ueda2012 unmet needs in diabetes management-d.mgahed

Unmet Needs

in Diabetes Management

BY PROFESSOR MEGAHID ABUELMAGD

HEAD OF DIABETES AND ENOCRINE UNIT

MANSOURA EGYPT

The Nile

The corniche of the

Nile

The corniche of the Nile

The

corniche

of the

Nile

Top 10 countries in number of people with diabetes

(20-79 age group)

International diabetes federation www.worlddiabetesday.org/files/docs/Top_10_countries.pdf Cited 10-may2011

http://www.worlddiabetesday.org/files/docs/Top_10_countries.pdf





Egypt will face explosive growth of diabetes

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

Egy

ptIra

nIra

q

Sau

di A

rabia

Alger

ia

Mor

occo

Syr

ia

Sud

anUAE

Tunisia

Jord

an

Kuw

ait

Leba

non

Liby

a

Bah

rain

2003

2025

Due to a rapidly increasing & ageing population, Egypt will have the largest number of people with diabetes in the region by 2025

Sourc

e:

Dia

bete

s A

tlas,

2nd e

ditio

n,

IDF

Diabetes Atlas, 2nd edition, IDF

Unmet Needs in Patients with Type 2 DM

A. Achieving Goals

B. Beta Cells Deterioration

C. Complications of Therapy

D. Drugs Available can not Cover All Disease

Aspects ( Limited efficacy )

aHbA1c ≤6.5%.

HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.

Liebl A, et al. Diabetologia. 2002; 45: S23–S28.

In CODE study of a European cohort of over 7000 patients

with T2DM, ONLY 31% of patients had adequate glycemic

control

Pa

tie

nts

with

ad

eq

ua

te g

lyca

em

ic

co

ntr

ol (%

)

Approximately 70% of patients with T2DM do not

reach HbA1c goalsa

Percentages of adults reaching targets

(Data from European countries)

Most of patients with T2DM do not achieve HbA1c

goals

25.5

49

0

10

20

30

40

50

60A1C <6.5%

A1C 6.5-7.6%

% p

ati

en

ts r

each

ing

targ

et

Alvarez Guisasola F. et al. Diab Metab Obes. 2008. 10 (suppl 1): 8-15

Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study

Incidence of microvascular complications

increases with mean HbA1c

HbA1c=haemoglobin A1c.

Incidence rates and 95% confidence intervals for myocardial infarction and microvascular complications by category of mean HbA1c concentration, adjusted for age,

sex and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years.

Stratton IM. et al. BMJ. 2000; 321: 405–412.

80

60

40

20

0

Ad

jus

ted

in

cid

en

ce

pe

r 1000 p

ers

on

ye

ars

(%

)

5 6 7 8 9 10 11

Mean HbA1c (%)

Myocardial infarction

Microvascular endpoints

0

15

30

45

UKPDS : Significant Risk Reduction for T2DM

Complications with Each 1% Reduction in Mean HbA1c

Risk Reduction with 1% Decline in HbA1c

Micro- vascular disease

PVD MI Stroke CHF Cataract extraction

Death related to diabetes

P <0.0001 P <0.0001 P=0.035 P=0.021 P <0.0001

37% 43%

14% 12% 16% 19% 21%

CHF=congestive heart failure; HbA1c=hemoglobin A1c; PVD=peripheral vascular disease; MI=myocardial infarction

Adapted from Stratton IM, et al. BMJ. 2000; 321: 405–412.

N=3642

UKPDS: Acheiving early glycaemic control may generate a

good legacy effect

HbA1c=haemoglobin A1c.

Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed

12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.

Me

dia

n H

bA

1c

(%

)

0 6

7

8

9

UKPDS 1998

Conventional

Intensive

Holman et al 2008

Legacy effect

1997

Difference in HbA1c was lost after

first

year but patients in the initial

intensive arm still had lower

incidence of any complication

2007

Patients initially received intensive therapy had a lower

incidence of any complication

http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/

Reaching the target in late stages of the disease

does not reduce the vascular complications

P=0.14.

Primary outcome: first occurrence of a major cardiovascular event (a composite of myocardial infarction, stroke,

death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary

disease, and amputation for ischaemic gangrene).

Duckworth W, et al. N Engl J Med. 2009; 360: 129–139.

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8

Pro

ba

bil

ity o

f s

urv

iva

l

Years

Standard

therapy

Intensive

therapy

892

899

774

770

707

693

No. at risk

Intensive

Standard

639

637

582

570

510

471

252

240

62

55

0

0

VADT Primary outcome

Legacy effect: early glycemic control is the key to

long-term reduction in complications

Achieving glycemic control late in the disease, after a

prolonged period of poor control, does not improve long-

term risk of macrovascular complications2

Long-standing, preceding hyperglycaemia accounted for

the high rate of complications at baseline in VADT3

UKPDS=UK Prospective Diabetes Study; VADT=Veterans Affairs Diabetes Trial. 1Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589. 2Duckworth W, et al. N Engl J Med. 2009; 360: 129–139; 3Del Prato S. Diabetologia. 2009; 52: 1219–1226.

Good legacy effect Early, strict glycemic control brings benefits,

reducing the long-term risk of microvascular and

macrovascular complications (UKPDS1)


A. Achieving Goals





Evidence of β-Cell Function Decline Even Before

Diagnosis of T2DM

Adapted from UK Prospective Diabetes Study Group (UKPDS 16). Diabetes. 1995;44:1249-1258.

0

20

40

60

80

100

–12 –10 –8 –6 –4 –2 0 2 4 6

Years Before and After Diagnosis of T2DM

β-C

ell

Fu

nc

tio

n (

%)

Normal Glucose

Tolerance

Prediabetes (IFG/IGT)

Progressive loss of β-cell function

occurs before diagnosis

T2DM

Diagnosis

Causes of Beta-Cells Dysfunction

Recent studies indicated that pancreatic-cell failure arises from

a combination of :

1.Glucotoxicity

2.lipotoxicity

3.Increased proinflammatory cytokines and leptin

4.Islet cell amyloidal deposition1

5.Insulin secretion

• Response to increased insulin demand B-cell

proliferation

• Response to increased insulin demand Neogenesis

• Response to increased insulin demand apoptosis 2

22 1-Clinical Therapeutics/Volume 33, Number 5, 2011

2-Rev Endocr Metab Disord (2008) 9:329–343

β-cell Function Continues to Decline Regardless of

Intervention in T2DM

T2DM=type 2 diabetes mellitus.

*β-cell function measured by homeostasis model assessment (HOMA).

Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.

0

20

40

60

80

100

–5 –4 –3 –2 –1 0 1 2 3 4 5 6

Years since Diagnosis

β-c

ell F

un

cti

on

(%

)*

Progressive Loss of β-cell Function

Occurs prior to Diagnosis

Metformin (n=159)

Diet (n=110)

Sulfonylurea (n=511)


A. Achieving Goals





Hypoglycemia is defined as...

• ADA defined hypoglycemia as: “Any abnormally low plasma glucose concentration that exposes the subject to potential harm”. Plasma glucose <70 mg/dL (<3.9 mmol/L), with or without symptoms.

• The European Medicines Agency (EMA): Recommended a lower

threshold of plasma glucose (<3 mmol/L) to define hypoglycemia

• Most recent trials defined hypoglycemia as:

(<54 mg /dl - <70 mg/dl)

Clinically severe hypoglycemia as any episode in which a patient is

unable to self-treat

Mild hypoglycemic events, usually defined as self-treated episodes

Minimizing the Risk of Hypoglycemia with Vildagliptin Diabetes Ther (2011) 2(2)

Pathophysiology: Hierarchy and thresholds of physiological

mechanisms involved in the response to low blood glucose level

27

This material can only be shown reactively to answer specific questions from physicians.

Art

eri

ali

se

d v

en

ou

s b

loo

d g

luc

ose

co

nce

ntr

ati

on

(mm

oI/

L)

5.0

0.0

1.0

2.0

3.0

4.0

Cognitive Dysfunction

• Inability to perform

complex tasks

2.8 mmoI/L

Severe

Neuroglycopenia

• Reduced

conscious level

• Convulsions

• Coma

<1.5 mmoI/L

Counter regulatory

hormone release

• Glucagon

• Epinephrine

3.8 mmoI/L

Onset of symptoms

• Autonomic

• Neuroglycopenic

3.2 –

2.8mmoI/L

Neurophysiological Dysfunction

• Evoked responses

3.0 – 2.4mmoI/L

Inhibition of

endogenous insulin

secretion

4.6 mmoI/L

Zammit N, et al. Diabetes care. 2005;28(12):2948–961

82.8 mg/dL

68.4 mg/dL

68.4- 50.4 mg/dL 54- 43.2mg/dL 50.4 mg/dL

<27 mg/dL

Treat to Target increases the risk of hypoglycemia

28

1. ACCORD Study Group. N Engl J Med. 2008;358:2545–2559 2. Duckworth W, et al. N Engl J Med. 2009;360:129–139 3. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560–2572

ACCORD1 VADT2 ADVANCE3

P <0.001

Eve

nts

(%

)

Standard Intensive

16

6

4

2

0

14

12

10

8

18

P <0.01

Standard Intensive

Eve

nts

pe

r 100 p

ati

en

t-ye

ars

6

4

2

0

14

12

10

8

P <0.001

Standard Intensive

Eve

nts

pe

r 100 p

ati

en

ts p

er

ye

ar

0.6

0.4

0.2

0

0.8

0.7

0.5

0.3

0.1


Consequences of hypoglycaemia (1)

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

aDiet initially then sulfonylureas, insulin and / or metformin if FPG >15 mmol/L.

CI=confidence interval; FPG=fasting plasma glucose.

n=number of patients at baseline. 1UKPDS 34. Lancet. 1998; 352: 854–865; 2Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443.

UKPDS: up to 8 kg in 12 years1 ADOPT: up to 4.8 kg in 5 years2

0

88

92

96

100

0 1 2 3 4 5

0

0 1 6 9 12

1

2

3

4

5

6

7

8

Years from randomisation Years

Annualised slope (95% CI)

We

igh

t (k

g)

Treatment difference (95% CI) Rosiglitazone vs metformin 6.9 (6.3 to 7.4); P <0.001 Rosiglitazone vs glyburide 2.5 (2.0 to 3.1); P <0.001

Ch

an

ge

in

we

igh

t (k

g)

Insulin (n=409)

Glibenclamide (n=277)

Metformin (n=342)

Conventional treatment

(n=411)a

Rosiglitazone, 0.7 (0.6 to 0.8)

Glyburide, -0.2 (-0.3 to 0.0)

Metformin, -0.3 (-0.4 to -0.2)

Most therapies result in weight gain over time

The consequences of hypoglycaemia (2)

Hypoglycaemia

Cardiovascular

complications3

Weight gain


Coma3

Increased risk

of car accident6

Hospitalisation

costs4

Loss of

consciousness3

Increased risk

of seizures3

Death2,3

Increased risk

of dementia1


.

Reduced

quality of life7

Hypoglycemic events may

trigger inflammation by

inducing the release of C-

reactive protein (CRP), IL-

6, and vascular endothelial

growth factor (VEGF)

Underlying endothelial

dysfunction leading to

decreased vasodilatation

may also contribute to

cardiovascular risk.

32


Desouza CV, et al. Diabetes Care. 2010; 33:1389–394

Cardiovascular Complications with Hypoglycemia

*P=0.01; **P=0.02; ***P <0.01.

CL=confidence limit; HDL-C=high-density lipoprotein cholesterol.

Abraira C. Oral Presentation. Presented at the 68th Scientific Sessions of the American Diabetes Association; 6–10 June 2008, San Francisco, USA.

HR (Lower CL, Upper CL)

Risk of death

Lower Higher

Hypoglycemia

HbA1c

HDL-C

Age

Prior event

4.042 (1.449, 11.276)*

1.213 (1.038, 1.417)**

0.699 (0.536, 0.910)*

2.090 (1.518, 2.877)***

3.116 (1.744, 5.567)***

Hypoglycemia was a Strong Predictor of CV

Deaths in VADT study

0 2 4 6 8 10 12

Hazard Ratio

34 ©2008 New England Journal of Medicine. Used with permission

Gerstein HC, et al, for the Action to Control Cardiovascular Risk in Diabetes Study Group.

N Engl J Med 2008;358:2545-2559.

Intensive Glycemic Control and Cardiovascular

Outcomes: ACCORD Study

Primary Outcome: Nonfatal MI, Nonfatal Stroke, CVD

death

Intensive

n (%)

Standard

n (%)

HR

(95% CI) P value

Primary 352 (6.86) 371 (7.23) 0.90

(0.78-1.04) 0.16

Secondary

Mortality 257 (5.01) 203 (3.96) 1.22

(1.01-1.46) 0.04

Nonfatal MI 186 (3.63) 235 (4.59) 0.76

(0.62-0.92) 0.004

Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06

(0.75-1.50) 0.74

CVD Death 135 (2.63) 94 (1.83) 1.35

(1.04-1.76) 0.02

CHF 152 (2.96) 124 (2.42) 1.18

(0.93-1.49) 0.17

ACCORD: increased mortality rate in the intensive arm

compared with the standard arm

CHF=congestive heart failure; CI=confidence interval; CVD=cardiovascular disease; HR=hazard ratio; MI=myocardial infarction.

Gerstein HC. Oral Presentation. Presented at: 68th Scientific Sessions of the American Diabetes Association;

June 6-10, 2008; San Francisco, CA; Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358:2545-2559.

Consequences of hypoglycaemia (3)

Hypoglycaemia

Cardiovascular

complications3

Weight gain


Coma3

Increased risk

of car accident6

Hospitalisation

costs4

Loss of

consciousness3

Increased risk

of seizures3

Death2,3

Increased risk

of dementia1


.

Reduced

quality of life7

ADA Recommendations include...

Prevention of hypoglycemia is

critical in treatment strategy for

Type 2 DM

37

Phung et al. Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes. JAMA. 2010;303(14):1410-1418

CVD=cardiovascular; HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.

American Diabetes Association. Diabetes Care. 2011; 34 (Suppl 1): S4–S10.

Normal Controlled T2DM Uncontrolled T2DM

≥7% 6.1–6.9% HbA1c <6%

Initiate or change

treatment whenever

HbA1c levels are ≥7%

• Initiate or change therapy when HbA1c

≥7% without hypoglycaemia

• Less stringent HbA1c goals may be

appropriate for patients with a history of

hypoglycaemia and CVD

ADA Recommendations include...

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

* Abraira C. Oral Presentation. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA.

Duckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360: 129–139..

Decreasing HbA1c is associated with increased risks

of hypoglycaemia, weight gain and CV death*

Weight gain

and

hypoglycaemia

Body w

eig

ht

HbA1c

Pla

sm

a g

lucose


A. Achieving Goals





Factors to Consider when Choosing an

Anti-hyperglycemic Agent

• Effectiveness in lowering glucose

• Glycemic control that may reduce long-term complications

• Patient profile

• Safety profile

• Tolerability

• Expense

41 Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Pancreatic Islet Dysfunction Leads to Hyperglycemia

in T2DM

↑ Glucose

Fewer

-cells

-cells

Hypertrophy

Insufficient

Insulin

Excessive

Glucagon – +

↓ Glucose

Uptake

↑ HGO

+

HGO=hepatic glucose output.

Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198.

Pharmacologic targets of current drugs used in

the treatment of T2DM

-glucosidase inhibitors Delay intestinal carbohydrate

absorption

Thiazolidinediones

Decrease lipolysis in

adipose tissue,

increase glucose

uptake in skeletal

muscle and decrease

glucose production in

liver Sulfonylureas Increase insulin secretion

from pancreatic -cells

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.

Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract. 2008; 62: 8–14.

Glinides Increase insulin secretion

from pancreatic -cells

Current Oral Therapies do not Address Islet Cell

Dysfunction

Pancreatic Islet Dysfunction

Inadequate

glucagon

suppression

(-cell

dysfunction)

Progressive

decline of β-cell

function

Insufficient

Insulin secretion

(β-cell

dysfunction)

Sulfonylureas

Glinides

TZDs

Metformin

TZDs

Ins. Resistance

(Impaired insulin action)

TZD= Thiazolidinedione; T2DM= Type 2 Diabetes Mellitus

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24–S40

Metformin

TZDs

α-Glucosidase

inhibitors

*Role uncertain

Adapted from Inzucchi SE. JAMA. 2002;287:360-372. Kolterman OG, et al. Am J Health-Syst Pharm 2005;62:173-181; DeFronzo RA, et al. Diabetes Care 2005;28:1092-1100.

Weight gain, edema, CHF

GI effects (flatulence, diarrhea)

GI effects (nausea, diarrhea), lactic acidosis (rare)

SUs

Meglitinides

Hypoglycemia, weight gain, hyperinsulinemia*

Major Adverse Events of Current Treatments

for T2DM Limit the Efficacy

Risk of hypoglycemia with different

Sulfonylureas

*<50 mg/dL.

Tayek J. Diabetes Obes Metab. 2008; 10: 1128–1130.

0

5

10

15

20

25

30

Glipizide

8.70

Tolbutamide

3.50

Chlorpropamide

16.00

Glyburide

16.00

Severe hypoglycaemia*

n/1000 person years =

Rela

tive R

isk (

%)

Gliclazide 0.85

Glimepiride 0.86

4.6*

8.0*

11.5* 12.3* 12.3*

24.0*

RECORD study results: secondary endpoints –

cardiovascular

All cause

Heart failure*

Hazard Ratio (95% CI)

0.86 (0.68, 1.08); P=0.19

0.84 (0.59, 1.18); P=0.32

0.72 (0.49, 1.06); P=0.10

0.93 (0.74, 1.15); P=0.50

2.10 (1.35, 3.27); P=0.001

MI

Stroke

CV death,

MI or stroke

*Fatal and non-fatal.

CI=confidence interval; CV=cardiovascular; MI=myocardial infarction.

Home PD et al. Lancet. 2009; 373: 2125–2135.

Rosiglitazone

(n=2220)

Control

(n=2227)

46

64

154

63

29 61

165

56 1.14 (0.80, 1.63); P=0.47

Hazard ratio (95% CI)

0.5 1.0 2.0 3.0 4.0

Death

CV

136

60

157

71

Use of TZDs is Associated with Increased

Incidence Heart Failure

0 6 12 18 24 30 36

0

1

2

3

6

5

7

8

9

10

4

TZD 8.8%†

No TZD 5.5%

Subjects at Risk

TZD 5,441 2,474 1,203 580 266 108 26 0

No TZD 28,103 13,373 6,836 3,638 1,414 330 89 0

Months

Delea TE et al. Diabetes Care 2003; 26: 2983-2989, (a retrospective study using a healthcare insurance claims database)

Su

bje

cts

%*

*Adjusted estimates of the percentage of subjects with diagnosis of heart failure, † p<0.001

P<0.001

PROactive: incidence of edema and magnitude of

weight gain with Pioglitazone

21.6

13.0

0

5

10

15

20

25 3.6

-0.4-1

0

1

2

3

4

% of Edema without HF Weight Gain (kg)

Placebo

Pioglitazone <45 mg daily

HF=heart failure.

Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.

P <0.0001

Pharmacologic targets GLP-1 based therapy

used in the treatment of T2DM

GLP-1 analogs Improve pancreatic islet glucose

sensing, slow gastric emptying,

improve satiety

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.

Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract. 2008; 62: 8–14.

DPP-4 inhibitors Prolong GLP-1 action leading to

improved pancreatic islet glucose

sensing, increase glucose uptake

Current Oral Therapies do not Address Islet Cell

Dysfunction

Pancreatic Islet Dysfunction

Inadequate

glucagon

suppression

(-cell

dysfunction)

Progressive

decline of β-cell

function

Insufficient

Insulin secretion

(β-cell

dysfunction)

Sulfonylureas

Glinides

TZDs

Metformin

TZDs

Vildagliptin Vildagliptin

Ins. Resistance

(Impaired insulin action)

TZD= Thiazolidinedione; T2DM= Type 2 Diabetes Mellitus

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24–S40

A1C ≥6.5%

OR

Fasting plasma glucose (FPG)

≥126 mg/dl (7.0 mmol/l) (Fasting: i.e. No calories intake for at least 8 hours)

OR

Two-hour plasma glucose ≥200 mg/dl (11.1

mmol/l) during an OGTT

OR

A random plasma glucose ≥200 mg/dl (11.1

mmol/l)

Criteria for the Diagnosis of Diabetes

ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 2.

2010 ADA Type 2 Diabetes Treatment Algorithm

• Regarding Diabetes Mellitus Diagnostic Criteria :

ADA 2011 Glycemic Goals

DIABETES CARE, VOLUME 34, SUPPLEMENT 1, JANUARY 2011

Categories of increased risk for diabetes

(Prediabetes)*

FPG 100-125 mg/dl (5.6-6.9 mmol/l): IFG

or

2-h plasma glucose in the 75-g OGTT

140-199 mg/dl (7.8-11.0 mmol/l): IGT

or

A1C 5.7-6.4%

Prediabetes: IFG, IGT, Increased A1C

*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately

greater at higher ends of the range.

ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 3.

Vildagliptin: in T2DM Management

Inhibition of DPP-4 increases active GLP-1

DPP-4 DPP-4

inhibitor

Meal

Intestinal GLP-1 release

Active GLP-1

Active GLP-1

DPP-4

GLP-1 inactive

(>80% of pool) GLP-1 inactive

No DPP-4

inhibitor present

DPP-4

inhibitor present

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.

Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.

Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.

DPP4 Inhibitors

• A different mechanism for overcoming the loss of

incretin activity in patients with diabetes involves

inhibition of the DPP-4 enzyme ( DPP4 Inhibitors ) thus prolonging the activity of endogenous GLP-1

• These agents are all orally administered and rapidly

absorbed, as 100% inhibition of enzyme activity can

be observed within 30 minutes after administration of

vildagliptin

Vildagliptin Comprehensive Clinical Development

Program

OAD mono

OAD combo Insulin combo

Insulin mono

Prediabetes Diet and

exercise

Mono vs placebo

TZD add-on

Insulin add-on

Metformin add-on vs placebo

SU add-on

Mono head to head

vs metformin

Overall and in elderly

Mono head to head

vs rosiglitazone

Initial combo

with TZD

Mono head to head

vs acarbose

Metformin add-on vs TZD

In IFG

In IGT

Metformin add-on vs SU

Initial combo with metformin

IFG=impaired fasting glucose; IGT=impaired glucose tolerance; OAD=oral antidiabetic drug; SU=sulfonylurea; TZD=thiazolidinedione.

Mono head to head

vs SU

Metformin add-on

metformin up-titration

Patients Exposure in Vildagliptin Clinical Programa

• Over 22,023 patients overall treated in the clinical program1

>13,856 exposed to vildagliptin

• Over 20,990 patients treated in completed studies2

13,253 exposed to vildagliptin in completed studies

• Patient exposure by treatment duration in completed studies

4034 patients exposed to vildagliptin >1 year

1800 patients exposed to vildagliptin >2 years

aData on file, Novartis Pharmaceuticals. Current as of April 19th, 2010. 1All Phase I-IV studies; numbers do not include EDGE study 2All completed Phase I-IV studies

EDGE study patients number:

Total: 56355 with 64% in vildagliptin arm and 35% in non vildagliptin arm

Vildagliptin as Monotherapy

Vildagliptin Dose-Ranging Study: Design and Objective

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus

Pi-Sunyer FX, et al. Diabetes Res Clin Pract 2007; 76: 132-138.

Drug-naïve

24 weeks 2 weeks

N=354

n=88: Vildagliptin 50 mg once daily

n=83: Vildagliptin 50 mg twice daily

n=91: Vildagliptin 100 mg once daily

n=92: Placebo

Design: a 24-week, double-blind, randomized, placebo-controlled,

parallel-group study

Objective: to demonstrate superior HbA1c reduction of vildagliptin

versus placebo

Target population: drug-naïve patients with T2DM; HbA1c 7.5–10%

7.0

7.4

7.8

8.2

8.6

9.0

-4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24

Vilda 50 mg once daily (n=84)

Vilda 50 mg twice daily (n=79)

Vilda 100 mg once daily (n=89)

PBO (n=88)

Vildagliptin Monotherapy: Reductions in HbA1c over

24 Weeks M

ean H

bA

1c (

%)

Time (weeks)

HbA1c=hemoglobin A1c; PBO=placebo; vilda=vildagliptin

Primary intention-to-treat population. *P=0.01; **P <0.001 vs placebo.

Pi-Sunyer F, et al. Diabetes Res Clin Pract 2007; 76: 132-138.

** ** *

Vildagliptin

As

Add-on to

Metformin

Vildagliptin add-on to metformin:

Study design and objective

Objective: to demonstrate superior HbA1c reduction with

vildagliptin + metformin vs metformin monotherapy

Target population: T2DM on maximal dose of metformin;

HbA1c 7.5–11%

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus.

*Patient number refers to primary intention-to-treat population.

Bosi E, et al. Diabetes Care. 2007; 30: 890–895.

n=130: Placebo + metformin

n=143: Vildagliptin 50 mg twice daily + metformin

n=143: Vildagliptin 50 mg once daily + metformin

24 weeks

Metformin >1500 mg

(monotherapy, stable dose)

4 weeks

N=416*

HbA1c=hemoglobin A1c; met=metformin;

PBO=placebo; vilda=vildagliptin

*P <0.001. Primary intention-to-treat population.

Bosi E, et al. Diabetes Care 2007; 30: 890-895.

Vildagliptin Add-on to Metformin: Reduction in

HbA1c over 24 Weeks

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

−4 0 4 8 12 16 20 24

Time (weeks of treatment)

Mean

Hb

A1

c (

%)

PBO + met (n=130)

Vilda 50 mg twice daily + met (n=143)

Vilda 50 mg once daily + met (n=143)

Add-on treatment to metformin (2.1 g mean daily)

−0.7% vs PBO

−1.1% vs

PBO

*

*

Vildagliptin produces clinically meaningful, dose

related decreases in A1C and

Placebo + metformin (n=130) Vildagliptin 50 mg twice daily + metformin (n=143)

Vildagliptin 50 mg once daily + metformin (n=143) FPG=fasting plasma glucose; HbA1c=hemoglobin A1c.

*P <0.001; **P=0.003 vs placebo; ***P <0.001 vs placebo.

Primary intention-to-treat population.

Bosi E, et al. Diabetes Care. 2007; 30: 890–895.

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

−4 0 4 8 12 16 20 24

Time (Weeks)

Mean

Hb

A1c (

%)

−0.7% vs placebo

−1.1% vs placebo

*

*

Time (Weeks)

Mean

FP

G (

mm

ol/L

)

−4 0 4 8 12 16 20 24

8

9

10

11

−0.8 vs placebo

−1.7 vs

placebo

**

***

Add-on Treatment to Metformin (2.1 g Mean Daily)

Duration: 24 weeks vildagliptin add on to metformin

Reduction in HbA1c Reduction in FPG

Initial combination

of

Vildagliptin and

Metformin

Initial combination of vildagliptin and metformin: Effective across the hyperglycemia spectrum (data from core

study and open-label sub-study)

~9.9%

96

Change from BL to EP

~8.7%

285

Overall*

>9%

High BL Open-label

Sub-study b

Me

an

Ch

an

ge

in

Hb

A1

c (

%)

≥10%

~10. 6%

35

~9.2%

201

>8%

Subgroups by BL HbA1ca

*P <0.001 vs BL; **100 mg once daily is not a recommended dosing regimen. Intent-to-treat population. aRaw mean change from baseline; bLS (least-square) mean change from baseline. BL=baseline; EP=end point; HbA1c=glycosylated hemoglobin; met=metformin; vilda=vildagliptin. Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515;

a Data on file, Novartis Pharmaceuticals, LMF237A2302 and LMF237A2302S1.

Vilda 100 mg daily** + met 2000 mg

daily open-label sub-study (P <0.001

vs BL)d

High-dose vilda + met (50/1000 mg twice daily)c

BL mean=

n =

>11%

~12. 1%

86

*

As with traditional OADs, vildagliptin as add-on

to metformin substantially reduces HbA1c in

patients with high baseline levels

Vildagliptin vs SU

as

Add-on to

Metformin

Vildagliptin vs. Glimepiride as add-on to Metformin:


Study purpose: To demonstrate long-term efficacy and safety of add-on therapy with

vildagliptin vs glimepiride in patients with T2DM inadequately controlled with ongoing

metformin monotherapy

Interim analysis: To demonstrate non-inferiority of vildagliptin vs glimepiride at 1 year

Target population: Patients with T2DM inadequately controlled on stable metformin

monotherapy (metformin minimum dose 1500 mg/day; baseline HbA1c 6.5–8.5%)

n=1393: Glimepiride up to 6 mg once daily + metformin


4 weeks

Metformin

HbA1c=haemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.* Randomised population.

Ferrannini E et al. Diabetes Obes Metab 2009; 11: 157–166.

1-year interim

analysis

N=2789*

104 weeks

In patients uncontrolled with metformin monotherapy

vildagliptin is as effective as Glimepiride over 1 year with

low incidence of hypoglycemia and no weight gain

Glimepiride up to 6 mg once daily + metformin

Vildagliptin 50 mg twice daily + metformin

Number of hypoglycaemic events

Patients with 1 hypos (%)

Number of severe hypoglycaemic

events c

Inc

ide

nc

e (

%)

1389 1383 1389 1383 1389 1383 n =

No

. o

f e

ve

nts

No

. o

f e

ve

nts

16.2

1.7 39

554

Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride

Mean HbA1c reduction a Incidence of hypoglycaemia b

BL=baseline; CI=confidence interval

NI=non-inferiority; aPer protocol population ; bSafety population. cGrade 2 or suspected grade 2 events.

*P <0.001; adjusted mean change from BL to Week 52,

between-treatment difference and P value were from

an ANCOVA model containing terms for treatment,

baseline and pooled centre.

Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166.

Me

an

Hb

A1

c (

%)

0.0

6.5

6.7

6.9

7.1

7.3

7.5

- 8 - 4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

NI: 97.5%

CI (0.02, 0.16)

−0.4%

−0.5%

Time (weeks)

Ad

jus

ted

me

an

ch

an

ge

in

bo

dy w

eig

ht

(kg

) fr

om

BL

(BL mean ~88.8kg)

1117 n = 1071

Change in body weight a

*

Vildagliptin vs TZD

as

Add-on to

Metformin

Vildagliptin vs Pioglitazone as add-on to metformin:


Objective: demonstrate efficacy and safety of vildagliptin as add-on to metformin vs

pioglitazone as add-on to metformin over 52 weeks (with interim analysis at 24 weeks)

Target population: patients with T2DM inadequately controlled with metformin monotherapy

(baseline HbA1c 7.5–11%)

Design: randomised, multicentre, active-comparator, 52-week study: 24-week,

double-blind phase (primary objective) followed by a 28-week single-blind phase

N=576*

24 weeks 4 weeks 28 weeks Interim

analysis

Double-blind1 Single-blind2

Metformin

≥1500 mg

HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.

1Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90; 2Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595.

n=281: Pioglitazone 30 mg once daily + metformin


BL=baseline; DPP-4=dipeptidyl peptidase-4; HbA1c=haemoglobin A1c.

Per protocol population. *Non-inferiority of vildagliptin to pioglitazone established at both 0.4% and 0.3% margins,

95% confidence interval=(-0.05, 0.26). Adjusted mean change derived from analysis of covariance model.

Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90.

Vildagliptin plus metformin: The only DPP-4 inhibitor with proven efficacy comparable to Pioglitazone plus

metformin at 24 weeks

-1.0

-1.5-1.5

-0.9

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Overall

Mean BL ~8.4%

Ad

juste

d m

ea

n

ch

an

ge

in

Hb

A1c (

%)

HbA1c >9%

Mean BL ~9.7%

n= 264 246

Pioglitazone 30 mg once daily + metformin

Vildagliptin 50 mg twice daily + metformin

73 69

Non-inferior*

Add-on treatment to metformin (2.0 g mean daily)

78

Vildagliptin vs Pioglitazone as add on to Metformin:

No Change in Mean Body Weight

n=277 n=293

Un

ad

jus

ted

Me

an

Ch

an

ge

in

BW

(k

g)

*

Overall

Mean BL BW ~91 kg

Intention-to-treat population.

BL=baseline; BW=body weight; pio=pioglitazone; vilda=vildagliptin.

*P <0.001 change from baseline.

Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595.

Data on file, Novartis Pharmaceuticals, LMF237A2354.

Add-on Treatment to Metformin

Duration : 52 weeks

Pio 30 mg once daily + met

Vilda 50 mg twice daily + met

Vildagliptin

and

Beta cell preservation

Vildagliptin increases pancreatic Beta cell mass in

neonatal rats

Duttaroy A. et al. European J Pharmacol. 2011; 650: 703–707

Control Vildagliptin

Day 7

BrdU+

cells

Day 7

Apoptag+

cells

Day 21

Insulin+

cells

*p<0.05; **p<0.01

Replication

Apoptosis

-cell Mass

ISR/G=insulin-secretory rate relative to glucose concentration

Scherbaum WA, et al. Diabetes Obes Metab. 2008; Epub ahead of print..

Durability of β-cell Function over 2 Years M

ea

n IS

R/G

(p

mo

l/m

in/m

2/m

M)

Time (weeks)

Treatment period Wk 0–52 Treatment period Wk 56–108 Washout Washout

Placebo (n=40)

Vildagliptin 50 mg once daily (n=49)

30

−8 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

35

40

45

50

81

Safety Profile

of

Vildagliptin

83

In more than 14,000 patients No Increased Risk for

Adjudicated CV Events, Relative to All Comparators*

AEs=adverse events; bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin. #Vs comparators (all non-vildagliptin treatment groups). All-study safety population.

‡Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, U.S. Department

of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008.

Schweizer A, et al. DOM 2010 in press.

Vildagliptin Reference M-H RR

n / N (%) n / N (%) (95% CI)

Vilda 50 mg qd# 10 / 1393 (0.72) 14 / 1555 (0.90) 0.88 (0.37–2.11)

Vilda 50 mg bid# 81 / 6116 (1.32) 80 / 4872 (1.64) 0.84 (0.62–1.14)

Risk Ratio

Incidences and Odds Ratios for Adjudicated CV Events by

Treatment

Vildagliptin better Vildagliptin worse

0.1 1 10

#Meta-analysis of vildagliptin 50 mg bid data vs all comparators according to the methodology set by

the US Food and Drug Administration‡ [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)].

In more than 14,000 patients, Vildagliptin Showed No

increase in liver enzymes Vs comparators

AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily;

SAEs=serious adverse events; vilda=vildagliptin. *Vs comparators

(all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.

Vildagliptin better Vildagliptin worse

Vildagliptin Reference Peto odds ratio

n / N (%) n / N (%) (95% CI)

Hepatic AEs

Vilda 50 mg qd* 15 / 1502 (1.00) 14 / 1662 (0.84) 1.29 (0.61–2.70)

Vilda 50 mg bid* 83 / 6116 (1.36) 84 / 4872 (1.72) 0.87 (0.64–1.19)

Hepatic SAEs

Vilda 50 mg qd* 2 / 1502 (0.13) 2 / 1662 (0.12) 1.08 (0.15–7.76)

Vilda 50 mg bid* 6 / 6116 (0.10) 5 / 4872 (0.10) 1.13 (0.35–3.67)

Odds Ratio

0.01 0.1 1 10 100

According to the Prescribing information, vildagliptin should not be used in patients with

hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal

(ULN).

Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should

be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter.

Ligueros-Saylan M, et al.DOM 2010 in press

Vildagliptin All Comparators Peto odds ratio

n / N (%) n / N (%) (95% CI)

Selected Skin-related AEs

•Vilda 50 mg qd 19/1502 (1.26) 11/1662 (0.66) 1.93 (0.93-3.99)

•Vilda 50 mg bid 89/6116 (1.47) 71/4872 (1.46) 1.10 (0.80–1.51)

Selected Skin-related SAEs

•Vilda 50 mg qd 0/1502 (0.00) 1/1662 (0.06) 0.23 (<0.01–7.11)

•Vilda 50 mg bid 6/6116 (0.10) 7/4872 (0.14) 0.84 (0.29–2.49)

0.01 100

Vildagliptin worse

Odds Ratio

Vildagliptin better

0.1 1 10

In more than 14,000 patients ,No increased risk of skin-

related AEs and SAEs with Vildagliptin vs all comparators

Odds ratios for selected skin and vascular- related AEs and SAEs in the all controlled studies (excluding open-label) safety population. (Vilda=

vildagliptin; All comparators= all non-Vilda treatment groups, that is placebo and active comparators. n = number of patients experiencing an AE, N =

total number of patients). Test for heterogeneity of selected skin- and/ or vascular – related AEs: Q = 9.58, p = 0.653 and I2 = 0.00 (vildagliptin 50 mg

qd); Q= 10.79, p= 0.702 and I2 = 0.00 (vildagliptin 50 mg bid). Test for heterogeneity of selected skin- and/ or vascular – related SAEs: Q = 0.20, p =

0.999 and I2 = 0.00 (vildagliptin 50 mg qd); Q= 10.31, p= 0.739and I2 = 0.00 (vildagliptin 50 mg bid).

Ligueros-Saylan M, et al. Diab Obes Metab 2010 ;12:495-509

Vildagliptin Monotherapy: Overall AE Profile

Comparable with Placebo (AEs >5%)

Preferred term

Vilda

50 mg

once daily

N=655

n (%)

Vilda

50 mg

twice daily

N=2251

n (%)

Met

<1 mg

twice daily

N=252

n (%)

Rosi

8 mg

once daily

N=267

n (%)

Acar

<100 mg

thrice daily

N=220

n (%)

PBO

N=586

n (%)

Nasopharyngitis 37 (5.6) 128 (5.7) 13 (5.2) 20 (7.5) 14 (6.4) 36 (6.1)

Headache 35 (5.3) 112 (5.0) 13 (5.2) 14 (5.2) 1 (0.5) 23 (3.9)

Dizziness 29 (4.4) 105 (4.7) 10 (4.0) 11 (4.1) 9 (4.1) 20 (3.4)

Upper respiratory

tract infection 11 (1.7) 75 (3.3) 5 (2.0) 8 (3.0) 11 (5.0) 20 (3.4)

Diarrhea 10 (1.5) 64 (2.8) 57 (22.6) 7 (2.6) 6 (2.7) 12 (2.0)

Nausea 10 (1.5) 53 (2.4) 23 (9.1) 2 (0.7) 0 13 (2.2)

Acar=acarbose; AE=adverse event; met=metformin; PBO=placebo; rosi=rosiglitazone; vilda=vildagliptin

Preferred terms are sorted by descending order of incidence in the vildagliptin 50 mg twice-daily group.

A patient with multiple AE occurrences on one treatment is counted once in the AE category for that treatment.

Adapted from Summary of Clinical Safety, 5 December 2007. Tables 4-1g. Novartis Pharmaceuticals.

Pooled analysis at 24 weeks

Vildagliptin Monotherapy: Incidence of Hypoglycemic

Events

Patients

Vilda

50 mg

once daily

N=655

n (%)

Vilda

50 mg

twice daily

N=2251

n (%)

Met

<1 mg

twice daily

N=252

n (%)

Rosi

8 mg

once daily

N=267

n (%)

Acar

<100 mg

thrice daily

N=220

n (%)

PBO

N=586

n (%)

With >1 hypoglycemic events 2 (0.3) 7 (0.3) 0 1 (0.4) 0 1 (0.2)

Discontinued for

hypoglycemic events 0 0 0 0 0 0

With grade 2 hypoglycemic

events 0 0 0 0 0 0

Hypoglycemic events are defined as: (a) symptoms patient is able to self-treat and plasma glucose is <3.1 mmol/L (grade 1); (b) symptoms patient is

unable to self-treat, and plasma glucose is <3.1 mmol/L (grade 2).

Acar=acarbose; met=metformin; PBO=placebo; rosi=rosiglitazone; vilda=vildagliptin

Adapted from Summary of Clinical Safety, 5 December 2007. Table 4-1g. Novartis Pharmaceuticals.

Pooled analysis at 24 weeks

Vildagliptin: Hypoglycemic Events in Add-on to

Metformin

Hypoglycemic events are defined as: (a) symptoms patient is able to self-treat, and plasma glucose is <3.1 mmol/L (grade 1); (b) symptoms patient is

unable to self-treat, and plasma glucose is <3.1 mmol/L (grade 2); and (c) symptoms patient is unable to self-treat, and no plasma glucose value

available (suspected grade 2).

met=metformin; pio=pioglitazone; vilda=vildagliptin

Data on file, Novartis Pharmaceuticals, CLAF237A2303, 2354.

Vilda

50 mg

once daily

+ met

N=177

n (%)

Vilda

50 mg

twice daily

+ met

N=183

n (%)

Placebo

+ met

N=181

n (%)

Vilda

50 mg

twice daily

+ met

N=295

n (%)

Pio

30 mg

once daily +

met

N=280

n (%)

With >1 hypoglycemic events 1 (0.6) 1 (0.5) 1 (0.6) 1 (0.3) 0

Discontinued due to hypoglycemic

events 0 0 0 0 0

With grade 2 hypoglycemic events 0 0 0 0 0

Patients

Add-on metformin vs placebo

Add-on metformin

vs pioglitazone

AACE October 2009.Avilable at www.aace.com/pub

A1c < 7%

Metformin

failure

Su

lfo

nylu

reas

TZ

Ds

DP

P-

4 I

nh

ibit

or

At a clinical crossroad: Which way you go?

• Efficacy

• Hypoglycemia

• Weight gain

• Effect on b-cell

• CV risk

• Safety & Tolerability

Take Home Messages (1/2)

Early and sustained glycemic control is crucial for prevention

of diabetic complications

Hypoglycemia is a major barrier for achieving optimal

glycemic control

DPP-4 inhibitors emerge as a novel approach for

management of type 2 DM

Take Home Message (2/2)

• If sustained glycemic control is important

• If avoidance of hypoglycemia is important

• If avoidance of weight gain is important

• If preservation of B-cell function is important

Then………

Vildagliptin is a good option

In management of patients with type 2

DM

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