Vildagliptin in the management of Type 2 Diabetes mellitus

WELCOME to

CME PROGRAM

VILDAGLIPTIN IN THE MANAGEMENT OF TYPE 2 DM

Presenter:DR. A.B.M. KAMRUL HASANMD Final Part (E&M)Department of EndocrinologyBSMMU

DM: GLOBAL BURDEN

• One of the greatest challenges faced by the modern world is diabetes mellitus and its consequences

• Once considered a disease of the West, diabetes is now a global health problem

• The prevalence of diabetes is rapidly rising all over the globe at an alarming rate

6.6

7.97.88.4

0123456789

DM IGT

Pre

vale

nce

(%)

DM and IGT

DM and IGT: World Prevalence and projection 2010 and 2030

2010

2030

International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009. Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.

DM: GLOBAL BURDEN

DM and IGT: World prevalence and projection- 2010 and 2030

285344

439472

0

100

200

300

400

500

DM IGT

DM and IGT

Num

ber o

f peo

ple

(milli

ons) 2010

2030

International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009. Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.

DM: GLOBAL BURDEN

Top 10 countries for numbers of diabetes in 2010 and 2030 (population aged 20-79 years)

2010 2030

Country No. of DM (millions)

No. of DM (millions)

Country

1 India 50.8 87.0 India 1

2 China 43.2 62.6 China 2

3 USA 26.8 36.0 USA 3

4 Russian Federation

9.6 13.8 Pakistan 4

5 Brazil 7.6 12.7 Brazil 5

6 Germany 7.5 12.0 Indonesia 6

7 Pakistan 7.1 11.9 Mexico 7

8 Japan 7.1 10.4 Bangladesh 8

9 Indonesia 7.0 10.3 Russian Federation

9

10 Mexico 6.8 8.6 Egypt 10

International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009.

Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.

Major Metabolic Defects in Type 2 Diabetes

Decreased pancreatic insulin secretion

Peripheral insulin resistance in muscle and fat tissue

Increased hepatic glucose output

Deficient incretin hormonesresponse

Recent research has implicated at least 5 other pathophysiological defects intimately involved in the development of T2DM

• Decreased incretin effects from GIT

• Dysregulated pancreatic α-cell activity

• Lipotoxicity

• Maldaptive kidney responses

• Central neurotransmitter dysfunction

Pathophysiology of T2DM

Hyperglycemia

DeFronzo R. Diabetes 2009;58:773-95.

Hepatic glucose production

glucagon secretion

Neurotransmitter dusfunction

Incretin effect

Glucose uptake

Insulin secretion

Lipolysis

glucose reabsorption

Traditional current oral therapies do not address all islet cell dysfunction

TZD=thiazolidinedione; T2DM=type 2 diabetes mellitusAdapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.

Pancreatic Islet Dysfunction

Inadequate glucagon

suppression(-cell

dysfunction)

Progressivedecline of β-cell

function

Insufficient Insulin secretion

(β-celldysfunction)

Sulfonylureas

Glinides

TZDsMetformin

Insulin Resistance (Impaired insulin action)

Traditional current oral therapies do not address all islet cell dysfunction

TZD=thiazolidinedione; T2DM=type 2 diabetes mellitusAdapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.

Pancreatic Islet Dysfunction

Inadequate glucagon

suppression(-cell

dysfunction)

Progressivedecline of β-cell

function

Insufficient Insulin secretion

(β-celldysfunction)

Sulfonylureas

Glinides

TZDsMetformin

Insulin Resistance (Impaired insulin action)

GLP-1DPP-4 inhibitors



Pharmacologic Targets of Current Drugs Used inthe Treatment of T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

SulfonylureasIncrease insulin secretion from pancreatic -cells

BiguanidesIncrease glucose uptakeand decreases hepatic glucose production

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

GlinidesIncrease insulin secretion from pancreatic -cells

Pharmacologic Targets of Current Drugs Used inthe Treatment of T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

SulfonylureasIncrease insulin secretion from pancreatic -cells

GLP-1 analoguesImprove pancreatic islet glucose sensing, slow gastric emptying, improve satiety

BiguanidesIncrease glucose uptakeand decreases hepatic glucose production

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitusAdapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.

GlinidesIncrease insulin secretion from pancreatic -cells

DPP-4 inhibitorsProlong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake

What is Incretin?

• Incretins are gut hormones that enhance glucose stimulated insulin secretion

• Incretin effect designates amplification of insulin secretion following oral glucose load

NATURAL INCRETINS

Two types:

1. Glucose dependent insulinotropic polypeptide (GIP)

2. Glucagon like peptides (GLPs) -GLP-1

These two hormones are rapidly degraded by an enzyme DPP-4

GLP-1 and GIP are the 2 major incretins in human

• Both are peptide hormones (30 and 42 amino acids)

• Secreted from endocrine cells in the small intestinal mucosa

• GLP-1: distal, L-cells (mainly ileum, colon)

• GIP: proximal, K-cells (mainly duodenum)

• Released in response to meal ingestion

GLP-1 positive endocrine L-cells in human small intestine

WHAT IS DPP-4?

• Dipeptidyl Peptidase-4 (DPP-4) is an enzyme found free in the circulation and tethered to endothelium and epithelial cells in most tissues, especially in the intestinal mucosa

• It clears and inactivates GLP-1 and GIP with in few minutes

• It cleaves the N-terminal dipeptide from peptides.

Pancreas

Stomach

Heart

Brain

Liver

Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131–57

Intestine

CardioprotectionCardiac function

Satiety

Gastricemptying

Glucose production

Glucose-dependentinsulin secretion

Insulin synthesis

Glucose-dependent glucagon secretion

β

GLP-1: an incretin hormone with multiple direct effects on human physiology

β

β

α

α

GLP-1

L-cells secrete GLP-1 degraded by DPP-4

EFFECTS OF GLP-1 & GIP

THE PROBLEM

Because of very short half life (1-2 min) therapeutic efficacy is challenged

This led to idea of producing drugs that act as analogue or receptor agonist but longer half life

Another idea was to develops drugs that inhibit DPP-4 enzyme responsible for breakdown of GLP-1 or GIP

Thus one group of drugs is called incretin mimetics and the other group is known as incretin enhancers

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Release ofactive incretinsGLP-1 and GIP

Blood glucose in fasting and

postprandial states

Ingestion of food

Glucagon(GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

X

Insulin(GLP-1and

GIP)

Glucose-dependent

Glucose depende

ntPancreas

InactiveGIP

Beta cells

Alpha cells

Glucose uptake by peripheral

tissue

Exenatide

Gliptin

NEW THERAPIES: INCRETIN SYSTEM

SITES OF ACTION OF GLIPTINS

INCRETIN MIMETICS AND DPP-4 INHIBITORS:MAJOR DIFFERENCESProperties/effect Incretin mimetics DPP-4 inhibitors

Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect

Yes Unknown

Restitution of insulin secretion (2 phases)

Yes (exenatide) Yes

Hypoglycaemia No No

Inhibition of gastric emptying Yes Marginal

Effect on body weight Weight loss Weight neutral

Side effects Nausea None observed

Administration Subcutaneous Oral

Gallwitz. Eur Endocr Dis. 2006

DIPEPTIDYL PEPTIDASE - 4 INHIBITORS

Drugs belonging to this class:

• Sitagliptin (FDA approved 2006)• Vildagliptin (EU approved 2008)• Saxagliptin (FDA approved 2009)• Linagliptin (FDA approved 2011)

25

VILDAGLIPTIN: PHARMACOKINETICS

• Rapidly absorbed (tmax <2 hours) & highly bioavailable (85%) after oral administration

• Low plasma protein binding (9%)

• Plasma half life 1.5 - 4.5 hours

• Majority (approx. 69%) undergo renal metabolism to inactive metabolites

VILDAGLIPTIN: PHARMACOKINETICS

• Negligible involvement of CYP450 isoforms in metabolism

• Most (85%) is eliminated via urine

• A dose of 50-100mg of vildagliptin provides:o Almost complete inhibition of DDP-4 for

approximately 12 hourso About 40% inhibition by 24 hours

| Presentation Title | Presenter Name | Date | Subject | Business Use Only

28

Series10

5

10

15

20

GIP

AU

C (

nm

ol/

L*2

40

min

)

Series10.0

0.5

1.0

1.5

2.0

2.5

3.0

GL

P-1

AU

C (

nm

ol/L

*24

0 m

in)

Secretion of incretins decreased in IGT and T2DM

T2DM patients vs healthy individuals – following meal

GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1; GT=glucose tolerance; T2DM=type 2 diabetes mellitusToft-Nielsen, et al. J Clin Endocrinol Metab 2001: 3717-3723.

P <0.001

P=0.095

NormalGT

ImpairedGT

T2DM

GLP-1 GIP

NormalGT

ImpairedGT

T2DM


30


31

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-ce

ll Fu

nctio

n (%

)*

Progressive Loss of β-cell Function Occurs prior to Diagnosis

Metformin (n=159)

Diet (n=110)

Sulfonylurea (n=511)

Neonatal rat model of pancreatic islet growth

Adapted from Duttaroy A, et al. Diabetes. 54 (suppl 1): A141.Abstract 572-P.

EFFECT OF VILDAGLIPTIN ON -CELL PRESERVATION AND -CELL REGENERATION

BrdU

-pos

itive

cel

ls /

isle

t are

a (

105 )

Week 1 Vildagliptin decreased islet apoptosis

and increased -cell replication

Week 3Resulted in increased

insulin-positive islet mass

Vehicle

P <0.05

0.04

0.06

0.08

0.10

0.12

0.14

Total islet mass

% is

let a

rea

x pa

ncre

atic

wei

ght (

mg)

Vildagliptin60 mg/kg/d

ApoptosisReplication

0

25

50

75

100

Vehicle Vildagliptin60 mg/kg/d

Vehicle

P <0.05

P <0.001

Vildagliptin60 mg/kg/d

Apop

totic

cel

ls /

isle

t are

a (

105 )

0.0

0.5

1.0

1.5

2.0

2.5

Vehicle Vildagliptin

Insulin

VILDAGLIPTIN ENHANCES ISLET CELL FUNCTION BY INCREASING INSULIN AND DECREASING GLUCAGON SECRETION

OGTT 30 min after single oral dose of vildagliptin (100 mg)

OGTT=oral glucose tolerance test *P <0.01.He YL, et al. J Clin Pharmacol 2007; 47: 633-641.

7.5

12.5

17.5

22.5Glucose (mmol/L)

0

60

80

100

120

40

20

Insulin (pmol/L)

60

80

100

120

140Glucagon(ng/L)

−90 −60 −30 0 30 60 90 120 150 180 210 240 270 300

−90 −60 −30 0 30 60 90 120 150 180 210 240 270 300

−90 −60 −30 0 30 60 90 120 150 180 210 240 270 300

Time

Placebo (n=16)Vildagliptin 100 mg (n=15)

75 g glucose

Dose

VILDAGLIPTIN ENHANCES Β-CELL SENSITIVITY TO GLUCOSE

Vildagliptin 50 mg once dailyPlacebo

Mari A, et al. J Clin Endocrinol Metab 2008; 93: 103-109.

Secr

etion

at 7

mM

glu

cose

(pm

ol/m

in/m

2 )

180

200

220

240

260

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

Time (weeks)

Basal secretory tone

45

50

55

60

65

70

75

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

Time (weeks)

Glu

cose

sen

sitiv

ity(p

mol

/min

/m2 /

mM

)

Glucose sensitivity

12

14

16

18

20

22

24

4.0 8.0 12.0 16.0 20.0 24.0 28.0

Glucose (mmol/L)

Glu

cago

n (p

mol

/L)

Placebo wk 0 (n=14)Placebo wk 12 (n=14)

Vilda wk 0 (50 mg twice daily, n=14)Vilda wk 12 (50 mg twice daily, n=14)

12

14

16

18

20

22

24

4.0 8.0 12.0 16.0 20.0 24.0 28.0

Glucose (mmol/L)

Glu

cago

n (p

mol

/L)

* * **

Vildagliptin Placebo

wk=week; vilda=vildagliptin*P <0.05 vs wk 0.Data on file, Novartis Pharmaceuticals, LAF237A2344.

VILDAGLIPTIN ENHANCES Α-CELL SENSITIVITY TO GLUCOSE

VILDAGLIPTIN ENHANCES INSULIN SENSITIVITY

Series14.0

4.5

5.0

5.5

6.0

6.5

7.0

Duration: 6 weeksVildagliptin vs placebo

Glu

cose

Rd

(mg/

kg•m

in)

Placebo (n=16)

Vildagliptin 50 mg twice daily (n=16)

Insulin infusion 80 mU/m2•min

Mean Rd difference=0.7 mg/kg•min

Rd=rate of disappearance*P <0.05.Azuma K, et al. J Clin Endocrinol Metab 2007; [Epub].

*6.1

5.4

Hyperinsulinemic euglycaemic clamp

Vildagliptin improves postprandial lipid and lipoprotein metabolism

TG=triglycerides; vilda=vildagliptinMatikainen N, et al. Diabetologia 2006; 49: 2049-2057.

Before vilda, week 0 (n=13)

Vilda 50 mg twice daily,week 4 (n=15)

0.8

0.6

0.4

0.2

0.0−1 0 1 2 3 4 5 6 7 8

0.08

0.06

0.04

0.02

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

0.50

0.40

0.30

0.20

0.10

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

4.0

3.5

3.0

2.52.0

1.51.0

−1 0 1 2 3 4 5 6 7 8

Plasma TG Chylomicron TG

Chylomicron apo B-48 Chylomicron cholesterol

mm

ol/L

mm

ol/L

mm

ol/L

mg/

L

0 12 24 52

Time (week)

* * †

0 12 24 52

Time (week)

* * *

pmol

/L 3

0 m

in/(

mm

ol/L

)

0 12 24 52

Time (week)

* *m

L · m

in-1

· m

-2

Insulinsecretio

n

Insulin sensitivit

y

Adaptation

index

VILDAGLIPTIN ENHANCES Β-CELL FUNCTION AND INSULIN SENSITIVITY OVER 52 WEEKS

Patients on stable metformin therapy

*P <0.05 vs placebo; †P <0.01 vs placebo.Adapted from Ahrén B, et al. Diabetes Care 2005; 28: 1936–1940.

Vildagliptin 50 mg daily / metforminPlacebo / metformin

nmol

C-pe

ptide

· m

mol

gluc

ose-1

· m

L-1 ·

m-2

300

250

275

200

225

0.050

0.040

0.045

0.025

0.030

0.035

14

10

12

6

8


40


41


42


43


44


45


46


47


48


49


50


51

COMPARISON OF OADs

VECTOR: Results 1

• Hypoglycaemic events (HE)• No patients treated with Vildagliptin experienced hypos including no severe events,

compared with 34 hypos in 15 patients, including one severe event with SU– Mean between-group difference in patients who experienced at least one HE was –41·7% (p = 0·0002)

53 1. VECTOR. doi:10.1185/03007995.2011.579951

VECTOR: Results1

• HbA1c• Vildagliptin significantly lowered HbA1c (7·7% to 7·2%) versus SU (7·2% to 7·3%) post-

Ramadan. The between group difference being −0·5% (p = 0·0262)

1. VECTOR. doi:10.1185/03007995.2011.579951

VECTOR: Results1

• Adherence• The mean number of missed doses was markedly lower with Vildagliptin than with

SU (0·2 vs 7·6; between-group difference −7·4 doses; p = 0·0204). That is, on average, patients had 7 fold more missed doses with SUs than Vildagliptin

1. VECTOR. doi:10.1185/03007995.2011.579951

Only 1 patient in the Vildagliptin group missed at least one dose, compared with 10 patients in the SU group

Vildagliptin Vs Other DPP-4i

Vildagliptine Vs. Sitagliptine & Sexagliptine: Powerful 1.1% reduction in HbA1c

Superior HbA1c reduction data from 2 separate studies with different baseline HbA1c values2

Vildagliptine Vs. Sitagliptine:Longer duration of DPP-4 binding & increased Active GLP 1 than sitagliptin

Tight substrate-like binding of galvus leads to potent DPP-4 inhibition

Greater increases in active GLP-1 levels with GALVUS compared with sitagliptin is likely due to tighter and longer-lasting binding

Vildagliptine Vs. Sitagliptine:

Vildagliptin•Efficacy in add on to metformin: 1.1% HbA1C reduction vs

•Skin reaction not observed

•Durability over 02 years

Sitagliptin•Efficacy in add on to metformin: 0.7% HbA1C reduction

•Hypersensitivity reaction observed in post marketing

•Durability 01 year

Recent Advancement of Vildagliptin Labeling:•No more Caution in CHF•Recommended in moderate to severe renal impairment also

VILDAGLIPTIN APPROVED IN EU FOR T2DM PATIENTS WITH MODERATE OR SEVERE RENAL

IMPAIRMENT

• Renal impairment affects approximately 25 percent of patients with T2DM

• Majority of currently available medications are not recommended, contraindicated or have to be taken with caution in this population


IMPAIRMENT

• 24-week, multi-center, randomized, double-blind, parallel-group, placebo-controlled study (n=515) assessed the safety and tolerability of vildagliptin (50 mg qd) in patients with type 2 diabetes and moderate or severe renal impairment

• The trial showed that vildagliptin had a similar safety profile to placebo in these patients6 and resulted in significant improvements in glycemic control when added to existing anti-diabetic therapy


IMPAIRMENT

TIME COURSE OF HBA1C DURING RESCUE-FREE TREATMENT IN PATIENTS WITH MODERATE RI

TIME COURSE OF HBA1C DURING RESCUE-FREE TREATMENT IN PATIENTS WITH MODERATE RI

Overall summery of AEs by Rx & severity of RI

Summery of common AEs by Rx & severity of RI

VILDAGLIPTIN IN HEPATIC IMPAIRMENT

• The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in subjects with mild, moderate, and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison to subjects with normal hepatic function.

• The exposure to vildagliptin (100 mg) after a single dose in subjects with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to vildagliptin for subjects with severe impairment was increased by 22%.


• The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which is not considered to be clinically relevant

• There was no correlation between the severity of hepatic function impairment and changes in exposure to vildagliptin


• The use of vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST > 2.5x the upper limit of normal


• Liver function should be monitored quarterly in the first year and periodically thereafter

• Vildagliptin should be stopped if ALT rises 3 times upper normal limit

TAKE HOME MESSAGE

• Incretins are gut hormones that enhance glucose

stimulated insulin secretion

• Amplification of insulin secretion following oral

glucose load- “incretin effect”

• This effect is severely reduced or lost in type 2 DM

TAKE HOME MESSAGE

• Biologic incretins are ineffective in clinical use

because of short half-life

• Therapeutic benefit is obtained by DPP-4 resistant

GLP-1 analogue and DPP-4 enzyme inhibitors

• Incretin based therapy has shown a new pathway

of treatment of T2DM, with a promise for weight

loss and β cell generation

TAKE HOME MESSAGE

• Gliptins are weight neutral and does not cause hypoglycaemia

• Gliptins may increase beta cell mass in human

• Vildagliptin is safe and effective in type 2 diabetic patients with moderate to severe renal impairment

Acknowledgement

• Prof. Md. Fariduddin Chairman & Course Co-ordinator, Department of Endocrinology, BSMMU

• Dr. M.A. Hasanat Associate Prof, Department of Endocrinology, BSMMU

• Novartis Pharma, Bangladesh

Thank You All

76

Health & Medicine

Vildagliptin in the management of Type 2 Diabetes mellitus