Learning Objectives - TBMS.CA of Interest Declaration: Nothing to Disclose Presenter: DR. A....

Learning Objectives

• Discuss individualization of therapy in Type Diabetes mellitus

• Identify relevant aspects each new class of drugs

• Assess cardiovascular effects of the new class of drugs

Conflict of Interest Declaration: Nothing to Disclose

Presenter: DR. A. ABU-BAKARE

Title of Presentation: CHOOSING THE RIGHT DRUG FOR TYPE 2 DIABETES

I have no financial or personal relationships to disclose

Faculty/Presenter Disclosure

• Faculty: Dr Asiru Abu-Bakare

• Relationships with commercial interests:– Grants/Research Support: None

– Speakers Bureau/Honoraria: Astra Zeneca: BoehringerIngelheim Pharmaceuticals, Inc.: Elil Lilly and Company: Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.: Novo Nordisk: Sanofi: Amgen Inc.: Abbott Laboratories:

– Consulting Fees: Novo Nordisk; Boehringer IngelheimPharmaceuticals; Eli Lilly; Sanofi

– Other: None

Disclosure of Commercial Support

• This program has received financial support from no organization.

• This program may have received support indirectly because of inclusion of materials I have used in previous talks sponsored by several Companies listed earlier.

• Potential for conflict(s) of interest:– Dr. Abu-Bakare has received no payments from any

organization supporting this program AND/OR organization whose product(s) are being discussed in this program].

28%

50%

67%

78%86%

91%

0%

20%

40%

60%

80%

100%

Target Achieved

≤6.5%

Target Achieved

≤7.0%

≤7.5% ≤8% ≤8.5% ≤9.0%

DM-SCAN: A1C Values Achievedin Primary Care

N=5123

% o

f P

ati

en

ts

A1C (%)

Leiter LA et al. Can J Diabetes. 2013;37(2):82-9.

CDA Treatment Algorithm

CDA: Canadian Diabetes Association. 1. CDA. Can J Diabetes. 2013;37(suppl 1):S61-8.

8

A1C <8.5% Symptomatic hyperglycemia with metabolic decompensation

A1C 8.5%

If not at glycemic target (2-3 mos)

Start/Increase metformin

L

I

F

E

S

T

Y

L

E

Patient CharacteristicsDegree of hyperglycemia

Risk of hypoglycemiaOverweight or obesity

Comorbidities (renal, cardiac, hepatic)Preferences & access to treatment

Other

AT DIAGNOSIS OF TYPE 2 DIABETES

Agent CharacteristicsBG lowering efficacy and durability

Risk of inducing hypoglycemiaEffect on weight

Contraindications & side-effectsCost and coverage

Other

Initiate insulin +/- metformin

Start metformin immediately

Consider initial combination with another antihyperglycemic agent

If not at glycemic targets

Make timely adjustments to attain target A1C within 3 to 6 months

Add an agent best suited to the individual:

Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

Noninsulin Agents Available for T2D

Class Primary Mechanism of Action Agent(s) Available as

-Glucosidase inhibitors

Delay carbohydrate absorption from

intestine

AcarboseMiglitol

Precose or genericGlyset

Amylin analogue

Decrease glucagon secretion

Slow gastric emptying

Increase satiety

Pramlintide Symlin

Biguanide Decrease HGP

Increase glucose uptake in muscleMetformin Glucophage or generic

Bile acid sequestrant Decrease HGP?

Increase incretin levels?Colesevelam WelChol

DPP-4 inhibitors

Increase glucose-dependent insulin

secretion


AlogliptinLinagliptinSaxagliptinSitagliptin

NesinaTradjentaOnglyzaJanuvia

Dopamine-2 agonist Activates dopaminergic receptors Bromocriptine Cycloset

Glinides Increase insulin secretionNateglinideRepaglinide

Starlix or genericPrandin

DPP-4 = dipeptidyl peptidase; HGP = hepatic glucose production.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

Continued on next slide

Noninsulin Agents Available for T2D

Class Primary Mechanism of Action Agent(s) Available as

GLP-1 receptor agonists

Increase glucose-dependent insulin

secretion


Slow gastric emptying

Increase satiety

AlbiglutideDulaglutideExenatideExenatide XRLiraglutide

TanzeumTrulicityByettaBydureonVictoza

SGLT2 inhibitors Increase urinary excretion of glucoseCanagliflozinDapagliflozinEmpagliflozin

InvokanaFarxigaJardiance

Sulfonylureas Increase insulin secretion

GlimepirideGlipizideGlyburide

Amaryl or genericGlucotrol or genericDiaeta, Glynase, Micronase, or generic

Thiazolidinediones

Increase glucose uptake in muscle

and fat

Decrease HGP

PioglitazoneRosiglitazone

ActosAvandia

GLP-1 = glucagon-like peptide; HGP = hepatic glucose production; SGLT2 = sodium glucose cotransporter 2.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.

Continued from previous slide

Effects of Agents Available for T2D

Met GLP1RA SGLT2I DPP4I TZD AGI Coles BCR-QRSU/

GlinideInsulin Pram

Renal impair-ment/ GU

Contra-indicated in stage 3B, 4, 5

CKD

Exenatide contra-

indicated CrCl <30 mg/mL

GU infection

risk

Dose adjust-ment

(except lina-

gliptin)

May worsen

fluid retention

Neutral Neutral Neutral

Increased hypo-

glycemia risk

Increased risks of hypo-

glycemia and fluid retention

Neutral

GI adverse effects

Mod Mod* Neutral Neutral* Neutral Mod Mild Mod Neutral Neutral Mod

CHF Neutral Neutral Neutral Neutral† Mod Neutral Neutral Neutral Neutral Neutral Neutral

CVDPossible benefit

Neutral Neutral Neutral Neutral Neutral Neutral Safe ? Neutral Neutral

Bone Neutral Neutral Bone loss NeutralMod bone

lossNeutral Neutral Neutral Neutral Neutral Neutral

Continued from previous slide

AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; CHF = congestive heart failure; CVD =

cardiovascular disease; DPP4I = dipeptidyl peptidase 4 inhibitors; GI = gastrointestinal; GLP1RA = glucagon-like peptide 1 receptor

agonists; GU = genitourinary; Met = metformin; Mod = moderate; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU =

sulfonylureas; TZD = thiazolidinediones.

*Caution in labeling about pancreatitis.†Caution: possibly increased CHF hospitalization risk seen in CV safety trial.

Individualizing A1C Targets

1. CDA. Can J Diabetes. 2013;37(suppl 1):S61-8.

Consider 7.1-8.5% if:

22

Food

intake

Stomach

GI tract

Intestine

Increases and prolongs GLP-1

effect on α-cells:

α-cells

Pancreas

Insulin release

Net effect:

Blood glucose

Beta-cells

Increases and prolongs GLP-1

and GIP effects on β-cells:

DPP-4

inhibitor

Glucagon secretion

Incretins

DPP-4

AEY

GT

FI

SD

YS

IA

MD

KI

H

HN

QT

I

Q

QD

FV

NW

LL

AQKG

KK

NDW

K

EFIWLVK

GR

GA K

AEH T

FT

SD

VS

SY

LE

GQ

AA

G

GIP: Glucose-dependent insulinotropic polypeptide

GLP-1: Glucagon-like peptide-1

The Incretins

DPP-4

DPP-4 Dipeptidyl Peptidase-4

1. Hansen L, et al. Endocrinology. 1999;140:5356–5363; 2. Deacon CF, et al. Am J Physiol. 1996;

271(3 pt 1):E458–E464.

More Than 50% of Secreted GLP-1 Is Degraded Before Plasma Absorption

– GLP-1 (green) released into intestinal capillaries is immediately exposed to DPP-4 (red)1

– > 50% of secreted GLP-1 is already degraded before it reaches the general circulation2

– > 40% of circulating GLP-1 is already degraded before it reaches β-cells2

Histochemistry by C. Ørskov, Panum Institute, Copenhagen. Copyright © 1999, The Endocrine Society.

GLP-1 (incretin)

Meal

(gut peptide hormone released from L-cells in the jejunum and ileum)

Inactive GLP-1

DPP-4

↓ glucagon secretion↑ insulin secretion

(glucose dependent)

↑ β-cell mass (long-term animal

studies)

DPP-4 Inhibitor

XGLP-1 analogue

GLP-1 analogues pharmacological level of GLP-1 action

DPP-4 inhibitors physiological level of GLP-1 action

↓ gastric emptying↓ food intake

↑ satiety

Effects of GLP-1 analogues and DPP-4 inhibitors

Sitagliptin Saxagliptin Linagliptin

Dosage 100 mg qd 5 mg qd 5 mg qd

Earliest approval 2005 2009 2011

Approximate half-life 12 hours 2 hours > 120 hours

Elimination Renal clearance (75%) Hepaticmetabolism to active metabolite( half as potent) Renal excretion ( 12% -29 % unchanged pant and 21%-52% as metabolite)

Entero-hepatic Eliminated unchangedin feces via biliary excretion (85%)

Important drug interactions

Low clinically meaningful interactions

Low clinicallyMeaningfulinteractions

Efficacy may be limited in patients receiving concurrent inducers of CYP3A4 or P-gp (eg, rifampicin)

Effect on weight Neutral Neutral Neutral

Adverse events Low Low Low

Currently Available DPP-4 Inhibitors Approved for Use in Patients with T2DM in Canada

Sitagliptin Saxagliptin Linagliptin

Usual dosage 100 mg qd 5 mg qd 5 mg qd

CrCl ≥ 50 mL/min No dose adjustment required

No dose adjustment required


CrCl ≥ 30 to <50 mL/min

Dose reduction to 50 mg/day

Dose reduction to 2.5 mg/day


CrCl < 30 mL/min Dose reduction to 25 mg/day

Dose reduction to 2.5 mg


End-stage renal disease Dose reduction to 25 mg/day

2.5 mg administered following dialysis


Peritoneal dialysis Dose reduction to 25 mg/day

No data available No dose adjustment required

Summary of Dose Reductions Recommended in Patients With Renal Impairment

Antihyperglycemic Agents and Renal Function

eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1

Acarbose Not recommended 25

Dapagliflozin 60Empagliflozin 45

Thiazolidinediones 30Contraindicated Caution and/or dose reduction

Canagliflozin 25 60†100 mg45

60†10 or 25 mg

Not recommended

Metformin 30 60

15Linagliptin

Sitagliptin 5030 50 mg25 mg

Saxagliptin 5015 2.5 mg

Alogliptin Not recommended 506.25 mg 12.5 mg30

Exenatide (BID/QW) 30 50Liraglutide* 50

Albiglutide 50

30

Repaglinide

Gliclazide/Glimepiride 15 30Glyburide 30 50

SGLT2 inhibitors

GLP-1R agonists

Alpha-glucosidaseInhibitors

Biguanide

DPP-4 inhibitors

Insulin Secreta-gogues

Dulaglutide 50

*Based on Saxenda Product Monograph June 2015; †Do not initiate if eGFR <60 ml/min.

1. CDA. Can J Diabetes. 2015;39:250-252; 2. Respective Product Monographs as of Nov 2015.

SafeNo dose adjustment but close monitoring of renal function

DPP-4 Inhibitors vs. Sulfonylureas

(added to Metformin): Efficacy by Baseline A1C

-0.14

-0.59

-1.11

-1.76

-0.26

-0.53

-1.13

-1.68

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-0.3

-0.58

-0.81

-1.72

-0.32

-0.45

-0.84

-1.05

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Sitagliptin 100 mg QD + MET

Glipizide + MET

Cha

nge

fro

m B

ase

line in A

1C

(%

)

Saxagliptin 5 mg QD + MET

Glipizide + MET

Ch

an

ge

fro

m B

ase

line in A

1C

(%

)

Sitagliptin vs. Glipizide1

52 weeks (n=793)

Saxagliptin vs. Glipizide2

52 weeks (n=858)

p values not available.

1. Nauck et al. Diabetes Obes Metab. 2007;9:194-205; 2. Goke et al. Int J Clin Pract. 2010;64:1619-31.

<7% 7-<8% 8-<9% ≥9% <7% 7-<8% 8-<9% ≥9%

112n= 117 167 179 82 82 21 33 n= 99 186 190 105 93 34 46105

Not head-to-

head trials

Nausea was generally mild to moderate, transientand rarely led to discontinuation of therapy.

Percentage of subjects with nausea through 26 weeks of treatment.

† † † p<0.05

† † p<0.001

† p<0.0001

Frequency of Nausea (LEAD 2)

Nauck et al. Diabetes Care 2009;32:84–90;

Gallwitz B et al. Int J Clin Pract. 2010;64(2):267-276.

0.0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

-1.6

-1.8

-2.0

*

Significant vs. comparator.

DULA vs.

Glargine

(AWARD-2)5

78 weeks

-1.1*

-0.6

BL~8.1%

DU

LA

1.5

GL

AR

EXE QW vs.

Glargine

(DURATION-3)4

26 weeks

-1.3

-1.5*

BL~8.3%

GL

AR

EX

E Q

W

LIRA vs.

Glargine

(LEAD-5)2

26 weeks

-1.3*

-1.1

BL~8.3%

GL

AR

LIR

A 1

.8

-1.9

-1.8*

LIRA vs.

Glargine

(EAGLE)3

24 weeksBL~9.1%

GL

AR

LIR

A 1

.8

ALBI vs.

Glargine

(HARMONY-4)6

52 weeks

-0.7-0.8

Noninferior

p=0.146

BL~8.3%

GL

AR

AL

BI

EXE BID vs.

Insulin

(4-Trial Analysis)1

26 weeksBL: N/A

-1.1-1.2

Noninferior

p=0.09

Δ in Wt. (kg): -1.9* 1.4-2.6* 1.4-1.8* 1.6 -3.0* 2.0 -1.1* 1.6-2.0 1.8

Ins dose (U/d): 293124 52 30NA

GL

AR

/ P

rem

ix

EX

E B

ID

p=0.0015

GLP-1R Agonists vs. Basal Insulin: Head-to-Head Trials

p=0.019 p=0.017 p<0.001

230 232 470 474 233 223 273 262 496 239n= 721 702

Me

an

ΔA

1C

Fro

m B

ase

line (

%)

R

Median Duration of Follow-upa

aApproximate median duration of follow-up for TECOS, based on the expected event rate at study initiation. EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome;SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes

Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin. CV = cardiovascular; MI = myocardial infarction; UA = unstable angina.

EXAMINE, SAVOR-TIMI, and TECOS

50

SAVOR-TIMI2

TECOS3

EXAMINE1

6.5–8.0

CV death, Nonfatal MI, Nonfatal stroke, or UA

req. hospitalization

RandomizationUp to Year 4

Year 3Year 2Year 1

CV death, Nonfatal MI, orNonfatal stroke

CV death, Nonfatal MI, orNonfatal stroke

Saxagliptin

Alogliptin

Placebo

Placebo

Placebo

6.5–12.0

6.5–11.0

HbA1c Range, % Primary End pointDuration of Treatment (as part of usual care)

Sitagliptin

1. White WB et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med 2013;369:1317–1326. 3. Green JB et al. Am Heart J. 2013;166:983–989.e7.

R

R

EXAMINE, SAVOR-TIMI, and TECOS

EXAMINE1 SAVOR-TIMI2 TECOS3

Alogliptin vs Placebo

Saxagliptin vs Placebo

Sitagliptin vs Placebo

Sample size, N 5,380 16,492 14,724

Median duration of diabetes, y

≈7.2 10.3 9.4

Baseline HbA1c, % 8.0 8.0 7.3

Number of events 621 1,222 >1,300

Median duration of exposure, y

1.5 2.1 ≈ 3.0

51

EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With

Sitagliptin.

Endpoint

2-year KM rate (%)

HRp value for superiorityPlacebo

(n = 8,212)Saxagliptin(n = 8,280)

CV death 2.9 3.2 1.03 (0.87-1.22) 0.72

MI 3.4 3.2 0.95 (0.80-1.12) 0.52

Ischemic stroke 1.7 1.9 1.11 (0.88-1.39) 0.38

Hosp. for cor.revasc.

5.6 5.2 0.91 (0.80-1.04) 0.18

Hosp. for UA 1.0 1.2 1.19 (0.89-1.60) 0.24

Hosp. for HF 2.8 3.5 1.27 (1.07-1.51) 0.007

All-cause mortality 4.2 4.9 1.11 (0.96-1.27) 0.15

SAVOR TIMI-53: Individual Endpoints

52Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.

Relevant Baseline Characteristics

Characteristic SAVOR-TIMI1 EXAMINE2 TECOS3

# patients 16492 5380 14724

Males (%) 67 68 71

Mean age (SD) 68.1 (8.5) 61 66 (8)

BMI 31.1 (5.5) 28.7 30.2 (5.7)

A1C % 8.0 8.0 7.3 +/-0.7

Duration of DM 10.3 7.2 9.4

North America 31.9% 15.9 18%

Western Europe 26.0% 11.3* 14%

531.Scirica BM et al, N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684. 2.White W. et al N Engl J Med 2013. DOI: 10.1056/NEJMoa1305889.

3.Bethel M.A. et al. DOM 2015 Jan 20. doi: 10.1111/dom.12441.

* Western Europe, Australia, New Zealand, and Middle East ** Eastern Europe, Western Europe

Relevant Baseline Characteristics (2)

Characteristic SAVOR-TIMI1 EXAMINE2 TECOS3

Established CVD 78.4% 100% 100%

MI 37.8% 88% 43%

CABG TBD 12.8% 25%

Stroke/TIA TBD 7.2% 21%

PAD TBD 9.6% 17%

CHF (all patients) 12.8% 28.5%4 18%

CHF (NYHA Class 3-4) 1.4% 5.65%4 2.5%

541-Scirica BM et al, N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684. 2-White W. et al N Engl J Med 2013. DOI: 10.1056/NEJMoa1305889

3- Bethel M.A. et al. DOM 2015 Jan 20. doi: 10.1111/dom.12441. 4-Zannad F. et al. Lancet 2015. Published online March 10, 2015. http://dx.doi.org/10.1016/S0140-6736(14)62225-X

Days

Pat

ien

ts W

ith

En

dp

oin

ts (

%)

14

12

10

8

6

4

2

00

180 360 540 720 900

HR 1.00; 95% CI, 0.89–1.12P<0.001 (NI)P=0.99 (superiority)

Saxagliptin: 7.3%*Rate/100 person-yrs – 3.7

Placebo: 7.2%*Rate/100 person-yrs – 3.7

SAVOR: Kaplan – Meier Rates of the Primary Composite Endpoint – CV Death, MI, or Stroke

55

SAVOR: n = 16,492 patients (mean age 65 years) with type 2 diabetes (median duration 10.3 years) and established CVD or multiple risk factors. Median duration of follow-up: 2.1 years. A1C at 2 yrs: Saxa, 7.6%, PBO 7.9%

*K-M event rates are presented after 2 yrs., HR: hazard ratio; K-M: Kaplan-Meier; Pbo: placebo; Saxa: saxagliptin, Scirica BM, et al. N Engl J Med. 2013;369:1317-1326.

0

8

0

6

4

180 360 540 720 900

Days

Ho

spit

aliz

atio

n f

or

HF

(%)

Saxagliptin

2

Placebo

n = 16,492

HR 1.80(1.29 – 2.54)

p = 0.001

Overall HR 1.27(1.07 – 1.51)

p = 0.007

HR 1.48(1.14 – 1.87)

p = 0.003

HR = hazard ratio1.1%

0.6%

1.9%

1.3%

3.5%

2.8%

SAVOR TIMI – 53: Rates of Risk of Hospitalization For Heart Failure Over Time

56

• Saxagliptin neither increased nor decreased the risk of the 1° and 2° endpoints in these high-risk populations

• There were no specific subgroups in which the RR associated with saxagliptin was particularly high or low

• The absolute risk with saxagliptin was smallest in patients at low risk of HF and correspondingly larger in patients at highest risk

HF, heart failure. Scirica BM et al. Circulation. 2014; 130:1579-88.

Renal Handling of Glucose in Healthy Patients

SGLT = Sodium-dependent glucose transporter

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

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

GlomerulusDistal tubule

Collecting duct

Loop of

Henle

Proximal tubule

S3 segment of proximal tubule

• ~10% glucose reabsorbed

• Facilitated by SGLT1

S1 segment of proximal tubule

• ~90% glucose reabsorbed

• Facilitated by SGLT2

Glucosereabsorption

S3~10%

S1

~90%Glucosefiltration

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

No/minimalglucose

excretion

SGLT2 Inhibitors: Mechanism of Action

GLU = facilitative glucose transporter. SGLT = sodium-dependent glucose transporter.Adapted from: Abdul-Ghani MA, et al. Endocr Pract 2008; 14(6):782-90. Bays H. Curr Med Res Opin 2009; 25(3):671-81. Wright EM. Am J Physiol Renal Physiol 2001; 280(1):F10-8. Lee YJ, et al. Kidney Int Suppl 2007; 106:S27-35. Han S, et al. Diabetes 2008 ; 57:1723-9.

Proximal tubuleS1

GlomerulusDistal tubule

Collecting duct

Glucosefiltration

S3

SGLT2 and GLUT2 SGLT1 and GLUT1

Increasedglucose

excretion

SGLT2 inhibitor

SGLT2 inhibition reduces renal glucose reabsorption and increases glucose elimination

Loop of Henle

Reduced glucosereabsorption

0

25

50

75

100

125

150

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

Adaptationin patients

with diabetes

Under treatment with SGLT2 inhibitors

Effects of SGLT2 Inhibitors on RTG

RTG= Renal Threshold of Glucose

Targeting Hyperglycemia: Insulin-Dependent vs Insulin-Independent Approaches

Insulin action• TZDs• Metformin

Adipose Tissues

Muscles

Liver

Insulin release• Sulfonylureas• GLP-1R agonists• DPP-4 inhibitors• Meglitinides

Pancreas

Insulin-Dependent Mechanisms Insulin-Independent Mechanism

Insulin-independent renal SGLT2

Insulin replacement• Insulin

Osmotic diuresis• Initial weight loss2

• Decrease in blood pressure2

Loss of excess calories2,3

• Sustained weight loss2

• Mitigation of weight gain caused by antihyperglycemics of other classes2

Insulin-independent mechanism3

• Efficacy at all stages of the disease• Possibility of combination with

antihyperglycemics of other classes2

• Stable control in combination with insulin and insulin secretagogues2

Treatment with an SGLT2 Inhibitor: Clinical Benefits in T2DM

1. Holman RR, et al. N Engl J Med 2008; 359:1577-89. 2. Neumiller JJ. Drugs 2010; 70:377-85. 3. Lo MC, et al. Am J Ther 2013; 20(6):638-653.

Sustained glucose lowering• Potential prevention of

microvascular morbidity1

• Decrease in glucotoxicity2

SGLT2

-0.78 -0.8

-0.7

-0.85

-0.64

-1.03

-0.95

-0.79

-1.06

-0.72

0.14

-0.17

0.04

-0.13

0.01

-1.25

-1

-0.75

-0.5

-0.25

0

0.25

Mono + Met + SU + Met + SU + Insulin

Canagliflozin 100 mg/d Canagliflozin 300 mg/d Placebo

Baseline A1c 8.0% 7.9% 8.4% 8.1% 8.3%

A1

c %

mm

ol/

LCanagliflozin – Summary of Clinical Studies

A1c Reduced: 0.64 to 1.06% (0.63 to 1.17% PBO Corrected)

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

ugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013

5.1 6.84.1

38.8

63.3

3.6

6.8

12.5

36.5

58.4

3.6 4.15.8

17.9

50.1

0

10

20

30

40

50

60

70

Mono + Met + SU + Met + SU + InsulinBaseline A1c 8.0% 7.9% 8.4% 8.1% 8.3%


%

hyp

ogl

yce

mia

Canagliflozin – Summary of Clinical Studies

Rare Hypoglycemia Except When Combined with Secretagogues or Insulin



-2.7

-3.5

-0.6

-2.0

-1.5

-3.8 -3.9

-2.0

-2.6-2.4

-0.6

-1.0

-0.2

-0.7

-4

-3

-2

-1

0

1

-0.1

We

igh

t -

kg


Baseline 86.8 kg 87.2 kg 83.0 kg 94.1 kg 97.0 kg

Canagliflozin – Summary of Clinical StudiesWeight Reduced by 0.6 to 3.9 kg (0.4-3.2 kg PBO Corrected)

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




Baseline SBP 127.7 128.2 136.2 130.5 137.8


-3.3

-3.9-3.5

-3.7

-5.15.0 -5.1 -5.2

-4.3

-6.9

0.4

1.5

-3.4

-2.6 -2.5

-7

-6

-5

-4

-3

-2

-1

0

1

2

mm

Hg

Canagliflozin – Summary of Clinical StudiesSystolic BP Decreased by 3.3 - 6.9 mmHg (0.1-6.6 PBO Corrected)



A1c - Comparative DataCanagliflozin vs Sitagliptin in Triple Therapy MET + SU

Superior A1c reduction

observed with CANA

compared to SITA

Cana Sita% achieving A1c < 7.0% 47.6% 35.3%

Sita 100 mg

Cana 300 mg

Mean Change in FPG and PPG Canagliflozin vs Sitagliptin in Triple Therapy MET + SU

Schernthaner G, et al. Diabetes Care. 2013;36(9):2508-2515.

Weight - Comparative DataCanagliflozin vs Sitagliptin in Triple Therapy MET + SU

Schernthaner G, et al. Presentation 243. Presented at: The 48th Annual EASDMeeting, Oct. 2012.

Blood Pressure - Comparative DataCanagliflozin vs Sitagliptin in Triple Therapy MET + SU

Schernthaner G, et al. Presentation 243. Presented at: The 48th Annual EASD

Meeting, Oct. 2012.

* Statistical comparison for CANA 300 mg vs SITA 100 mg not performed (not pre-specified)†p < 0.001 vs PBO.mITT, LOCF

Pla

ceb

o-0

.23

10

mg

-0.8

9

5m

g-0

.77

*

Pla

ceb

o-0

.30

10

mg

-0.8

4

5m

g-0

.70

*

Pla

ceb

o-0

.13

10

mg

-0.8

2

5m

g-0

.63

*

Pla

ceb

o-0

.30

10

mg

-0.9

0

5m

g-0

.82

*

A1C Reductions Across Continuum of T2DM

= 0.6-1.1% from Baseline with Dapa and Cana

1. Ferrannini E, et al. Diabetes Care 2010; 33:2217-24. 2. Bailey CJ, et al. Lancet 2010; 375:2223-33. 3. Strojek K, et al. Diabetes Obes Metab 2011; 13:928-38. 4. Wilding JP, et al. Ann Intern Med. 2012 Mar 20;156(6):405-15. 5. INVOKANA Product Monograph. Janssen Inc., November 2014.

*p < 0.0001 vs. placebo. **p = 0.0005 vs. placebo. ***p < 0.001 vs. placebo.

Bargraph denotes individual trials and is not intended for comparisons between dapagliflozin and canagliflozin.

Ch

ange

fro

m

bas

elin

e A

1C

(%

)

0

-1.25

-0.25

0.25

Baseline A1C

Monotherapy1

7.92

Add-on to Ins4

8.53

Add-on to Glim3

8.11

Add-onto Met2

8.06

Dapagliflozin

Pla

ceb

o0

.14

30

0 m

g-1

.03

10

0 m

g-0

.78

Pla

ceb

o-0

.17

30

0 m

g-0

.77

10

0 m

g-0

.62

Pla

ceb

o0

.04

30

0 m

g-0

.83

10

0 m

g-0

.74

Pla

ceb

o-0

.13

30

0 m

g-1

.06

10

0 m

g-0

.85

Monotherapy

8.0

Add-on toMet + SU

8.1

Add-on to SU

8.4

Add-onto Met

7.9

Canagliflozin5

Pla

ceb

o0

.01

30

0 m

g-0

.72

10

0 m

g-0

.64

Add-on to Ins

8.3

-0.5

-0.75

-1.0 **

**

****

***

***

*** ******

***

***

***

***

Body Weight Reductions Across Continuum of T2DM = 1.0 - 3.9 kg from Baseline with Dapa and Cana

Pla

ceb

o-2

.19

10

mg

-3.1

6

5m

g-2

.8

NS

Pla

ceb

o-0

.89

10

mg

-2.8

6

5m

g-3

.04

*

Pla

ceb

o-0

.72

10

mg

-2.2

6

5m

g-1

.56

*

Pla

ceb

o0

.02

10

mg

-1.6

7

5m

g-0

.98

*Ch

ange

fro

m

bas

elin

e b

od

y w

eig

ht

(kg)

0

-4

-1

1.0

Baseline weight

24-wkmonotherapy1

90.2 kg

24-wk add-on to Ins4

93.8 kg

24-wk add-on

to Glim3

81.1 kg

24-wk add-on to Met2

88 kg

Dapagliflozin

Pla

ceb

o-0

.6

30

0 m

g-3

.9

10

0 m

g-2

.7

Pla

ceb

o-1

.2

30

0 m

g-4

.2

10

0 m

g-3

.7

Pla

ceb

o-0

.2

30

0 m

g-2

.0

10

0 m

g-0

.6

Pla

ceb

o-0

.7

30

0 m

g-2

.6

10

0 m

g-2

.1

Monotherapy

86.8 kg

Add-on toMet + SU

94.1 kg

Add-on to SU

83.0 kg

Add-onto Met

87.2 kg

Canagliflozin5

Pla

ceb

o-0

.0

30

0 m

g-2

.7

10

0 m

g-1

.9

Add-on to Ins

97.0 kg

-2

-3

1. Ferrannini E, et al. Diabetes Care 2010; 33:2217-24. 2. Bailey CJ, et al. Lancet 2010; 375:2223-33. 3. Strojek K, et al. Diabetes Obes Metab 2011; 13:928-38. 4. Wilding JP, et al. Ann Intern Med. 2012 Mar 20;156(6):405-15. 5. . INVOKANA Product Monograph. Janssen Inc., November 2014.

*p < 0.0001 vs. placebo. **p = 0.0091 vs. placebo. ***p < 0.001 vs. placebo. ****p < 0.05.

Bargraph denotes individual trials and is not intended for comparisons between dapagliflozin and canagliflozin.

*

**

*

***

***

***

***

***

***

***

***

****

NS

NS

Sustained Body Weight Reduction withAdd-on Dapagliflozin vs. Add-on Glipizide* in Patients Taking

Metformin (104 weeks)

*Glipizide is approved and authorized for use but is not marketed in Canada.Nauck M, et al. Diabetes Obes Metab 2014; 16(11):1111-20.

Week 104 weight

+1.36 kg (0.88, 1.84)

-3.70kg (-4.16, -3.24)

GLI + MET (n = 401)

DAPA + MET (n = 400)

0

400401

-5.0Ch

ange

in t

ota

l bo

dy

we

igh

t (k

g)

6 12 18

369361

26 34 42 52

323315

65 78 91 104

234211

-4.0

-3.0

-2.0

-1.0

2.0

3.0

Baseline weightDAPA + MET: 88.4 kgSulfonylrea + MET: 87.6 kg

-0.0

1.0

Between-group difference:

−5.06 kg (95% CI; −5.73, −4.4)

Sample size per time pointDAPA + METSU + MET

Placebo+ METN=79

Dapa10 mg + MET

N=82

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

SGLT2 Inhibitors:

Predominant Fat Loss

DXA= Dual-energy X-ray Absorptiometry. ** Statistically significant vs. placebo by Hochberg’s method (p<0.001)

1. Toubro S et al. EASD Annual Meeting 2012. Poster 762.2. Bolinder J et al. J Clin Endocrinol Metab 2012;97:1020-1031.

Fat MassLean Mass

Canagliflozin1Dapagliflozin2

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

CANA 100 mgN=71

GlimepirideN=68

CANA 300 mgN=69

1.0

1.3

-1.3

-2.5

-0.9

-2.9

1

-5

-3

3

-4

0

-1

-2

2

Ch

ange

fro

m B

ase

line

(kg

)

Fat MassLean Mass

-1.1

-0.6

1

-5

-3

3

-4

0

-1

-2

2

Ch

ange

fro

m B

ase

line

(kg

)

-2.22**

-0.74

Dapagliflozin Pooled Data: 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

ald

iagn

osi

s o

f ge

nit

al in

fect

ion

MenWomenTotal

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

MenWomenTotal

DAPA 5 mg

DAPA 10 mg

Placebo

• More frequent 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 reccurred

Dapagliflozin Pooled Data: UTI

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 placeboUpper UTI were rare and balanced between groups

Volume-related AEs

• Polyuria dapagliflozin 10 mg (0.9%) vs. placebo (0.2%)

• Pollakiuria dapagliflozin 10 mg (2.1%) vs. placebo (0.7%)

• Rarely led to discontinuation from dapagliflozin

Johnsson et al. Presented at EASD 2014. Abstract 800-P.

Events of Volume Depletion with SGLT2 Inhibitors: Pooled Analyses

*Including dehydration, hypovolemia, or hypotension.

Serious events occurred in < 0.2% of patients and were comparable between groups.

Volume depletion AEAll

events*

Dapagliflozin 10 mg 0.8%

Dapagliflozin 5 mg 0.6%

Control 0.4%

INVOKANA Product Monograph. Janssen Inc., November 2014.FORXIGA Product Monograph. AstraZeneca. December 2014.

Volume depletion AEAll

events**

Canagliflozin 300 mg 1.3%

Canagliflozin 100 mg 1.2%

Control 1.1%

**Including postural dizziness, hypotension, orthostatic hypotension, dehydration and syncope.

• SGLT2 inhibitors not recommended for initiation in volume depleted patients.

• Temporary interruption of SGLT2 inhibitors is recommended for patients who develop volume depletion until the depletion is corrected.

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 diureticLoop diureticeGFR

≥30-<60

1.91.5

<60

8.1

4.7

eGFR

2.5

≥75<65

0.90.7

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

Efficacy of SGLT2 Inhibitors is Reduced

in Patients with Moderate Renal Impairment

1. Kohan D et al. Kidney Int. 2014;85: 962-971.2. Yale JF et al. Diabetes Obesity & Metabolism 2013;15:463-473.

*p < 0.001; †p <0.05

BL Mean A1C (%)BL Mean eGFR (mL/min/1.73m2)

LS m

ean

ch

ange

fro

m

bas

elin

e (

±9

5%

CI)

A1

C (

%)

0

-0.8

-0.2

-0.4

-0.6

0.2

Dapagliflozin ineGFR 30 to < 60 (N =

252)2

8.444.6

-0.32

-0.44

-0.11

8.039.4

Canagliflozin ineGFR 30 to < 50 (N = 269)1

-0.03

-0.33

-0.44

-0.30†

-0.40*

PlaceboCANA 100 mg CANA 300 mgDAPA 10 mgDAPA 5 mg

-0.41

-0.08

eGFR Changes in Normal Renal Function and in CKD

Weeks

Me

an c

han

ge f

rom

bas

elin

ee

GFR

(m

L/m

in/1

.73

m2)

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

841 10289766350372416

38.539.440.1

Canagliflozin in low eGFR2

eGFR decreases slightly at initiation of SGLT2 inhibitors, then returns slowly towards baseline

Canagliflozin Pooled Analysis: Hyperkalemia-related Endpoints

eGFR ≥ 60

PBO Cana 100

Cana 300

Mean % change from BL 0.5% 0.6% 1.0%

AE – blood K+ increased 0.2% 0.8% 0.7%

K+ level meeting outlier criteria* 4.7% 4.5% 6.8%

K+ level meeting outlier criteria*among patients on RAAS blockers or K-sparing diuretics

4.6% 5.1% 6.1%

*outlier criteria = potassium > 5.4 mmol/L with a > 15% increase from baseline

• In both populations, K+ elevations were usually < 6.5 mmol/L• Elevations ≥ 6.5 mmol/L were rare but more frequent in patients taking antihypertensive

agents that affect K+ excretion, in both the canagliflozin and placebo groups

Weir MR, et al. Curr Med Res Opin 2014; 30:1759-68.

eGFR ≥ 60 eGFR ≥ 45 and < 60

PBO Cana 100

Cana 300

PBO Cana 100

Cana 300

Mean % change from BL 0.5% 0.6% 1.0% 0.7% 1.7% 2.8%

AE – blood K+ increased 0.2% 0.8% 0.7% 1.5% 1.4% 2.1%

K+ level meeting outlier criteria* 4.7% 4.5% 6.8% 5.5% 5.2% 9.1%

K+ level meeting outlier criteria*among patients on RAAS blockers or K-sparing diuretics

4.6% 5.1% 6.1% 5.6% 4.9% 10.5%

Dapa: Changes in Lipids From Baseline

Hardy E, et al. Presented at ADA 2013. Poster 1188-P.

% c

han

ge f

rom

bas

elin

e (w

ith

95

% C

I)

8

-10

6

10

n =

4

2

0

BL mean =

Unit =

-2

-4

-6

-8

TC

989

5.04

mM

-0.4

834

5.06

mM

1.4

888

5.03

mM

1.1

838

0.56

mEq/L

-5.7

694

0.56

mEq/L

1.2

732

0.58

mEq/L

-0.5

984

2.12

mM

-0.7

831

2.19

mM

-5.4

886

2.15

mM

-3.2

985

2.96

mM

-1.9

828

2.95

mM

2.7

884

2.93

mM

0.6

990

1.15

mM

3.8

834

1.16

mM

5.5

889

1.16

mM

6.5

HDL-C LDL-C TG FFAs

Placebo (N = 1,393)DAPA 5 mg (N = 1,145) DAPA 10 mg (N = 1,193)

Bladder Cancer

• Across 22 clinical trials, newly diagnosed cases of bladder cancer were reported in 10/6,045 patients treated with dapagliflozin (0.17%) and 1/3,612 patient (0.03%) treated with placebo/comparator.

• Risk factors: 10/11 were male, 9/11 were > 55 years and 8/11 had smoking history.

• Pre-existing?

– 8/11 had hematuria at baseline

– 6/11 were diagnosed within 6 months of the start of treatment

PM: Dapagliflozin should not be used in patients with active bladder cancer and should be used with caution in patients with a prior history of bladder cancer.

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.FORXIGA Product Monograph. AstraZeneca. December 2014.

http://www.fda.gov/downloads/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf

SGLT2 Inhibitors:Ongoing CV Outcome Trials

www.clinicaltrials.gov.

Treatment n Population Endpoints Results

CANVAS

Canagliflozin

vs.Placebo

4,363CVD or high risk for CVD

CV death, nonfatal MI or nonfatal CVA

June 2018

EMPA-REG

OUTCOMES

Empagliflozinvs.

Placebo7,000 CVD


April

2015

DECLAREDapagliflozin

vs.Placebo

17,150CVD or high risk for CVD


April 2019

EMPA-REG OUTCOMES: Trial design

• Study medication was given in addition to standard of care

– Glucose-lowering therapy was to remain unchanged for first 12 weeks

• Treatment assignment double masked

• The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event

92

Randomised and treated(n=7020)

Empagliflozin 10 mg(n=2345)

Empagliflozin 25 mg (n=2342)

Placebo (n=2333)

Screening(n=11531)

93

EMPA-REG Outcome: n=7020 patients (mean age 63 years) with type 2 diabetes and established CVD. Median duration of follow-up: 3.1 years. Mean diff in A1C: 0.4% at wk 94. Mean diff in SBP 4 mm Hg.

EMPA-REG Outcome: Primary Composite

Endpoint CV Death, MI, or Stroke

CI: confidence interval; CV: cardiovascular; EMPA: empagliflozin; HR: hazard ratio; MI: myocardial infarction; PBO: placebo.

1. Zinman B et al. N Engl J Med. 2015;373:2117-28.

0

5

10

15

20

0 6 12 18 24 30 36 42 48

Placebo

Months

Pa

tie

nts

With

Eve

nt

(%)

Empagliflozin

PBO EMPA HRp

value

CV death, MI, stroke (%) 12.1 10.5 0.86 0.04

CV deaths (%) 5.9 3.7 0.62 <0.001

Nonfatal MI (%) 5.2 4.5 0.87 0.22

Nonfatal stroke (%) 2.6 3.2 1.24 0.16

Hosp. heart failure (%) 4.1 2.7 0.65 0.002

All-Cause mortality (%) 8.3 5.7 0.68 <0.001

4687

2333

4580

2256

4455

2194

4328

2112

3851

875

2821

1380

2359

1161

370

166

1534

741

No. of patients

Empagliflozin

Placebo

HR 0.86 (95% CI 0.74, 0.99)

p<0.001 for noninferiority

p=0.04 for superiority

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

414

177

1722

825

9

8

7

6

5

4

3

2

1

0

HR 0.62

(95% CI 0.49, 0.77)

p<0.001

Pa

tie

nts

With

Eve

nt (%

)

0 126 18 24 30 36 42 48

No. at riskMonths

Empagliflozin

Placebo

Placebo

Empagliflozin

Cumulative incidence function. HR: hazard ratio.

1. Zinman B et al. N Engl J Med. 2015;373:2117-28.

EMPA-REG Outcome: Death from CV cause

94

Patients with event/analysed

Empagliflozin Placebo HR (95% CI) p-value

3-point MACE490/468

7282/2333 0.86

(0.74, 0.99)*

0.0382

CV death 172/4687 137/2333 0.62(0.49, 0.77)

<0.0001

Non-fatal MI 213/4687 121/2333 0.87(0.70, 1.09)

0.2189

Non-fatal stroke 150/4687 60/2333 1.24(0.92, 1.67)

0.1638

0.25 0.50 1.00 2.00

EMPA-REG OUTCOMES: CV death, MI and stroke

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI95

Favours empagliflozin Favours placebo

• T2DM is associated with considerable CV risk• Some classes of antihyperglycemics are associated with off-target

effects (eg, weight gain, fluid retention, hypoglycemia) that may elevate CV risk• Other classes(e.g., GLP-1 RAs, SGLT2 inhibitors) have shown benefit on

those risk factors (eg, weight loss, BP reduction)

• CV safety studies in DPP-4 inhibitors have demonstrated CV neutrality, with perhaps a slight HF signal

• EMPA-REG, the first trial in the SGLT2 inhibitor class, reported a substantial reduction in CV mortality

• The first GLP-1 RA trial, with lixisenatide, showed CV neutrality• All CV safety studies have been conducted in high risk populations• A number of other GLP-1 RA CV safety trials (eg, LEADER) will be

reporting soon

Summary

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