Ueda2016 symposium -managing t2 dm with no compromise - khaled el hadidy

42
Managing T2DM with no compromise BY DR. Khaled El Sayed El Hadidy. MD Professor of Internal Medicine. Head of Internal Medicine Department. Head of Diabetes and Endocrinology Unit. Beni - Suef University. UEDA ( IDF member )

Transcript of Ueda2016 symposium -managing t2 dm with no compromise - khaled el hadidy

Page 1: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Managing T2DM with no compromise

BYDR. Khaled El Sayed El Hadidy. MD

Professor of Internal Medicine.Head of Internal Medicine Department.

Head of Diabetes and Endocrinology Unit.Beni - Suef University.UEDA ( IDF member )

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Multiple Pathophysiological Failures Contribute to Hyperglycaemia: The ‘Ominous Octet’

Islet α-cell

Increased

lipolysis

Increased

glucose

reabsorption

Increased glucagon

secretion

Increased

hepatic glucose

production

Neurotransmitter dysfunction

Decreased

glucose uptake

Islet β-cell

Decreased incretin effectImpaired insulin

secretion

Hyper-

Adapted from DeFronzo RA. Diabetes 2009;58:773–795. Wolters Kluwer Health

Hyper-

glycemia

2

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HbA1c=haemoglobin A1c; OAD, oral antidiabetic drugs.

Jacob AN, et al. Diabetes Obes Metab. 2007; 9:386–393;

Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443;

Wright AD, et al. J Diabetes Complications. 2006; 20: 395–401.

Decreasing HbA1c is associated with increased risks

of hypoglycaemia and weight gain

Weight gain

and

hypoglycaemia

Body w

eig

ht

HbA1c

Pla

sma

glu

cose

Page 4: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Consequences of hypoglycaemia

Hypoglycaemia

Cardiovascular

complications3

Weight gain

by defensive eating5

Coma3

Increased risk

of car accident6

Hospitalisation

costs4

Loss of

consciousness3

Increased risk

of seizures3

Death2,3

Increased risk

of dementia1

1Whitmer RA, et al. JAMA. 2009; 301: 1565–1572; 2Bonds DE, et al. Br Med J. 2010; 340: b4909;

3Barnett AH. Curr Med Res Opin. 2010; 26: 1333–1342; 4Jönsson L, et al. Value Health. 2006; 9: 193–198;

5Foley JE, Jordan J. Vasc Health Risk Manag. 2010; 6: 541–548; 6Begg IS, et al. Can J Diabetes. 2003; 27: 128–140; 7McEwan P, et al. Diabetes Obes Metab. 2010; 12: 431–436.

.

Reduced

quality of life7

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Mechanisms ( Hypoglycemia -------------- CVS )

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CVD=cardiovascular disease; DM=diabetes mellitus; HDL-C=high-density lipoprotein cholesterol; HTN=hypertension;

IGT=impaired glucose tolerance; IR=insulin resistance; LDL-C=low-density lipoprotein cholesterol; TG=triglyceride.

Eckel RH, Grundy SM, Zimmet PZ.

The metabolic syndrome. Lancet. 2005; 365: 1415 428.

Weight Gain and Co-morbidities

Weight gain

Hyperinsulinaemia and IR

Dyslipidemia

TG

small dense LDL-C

Apo-B

HDL-C

HTNProthrombotic state

PAI-1 , Factor VII

Fibrinogen

IGT and DM

Proinflammatory state

CVD

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L L L

GLP-1 GLP-1 GLP-1

InsulinGlucagon

Slowed gastric

emptying

Early

Satiety

Inactive

GLP-1

DPP-4

enzyme

(DPP-4

inhibitor)

GLP-1

Page 8: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Guidelines recommend the combinationADA

/EASD

& AACE

24 hours glycemic control with once daily dose

Ideal Criteria of OAD* in treatment of T2DM Patientsin order to get High Glycemic Control with Confidence (1/2) :

Why Saxagliptin / Metformin XR

can be an Ideal FDC# in management of T2DM patients ?

Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.

Jadzinsky et al – Diabetes, Obesity & metabolism (2009)

Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365–371.

Full Prescribing Information

* OAD: Oral Antidiabetic

# FDC: Fixed dose combination

**HbA1c: Haemoglobin A1c

##: Fasting plasma glucose

***: Postprandial plasma glucose

Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

4 years sustained Efficacy (Evidence based)

3.3% A1c reduction from baseline 10%

Comparable efficacy to Sulphonylurea without risk of hypoglycemia

Page 9: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy
Page 10: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

HbA1c≥9%

Me orminintoleranceorcontraindica on

Uncontrolledhyperglycemia

(catabolicfeatures,BG≥300-350mg/dl,HbA1c≥10-12%)

Insulin (basal)

+

or

or

or

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0 American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1)

Guidelines recommend the combination

MANAGE EARLY AND TIGHTLY

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Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Figure2A.An -hyperglycemictherapyinT2DM:Avoidanceofhypoglycemia

or

or

or

Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0 American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1)

Page 12: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Insulin (basal)

+

or

or

or

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Figure2B.An -hyperglycemictherapyinT2DM:Avoidanceofweightgain American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1)

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Page 14: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy
Page 15: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Secondary failure of metformin monotherapy is increased when initial HbA1C is ≥8%

Figure shows a Kaplan–Meier plot of secondary failure of metformin monotherapy by categories of HbA1C at metformin initiation

adjusted for age and diabetes duration at initiation and the percent per year (95% CIs) experiencing secondary failure.

Brown JB, et al. Diabetes Care 2010;33:501‒6

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• RAZ I. Guideline Approach to therapy in patients with Newly diagnosed type 2 diabetes. Diabetes Care 2013; 36

(suppl 2 ) (suppl 2 ): S 139 – S 144

Page 17: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Specific reasons why early combination therapy may be beneficial in Type 2 diabetes

Rationale for early combination therapy in Type 2 diabetes

Early, robust lowering of HbA1C

Avoidance of clinical inertia associated with a stepwise approach to therapy

Potential for early combination therapy to improve β-cell function

Initiation of a therapeutic intervention with a complimentary mechanism of action

Potential to use less than maximal doses of individual agents, minimizing side effects

11 Confidential. Contains unpublished data. For training purpose only. Not to be distributed. 732HQ12NP149Zinman B. Am J Med 2011;124:S19‒34.

Page 18: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Guidelines recommend the combination

ADA

/EASD

& AACE

2013

24 hours glycemic control with once daily dose

Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.

Jadzinsky et al – Diabetes, Obesity & metabolism (2009)

Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365–371.

Full Prescribing Information

* OAD: Oral Antidiabetic

# FDC: Fixed dose combination

**HbA1c: Haemoglobin A1c

##: Fasting plasma glucose

***: Postprandial plasma glucose

Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

4 years sustained Efficacy (Evidence based)

3.3% A1c reduction from baseline 10%

Comparable efficacy to Sulphonylurea without risk of hypoglycemia

Ideal Criteria of OAD* in treatment of T2DM Patientsin order to get High Glycemic Control with Confidence (1/2) :

Why Saxagliptin / Metformin XR

can be an Ideal FDC# in management of T2DM patients ?

Page 19: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

19

Muscle/Fat

…in response to ↑ insulin release:

↑ peripheral glucose uptake

Liver

…in response to ↓ glucagon release:

↓ hepatic glucose output

Pancreas

↓ glucagon release from cells

↑ insulin releasefrom cells

…in response to ↑ GLP-1 concentrations:

Muscle/Fat

Improves insulin sensitivity and ↑ glucose uptake and utilization

Liver

↓ glucose output by the liver

Pancreas

Insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease

Muscle/Fat

…in response to ↑ insulin release:

↑ peripheral glucose uptake

Liver

…in response to ↓ glucagon release:

↓ hepatic glucose output

Muscle/Fat

Improves insulin sensitivity and ↑ glucose uptake and utilization

Liver

↓ glucose output by the liver

Pancreas

Insulin secretion remains unchanged while fasting insulin levels and

day-long plasma insulin response may decrease

GLP=glucagon-like peptide; DPP=dipeptidyl peptidase.

1. Verspohl EJ. Pharmacol Ther 2009;124:113-138.

Saxagliptin Metformin XR

Gut

Decreases (↓) intestinal glucose absorption

Gut

Decreases (↓) intestinal glucose absorption

Lower levels of the incretin hormoneGLP-1 are released from the gut in patients with type 2 diabetes

Saxagliptin increases (↑) incretinconcentrations in the bloodstream

Gut

Saxagliptin inhibits DPP-4 enzyme activity

DPP-4Enzymes

S

Lower levels of the incretin hormone GLP-1 are released from the gut in patients with type 2 diabetes

Saxagliptin increases (↑) incretinconcentrations in the bloodstream

Gut

Saxagliptin inhibits DPP-4 enzyme activity

DPP-4Enzymes

S

Pancreas

↓ glucagon release from cells

↑ insulin releasefrom cells

…in response to ↑ GLP-1 concentrations:

Once-a-Day Saxagliptin/Metformin XR : Complementary & synergistic mechanism of action

# FDC: Fixed dose combination

Page 20: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Saxagliptin/ Met XR

Saxagliptin/ Met XR

Page 21: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Guidelines recommend the combination

ADA

/EASD

& AACE

2013

24 hours glycemic control with once daily dose

Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.

Jadzinsky et al – Diabetes, Obesity & metabolism (2009)

Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365–371.

Full Prescribing Information

* OAD: Oral Antidiabetic

# FDC: Fixed dose combination

**HbA1c: Haemoglobin A1c

##: Fasting plasma glucose

***: Postprandial plasma glucose

Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

4 years sustained Efficacy (Evidence based)

3.3% A1c reduction from baseline 10%

Comparable efficacy to Sulphonylurea without risk of hypoglycemia

Ideal Criteria of OAD* in treatment of T2DM Patientsin order to get High Glycemic Control with Confidence (1/2) :

Why Saxagliptin / Metformin XR

can be an Ideal FDC# in management of T2DM patients ?

Page 22: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

22

Saxagliptin/Met XR

Page 23: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Guidelines recommend the combination

ADA

/EASD

& AACE

2013

24 hours glycemic control with once daily dose

Ideal Criteria of OAD* in treatment of T2DM Patients in order to get High Glycemic Control with Confidence (1/2) :

Why Saxagliptin / Metformin XR can be an Ideal FDC# in

management of T2DM patients ?

Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.

Jadzinsky et al – Diabetes, Obesity & metabolism (2009)

Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365–371.

Full Prescribing Information

* OAD: Oral Antidiabetic

# FDC: Fixed dose combination

**HbA1c: Haemoglobin A1c

##: Fasting plasma glucose

***: Postprandial plasma glucose

Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

4 years sustained Efficacy (Evidence based)

3.3% A1c reduction from baseline 10%

Comparable efficacy to Sulphonylurea without risk of hypoglycemia

Page 24: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

24

Page 25: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Guidelines recommend the combination

ADA

/EASD

& AACE

2013

24 hours glycemic control with once daily dose

Ideal Criteria of OAD* in treatment of T2DM Patients in order to get High Glycemic Control with Confidence (1/2) :

Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.

Jadzinsky et al – Diabetes, Obesity & metabolism (2009)

Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365–371.

Full Prescribing Information

* OAD: Oral Antidiabetic

# FDC: Fixed dose combination

**HbA1c: Haemoglobin A1c

##: Fasting plasma glucose

***: Postprandial plasma glucose

Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

4 years sustained Efficacy (Evidence based)

3.3% A1c reduction from baseline 10%

Comparable efficacy to Sulphonylurea without risk of hypoglycemia

Why Saxagliptin / Metformin XR

can be an Ideal FDC# in management of T2DM patients ?

Page 26: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

26 Moses RG, et al. A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and

inadequate glycaemic control on metformin plus a sulphonylurea. Diabetes, Obesity and Metabolism 2014;16(5):443-450.

Saxagliptin/ Met XR + SU

Saxagliptin/ Met XR

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27

Bioequivalence of Kombiglyze XR with coadminstered saxagliptin and metformin hydrochloride extended release tablets has been demonstrated Gummesson A, et al Clin Drug Investig. 2014 Nov;34(11):763-72”

Göke B et al. Int J Clin Pract. 2010;64(12):1619-1631. Onglyza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December 2011.

Stenlof K, Raz I, Neutel J, et al. Current Medical Research & Opinion 2010 ;26 (10): 2355-2363.

Goke trial

Glycemic control without risk of hypoglycemia

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28

The between-group mean difference was -0.37 % (95 % CI -0.55 to -0.19; post hoc P<0.0001).

Barnett AH, et al. EASD 2011:243; Charbonnel B, et al. ADA 2011:1108-P.

3 folds reduction in

A1C

2 folds reduction in

A1C

Saxagliptin- Add-On to Insulin

Saxa/Metformin XRSaxagliptin

Saxagliptin

Page 29: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Guidelines recommend the combination

ADA

/EASD

& AACE

2013

24 hours glycemic control with once daily dose

Ideal Criteria of OAD* in treatment of T2DM Patients in order to get High Glycemic Control with Confidence (1/2) :

Why Saxagliptin / Metformin XR can be an Ideal FDC# in

management of T2DM patients ?

Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.

Jadzinsky et al – Diabetes, Obesity & metabolism (2009)

Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365–371.

Full Prescribing Information

* OAD: Oral Antidiabetic

# FDC: Fixed dose combination

**HbA1c: Haemoglobin A1c

##: Fasting plasma glucose

***: Postprandial plasma glucose

Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

3.3% A1c reduction from baseline 10%

Comparable efficacy to Sulphonylurea without risk of hypoglycemia

Page 30: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Diabetes Is Associated With Increased Risk of CV Disease

• Diabetes confers an increased risk for MI, stroke, and PAD1–3

• It is not clear whether diabetes should be considered a cause or a comorbidity of heart failure4

– Diabetes is associated with an increased risk of developing HF in patients with other causes (eg, acute MI) and is believed to promote diastolic dysfunction

• Diabetes is associated with a 2- to 3-fold increase in the risk of CV and all-cause mortality5

CV = cardiovascular; MI = myocardial infarction; PAD = peripheral artery disease; CHD = coronary heart disease; HF = heart failure.

1. Emerging Risk Factors Collaboration. Lancet. 2010;375:2251–2222. 2. American Diabetes Association. Diabetes Care. 2003;26:3333–3341. 3. American Diabetes Association. Diabetes Care.

2014;37:S14–S80. 4. McMurray JJV et al. Lancet Diabetes Endocrinol. 2014; DOI 10.1016/S2213-8587(14)70031-2. 5. Gregg EW et al. Ann Int Med. 2007;147:149–156.

Page 31: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

SAXAGLIPTIN5 mg/d

PLACEBO

Follow up Visits

Q 6 months

Final Visit

Documented Type 2 DiabetesN = 16,492

Primary EP CV Death, MI,

Ischemic Stroke

Duration

Event driven (n=1040)

Median duration 2.1y

Age ≥40 y ….. Established CV Disease or Age ≥55y M / 60y F ….. ≥ 1 CVD RF.

Major Secondary EP: CV death, MI, ischemic stroke, or hosp.

for heart failure, unstable angina, or coronary revascularization

RANDOMIZED 1:1 DOUBLE BLIND

All other DM Rx per treating MD

SaxagliptinAssessment of Vascular Outcomes Recorded in Patients with DM -TIMI 53

2.5 mg/d if eGFR ≤ 50 ml/min

Scirica BM, Bhatt DL, Braunwald E, et al…. Raz I. NEJM 2013 at www.NEJM.org.

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

HbA1c ≥6.5%

Page 32: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Primary Composite Endpoint *

CV Death, MI, or Stroke

•Kaplan-Meier Rates 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. 2013.10.1056/NEJMoa1307684.

Days

79838071

77617836

72677313

48554920

851847

PlaceboSaxagliptin

82128280

Pat

ien

ts W

ith

En

dp

oin

ts (

%)

14

12

10

8

6

4

2

0

0 180 360 540 720 900

HR 1.00; 95% CI, 0.89–1.12

(P≤0.001 non-inferiority)

(P=0.99 superiority)Saxagliptin: 7.3%*

Rate/100 person-yrs – 3.7%

Placebo: 7.2%*

Rate/100 person-yrs – 3.7%

Saxagliptin met the primary safety objective demonstrating

non-inferiority but, didn’t meet the criteria for the superiority

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Page 33: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Major Secondary Endpoint*

*K-M event rates are presented after 2 yrs. Composite of CV death, MI, stroke, and hosp for HF, UA, or coronary revascularization.

Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.

Days

78437880

75027539

69266963

46024660

813817

PlaceboSaxagliptin

82128280

14

12

10

8

6

4

2

0

0 180 360 540 720 900

HR 1.02; 95% CI 0.94-1.11

P=0.66

Saxagliptin: 12.8%*

Rate/100 person-yrs – 6.6%

Placebo: 12.4%*

Rate/100 person-yrs – 6.5%

Pat

ien

ts W

ith

En

dp

oin

ts (

%)

No significant differences were observed between saxagliptin and placebo

CVD, MI, Ischemic Stroke, or Hospitalization for Unstable Angina, Coronary Revascularization, or CHF (%)

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Page 34: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Individual Components

of the Composite Endpoints

*K-M event rates are presented after 2 yrs.

Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.

Saxagliptin Placebo n (%)* n (%)*

Efficacy endpoint (N = 8,280) (N = 8,212) HR (95% CI) P value

CV death 269 (3.2) 260 (2.9) 1.03 (0.87–1.22) 0.72

MI 265 (3.2) 278 (3.4) 0.95 (0.80–1.12) 0.52

Ischemic stroke 157 (1.9) 141 (1.7) 1.11 (0.88–1.39) 0.38

Hosp for UA 97 (1.2) 81 (1.0) 1.19 (0.89–1.60) 0.24

Hosp for HF 289 (3.5) 228 (2.8) 1.27 (1.07–1.51) 0.007

Hosp for coronary revasc. 423 (5.2) 459 (5.6) 0.91 (0.80–1.04) 0.18

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Page 35: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Adjudicated Causes of CV Death

*Event rates are presented after 2 yrs.Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.

Although more frequently Hospitalized HF., there was no imbalance in deaths due to heart failure between saxagliptin and placebo

3.2

0.50.3 0.3

1.6

0.20.4

2.9

0.5

0.20.4

1.3

0.20.4

0

0.5

1

1.5

2

2.5

3

3.5

4

Onglyza™ (%) (n = 8,280)

Placebo n (%)(n = 8,212)

CerebrovascularAcute MI Presumed CV death

HF Sudden cardiac death

Any CV death Other

Adjudicated Causes of CV Death1

% o

f p

atie

nts

Page 36: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Risk of Hospitalization for HF According to Baseline NT-proBNP

Ho

spit

aliz

atio

n f

or

HF

(%)

HR 1.0495% CI 0-26.3

P=0.98

HR 1.8295% CI 0.9-4.1

P=0.12

HR 0.9495% CI 0.6-1.6

P=0.82

HR 1.3195% CI 1.0-1.6

P=0.021

0.7% 0.7% 1.1%0.3%

2.2% 2.0%

10.9%

8.9%

20%

18%

16%

14%

12%

10%

8%

6%

4%

2%

0%N = 3076

Q1(5 - 64)

N = 3076

Q2(65 - 140)

N = 3076

Q3(141 - 332)

N = 3073

Q4(333 - 46,627)

Quartiles of NT-proBNP (pg/mL)

# of HHF events/1000 pt-years 0 5 1 10

P for interaction = 0.46

Saxagliptin Placebo

Scirica BM, et al. American Heart Association Scientific Sessions. November 2013.

NT-proBNP: N-terminal pro-brain natriuretic peptide; HHF: hospitalization for heart failure

Page 37: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Hospitalization for heart failure was the only component of the 2ry composite endpoint increased with Saxagliptin vs. placebo early during the first 6 months of therapy, However;

This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease

Difference between the 2 treatment groups stabilised after 6 - 9 months.

No evidence that subjects treated with saxagliptin had a more complicated course while hospitalised

No evidence of clinically detectable fluid overload (i.e., no increase in oedema or weight gain) for the overall study population.

No clinically significant change in biomarkers at 2 years/EOT for

NT-proBNP

hs-TNT

hs-CRP

Investigators’ Conclusions Hospitalization for Heart Failure

hs TNT; High-sensitivity cardiac troponin

NT-proBNP ; N-terminal pro-brain natriuretic peptide.

Page 38: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

No Evidence of Increased Risk of hHF for

`(DPP-4i Relative to SU) or for (Saxagliptin Relative to Sitagliptin)

*Reference category for HR; HR<1 indicates lower risk for DPP-4i or saxagliptin

DPP-4i SU

Patients Events Patients Events

DPP-4i vs. SU

No baseline CVD

82,019 35 82,019 58 0.59 (0.38,0.89)

Baseline CVD 27,259 200 27,259 202 0.95 (0.78, 1.15)

SAXA SITA

Patients Events Patients Events

SAXA vs. SITA

No baseline CVD

43,402 23 43,402 240.99 (0.56,

1.75)

Baseline CVD 13,042 82 13,042 870.95 (0.70,

1.28)

0.2 1 5

Hazard Ratio(95% CI)

Favors SAXA Favors SITA

Favors DPP-4i Favors SU

0.2 1 5

American Diabetes Association 75th Scientific Sessions,

Boston, MA, 5–9 June2015 3340-0615-AZ-DL-0617 FU et al. 2015. ADA abstract accepted

Page 39: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Conclusions No evidence of increased risk for hospitalization for heart failure with DPP-4i

treatment compared with SU treatment

Among patients without prior CVD, DPP-4i treatment was associated with

statistically significant lower risk for hospitalization for heart failure compared with

SU treatment.

DPP-4i treatment was associated with statistically significant lower risk of

cardiovascular events across a range of cardiovascular outcomes compared with

SU treatment among patients without prior CVD.

DPP-4i treatment was associated with statistically significant lower risk of

cardiovascular events on the composite measure of all CV events in both the no

prior CVD and prior CVD strata.

These results were robust across multiple sensitivity analyses.

No evidence of an increased risk of hospitalization for heart failure compared with

sitagliptin.

No evidence was found of statistically significant differences in cardiovascular

risk between saxagliptin and sitagliptin on any cardiovascular outcome, including

the composite outcome.

These results were robust across multiple sensitivity analyses.

American Diabetes Association 75th Scientific Sessions, Boston, MA, 5–9 June2015 3340-0615-AZ-DL-0617

FU et al. 2015. ADA abstract accepted

Page 40: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy
Page 41: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Guidelines recommend the combinationADA

/EASD

& AACE

24 hours glycemic control with once daily dose

Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.

Jadzinsky et al – Diabetes, Obesity & metabolism (2009)

Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365–371.

Full Prescribing Information

* OAD: Oral Antidiabetic

# FDC: Fixed dose combination

**HbA1c: Haemoglobin A1c

##: Fasting plasma glucose

***: Postprandial plasma glucose

Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

4 years sustained Efficacy (Evidence based)

3.3% A1c reduction from baseline 10%

Comparable efficacy to Sulphonylurea without risk of hypoglycemia

To Conclude regarding

Saxagliptin/Metformin XR Combination

Page 42: Ueda2016 symposium -managing t2 dm with no compromise -  khaled el hadidy

Thanks