Rafael Castillo, MD, FPCP, FPCC PHA Scientific Sessions Crowne Plaza Hotel May 24, 2012.

Cardiovascular Safety of Linagliptin

Rafael Castillo, MD, FPCP, FPCCPHA Scientific Sessions

Crowne Plaza HotelMay 24, 2012

DISCLOSURESReceived during the last 2 years consulting and/or

lecturing fees from Boehringer Ingelheim, Therapharma, AstraZeneca, Abbott, LRI, Otsuka, Sanofi Aventis, Pfizer, GSK and Takeda

Received during the last 2 years research grants from Boehringer Ingelheim, Novartis Philippines Inc., Unilab, Therapharma

Owns stocks in some pharmaceutical and diagnostics/devices companies, and a medical publishing company

THE INCRETIN EFFECT

* Adapted om Nauck M et al Diabetologia 1986;29:46–52. fr

Healthy controls Type 2 diabetes

Diminishedincretin effect

Normal incretin effect

Time (minutes)

0

40

60

80

IR i

nsu

lin

(m

U/L

)

20

Time (minutes)

0

40

60

80

IR i

nsu

lin

(m

U/L

)

20

–10 60 120 180–5 –10 60 120 180–5

** * * *

**

* **

DPP4 Therapy

The incretins GLP-1 and GIP mediate glucose-stimulated insulin release

Drucker DJ. Expert Opin Invest Drugs. 2003; 12(1): 87-100.Ahrén B. Curr Diab Rep. 2003; 3: 365–372.

GLP-1=Glucagon-like peptide-1, secreted from L-cells in the distal gut; GIP=glucose-dependent insulinotropic peptide, secreted from K-cells in the proximal gut.

Intestine

Pancreas

Glucose-dependent

insulin secretion

Increases glucose utilizationby muscle and adipose

Decreases hepatic glucose release

Glucose-dependent glucagon suppression

β-cells

α-cells

Glucose homeostasis

Food intake

Active GLP-1 (7-36)Active GIP

Effects of GLP-1 on the β Cell in Healthy Subjects

Postprandial

Insulin release

GLP-1 Is Cleaved and Inactivated by DPP-4

DPP-4 inhibitors: mechanism of action

Data from Drucker DJ. Expert Opin Invest Drugs. 2003; 12(1): 87–100.Ahrén B. Curr Diab Rep. 2003; 3: 365–372.

Intestine

Food intake

Active GLP-1

(7–36)DPP-4

Inactive GLP-1

(9–36) amideHis-Ala

cleaved fromamino terminus

PancreasInsulin secretion

Increases glucose utilizationby muscle and adipose

Decreased hepatic glucose release improves overall glucose control

Glucagon suppression

β-cells

α-cells

DPP-4inhibitors

Linagliptin inactivates the action of the DPP-4 serine protease

DPP-4i DPP-4i

X X

Linagliptin clinical profile

Convenience

Safety & Tolerability

No dose adjustment in renal or hepatic impairment

Efficacy

Meaningful and reliable efficacy across complete range of oral diabetes therapies

Sustained efficacy in longer term treatment up to 2 years

Overall safety profile similar to placebo:• No clinically relevant weight

gain• Very low risk of

hypoglycemiaMost common adverse reaction1: nasopharyngitis

Not associated with an increase in CV risk

One dose fits all*Primarily excreted

via bile & gutRenal excretion =

5%Once-daily

With or without food

Linagliptin

Cardiovascular risk with linagliptin in patients with type 2 diabetes: A pre-specified, prospective, and adjudicated meta-analysis from a large phase 3 program

Johansen O-E., et al. ADA 2011 Late breaker 30-LB

Linagliptin CV meta-analysis

Linagliptin CV meta-analysis: Setting and methodology

Study Description Duration Treatments Treated patients

NCT00641043 Efficacy and safety vs. placebo as add-on to pioglitazone 24 weeks ▪ Linagliptin 5 mg▪ Placebo

259130

NCT00621140 Efficacy and safety vs. placebo as monotherapy 24 weeks ▪ Linagliptin 5 mg▪ Placebo

336167

NCT00601250 Efficacy and safety vs. placebo as add-on to metformin 24 weeks ▪ Linagliptin 5 mg▪ Placebo

523177

NCT00602472Efficacy and safety vs. placebo as add-on to metformin + SU 24 weeks

▪ Linagliptin 5 mg▪ Placebo

792263

NCT00622284 Efficacy and safety vs. glimepiride as add-on to metformin 52 WeeksInterim results

▪ Linagliptin 5 mg▪ Glimepiride 1 - 4 mg

778781

NCT00654381 Efficacy and safety vs. placebo and voglibose as monotherapy (In Japanese subjects)

26 weeks of controlled treatment

▪ Linagliptin 5 mg▪ Linagliptin 10 mg▪ Voglibose 0.6 mg▪ Placebo

15916016280

NCT00819091 Efficacy and safety vs. placebo as add-on to SU 18 weeks▪ Linagliptin 5 mg▪ Placebo

16184

NCT00740051Efficacy and safety vs. placebo where metformin therapy is inappropriate (placebo patients are switched to glimepiride after primary endpoint at 18 wks)

18 weeks interim results

▪ Linagliptin 5 mg▪ Placebo/Glimepiride

1 - 4 mg

15176


• CV events were adjudicated by an independent committee

• Composite primary endpoint was the occurrence, or time to first occurrence, of: CV death (including fatal myocardial infarction and fatal stroke); Non-fatal myocardial infarction; Non-fatal stroke; Hospitalization for unstable angina pectoris

CV risk of linagliptin was assessed in a prospective, pre-specified meta-analysis on the following 8 phase III double-blind randomized controlled trials

Linagliptin CV meta-analysis: Existing morbidity and CV risk

characteristics at baselineLinagliptin (n = 3319)

Placebo(n = 977)

Active Comparator

(n = 943)

Total Comparator(n = 1920)

CV risk factors (%)

• Metabolic syndrome 60.3 55.9 67.8 61.7

• Previous coronary artery disease 10.4 10.1 11.9 11.0

• Previous cerebrovascular disease 2.9 3.6 4.1 3.9

• Previous peripheral artery disease 2.3 2.7 3.3 3.0

• Hypertension 63.8 60.2 72.1 66.0

• Ex-/current smoker 22.6/14.4 19.1/16.1 29.5/15.7 24.2/15.9

eGFR (based on MDRD),%

• Normal 55.4 58.3 52.3 55.4

• Mildly impaired 37.3 34.9 41.4 38.1

• Moderately impaired 4.3 4.5 4.1 4.3

• Severely impaired 0.1 0.1 0.0 0.1

Framingham 10 year CV risk score

• Framingham risk score (%) 9.8 ±8.2 9.1 ±8.1 11.6 ±8.6 10.3 ±8.4

• Framingham risk > 15% (%) 27.8 24.7 37.8 31.1


Linagliptin CV meta-analysis CV treatment regimens at baseline

Linagliptin (n = 3319)

Placebo(n = 977)

Active Comparator

(n = 943)

Total Comparator(n = 1920)

Acetylsalicylic acid (aspirin) (%) 29.5 28.8 32.2 30.5

Anti-hypertension therapy* (%) 60.0 56.4 69.8 63.0

Lipid lowering therapy (%) 39.5 36.5 47.9 42.1

Any of the above therapies (%) 72.8 69.7 81.5 75.5

Johansen O-E., et al. ADA 2011 Late breaker 30-LB; Linagliptin data on file

Breakdown: Use of anti-hypertension treatments at baseline (%)

Linagliptin Placebo Active Comparator Total Comparator

Beta-blockers 32.7 31.8 34.3 33.2

ACE inhibitors 44.8 45.6 34.3 43.5

ARBs 22.0 21.8 21.0 21.9

Diuretics 22.9 23.3 41.3 22.0

Others 46.9 64.0 77.7 49.6

* included beta-blockers, ACE inhibitors, ARBs, diuretics and others antihypertensive agents

In a prospective, pre-specified meta-analysis, linagliptin was not associated with an increased CV risk

Incidence rate of CV events1

Number and percentage of patients

Out of 3,319 patients= 0.3%

1. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 voglibose

Comparator2

Linagliptin

Out of 1,920 patients= 1.2%

Risk ratio0.34 95% CI(0.15/0.74) p<0.05


Years of exposure 2,060 1,372

In a prospective, pre-specified meta-analysis, linagliptin was not associated with an increased CV risk

*Individual components are tertiary endpoints


21

6

2 23

7

11

0

2

4

6

8

10

12

CV deathHospitalization due to

unstable angina

Non-fatal MI

Non-fatal stroke

Total comparators n = 1,920

Linagliptin n = 3,319

Individual components of composite primary endpoint*N

um

ber

of

eve

nts

95% CI

0.11

Hazard ratio 0.52

0.740.240.02/0.51 0.17/1.54 0.10/5.330.02/2.34

Linagliptin CV meta-analysis: Incidence for secondary composite CV endpointsIncidence rate per 1,000 patient-years

FDA custom MACE

All major CV events

CV death/MI/stroke

Linagliptin

Total comparators

CV events

Exposure, years

Patient

20

1,372

1,920

10

2,060

3,319

32

1,372

1,920

26

2,060

3,319

19

1,372

1,920

9

2,060

3,319


95% CI 0.36Hazard

ratio0.56 0.34

0.17/0.78 0.33/0.94 0.15/0.75

Safety observations so far are promising, therefore all DPP-4 compounds are currently involved in outcome studies

Risk ratio for major CV events1-5

1. Johansen O-E., et al. ADA 2011 Late breaker 30-LB; 2. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7. 3. Schweizer A, et al. Diabetes Obes Metab. 2010;12(6):485–494; 4. Frederich R, et al. Postgrad Med. 2010;122(3):16–27;5. White et al. 2010, ADA Scientific Sessions. Abstract 391-PP

Total patients in

analysis

5,239

10,246

10,988

4,607

3,489

Primaryendpoint

CV death, MI, stroke,hospitalisation due to angina pectoris

Med DRA termsfor MACE

Acute coronary syndrome, transient ischaemic attack, stroke, CV deathMI, stroke, CV death

Non-fatal MI, non-fatalstroke, CV death

Comments

Pre-specified/independent adjudication

No formal adjudication;Post-hoc analysis

Pre-specified/Independent adjudication



DPP-4 inhibitor better Comparator better

11/21/41/8 2 4 8

Linagliptin1

Sitagliptin2

Vildagliptin3

Saxagliptin4

Alogliptin5

0.34

0.68

0.84

0.42

0.63

0.15 0.74

0.41 1.12

0.62 1.14

0.23 0.80

0.21 1.19

No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors

Linagliptin CV Meta-analysis: Study summary

▪ This pre-specified, prospective, and independently adjudicated CV meta-analysis of a large Phase III program provides new insight on the CV safety profile of linagliptin

▪ Although a meta-analysis, with distinct limitations, the data support a potential reduction of CV events with linagliptin compared with pooled comparators

▪ This hypothesis is being tested prospectively in CAROLINA, a large CV outcomes trial of linagliptin that is currently ongoing1,2

Source: Johansen O-E., et al. ADA 2011 Late breaker 30-LB

CV risk of linagliptin was assessed in a prospective, pre-specified meta-analysis on the 8 phase III double-blind randomized controlled trials

1. Rosenstock J., et al. ADA 2011 Poster 1103-P2. Clinicaltrials.gov - NCT01243424

CAROLINA:Cardiovascular safety of Linagliptin or glimepiride in subjects with type 2 diabetes mellitus at high CV risk

Clinical characteristics and associated increased cardiovascular risk in type 2 diabetes mellitus

Rosenstock J., et al. ADA 2011 Poster 1103-PClinicaltrial.gov NCT01243424

Diabetes therapy algorithm and target patients for CAROLINA1,2

Target patients

for CAROLINA

ADA/EASD type 2 diabetes consensus algorithm for the initiation and adjustment of therapy. Diabetologia 2009;52:17–30 (modified)

TZDs or GLP-1 agonistAdd or intensify insulin

SU (2nd generation preferred) or basal

insulinLifestyle interventions/metformin

Consider other

agents or insulin therapy

Step 1

Step 2

Step 3

Tier 1

Tier 2

Therapy algorithm

CAROLINA1,2 compares Linagliptin with the current gold-standard as recommended by ADA and EASD

1. Rosenstock J., et al. ADA 2011 Poster 1103-P2. Clinicaltrial.gov NCT01243424

With or without metformin background therapy (including patients with contraindication to Metformin use in renal

impairment)

n= 6,000; approx. 6-7 year follow up

Inclusion if at least one of the following is fulfilled

1. Previous vascular complications

2. Evidence of end organ damage such as e.g. albuminuria

3. Age > 70 years

4. Two or more specified traditional CV risk factors

Primary endpoint: Time to the first occurrence of the primary composite endpoint:

1. CV death (including fatal stroke and fatal MI) 2. Non-fatal MI

3. Non-fatal stroke4. Hospitalization for unstable angina pectoris

Glimepiride 1-4mg1Linagliptin 5mg vs.

1 16 weeks titration phase of glimepiride up to 4mg/day

CAROLINA will evaluate CV safety of Linagliptin in patients with T2DM at high CV risk


CAROLINA: Main inclusion criteria

1 A) MDRD defined moderate renal impairment: eGFR 30-59 mL/min/1.73 m2, B) Random spot urinary albumin:creatinine ratio ≥ 30 μg/mg in two of three unrelated specimens in previous 12 months prior Visit 1a, C) Retinopathy

• Insufficient glycemic control (HbA1c 6.5% - 7.5% / 6.5% - 8.5% depending on medication)

• High risk of CV events defined as any one (or more) of the following:

A. Previous CV diagnosis or manifestation

B. Evidence of vascular related end-organ damage1

C. Age ≥ 70 years

D. At least two of the following CV risk factors:– T2DM > 10 years– Systolic blood pressure > 140 mmHg (or on at least one blood pressure

lowering treatment)– Current daily cigarette smoking– LDL cholesterol ≥ 135 mg/dL (3.5 mmol/L) or on specific current

treatment for lipid abnormality

• Body Mass Index ≤ 45 kg/m2

• Age ≥ 40 and ≤ 85 years


CAROLINA1 TECOS2 SAVOR-TIMI533 EXAMINE4

DPP-4 inhibitor Linagliptin Sitagliptin Saxagliptin Alogliptin

Comparator SU (Active) Placebo Placebo Placebo

Number of patients 6,000 14,000 16,500 5,400

Trial initiation Oct 2010 Nov 2008 May 2010 Sept 2009

Background diabetes therapy per protocol

Predominantly on metformin Any Any Any

Expected diabetes disease stage

Early Advanced Advanced All, but limited to CV events

CAROLINA has a truly unique trial design

PRIMARY ENDPOINTS:1,2,4 CV death, non-fatal MI, non-fatal stroke, hospitalization due to unstable angina

pectoris3 Major Adverse Cardiovascular Events (CV death, non-fatal MI, non-fatal stroke)ClinicalTrials Identifiers: 1. NCT01243424, 2. NCT00790205, 3. NCT01107886, 4. NCT00968708

Summary:

Linagliptin is a novel DPP4 inhibitor that gives meaningful and sustained HbA1c reductions.

It is the only DPP4 inhibitor that is excreted mainly through the bile and gut – providing care to the kidneys of patients with type 2 DM.

Meta-analysis on 8 Phase III clinical trials showed potential reductions of CV events – this hypothesis is being tested presently with the CAROLINA study.

Rafael Castillo, MD, FPCP, FPCC PHA Scientific Sessions Crowne Plaza Hotel May 24, 2012.

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Transcript of Rafael Castillo, MD, FPCP, FPCC PHA Scientific Sessions Crowne Plaza Hotel May 24, 2012.