DPP4 is: Earlier the better!DR FARAZ FARISHTA

CONSULTANT ENDOCRINOLOGISTMEDWIN HOSPITAL

MD OF SPARSH ENDOCRINOLOGY & DIABETIC CENTERSPRESIDENT OF DIABETES AWARENESS FOUNDATION

ASSISTANT PROFESSOR IN MIMS

AgendaDiabetes-Global concernChallenges associated with achieving optimal

glycemic goals Clinical inertiaConventional management approachWhat guidelines say?What DPP4 inhibitors brought?Vildagliptin efficacyVildagliptin value propositionSummary

Diabetes is a huge and growing problem, and the costs to society are high and escalating

382 million people have diabetes

By 2035, this number will rise to 592 million

Ref. IDF atlas 06, 2013

Almost half of all people with diabetes live in just three countries

ChinaIndiaUSA

Ref. IDF atlas 06, 2013

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

5Ref. IDF atlas 06, 2013

The ominous octet

DEFRONZO, DIABETES, VOL. 58, APRIL

2009DEFRONZO, DIABETES, VOL. 58, APRIL 2009

The natural course of HbA1c

Ferrannini et al. J Clin Endocrinol Metab 2005

Hafner SM et al. JAMA 1990;263: 2893-2898

Type 2 Diabetes is a Global Cardio-metabolic Risk (CMR)

The ticking clock

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.

Med

ian

Hb

A1c

(%

)

06

7

8

9

UKPDS 1998

ConventionalMetformin

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:• 24% reduction in microvascular complications

• 15% reduction in MI• 13% reduction in all-cause mortality

2007

Achieving early glycaemic control may generate a “good legacy effect“

ADA/EASD1 AACE/ACE2 IDF3

HbA1c <7.0% (general goal)

≤6.5% <6.5%

Preprandial capillary plasma glucose

70–130 mg/dL

(3.9–7.2 mmol/L)

<110 mg/dL

(<6.0 mmol/L)

<110 mg/dL

(<6.0 mmol/L)

Peak postprandial capillary plasma glucose

<180 mg/dL

(<10.0 mmol/L)

<140 mg/dL

(<7.7 mmol/L)

<145 mg/dL

(<8.0 mmol/L)

ACE=American College of Endocrinology; ADA=American Diabetes Association; HbA1c=hemoglobin A1c; IDF=International Diabetes Federation.Adapted from: 1ADA / EASD consensus statement: Nathan DM, et al. Diabetes Care, 2009; 32:193–203;2American Association of Clinical Endocrinologists, American College of Endocrinology. Endocr Pract. 2007; 13 (Suppl 1): 3–68;3International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation; 2005.

Current Treatment Goals for Glycemic Control

Challenges associated with achieving optimal glycaemic goals

2001 2002 2003 2004 2005 2006 20076.5

7.0

7.5

8.0

8.5

9.0

2001 2002 2003 2004 2005 2006 20073.5

4.0

4.5

5.0

5.5

6.0Type 1 diabetes

Type 2 diabetes + insulin

YearYear

Mean

Hb

A1c (%

)

Mean

Tch

ol

(mm

ol/

l)

In patients with type 1 diabetes or type 2 diabetes on insulin, there was a 0.1% relative improvement in HbA1c vs. improvements in total cholesterol of 15% and

29%, respectively between 2001 and 2007

Currie et al. Diabetic Medicine 2010; 27:938-948

Clinical inertia in T2DM

• Retrospective cohort study of over 80,000 people• Time to treatment intensification from first HbA1c above 7.5%, by

number of OADs and type of intensification

Khunti K, et al. Diabetes Care 1013;Epub ahead of print.

*Proportion of people with HbA1c >7.5% having any intensification to their treatment at end of follow-up according to number of OADs

Median: 1.5 years Median: >7.2 years Median: >6.1 years

Cut-off HbA1c 7.5% (58 mmol/mol)

Clinical inertia and CV events

105477 newly diagnosed T2DM (11.3% previous CVD)5.3 years median follow-up

6 month delay in first 2 years of treatment with HbA1c > 7.0%

MI Stroke HF Any CVE

All patients 1.38 (1.16-1.82)

1.07 (0.89-1.29)

1.28 (1.10-1.48)

1.25 (1.13-1.39)

No Previous CVD

1.21 (1.00-1.47)

1.07 (0.87-1.31)

1.28 (1.07-1.52)

1.20 (1.07-1.35)

Previous CVD 1.91 (1.40-2.60)

1.08 (0.73-1.61)

1.27 (0.95-1.70)

1.42 (1.15-1.75)

Paul S et al. Poster presented at EASD 2013.

Values in table correspond to HR (95% CI)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 166.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

Consequences of delayed intervention – Interpreting the VADT results

Time (years since diagnosis)

Hb

A1c

(%

)

Bad glycaemic“legacy”

Before entering VADT intensive treatment arm

After entering VADT intensive treatment arm

Drive risk for complications

Adapted from: Del Prato S, et al. Diabetologia 2009;52:1219-1226.

Earlier and Appropriate Intervention MayImprove Patients’ Chances of Reaching Goal

OAD=oral antidiabetic agent. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

Published Conceptual Approach

Hb

A1

c G

oal

Mean HbA1c

of patients

Duration of Diabetes

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD + multiple daily

insulininjections

OAD + basal insulin

Conventional stepwisetreatment approach

Earlier and more aggressive intervention approach

6

7

8

9

10

1 Gastrointestinal2 Thiazolidinedione

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

Conventional Oral Therapies Do Not Address the Multiple Defects in Type 2 Diabetes

Sulfonylureas

Glinides

Impaired insulinaction

Inadequate glucagon

suppression(-cell

dysfunction)

Glucoseinflux from

GI1 tract

α-Glucosidaseinhibitors

TZDs2

Metformin

Chronicβ-cell

decline

Plasma glucose and disease progression

Acuteβ-cell

dysfunction

unmet need unmet need

Metformin1

TZDs1-3

α-glucosidase inhibitors1

CHF=congestive heart failure; GI=gastrointestinal; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione aRole uncertain1Inzucchi SE. JAMA. 2002; 287: 360–372; 2Avandia US Prescribing Information; 3Dormandy JA, et al. Lancet. 2005; 366: 1279–1289; 4Buse JB, et al. Diabetes Care. 2004; 27: 2628–2635; 5DeFronzo RA, et al. Diabetes Care. 2005; 28: 1092–1100; 6Kendall DM, et al. Diabetes Care. 2005; 28: 1083–1091; 7Kolterman OG, et al. Am J Health-Syst Pharm. 2005; 62: 173–181; 8Byetta US Prescribing Information.

Incretin mimetics4-8

Weight gain, edema, CHF, bone fractures (pioglitazone, rosiglitazone)

GI effects (flatulence, diarrhea)

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

GI effects (nausea, vomiting, diarrhea), pancreatitis, hypoglycemia (in add-on to SU)

SUs1

Meglitinides1

Hypoglycemia, weight gain, hyperinsulinemiaa

Major Adverse Events of Traditional Treatments for T2DM- Limits Efficacy

What did the major guidelines say...?

Reference: A. Garber et. al., ENDOCRINE PRACTICE Vol 19 (Suppl 2) May/June 2013

AACE’ 2013 Treatment Algorithm

23

T2DM Anti-hyperglycemic Therapy: When goal is to avoid hypoglycemia

Diabetes Care, Diabetologia. 19 April 2012

24

T2DM Anti-hyperglycemic Therapy: When goal is to avoid weight gain

Diabetes Care, Diabetologia. 19 April 2012

| Presentation Title | Presenter Name | Date | Subject | Business Use Only25

Concluding remarks on guidelines

In AACE/ ACE guidelines priority has been given to Incretin based therapies most likely because of glycemic control along with added benefit like weight reduction with GLP1-RA (weight neutral with DPP4-i), and extra glycemic effects like triglyceride reduction, reduced hepatic fat and reduction in systolic and diastolic blood pressure.

In ADA/EASD 2012 guidelines : guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs

Reference: Timothy Bailey, The American Journal of Medicine (2013) 126, S10-S20 Diabetes CDiabetes Care, Diabetologia. 19 April 2012 are, Diabetologia. 19 April 2012

GLP1 (7-36)agonist

DPP4 inhibition rationale in T2DM treatment

Oral glucoseor mixed

meal GLP1 (9-36)inactive

GLP1actions

>80% of total pool

Intestinal wall

Ahrén et al. Diabetes Care 2003; 26: 2860–2864;Deacon et al. Diabetes 1995;44:1126–1131;

Deacon, Holst. Biochem Biophys Res Commun 2002;294:1–4;Demuth et al. Biochem Biophys Res Commun 2002;296:229–232;

Drucker. Diabetes Care 2003;26:2929–2940

L-cell

DPP4

HGO= Hepatic Glucose OutputAdapted from Unger RH. Metabolism. 1974;23:581.

Insulin

Glucagon

IMPROVED GLYCEMIC CONTROL

Incretin Activity

Prolonged

Improved islet function

DPP-4 Inhibitor

Insulin

Glucagon

HYPERGLYCEMIA

Incretin Response Diminishe

d

Further impaired islet function

T2DM

DPP-4 Inhibition enhances the physiological effects of incretin hormones

Non Glucose dependent action of Sulphonylurea (Sus)

Glucose dependent action of

DPP4 inhibitors (DPP4i)

High risk of hypoglycemia & Beta cell stress/exhaution in Sulphonylurea

Lesser risk of hypoglycemia & Beta cell preservation in DPP4 inhibitors

The Glucose dependent action of DPP4i Vs SUs

Lesser chances of Hypoglycemia & lesser Beta cell stress

DPP4-i addresses the unmet need in the management of diabetes

Adapted from Drucker. Diabetes Care 2003;26:2929–2940

Physiological levels of GLP1 – multiple effects on plasma glucose

• Improves glucose uptake in fat andmuscle tissue

Insulinresistance

• Suppresses glucagon secretion

Inadequate glucagon

suppression (-cell dysfunction)

• Improves insulin secretion

Acuteβ-cell

function

• Increases insulinbiosynthesisa

• Promotes β-cell differentiationa

• Decreases β-cell apoptosisa

Chronicβ-cell

function

aPreclinical data.GLP1=glucagon-like peptide-1.

ED50

Insulincapacity

Glucose Concentration (mmol/L)

Insu

lin S

ecre

tory

Res

pons

e

4.5 5.0 5.5 6.0 6.5 7.0

Glucose sensitivity

Can we increaseinsulin secretion capacity?

Short-term effect

Increasedglucosesensitivity

Glucose-dependent stimulation ofinsulin secretion

No danger ofhypoglycemia

ED50

Insulincapacity

Effect of GLP-1 on Insulin Response to Glucose in Patients with T2DM

ED50=effective dose at 50%; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441;Zander M, et al. Lancet. 2002;359:824–30.

Sustainability of β-cell Function: No sustainability of Glycemic Control with Sulfonylureas

DeFronzo (Diabetes 2009; 58:773-795)

ADA/EASD Algorithm: • As the progressive decline in beta cell function is a key factor limiting long-term glycaemic

control, more consideration should be given to drugs with beta cell-preserving properties

Schernthaner G et al Diabetologia (2010) 53:1258–1269

Sustainability of β-cell Function :Vildagliptin versus glimepiride over 2 years

33

Initial response was defined as a reduction from baseline in HbA1c ≥0.5% or a HbA1c ≤6.5% during the first 6 months of treatment. Sustainability was defined as the time (in days) from initial response (when the patient reached their lowest HbA1c level within the first 6 months), until an increase of >0.3% above that initial response was detected.

Vildagliptin Glimepiride250

260

270

280

290

300

310

320

309

270

Mean Sustainability of Initial Response

(IR) in days

Day

s

Mathews etal, Diabetes, Obesity and Metabolism 12: 780–789, 2010

* * *

0 12 24 52

Time (Week)

* * †

0 12 24 52

Time (Week)

pm

ol/

L 3

0 m

in/(

mm

ol/

L)

0 12 24 52

Time (Week)

* *

mL

· m

in-1 ·

m -2

0.050

0.040

0.045

0.025

0.030

0.035

300

250

275

200

225

14

10

12

6

8

InsulinSecretio

n

Insulin Sensitivit

y

Adaptation

Index

Effects of vildagliptin treatment on -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 / metformin

Placebo / metformin

nm

ol C

-pe

pti

de ·

mm

ol g

luc

os

e-1 ·

m

L-1 ·

m-2

Efficacy as Monotherapy compared to Metformincomparable efficacy at 2 yrs

At 1 yr (52 weeks) At 2 yrs (104 weeks)

Intention-to-treat population.*Non-inferiority end point not met, confidence interval = 0.28–0.65 (non-inferiority margin is defined by confidence interval upper limit of 0.4%).*Not non-inferior; **P <0.001 vs metformin (Fisher’s exact test). Schweizer A, et al. Diabet Med. 2007; 24: 955–961. Göke B, et al. Horm Metab Res. 2008; 40: 892–895.

Rationale for the fixed dose combination of vildagliptin plus metformin used as initial therapy

1. The Mechanistic Rationale –

• Vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect

• Synergistic Effect – Higher intact GLP-1 levels with combination

2. The Clinical Rationale –

• Equivalent or superior HbA1c lowering without the GI tolerability issues associated with higher doses of metformin

• Comparable overall tolerability profile and low risk of hypoglycaemia

3. The Compliance Rationale • Single pill Combination tends to improve patient compliance.

Initial combination of Vildagliptin + MetforminEffective across the hyperglycemia spectrum

37

Preferred term, %

Mono vilda

n=297

Mono met

n=295

Low-dose vilda + met

n=290

High-dose vilda + met

n=292

Diarrhoea 2.4 11 7.2 6.5

Headache 5.4 4.5 6.2 5.5

Nasopharyngitis 3.7 4.8 5.5 7.5

Dizziness 2.7 4.1 4.8 5.1

Nausea 2.4 5.8 4.8 6.5

Pain in extremity 1.7 2.4 3.1 1.4

Upper respiratory tract infection 3.4 2.7 3.1 1.4

Fatigue 2.0 5.1 2.4 2.4

Dyspepsia 1.0 1.7 2.1 3.4

Asthenia 1.3 1.4 1.4 3.1

Cough 2.7 3.1 1.4 1.7

Vomiting 0.3 2.4 1.4 3.1

Back pain 2.0 3.8 1.0 3.8

Hypertension 2.4 3.4 1.0 2.1

Abdominal pain 2.0 3.4 0.7 0.7

Constipation 3.4 1.7 0.7 2.1

High-dose vildagliptin + metformin (50/1000 mg bid); low-dose vildagliptin + metformin (50/500 mg bid).Met=metformin; vilda=vildagliptin. Data on file, Novartis Pharmaceuticals, LMF237A2302.

Initial Combination of Vildagliptin + Metformin:incidence of AEs > in any group

Vildagliptin in combination with insulin

42

40% fewer incidences of hypoglycemia, no severe hypoglycemia

BL=baseline; HbA1c=hemoglobin A1c. *P <0.001; **P <0.05 between groups.Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.

43

Vildagliptin role in hypoglycemia situations – emerging data

43

44

Possible mechanism for low risk of hypoglycemia

Response to meal (−80%)

0

400

600

1000

Response to hypoglycemia (+38%)

200

0

40

60

Placebo

10Glu

cag

on

ΔA

UC

0-12

0 (

ng

/L*m

in)

VildagliptinPlacebo

*

800

20

30

50

Δ g

luca

go

n (

ng

/L)

**

Vildagliptin

Vildagliptin inhibits glucagon at high glucosebut increases glucagon at low glucose

*P=0.025; **P=0.039

Ahrén, et al. J Clin Endocrinol Metab 94:1236, 2009

Vildagliptin has specific role at low glucose

IncreasedGIP levels

Increased glucose sensitivity in islet

α- and β-cells

Potential mechanisms to Mitigate the risk of Hypoglycaemia

Insulin Glucagon

↑ Insulin secretion ↓ Glucagon at high glucose

↑ Glucagon at low glucose

GLP-1

GIP ()

Vildagliptin increases both GLP-1 and GIP and therefore lowers glucose with low risk of hypoglycemia

GLP-1 and GIP: dual effects on islet hormone secretion

Cardio Vascular

Renal

Elderly

Fasting Patients

Vildagliptin – Safety

Odds ratio [95% CI]

p-value

Major CV event1 0.71 [0.59, 0.86] < 0.001

Acute MI 0.64 [0.44, 0.94] 0.023

Stroke 0.77 [0.48, 1.24] 0.29

Mortality 0.60 [0.41, 0.88] 0.008

CV mortality 0.67 [0.39, 1.14] 0.14

Meta-analysis of 70 short- and medium-term trials, with 41,959 patients and mean follow-up of 44.1 weeks

DPP4 inhibitor better

Comparator better

Cardiovascular Safety:In a large meta-analysis of CV events, DPP-4is were better than the comparator in terms of CV safety

AMI, acute myocardial infarction; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitors; MACE, major CV events; MH–OR, Mantel–Haenzel odds ratio.1.Analysis of MACE as serious adverse events supports the safety of DPP4 inhibitors, but does not demonstrate their efficacy in reducing CV risk ion a long-term basis.Monami M, et al. Diabetes Obes Metab. 2013;15:112–120.

0.0 1.0 10.0

53

Cardiac safety: Vildagliptin vs Competition

Monami et al, Diabetes, Obesity and Metabolism 15: 112–120, 2013

Benefit was only significant with Vildagliptin and Saxagliptin

Significant (p=0.005) 39% reduction in MACE with Vildagliptin

SAVOR-TIMIPrimary End-point: Composite of CVD death, MI or ischemic stroke

Secondary end-point: Primary + hospitalisation for unstable angina, coronary revascularization or HF

Scirica BM et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684

16,492 T2DM with CVD or at riskSaxagliptin vs placeboMedian follow-up 2.1 years

More patients on saxagliptin had hospitalisation with HFHR 1.27 (95% CI 1.07 to 1.51)

Placebo + Current therapy

Vildagliptin (50 mg qd2 or bid3) + Current therapy

Run-in Double-blind Treatment

52 weeks2 weeks

Screening Randomization

Stable dose of current therapy1

● This was a multi-center, randomized, double-blind clinical trial to evaluate the safety of vildagliptin versus placebo when given as monotherapy or as add-on therapy to other anti-diabetic drugs for 52 weeks in patients with T2DM and CHF (NYHA class I-III).

Stratification occurred at Visit 2 for baseline CHF status (NYHA class I, II or III) 1Patients remained on their current anti-diabetic therapy (for at least 8 weeks prior to Visit 1 and on a stable dose for at least 4 weeks prior to Visit 1).

2Patients who were taking background sulfonylurea therapy were instructed to take one tablet (vildagliptin 50 mg or vildagliptin 50 mg matching placebo) before the breakfast meal every day.

3Patients who were not taking background sulfonylurea therapy were instructed to take one tablet (vildagliptin 50 mg or vildagliptin 50 mg matching placebo) before breakfast and one tablet before the evening meal every day.

N=128

N=126

CHF, congestive heart failure; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus.

Vildagliptin In Ventricular Dysfunction Diabetes Study

PPS: †p=0.667 (95% CI=-2.21, 3.44); FAS ‡p=0.670 (95% CI=-1.97, 3.06). Indicates non-inferiority to comparator at the 2.5% alpha level. Non-inferiority margin is -3.5. FAS, full analysis set; LVEF, left ventricular ejection fraction; PPS, per protocol set.Study 23118, Novartis Data on file, CSR Table 11-6.

Primary endpoint: Change in LVEF from baseline to Week 52 endpoint

.

VildagliptinPlaceboBetween-treatment difference

Full analysis setPer protocol set

N= 89 90 N= 114 111

*p=0.04, indicates statistical significance at 5% level. #Full analysis set. BL, baseline.Study 23118, Novartis Data on file, CSR Table 11-8.

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

-0.21

0.15

-0.36*

Ad

jus

ted

me

an

(S

E)

ch

an

ge

in H

bA

1c

, %

N = 115 107BL = 7.8 7.8

Strictly Confidential. Proprietary information of Novartis. For internal use ONLY.

Secondary endpoint: Change in HbA1c from baseline to rescue-censored 52 week endpoint#

VildagliptinPlaceboBetween-treatment difference

Similar incidence of SAEs, discontinuations due to AEs, or death for vildagliptin and comparators

n (%)Vilda

50 mg bidN=6116

Total comparators

N=6210

Any AE 4225 (69.1) 4228 (69.0)

Drug-related AEs 961 (15.7) 1349 (21.7)

SAEs 545 (8.9) 557 (9.0)

Discontinuation of study drug due to AEs 347 (5.7) 400 (6.4)

Deaths 24 (0.4) 23 (0.4)

AEs=adverse events; bid=twice daily; PBO=placebo; SAEs= serious adverse events; vilda=vildagliptin.All-study safety (excluding open-label) population.Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version)

Renal safety of Vildagliptin- 1 year dataSignificant HbA1c reduction

• 1 year safety study adding Vildagliptin 50mg od to background therapy in those with moderate or severe renal failure

• Better HbA1c reduction of 0.6% and 0.8% with Vildagliptin in moderate and severe RI respectively

Kothny et al. Diabetes Obesity Metabolism,2012

No deterioration of renal function with vildagliptin

Renal impairment Moderate Severe

eGFR (MDRD) (mL/min/1.73 m2) Vilda 50mg qd

N=163PlaceboN=129

Vilda 50mg qdN=124

PlaceboN=97

Mean Baseline 39.3 40.3 21.9 20.9

Mean Change from baseline 0.865 0.572 -1.456 -1.121

Median Change from baseline -0.068 -0.067 -1.291 -1.872

Estimated *GFR (MDRD) in patients with severe and moderate RI at 24 wks

* eGFR (MDRD)= GFR estimated using the MDRD formula. Baseline eGFR is defined as the lowest of eGFR (MDRD) values before visit 2 that were calculated using the

serum creatinine value before visit 2 and the age at the associated creatinine measurement date

• The overall incidences of AEs, SAEs, discontinuations due to AEs and deaths were comparable between vildagliptin 50 mg qd and placebo

treatment groups

• No statistically significant or clinically relevant differences for events of identified risk observed for vildagliptin

MDRD = Modification of Diet in Renal DiseaseLukashevich et al. Diabetes Obesity Metabolism,2011

Mechanistic basis of Vildagliptin in T2DM patients with renal impairment

Yan –Ling He-Int J Clin Pharmacol Ther. 2013; 51:693–703

Only ~23% of vildagliptin is excreted unchanged by kidney (main excretion mode is hydrolysis to inactive metabolite)

In Mild/Moderate/severe : similar and minimal increase in Cmax

In moderate and severe RI: 1.7~2 fold increase in exposure of vildagliptin(AUC0-24hrs)

Doubling of exposure (AUC) but no expected increased in concentration (Cmax) in Moderate/Severe RI

Effectively with vildagliptin in RI there is,

• Reduced dose frequency, dose strength unchanged, maintained 24-hour DPP4 blockage (50 mg once daily Vildagliptin in

moderate/severe RI = 50 mg twice daily Vildagliptin in normal renal function)

• A1c reductions with 50 mg OD similar to reduction with 50 mg BD with normal renal function

• 50% reduced therapy cost

In patients with moderate-severe RI with vildagliptin,

How does Vildagliptin add value in terms of Renal safety to T2DM patients

Reduce dose frequency by half

65

Summary and Take Home Messages

• Tight glycaemic control should be targeted from the day of diagnosis

• Intensive glycaemic control:

Reduces risk of micro-vascular complications

Some benefit in reducing cardiovascular events

No reductions in mortality

Clinical inertia a major issue in achieving tight targets

DPP-4 inhibitors are an important therapy option as reflected by current guidelines and clinical evidence

• Vildagliptin is efficacious, weight neutral, with a low risk of hypoglycaemia as monotherapy, and in combination with other anti-diabetic agents including metformin.

66

67

Thank You

Basic Succinct Statement - GALVUS®

Presentation: Tablets containing 50 mg of Vildagliptin.

Indications: ♦Galvus is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). It is indicated: as monotherapy, IN COMBINATION: with metformin, when diet, exercise and metformin alone do not result in adequate glycemic control. with a sulphonylurea (SU), when diet, exercise and a SU alone do not result in adequate glycemic control. with a thiazolidinedione (TZD), when diet, exercise and a TZD alone do not result in adequate glycemic control. IN TRIPLE COMBINATION: with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycemic control.

♦Galvus is also indicated in combination with insulin (with or without metformin) when diet, exercise and a stable dose of insulin do not result in adequate glycemic control. ♦Galvus is also indicated as initial combination therapy with metformin in patients with T2DM whose diabetes is not adequately controlled by diet and exercise alone.

Dosage and administration: ♦Adults: The recommended dose is 50 mg or 100 mg daily for monotherapy, and for combination with metformin, with a TZD or with insulin (with or without metformin); 50 mg daily in combination with a SU; 100 mg daily for triple combination with metformin and a SU. Maximum dose is 100 mg/day (in two divided doses of 50 mg).♦Children (under 18 years of age): Not recommended. ♦Special population: In patients with moderate to severe renal impairment or End Stage Renal Disease (ESRD), the recommended dose is 50 mg once daily.

Contraindications: Hypersensitivity to vildagliptin or to any of the excipients.

Warnings and precautions: ♦Galvus should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. ♦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 tests (LFT) to be performed prior to treatment initiation, at three-month intervals during the first year and periodically thereafter. Withdrawal of therapy with Galvus recommended if an increase in AST or ALT of 3X upper limit normal or greater persist. Following withdrawal of treatment with Galvus and LFT normalisation, treatment with Galvus should not be reinitiated. ♦Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive. ♦Not recommended in patients with NYHA Class IV.

Women of child-bearing potential, pregnancy: Should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Breast-feeding: Should not be used.

Special excipients: Contains lactose

Adverse reactions: Rare cases of angioedema. Rare cases of hepatic dysfunction (including hepatitis) ♦Monotherapy - Common: dizziness - Uncommon: headache, constipation, oedema peripheral. ♦Combination with metformin - Common: tremor, dizziness, headache. ♦Combination with a sulphonylurea - Common: tremor, headache, dizziness, asthenia. ♦Combination with a thiazolidinedione - Common: weight increase, oedema peripheral. ♦Combination with insulin - Common: headache, nausea, gastrooesophageal reflux disease, chills, decreased blood glucose – Uncommon: Diarrhoea, flatulence. ♦Combination with metformin and a sulphonylurea - Common: dizziness, tremor, asthesia, hypoglycaemia, hyperhidrosis. ♦Post-marketing experience - Rare: hepatitis (reversible with drug discontinuation) – Unknown: urticaria, pancreatitis, localized exfoliation or blisters.

Interactions: ♦Vildagliptin has a low potential for drug interactions. ♦No clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin.

Packs: Box of 2 strips of 14 tablets each

Note: Before prescribing, please consult full prescribing information available from Novartis Healthcare Private limited, Sandoz House, Dr. Annie Besant Road, Worli, Mumbai- 400 018, Tel: 022 2495 8888

For the use only of a registered medical practitioner or a hospital or a laboratory.

India BSS dtd 27 Jan 2014 based on international BSS dtd 18 Dec 2013

Basic Succinct Statement – GalvusMet®

Presentation: Tablets containing Vildagliptin/Metformin hydrochloride fixed dose combination: 50 mg/500 mg, 50 mg/850 mg, 50 mg/1,000mg.

Indications: ♦Galvus Met is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) whose diabetes is not adequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of vildagliptin and metformin hydrochloride, as separate tablets. ♦Galvus Met is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulphonylurea. ♦Galvus Met is indicated in combination with insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycemic control. ♦ Galvus Met is also indicated for the treatment of Type 2 Diabetes mellitus having HbA1c > 8% where diabetes is not adequately controlled by diet and exercise alone.

Dosage and administration: ♦Do not exceed the maximum recommended daily dose of vildagliptin (100 mg). ♦Should be given with meals. ♦Adults: Starting dose for patients inadequately controlled on vildagliptin or metformin hydrochloride monotherapy: 50 mg/500mg twice daily and gradually titrated after assessing adequacy of therapeutic response. ♦Starting dose for patients switching from combination therapy of vildagliptin plus metformin hydrochloride as separate tablets: 50 mg/500 mg, 50 mg/850 mg or 50 mg/1,000 mg based on the dose of vildagliptin or metformin already being taken. ♦Starting dose for treatment naïve patients: may be initiated at 50 mg/500 mg qd and gradually titrated to a maximum dose of 50 mg/1,000 mg bid after assessing adequacy of therapeutic response. ♦Use in combination with a sulphonylurea or with insulin: the dose of Galvus Met should provide vildagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. ♦Children (under 18 years of age): Not recommended.

Contraindications: Known hypersensitivity to vildagliptin or metformin hydrochloride or to any of the excipients ♦renal disease or renal dysfunction ♦congestive heart failure ♦acute or chronic metabolic acidosis including diabetic ketacidosis with or without coma ♦should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.

Warnings and precautions: ♦Risk of lactic acidosis. ♦Monitoring of renal function. ♦Caution with concomitant use of medications that may affect renal function or metformin hydrochloride disposition. ♦Should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. ♦Discontinue treatment in case of hypoxemia. ♦Temporary discontinuation in patients undergoing surgical procedure. ♦Excessive alcohol intake to be avoided. ♦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 tests (LFT) to be performed prior to treatment initiation, at three-month intervals during the first year and periodically thereafter. Withdrawal of therapy with Galvus Met recommended if an increase in AST or ALT of 3X upper limit normal or greater persist. Following withdrawal of treatment with Galvus Met and LFT normalisation, treatment with Galvus Met should not be reinitiated. ♦Risk of decreased vitamin B12 serum levels. ♦Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. ♦Risk of hypoglycemia. ♦May be temporarily withheld in case of loss of glycemic control. ♦Should only be used in elderly patients with normal renal function. ♦Not recommended in pediatric patients.

Women of child-bearing potential, pregnancy: Should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus.

Breast-feeding: Should not be used during breast-feeding.

Adverse reactions:

♦Vildagliptin: Rare cases of angioedema. Rare cases of hepatic dysfunction (including hepatitis). ♦Vildagliptin monotherapy - Common: dizziness – Uncommon: headache, constipation, oedema peripheral. ♦Metformin monotherapy – Very common: loss of appetite, nausea, vomiting, diarrhoea, abdominal pain. Common: dysgeusia. Very rare: lactic acidosis, hepatitis, skin reactions such as erythema, pruritus and urticarial, decrease of vitamin B12 absorption, liver function test abnormalities. ♦Other effects with combination of Vildagliptin and Metformin - Common: tremor, dizziness, headache. ♦Other effects with combination of Vildagliptin and Metformin with insulin – Common: headache, nausea, gastrooesophageal reflux disease, chills, blood glucose decreased– Uncommon: diarrhoea, flatulence. ♦Other effects with combination of Vildagliptin and Metformin with a sulphonylurea – Common: dizziness, tremor, asthenia, hypoglycemia, hyperhidrosis. ♦Post-marketing experience: - Rare: hepatitis (reversible with drug discontinuation) - Unknown: urticaria, pancreatitis, localized exfoliation or blisters.

Interactions: ♦Interactions with Vildagliptin: low potential for drug interactions, no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin. ♦Interactions with metformin hydrochloride: furosemide, nifedipine, cationic drugs, drugs tending to produce hyperglycemia, alcohol.

Packs: Box containing 6 strips of 10 tablets each

Note: Before prescribing, consult full prescribing information available from Novartis Healthcare Private Limited, Sandoz House, Dr. Annie Besant Road, Worli, Mumbai- 400 018, Tel: 022 2495 8888

For the use only of a registered medical practitioner or a hospital or a laboratory.

India BSS dtd 31 Jan 2014 based on international BSS dtd 18 Dec 2013, effective from 1 Apr 14.

 

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Basic Succinct Statement – GalvusMet®

DisclaimerThe views, opinions, ideas etc expressed therein are solely those of the author. Novartis does not certify the accuracy, completeness, currency of any information and shall not be responsible or in anyway liable for any errors, omissions or inaccuracies in such information. Novartis is not liable to you in any manner whatsoever for any decision made or action or non-action taken by you in reliance upon the information provided. Novartis does not recommend the use of its products in unapproved indications and recommends to refer to complete prescribing information prior to using any of the Novartis products.”

Issued in scientific service to medical professionals

For full product information please write to :

Novartis Healthcare Private Limited,

Sandoz House, 7th floor,

Shivsagar Estate, Dr. Annie Besant Road,

Worli, Mumbai, 400 018, INDIA

ScientificPresentation/Galvus/CVM/279309/Aug/2014I

For use of RMP, hospital or lab only