Ueda2015 patient centered approach dr.mesbah

Patient Centered approach in handling challenges with type 2 diabetes

Increased Prevalence of CV Disease in Patients With

Type 2 Diabetes

ADA = American Diabetes Association; AHA = American Heart Association.

1. American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S11-S66.

2. Ban K, et al. J Am Soc Hypertens. 2009;3(4):245-259.

3. Buse JB, et al. Circulation. 2007;115(1):114-126.

4. American Diabetes Association. Diabetes statistics. http://www.diabetes.org/diabetes-basics/diabetes-statistics/. Accessed August 13, 2013.

According to a scientific statement from the AHA and ADA

Up to 80% of patients with diabetes will develop macrovascular disease3

CV disease was noted on 68% of

diabetes related death certificates among

patients aged 65 years or older4

• Cook MN, et al. Glycemic control continues to deteriorate after Sulfonylurea are added to Metformin

amongpatients with type 2 diabetes. Diabetes Care 2005; 28 (5) : 995-1000

• NICE clinical guideline 87. Type 2 diabetes: The management of type 2 diabetes 2014

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

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

An alternative approach for managing Type 2 diabetes

Early use of combination therapies

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 Contains unpublished data.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.

Guidelines recommend the combination

ADA

/EASD

& AACE

2013

Complementary mechanism of action in Fixed dose combination #

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

24 hours glycemic control with once daily dose

4 years sustained Efficacy (Evidence based)

Without risk of hypoglycemia


ADA

/EASD

& AACE

2013





Why Saxagliptin / Metformin XR can be an Ideal FDC# in management of T2DM patients with high CV risks











Patients Centered ApproachPosition Statement of (ADA) and (EASD) - 2015

Diabetes Care, Diabetologia. 19 April 2012


MANAGE EARLY AND TIGHTLY

Diabetes Care, Diabetologia

Diabetes Management Guidelines

Patients Centered Approach - Position Statement of (ADA) and (EASD)

Specific patient preferences should play a major role in drug selection1

Characteristics, Susceptibilities to side effects, Potential for weight gain & Hypoglycemia

1. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.

2. Cook W, et al. Postgrad Med. 2013;125(3):146-155.

Medications for type 2 diabetes should

provide

Glucose Control

Without increasing the risk for

additional adverse CV effects or

exacerbating CV risk 1,2


ADA

/EASD

& AACE

2013

Complementary mechanism of action in Fixed dose combination # Saxagliptin / Metformin XR



24 hours glycemic control with once daily dosing












15

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 (↑) incretin concentrations 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



ADA

/EASD

& AACE

2013












24 hours glycemic control with once daily dosing

4 years sustained Efficacy (evidence based)



Full Prescribing ‘Information

Saxagliptin –Meformin XR

18Full Prescribing ‘Information


19

Stenlof trial

Saxagliptin/Met XR

• Evidence Based

• Proven efficacy & Safety of Saxagliptin + Metformin XR

20

Saxagliptin/Met XR


22

Saxagliptin/Met XR


25


26Moses 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


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

29

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

Saxagliptin –

Meformin XR

Saxagliptin- Add-On to Insulin didn’t increase risk of hypoglycemia

Saxagliptin 5 mg

+ insulin

(n=304)

Placebo

+ insulin

(n=151)

Reported Hypoglycemia 22.7 % 26.5%

Confirmed Hypoglycemia 7.6 % 6.6 %

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


ADA

/EASD

& AACE

2013


4 years sustained efficacy (evidence based)














32Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.

*

*CV: Cardiovascular disease


#

# Kaplan-Meier Rates K-M event rates are presented after 2 yrs. HR: hazard

ratio; K-M: Kaplan-Meier; Pbo: placebo; Saxa: saxagliptin

* CV: Cardiovascular

**MI: Myocardial Infarction

#


To Concludeo Limitations of monotherapy due to;

Multiple pathophysiological disorders of Type 2 diabetes

Progressive nature of Type 2 DM.

o International guidelines recommendation early combination therapy.

o FDC Kombiglyze-XR Once daily;

Saxagliptin + Metformin XR: FDC with complementary mechanism of action

Proved Significant reductions of key glycemic parameters (PPG., FPG. & HbA1c) in new onset patients & uncontrolled patients on Metformin alone and/or SU.


4 years sustained efficacy without risk of hypoglycemia


Thank You

38

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;

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 (i.e., similar length of stay, similar treatments—usually intravenous diuretics).

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

The evidence argues against the possibility that treatment with saxagliptin might be associated with a direct toxic effect on the myocardium

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

Investigators’ Conclusions

Hospitalization for Heart Failure

hs TNT; High-sensitivity cardiac troponin

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

6-Month Landmark Analysis of Hospitalization for HF

Saxagliptin (2-yr KM%)

Placebo (2-yr KM%)

HR (95% CI) P Value

Patient Level

> 6 months 2.4 2.3 1.11 (0.90 – 1.36) 0.3301

>12 months 1.6 1.5 1.08 (0.85 – 1.39) 0.5343

Event Level

> 6 months 2.7 2.3 1.17 (0.97 – 1.42) 0.1082

>12 months 2.0 1.7 1.17 (0.94 – 1.46) 0.1691


KM: Kaplan-Meier

An imbalance between the 2 treatment groups was observed early, but

stabilised after 6 to 9 months.


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Ueda2015 patient centered approach dr.mesbah