Transcript core_defects_of_type2_diabetes_part_1_of_4

Core Defects of Type 2 Diabetes
Targeting Mechanisms for a
Comprehensive Approach
Part 1
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Objectives
•
Discuss challenges in treating type 2 diabetes and rationale
for earlier and more aggressive treatment approaches
•
Review the physiologic regulation of glucose homeostasis,
the role of incretins, and core defects of type 2 diabetes
•
Describe the complementary MOAs of agents used in the
treatment of type 2 diabetes to address the 3 core defects
•
Provide a clinical overview of JANUVIA™ (sitagliptin)
•
Provide an overview of the prescribing information for
JANUMET™ (sitagliptin/metformin HCl)
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Insulin Resistance:
An Underlying Cause of Type 2 Diabetes
Obesity and
inactivity
Genetic
abnormalities
Type 2
diabetes
Aging
Medications
INSULIN
RESISTANCE
Rare
disorders
PCOS
Hypertension
Atherosclerosis
Dyslipidemia
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.
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Development and Progression of Type 2
Diabetes (Conceptual Representation)
NGT  Insulin  IGT/ IFG  Type 2 Diabetes
Resistance
Postprandial glucose
Glucose
Regulation
Fasting glucose
–10
Metabolic
Activity
–5
0
5
Insulin level
10
15
20
25
30
Insulin resistance—
hepatic and peripheral
Beta-cell function
–10
–5
0
5
10
15
20
Years From Diabetes Diagnosis
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NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.
Kendall DM, Bergenstal RM. ©2005 International Diabetes Center, Minneapolis, MN. All rights reserved.
Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.
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UKPDS: -Cell Loss Over Time
-Cell Function (%)*
100
75
Patients treated
with insulin,
metformin,
sulfonylureas‡
50
25
IGT†
0
-12 -10
Type 2
Postprandial
Diabetes
Hyperglycemia
Phase I
-6
-2 0
Type 2
Diabetes
Phase II
2
6
Type 2 Diabetes
Phase III
10
14
Years From Diagnosis
*Dashed
line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model
Assessment (HOMA) data from UKPDS.
†IGT=impaired glucose testing
‡The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a
subset of the UPKDS population
and were determined by the HOMA model.
Lebovitz HE. Diabetes Rev. 1999;7:139-153.
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Intensive Treatments and Increase in
HbA1c Over Time
United Kingdom Prospective Diabetes Study (UKPDS)
Median HbA1c (%)
9
8
ADA action
7
ADA goal
6
0
Conventional
Insulin
Chlorpropamide
Glibenclamide
(glyburide)
Metformin
Upper limit of normal range (6.2%)
0
3
6
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Time From Randomization (years)
UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-65.
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Guideline Recommendations Are Becoming
More Aggressive
• 2007 ADA standards1
– “The A1C goal for patients in general is an A1C goal
of <7%.”
– “The A1C goal for the individual patient is an A1C as
close to normal (<6%) as possible without significant
hypoglycemia.” [boldface added]
• ADA/EASD consensus statement2
– “If lifestyle intervention and maximal tolerated dose of
metformin fail to achieve or sustain glycemic goals, another
medication should be added within 2–3 months of the
initiation of therapy or at any time when A1C goal is not
achieved.” [boldface added]
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.
1. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41.
2. Nathan DM et al. Diabetes Care. 2006;29:1963–1972.
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Most Patients With Type 2 Diabetes May Fail to Attain
A1C Goal With Conventional Treatment Paradigm
Published Conceptual Approach
Mean A1C
of patients
Diet and
OAD
exercise monotherapy
OAD
OAD
up-titration combination
OAD +
basal insulin
OAD +
multiple daily
insulin
injections
10
A1C, 9
%
8
7
6
Duration of Diabetes
OAD=oral antihyperglycemic drug.
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
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Earlier and More Aggressive Intervention May Improve
Treating to Target Compared With Conventional Therapy
Published Conceptual Approach
Diet and
OAD
exercise monotherapy
OAD
OAD
up-titration combination
OAD +
basal insulin
OAD +
multiple daily
insulin
injections
10
A1C, 9
%
8
Mean A1C
of patients
7
6
Duration of Diabetes
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
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Challenges in Achieving Glycemic Goals
in Diabetes
• Less aggressive treat-to-target approach by
some clinicians1
• Suboptimal use of available therapies1
• Inability of any single agent’s MOA to address all core
defects of type 2 diabetes2
• Potential for increased side effects with use of
multiple agents3
• Suboptimal adherence to lifestyle measures1
• Underuse of medications as a result of
– Cost4
– Complexity of therapy5
1. Blonde L. Clin Cornerstone. 2005;7(suppl 3):S6–S17.
2. Van Gaal LF et al. Diabetologia. 2003;46(suppl 1):M44–M50.
3. McDonald HP et al. JAMA. 2002;288:2868–2879.
4. Piette JD et al. Diabetes Care. 2004;27:384–391.
5. Donnan PT et al. Diabet Med. 2002;19:279–284.
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Major Pathophysiologic Defects
in Type 2 Diabetes
Islet-cell dysfunction
Glucagon
(alpha cell)
Pancreas
Hepatic
glucose
output
Insulin
(beta cell)
Insulin
resistance
Glucose uptake in
muscle and fat
Hyperglycemia
Liver
Muscle
Liver
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adipose
tissue
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Major Targeted Sites of Oral Drug Classes
The glucose-dependent
mechanism of DPP-4 inhibitors
targets 2 key defects: insulin
release and unsuppressed
hepatic glucose production.
Liver
Pancreas
Beta-cell
dysfunction
Sulfonylureas
Meglitinides
Muscle
and fat
DPP-4 inhibitors
GLP-1
Hepatic glucose
overproduction
Biguanides
↓Glucose level
Insulin
resistance
Gut
TZDs
TZDs
Biguanides
DPP-4 inhibitors
Glucose
absorption
Alphaglucosidase
inhibitors
Biguanides
DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.
DeFronzo RA. Ann Intern Med. 1999;131:281–303.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
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