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


Hypo-glycemia

Weight


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


Hypo-glycemia

Weight


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

, %


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, %


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


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)*



-2.5


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


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


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)*




EFFECTS OF SGLT-2 INHIBITORS ON BODY WEIGHT


(-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




-4

-3

-2

-1

0

1

2


*


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


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



Canagliflozin 300 mg/d Dapagliflozin 10 mg/d Placebo


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


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






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?




.


0

5

10

15

20


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

https://exchange.mcgill.ca/owa/redir.aspx?C=8gqOvT2IiUqEiROWhOiTUkUi12M9uNAIMwJqw_UxGDY6NHM7OPLkW20vOLoxnCcgVVGr6QmwlDI.&URL=http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs





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.


Dapagliflozin 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

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs

-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


/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



in presence of moderate renal failure

Yale JF et al. ADA Annual Meeting 2013. Abstract 1075-P.

EFFECTS of SGLT2 Inhibitors on eGFR


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

-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.


/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:


April 2019

EMPA-REG Outcome

Empagliflozin/ Placebo

7,034 CVD

Noninferiority (test for superiority if noninferiority met)


April 2015

Ertugliflozin CVOT

Ertugliflozin/ Placebo

3,900 CVD

Noninferiority:


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


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


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=137) PBO + MET (BL body weight 87.7 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)


−4.38 kg (95% CI; −5.31, -3.46)

GLI + MET (n = 401)

DAPA + MET (n = 400)



−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


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


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


81.0


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.


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.


81.0


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.

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

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http://www.interscience.wiley.com/

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

http://www.interscience.wiley.com/

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