enrich programme

DPP4 Inhibitors: How early is appropriate?

Diabetics with early vascular risk

Case 1: Case 2:

Newly diagnosed diabetics

Cases from Linagliptin

DCCT / EDIC & UKPDS follow up studies underscore

the fact that good control of diabetes achieved

early in the natural history of diabetes has a long

lasting effect in improving long term outcomes–

“Metabolic memory”/ “Legacy effect”

Why legacy effect?

Initial oral combination therapy in newly diagnosed: can we achieve a good legacy

effect?

Case 1:

Case 1

45 year MaleNewly diagnosed Type 2

Diabetes Mellitus 3 months back., asymptomatic

HbA1C :9.6% , FPG :190mg/dl, PPG :234 mg/dl

Serum creatinine – 1.4mg/dl

eGFR – 70 ml/min

What should be the glycemic target?

ADA Recommends:Lowering HbA1c to <7.0% to reduce the

incidence of micro-vascular disease

Stringent target: 6-6.5% Young patients, high life expectancy, short duration of disease,

no CV events.

Less stringent target: 7.5-8% Elderly, less life expectancy, long duration of disease,

advanced complications, co-morbidities, past history of severe hypoglycemia.

What drug options do we have?

• Pros: Fast A1c reduction• Cons: secondary failure; non-beta cell sparing, risk of hypo and weight gain, ? CV risk

Metformin+ Sulfonylurea

• Pros: Complementary mechanism , low risk of hypo or weight gain; low CV risk

• Cons: Less long term dataMetformin+ Gliptins

• Pros: Complementary mechanism, low risk of hypoglycemia

• Cons: Fluid retention, exacerbation of HF, ? Cancer

Metformin + TZD’s

• Pros : complimentary mechanism, low hypo, weight gain; low CV risk

• Cons: lower efficacy

Metformin + Glucosidase inhibitors

• Pros: Fast A1c reduction• Cons: weight gain, hypo riskEarly insulin

• 45 year Male• Newly diagnosed Type 2


• HbA1C :9.6% , FPG :190mg/dl, PPG :234 mg/dl

• Serum creatinine – 1.4mg/dl

• eGFR – 70 ml/min

Loss of efficacy over years with monotherapy is inevitable in T2DM

HbA1c (%)

Years

IDF Treatment Goal:<6.5%

7.6

7.2

6.8

6.4

00 1 2 3 4 5

-0.13% (P=0.002)

-0.42% (P<0.001)

Glyburide Metformin Rosiglitazone

Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.

Drawbacks of the stepwise approach

Even short periods of hyperglycemia increase risk of complications1–3

A proactive approach is required to get patients to achieve their glycemic goals sooner

Microvascular complications

Myocardial infarctionIn

cide

nce

per

1000

pat

ient

-yea

rs

Updated mean HbA1c (%)

20

40

60

80

5 6 7 8 9 10 110

0

NormalHbA1clevels

1EDIC Group. JAMA 2003; 290:2159–2167. 2EDIC Group. JAMA 2002; 287:2563–2569.3Nathan DM, et al. N Engl J Med 2003; 348:2294–2303.

Gliptin + Metformin: similar efficacy as other commonly used combinations

Metformin+ SUMetformin+ GlitazoneMetformin+ DPP4i

Diabetes Metab J 2013;37:465-474

Korean T2DM patients

Linagliptin and Glimepiride

Variables Linagliptin Glimepiride HbA1CFPG, PPG

PP Glucagon No change

Pro-Insulin(marker of decreasing Beta cell function)PAI-1 (procoagulant & marker of endothelial dysfunction)

Forst T et al. Diabetes Metab Res Rev. 2014 Jan 23. doi: 10.1002/dmrr.2525. [Epub ahead of print]

GLP-1 based therapies improve the conversion of intact pro-insulin into insulin and c-peptide

2014 Forst et al

Met+Gliptin: an ideal initial combination

• Pros: Fast A1c reduction• Cons: secondary failure; non-beta cell sparing,

risk of hypo and weight gain, ? CV riskMetformin+ Sulfonylurea


• Cons: Less long term dataMetformin+ Gliptins



Metformin + TZD’s

• Pros : complementary mechanism, low hypo, weight gain; low CV risk

• Cons: lower efficacyMetformin + Glucosidase

inhibitors


ADA/EASD 2012 guidelines on T2DM management

Oral Glucose Lowering With Linagliptin Plus Metformin is a Viable Initial Treatment

Strategy in Patients With Newly Diagnosed Type 2 Diabetes and Marked Hyperglycemia

The first RCT (double bilnd) in newly diagnosed patients with marked

hyperglycemia

Source: Ross S, et al. American Diabetes Association Congress 2014. Oral 150-OR

ADA 2014 Ross et al

Oral presentation

Why initial combination?

Baseline characteristics

Data are mean ± SD for Source: Ross S, et al. American Diabetes Association Congress 2014. Oral 150-OR.

Linagliptin + metformin

Linagliptin monotherapy +

placeboAge, years 49.0 48.6 Male, n (%) 69 77

Asian 57 64 Diabetes duration <1 year, n (%) 159 (100) 155 (98.7)*

HbA1c, % (mmol/mol)† 9.8 ± 1.2 (83 ± 13) 9.9 ± 1.1 (84 ± 12)Fasting plasma glucose, mg/dL† 196 ± 54 198 ± 61

Body-mass index, kg/m2 29.8 ± 5.8 29.6 ± 5.4Macrovascular disease, n (%) 67 72

Microvascular disease, n (%) 20 18

*Metformin (immediate-release tablet)• Week 1: initiated at 1000 mg/day• Week 2: Up-titrated to 1500 mg/day• Weeks 3–6: Up-titrated to a maximal dose of 2000 mg/day if fasting plasma

glucose was > 110 mg/dL (6.1 mmol/L) and depending on tolerability• Titration conducted under double-blind conditions

HbA1c reductions in both treatment groups were notable

Source: Ross S, et al. American Diabetes Association Congress 2014. Oral 150-OR.

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

6.92%

7.09%

7.67%

7.96%

LINA+ MET LINALINA+ MET

LINA

Adjusted mean change from baseline at Week 24 by baseline HbA1c (PPCC) A

djus

ted

mea

n (S

E) c

hang

e fr

om b

asel

ine

in H

bA1c

(%)

≥ 9.5%

Baseline 9.73% 9.69% 10.46% 10.49%

OVERALL POPULATION HIGHER BASELINE

p < 0.0001

Adjusted mean difference in weight with Lina + Met: –1.31 kg (95% CI: –2.18, –0.44; p=0.0033)

-2.81

% -3.37%

-2.02

%-

2.53%

Change in HbA1c at Week 24 in subgroups


HbA1c reductions occurred consistently across subgroups

Age (years) BMI (kg/m2) Race

< 3535 to < 50

50 to < 65

≥ 65

-5

-4

-3

-2

-1

0

-2.45

-2.97-2.69

-3.53

-2.22-2.25

-1.94

-1.10

-0.23-0.71

-0.75

-2.43

Adj

uste

d m

ean

(SE)

cha

nge

from

bas

elin

e in

HbA

1c (%

)

Linagliptin + metforminLinagliptin

n 12 13 47 35 66 58 7 7 < 2525 to < 30

30 to < 35

≥ 35

-5

-4

-3

-2

-1

0

-3.00 -2.89-2.66

-2.66

-1.99 -1.90 -2.03 -2.24

-1.01-0.99

-0.63-0.42

N 12 28 46 40 31 34 27 21

White Black Asian

-4

-3

-2

-1

0

-2.11

-1.22

-1.96

-0.61-1.05 -1.06

n 83 65 3 4 46 44

Adj

uste

d m

ean

(SE)

cha

nge

from

bas

elin

e in

HbA

1c (%

)

HbA1c over time up to Week 24


HbA1c over time to Week 24 (PPCC, OC)

0 6 12 18 245

6

7

8

9

10 9.73

7.75

7.03 6.93 6.9

Linagliptin + metformin

153 132 131 132 131 132150 113 110 113 112 113

FAS PPCCnn

Mea

n ±

SD

HbA

1c (

%)

Week

Patients reached target

by week 12

FPG reduction starts early and is sustained

Baseline wk2 wk6 wk12 wk18 wk 24140

155

170

185

200

215

198

163 161

196

157

145

Lina + Met 1000

43.4 mg/dl

59.5 mg/dl

Haak T, et al. Diabetes Obes Metab. 2012;14:565-574

Safety of Linagliptin+ metformin versus Metformin

Asymptomatic or symptomatic

Symptomatic PG ≤70 mg/dL

SymptomaticPG <54 mg/dL

Severe0

2.5

5

1.4

0.1 0.0 0.0

2.5

0.80.3 0.2

Linagliptin + metformin (n=1461)Placebo + metformin (n=612)

AEs, adverse events; TS, treated set*AEs by preferred term occurring at rate >1%; All values are %.

Source: Ross SA, et al. ADA 2014. Poster 1071-P.

TS population: all patients who received ≥1 dose of study medication

Linagliptin + metforminn = 1527

Placebo + metforminn = 683

Gastrointestinal disorders Diarrhea Gastritis Nausea

10.23.01.11.4

10.83.20.32.0

The overall incidence of common AEs (occurring in >1% patients) was similar for linagliptin + metformin and placebo + metformin

Patie

nts

(%)

Severity of hypoglycemia

Hypoglycemia

(Pooled data of 5 RCT)

*For clarity, only baseline and end-of-study data points are provided for the 6-month study; detail has been provided for the extension study. Source: Haak Int J Clin Phar 2013

Mean change in HbA1c from baseline of 6-month study* (OC)Percent

Baseline of 6-month study Extension study

begins1.5 yearsPatients

(n)Metformin 1,000 bidTrajenta® 2.5/Metformin 500

bidTrajenta® 2.5/Metformin 1,000 bid

109113111

105113111

102103108

909295

818187

747384

666678

0

-1

-2

-1.25-1.32

-1.63

Metformin 1,000 bidTrajenta® 2.5/Metformin 500 bidTrajenta® 2.5/Metformin 1,000 bid

Durable efficacy - Linagliptin + Metformin

Impact on renal outcomes

von Eynatten M, et. American Society of Nephrology 2012, Poster TH-PO530.

Incidence of renal events*Meta-analysis of 13 studies

~16% reduction in renal events with linagliptin

versus placebo

Placebo LinagliptinRenal events 306 448Time at risk, years

991 1679

Patients, n 1961 3505

Placebo Linagliptin200

250

300

350

308.9

266.8

16%reduction*

Inci

denc

e ra

te p

er 1

000

pati

ent-

year

s HR 0.8495% CI 0.72,

0.97 (p < 0.05)

Renal events included new onset of

microalbuminuria, new onset

of macroalbuminuria, new onset of CKD, worsening of

CKDReduction in renal events was mainly due to

reduction in new onset microalbuminuria

54% significant relative risk reduction in CV events for Trajenta® compared with glimepiride

Source: Gallwitz B, et al. Lancet. 2012;380:475–483

Composite endpoint (patients)1

SUAdd on METN=775

Relative risk3

Trajenta® betterSU better

x

11/21/41/8 2 4 8

Trajenta®Add on MET N= 776

12 26 0.46 [0.23, 0.91]

p-value2

0.02

Note: All events independently adjudicated by CEC, all endpoints prespecified (also for individual studies) from CV meta-analysis statistical plan. Individual events may not add up to total of the composite endpoint, because one patient could have experienced more than one CV event

Overall CV events

No increase in CV risk

Linagliptin improves β-cell survival in isolated human pancreatic islets

Note: Human isolated islets in suspension were exposed for 48 h. ß-cell apoptosis was analyzed by double labelling for the TUNEL assay and insulin. Results are means from 3 independent experiments from 3 donors *p < 0.05 to 5.5 mM glucose alone, **p < 0.05 to vehicle.Source: Shah P, et al.

Lipotoxicity Inflammatory stressPhysiological condition

Oxidative stress

Vehicle

Linagliptin (100 nM)

Insulin (ß-cell marker)TUNEL (marker for apoptosis)

H2O2

Glucotoxicity

Glucose 5.5mM

11.1 mM 33.3 mM Palmitate IL1/IFN H2O2

**

*

*

****

*

**

*

**

*

4

3

2

1

0

5 LinagliptinVehicle

% T

unel

+ß-

cells

Summary: Early Glycemic control Early and durable

– To avoid a vascular legacy of ‘hyperglycemic memory’

Intensive enough, but safely– To minimize complications without causing

hypoglycemic events– And to be practicable without undue imposition

Integrated– Within a comprehensive program to reduce

cardiovascular risk

Gliptin-Metformin initial combination with metformin can be a ideal option for early aggressive therapy specially in Indians

Case 2:

Diabetics with vascular risk in early stage: can we achieve a good legacy effect?

Case 2

47 year MaleNewly diagnosed Type 2


HbA1C :8.2% , FPG :150mg/dl, PPG :200 mg/dl

On metformin since 3 monthsOverweightSerum creatinine – 1.4mg/dlUACR - +eGFR – 70 ml/min

What are the vascular risks?

OverweightDeclining renal function

Serum creatinine – 1.4mg/dl; UACR - +; eGFR – 70 ml/min

Inzucchi et al. Diabetes Care 2012;35:1364–1379

What should be the targets?ADA /EASD 2012 - Glycemic Target HbA1c (%)Most patients <7Individualize goals for patients with short disease duration, long life expectancy, no significant CVD

6-6.5

if this can be achieved without significant hypoglycemia or other adverse effects of treatment

Appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbid conditions and those in whom the target is difficult to attain despite intensive self-management education, repeated counseling, and effective doses of multiple glucose-lowering agents, including insulin

7.5-8%/ >


0

5

10

15

20

25

Metformin onlyn = 513

14.5 months

Length of time between first monotherapy HbA1c > 8.0% and switch/addition to therapy (months)

Brown, JB et al. Diabetes Care. 2004;27:1535–1540.

Mon

ths

HbA

1c >

8.0

%

Delays occur between stepping up from monotherapy to combination therapy

Delay in uptitration or adding second therapy can lead to bad legacy effect

Up-titrating monotherapy to the maximum recommended dose may not

provide benefit

Gastrointestinal side effects

Pati

ents

sto

ppin

g tr

eatm

ent

(%)

0

2

4

6

8

10

500 1000 1500 2000 2500Metformin dosage (mg)

HbA1c

-2.5

-2

-1.5

-1

-0.5

500 1000 1500 2000 2500

Cha

nge

in H

bA1c

fro

m p

lace

bo

(%)

0

Metformin dosage (mg)

Garber AJ, et al. Am J Med 1997; 103:491–497.

Metformin Dose-Response Curve

Riddle M. Combining sulfonylureas and other oral agents. Am J of Med. 2000; 108(6A):15S-22S.

Dose-response curve showing GI related effects

30

20

10

0 500 1000 1500 2000 25000

0.5

1.0

1.5

2.0

Dose

GI D

istr

ess

Patie

nts

(%)

Red

uctio

n vs

. pla

cebo

, HbA

1c (%

)

Metformin

What are the options available for this patient?

Add on DPP4i SU Pioglitazone AGI GLP-1

All of the above as we know may help achieve required goal of < 7% except AGI which may provide lesser A1c reduction than other oral

agents like DPP4 I or GLP or pioglitazone

An ideal add on therapy

• Pros: Fast A1c reduction• Cons: secondary failure; non-beta cell sparing,

risk of hypo and weight gain, ? CV riskSulfonylurea


• Cons: Less long term dataGliptins



TZD’s

• Pros : complementary mechanism, low hypo, weight gain; low CV risk

• Cons: lower efficacyGlucosidase inhibitors


ADA/EASD 2012 guidelines on T2DM management

Efficacy of linagliptin in early stage disease

1. Barnet et al. Lancet. 2013; 382(9902): 1413-23. 2.Taskinen MR, et al. Diabetes, Obesity and Metabolism. 2011; 13: 65–74.

What is role of linagliptin in addressing the vascular risks?

In this case, patient is

OverweightDeclining renal function

Serum creatinine – 1.4mg/dl; UACR - +; eGFR – 70 ml/min


Linagliptin vs. glimepiride: Patients achieving goal (Gallwitz et al ADA 2012)

† Treated Set: linagliptin + metformin n=776; glimepiride + metformin n=775Hypoglycemic episode defined by a blood glucose ≤70 mg/dl (<3.9 mmol/l)* Event requiring assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions (as defined by ADA Workgroup on hypoglycemia. Diabetes Care 2005;28:1245-1249)

Significantly higher number of patients achieving HbA1c target

<7% without hypoglycemia or weight

gain

0

20

40

60

80

100

54.1%

22.9%

Linagliptin+ MET

Glimepiride+ MET

Gallwitz B., et al. ADA 2012

Adjusted2 means for body weight change from baseline ± SE Kg - FAS (OC)

2.0

1.5

1.0

0.5

0

-0.5

-1.0

-1.5

-2.0

GlimepirideLinagliptin+

p<0.0001

28

104weeks

52

78

12

- 2.9 kg

+1.4

-1.5

- 2.9 kg Relative weight loss

Linagliptin+ LinagliptinLMetformin

Linagliptin significantly lowers albuminuria on top of recommended standard treatment for diabetic nephropathy

1. Inclusion criteria: Stable ACE/ARB background; albuminuria 30–3000 mg/g creatinine; GFR > 30.

*MARLINA (1218.89) will aim to demonstrate albuminuria-lowering evidence for linagliptin.

Adjusted mean change in albuminuria(24 weeks)1

24 weeks’ treatmentEffect of linagliptin on albuminuria in humans*

n 55

163

Placebo Linagliptin

Chart Title–4%

–33%

–29%p = 0.0305

95% CI –48%, –3%

Albuminuria: Early marker for renal damage Marker for endothelial

dysfunction Cardiovascular risk factor Lowering of albuminuria might

be associated with kidney and cardiovascular protection

Definitions

Microalbuminuria UACR ≥ 30, < 300 mg/g

creatinine

Macroalbuminuria UACR ≥ 300 mg/g creatinine

–29% in albuminuria versus placeboafter 24 weeks’ treatment

Groop P-H et al: Diabetes 61 (Suppl 1):A243; 2012

The albumin lowering effect demonstrated in the study is based on pooled Phase III trial analysis. Additional long term data from MARLINA and CARMELINA outcome trial are ongoing.

Albuminuria Lowering by Linagliptin is independent of the Improvement in Glucose and blood pressure control

Groop P-H et al: Diabetes 61 (Suppl 1):A243; 2012

• Inhibition of podocyte damage

• Inhibition of myofibroblast transformation

• Increased GLP-1 receptor expression in the kidney

• Similar MA reduction seen irrespective of modest or profound A1c control1

• Additional MA reduction seen after stabilization of BP with ACEI/ARB1

J Hypertens. 2014 Nov;32(11):2211-23; discussion 2223. doi: 10.1097/HJH.0000000000000328.

Inhibition of podocyte damage

The renoprotective effects of linagliptin may be due to:

http://www.ncbi.nlm.nih.gov/pubmed/25215436



Cardiovascular risk is not increased with linagliptinADA 2013 -UPDATED META ANALYSIS in > 9000 patients

1. Primary endpoint, composite of: the occurrence or time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina.

Source: Trajenta® EU summary of product characteristics May 2013;

Incidence rate of primary CV events1

Number and percentage of patients

Series10

5

10

15

20

13.4

18.9 Chart Title

Inci

denc

e ra

te

(per

1,0

00 p

atie

nt-

year

s)

Comparator(pooled active and

placebo comparators)

Linagliptin

5,847 patients

3,612 patients

Hazard ratio 0.78 (95% CI 0.55,1.12)

No significant difference

In a prospective meta-analysis (19 trials, 9459 patients), linagliptin was not associated with an increased cardiovascular risk versus comparators

Source: Johansen O-E, et al. ADA 2013, Abstract 376-OR.

Future trials on CV with Linagliptin

Johansen O-E, et al. 49th Ann Mtg of the European Association for the Study of Diabetes (EASD), Barcelona, 23 - 27 Sep 2013, OP

CAROLINALinagliptin versus SU

on background of Metformin

CARMELINALinagliptin versus

placebo on background of OAD or insulin

Back to the CaseWhat are the other factors to be considered?

CreatinineLiver enzymes

Would there by any change in treatment if patient had higher creatinine levels or elevated liver enzymes?

DPP4 Selectivity and free drug concentrationsConcentration of free circulating DPP-4 inhibitor1

Average daily concentration in nmol

Vildagliptin

> 267

Sitagliptin

219

Saxagliptin*

~10.1

Linagliptin

0.35

1.. Schernthaner, et al. Diabetes Obes Metab. 2012, 2. Graefe Mody et al. BJCP 2012, 3. Graefe Mody DOM 2011, 4. . Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.

*The calculated value for saxagliptin is conservative. Major metabolite of saxagliptin is active and has two- to sevenfold higher plasma exposure than the parent compound.

Selectivity for DPP-4 compared to the DPP gene family

* Quiescent cell proline dipeptidase

Sitagliptin Vildagliptin Saxagliptin LinagliptinDPP4 vs

DPP8>2600 <100 <100 40,000

DPP4 vs DPP9

>5550 <100 <100 >10,000

DPP4 vs DPP2

>5550 >100,000 >50,000 >100,000

“Free drug could potentially cause off-target effects, the low concentration of unbound linagliptin may be a hypothesis for its placebo-like rate of associated adverse events” 1

Linagliptin: One dose (5 mg) across all stages of renal dysfunction including ESRD

Schenthaner. Et al. Diabetes & Vascular Disease Research 2014

Linagliptin: Safety & efficacy across hepatic dysfunction

Hepatic Function

Linagliptin Sitagliptin Saxagliptin

Vildagliptin

Major Metabolism via CYP 450

No No Yes No

Dose reduction with CYP3A4*

No No Yes (2.5 mg)

No

Dose adjustment Same dose in all stages

Not studied in Severe cases

No (US)With Caution in EU label

Contraindicated in all stages and with elevated liver enzymes

Source1)US Prescribing information of all gliptins except EU wherein EU PI was used

as source2) AJ. Scheen Diabetes, Obesity and Metabolism 12: 648–658, 2010 *Linagliptin

USPI

HbA1C reduction up to 0.78% in patients with hepato-biliary dysfunction

Using linagliptin early can prepares the patient for the challenges ahead !

HbA1C reduction• upto 2% as

monotherapy• upto 1.2% in

OAD failure

Studied in RCT in combination with metformin for newly diagnosed T2DM with marked hyperglycemia

>9%

Efficacy across spectrum in newly diagnosed• Age• BMI• Race• Early renal

dysfunction• Ethnicity

Simple Flexible dosing with Long duration of action

No dose adjustment across any disease

Reduction in micro-albuminuria

independent of glucose control

Conserves beta cell function (in vitro human pancreatic

islet cell study)

Linagliptin

Thank you

enrich programme

Health & Medicine