Transcript 5th Annual Endocrine Conference

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
 Metformin: CVD benefit (UKPDS)
- Coronary Disease
 Avoid hypoglycemia
- Heart Failure
 ? SUs & ischemic preconditioning
- Renal disease
- Liver dysfunction
 ? Pioglitazone &  CVD events
 ? Effects of incretin-based
therapies
- Hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Peptide Therapeutics:
Incretins (GLP-1 and GIP)
Brain
Ghrelin
Visfatin
Resistin
Hind Brain
Hypothalmus
Stomach
Adiponectin
Vagal Afferents
Cardiovascular Outcome Trials
Leptin
Incretins
TECOS
- sitagliptin
Exenatide – Bydureon, Byetta
EXSCEL
– weekly
Insulin
Liraglutide
- Victoza exenatide
Visceral Fat Cell
LEADER – liraglutide
Amylin
DPP-IV
ELIXAInhibitors
– lixisenitide
Sitagliptin – Januvia
SAVOR
saxagliptin
Glucagon
Linagliptin – -Tradjenta
PYY3-36
GI
Tract
GLP-1
GIP
Glicentin
Oxyntomodulin
Saxagliptin - Onglyza
CCK
Islet
Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914
Cardiovascular
RR
ACCORD:Mortality Hazard Ratios for PostRandomization Prescription of Glycemia Medications
Adjusted for Baseline Participant Characteristics
ACCORD Study Group. Presented at the ADA Scientific Sessions, San Francisco, June 2008
Peptide Therapeutics:
Incretins (GLP-1 and GIP)
Exenatide vs. Non-Exenatide – Cardiovascular Events
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Comorbidities
 Metformin: CVD benefit (UKPDS)
- Coronary Disease
 Avoid hypoglycemia
- Heart Failure
 ? SUs & ischemic preconditioning
 ? Pioglitazone &  CVD events
- Renal disease
- Liver dysfunction
 ? Effects of incretin-based
therapies
- Hypoglycemia
Glyburide (and older) – Should never be used
Glimepiride or Glipizide if any SU
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Healthy eating, weight control, increased physical activity
Initial drug
monotherapy
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination
(order not meant to denote any specific preference):
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
Two drug
combinations*
Efficacy (! HbA1c)
Hypoglycemia
Weight
Major side effect(s)
Costs
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Sulfonylurea†
Thiazolidinedione
DPP-4
Inhibitor
GLP-1 receptor
agonist
Insulin (usually
basal)
high
moderate risk
gain
hypoglycemia ‡
low
high
low risk
gain
edema, HF, fx’s‡
high
intermediate
low risk
neutral
rare‡
high
high
low risk
loss
GI‡
high
highest
high risk
gain
hypoglycemia ‡
variable
If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination
(order not meant to denote any specific preference):
Metformin
Three drug
combinations
+
Sulfonylurea†
+
Metformin
+
Thiazolidinedione
+
+
DPP-4
Inhibitor
+
Metformin
+
GLP-1 receptor
agonist
+
SU†
SU†
TZD
More complex
insulin strategies
Metformin
Metformin
+
Insulin (usually
basal)
+
SU†
TZD
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
DPP-4-i
or
GLP-1-RA
or
GLP-1-RA
or
Insulin §
or
Insulin §
or
GLP-1-RA
or
Insulin §
or
Insulin §
Insulin #
(multiple daily doses)
Adapted Recommendations: When Goal is to Avoid Hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]
T2DM– Treatment Strategies
Islet b-cell
Decreased
Incretin Effect
Impaired
TZDs
Insulin Secretion
TZDs
Increased
Lipolysis
Islet a-cell
TZDs
Increased
Glucagon Secretion
Increased Glucose
Reabsorption
TZDs
TZDs
Increased
HGP
Neurotransmitter
Dysfunction
TZDs
Decreased Glucose
Uptake
PROactive: Pioglitazone Reduced “Hard”
Coronary Heart Disease Endpoints
Time to Fatal/Nonfatal MI
(Excluding Silent MI)
Kaplan-Meier Event Rate
0.10
Pioglitazone (65/1230)
Placebo (88/1215)
0.08
0.06
–28%
0.04
0.02
0.00
Pioglitazone vs Placebo:
HR 0.63 (95% CI 0.41–0.97);
p=0.035
0.06
Kaplan-Meier Event Rate
Pioglitazone vs Placebo:
HR 0.72 (95% CI 0.52–0.99);
p=0.045
Time to Acute Coronary Syndrome
Pioglitazone (35/1230)
Placebo (54/1215)
0.05
0.04
–37%
0.03
0.02
0.01
0.00
0
6
12
18
24
30
36
Time from Randomization (Months)
Prespecified Analysis
0
6
12
18
24
30
36
Time from Randomization (Months)
Post Hoc Exploratory Analysis
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.
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Type 2 Diabetes:
Benefits vs Risks of TZDs
Type 2 Diabetes:
Benefits vs Risks of TZDs
But????
Actos causes Bladder Cancer!!!...Right?
Healthy eating, weight control, increased physical activity
Initial drug
monotherapy
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination
(order not meant to denote any specific preference):
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
Two drug
combinations*
Efficacy (! HbA1c)
Hypoglycemia
Weight
Major side effect(s)
Costs
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Sulfonylurea†
Thiazolidinedione
DPP-4
Inhibitor
GLP-1 receptor
agonist
Insulin (usually
basal)
high
moderate risk
gain
hypoglycemia ‡
low
high
low risk
gain
edema, HF, fx’s‡
high
intermediate
low risk
neutral
rare‡
high
high
low risk
loss
GI‡
high
highest
high risk
gain
hypoglycemia ‡
variable
If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination
(order not meant to denote any specific preference):
Metformin
Three drug
combinations
+
Sulfonylurea†
+
Metformin
+
Thiazolidinedione
+
Metformin
+
DPP-4
Inhibitor
+
+
GLP-1 receptor
agonist
+
SU†
SU†
TZD
Metformin
Metformin
+
Insulin (usually
basal)
+
SU†
TZD
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
DPP-4-i
or
GLP-1-RA
or
GLP-1-RA
or
Insulin §
or
Insulin §
or
GLP-1-RA
or
Insulin §
or
Insulin §
If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months,
proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:
More complex
insulin strategies
Insulin #
(multiple daily doses)
T2DM Anti-hyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]
The Ominous Octet – Treatment Strategies
Islet b-cell
Decreased
Incretin Effect
Impaired
Insulin
Insulin Secretion
Insulin
Increased
Lipolysis
Islet a-cell
Insulin
Increased
Glucagon Secretion
Increased Glucose
Reabsorption
Insulin
Insulin
Increased
HGP
Neurotransmitter
Dysfunction
Insulin
Decreased Glucose
Uptake
New Basal Insulins: insulin degludec
molecular structure
DesB30 LysB29(Nε-γ-glu-hexadecandioyl) human insulin
s
G I
V E Q C C T S
A chain
Degludec
s
I
(Tresiba)
C S L Y Q L E N Y C N
s
s
s
s
F V N Q H L C G S H L V E A L Y L V C G E R G F
B chain
F Y T P K
T
desB30 Insulin
NH
O
L-g-Glu
O
HO
O
N
H
Hexadecandioyl
OH
O
Multi-hexamer formation
after injection
[
Phenol;
Zn2+]
Insulin degludec in pen
Injection site
Long multi-hexamer chains
assemble
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
Subcutaneous depot
[Zn2+
Insulin degludec
multi-hexamers
- zinc
As zinc slowly diffuses out of the
multi-hexamers, insulin degludec
monomers are formed
Monomers are absorbed from
the depot into the circulation
Jonassen I et al. Diabetes. 2010;59(suppl 1):A11
]
Clamp profile in type 2 diabetes: ultralong, flat and consistent
Glucose infusion rate (mg/(kg*min))
Treatment
5
4
3
2
1
0
Nosek L et al. ADA 2011;49-LB (NN1250-1987)
Nosek L. EASD 2011; 093-P #1055 (NN1250-1987)
IDeg 100 U/mL 0.8 U/kg
IDeg 100 U/mL 0.6 U/kg
IDeg 100 U/mL 0.4 U/kg
Consistently lower within-subject variability
over time for insulin degludec
220
IDeg
Day-to-day variability (CV%)
200
180
160
140
120
100
80
60
40
20
0
Area under the GIR curve (time interval, hours)
Heise et al. Diabetes 2011;60(Suppl. 1):A263c
Consistently lower within-subject variability
over time for insulin degludec
220
IDeg
IGlar
Day-to-day variability (CV%)
200
180
160
140
120
100
80
60
40
20
0
Area under the GIR curve (time interval, hours)
Heise et al. Diabetes 2011;60(Suppl. 1):A263c
Study design
ONCE LONG (3579)
IDeg OD+ metformin ±DPP-4 (n=773)
Insulin-naïve
patients with type
2 diabetes
(n=1030)
Inclusion criteria
• Type 2 diabetes ≥6 months
• Insulin naïve treated with
metformin ± SU, DPP-4 or
acarbose for ≥3 months
IGlar OD + metformin ±DPP-4 (n=257)
52 weeks
0
Randomized 3:1 (IDeg OD:IGlar OD)
Open label
• HbA1C 7.0–10.0%
• BMI ≤40 kg/m2
• Age ≥18 years
DPP-4: dipeptidyl peptidase-4 inhibitor
SU: sulphonylurea
OD: once-daily
NN1250-3579; IDeg OD vs IGlar OD in T2DM.
Nocturnal confirmed hypoglycemia
ONCE LONG (3579)
IDeg OD (n=766)
IGlar OD (n=257)
36% lower rate
with IDeg OD
p<0.05
SAS Comparisons: Estimates adjusted for multiple covariates
NN1250-3579; IDeg OD vs IGlar OD in T2DM.
Pre-specified hypoglycemia
meta-analyses Type 1 & type 2 diabetes
Maintenance
period
Reduction in confirmed
hypoglycemia with
degludec
(all IDeg vs. IGlar studies,
maintenance period)
Nocturnal
T1 and T2
32%*
T2 basal only
49%*
Overall
T1 and T2
16%*
T2 basal only
28%*
*statistically significant improvement
http://www.novonordisk.com/images/investors/investor_presentations/2011/CMD2011/04_Diabetes_treatment_tomorrow_CMD2011.pdf’
Treatment Strategies for Type 2 Diabetes
(My Approach – T2DM + Metabolic Syndrome)
Islet b-cell
Decreased
Incretin Exercise
Effect
Exercise
GLP-1
Impaired
TZDs
GLP-1
Insulin
Secretion
Islet a-cell
Insulin
GLP-1
Insulin
Increased
Lipolysis
TZDs
Insulin
TZDs
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
Exercise
Metformin
TZDs GLP-1
Increased
HGP
Insulin
Exercise
GLP-1
TZDs
Insulin
Neurotransmitter
Dysfunction
Exercise
TZDs
Insulin
Decreased Glucose
Uptake
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?
Energy In
(Caloric Intake)
Body Weight
Energy Out
(Metabolism)
Evolving Treatment Strategies:
The Complexity of Energy Homeostasis
Brain
Ghrelin
Visfatin
Resistin
Hind Brain
Hypothalmus
Stomach
Adiponectin
Vagal Afferents
The Science of
Willpower
Leptin
PYY3-36
GI
Tract
Insulin
Amylin
GLP-1
Visceral Fat Cell
GIP
Glucagon
Glicentin
Oxyntomodulin
CCK
Islet
Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914