Download Type 2 Diabetes

GLP-1 Receptor Agonists: Emerging
Treatments in Diabetes Therapeutics
Shannon I. Brow, RN, CDE, FNP-C
Medical Science Liaison
Amylin Pharmaceuticals, Inc
1
Faculty Disclosures:
• Shannon I. Brow, RN, CDE, FNP-C
– Employee of Amylin Pharmaceuticals, Inc
– Stockholder: Amylin Pharmaceuticals, Inc
2
Learning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan
2010
• Review incretin physiology in healthy individuals and in patients with
type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors
and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type
2 diabetes
3
Learning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan
2010
• Review incretin physiology in healthy individuals and in patients with
type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors
and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type
2 diabetes
4
Glucose (mg/dL)
Progressive Nature of Type 2 Diabetes
350
300
Prediabetes
(Obesity, IFG, IGT)
Postmeal Glucose
Diabetes
diagnosis
250
200
Fasting glucose
150
100
50
Relative Amount
-15
-10
-5
0
5
250
10
15
20
25
30
Years
β-cell failure
200
Insulin resistance
150
100
Insulin level
50
0
-15
-10
-5
0
Onset
diabetes
Clinical
features
5
10
15
20
25
30
Years
Macrovascular changes
IFG, impaired fasting glucose;
IGT, impaired glucose tolerance.
Microvascular changes
Kendall DM, et al. Am J Med 2009;122:S37-S50.
Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
5
Postprandial Glucose Contribution to A1C
FPG (Fasting Plasma Glucose)
PPG (Postprandial Plasma Glucose)
100
% Contribution
30%
50%
80
55%
60
40
60%
70%
70%
50%
45%
20
40%
30%
0
<7.3
7.3-8.4
8.5-9.2
9.3-10.2
>10.2
A1C Range (%)
Data from Monnier L, et al. Diabetes Care 2003; 26:881-885.
6
Plasma Glucose Is Normally
Maintained in a Narrow Range
Healthy Subjects
Type 2 Diabetes
Plasma Glucose (mg/dL)
400
300
200
100
0
06.00
Breakfast Lunch
10.00
14.00
Dinner
18.00
22.00
Time of Day (h)
N = 30; Mean (SE)
Data from Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239
02.00
08.00
7
A1C Goals Unmet in Majority of
Patients With Diabetes
10.0
12.4% have A1C >10%1
9.5
9.0
A1C (%)
20.2% have A1C >9%
8.5
8.0
37.2% have A1C >8%
7.5
64.2% of patients with type
2 diabetes have A1C 7%2
7.0
ADA recommended target (<7%)3
6.5
ACE recommended target (<6.5%)4
6.0
Upper limit of normal range (6%)
5.5
1. Data from Saydah SH, et al. JAMA 2004; 291:335-342.
2. Calculated from Koro CE, et al. Diabetes Care 2004; 27:17-20.
3. Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S50.
4. Data from ACE. Endocrine Practice 2002.
8
Learning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan
2010
• Review incretin physiology in healthy individuals and in patients with
type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors
and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type
2 diabetes
9
Criteria for the Diagnosis of Diabetes
1. A1c ≥ 6.5%. This test should be performed in a laboratory using a method that is NGSP
certified and standardized to the DCCT assay.*
OR
2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*
OR
3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. This test should be
performed as described by the World Health Organization, using a glucose load
containing the equivalent of 75 g anhydrous glucose dissolved in water.*
OR
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random
plasma glucose ≥ 200 mg/dl (11.1 mmol/l).
* In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat
testing
American Diabetes Association. Diabetes Care 2010;33(suppl 1):S62-S69.
10
The Pathogenesis of Type 2 Diabetes
A New Perspective of the Core Defects Paradigm
Increased
Beta-Cell Workload
Insulin
(Insulin Resistance)
Resistance
Diminished
Beta-Cell
Response
Insulin
(Insulin Deficiency)
Deficiency
Hyperglycemia
Adapted from ©2005 International Diabetes Center, Minneapolis, MN All rights reserved
11
The Pathogenesis of Type 2 Diabetes
An Imbalance of Beta-Cell Workload and Beta-Cell Response
  Insulin resistance
 Obesity
  Food intake
  Gastric Emptying –  Rate of nutrient absorption
  Glucagon secretion
  Hepatic glucose output
Increased
Beta-Cell
Workload
Decreased
Beta-Cell
Response
  Insulin secretion in
response to elevated
glucose
  First-phase
insulin response
Hyperglycemia
12
The Pathophysiology of Type 2 Diabetes
Incretin
“Defect”
Insulin
Resistance
Relative Insulin
Deficiency
Hyperglycemia
Type 2 Diabetes
13
Clinical Challenges With Type 2 Diabetes
Weight
A1C
Diet and Exercise
MET
SFU
Insulin
10
 Weight (kg)
Median A1C (%)
9
8
7
6.2% A1C Upper limit of normal
6
0
2
4
Diet and Exercise
MET
SFU
Insulin
6
Time From Randomization (y)
5
0
-5
0
2
4
6
Time From Randomization (y)
n = 1704; A1C indicates glycosylated hemoglobin A1c; MET, metformin; SFU, sulfonylurea
Data from UKPDS Group (34). Lancet 1998;352:854-865.
14
Blood Glucose Concentrations Are
Largely Determined by Beta-Cell Function
• Beta-Cell Function
– Insulin synthesis
– Insulin secretion
• Beta-Cell Functional Capacity
– Beta-cell mass (cell turnover and neogenesis)
– First-phase/second-phase insulin release
– Insulin processing (proinsulin to insulin)
– Glucose sensitivity
• Beta-Cell Functional Demand
– Glucose absorption (diet, gastric emptying)
– Hepatic glucose production (glycolysis, gluconeogenesis)
– Peripheral glucose uptake (insulin sensitivity, exercise)
15
Multihormonal Regulation of Glucose
Appearance and Disappearance
Mixed Meal (With ~85 g Dextrose)
Grams of Glucose (flux/min)
0.6
Regulated by hormones:
GLP-1, amylin, CCK, etc.
0.4
0.2
0
Meal-Derived Glucose
Hepatic Glucose Production
Total Glucose Uptake
Balance of
insulin suppression and
glucagon stimulation
-0.2
Insulin-mediated
glucose uptake
-0.4
-0.6
-30 0
120
240
360
480
Time (min)
N = 5; Mean (SE)
Data from Pehling G, et al. J Clin Invest 1984;74:985-991.
16
Learning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan
2010
• Review incretin physiology in healthy individuals and in patients with
type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors
and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type
2 diabetes
17
The Incretin Effect in Healthy Subjects
Oral Glucose
Intravenous (IV) Glucose
*
2.0
*
C-Peptide (nmol/L)
Plasma Glucose (mg/dL)
200
100
0
1.5
*
*
Incretin Effect
*
*
1.0
*
0.5
0.0
0
60
120
180
Time (min)
N = 6; Mean (SE); *P0.05
Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492-498.
0
60
120
Time (min)
180
18
Incretins
• Gut-derived factors that potentiate insulin secretion following
meal ingestion
• 2 principal incretins identified to date:
GIP
GLP-1
42-amino acid peptide
30-amino acid peptide
Adapted from Holst JJ, et al. Am J Physiol Endocrinol Metab 2004; 287:E199-E206.
Drucker DJ. Diabetes Care 2003; 26:2929-2940.
19
Comparison of the Incretins
GLP-1
L-cells
(Ileum and Colon)
GIP
K-cells
(Duodenum
and Jejunum)
Decreases secretion in T2DM
Yes
No
Inhibits glucagon secretion
postprandially
Yes
No
Reduces food intake
Yes
No
Slows gastric emptying
Yes
No
Stimulates beta-cell mass/growth
Yes
Yes
Promotes insulin biosynthesis
Yes
Yes
Knockout mice (result in IGT)
Yes
Yes
Site of Production
Adapted from Mayo KE, et al. Pharmacol Rev 2003;55:167-194.
Adapted from Drucker DJ. Diabetes Care 2003;26:2929-2940.
Adapted from Nauck M, et al. Diabetologia 1986;29:46-52.
20
The Incretin Effect Is Reduced in
Type 2 Diabetes
Oral Glucose
Intravenous (IV) Glucose
Type 2 Diabetes
Healthy Subjects
*
80
*
*
60
*
Incretin Effect
*
*
40
*
20
0
Insulin (mU/L)
Insulin (mU/L)
80
Incretin Effect
60
* *
*
40
20
0
0
60
120
Time (min)
N = 22; Mean (SE); *P0.05
Data from Nauck M, et al. Diabetologia 1986;29:46-52.
180
0
60
120
Time (min)
180
21
Glucagon-Like Peptide-1 (GLP-1) is an
Important Incretin Hormone
• The “incretin effect” started the search
• Incretins
– Gut hormones that enhance insulin secretion in response to food
– Glucose-dependent insulin secretion
• GLP-1
– Secreted from L cells of the intestines
– Most well-characterized incretin
– Diminished in type 2 diabetes
• Glucagon
– Secreted from pancreatic alpha cells
– Counterregulatory hormone to insulin
– Elevated in type 2 diabetes
Adapted from Aronoff SL, et al. Diabetes Spectrum 2004;17:183-190.
22
Postprandial GLP-1 Concentrations Are Lower
in Subjects With IGT and Type 2 Diabetes
Healthy Subjects
Impaired Glucose Tolerance
Type 2 Diabetes
Meal
GLP-1 (pmol/L)
20
* * * *
*
*
15
*
10
*
5
0
0
60
120
180
240
Time (min)
N = 102; Mean (SE); *P<0.05 between type 2 diabetes and healthy subjects
Data from Toft-Nielsen MB, et al. J Clin Endocrinol Metab 2001;86:3717-3723.
23
Insulin and Glucagon Responses Are Altered
in Type 2 Diabetes
Healthy Subjects
Type 2 Diabetes
Carbohydrate Meal
Insulin
(µU/mL)
120
60
0
140
Meal
Glucagon 120
(pg/mL)
100
360
300
Glucose
(mg/dL) 240
140
80
-60
0
60
120
180
240
Time (min)
N = 26; Mean (SE)
Data from Mϋller WA, et al. N Engl J Med 1970;283:109-115.
24
GLP-1 Modulates Numerous Functions
in Humans
GLP-1: Secreted upon
the ingestion of food
Promotes satiety and
reduces appetite
Alpha cells:
 Glucose-dependent
postprandial
glucagon secretion
Liver:
Beta cells:
 Glucagon reduces
hepatic glucose output
Enhances glucose-dependent
insulin secretion
Stomach:
Helps regulate
gastric emptying
Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422.
Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169.
25
GLP-1 Effects Are Glucose Dependent
in Type 2 Diabetes
Placebo
GLP-1
180
90
*
*
*
*
300
* *
*
0
-30 0 60 120 180 240
Insulin (pmol/L)
Glucose (mg/dL)
270
PBO
GLP-1
PBO
GLP-1
200
*
100
* *
* *
*
* *
0
-30 0 60 120 180 240
Time (min)
N = 10; Mean (SE); *P<0.05
Data from Nauck MA, et al. Diabetologia 1993;36:741-744.
Time (min)
Glucagon (pmol/L)
PBO
GLP-1
20
10
* *
* *
0
-30 0 60 120 180 240
Time (min)
26
GLP-1 Has a Short Duration of Effect Due to
Degradation by Dipeptidyl Peptidase IV (DPP-IV)
DPP-IV
His
Ala
7
Glu
Gly
Thr
Phe
Thr
Ser
Asp
Val
9
Ser
Lys
Ala
Ala
Gln
Gly
Glu
Leu
Tyr
Ser
Glu
37
Phe
Ile
Ala
Trp
Adapted from Mentlein R. Eur. J. Biochem 1993;214:829-835.
Leu
Val
Lys
Gly
Arg
Gly
27
Leveraging the Therapeutic Potential of GLP-1
• GLP-1
– Short half-life (2 minutes)
 Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV)
• DPP-IV inhibition
– Extends endogenous GLP-1 half-life
 Approved in US:
– Sitagliptin (Merck)
– Saxaglitpin (BMS and AZ)
 In development, e.g.,
– Alogliptin (Takeda)
– Denagliptin (Glaxo)
– Melogliptin (Glenmark)
– Vildagliptin – LAF 237 (Novartis)
28
Leveraging the Therapeutic Potential of GLP-1
• GLP-1 receptor agonists
– Mimic many of the glucoregulatory effects of GLP-1
– Resistant to DPP-IV
 Approved in US:
– Exenatide (Amylin and Lilly)
– Liraglutide (Novo Nordisk)
 In development, e.g.,
–
–
–
–
–
Albiglutide (Glaxo Smith Kline)
CJC 11134 (ConjuChem)
Exenatide once weekly (Amylin, Lilly, Alkermes)
Lixisenatide (Sanofi- Aventis)
Taspoglutide (Roche)
29
Learning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan
2010
• Review incretin physiology in healthy individuals and in patients with
type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors
and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type
2 diabetes
30
DPP-4 Inhibitor and GLP-1 Receptor Agonist
Discussion
• The slides that follow include data from the first FDA approved
agent in each class
• Concepts are broad, yet representative of drugs that are FDA
approved in each class
• There is no intent to claim superiority of the drug discussed
compared to the other same class agent
31
Continuously Infused GLP-1 Improved the
Defects of T2D
T2D
Defects1
Continuously Infused
GLP-11,2
Insulin production
First-phase
insulin response
Glucagon;
glucose output
Gastric emptying
Food intake
1. Aronoff SL, et al. Diabetes Spectrum 2004;17:183-190.
2. Nielsen LL, et al. Regul Pep. 2004;117:77-88.
32
Effects of GLP-1 on the b cell in Healthy Subjects
33
GLP-1 in T2D
34
GLP-1 Is Cleaved and Inactivated by DPP-4
35
Mechanism of Action: DPP-4 Inhibitors
• Sitagliptin example
www.januvia.com/januvia/hcp/januvia/documents/MOAcard_JANUVIA.pdf
36
Sitagliptin Decreased A1C From Baseline Over
24 wks
Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009
37
Sitagliptin Decreased A1C Over 52 wks
Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009
38
DPP-4 Inhibitors Prevent the Inactivation
of GLP-1
39
The Beginning
• Exenatide
– Synthetic version of salivary protein found in
the Gila monster
– More than 50% amino acid sequence identity with human GLP-1
 Binds to known human GLP-1 receptors on beta cells (in vitro)
 Resistant to DPP-IV inactivation
Site of DPP-IV Inactivation
• Following injection, exenatide is measurable in plasma
for up to 10 hours
Adapted from Nielsen LL, et al. Regul Pept 2004;117:77-88.
Adapted from Kolterman OG, et al. Am J Health-Syst Pharm 2005;62:173-181.
40
Exenatide Restored
First-Phase Insulin Response
Type 2 Diabetes
Healthy Controls
Placebo
Insulin (pM/kg/min)
Insulin (pM/kg/min)
Exenatide
30
30
20
10
20
Exenatide
10
Placebo
0
0
-180 -90
0
30
60 90
120
IV Glucose
Time (min)
Evaluable; N = 25; Mean (SE)
Fehse F, et al. J Clin Endocrinol Metab 2005;90(11):5991-5997.
-180 -90
0
30
60
90
120
IV Glucose
Time (min)
41
Exenatide Suppressed Postprandial Glucose
and Glucagon in Type 2 Diabetes
360
270
180
90
0
60
120 180
240
300
Standardized Breakfast
Exenatide or Placebo
Time (min)
N = 20; Mean (SE)
Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089.
Plasma Glucagon (pg/mL)
Plasma Glucose (mg/dL)
Placebo
0.10 µg/kg Exenatide
200
150
100
50
0
60
120
180
Standardized Breakfast
Exenatide or Placebo
Time (min)
42
Exenatide Acutely Reduced Glucose Through
Enhanced Glucose-Dependent Insulin Secretion
225
180
135
90
0
2
4
6
8
SC Injection
Serum Insulin (pmol/L)
Plasma Glucose (mg/dL)
Placebo
0.05 µg/kg Exenatide
0.10 µg/kg Exenatide
250
200
150
100
50
0
2
4
6
8
SC Injection
Time (h)
Type 2 Diabetes; N = 34; Mean (SE)
Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089.
Time (h)
43
Exenatide Is Not Inactivated by DPP-4
44
Exenatide vs Sitagliptin MOA Study:
Study Design
• Primary endpoint: comparison of the effects of exenatide and
sitagliptin on 2-hour PPG concentrations in patients with T2D
Randomization
Study
Termination
Crossover
Treatment Period 1
Treatment Period 2
Exenatide 5 µg BID Exenatide 10 µg BID
Exenatide 5 µg BID Exenatide 10 µg BID
Sequence A
Placebo Lead-in
Sequence B
Sitagliptin 100 mg QAM
1 week
Standard
Meal Test
Sitagliptin 100 mg QAM
2 weeks
2 weeks
Standard
Meal Test
MET background; MOA indicates mechanism of action; QAM, once per day in the morning
DeFronzo RA, et al. Curr Med Res Opin 2008;24;2943-2952.
Standard
Meal Test
45
75
Baseline
Exenatide
Sitagliptin
75
63.8
50
50
25
25
15.1
7.2
2-h Plasma Exenatide (pM)
2-h Postprandial Plasma GLP-1 (pM)
Postprandial Plasma Levels of Exenatide
Exceeded Physiologic Levels of GLP-1
7.9
0
0
Plasma GLP-1
Plasma Exenatide
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE
2-wk posttreatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
46
Exenatide Reduced PPG Concentrations To a
Greater Extent Than Sitagliptin
Primary Endpoint
Baseline
Exenatide
Sitagliptin
280
PPG (mg/dL)
240
200
160
120
-30
0
30
Standard Meal
60
90
120
150
180
210
240
Time (min)
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P<0.0001
DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
47
Reductions in 2-Hour PPG Were Greater With
Exenatide Than With Sitagliptin
270
Exenatide
Sitagliptin
250
2-hr PPG (mg/dL)
230
210
190
170
150
130
110
Baseline
End of
Period 1
End of
Period 2
• After Period 1, patients were switched to the other therapy
Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32
Mean ± SE; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
48
Improvement in Insulinogenic Index Was
Greater With Exenatide Than With Sitagliptin
P = 0.02
1.0
Geometric Mean Baseline
Insulinogenic Index2: 0.4
Insulinogenic Index1
0.9
0.8
0.82
0.7
0.6
0.55
0.5
0.4
Exenatide
Sitagliptin
Patients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean ± SE
Standard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
2. Data on file, Amylin Pharmaceuticals, Inc.
49
Exenatide Reduced Postprandial Glucagon
Levels to a Greater Extent Than Sitagliptin
Baseline
Exenatide
Sitagliptin
Plasma Glucagon (pg/mL)
120
110
100
90
80
70
-30
0
30
Standard Meal
60
90
120
150
180
210
240
Time (min)
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE
DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
50
Exenatide Slowed Gastric Emptying Compared
to Sitagliptin
Baseline
Exenatide
Sitagliptin
Plasma Acetaminophen (µg/mL)
20.0
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
-30
0
30
Standard Meal
60
90
120
150
180
210
240
Time (min)
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophen
was administered immediately before the standard meal; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
51
Actions of Incretin-Based Therapies for T2D:
GLP-1 Receptor Agonists and DPP-4 Inhibitors
GLP-1 Receptor
Agonists1,2
DPP-4
Inhibitors1,2
Insulin
production
+++
++
First-phase
insulin
response
+++
++
Glucagon;
glucose output
+++
+
Delayed
No effect
Decreased
No effect
Action
Gastric emptying
Food intake
1. DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
2. Drucker DJ and Nauck MA. Lancet 2006;368:1696-1705.
52
Learning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan
2010
• Review incretin physiology in healthy individuals and in patients with
type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors
and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type
2 diabetes
53
Algorithm for Type 2 Diabetes
Tier 1: well-validated core therapies
Diagnosis:
Lifestyle
+
Metformin
Step 1
Lifestyle + Metformin
+
Basal insulin
Lifestyle + Metformin
+
Intensive insulin
Lifestyle + Metformin
+
Sulfonylurea
Step 2
Step 3
Tier 2: less well-validated core therapies
Lifestyle + Metformin
+
Pioglitazone
(no hypoglycemia /edema (CHF)/ bone loss)
Lifestyle + Metformin
+
GLP-1 agonist
(no hypoglycemia/weight loss /nausea/vomiting )
Validation based on clinical trials & clinical judgment
Nathan DM, et al. Diabetes Care 2008;31(12):1-11.
Lifestyle + Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle + Metformin
+
Basal insulin
54
AACE/ACE Glycemic Control Algorithm:
T2 Diabetes
A1C
6.5%
7.5%
7.6%
9.0%
>9.0
Increase therapy every 2-3 months if glycemic goal is not achieved
Lifestyle
Modification
(to be
considered
throughout
treatment)
Monotherapy
Can include:
• MET
• DPP4
• GLP-1
• TZD
• AGI
Dual Therapy
• MET+GLP1, DPP4,or
TZD
• TZD+GLP-1
or DPP4
• MET+Colse
velam or
AGI
Dual Therapy
• MET+GLP1, DPP4, or
TZD
• MET+SFU
or Glinide
Triple Therapy
• MET+GLP-1
or DPP4 with
TZD or SFU
After Orals
• Insulin ±
other agents
Triple Therapy
• MET+GLP-1
or DPP4 +
TZD or SFU
• MET + TZD
+ SFU
Symptoms
• Insulin ±
other agents
No Symptoms
• MET+GLP-1 or
DPP4 + TZD or
SFU
• MET + TZD + SFU
• Insulin ± other
agents
Adapted from AACE Glycemic Control Algorithm, Rodbard HW, et al. Endocr Pract 2009. Reproductions can be found at www.aace.com/pub
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AACE/ACE Algorithm Summary
• The algorithm is intended for use in conjunction with more
detailed and comprehensive information (e.g., prescribing
information, ACE/AACE Road Maps, etc)
• The algorithm is intended to provide guidance
• A1C goal of ≤ 6.5% or less
– Needs to be individualized to minimize risks of hypoglycemia
• Therapeutic pathways stratified based on current A1C values
• 8 major classes of medications
– Prioritized by safety, efficacy, risk of hypo, simplicity, patient
adherence and cost of medication
– Combination medications that have complimentary mechanisms of
action
Rodbard HW, et al. Endocr Pract 2009;15(6):541-559.
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