DR. SUBHASH K. WANGNOO M.D, D.M, FRCP (London)

•Established and currently heading the Apollo Centre for

Obesity, Diabetes and Endocrinology (ACODE)

•Has numerous publications in International and National

journals of repute, is on various Advisory boards and Guideline

forming bodies

•Actively involved in teaching and training of DNB

Endocrinology students for last 8 years, the only amongst the

Apollo group of hospitals having DNB Endocrinology program

Senior Consultant, Endocrinologist & Diabetologist

Apollo Centre for Obesity, Diabetes and Endocrinology

Indraprastha Apollo Hospital, Sarita Vihar, Delhi

Photograph

Incretin Based Therapy-

Now and Down the Road

Subhash Kumar Wangnoo MD, DM, FRCP (London)

Apollo Centre for Obesity, Diabetes and Endocrinology (ACODE)

Indraprastha Apollo Hospital

New Delhi

Incretin Based Therapy

Current Understanding

Medical Clinics 2015;99:107-129

GLP-1 receptor agonists

• Pharmacological levels of GLP-1

• Not limited by endogenous

secretion

• Greater efficacy

HbA1c reduction (0.6 – 1.9%)

• Weight loss (3-5 kg)

• Virtually no hypoglycemia

• GI side effects

• Injection

DPP-4 inhibitors

• GLP-1 in physiological range

• Limited by endogenous

secretion

• Moderate efficacy

HbA1c reduction (0.5 – 1 %)

• Weight neutral

• Virtually no hypoglycemia

• Well tolerated

• Oral

What is known about GLP-1 receptor agonists and DPP-4 inhibitors

Year 2015

• Complimentary to other OADs and insulins

• As of yet no specific cardiovascular, pancreatic or malignancy signals

GLP-1 analogs. Cochrane Database 2013

DPP-IV inhibitors. Cochrane Database 2013

Incretin Based Therapies

Exenatide

approval

Sitagliptin

approval

Vildagliptin

(+metformin)

approval*

Saxagliptin

approval*

*EMA

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Linagliptin

approval

Alogliptin

approval

(Japan)

Teneligliptin

approval

(DCGI)

Liraglutide

approval Exenatide

(Extended

Release)

approval

Albiglutide

approval

2016-

Dulaglutide

approval

Lixisenatide

approval*

Incretin Based Therapies Approved In India

GLP-1 receptor agonists

Exenatide

Liraglutide

DPP IV inhibitors

Sitagliptin

Vildagliptin

Saxagliptin

Linagliptin

Teneligliptin

GLP-1 receptor agonists increase GLP-1 concentrations 8-10 fold

DPP IV inhibitors increase GLP-1 concentrations 2-3 fold

GLP-1 receptor agonists DPP-4 inhibitors

Exenatide BID

Liraglutide

Exenatide OW

Lixisenatide

Albiglutide

Dulaglutide

Sitagliptin

Vildagliptin

Saxagliptin

Linagliptin

Alogliptin (Japan)

Teneligliptin (Japan & India)

Gemigliptin (Korea)

GLP-1 Receptor Agonists And DPP-4 Inhibitors:

Worldwide

Are GLP-1 Analogues different?

Structurally – YES

Functionally – Not So!

All are

suffering from

Me-too syndrome

What about DPP IV inhibitors?

The answer is still the same!

Structurally – YES

Functionally – Not So!

We need to live by the fact that comparative data will be limited to begin with

when a new drug hits the market !!

“Head-to Head data are often too limited to allow a firm

conclusion about comparative effectiveness”

Safety Issues • C- cell

– No evidence to support the concern that GLP-1 agonists increase the risk of C-cell cancer development in humans

– Contraindicated in patients with personal or family history of medullary carcinoma and multiple endocrine neoplasia type 2

• Pancreatitis – Several large claims database studies have found no association between pancreatitis and exenatide

and sitagliptin use in >1,000,000 patients

• Immunogenicity – No bearing on clinical response or outcomes

• Renal Parameters – Appropriate dose adjustments depending upon the class used

• CVD – Available data encouraging

– CAROLINA (phase 3), EXAMINE, SAVOR-TIMI, TECOS – data re-assuring

– Ongoing trials – EXCEL, LEADER, CAROLINA, AWARD, HARMONY

– will give us the rosy picture (hopefully?) by 2018

FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain (September 2015)

Garg et al. Diabetes Care 2010 Pendergrass et al. Diabetes 2010 Dore et al. Curr Med Res Opin 2009

Wenten et al. Diabetes 2010 Dore et al. Diabetes Obes Metab 2011 Romley et al. Diab Techn Ther 2012

Bjerre K et al. Endocrinology 2010 Buse et al JCEM 2011 Nauck: Diabetes Care 2013

NEJM 2013 NEJM 2015

CV Trials GLP-1 RA

DPP 4

Inhibitors

Completed

Incretin Based Therapies: Position in Diabetes Management Algorithms

Type 2 Diabetes Management Algorithm: An Update to ADA/ EASD Position Statement

Diabetes Care 2015;38:140-149

AACE Diabetes Management Algorithm

Incretin Based Therapy-

Down the Road

Need of the Hour

• Cost Issues

• Once weekly therapy

• Alternative routes of administration eg. Oral

• Fixed dose combinations with basal insulin

• Better tolerability

Lixisenatide (once daily)

• September 2015: Accepted for review by FDA

FIX-FLEX DEVICE FOR JOINT ADMINISTRATION OF LIXISENATIDE+ LANTUS

• Phase 3 trials completed recently

Albiglutide

FDA approved April 2014

• t1/2: 6 – 8 days

• Once a week GLP-1 analog

Dulaglutide

EASD 2013

• t1/2 ~4 days

• Once a week

FDA Approved September 2014

Semaglutide

• T ½: 160 hrs

• Once a week GLP-1 analog

• Phase 3 trials

Langlenatide (HM11260C)

EASD 2013

t1/2 150h

Once a week

GLP-1 Agonist/Basal Insulin Fixed-dose Combinations

CURRENT STATUS:

1. Liraglutide + Degludec

• Approved in Europe 2014

• FDA approval pending

2. Lixisenatide + Glargine

• Submitted for FDA approval

TGR5 agonist – Oral GLP-1 GPCR119 – Oral GLP-1

In pipeline: Oral Exenatide

In pipeline: Oral Semaglutide

Oral Semaglutide

• Once daily

• Doses of 3 mg, 7 mg and 14 mg

• Phase 3 trials (PIONEER) to begin in 2016

Addressing Unmet Needs via GLP-1 Based

Multifunctional Peptides

Other Novel approaches

VRS-859

(Peptides coupled to

biological polymers–Xtenylation )

Xten is genetically fused

to exenatide

t1/2 150h

Once a month

Phase 1 trials

GLP-1/glucagon

co-agonists

ZP2929

TT401

t1/2 ?

Once a month

GLP-1/GIP co-

agonists

Mar701

MAR709

Phase 1

Hamilton, B.; Herring, C.; Paulik, M. WO 2011/039096, 2011.

GLP-1/PYY

Combination

Phase 1 trial

http://www.diartispharma.com/content/newsandevents/releases/100212.htm

Habegger et al. Diabetes 2013, 62, 1453.

NCT01676584 NLM Identifier: NCT01676584.

Newer Gliptins on the Horizon

• Trelagliptin

– Once weekly oral DPP 4 inhibitor

– Approved in Japan, March 2015

• Omarigliptin

– Once weekly oral DPP 4 inhibitor

– Approved in Japan, September 2015

• Dutogliptin

– Phase 3 studies done

That`s all Folks

till we discover

something new!