Post on 26-Dec-2015
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
Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone & CVD events ? Effects of incretin-based
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
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
Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone & CVD events ? Effects of incretin-based
therapies
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Glyburide (and older) – Should never be usedGlimepiride or Glipizide if any SU
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Comorbidities
-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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
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
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
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
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
DecreasedDecreasedIncretin EffectIncretin Effect
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
IDeg 100 U/mL 0.8 U/kg
IDeg 100 U/mL 0.6 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
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
DecreasedDecreasedIncretin EffectIncretin Effect
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
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
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