sglt2 inhibitors: a novel and important new class of ...icdm2013.diabetes.or.kr/slide/ot1-3 lawrence...

1

SGLT2 Inhibitors: A novel

and important new class of

antihyperglycemic agent

Lawrence A Leiter, MD FRCPC FACP FAHA Division of Endocrinology & Metabolism,

St. Michael’s Hospital

Professor of Medicine & Nutritional Sciences,

University of Toronto

Disclosure

Lawrence Leiter has received research funding from, has

provided CME on behalf of, and/or has acted as a consultant

to:

AstraZeneca, BMS, BI, Eli Lilly

GSK, Janssen, Merck, Novo Nordisk

Roche, Sanofi, Servier, Takeda

Diabetes and Lifetime Risk for CHD

Lloyd Jones et al Circ 2006;113:791

Diabetes No Diabetes

67%

30%

57%

16%

Attained Age

0.1

0.2

0.3

0.4

0.5

0.6

0.7

50 60 70 80 90

0

Ad

juste

d c

um

mu

lati

ve

incid

en

ce

Men Women

0.1

0.2

0.3

0.4

0.5

0.6

0.7

50 60 70 80 90

0

Diabetes confers the highest lifetime risk for CHD

of any single risk factor

Americans More Fearful of Shark Bites

than Diabetes

Fear of health problem - Cancer 49%

- Heart disease 12%

- Stroke 11%

- Shark bite 4%

- Diabetes 3%

ADA Survey 2008

Shark attacks 70 / year

Deaths related to diabetes 233,000 /year

Pathophysiological Defects of Type 2 Diabetes

DeFronzo's "Ominous Octet”

Islet b-cell

Impaired

Insulin Secretion

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

Increased Lipolysis

Increased Glucose

Reabsorption

Increased

HGP

Decreased Incretin Effect

DeFronzo RA Diabetes 2009; 58:773

Initial drug monotherapy

Efficacy (! HbA1c)

Hypoglycemia

Weight

Side effects

Costs

Healthy eating, weight control, increased physical activity

Metformin

high

low risk

neutral/loss

GI / lactic acidosis

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c)

Hypoglycemia

Weight

Major side effect(s)

Costs

high

low risk

gain

edema, HF, fx’s‡

high

Thiazolidine- dione

intermediate

low risk

neutral

rare‡

high

DPP-4 Inhibitor

highest

high risk

gain

hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea†

+

Thiazolidine-dione

+

DPP-4 Inhibitor

+

GLP-1 receptor agonist

+

Insulin (usually basal)

+

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high

low risk

loss

GI‡

high

GLP-1 receptor agonist

Sulfonylurea†

high

moderate risk

gain

hypoglycemia‡

low

If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference):

Diabetes Care, Diabetologia.

19 April 2012 [Epub ahead of print]

What is the ideal first add-on to metformin?

Network meta-analysis comparing non-insulin antihyperglycaemic

drugs with placebo as add-on to metformin

Change in

HbA1C

HbA1C goal

achieved

Change in body

weight

Overall

hypoglycemia

Mean

difference RR

Mean

difference RR

Placebo (ref) 0 1 0 1

Sulfonylureas –0.79 2.49 2.06 4.57

Meglitinides –0.65 2.25 1.77 7.50

TZDs –0.85 2.71 2.08 0.56

AGIs –0.64 ND –1.80 0.42

DPP-4 inhibitors –0.78 2.51 –0.14 0.63

GLP-1 agonists –0.97 3.20 –1.74 0.89

Phung O, et al. JAMA 2010;303:1410–18.

Renal handling of glucose in non-diabetic individuals

Glomerulus

Loop

of Henle

Distal

tubule

Collecting

duct Proximal

tubule

S3 segment of proximal tubule

- ~10% glucose reabsorbed

- Facilitated by SGLT1

S1 segment of proximal tubule

- ~90% glucose reabsorbed

- Facilitated by SGLT2

Glucose reabsorption

S3 ~10%

S1

~90% Glucose filtration

(180 L/day) (1000 mg/L) =180 g/day

Adapted from: 1. Bailey CJ. Trends in Pharmacol Sci 2011;32:63-71.

2. Chao EC. Core Evidence 2012;7:21-28.

No/minimal glucose

excretion

SGLT = Sodium-dependent glucose transporter

SGLT Family of Transporters

Adapted from:

1. Bays H. Curr Med Res Opin. 2009;25:671-681.

Transporter Distribution Function

SGLT1

Small intestine, heart,

trachea, kidney

Active cotransport of sodium, glucose, and

galactose across the brush border of

intestine and proximal tubule of kidney

SGLT2 Kidney

Active cotransport of sodium and glucose in

the S1 segment of the proximal tubule of

kidney

SGLT3 Small intestine, uterus, lungs,

thyroid, and testis Active transport of sodium (not glucose)

SGLT4 Small intestine, kidney, liver,

stomach, lung Transport of glucose and mannose

SGLT5 Kidney Unknown

SGLT6 Spinal cord, kidney, brain, and

small intestine Transport of myo-inositol and glucose

SGLT = Sodium-dependent glucose transporter

SGLT1 and SGLT2 Inhibitors

Tahrani AA. The Lancet Diabetes & Endocrinology. 2013. http://dx.doi.org/10.1016/S2213-8587(13)70050-0.

Dapagliflozin

Ipragliflozin

Luseogliflozin LX-4211

Tofogliflozin

Canagliflozin

Phlorizin

Empagliflozin

Ertugliflozin

KGA-2727

Effect of SGLT2 Inhibition

(Mode of Action)

Glucosuria Direct excretion of glucose and

its associated calories

Potential Benefits Potential Risks

• Hypoglycaemia

• Renal function

• Diuretic effect

• Hypovolaemia

• Hypotension

• Dehydration

• Bone mineral metabolism

• Urinary tract infections, vulvovaginitis, balanitis

• Insulin-independent

• Glycaemic benefits

• HbA1c

• Fasting plasma glucose (FPG)

• Postprandial glucose (PPG)

• Body weight benefits

• Blood pressure benefits

FDA Advisory Committee 19th July 2011: http://www.fda.gov

SGLT: sodium-glucose co-transporter

http://www.fda.gov/

Increased Urinary Glucose Excretion in Longer Term

with Dapagliflozin

Titration Period Maintenance Period

0 6 12 18 26 34 42 52

-50

-25

0

25

50

75

100

125

150

175

200

225

250

275

Uri

na

ry g

luc

os

e (

mm

ol/

L)

Study Week

Dapagliflozin + Metformin (n = 406) Glipizide + Metformin (n = 408)

Nauck MA, et al. Diabetes 2011;34:2015-22.

Dapagliflozin: A1C Change from Baseline

in Placebo-Controlled Studies

1. Ferrannini E, et al. Diabetes Care 2010; doi:10.2337/dc10-0612.

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

3. Nauck M, et al. Diabetologia 2010; 53 (suppl 1):S107. Abstract 241.

4. Stroiek K. Diabetologia 2010; 53 (suppl 1):S347. Abstract 870.

5. Wilding J, et al. Diabetes 2010; 59 (suppl 1):A21-A22. Abstract 0078-OR.

6. Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/

Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm

∆ A

1C

(%

) w

ith

95

% C

I

*Statistically significant vs. placebo using Dunnett’s correction

Adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF)

10 mg Placebo

-1.2

-1.0

0

-0.2

-0.4

-0.8

-0.6 -0.23

-0.89*

-0.30

-0.84*

-0.13

-0.82*

-0.42

-0.97*

-0.30

-0.90*

Add-on to PIO

N = 420

8.38 %

Add-on to MET

N = 546

8.06 %

Add-on to

Insulin N = 807

8.53 %

Add-on to SU

N = 596

8.11 %

Monotherapy

N = 558

7.92 % BL (%)

http://www.ncbi.nlm.nih.gov/pubmed/20566676






http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm



Canagliflozin: A1C Change from Baseline

in Placebo-Controlled Studies

-0.77

-0.17 -0.13

-0.26

0.01 0.04

-0.03

-0.79

-0.85 -0.89

-0.63

-0.7

-0.6

-1.03

-0.95

-1.06 -1.03

-0.72

-0.79 -0.73

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Placebo

CANA 100 mg

CANA 300 mg

Ch

an

ge

in

A1

C (

%)

\

0.14

P <0.05 vs

placebo for

both CANA

doses in all

studies

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

/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013

Mono

8.01%

Add on to

MET

7.94%

Add on

to

MET/SU

8.13%

Add on

to

Met/Pio

7.9%

Add on

to

Insulin

8.27%

Add on

to

SU

8.35%

Add on to

AHA’s in older

subjects

7.7% Baseline

A1C (%)

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



Placebo

Empagliflozin: A1C Change from Baseline

in Placebo-Controlled Trials

0.0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

Add-on to

Pio ± MET

(24 wks)

8.1%

Add-on to

MET

(24 wks)

7.9%

Add-on to

Basal Insulin

(78 wks)

8.3%

-1.6

-0.64* -0.72*

-0.59*

-0.77*

-0.13

-0.78*

-0.66*

-0.48*

0.08

-0.70*

-0.11

Empagliflozin 25 mg Empagliflozin 10 mg

*Significant vs placebo

Ch

an

ge

in

A1

C (

%)

Add-on to

MET + SU

(24 wks)

8.1%

-0.82* -0.77*

-0.17

Monotherapy

(24 weeks)

7.9%

Roden M et al. ADA Annual Meeting 2013. Abstract 1085-P. Haring H et al. ADA Annual Meeting 2013. Abstract 1092-P.

Haring H et al. ADA Annual Meeting 2013. Abstract 1082-P. Kovacs C et al. ADA Annual Meeting 2013. Abstract 1120-P.

Rosenstock J et al. ADA Annual Meeting 2013. Abstract 1102-P.

0.2

-0.02

BL (%)

-0.66*

–2.0

–1.5

–1.0

–0.5

0

Sita

100 od

Me

an

ΔA

1C

Fro

m B

as

eli

ne

(%

)

0.5

Change in A1C with SGLT2 Inhibitors

vs DPP-4 Inhibitors

-1.03**

-0.66

Sita

100 od

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

(24wks)

7.9%

-0.66*

-0.78*

Empa

10 od

Empa

25 od

Add-on to Met +SU

(52wks)

8.1%

Cana

300 od PBO

Add-on to Met

(52 wks)

7.9%

Sita

100 od

-0.73

-0.88**

Cana

300 od

Cana

100 od

-0.73

0.08

Empa 10 & 25 NS vs. Sita Cana 100 noninferior to Sita

**Cana 300 superior to Sita

**Cana 300 superior

to Sita

*p<0.001 vs. PBO

NS=non-significant

BL (%)

BL 3 6 9 12 15 18 26 34 42 52

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

∆ H

bA

1c

(%

) w

ith

95

% C

I

Study Week

Dapa + MET Glipizide + MET

# Adjusted percent using modified logistic regression analysis:

** Statistically significant by heirarchical testing rule.

Titration period Maintenance period

Adjusted mean change from baseline using ANCOVA (LOCF)

N’s at Week 52 equal N’s at baseline

†Non-inferior compared to limit of 0.35%

N 400 401

BL Mean (%) 7.69 7.74

-0.52

-0.52

difference 0.00

(95% CI −0.11 to 0.11) † Pe

rce

nt

wit

h 9

5%

CI

Change in HbA1c at 52 Weeks in Dapagliflozin vs.

SU Add-on to Metformin Study

Nauck M, et al. Diabetes Care 34:2015-2022, 2011

Change in HbA1c to 104 Weeks in Dapa vs. SU

Add-on to Met Study

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2 C

ha

ng

e i

n H

bA

1c

* (%

)

0 6 12 18 26 34 42 52 65 78 91 104

Study Week

Number of Patients per Time Point

DAPA + MET GLIP + MET

400 385 367 369 354 339 334 321 311 271 242 233 401 379 364 361 354 342 331 315 303 248 226 208

DAPA + MET (N=400) GLIP + MET (N=401)

titration maintenance

short-term DB treatment period long-term DB extension period 1

Week 104 HbA1c

Baseline HbA1c

-0.14% (-0.25, -0.03)

-0.32% (-0.42, -0.21)

7.69%

7.74% *Data are adjusted mean change from baseline ± 95% CI derived from a repeated measures mixed model.

DAPA, dapagliflozin. DB, double-blind. MET, metformin.

Del Prato S, et al. Annual Meeting of the EASD, 12-16 September, 2011

(Presentation no #852).

Canagliflozin Demonstrates Durable Glycaemic Improvements Over 104 Weeks Compared With Glimepiride in Subjects With Type 2 Diabetes Mellitus on Metformin

Gisle Langslet,1 William T. Cefalu,2 Lawrence A. Leiter,3 Kun-Ho Yoon,4 Pablo Arias,5 John Xie,6 Dainius Balis,6 Dawn Millington,6 Frank Vercruysse,7 William Canovatchel,6 Gary Meininger6

1Lipid Clinic, Oslo University Hospital, Oslo, Norway 2Pennington Biomedical Research Center, Baton Rouge, LA, USA and

LSUHSC School of Medicine, New Orleans, LA, USA 3Keenan Research Centre in the Li Ka Shing Knowledge Institute of St.

Michael’s Hospital, University of Toronto, Toronto, ON, Canada 4The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea 5University of Rosario Medical School, Rosario, Argentina and Litoral

University Medical School, Santa Fe, Argentina 6Janssen Research & Development, LLC, Raritan, NJ, USA 7Janssen Research & Development, Beerse, Belgium

EASD 26 September 2013

Study Design

*Protocol-specified = ≥2,000 mg (or ≥1,500 mg, if unable to tolerate higher dose). †To be discontinued before titrating MET.

Pretreatment Period Core Double-blind Treatment Period

Screening visit

Week –2 Run-in start

Day 1 Baseline

AHA adjustment period start

• On protocol-specified doses* of MET • HbA1c ≥7.0% and ≤9.5%

Week 104

Continue stable protocol-specified* dose of MET

CANA 300 mg

CANA 100 mg

GLIM (titrated)

Not on protocol-specified doses* of MET

- Low-dose MET: HbA1c

≥7.5 and ≤10.0% - MET + another AHA†:

HbA1c ≥6.5 and

≤9.0%

1. Titrate MET (up to 2 weeks)

2. Stable MET dose (10 weeks)

HbA1c ≥7.0% and ≤9.5%

2-week, single- blind

placebo run-in

R

Extension Double-blind Treatment

Period

Week 52 Primary endpoint

20 26.09.2013

Change in HbA1c

GLIM CANA 100 mg CANA 300 mg

0 8 12 18 26 36 44 52

Time point (wk)

Baseline (%)

64 78 88 104

LS mean change

–0.74%

–0.65%

–0.55% –0.09% (95% CI: –0.20, 0.01)

–0.18% (95% CI: –0.29, –0.08)

7.8 7.8 7.8

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

0

LS m

ean c

hange (±

SE)

fr

om

baseline (

%)

mITT, LOCF

• Coefficient of durability was lower with CANA 100 and 300 mg than GLIM (0.16%, 0.16%, and 0.37%, respectively)

21 26.09.2013


Baseline (mmol/L)

–1.3 mmol/L

–1.1 mmol/L

–0.6 mmol/L

–0.5 mmol/L (95% CI: –0.7, –0.3)

–0.7 mmol/L (95% CI: –0.9, –0.4)

9.2 9.2 9.1

Change in FPG

mITT, LOCF

0

–0.2

–0.4

–0.6

–0.8

–1.0

–1.2

–1.4

–1.6

–1.8

LS m

ean c

hange (±

SE)

fr

om

baseline (

mm

ol/

L)

22 26.09.2013

0 8 12 18 26 36 44 52

Time point (wk)

64 78 88 104 4

LS mean change

Percent Change in Body Weight


Baseline (kg) LS mean

% change

–4.2% (–3.6 kg)

–4.1% (–3.6 kg)

0.9% (0.8 kg)

–5.1% (95% CI: –5.6, –4.5) (–4.3 kg)

–5.2% (95% CI: –5.7, –4.6) (–4.4 kg)

86.6 86.8 86.6

–6

–5

–4

–3

–2

–1

0

1

2

mITT, LOCF

LS m

ean %

change (±

SE)

fr

om

baseline

23 26.09.2013

0 8 12 18 26 36 44 52

Time point (wk)

64 78 88 104 4

Change in Systolic BP


Baseline (mmHg)

LS mean change

–3.1 mmHg

–2.0 mmHg

1.7 mmHg

–3.7 mmHg (95% CI: –5.2, –2.3)

–4.8 mmHg (95% CI: –6.2, –3.4)

129.5 130.0 130.0

–6

–5

–4

–3

–2

–1

0

1

2

3

• With CANA 100 and 300 mg and GLIM, LS mean changes from baseline in diastolic BP were −1.3, –2.2, and –0.02 mmHg, respectively; no notable changes in pulse rate were observed across groups

mITT, LOCF

LS m

ean c

hange (±

SE)

fr

om

baseline (

mm

Hg)

24 26.09.2013

0 8 12 18 26 36 44 52

Time point (wk)

64 78 88 104 4

0

2

4

6

8

10

12

14

16

18


Percent Change in LDL-C

Baseline (mmol/L)

LS mean % change

6.3% (0.06 mmol/L)

11.2% (0.14 mmol/L)

14.3% (0.24 mmol/L) 8.0%

(95% CI: 2.7, 13.3)

4.9% (95% CI: –0.4, 10.1)

2.7 2.6 2.8

mITT, LOCF

LS m

ean %

change (±

SE)

fr

om

baseline

25 26.09.2013

0 26 52

Time point (wk)

78 104


Percent Change in HDL-C

0.7% (0.00 mmol/L)

9.4% (0.10 mmol/L)

10.0% (0.11 mmol/L) 9.3%

(95% CI: 7.1, 11.4)

8.7% (95% CI: 6.5, 10.8)

1.2 1.2 1.2

mITT, LOCF

• Relative to GLIM, CANA 100 and 300 mg were associated with decreases in triglycerides and LDL-C/HDL-C ratio, and increases in non–HDL-C that were smaller than those seen in LDL-C; changes in lipids were generally similar at Week 52 and Week 104

26 26.09.2013

LS m

ean %

change (±

SE)

fr

om

baseline

Baseline (mmol/L)

0 26 52

Time point (wk)

78 104

LS mean % change

–2

0

2

4

6

8

10

12

Documented Hypoglycaemia Episodes

40.9

6.8 8.2

0

20

40

60

80

100

GLIM

CANA 100 mg

CANA 300 mg

Perc

enta

ge o

f subje

cts

• Rates of severe hypoglycaemia were lower with CANA 100 and 300 mg relative to GLIM (0.6%, 0.2%, and 3.3%, respectively)

27 26.09.2013

Mean eGFR Over Time


12 26 36 44 52

Baseline (mL/min/1.73 m2)

64 78 88 104

Mean change from baseline (Observed)

–1.6 mL/min/1.73 m2

88.6 90.1 93.5

4

–3.5 mL/min/1.73 m2

–6.1 mL/min/1.73 m2

Mean change from baseline

(LOCF)

–2.0 mL/min/1.73 m2

–3.8 mL/min/1.73 m2

–6.2 mL/min/1.73 m2

60

65

70

90

75

80

85

Mean (±

SE)

eG

FR

(mL/m

in/1

.73 m

2)

28 26.09.2013

0

Time point (wk)

95

100

Summary

• In subjects with T2DM on background MET, CANA 100 and 300 mg provided HbA1c reductions that were durable over 104 weeks; reductions in FPG, body weight, and systolic BP at Week 104 were similar to those seen at Week 521

• Both CANA doses were associated with increases in HDL-C and LDL-C that were stable from Week 26 to Week 104

• The overall safety profile of CANA over 104 weeks was generally consistent with that seen at 52 weeks1

– CANA was associated with increased incidences of genital mycotic infections, UTIs, and osmotic diuresis-related AEs compared with GLIM; these led to few discontinuations

• The incidence of hypoglycaemia was lower with both CANA doses than with GLIM

1. Cefalu WT, et al. Lancet. doi: 10.1016/S0140-6736(13)60683-2.

29 26.09.2013

Liraglutide: Effect on Body Weight (Kg)

Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride

Rosiglitazone Placebo Exenatide Sitagliptin

Glargine

-3.5

+2.5

-2.5

-1.5

-0.5

0

+0.5

+1.5

LEAD 3

Mono1

LEAD 2

+ Met2

LEAD 1

+SU3

LEAD 4

+Met + TZD4

LEAD 5

+Met +SU5

LEAD 6

+Met +SU6

Lancet 2010

+Met7

Ch

an

ge

in

bo

dy w

eig

ht

(kg

)

1. Marre M, et al. Diabet Med 2009;26:268-78.

2. Nauck M, et al. Diabetes Care 2009;32:84-90.

3. Garber A, et al. Lancet 2009;373:473-81.

4. Zinman B, et al. Diabetes Care 2009;32:1224-30.

5. Russell-Jones D, et al. Diabetologia 2009;52:2046-55.

6. Buse JB, et al. Lancet 2009;374:39-47.

7. Pratley RE, et al. Lancet 2010;375:1447-56.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871176/?tool=pubmed






























Dapagliflozin: Effect on Body Weight

in Placebo-Controlled Studies (Kg)

10 mg Placebo

∆ w

eig

ht

(kg

) w

ith

95

% C

I

*Statistically significant vs. placebo by hierarchical testing rule: *p<0.05; **p<0.001 Adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF)

-5.0

2.0

-4.0

1.0

0

-1.0

-3.0

-2.0

3.0

-2.2

-3.2

-0.90

-2.9**

-0.70

-2.3**

1.6

-0.1** 0.0

-1.7**

BL (kg)

1. Ferrannini E, et al. Diabetes Care 2010; doi:10.2337/dc10-0612.

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

3. Nauck M, et al. Diabetologia 2010; 53 (suppl 1):S107. Abstract 241.

4. Stroiek K. Diabetologia 2010; 53 (suppl 1):S347. Abstract 870.

5. Wilding J, et al. Diabetes 2010; 59 (suppl 1):A21-A22. Abstract 0078-OR.

6. Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/

Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm

7. Bolinder J et al. J Clin Endocrinol Metab. 97; 2012.

2/3 of the weight loss is fat mass

Add-on to PIO

N = 420

84.8

Add-on to MET

N = 546

86.3

Add-on to

Insulin N = 807

94.6

Add-on to SU

N = 596

80.6

Monotherapy

N = 558

94.2










Canagliflozin: Effect on Body Weight

in Placebo-Controlled Studies (%) % LS Mean Change from Baseline

-0.6

-1.0

-0.7

-0.1 -0.1 -0.2 -0.1

-2.8

-3.5

-2.1

-2.8

-1.8

-0.6

-2.4

-3.8 -3.9

-2.6

-3.8

-2.0

-2

-3.1

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

% L

S m

ea

n C

ha

ng

e f

rom

Ba

se

lin

e Placebo

CANA 100 mg

CANA 300 mg

P <0.05 vs

placebo for

both CANA

doses in all

studies except

CANA 100 mg

in Add-on to

SU Study

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

/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013. Toubro S et al. EASD Annual Meeting 2012. Abstract 762

More than 2/3 of the weight loss is fat mass

Baseline

(kg)

Mono

86.8 kg

Add on to

MET

87.2 kg

Add on

to

MET/SU

92.8 kg

Add on

to

Met/Pio

94.1 Kg

Add on

to

Insulin

97 kg

Add on

to

SU

97 Kg

Add on to

AHA’s in older

subjects

89.5 kg




Placebo

Empagliflozin: Effect on Body Weight

in Placebo-Controlled Trials (Kg)

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

Add-on to

Pio ± Met

(24 wks)

Add-on

to Met

(24 wks)

Add-on to

Basal Insulin

(78 wks)

-4.0

-2.00*

-1.47* -1.62*

-2.46*

-0.45

-2.48* -2.26* -2.20*

-0.33

-2.08*

0.34



Ch

an

ge

in

We

igh

t (k

g)

Add-on to

Met + SU

(24 wks)

-2.16* -2.39*

-0.39

Monotherapy

(24 wks)




0.5

0.7 1.0

BL (kg) 78.2 78.4 77.8 79.7 81.6 82.2 76.2 77.1 77.5 78.1 78.0 78.9 90.5 91.6 94.7

-0.74

-2.22

-0.6

-1.1

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Placebo + MET N=79

Dapa + MET N=82

kg

Body Fat and Lean Mass (kg) at Week 24 by DXA (SE)

Lean mass

Fat

**

** Statistically significant vs. placebo

by Hochberg’s method (p<0.001) Toubro S et al. EASD Annual Meeting 2012. Abstract 762.

Bolinder J et al. J Clin Endocrinol Metab. 97; 2012.

SGLT2 Inhibitors: Weight loss is Mostly Fat

1.06

-0.89 -1.12

1.02

-2.89 -2.51

-5

-4

-3

-2

-1

0

1

2

3

Ch

an

ge

fro

m B

ase

lin

e (

kg

)

CANA 100 mg N=71

Glimepiride N=68

CANA 300 mg N=69

Fat Mass

Lean Mass

1.02

1.06

Canagliflozin Dapagliflozin

Body Fat and Lean Mass (kg) at Week 52 by DXA

Dapagliflozin: Rates of Hypoglycemia

Rates of Hypoglycemia Across all Dapagliflozin

Treatment Regimens

Percent of patients

Dapa 2.5 mg Dapa 5 mg Dapa 10 mg Placebo

Placebo-controlled

pool

n=814

15.5

n=1,145

10.9

n=1,193

10.2

n=1,393

7.0

Monotherapy pool n=321

2.5

n=316

2.2

n=245

2.9

n=251

2.0

Add-on combination

+ MET (pool)

n=226

3.1

n=228

3.1

+ PIO n=141

2.1

n=140

0

n=139

0.7

+ SU n=154

7.1

n=145

6.9

n=151

7.3

n=146

4.8

+ insulin n=202

51.5

n=212

45.3

n=196

42.3

n=197

35.0

List J. Presented at the FDA Endocrinologic and Metabolic Drugs Advisory Committee Meeting, July 19, 2011.

Available at: www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm




Canagliflozin: Rates of Hypoglycemia

• Increased with insulin and SU background therapy

• Low rate of hypoglycemia in studies of subjects not on

agents associated with hypoglycemia

Placebo CANA 100 mg CANA 300 mg

Not on SU or insulin therapies % % %

PBO-controlled population 2.2 3.8 4.3

On SU or insulin therapies

MET + SU 15.4 27.4 30.1

SU 5.8 4.1 12.5

Insulin (initial 18 weeks) 36.8 49.3 48.6




Canagliflozin: Systolic Blood Pressure Change

from Baseline in Placebo-Controlled

Phase 3 Studies

-1.33 Pulse rate (bpm) LS mean change

-0.95 -4.03 -0.16 1.02 -0.70 -0.24 -3.75 -0.53 -0.08 -1.11 -0.22

Pla

ceb

o-s

ub

tra

cte

d

LS

Mea

n C

ha

ng

e i

n S

BP

(m

mH

g)

(95%

CI)

127.7 BL Mean

SBP (mmHg) 128.2 136.2 130.5 127.2 137.8

CANA 100 mg CANA 300 mg

Add-on to

Diet/Exercise (3005)

Wk 26

Add-on to

Met (3006)

Wk 26

Add-on to

SU (3008)

Wk 18

Add-on to

Met/SU (3002)

Wk 26

Add-on to

Met/Pio (3012)

Wk 26

Add-on to

Ins (3008)

Wk 18

-0.61




Week 2

4 o

r 48 m

ean

ch

an

ge f

rom

baselin

e m

mH

g

Monotherapy

-6

-5

-4

-3

-2

-1

0

1

2

Add-on to

Met

Add-on to

SU

Add-on

to insulin

Add-on to

TZD

Excluding data after rescue

Dapagliflozin: Systolic Blood Pressure Change

from Baseline in Placebo-Controlled

Phase 3 Studies

Presented at the FDA Endocrinologic and Metabolic Drugs Advisory Committee Meeting, July 19, 2011.


-

-




Placebo

Empagliflozin: Systolic Blood Pressure Change from

Baseline in Placebo-Controlled Phase 3 Studies

0.0

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

Add-on to

Pio ± Met

(24 wks)

Add-on to

Met

(24 wks)

Add-on to

Basal Insulin

(78 wks)

-2.4

-4.0*

-3.1*

-5.2*

-0.4

-3.7*

-2.9*

-4.1*

-0.3

-4.5*

0.7



Ch

an

ge i

n S

BP

(m

mH

g)

Add-on to

Met + SU

(24 wks)

-4.1*

-3.5*

-1.4

Monotherapy

(24 wks)




1.0 0.1

Baseline: 130.4 133.0 129.9 128.6 129.6 130.0 128.8 128.7 129.3 125.7 126.5 125.9 133.9 132.4 132.8

Dapagliflozin: Genital Infections – Summary

Most mild-to-moderate in intensity with dapa

Most responded to initial course of standard treatment

Rarely led to discontinuation (0.2%)

Most patients who had an event had only one over 102 weeks (74.6% dapa vs 77.8% placebo)

24 weeks

Dapa 10mg Placebo Dapa 10mg Placebo

102 weeks

Pati

en

ts (

%)

WOMEN (24 weeks)


MEN (24 weeks)

Pa

tien

ts (

%)

4.8

0.9

8.2

1.3

0

2

4

6

8

10

6.9

1.5

2.7

0.3

0

2

4

6

8

10


Available at:

www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm252891.htm




Canagliflozin: Frequency of Genital Infections Over

26 Weeks in Four Placebo-Controlled Studies

Most mild or moderate in intensity with cana

More common in women than men and in those with history of genital infection

Rarely led to discontinuation (0.5-0.9%)

Most patients had only one event over 26 weeks

women: 79% with GTI on cana had one one event

men: 78% with GTI on cana had one event

WOMEN

Cana 100mg Placebo

MEN

Pa

tien

ts (

%)

Cana 100mg Cana 300mg Placebo

Pa

tien

ts (

%)

4.2 3.7

0.6

0

2

4

6

8

10

10.4 11.4

0

4

8

12

16

20

3.2

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23,

2013.

Nyirjesky P et al. ADA Annual Meeting 2013. Abstract 1069-P.

Cana 300mg


Nyirjesky P et al. ADA Annual Meeting 2013. Abstract 1069-P.

Canagliflozin: Time to First Female Genital Mycotic

Infection Over 78 Weeks in 8 Pooled Studies

The highest rate of occurrence was observed during the first 4 months

of treatment, followed by an attenuation in the rate of increase

Empagliflozin: Frequency of Genital Infections

Over 24 Weeks in Four Placebo-Controlled Studies

Most mild in intensity with empa

More common in women than men and in those with history of genital infection



(84.6% of empa vs 83.3% placebo)

WOMEN

Empa 10mg Placebo

MEN

Pati

en

ts (

%)

All Patients

Empa 10mg Empa 25mg Placebo

Pati

en

ts (

%)

4.2

3.6

0.7

0

1

2

3

4

5

6.3 7.0

2.6

0

2

4

6

8

10

Empa 25mg

1.0


0.5 1.1

Kim G et al. ADA Annual Meeting 2013. Abstract 74-LB

Canagliflozin: Frequency of UTI Over 26 Weeks

in Four Placebo-Controlled Studies

Most mild to moderate in intensity with cana

More common in women than men



(83% of cana vs 82% placebo)

Upper UTI were rare and balanced between groups (0-0.1%)

WOMEN

Cana 100mg Placebo

MEN

Pa

tie

nts

(%

)

All Patients


Pa

tie

nts

(%

)

5.9

4.3 4.0

0

2

4

6

8

10

11.1

0.5

0

4

8

12

16

20

Cana 300mg

7.7


0.6 2.2

Nicolle L et al. ADA Annual Meeting 2013. Abstract 1139-P.

6.3

Dapagliflozin: Frequency of UTI – Summary

Most mild-to-moderate in intensity with dapa

Most responded to initial course of standard treatment



(74.6% of dapa vs 86.4% placebo)

Upper UTI were rare and balanced between groups

WOMEN (24 weeks)


MEN (24 weeks)

Pa

tie

nts

(%

)

24 weeks


102 weeks

Pa

tie

nts

(%

)

4.3 3.7

7.7

6.3

0

2

4

6

8

10

7.7 6.6

0.8 1

0

2

4

6

8

10






Empagliflozin: Frequency of UTI Over 24 Weeks

in Four Placebo-Controlled Studies

Most mild in intensity with empa

More common in women than men and in those with history of UTI



(87.1% of empa vs 91.1% placebo)

Severe UTI were rare and balanced between groups (0-0.2%)

WOMEN

Empa 10mg Placebo

MEN

Pati

en

ts (

%)

All Patients

Empa 10mg Empa 25mg

Pati

en

ts (

%)

7.5

9.3

0

2

4

6

8

10

Placebo

8.2

18.5 15.9

1.9

0

4

8

12

16

20

Empa 25mg

13.0


3.8 1.1

Kim G et al. ADA Annual Meeting 2013. Abstract 74-LB

SGLT2 Inhibitors and Cardiovascular Effects

• Pooled phase 3 trials do not show cardiovascular harm

• Reduction in SBP and body weight

• Lipid effects (Pooled data;PBO-corrected)

- LDL-C: 0.1-0.2 mmol/L

- HDL-C: 0.02-0.07 mmol/L

- TG: 0.05-0.22 mmol/L

• Ongoing CV outcome trials will help to determine

the CV effects of this class

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf.

Accessed January 23, 2013. Langkilde A el al. American Heart Assoication Annual Meeting 2011; Abstract 8947.

Hardy P et al. ADA Annual Meeting 2013. Abstract 1188-P. Hach T et al. ADA Annual Meeting 2013. Abstract 69-LB. www.Clinicaltrials.gov

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf



Ongoing Cardiovascular Outcome Trials:

SGLT2 Inhibitors

Therapies # Population Endpoints Results

CANVAS Canagliflozin/

Placebo

4,363 CVD or high-

risk for CVD

CV death, NF MI

or NF stroke

June 2018

EMPA-REG

OUTCOME

Empagliflozin/

Placebo

7,000 CVD CV death, NF MI

or NF stroke

March

2018

DECLARE Dapagliflozin/Pl

acebo

17,150 CVD or high-

risk for CVD

CV death, NF MI

or NF stroke

April 2019

Adapted from: www.Clinicaltrials.gov

Summary: Which agent to choose after

metformin ?

The decision must be individualized

CDA 2013 Guidelines. Can J Diabetes. 2013;37:S61-68.

Which patients will benefit from SGLT2 inhibitors?

• Patients who have not achieved glycemic contorol with

metformin, or those not able to take metformin

• Patients who would benefit from weight loss

• Patients with greater risk for hypoglycemia

• SGLT2 inhibitors offers improved glycemic control, weight

loss and SBP reduction without increasing risk of

hypoglycemia

Summary of SGLT2 Inhibitors

Sustained glucosuria with resultant decrease in HbA1c, FPG

and PPG1

Effective as monotherapy and in combination with other oral

agents and insulin

Weight loss

Blood pressure lowering

Sustained efficacy over duration of the long-term studies (up to

2 yrs)

Increase in frequency of genital infections and possibly in UTIs

(Infections are manageable and did not result in discontinuation of in most

cases)

1. Wilding et al. Diabetes Care. 2009;32:1656-62

?

Reduce Hyperglycemia

Metformin

Thiazolidinediones

GLP-1 analogues DPP-4 inhibitors

SGLT2 inhibitors

-glucosidase inhibitors

Sulfonylureas Glitinides

GLP, glucagon-like peptide;

DPP, didpeptidyl peptidase

Targets for Oral Antidiabetic Therapies

sglt2 inhibitors: a novel and important new class of ...icdm2013.diabetes.or.kr/slide/ot1-3 lawrence...

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