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 Contains unpublished data.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

Patients Centered Approach
Position Statement of (ADA) and (EASD) - 2015
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
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 release
from  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 hormone
GLP-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-4
Enzymes
S
Lower levels of the incretin hormone
GLP-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-4
Enzymes
S
Pancreas
↓ glucagon release
from  cells
↑ insulin release
from  cells
…in response to ↑ GLP-1 concentrations:
 
Once-a-Day Saxagliptin/Metformin XR :
Complementary & synergistic mechanism of action

ADA
/EASD
& AACE
2013
combination #
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

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
combination #
4 years sustained efficacy (evidence based)

32Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.
*
*CV: Cardiovascular disease

35Scirica BM, et al. N Engl J Med.
2013.10.1056/NEJMoa1307684.
#
# 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
#

36Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684.

To Conclude
o 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.
 24 hours glycemic control with once daily dose
 4 years sustained efficacy without risk of hypoglycemia

 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
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
Scirica BM, et al. American Heart Association Scientific Sessions. November 2013.
KM: Kaplan-Meier
An imbalance between the 2 treatment groups was observed early, but
stabilised after 6 to 9 months.

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

Ueda2015 patient centered approach dr.mesbah

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