Incretins: Expanding Role in Treatment Strategies Pediatric Type 1 Diabetics (n=8) Insulin dose...

Incretins:Expanding Role in Treatment Strategies

Pediatric Type 1 Diabetics (n=8)

Insulin dose reduced 20%with exenatide dosing – mixed meal

Incretins (DPP-IV inhibitors):Special Populations: Geriatrics

Pharmacology Recommendations•Metformin – still first line for most

• Less effective in many• GFR - <30 – no, 30-50 reduce dose

•Glyburide – never•DPP-IV inhibitors - recommended

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS•Comorbidities

-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone & CVD events ? Effects of incretin-based

therapies


therapies

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Stomach

Islet

GI Tract

Brain

HypothalmusHind Brain

Peptide Therapeutics:Incretins (GLP-1 and GIP)

Visceral Fat Cell

Vagal Afferents

LeptinLeptin

AmylinAmylin

InsulinInsulinGLP-1GLP-1

GlicentinGlicentinOxyntomodulinOxyntomodulin

GhrelinGhrelin

GIPGIP

AdiponectinAdiponectin

VisfatinVisfatin

ResistinResistin

GlucagonGlucagon

CCKCCK

Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914

PYY3-36PYY3-36

Cardiovascular

IncretinsExenatide – Bydureon, Byetta

Liraglutide - Victoza

DPP-IV InhibitorsSitagliptin – Januvia

Linagliptin – TradjentaSaxagliptin - Onglyza

IncretinsExenatide – Bydureon, Byetta

Liraglutide - Victoza

DPP-IV InhibitorsSitagliptin – Januvia

Linagliptin – TradjentaSaxagliptin - Onglyza

Cardiovascular Outcome TrialsTECOS - sitagliptin

EXSCEL – weekly exenatideLEADER – liraglutideELIXA – lixisenitideSAVOR - saxagliptin

ACCORD:Mortality Hazard Ratios for Post-Randomization Prescription of Glycemia Medications

Adjusted for Baseline Participant CharacteristicsACCORD Study Group. Presented at the ADA Scientific Sessions, San Francisco, June 2008

RR

Peptide Therapeutics:Incretins (GLP-1 and GIP)

Exenatide vs. Non-Exenatide – Cardiovascular Events



-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia


therapies


therapies


Glyburide (and older) – Should never be usedGlimepiride or Glipizide if any SU



-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia Emerging concerns regarding

association with increased mortality

Proper drug selection in the hypoglycemia prone

Emerging concerns regarding association with increased mortality

Proper drug selection in the hypoglycemia prone


Adapted Recommendations: When Goal is to Avoid Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

T2DM– Treatment Strategies

Islet -cell

ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion

NeurotransmitterNeurotransmitterDysfunctionDysfunction

Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake

Islet -cell

IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion

IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis

Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption

IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP

DecreasedDecreasedIncretin EffectIncretin Effect


TZDs

TZDs

TZDs

TZDsTZDs

TZDs

Slide Source:Lipids Online Slide Librarywww.lipidsonline.org

Time to Fatal/Nonfatal MI(Excluding Silent MI)

Kapla

n-M

eie

r E

ven

t R

ate

Prespecified AnalysisPrespecified Analysis

0 6 12 18 24 30 36

Time from Randomization (Months)

Time to Acute Coronary Syndrome

Kapla

n-M

eie

r E

ven

t R

ate

Post Hoc Exploratory AnalysisPost Hoc Exploratory Analysis

0 6 12 18 24 30 36

Time from Randomization (Months)

––28%28% ––37%37%

Reprinted with permission from Erdmann E et al. J Am Coll Cardiol. 2007;49:1772-1780.Copyright © 2007 American College of Cardiology Foundation. All rights reserved.

Pioglitazone (65/1230)Placebo (88/1215)

Pioglitazone (35/1230)Placebo (54/1215)

PROactive: Pioglitazone Reduced PROactive: Pioglitazone Reduced ““HardHard”” Coronary Heart Disease EndpointsCoronary Heart Disease Endpoints

Pioglitazone vs Placebo:Pioglitazone vs Placebo:HR 0.72 (95% CI 0.52HR 0.72 (95% CI 0.52––0.99); 0.99);

p=0.045p=0.045

Pioglitazone vs Placebo:Pioglitazone vs Placebo:HR 0.63 (95% CI 0.41HR 0.63 (95% CI 0.41––0.97); 0.97);

p=0.035p=0.035

Type 2 Diabetes: Benefits vs Risks of TZDs

Type 2 Diabetes: Benefits vs Risks of TZDs

But????Actos causes Bladder Cancer!!!...Right?

T2DM Anti-hyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

The Ominous Octet – Treatment StrategiesThe Ominous Octet – Treatment Strategies

Islet -cell




Islet -cell







Insulin

Insulin

Insulin

InsulinInsulin

Insulin

New Basal Insulins: insulin degludec molecular structure

DesB30 LysB29(Nε-γ-glu-hexadecandioyl) human insulin

Degludec

(Tresiba)

s

s

s

FF VV NN QQ HH LL CC GG SS HH LL VV EE AA LL YY LL VV CC GG EE RR GG FF FF YY TT PP

GG II VV EE QQ CC TT SS II CC SS LL YY QQ LL EE NN YY CC NNCC

s

s s

A chain

B chainKK

NH

O

OH

O NH

O

OH

OHexadecandioyl

L-g-Glu

desB30 Insulin

TT

Multi-hexamer formation after injection

Insulin degludec in pen

Long multi-hexamer chains assemble

[ Phenol; Zn2+]

Injection site

Jonassen I et al. Diabetes. 2010;59(suppl 1):A11

Insulin degludec multi-hexamers

Main picture shows elongated IDeg structures in absence of phenol; inset (white box) shows absence of elongated IDeg structures in presence of phenol.

Kurtzhals P et al. ADA 2011;32-LB (MoP + NN1250-1993)Kurtzhals P. EASD 2011; 092-P #1049 (MoP + NN1250-1993)

Following injection

[Zn2+ ]

Insulin degludec multi-hexamers

Subcutaneous depot

Monomers are absorbed from the depot into the circulation

- zinc

As zinc slowly diffuses out of the multi-hexamers, insulin degludec

monomers are formed

Jonassen I et al. Diabetes. 2010;59(suppl 1):A11

Clamp profile in type 2 diabetes: ultra-long, flat and consistent

Glu

cose

in

fusi

on r

ate

(m

g/(

kg*m

in))

5

4

3

2

1

0

Treatment

IDeg 100 U/mL 0.4 U/kg



Day 6

Day 7

Nosek L et al. ADA 2011;49-LB (NN1250-1987)Nosek L. EASD 2011; 093-P #1055 (NN1250-1987)

Consistently lower within-subject variability over time for insulin degludec

0

20

40

60

80

100

120

140

160

180

200

220

Day-

to-d

ay v

ari

ability (

CV

%)

Area under the GIR curve (time interval, hours)

Heise et al. Diabetes 2011;60(Suppl. 1):A263c

IDeg

Consistently lower within-subject variability over time for insulin degludec

0

20

40

60

80

100

120

140

160

180

200

220

Day-

to-d

ay v

ari

ability (

CV

%)

Area under the GIR curve (time interval, hours)

IDegIGlar

Heise et al. Diabetes 2011;60(Suppl. 1):A263c

IDeg OD+ metformin ±DPP-4 (n=773)

IGlar OD + metformin ±DPP-4 (n=257)

Insulin-naïve patients with type

2 diabetes(n=1030)

0 52 weeksInclusion criteria

• Type 2 diabetes ≥6 months

• Insulin naïve treated with metformin ± SU, DPP-4 or acarbose for ≥3 months

• HbA1C 7.0–10.0%

• BMI ≤40 kg/m2

• Age ≥18 years

Study designONCE LONG (3579)

Randomized 3:1 (IDeg OD:IGlar OD)Open label

NN1250-3579; IDeg OD vs IGlar OD in T2DM.

DPP-4: dipeptidyl peptidase-4 inhibitorSU: sulphonylureaOD: once-daily

Nocturnal confirmed hypoglycemiaONCE LONG (3579)

36% lower ratewith IDeg OD

p<0.05

NN1250-3579; IDeg OD vs IGlar OD in T2DM.

IDeg OD (n=766)IGlar OD (n=257)

SAS Comparisons: Estimates adjusted for multiple covariates

Reduction in confirmed hypoglycemia with

degludec (all IDeg vs. IGlar studies,

maintenance period)

*statistically significant improvement

Overall

Nocturnal

T1 and T2 32%*

T2 basal only 49%*

16%*T1 and T2

28%*T2 basal only

http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf’

Maintenance period

Pre-specified hypoglycemia meta-analyses Type 1 & type 2 diabetes

Treatment Strategies for Type 2 Diabetes (My Approach – T2DM + Metabolic Syndrome)

Islet -cell




Islet -cell







GLP-1

GLP-1

GLP-1

GLP-1

GLP-1

Insulin

Insulin

Insulin

Insulin

Insulin

Insulin

Metformin

Exercise

Exercise

Exercise

Exercise Exercise

TZDs

TZDs

TZDs

TZDs TZDs

TZDs


4. OTHER CONSIDERATIONS•Weight

-Majority of T2DM patients overweight / obese-Intensive lifestyle program-Metformin-GLP-1 receptor agonists-? Bariatric surgery-Consider LADA in lean patients


Energy Balance and Body Weight:Simple Right?

Body WeightEnergy In(Caloric Intake)

Energy Out(Metabolism)

Stomach

Islet

GI Tract

Brain

HypothalmusHind Brain

Evolving Treatment Strategies:The Complexity of Energy Homeostasis

Visceral Fat Cell

Vagal Afferents

LeptinLeptin

AmylinAmylin

InsulinInsulinGLP-1GLP-1

GlicentinGlicentinOxyntomodulinOxyntomodulin

GhrelinGhrelin

GIPGIP

AdiponectinAdiponectin

VisfatinVisfatin

ResistinResistin

GlucagonGlucagon

CCKCCK

Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914

PYY3-36PYY3-36

The Science ofWillpower

Incretins: Expanding Role in Treatment Strategies Pediatric Type 1 Diabetics (n=8) Insulin dose...

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