7 0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208
-0.2 mmHg (95% CI: -1.56, 1.61)
Dif. -3.67 mmHg (95% CI: -5.92, -1.41)
-3.69 mmHg (95% CI: -5.24, -2.14)
Ch
ange
in S
BP
(m
mH
g)*
Sample size (excluding data after rescue), a DAOA + MET 399 323 234 159 GLP + MET 396 314 211 140
EGFR CHANGES IN NORMAL RENAL
FUNCTION AND IN CKD
Weeks
Me
an c
han
ge f
rom
bas
elin
e
eG
FR (
mL/
min
/1.7
3m
2)
10
-15
5
0
-5
-10
15
Baseline
1. Ptaszynska, et al. Presented at EASD 2014. 2. Yale JF, et al. Presented at ADA 2013. Abstract 1075-P.
BL Mean eGFR (mL/min/1.73m2)
81.0
Dapagliflozin in normal eGFR1
80.7
8 4 1 102 89 76 63 50 37 24 16
Placebo
DAPA 10 mg
EGFR CHANGES IN NORMAL RENAL
FUNCTION AND IN CKD
Weeks
Me
an c
han
ge f
rom
bas
elin
e
eG
FR (
mL/
min
/1.7
3m
2)
10
-15
5
0
-5
-10
15
Baseline
BL Mean eGFR (mL/min/1.73m2)
81.0
Dapagliflozin in normal eGFR1
80.7
8 4 1 102 89 76 63 50 37 24 16
38.5 39.4 40.1
Canagliflozin in low eGFR2
Placebo
DAPA 10 mg
CANA 100
CANA 300
Note: These are separate pooled analysis for Dapagliflozin and Canagliflozin. 1. Ptaszynska, et al. Presented at EASD 2014. 2. Yale JF, et al. Presented at ADA 2013. Abstract 1075-P.
EGFR CHANGES IN NORMAL RENAL
FUNCTION AND IN CKD
Weeks
Me
an c
han
ge f
rom
bas
elin
e
eG
FR (
mL/
min
/1.7
3m
2)
10
-15
5
0
-5
-10
15
Baseline
Note: These are separate pooled analysis for Dapagliflozin and Canagliflozin. 1. Ptaszynska, et al. Presented at EASD 2014. 2. Yale JF, et al. Presented at ADA 2013. Abstract 1075-P.
BL Mean eGFR (mL/min/1.73m2)
81.0
Dapagliflozin in normal eGFR1
80.7
8 4 1 102 89 76 63 50 37 24 16
38.5 39.4 40.1
Canagliflozin in low eGFR2
eGFR decreases slightly at initiation of SGLT2 inhibitors, then returns slowly towards baseline
DAPA POOLED DATA: TUMOUR INCIDENCE
Tumour origin Patients with
Events
Overall 140
Bladder 10
Breast (female only) 15
Pancreatic 8
Prostate (male only) 17
Hepatobiliary 3
Thyroid and endocrine 10
Skin 31
Respiratory and mediastinal 15
Reproductive (female only) 4
Metastases and site unspecified 5
Gastrointestinal 10
Renal tract 5
Blood and lymphatic 7
Musculoskeletal and soft tissue 1
0.01 0.1 1 10 100
DAPA N = 5,936
Control N = 3,403
Incidence Rate Ratio (95% CI)
1.03 (0.71, 1.51)
5.17 (0.68, 233.55)
2.47 (0.64, 14.10)
1.84 (0.31, 19.46)
1.60 (0.53, 5.35)
0.92 (0.04, 61.49)
0.88 (0.19, 4.46)
0.83 (0.37, 1.91)
0.79 (0.24, 2.81)
0.74 (0.05, 10.74)
0.66 (0.07, 8.96)
0.61 (0.13, 3.19)
0.40 (0.03, 3.82)
0.37 (0.05, 2.35)
∞ (0.010, ∞)
IRR with 95% CI
Favours DAPA
Favours Control
One additional case of bladder cancer was found in study 93-005 which was not finished at the time of data cut for FDA resubmission. The incidence rate ratio with 95% CI including this case is 6.11 (0.827, 272.0).
DAPAGLIFLOZIN BMS-512148 NDA 202293. US Food & Drug Administration (FDA) Endocrinologic & Metabolic Drug Advisory Committee (EMDAC) Background Document. 2013. Available at: http://www.fda.gov/downloads/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf.
VOLUME-RELATED ADVERSE EFFECTS:
WHICH PATIENTS ARE MORE AT RISK?
eGFR measured in mL/min/1.73m2 1. Johnsson et al. Presented at EASD 2014. Abstract 800-P. 2. Adapted from: http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013.
Pat
ien
ts (
%)
0
8
6
4
2
10
DAPA 10 mg
Placebo
Dapagliflozin1
Yes
2.5
1.5
8.8
3.2
4.7
Yes
Loop diuretic Loop diuretic eGFR
≥30-<60
1.9 1.5
<60
8.1
4.7
eGFR
2.5
≥75 <65
0.9 0.7
3.1
1.2
≥65
1.7
0.8
Age (years)
<75 ≥75
3.1
2.2
8.7
4.9
Age (years)
2.6
1.4
CANA 100
CANA 300
All non-cana
Canagliflozin2
Not intended for comparisons between trials
Phlorizine is found in the bark of apple trees, cherry trees and other fruit trees.
It is a competitive inhibitor of SGLT-2 and SGLT-1.
Phlorizine was isolated in 1885. Its
glucosuric action was described in 1886.
Not practical Low Bioavailability : 15%
Causes diarrhea (SGLT-1)
Phlorizine was the first inspiration for
the inhibition of SGLT in the treatment
of diabetes
1. Ehrenkranz JR et al, Diabetes Metab Res Rev 2005; 21: 31–38.
2. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/dmrr.532 2. Chao EC. Core Evidence 2012;7:21-28.
The First SGLT Inhibitor: Phlorizine
MENU
FAMILIAL RENAL GLUCOSURIA
MENU DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE Diabetes Metab Res Rev 2005; 21: 31–38.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/dmrr.532
• A benign autosomal dominant condition
• Results from a decrease in SGLT2 activity (lower number of transporters or decreased activity of the transporters)
• Asymptomatic condition that does not lead to renal failure
• Does not preclude the need for long-term safety data with SGLT2 inhibitors