glycaemic)control) start&staywith linaglipn %– · pdf...

Glycaemic Control

SP Chan Visi1ng Professor UMMC Consultant Endocrinologist MBBS (Mal), FRCP (Edinburgh)

Start & Stay with Linaglip0n – Transla0on of Benefits from Monotherapy to

Combina0on with Me=ormin

Early and Intensive approach to T2DM management is needed

At diagnosis of type 2 diabetes:

•  50% of pa1ents already have complica1ons1

•  < 50% of β-‐cell func1on has already been lost2

1. UKPDS Group. Diabetologia. 1991;34:877–890; 2. Holman RR. Diabetes Res Clin Prac. 1998;40:S21–S25; 3. Saydah SH, et al. JAMA. 2004;291:335–342; 4. Liebl A, et al. Diabetologia. 2002;45:S23–S28; 5. Turner RC, et al. JAMA. 1999;281:2005–2012.

Current management:

•  2/3 of pa1ents do not achieve target HbA1c3,4

•  Majority of pa1ents require polypharmacy to meet glycaemic goals across 1me5

Early glycaemic control provides lasBng protecBon:

Legacy effect 10-‐year post-‐trial monitoring : 1997 to 2007 of UKPDS Study*

The legacy effect – a reducBon in complicaBons persists 10 years aIer intensive therapy

Turner RC et al. JAMA. 1999;281:2005-‐2012.

0

25

50

75

100

Patents With

A1C

<7, % 3 Years 6 Years 9 Years

One Drug only – unable to keep glucose controlled

Monotherapy Is Not Durable – UKPDS 49

Treatment failure on monotherapy -‐ lack of treatment durability with SUs

DeFronzo R. Diabetes 2009;58:773-‐795

RaBonale for iniBal combinaBon therapy in T2DM

•  Early robust lowering of HbA1c •  Avoidance of clinical iner1a associated with a stepwise

approach to therapy

•  Ini1a1on of therapeu1c interven1ons with complimentary mechanisms of ac1on

•  Poten1al to use less than maximal doses of individual agents to minimise side effects

•  Poten1al for early combina1on therapy to improve β cell func1on

Zinman B. Am J Med 2011; 124 (1 Suppl): S19-‐S34

RaBonale for use of a DPP-‐4 inhibitor + me]ormin as iniBal combinaBon therapy in type 2 diabetes

" Me]ormin + DPP-‐4 inhibitor have complementary mechanisms of acBon1,2

" Me]ormin improves insulin sensiBvity in liver and muscle & reduces hepaBc glucose output and

" DPP-‐4 inhibitors increase GLP-‐1 levels and thereby sBmulate insulin secreBon and inhibiBon of glucagon secreBon

1. Migoya EM, et al. Clin Pharmacol Ther. 2010;88(6):801–808; 2. Ahrén B. Vasc Health Risk Manag. 2008;4(2):383–394.

Target site Action Metformin DPP-4 inhibitors

Enhances glucose-dependent insulin secretion ü Suppresses glucagon secretion ü Lowers hepatic glucose production ü ü Improves insulin resistance ü

Safety and tolerability

Low risk of hypoglycaemia ü ü No additional weight gain ü ü

PancreaBc β-‐cell

Metformin + DPP-‐4 inhibitors: Combination of oral glucose lowering agents with complementary mechanisms of action

PancreaBc α-‐cell

Drucker DJ, Nauck MA. Lancet. 2006;368:1696–1705. Del Prato S, et al. Int J Clin Pract. 2005; 59:1345–1355. Inzucchi SE. JAMA. 2002;287:360–372.

LinaglipBn treatment effect across treatment regimens Adjusted mean change from baseline HbA1c, placebo-‐corrected

BL HbA1c 8.00

Inter-‐ naBonal1,4

8.1

Me]ormin ineligible2,5

8.07

Japan3,6

8.1

Add-‐on to met1,7

8.6

Add-‐on to SU2,8

8.1

Add-‐on to met + SU1,10

8.7

Met 1,000 mg BID1,12

11.8

OL: met 1,000 mg BID12

8.3

Add-‐on to basal

insulin1,11

8.7

Met 500 mg BID1, 12

-‐3.7 -‐4.0

-‐2.0

-‐1.0

p < 0.0001 for all studies vs baseline, for iniBal combinaBon vs respecBve monotherapy

Mono Dual combi Triple combi IniBal combi therapies Insulin

LinaglipBn: Meaningful efficacy across complete range of AnBdiabeBc therapies

1. 24 weeks’ treatment dura1on; 2. 18 weeks’ treatment dura1on; 3. 12 weeks’ treatment dura1on. Source: 4. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258–267; 5. Barnek AH, et al. Diabetes Obes Metab. 2012 doi: 10.1111/dom.12011; 6. Kawamori R, et al. Diabetes Obes Metab. 2012;14:348–357; 7.Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74; 8. Lewin AJ, et al. Clin Ther. 2012;34:1909–1919.e15; 9. Gomis R, et al. Diabetes Obes Metab. 20111;13:653 – 661 ; 10. Owens DR, et al. Diabe1c Med. 2011;28:1352-‐1361; 11 Yki-‐Järvinen H, et al. Diabetes Care 2013 [submiked]; 12. Haak T, et al. Diabetes Obes Metab. 2012;14:565–575.

Effec0ve Glycaemic Control in Asians – Linaglip0n

Asian T2DM: Pivotal trials included in the pooled efficacy analysis

[1] full analysis set, pivotal trials; data on file. Asian popula1on was defined as all pa1ents of Asian race (as stated by the pa1ent) enrolled in any country (note majority of Asian pa1ents were enrolled in Asian countries of China, Taiwan, Korea, Japan, and India)

Monotherapy: 128.16

Add-‐on to me]ormin: 1218.17

IniBal combo+ piog: 1218.15

Add-‐on to me]ormin + SU : 1218.18

Del Prato S, et al. DOM 2011;13:258-‐67 [NCT00621140].

Taskinen MR, et al. DOM 2011;13:65-‐74 [NCT00601250].

Owens DR, et al. Diabet Med 2011; 28:1352-‐61 [NCT00602472].

Gomis R, et al. DOM 2011;13:653-‐61 [NCT00641043].

Treatment comparison Source

Ini1al combina1on of 30 mg pioglitazone + 5 mg linaglip1n vs pioglitazone + placebo q.d.

5mg q.d. linaglip1n vs placebo

Con1nued metormin ≥1500mg/day plus linaglip1n 5 mg/day or placebo add-‐on

Study group

T2DM pa1ents inadequately controlled on MF and ≤ 1 addi1onal OAD med (discon1nued at screening).

Inadequately controlled T2DM pa1ents (drug-‐naïve or previously treated)

T2DM pa1ents who were drug-‐naive or who had received 1 OAD drug

Con1nued metormin ≥1500mg/day and SU plus linaglip1n 5 mg/day or placebo add-‐on

T2DM pa1ents inadequately controlled by metormin and SU dual therapy

Compared with the overall populaBon, Asian paBents are younger and leaner1

Overall (n=2604)

Asian (n=1029)

Age, years 57.2 (10.0) 54.4 (10.1) Gender, n (%) Male Female

1334 (51.2) 1270 (48.8)

540 (52.5) 489 (47.5)

Body weight, kg 79.1 (16.9) 68.3 (12.7) BMI, kg/m2 29.0 (4.9) 26.1 (4.0) HbA1c, % 8.2 (0.9) 8.2 (0.9) FPG, mg/dL 168 (41) 158 (37) Time since diagnosis, n (%) ≤ 1 year >1 to 5 years >5 years

381 (14.6) 797 (30.6) 1426 (54.8)

181 (17.6) 301 (29.3) 547 (53.2)

Data are mean (SD) or number (%) of pa1ents.; [1] full analysis set, pivotal trials; data on file. Asian popula1on was defined as all pa1ents who self-‐iden1fied as Asian par1cipated in centers based in China, India, Israel, Japan, Republic of Korea, Malaysia, the Philippines, Taiwan, Thailand, and Turkey. Source: Zeng Z, et al. Diabetes Res Clin Pract [manuscript in prepara1on]

Monotherapy Dual combinaBon

Triple combinaBon

1. 24 weeks’ treatment duration; 2. 18 weeks’ treatment duration; 3. 12 weeks’ treatment duration. Source: Del Prato S, et al. Diabetes Obes Metab. 2011;13:258–267 (International); Barnett AH, et al. EASD 2010; Poster 823-P1 (Metformin

ineligible); Kawamori, et al. Diabetes Obes Metab. 2011 [Epub ahead of print] (Japan); Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74 (Add-on to metformin); Lewin, et al. EASD 2010; Poster 821-P (Add-on to SU); Owens DR, et al. Diabetic Med.

2011;28:1352-1361 (Add-on to metformin+SU); Haak T, et al. Diabetes Obes Metab. 2012 Feb 22. doi: 10.1111/j.1463– 1326.2012.01590.x (Initial combined with met); Yki-Järvinen H, et al. accepted for presentation at ADA 999, P-(Add-on to basal insulin).

BL HbA1c

Insulin

8.0

Inter- national1

8.1

Metformin ineligible2

8.0 Japan3

8.1

Add-on to met1

8.6

Add-on to SU2

8.3

Overall1

8.5

Asian patients

p < 0.0001 for all studies vs baseline, for initial combination vs respective monotherapy Open-label (OL) arm (patients with poor glycaemic control at baseline)

Overall1 Korean patients

8.1 8.2

Placebo-‐corrected, adjusted mean change from baseline HbA1c

LinaglipBn treatment effect across treatment regimens

Meaningful efficacy with LinaglipBn – Asian subgroup

Linagliptin 8.3%

Sitagliptin1

8.7% Saxagliptin2

8.7% Elderly3 8.2%

Mod. RI4 8.2%

+ Glargine 8.3%

+ Detemir 8.4%

+ NPH 8.3%

LinaglipBn add-‐on to basal insulin (1218.36) Predefined subgroup analyses (24 weeks)

Phase IIIb studies: add-‐on to insulin (24 weeks)*

Treatment effect of linaglipBn and other DPP-‐4 inhibitors as add-‐on to basal insulin Adjusted mean change from baseline HbA1c, placebo-‐corrected

Incidence of hypoglycaemic events not higher with linaglip1n compared with placebo5

-‐0.7 -‐0.7 -‐0.6

-‐0.7

-‐0.9

-‐0.4 -‐0.6

-‐0.7

all p <0.001 vs placebo n=641 n=455 n=1261 n = 584 n = 221 n = 429

n = 74

n = 124 all p < 0.001 vs placebo

LinaglipBn Efficacy and safety in combinaBon with basal insulin

No head-‐to-‐head comparison

Source: Phase 3 study evaluaBng linaglipBn vs placebo as add-‐on therapy to basal-‐insulin (1218.36). 1. US PI. 2. SmPC. 3. Defined by age > 75 years. 4. Moderate renal impairment (RI) defined by eGFR < 60 and > 30. InvesBgator defined hypoglycaemic events: 21.4% linaglipBn; 22.9% placebo * VildaglipBn is not indicated with insulin (EU); AloglipBn not yet approved in US/EU.

LinaglipBn can be used with no dose adjustment in various paBent populaBons

Source: Linagliptin US prescribing information

No limitaBons

No dose adjustment

HepaBc impairment

Any age group including geriatric

Ethnicity

Long disease duraBon Obese vs lean

Cardiovascular disease

Declining renal funcBon

Fixed Dose Combination of Linagliptin and Metformin

Studies supporting the Fixed Dose Combination of linagliptin and Metformin

–  Bioequivalence studies

–  Efficacy of linagliptin 5 mg qd vs. 2.5 mg bid

–  Initial combination with metformin

–  1-‐year combination with metformin

Linagliptin 2.5 mg bid and 5 mg qd have similar exposure and DPP-‐4 inhibition

Source: Study 1218.45, Data on file.

0 4 8 12 16 20 24 Time (hours)

LinaglipBn 5 mg qd (N = 15) LinaglipBn 2.5 mg bid (N = 15)

0 10 20 30

40 50 60 70 80 90

100 DPP-‐4 inhibiBon %

Parameter (secondary endpoint)

5 mg qd 2.5 mg bid

Eavg0-24,ss 85.3% 85.8%

Comparable DPP-‐4 inhibiBon with 5 mg qd and 2.5 mg bid Treatments with 5 mg qd and 2.5 mg bid are bioequivalent

FDC tablets and the free combination of linagliptin (L) / metformin (M) are bioequivalent

2.5 mg L / 1,000 mg M (Study 1288.1)

LinaglipBn plasma concentraBon nmol/L

2.5 mg L / 850 mg M (Study 1288.3) 5

0 16 32 48 72 Time (hours)

0

1

3

4

8 24 40 56 64

2

Single tablets (N = 94) FDC (N = 96)

0 16 32 48 72 Time (hours)

0

1

2

3

5

8 24 40 56 64

4

2.5 mg L / 500 mg M (Study 1288.2)

0 16 32 48 72 Time (hours)

0

1

3

4

5

8 24 40 56 64

2



No meaningful difference in the exposure of linaglipBn between FDC tablets and the free combinaBon of linaglipBn/me]ormin

Source: Studies 1288.1, 1288.2, 1288.3, Data on file.

FDC tablets and the free combination of linagliptin (L) / metformin (M) are bioequivalent

2.5 mg L / 1,000 mg M (Study 1288.1)

Me]ormin plasma concentraBon ng/mL

2.5 mg L / 850 mg M (Study 1288.3)


2.5 mg L / 500 mg M (Study 1288.2)


Single tablets (N = 95) FDC N = 94)

0 16 32 48 72 Time (hours)

0

500

1,000

1,500

2,000

8 24 40 56 64 0 16 32 48 72 Time (hours)

0

500

1,000

1,500

2,000

8 24 40 56 64 0 16 32 48 72 Time (hours)

0

250

500

1,000

1,250

8 24 40 56 64

750

Source: Studies 1288.1, 1288.2, 1288.3, Data on file.

No meaningful difference in the exposure of me]ormin between FDC tablets and the free combinaBon of linaglipBn/me]ormin

Source: Registered with Clinicaltrials.gov: http://clinicaltrials.gov/ct2/show/NCT01012037 and data on file.

Placebo + me]ormin n = 44

LinaglipBn 5 mg qd + me]ormin n = 224

Placebo run-‐in period (2 weeks)

Assessment of eligibility Excluded: n = 280 Washout of

OAD except me]ormin (4 weeks)

Assessment of eligibility Enrolled: n = 771

Rand

omizaB

on

Treatment duration: 12 weeks

Efficacy and safety of linaglipBn vs placebo in T2DM paBents inadequately controlled with me]ormin

ConBnuaBon of me]ormin therapy

LinaglipBn 2.5 mg bid + me]ormin n = 223

Study design

Treatments with linagliptin 5 mg qd and 2.5 mg bid are equivalent and superior over placebo in HbA1c reduction

1. ANCOVA model includes treatment, continuous baseline HbA1c, and number of prior OADs in addition to background metformin. bNon-‐inferiority in treatment effect is established, as prespecified, based on an upper bound of < 0.35% for the 95% CI of the treatment difference (linagliptin 2.5 mg bid – linagliptin 5 mg qd); *p <0.0001 vs placebo; SE, standard error of the mean.

Source: Rafeiro et al. Diabetologia 2011 Sep;54 Suppl 1:S338-‐339

LIN 2.5 mg bid + MET

Placebo-‐corrected change in HbA1c from baseline to Week 12 Percent

Baseline HbA1c, %

LIN 5 mg qd + MET

Adjusted1 mean (SE) HbA1c change from baseline (%)

7.96 7.98

Treatment difference 0.06 95% CI: -‐0.07, 0.19b

The incidence of hypoglycaemia was low with with linagliptin 5 mg qd and 2.5 mg bid

aConfirmed plasma glucose concentration ≤ 70 mg/dL (3.9 mmol/L). *There were no reported cases of severe hypoglycaemia (event requiring assistance of another person to actively administer carbohydrate, glucagon, or resuscitative actions). Source: Rafeiro et al. Diabetologia 2011 Sep;54 Suppl 1:S338-‐339

LIN 2.5 mg bid + MET

InvesBgator-‐defined hypoglycaemiaa Percent paBents with ≥ 1 event (treated set)

LIN 5 mg bid + MET

PaBe

nts w

ith

≥ 1 even

t (%)

Placebo + MET

3.1* 0.9* 2.3*

PaBents not pretreated with

an oral anBdiabeBc

drug

PaBents pretreated with 1 oral

anBdiabeBc drug

Placebo run-‐in period

(2 weeks)

Assessment of eligibility Excluded: n = 913

N= 791 incl Washout period

(4 weeks)

Assessment of eligibility Enrolled: n = 1,770

Rand

omizaB

on

Open-‐label arm linaglipBn 2.5 mg bid + MF 1,000 mg bid

n = 66

LinaglipBn 2.5 mg bid + MF 500 mg bid

n = 143

Me]ormin 1,000 mg bid n = 147

Me]ormin 500 mg bid n = 144

LinaglipBn 2.5 mg bid + MF 1,000 mg bid

n = 143

LinaglipBn 5 mg qd n = 142

Placebo n = 72

Initial combination with metformin -‐ a Phase III randomized, double blind, placebo-‐controlled study

Treatment duraBon: 24 weeks

Source: Haak T, et al. Diab Obes Metab 2012 Jun;14(6):565-74. doi: 10.1111/j.1463-1326.2012.01590.x.

Study design

Initial combination of linagliptin + metformin: superior to the respective monotherapy arms

LIN, linaglip1n; MET, metormin. *** p < 0.0001, combina1on therapy versus respec1ve monotherapy. 1. Randomized arm: mean (SE); full analysis set, last observa1on carried forward. 2. Open-‐label arm in pa1ents with poor glycaemic control: mean (SE); full analysis set, observed cases (n = 48). Source: Haak T, et al. Diab Obes Metab. 2012;14:565–574.

-‐1.0

-‐1.5

-‐2.0

-‐3.0

-‐3.5

-‐1.3 -‐1.2 -‐0.8 -‐0.6

-‐3.7

0

-‐1.7 -‐0.5

8.7 135

8.7 141

8.5 138

8.7 137

8.7 140

11.8 66

Lina 2.5 BID + Met 1,000 mg

BID

Lina 2.5 BID + Met 1,000 mg

BID Met 1,000 mg

BID Met 500 mg

BID Lina 5 mg QD

Lina 2.5 BID + Met 500 mg

BID

Randomized arm1 (placebo-‐corrected), Week 24 Open-‐label arm2

Baseline HbA1c, % PaBents, n

Chan

ge in HbA

1c from

ba

selin

e, %

***

***

-‐1.0

-‐2.0

-‐3.0

-‐4.0 Both combinaBon regimens were superior to the respecBve me]ormin monotherapy arms

Safety results Open-‐label arm

MET 1,000 mg bid MET 500 mg bid

LIN 5 mg qd

LIN 2.5 bid + MET 500 mg

bid

LIN 2.5 bid + MET 1,000 mg bid

Randomized arm1

LIN 2.5 bid + MET 1,000 mg

bid Placebo

Serious2 AEs, % 1.5 1.4 4.1 2.1 2.1 1.4 1.4

Drug-‐related AEs, %

PaBents, n 66 143 147 144 142 143 72

AEs leading to disconBnuaBon, % 6.1 2.1 4.1 2.1 4.2 3.5 6.9

1. Treated set: all paBents who received at least 1 dose of randomized study medicaBon. 2. Included any untoward medical occurrence that results in 1 of the following outcomes: death, a life-‐threatening adverse drug experience, inpaBent hospitalizaBon or prolongaBon of exisBng hospitalizaBon, a persistent or significant disability/incapacity and a congenital anomaly/birth defect. Source: Haak T, et al. Diab Obes Metab 2012 Jun;14(6):565-‐74. doi: 10.1111/j.1463-‐1326.2012.01590.x.

Overall safety results were similar across treatment groups

≥1 AE, %

9.1 9.1 8.8 9.7 10.6 11.2 13.9

53.0 56.6 50.3 52.1 56.3 49.0 54.2

Safety and tolerability results

1. Treated set: all paBents who received at least 1 dose of randomized study medicaBon. 2. Hypoglycaemic episode defined by a blood glucose ≤70 mg/dL. 3. For paBents with hypoglycemia, number of events requiring the assistance of another person to acBvely administer carbohydrate, glucagon, or other resuscitaBve acBons; percent of all paBents in treated set. Source: Haak T, et al. Diab Obes Metab 2012 Jun;14(6):565-‐74. doi: 10.1111/j.1463-‐1326.2012.01590.x.

Open-‐label arm Randomized

arm1

GI AEs, %

Hypoglycaemia2, % •  Severe hypoglycemia3

PaBents, n

19.7

1.5 0.0

66


bid

19.6

0.0 0.0

143

MET 1,000 mg bid

15.6

3.4 0.7

147

MET 500 mg bid

9.7

1.4 0.0

144

LIN 5 mg qd

12.0

0.0 0.0

142

LIN 2.5 bid + MET 500 mg

bid

14.0

3.5 0.0

143


bid Placebo

13.9

1.4 0.0

72

•  Total number of hypoglycaemic events during combinaBon treatment was low (in total, 5 [1.8%] randomized paBents receiving linaglipBn 2.5 + MET 500 or 1,000

•  Diff in body weight aIer Rx with linaglipBn 2.5 + MET 1,000 vs MET 1,000 was −0.23 kg

1-‐year extension of the initial combination with metformin study

Mean change in HbA1c % from baseline of 6-‐month study* (non-‐switched paBents, OC)

Baseline of 6-‐month study

Extension study begins 1.5 years

PaBents (n) Met 1,000 L2.5/M 500 L2.5/M 1,000

*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 T, et al. AACE 2012 (submiKed).

109 113 111

105 113 111

102 103 108

90 92 95

81 81 87

74 73 84

66 66 78

" DPP 4 inhibitors – IncreBn class minimal risk of hypoglycaemia, weight neutral

" LinaglipBn safe, effecBve, side-‐effects minimal no dose adjustment required – in vulnerable paBents / elderly, renal / hepaBc impairment

" Lina + MF – effecBve combinaBon

Summary – Start & Stay

Start with Lina + MF, Stay with Lina …

Thank You

glycaemic)control) start&staywith linaglipn %– · pdf...

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