Download 5th Annual Endocrine Conference

Treatment Strategies for Diabetes and Obesity:
Update 2013
Christopher Sorli, MD/PhD, FACE
Chair, Department of Diabetes,
Endocrinology and Metabolism
Billings Clinic
Billings, MT
Pathogenesis of Type 2 Diabetes
Islet b-cell
Impaired
Insulin Secretion
Insulin
Metformin
Increased
HGP
HGP=hepatic glucose production.
SUs
Insulin
Decreased Glucose
Uptake
Advances in Therapy,
but Falling Short of Goals
10
Pre-DCCT
9.0%
NHANES
1999-2000
9
HbA1c (%)
2003: ADA eliminated HbA1c
2008:HbA
ACCORD,
2005:
1c goal
“action point”
ofADA
<8% added
from
ADVANCE,
VADT,
and
of
<6%
for
“individual
guidelines
UKPDS
80 published
patients”
to guidelines
1997: ADA1998:
lowered
T2DM
UKPDS
results
diagnosis from published
FPG ≥140
mg/dLto ≥126 mg/dL
NHANES
2003-2004
7.8
8
7
General ADA
Target: <7%
7.2
7.7
NHANES
1988-1994
6
SU / Insulin
Metformin (1995)
7.5
NHANES
2001-2002
TZDs (1999)
Incretins (2004)
5
 1980s
1990s
2000s 
SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes.
Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.
Future
6.0% ?
Type 2 Diabetes
Evolving Treatment Strategies
Mortality
HR = 1.22
(95% CI =1.01-1.46)
p = 0.04
intensive
standard
Advances in Therapy,
but Falling Short of Goals
10
NHANES
1999-2000
9
HbA1c (%)
2009: ADA added “less
stringent” HbA1c goal for
patients with significant
comorbidities or risk of
hypoglycemia, or short
life expectancy
NHANES
Pre-DCCT
9.0%
7.8
2003-2004
8
7
General ADA
Target: <7%
7.2
7.7
NHANES
1988-1994
6
SU / Insulin
Metformin (1995)
7.5
NHANES
2001-2002
TZDs (1999)
Incretins (2004)
5
 1980s
1990s
2000s 
SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes.
Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.
Future
6.0% ?
Group
Intensive
A1C
Targets
< 6%
Intensification Thresholds
A1C
> 50% of SMBG Results/4 Days
> 5.9%
Fasting > 100 (5.6)
OR
2 Hr PP > 140 (7.8)
Rx was reduced in the presence of
significant hypoglycemia.
Even if the A1C is <6.0
Mortality
Primary outcome (composite nonfatal MI,
nonfatal stroke, CVD death)
Diabetes Management Strategies
Making Sense of ACCORD
Mortality vs Treatment A1c
Death Rate vs Drop in A1c
No drop in A1c = higher death rate
10 x more
10 x less
Pathogenesis of Type 2 Diabetes
Islet b-cell
Impaired
Insulin Secretion
Increased
HGP
HGP=hepatic glucose production.
Decreased Glucose
Uptake
The Ominous Octet
Islet b-cell
Decreased
Incretin Effect
Impaired
Insulin Secretion
Increased
Lipolysis
Islet a-cell
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
Increased
HGP
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Type 2 Diabetes: A Heterogeneous
Disorder
20-30% of
population
70-80% of
population
Functional b-cell
Insulin resistance
Metabolic syndrome
Failing b-cell
Insulin resistance
Hyperglycemia
Nephropathy
CVD
Cancer
Retinopathy
Heine RJ, Spijkerman AM. 2006.
Neuropathy
DIABETES/OBESITY
Management Strategies
Insulin Resistance
Insulin Supply
Metabolic Syndrome
Energy Storage
Beta Cell Dysfunction
Hyperglycemia
Relative
Function
100 (%)
Prevention!
Damage
Control!
Insulin
Resistance
Intensive managment of
Less intensive
Insulin
resistance
Macrovascular
Risk/ Cancer
Risk goals
glycemic
β cell dysfunction
β cell function
Avoid
hypoglycemia
CVD risks
β cell mass
-20
-10
0
10
20
Years of Diabetes/Metabolic
Syndrome
30
Adapted from IDC, Minneapolis, MN
History of Diabetes Therapy:
What More Could We Possibly Want?
Glucagon R antangonists
Degludec
11-β-HSD1 inhib
SGLT-2 inhib
Weekly Exenatide
Liraglutide
Bromocriptine
Saxagliptin
Sitagliptin
The End of Protocol
Driven Therapy
Detemir
Pramlintide
Exenatide
Aspart
Glinides
Glitazones
Lispro
Metformin
Human Insulin
Sulfonylurea
Animal Insulin
1922
1950’s
1982-85
1995 1996
2001
2003 2005
2007
2009 2013
Management of Hyperglycemia in Type 2
Diabetes: A Patient-Centered Approach
Position Statement of the American Diabetes Association (ADA) and
the European Association for the Study of Diabetes (EASD)
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
3. ANTI-HYPERGLYCEMIC THERAPY
•
Glycemic targets
-
HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])
-
Pre-prandial PG <130 mg/dl (7.2 mmol/l)
- Post-prandial PG <180 mg/dl (10.0 mmol/l)
-
Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%+) - older, comorbidities,
hypoglycemia prone, etc.
-
Avoidance of hypoglycemia
PG = plasma glucose
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Approach to management
of hyperglycemia:
more
less
stringent
stringent
Figure 1
Patient attitude and
expected treatment efforts
highly motivated, adherent,
excellent self-care capacities
Risks potentially associated
with hypoglycemia, other
adverse events
low
Disease duration
newly diagnosed
Life expectancy
long
Important comorbidities
absent
few / mild
severe
Established vascular
complications
absent
few / mild
severe
Resources, support system
readily available
less motivated, non-adherent,
poor self-care capacities
high
long-standing
short
limited
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)
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
Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]
Insulin #
(multiple daily doses)
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]
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
+
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
+
Sulfonylurea†
+
Metformin
+
Thiazolidinedione
+
Metformin
+
DPP-4
Inhibitor
+
Metformin
+
GLP-1 receptor
agonist
+
SU†
SU†
TZD
More complex
insulin strategies
Metformin
Sulfonylurea†
Metformin
Three drug
combinations
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 Weight Gain
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
Incretins
(injectables)
Exenatide – Bydureon, Byetta
Liraglutide
Insulin - Victoza
Leptin
Amylin
DPP-IV Inhibitors
Visceral Fat Cell
(orals)
Sitagliptin – Januvia
Glucagon Linagliptin – Tradjenta
Saxagliptin - Onglyza
Vagal Afferents
PYY3-36
GI
Tract
GLP-1
GIP
Glicentin
Oxyntomodulin
CCK
Islet
Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914
Incretins:
GLP-1 Agonists vs. DPP-IV Inhibitors
Differential Effects:
Glycemic Control
Energy Balance
Pharmacology vs Physiology
DPP-IV – increases endogenous
GLP-1
GLP-1 agonist – super physiologic
effect
…Not quite that simple
T2DM – Treatment Strategies
Islet b-cell
GLP-1 > DPP-IV
Decreased
Incretin Effect
GLP-1 > DPP IV
(A1c, FPG, b-cell function)
Impaired
Insulin Secretion
Increased
Lipolysis
Islet a-cell
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
Increased
HGP
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Incretins (Exenatide):
Sustained Efficacy- Improved Beta Cell Function
Buse et.al., Oct 2012, EASD, Berlin
T2DM – Treatment Strategies
Islet b-cell
GLP-1 > DPP-IV
Decreased
Incretin Effect
GLP-1 > DPP IV
(A1c, FPG, b-cell function)
Impaired
Insulin Secretion
Increased
Lipolysis
Islet a-cell
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
GLP-1
(weight loss)
Increased
HGP
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Incretin Therapy
Effect on Energy Homeostasis
T2DM– Treatment Strategies
Islet b-cell
GLP-1 > DPP-IV
Decreased
Incretin Effect
GLP-1 > DPP IV
(A1c, FPG, b-cell function)
Impaired
Insulin Secretion
Increased
Lipolysis
Islet a-cell
GLP-1 > DPP IV
(Glucagon inhibition, FPG,
Prandial control)
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
GLP-1 > DPP IV
(glucagon inhibition, FPG,
Prandial control)
GLP-1
(weight loss)
Increased
HGP
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake