Download The Incretin Concept: A Case-study Approach to Glycemic Control in

The Incretin Concept:
A Case-study Approach to
Glycemic Control in
Type 2 Diabetes
Conducted during the 42nd ASHP Midyear
Clinical Meeting and Exhibition
Las Vegas, Nevada
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The Incretin Concept: A Case-study Approach to Glycemic Control
in Type 2 Diabetes
Program Overview
The prevalence of type 2 diabetes has increased dramatically in the United States over the past several
decades. Many patients with type 2 diabetes do not achieve goals for glycemic control recommended by the
American Diabetes Association and the American Association of Clinical Endocrinologists. Clinical research
to address this problem has led to a greater understanding of the role of incretins in postprandial glycemic
control in healthy persons and patients with type 2 diabetes. Incretins are gastrointestinal hormones that
enhance the secretion of insulin after the ingestion of food, thereby minimizing postprandial hyperglycemia.
The incretin effect in response to meals is diminished in patients with type 2 diabetes, possibly because of
reduced incretin secretion or decreased responsiveness of pancreatic beta cells to incretins. Exenatide is an
analog of the incretin glucagon-like peptide-1 (GLP-1) that was introduced in 2005. It is rapidly inactivated
by dipeptidyl-peptidase-4 (DPP-4), a widely expressed enzyme. Inhibitors of the DPP-4 enzyme have been
developed to increase plasma GLP-1 levels.
This symposium will discuss trends in the prevalence of type 2 diabetes and strategies to achieve goals for
glycemic control. The role of incretins in postprandial glycemic control in healthy persons and the incretin
abnormalities that contribute to type 2 diabetes will be explained. The mechanisms of action, routes of
administration, efficacy, and safety of currently available and investigational incretin analogs and DPP-4
enzyme inhibitors in patients with type 2 diabetes will be described. The role of incretin analogs and DPP-4
inhibitors in managing type 2 diabetes will be illustrated through a patient case study. Audience participation
was encouraged during the live CE program.
Learning Objectives
At the conclusion of this program, participants should be able to:
• Discuss the prevalence of type 2 diabetes and extent to which goals for glycemic control are achieved
with currently available therapeutic approaches.
•
Explain the role of incretins in postprandial glycemic control in healthy persons and the incretin
abnormalities that contribute to type 2 diabetes.
•
Describe the mechanisms of action, routes of administration, efficacy, and safety of currently available
and investigational incretin analogs and DPP-4 enzyme inhibitors in patients with type 2 diabetes.
•
Recommend appropriate use of an incretin analog or DPP-4 inhibitor in a patient with type 2 diabetes
who is a suitable candidate for such therapy.
Program Faculty
Susan Cornell, B.S., Pharm.D., CDE, CDM
Assistant Director of Experiential Education
Assistant Professor
Department of Pharmacy Practice
Midwestern University Chicago College of Pharmacy
Downers Grove, Illinois
John T. Johnson, Pharm.D., CDE
Clinical Associate Professor
The University of Georgia
College of Pharmacy
Athens, Georgia
The Incretin Concept: A Case-study Approach to Glycemic Control
in Type 2 Diabetes
Disclosure Statements
In accordance with the Accreditation Council for Continuing Medical Education’s Standards for
Commercial Support, ASHP Advantage requires that all individuals involved in the development of
program content disclose their relevant financial relationships. A person has a relevant financial
relationship if the individual or his or her spouse/partner has a financial relationship (e.g.,
employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount
occurring in the last 12 months with a commercial interest whose products or services may be
discussed in the CME activity content over which the individual has control. The existence of these
relationships is provided for the information of participants and should not be assumed to have an
adverse impact on presentations.
All faculty and planners for ASHP Advantage education activities are qualified and selected by
ASHP Advantage and required to disclose any relevant financial relationships with commercial
interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s
participation in development of content for an educational activity.
The faculty and planners report the following relationships:
Susan Cornell, B.S., Pharm.D., CDE, CDM
Dr. Cornell declares that she has served as a speaker for Abbott, Bayer, Merck, LifeScan,
Takeda, Novo-Nordisk, Omron, and Pfizer.
John T. Johnson, Pharm.D., CDE
Dr. Johnson declares that he has served as a consultant for GlaxoSmithKline and Novartis and as
a speaker for Eli Lilly, DIN Network, and Pfizer.
Cathy C. Bowles, R.Ph.
Ms. Bowles declares that she has no relationships pertinent to this activity.
Susan R. Dombrowski, M.S., R.Ph.
Ms. Dombrowski declares that she has no relationships pertinent to this activity.
The Incretin Concept: A Case-study Approach to Glycemic Control
in Type 2 Diabetes
Case Study
Description of presentation: Today’s session will include an interactive discussion of the
attached case study. The case involves a patient who has been recently diagnosed with type 2
diabetes with related conditions. Based on the data available in the case study, the facilitators and
audience will discuss practical management strategies and the scientific rationale that support
these strategies. Specific questions the audience will be asked to address include an assessment
of the patient’s glycemic control and strategies for improvement to the diabetes management plan.
Premise: You (audience members) are pharmacists working in a setting where you collaborate
with a group of physicians. You have access to the patient’s medication records. You are
responsible for evaluating and monitoring the patient’s therapy. You are responsible for providing
comprehensive patient management and education.
Initials
TC
DOB/Age
48 yr.
Sex
M
Race/Ethnicity
Hispanic
Source
Patient and medical records
CC/HPI (including sx analysis for CC):
“I’m feeling great. I know my doctor told me I need to control my sugar better; but I don’t want any needle
medicine!”
Patient here for a follow-up BG check. The patient states that he has been taking his medication “every day”
including this morning. He denies any feelings of dizziness, lightheadedness, or fatigue. He denies lower
extremity edema, palpitation, and chest pain. He is able to walk 3-4 blocks “easily” and a flight of stairs without
stopping.
The physician ordered routine labs (metabolic panel, TSH, and fasting lipids); the patient states he had them
done last week and had been fasting for at least 12 hours when the blood was drawn.
The Incretin Concept: A Case-study Approach to Glycemic Control
in Type 2 Diabetes
TC Patient Case-study
6/2005
Aspirin 81mg daily
CVD Prevention
2/2003
Atorvastatin 20 mg daily
Dyslipidemia
3/2006
Metformin 1000mg BID
T2DM
Vaccinations:
Influenza vaccine fall 2007
Drug Allergies/Adverse Effects: NKDA
Family Medical History:
Social History
Mother – T2DM, CVD
Residence: lives at home w/ wife
Wife does all the cooking
Smoking: Denies smoking, illicit drug use
Brother – T2DM, CVD
Occupation: Construction worker
EtOH: 1-2 beers on weekends
Objective Data (observations/vital signs/physical examination/labs)
General: pleasant male in NAD; A&0 x 3
BP = 132/78 mm Hg
Pulse = 68, regular
R=12
T=97.9 (oral)
Height = 5’ 6”
Weight = 193 lb.
BMI =31.4 kg/m2
Physical Exam – WNL
Laboratory Tests (measured 10/10/2007) - FASTING
Na = 139 K = 4.3 Cl = 99 CO3 = 23 BUN = 11 SCr = 0.9
Glucose = 148
A1C = 7.6
AST = 22
ALT = 44
Total Cholesterol = 178
LDL-C = 112
HDL-C = 29
TG = 217
Previous Laboratory Tests (measured 6/28/2007) - FASTING
Na = 137
K = 4.7
Cl = 101
CO3 = 22
BUN = 9
SCr = 0.8
Glucose = 136
A1C = 7.2
AST = 22
ALT = 44
Total Cholesterol = 174
LDL-C = 104
HDL-C = 30
TG = 202
The Incretin Concept: A Case-study Approach to Glycemic Control
in Type 2 Diabetes
The Burden of Uncontrolled Type 2 Diabetes
John T. Johnson, Pharm.D., CDE
Clinical Associate Professor
University of Georgia
College of Pharmacy
Athens, Georgia
John T. Johnson, Pharm.D., CDE received his Bachelor of Science in Pharmacy and Doctor of
Pharmacy degrees from the University of South Carolina. He has practiced in retail pharmacy, as
a hospital diabetes coordinator and currently serves as a Clinical Associate Professor at the
University of Georgia College of Pharmacy. Dr. Johnson lectures on diabetes and teaches a
course on diabetes management. His clinical practice sites include an indigent clinic where he
serves as a pharmacist and diabetes educator.
Dr. Johnson serves as Director of Professional Affairs for the Georgia Pharmacy Association,
where he oversees the delivery of the American Pharmacy Association Diabetes and
Cardiovascular Ten City Challenge program in Dalton, Georgia, along with other disease
management programs. Dr. Johnson has presented numerous professional continuing education
programs locally and nationally on improving the clinical management of diabetes. He has
published several journal articles and three book chapters.
Dr. Johnson is a member of the American Association of Diabetes Educators, where he currently
serves as 2nd Vice President on the Board of Directors. He is also a member of the Georgia
Pharmacy Association and the American College of Clinical Pharmacy.
The Incretin Concept: A Case-study Approach to Glycemic Control
in Type 2 Diabetes
A New Target in the Treatment of Type 2 Diabetes: The Incretin Effect
Susan Cornell, B.S., Pharm.D., CDE, CDM
Assistant Director of Experiential Education
Assistant Professor, Department of Pharmacy Practice
Midwestern University Chicago College of Pharmacy
Downers Grove, Illinois
Susan Ann Cornell, B.S., Pharm.D., CDE, CDM is Assistant Director of Experiential Education and
Assistant Professor, Department of Pharmacy Practice at Midwestern University Chicago College
of Pharmacy in Downers Grove, Illinois. Dr. Cornell is also a clinical pharmacy consultant and
certified diabetes educator, specializing in community and ambulatory care practice. She has over
18 years of practice in community pharmacy where she has served as a clinical pharmacist,
diabetes educator and preceptor. Dr. Cornell has also served as coordinator of Dominick’s
Pharmacy Diabetes Self-Management Education, a program which received ADA recognition in
December of 2001.
Dr. Cornell received a Bachelor of Science in Pharmacy from the University of Illinois College of
Pharmacy in 1986 and a Doctor of Pharmacy from Midwestern University in May of 2002.
Dr. Cornell’s current clinical practice is with Access Community Health Network, where she trains,
educates, and supervises students from the colleges of medicine, pharmacy, and health sciences,
as they provide diabetes education classes for patients in underserved clinics.
Dr. Cornell was awarded the 2006 Midwestern University Chicago College of Pharmacy Alumnus
of the Year Award, the 2005 Midwestern University Golden Apple Teaching Award and the 2003
Illinois Pharmacists Association’s Pharmacist of the Year award. Dr. Cornell is an active member
of the American Diabetes Association (ADA) and a counselor for the ADA Kids Summer Camp.
She is also a member of the American Association of Diabetes Educators, serving on the Board
of Directors.
Dr. Cornell has given numerous presentations to various healthcare professionals and community
groups. She has published and contributed to numerous professional publications, including a
chapter in the newly released text The Art and Science of Diabetes Self-Management Education:
A Desk Reference for Healthcare Professionals.
The Incretin Concept: A Casestudy Approach to Glycemic
Control in Type 2 Diabetes
Conducted during the
42nd ASHP Midyear Clinical Meeting
Las Vegas, Nevada
Learning Objectives
The Burden of Uncontrolled
Type 2 Diabetes
John T. Johnson, Pharm. D., CDE
Clinical Associate Professor
University of Georgia College of Pharmacy
Athens, Georgia
Diabetes is a Growing Threat to Our
Nation’s Health
• Explain the prevalence of type 2 diabetes in the
United States, and the economic and public
health burden of diabetes-related complications.
• Summarize the advantages and disadvantages
of current approaches to glycemic control in type
2 diabetes.
Every 21 seconds, someone in America is
diagnosed with diabetes.
http://diabetes.org/uedocuments/Every21Seconds.PR.pdf
Prevalence of Diabetes in the
United States
• 20.8 million people have diabetes
> 6 million people with diabetes remain undiagnosed
• 10.3 million adults over the age of 60 have
diabetes
• ~ 53 million people have pre-diabetes
• 25-50% increase in children with type 2 diabetes
• 6th leading cause of death listed on U.S. death
certificates in 2002
Why is Glucose Control Important?
• 60% of people with type 2 diabetes have
at least 1 complication because of
diabetes.
• 7% of PWD have 4 or more complications.
PWD = people with diabetes
www.stateofdiabetes.com
Centers for Disease Control and Prevention. National diabetes fact sheet:. Atlanta, GA: U.S.
Department of Health and Human Services, Centers for Disease Control and Prevention, 2005.
1
Future Generations At Risk
• One in every three babies born today will
eventually develop type 2 diabetes.
• For “at risk” populations, one in two babies will
develop type 2 diabetes.
UNLESS AGGRESSIVE STEPS ARE TAKEN TO
PREVENT DIABETES, THIS EPIDEMIC WILL
GROW
What About Type 2 Diabetes in Children?
• 5 x higher prevalence since 1960
– 1992: < 3% of new cases
– 2007: > 45 % all new cases
• 20% of people under the age of 20 with diabetes have
type 2
• Increased risk with family history, obesity, race and
being female
• Acanthosis nigricans common
www.asu.edu/educ/epsl/CERU/Articles/CERU-0306-116-OWI.doc
Long-Term Problem for Children
Diagnosed with Type 2 Diabetes
www.ndep.nih.gov/diabetes/youth/youth_FS.htm
What About Adults?
• 30% of children diagnosed with type 2
diabetes will die because of diabetesrelated problems by age 50.
http://diabetes.niddk.nih.gov/dm/pubs/statistics
/
Why Should We Be Concerned?
• During one 24-hour period:
– 4100 people will be diagnosed with diabetes
– 230 patients will undergo amputations
– 120 patients will enter end-stage renal disease
programs
– 55 patients will go blind
– 810 patients will die
Derived from NIDDK, National Diabetes
Statistics fact sheet. HHS, NIH, 2005.
Glycemic Control is Key to
Managing Diabetes
• Tight glycemic control
– Minimizes and prevents microvascular
complications
• Results of the DCCT, Kumamoto, UKPDS
• Narrow target range
– Minimal fluctuation reduces macrovascular
complications
Buckley B, et al. Diabetes Trends. 2003;15:14-20.
Avignon A, et al. Diabetes Care. 1997;20:1822-1826.
Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-17.
2
Lowering HbA1c Reduces the Risk of
Complications
Why We Do It
Better Control Reduces Complications
21%
HbA1c
Microvascular
complications
37%
1%
Cumulative Incidence (%)
60
Deaths related
to diabetes
50
76%
Risk Reduction
59%
Risk Reduction
39%
Risk Reduction
30
29.8
•23.9
20
16.4
10
Retinopathy
Progression
Stratton IM, et al. BMJ 2000; 321:405 –412.
•13.4
13.0
•5.1
0
Myocardial
infarction
14%
64%
Risk Reduction
Conventional
Intensive
40
7.9
The power of 1%
54%
Risk Reduction
•55.0
Laser Rx1
Microalbuminuria2
5.0
2.5
Albuminuria2
Clinical
Neuropathy3
1.
DCCT Research Group, Ophthalmology. 1995;102:647-661.
2.
DCCT Research Group, Kidney Int. 1995;47:1703-1720.
3.
DCCT Research Group. Ann Intern Med. 1995;122:561-568.
Healthcare Costs* for Patients With
Diabetes by Age and CVD
No CVD
12,000
The American Diabetes Association
Estimates That By The Time A Patient Is
Finally Diagnosed With Type 2 Diabetes
They Have Actually Had Diabetes For
About 9 Years!
CVD
10,000
Mean
per
capita
costs
($)
8,000
6,000
4,000
2,000
0
All
*Estimated annual average
<45
45-54
55-64
65-74
75-84
Kendall DM, et al. 2004 International Diabetes Center,
Minneapolis, MN.
85+
Age (yr)
Nichols GA, Brown JB. Diabetes Care. 2002;25:482-486.
Prevalence of Complications at Time of Diagnosis
United Kingdom Prospective Diabetes Study
“NEWLY DIAGNOSED”
Complication
Prevalence (%)*
Any complication
Retinopathy
Abnormal ECG
Absent foot pulses (≥2) and/or ischemic feet
Impaired reflexes and/or decreased vibration sense
Myocardial infarction/angina/claudication
Stroke/transient ischemic attack
50
21
18
14
7
~2-3
~1
*Some patients had more than 1 complication at diagnosis.
Adapted from Holman RR. Consultant. 1997;37(suppl):S30-S36. UKPDS. Diabetologia.
1991;34:877-890.
Type 2 Diabetes Timeline
Genetic susceptibility
Environmental factors
— poor nutrition
— obesity
— physical inactivity
Diagnosed
diabetes
Retinopathy
Nephropathy
Neuropathy
symptoms
Pre-Diabetes
Ongoing Hyperglycemia
Insulin Resistance
HDL cholesterol
Triglycerides
CVD
Death
Blindness
Renal failure
Heart disease
Stroke
Amputation
Disability
Postprandial blood
glucose levels
Adapted from slides by Donald Zettervall, RPh, CDE.
3
Correlation Between A1C and Mean
Plasma Glucose Levels
Targets for Glycemic Control
A1C
ADA
American Diabetes
Association
AACE
American Association of
Clinical Endocrinologists
Normal
FPG
PPG
(mg/dL)
(mg/dL)
<7.0%
90-130
<180
(1-2hr)
<6.5%
<110
<140
(2hr)
<6.0%
<110
<140
Diabetes Care.
Care. 2007;30(supp1):S42007;30(supp1):S4-S41.
Endocrine Practice. 2002;8(suppl 1):6-11.
mean plasma glucose levels (mg/dL)
65
100
135
170
4
5
6
7
Blood pressure
<130/80 mm Hg
Lipids
LDL
<100 mg/dL*
Triglycerides
<150 mg/dL
HDL
>40 mg/dL men
>50 mg/dL women
*LDL <70 mg/dL is a therapeutic option
8
9
275
10
310
11
345
12
380
13
Diabetes Care. 2003; 26 (Suppl 1):S33-50.
PPG Contribution to A1C
FPG
PPG
Percentage of Contribution
Goal
240
A1C%
Other ADA Recommendations
Parameter
205
100
80
30%
50%
55%
60
40
60%
70%
70%
50%
20
0
<7.3
7.3–8.4
45%
8.5–9.2
40%
9.3–10.2
30%
>10.2
A1c Range (%)
Monnier L et al. Diabetes Care. 2003;26:881-885.
How well are blood glucose levels being
controlled?
If treating to target is the goal,
how are we doing ?
• National averages of blood glucose values are
above desired goals.
– Fasting plasma glucose (FPG) > 200 mg/dL
– Postprandial plasma glucose (PPG) > 300 mg/dL
– A1C > 9.5%
Beckles GLA, et al. Diabetes Care. 1998;21: 1432-38.
4
Aggressive Control of Type 2
Diabetes is a Challenge
Distribution of A1C (%) Among Patients with Recorded Test Results
(n=270,758) in Community Practice
Percent of Patients
100
76% of patients
surveyed had an
A1c level recorded
in the chart in the
previous 12 months
75
45
50
23
25
13
12
8
Percent of Type 2 Patients
Changes in Diabetes Treatment
60%
53%
50%
45%
40%
30%
27%
24%
20%
16%
10%
20%
11%
Insulin Only
Pills Only
Pills + Insulin
Diet Only
3%
0%
0
<7%
7-7.9%
8-8.9%
9-9.9%
>9.9%
(n=122,453)
(n=62,252)
(n=35,472)
(n=20,688)
(n=29,893)
1988-1994
1999-2000
NHANES III
NHANES IV
Koro CE, et al. Diabetes Care. 2004; 27:17-19.
Graham, et al. Diabetes. 2002;51(Suppl 2):A274.
..Appear to Have Resulted in a
Worsening of Glucose Control!
Percentage of People with Diabetes under Good Glucose Control
(American Diabetes Association A1C < 7.0%)
Percent of Patients
50%
• Euglycemia
• Pre Diabetes and Diabetes
44.5%
40%
How Did Our Bodies Function
Before and After Diabetes?
35.8%
30%
20%
10%
0%
1988-1994
1999-2000
NHANES III
NHANES IV
Koro CE, et al. Diabetes Care. 2004; 27:17-19.
Glucagon-Like Peptide 1
Pathophysiology
Islet Cell Dysfunction & Insulin Resistance
Glucagon
(alpha cells)
Mixed
meal
Gut
Pancreas
Glucose output
Liver
GLP-1
Insulin
Amylin
(beta cells)
Blood glucose
Long-term GLP-1 actions:
•Increase insulin synthesis
•Promote β-cell differentiation
Intestinal
GLP-1
release
Active
GLP-1
Glucose uptake
Muscle
Adipose
tissue
1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.
2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
Acute GLP-1 Actions:
• Augment glucose-induced insulin
secretion
• Inhibit glucagon secretion and hepatic
glucose production
• Slow gastric emptying
• Increase glucose disposal
DPP-4
DPP-4
inhibitor
Inactive GLP-1
Adapted from Rothenberg P. Diabetes. 2000;49(suppl 1):A39.
Drucker DJ. Diabetes Care. 2003;26:2929-2940.
5
Treatment Options in the
Management of Type 2 Diabetes
• Pharmacological
• Non-Pharmacological
Management of Diabetes
–
–
–
–
–
–
–
–
– DSME education
– Physical Activity
– Medical Nutrition
Therapy
– SMBG
– Stress management
α-Glucosidase Inhibitors
Biguanides
DPP-4 inhibitors
Glitinides
Incretins
Insulin
Sulfonylureas
Thiazolidinedones
DSME = diabetes self-management education
SMBG = self-monitoring of blood glucose
Diabetes SelfSelf-Management Education (DSME) is
the Cornerstone.
Lifestyle plays a crucial role.
80% of Diabetes Management is about Lifestyle.
Anderson RM, The Art of Empowerment. American Diabetes Association. 2005.
Weight
Management
Self-Monitoring
Activity
Patient Case: TC
• TC is a 48 y/o Hispanic male who refuses to “take any needle
medicine”
– Past Medical History
• Type 2 DM x 2 yrs
• Dyslipidemia x 4 yrs
– Social History
•
•
•
•
Lifestyle
Education
Construction worker
Wife does all the cooking
Denies smoking, illicit drug use
1-2 beers on weekends
– Current Medications
• Metformin 1000mg twice daily
• Aspirin 81mg daily
• Atorvastatin 20 mg daily
– He is adherent to his medication, medical nutrition therapy, and
exercise regimen (30 min walking 3-4 days/wk)
Nutrition
Patient Case: TC (cont’d)
Objective Data
Questions:
BP = 132/78 mm Hg
Pulse = 68 bpm, regular
Weight = 193 lb. Height = 5’ 6”
Physical Exam - WNL
Labs:
Na = 139
BUN = 11
FBG = 148
TChol = 178
K = 4.3
SCr = 0.9
A1C = 7.6
LDL = 112
Patient Case: TC
Based on his A1c of 7.6, approximately what
percentage does the post-prandial blood glucose
contribute?
Cl = 99
AST = 22
CO3 = 23
ALT = 44
HDL = 29
TG = 217
95%
65%
35%
6
Learning Objectives
A New Target in the Treatment of
Type 2 Diabetes: The Incretin Effect
• Explain the role of incretins in postprandial glycemic
control in healthy persons and the incretin abnormalities
that contribute to type 2 diabetes mellitus.
• Describe the mechanisms of action, routes of
administration, efficacy, and safety of currently available
and investigational incretin analogs and DPP-4 enzyme
inhibitors in patients with type 2 diabetes.
Susan Cornell, B.S., Pharm.D., CDE, CDM
Assistant Professor
Midwestern University
Chicago College of Pharmacy
Downers Grove, Illinois
“The consistent failure to achieve
treatment goals in diabetes reflects the
inadequacies in our treatment strategies.
We need to adopt an uncompromising
approach to achieving glycemic goals”
• Recommend appropriate use of an incretin analog or
DPP-4 inhibitor in a patient with type 2 diabetes who is a
suitable candidate for such therapy.
Key Points to Consider when Selecting
Pharmacotherapy for T2DM
•
•
•
James R. Gavin, M.D., Ph.D.
Former President, ADA
•
•
How long the patient has had diabetes (duration of
disease).
Which blood glucose level is not at target (e.g.,
fasting, postprandial, or both).
Patient preference for route of administration (e.g.,
oral, inhaled, injectable)
The degree of A1C-lowering effect required to
achieve goal.
The side effect profile and the patient’s tolerability.
ADOPT: Cumulative Incidence of Monotherapy
Failure (FPG >180 mg/dL)
40
Yes
No
Maybe
Rosi vs Met; 0.68 (0.55-0.85) P<.001
32% risk reduction,
30
Percent (%)
Is There a Role for Monotherapy in
the Treatment of Type 2 Diabetes?
Glyburide
Rosi vs Glyburide; 0.37 (0.30-0.45) P<.001
63% risk reduction,
Metformin
20
Rosiglitazone
10
0
0
1
Rosiglitazone 1393
Metformin
1397
Glyburide
1337
2
3
4
5
844
818
617
324
311
218
Time (years)
Patients at Risk
1207
1205
1114
1078
1076
958
957
950
781
Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.
7
Need for an Early and Intensive Approach
to Type 2 Diabetes Management
Key to Optimal Control is Early
Diagnosis and Treatment with
Agents That Address the
Underlying Pathophysiologic
Abnormalities
• Current management:
4two-thirds of patients do not
achieve target HbA1c
4majority require
polypharmacy to meet
glycemic goals over time
1
UKPDS Group. Diabetologia 1991; 34:877–890. 2Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25.
3
Saydah SH, et al. JAMA 2004; 291:335–342.
4
Liebl A, et al. Diabetologia 2002; 45:S23–S28. 5Turner RC, et al. JAMA 1999; 281:2005–2012.
“Therapeutic Inertia”
Failure to advance therapy when required
Last A1C Value Before Abandoning Treatment
10
9.6%
9.1%
Length of time between first monotherapy HbA1c > 8.0%
and switch/addition in therapy (months)
8.8%
8.6%
25
20.5 months
8
7
20
ADA Goal
Months
% Mean HbA1C
at last visit1
9
Delays Often Occur Between Stepping Up from
Monotherapy to Combination Therapy
Sulfonylurea
14.5 months
15
10
5
Combination
Diet/Exercise
0
Metformin
2.5 years
1Brown
2.9 Years
2.2 Years
Metformin only
n = 513
2.8 Years
Sulfonylurea only
n = 3394
Brown, JB et al. Diabetes Care 2004; 27:1535–1540.
et al. The Burden of Treatment Failure in Type 2 Diabetes. Diabetes Care 27: 1535-1540, 2004
The Incretin Effect in Healthy Subjects
Oral Glucose
Intravenous (IV) Glucose
200
*
2.0
*
C-peptide (nmol/L)
Plasma Glucose (mg/dL)
So, What’s New and Emerging in
the Treatment of T2DM?
100
0
1.5
*
1.0
*
Incretin Effect
*
*
*
0.5
0.0
0
60
Time (min)
120
180
0
60
120
Time (min)
180
N = 6; Mean (SE); *P≤0.05
Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
8
Decreased Postprandial Levels of GLP-1
in Patients with Type 2 Diabetes
The Incretin Effect in Subjects Without and
With Type 2 Diabetes
Control Subjects
(n=8)
Patients With Type 2 Diabetes
(n=14)
Incretin
Effect
0.3
0.2
20
0.1
0
0
0
60
120
*
0.5
0.4
0.3
40
nmol/L
0.4
40
60
0.2
20
*
*
IGT, n=15
*
*
15
NGT, n=33
*
10
5
0
0
60
120
0
0
180
Time, min
(10-15)
60
Intravenous (IV) glucose infusion
180
120
240
Time after start of meal, minutes
Meal
Meal
Started Finished
Oral glucose load
*P<0.05, Type 2 diabetes vs NGT.
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab.
2001;86:3717–3723. Copyright © 2001, The Endocrine Society.
Selected Peptide Hormones of the
Gastrointestinal (GI) Tract
Non-Incretin Hormones
– Gastrin
– Cholecystokinin
– Secretin
– Ghrelin
– Motilin
– Somatostatin
– Neurotensin
– PYY (peptide YY)
– GLP-2 (glucagon-like
peptide 2)
*
0.1
0
180
Time, min
Type 2 diabetes, n=54
20
0.6
The incretin effect
is diminished
in type 2 diabetes.
0.5
IR Insulin, mU/L
60
80
nmol / L
IR Insulin, mU/L
80
GLP-1, pmol/L
0.6
GLP-1 and GIP are Incretin Hormones
GLP-1
Incretin Hormones*
– GIP (glucose-dependent
insulinotropic polypeptide)
– GLP-1 (glucagon-like
peptide 1)
GIP
ƒ Is released from L cells in ileum
and colon1,2
ƒ Is released from K cells in
duodenum1,2
ƒ Stimulates insulin response from
beta cells in a glucose-dependent
manner1
ƒ Stimulates insulin response from
beta cells in a glucose-dependent
manner1
ƒ Inhibits gastric emptying1,2
ƒ Has minimal effects on gastric
emptying2
ƒ Reduces food intake and
body weight2
ƒ Has no significant effects on satiety
or body weight2
ƒ Inhibits glucagon secretion from
alpha cells in a glucose-dependent
manner1
ƒ Does not appear to inhibit glucagon
secretion from alpha cells1,2
* Gut hormones that enhance insulin secretion in response to food
Current Pharmacological Strategies to
Enhance Incretin Activity
1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
Effect of Exenatide on Postprandial
Glucose and Glucagon in Type 2 Diabetes
• Exenatide (Byetta®)
• Liraglutide
• Block the degradation of GLP-1
– Inhibit DPP-4 enzyme (DPP-4 inhibitors)
• Sitagliptin (Januvia®)
• Vildagliptin (Galvus®)
• Saxagliptin
Exenatide or Placebo
Exenatide or Placebo
Plasma Glucose (mmol/L)
– Long-acting GLP-1 analogs (incretin mimetics)
Placebo
Exenatide 0.1 µg/kg
Placebo
Exenatide 0.1 µg/kg
• Activate GLP-1 receptors
20
Standardized Breakfast
Plasma Glucagon (pg/mL)
Boushey RP et al. In: Larsen PR et al. Williams Textbook of Endocrinology.
10th ed. WB Saunders Co. 2003.
15
10
5
0
250
Standardized Breakfast
200
150
100
50
0
60
120
180
Time (min)
240
300
0
30
60
90 120 150 180
Time (min)
Data adapted from Kolterman OG, et al. J Clin Endocrinol Metab. 2003; 88:3082-3089.
9
Effect of Exenatide on Insulin
Secretion in Type 2 Diabetes
250
200
150
100
50
-1.0
-0.6
-0.9
0
1
2
3
4
5
6
7
-1.6*
-2.0
-2.8*
(n=377)
Major Adverse Events Associated with
Exenatide Across All Studies
Adverse Event
Placebo
Exenatide
Nausea
7-23%
36-45%
Severe Nausea
2%
3-5%
Hypoglycemia
3-13%
25%
Dizziness
6-7%
4-15%
Vomiting
2-5%
11-15%
Diarrhea
4-8%
10-17%
Headache
5-7%
7-11%
Mean Change in FPG
Mean Change (mg/dL)
Mean Change (%)
-0.1
-0.5
-0.6
-0.7
-0.8
-0.9
-0.8
Mean Change in Weight
(BL Mean ~100 kg)
0
0
-5
-1
-10
-15
-20
-25
-30
-24
*P < 0.05 vs placebo
•Objective: To assess the effects of exenatide on cardiovascular risk
factors, glycemic control, and weight reduction in patients with T2DM
already receiving metformin and/or a sulfonylurea
•Design: Open-label extension study with completers of 30-week placebocontrolled trials for total duration of 3.5 years
Background
regimen of
metformin
and/or a
sulfonylurea
Exenatide twice daily
30-week placebocontrolled phase
Open-label
extension phase
Total duration: 3.5 years
T2DM=type 2 diabetes mellitus
Kendall D, et al. Abstract 557-P. Poster Presentation, 67th Scientific Sessions ADA 2007.
Study Results
Mean Change (%)
0
(n=733)
Study of Exenatide and CVD Risk Factors
Study Results
(BL Mean ~170 mg/dL)
(n=336)
1. Buse Diabetes Care. 2004;27:2628.
2. DeFronzo. Diabetes Care. 2005;28:1092.
3. Kendall. Diabetes Care. 2005;28:1083.
N=151
Buse JB, et al for the Exenatide-113 Clinical Study Group. Diabetes Care. 2004;27:2628-2635.
DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.
Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.
Mean Change in A1C
(BL Mean ~8.2%)
-1.6* -1.6*
Exenatide + SU 1 Exenatide + Met 2 Exenatide + SU + Met 3
Data adapted from: Kolterman OG, et al. J Clin Endocrinol Metab. 2003; 88:3082-3089.
-0.4
-1.6*
-2.5
8
Time (h)
-0.3
-0.9
-1.5
-3.0
-1
Exenatide 10 mcg
-0.3
-0.5
0
-0.2
Exenatide 5 mcg
0.0
Change in Weight (kg)
Serum Insulin (pmol/L)
Placebo
Placebo
0.05 µg/kg exenatide
0.1 µg/kg exenatide
0.2 µg/kg exenatide
300
Weight Changes: Exenatide + Oral Agent Therapy
30-Week, Randomized, Placebo-Controlled Trials
Baseline
(Mean ± SD)
Change from
Baseline*
(Mean ± SE)
Average of %
Change
Triglycerides (mg/dL)
225 ± 142
-44.4 ± 12.1
-12%
Total cholesterol (mg/dL)
184 ± 37
-10.8 ± 3.1
-5%
Parameter
HDL-C (mg/dL)
39 ± 10
+8.5 ± 0.6
+24%
LDL-C (mg/dL)
114 ± 33
-11.8 ± 2.9
-6%
SBP (mm Hg)
129 ± 13
-3.5 ± 1.2
-2%
DBP (mm Hg)
79 ± 8
-3.3 ± 0.8
-4%
-2
-3
-4
-5
-6
BL=baseline; FPG=fasting plasma glucose
Kendall D, et al. Abstract 557-P. Poster Presentation, 67th Scientific Sessions ADA 2007.
-5.3
*All changes from baseline statistically significant
SD=standard deviation; SE=standard error; HDL-C=high-density lipoprotein cholesterol; LDL-C=lowdensity lipoprotein cholesterol; SBP=systolic blood pressure; DBP=diastolic blood pressure
Kendall D, et al. Abstract 557-P. Poster Presentation, 67th Scientific Sessions ADA 2007
10
Liraglutide
Exenatide – Dosing
• Administer before morning and evening
meals
Needles not included with pen device
• Starting dose: 5 mcg twice daily
• Increase to 10 mcg twice daily after
30 days
• Does not replace insulin
• Dose should not be adjusted for meals or
exercise
• Store in refrigerator; “in use” syringe may
be kept at room temperature up to 30 days
• Currently in Phase 3 trials
• Has a prolonged half-life (11-15 hours) compared
with native GLP-1
– Once daily administration
• In Phase 2 clinical trials:
–
–
–
–
–
Increased meal-related insulin secretion
Suppressed postprandial glucagon secretion
Decreased A1C modestly (0.7-0.8%)
Modest weight loss (0.7-1.2 kg)
Possible CVD risk improvements
• ↓ SBP
• ↓ TG
• Only prime prior to first injection
Liraglutide
Madsbad S, et al. Diabetes Care 2004; 27: 1335-42.
Harder H, et al. Diabetes Care 2004; 27: 1915-21.
DPP-4 Inhibitors
(a.k.a. Gliptins)
• Monotherapy
– 165 patients with DM type 2 (diet controlled) and
baseline A1C = 8.1- 8.5%
– Liraglutide 0.65 mg, 1.25 mg, 1.9 mg s.c. daily vs.
placebo for 14 weeks
– Fasting plasma glucose ⇓ 16.7 mg/dL (p<0.001)
– A1C ⇓ 1.74% (mean improvement in 3 groups, p<0.001)
– 43-50% of patients reached A1C < 7% vs. only 8% on
placebo
– Weight change -3 kg vs 1.2 kg (p=0.039)
– GI side effects common; diarrhea (19.5%) and nausea
(10%) occurred most frequently
• Sitagliptin
• Vildagliptin
• Saxagliptin
Vilsboll T, et al. ADA 2006 Annual Meeting, Abstract 115-OR.
Sitagliptin Plus Sulfonylurea or
Sulfonylurea and Metformin
DPP-4 Inhibitors
• Mechanism of action
– Inhibit breakdown of GLP-1 and GIP
– Hence, levels of GLP-1 and GIP rise, especially
in response to meals
• This inhibits glucagon
• Stimulates endogenous insulin secretion when glucose
is highest
• Regulates GI motility
– Since these agents increase only glucosestimulated insulin secretion, there is little risk of
hypoglycemia.
Objective:
Design:
To assess efficacy and safety of sitagliptin added to sulfonylurea
or sulfonylurea/metformin in patients with T2DM
Randomized, double-blind, placebo-controlled trial
n=106 Sitagliptin 100 mg QD
n=212 Glimepiride ≥4 mg QD
+
n=106 Placebo
N=441
n=116 Sitagliptin 100 mg QD
Inadequate glycemic control n=229 Glimepiride ≥4 mg +
Metformin ≥1500 mg QD
on Glim or Met+Glim
+
n=113 Placebo
(HbA1c 7.5%-10.5%)
Titration/stabilization
Randomization
24 Weeks
Glim=glimepiride; Met=metformin; T2DM=type 2 diabetes mellitus
Hermansen K, et. al. Poster Presentation, 67th Scientific Session ADA 2007.
11
Sitagliptin Plus Sulfonylurea or
Sulfonylurea and Metformin : Study Results
Mean Change HbA1c (%)
Change in A1C at the end of 24th Week
PBO + Glim/ PBO + Glim + Met
0.5
0.3
Mean Difference
vs. Placebo
Sita + Glim/ Sita + Glim + Met
0.3
0.1
-0.1
-0.3
-0.5
-0.5
-0.7
*
-0.7
-0.9
* P<0.001
BL=baseline; Glim=glimepiride; Met=metformin; T2DM=type 2 diabetes mellitus
Hermansen K, et. al. Poster Presentation, 67th Scientific Session ADA 2007.
Sitagliptin Plus Sulfonylurea or Sulfonylurea
and Metformin : Study Results
Mean PBO-Subtracted Change (mmol/L)
FPG
0
-0.2
Sitagliptin +
Glimepiride
-0.4
-0.6
Sitagliptin +
Glimepiride +
Metformin
-0.6
-0.8
-0.9
-1
Hermansen K, et. al. Poster Presentation, 67th Scientific Session ADA 2007.
Sitagliptin
• Dose 100 mg daily with or without food
• No dose adjustment in mild-moderate
hepatic insufficiency
2-h PPG
0.5
Sita + Glim/ Sita + Glim + Met
0
– Not studied in severe hepatic impairment
• Dose adjustment in renal impairment
-0.5
– Cr Cl > 30 to < 50 mL/min is 50 mg daily
-1
*
-1.5
Mean Placebo-Subtracted
Change HbA1c (%)
Mean Change from BL
(BL Mean=8.3%)
Sitagliptin Plus Sulfonylurea or Sulfonylurea
and Metformin : Study Results
• Males: Cr > 1.7 to < 3 mg/dL
• Females: Cr > 1.5 to < 2.5 mg/dL
-1.1
20 mg/dl
-2
– Cr Cl < 30 mL/min is 25 mg daily
*
-2
36 mg/dl
-2.5
* P<0.001
FPG=fasting plasma glucose; Glim=glimepiride; Met=metformin; PPG=postprandial glucose
Hermansen K, et. al. Poster Presentation, 67th Scientific Session ADA 2007.
Sitagliptin
• Effects on A1C, BG, Weight
– If A1C is ~8-9%
• A1C ↓ 0.6 to 0.8%
– If A1C is 9-10%
• A1C ↓ 1.4%
– FBG ↓ ~12 to 17 mg/dL
– PPG ↓ ~ 50-60 mg/dL
– Weight neutral
• Males: Cr > 3 mg/dL
• Females: Cr > 2.5 mg/dL
• On dialysis
Sitagliptin
• Side effects
– Headache
– Nasopharyngitis
– Upper respiratory infections
• Drug Interactions
– Studied in combination with SUs, metformin,
pioglitazone
– 38% protein bound
– Does not inhibit or induce isoenzyme systems
• Minor metabolism through CYP 3A4 and 2C8
– Small ↑ in digoxin serum drug conc. (11-18%)
12
Effects of the DPP-4 Inhibitor Vildagliptin
on Glycemic Control
Vildagliptin
– In severe dysfunction, AUC increases 30%, but not half-life.
– No adjustment needed for severe hepatic dysfunction.
)LAF/MET (Core, ITT n = 56
)PBO MET(Core, ITT n = 51
8.4
Hemoglobin A1C (%)
• An oral selective DPP-4 inhibitor
• Similar to sitagliptin, has prolonged half-life and can be
administered once daily.
• In rat models, increased beta cell mass and enhanced
endogenous incretin activity.
• Reduces fasting and postprandial BG, reduces
postprandial glucagon, without changing 24-hour insulin
secretion.
• Primarily hepatically metabolized
)LAF/MET (Extension, ITT n = 42
)PBO/MET (Extension, ITT n = 29
8.0
7.6
7.2
6.8
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Time (weeks)
American Diabetes Association 2005 Annual Meeting, Abstracts 572-P and 2192-PO
Ahrén B, et al. Diabetes Care 2004; 27: 2874-80.
Ahrén B, et al. J Clin Endocrinol Metab 2004; 89: 2078-84.
Ahrén B, et al. Diabetes Care. 2002; 25: 869-875.
Efficacy and Tolerability of Vildagliptin Added
to a Sulfonylurea
Efficacy and Tolerability of Vildagliptin Added
to a Sulfonylurea : Study Results
Objective: To assess the efficacy and tolerability of vildagliptin added to
glimepiride in patients with T2DM
Design:
Double-blind, randomized, controlled study
A1C Change from BL to EP
(BL Mean ~8.5%)
n
132
n=132 Vildagliptin 50 mg QD + Glimepiride 4 mg QD
N* = 408
n=132
Continuing glimepiride 4 mg
QD treatment
Vildagliptin 50 mg BID + Glimepiride 4 mg QD
n=144
Placebo + Glimepiride 4 mg QD
4 Weeks
24 Weeks
Efficacy and Tolerability of Vildagliptin
added to a Sulfonylurea: Study Results
144
n
Vildagliptin 50 mg QD
0.3
0.2
0.2
Placebo
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.3
-0.5
*P=0.118 vs placebo
9 mg/dl
21
23
Vildagliptin 50 mg QD
0.4
0.2
0.2
Placebo
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
-1.4
-1.3
-1.6
-1.5
27 mg/dl
*P=0.008 vs placebo
BL=baseline; EP=study endpoint
Garber AJ,, et. al. Poster Presentation, 67th Scientific Session ADA 2007.
Placebo
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
*
*P<0.001 vs placebo
-0.6
*
-0.7
Mean Difference vs. Placebo
Efficacy and Tolerability of Vildagliptin
Added to a Sulfonylurea : Study Results
Mean Change in β-cell Function from BL to EP
Peak Glucose Excursion Change from BL to EP
(BL Mean ~6.1 mmol/L)
Adjusted Mean Change (mmol/L)
Adjusted Mean Change (mmol/L)
132
Vildagliptin 50 mg QD
0
*Primary ITT population
BL=baseline; EP=study endpoint
Garber AJ, et. al. Poster Presentation, 67th Scientific Session ADA 2007.
(BL Mean ~18.6 pmol/min/m2/mM)
Adjusted Mean Change† (pmol/min/m2/mM)
Fasting Plasma Glucose Change from BL to EP
(BL Mean ~10.4 mmol/L)
144
0.1
0.1
-0.8
*Primary ITT population (patients treated with SU monotherapy at least 3 months prior to randomization).
Garber AJ, et. al. Poster Presentation, 67th Scientific Session ADA 2007.
n
Adjusted Mean Change (%)
0.2
n
20
23
5
4.1 *
Vildagliptin 50 mg QD
Placebo
4
3
2.9
2
1
0
Mean Difference vs. Placebo
-1
-2
-1.2
*Primary ITT population
*P=0.024 vs. placebo
†Insulin secretion rate relative to glucose (0–
(0–2 hr)
BL=baseline; EP=study endpoint
Garber AJ, et. al. Poster Presentation, 67th Scientific Session ADA 2007
13
Saxagliptin Added to Metformin
Study Objective and Design
Saxagliptin Added to Metformin:
Study Results
Saxagliptin 5 mg QD + Metformin
N=743
Saxagliptin 10 mg QD + Metformin
Placebo + Metformin
24 Weeks
Study Results
A1C ≤7% (BL~8.0%)
*
*
44
44
5 mg
10 mg
37
Patients (%)
35
30
25
20
17
15
10
5
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.72
-0.73
*
-0.83
*
*
2.5 mg
5 mg
10 mg
0
-5
-10
-15
-16
-20
-23
-25
-30
-22
*P<0.0001 vs placebo.
Take Home Message
• Control to goal
*
40
-0.1
-0.8
FPG Change from BL to EP (BL~176 mg/dL)
10 mg
LOCF=last observation carry forward; BL=baseline; EP=study end point
DeFronzo RA, et. al. Oral Presentation, 67th Scientific Session ADA 2007.
Saxagliptin Added to Metformin:
Metformin:
45
5 mg
0
-0.9
T2DM=type 2 diabetes mellitus
DeFronzo RA, et. al. Oral Presentation, 67th Scientific Session ADA 2007.
50
2.5 mg
Mean Placebo-Subtracted Chang
Saxagliptin 2.5 mg QD + Metformin
Inadequate glycemic control
(A1C 7%-10%) on stable
dose of metformin
(1500-2550 mg/day)
A1C Change from BL to EP (BL~8.0%)
Mean Placebo-Subtracted Change (m
Objective: To assess efficacy and safety of saxagliptin added to
metformin in patients with T2DM
Design:
Phase III randomized, placebo-controlled trial
*P<0.0001 vs placebo.
– Treat aggressively to achieve A1C< 7%
(preferably < 6.5%).
– If not at goal after 3 months, adjust therapy,
which most likely will be combination
pharmacotherapy.
– Use combination therapy that targets the
different dysfunctional organs.
0
Placebo
2.5 mg
BL=baseline
DeFronzo RA, et. al. Oral Presentation, 67th Scientific Session ADA 2007.
Take Home Message
Key Points to Consider when Selecting
Pharmacotherapy for T2DM
•
•
•
•
•
Duration of disease
Blood glucose level to be targeted
– fasting
– postprandial
The degree of A1C lowering
ADRs and patient tolerability
Patient preference for route of administration
Back to our Patient
TC
Questions:
Should an additional blood glucose-lowering
agent be added to TC’s medication therapy?
YES
NO
14
Patient Case: TC
Questions:
Which of the following blood glucose-lowering
medications is the best choice for TC at this
time?
Pioglitazone
Glipizide
End of Presentation
Please go to www.ashp.org/advantage/ce/
to take the CE Test.
Sitagliptin
15
The Incretin Concept: A Case-study Approach to Glycemic Control
in Type 2 Diabetes
Selected References
Bloomgarten ZT. Gut hormones and related concepts. Diabetes Care 2006; 29: 2319-24.
DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular disease in
patients with type 1 diabetes. NEJM 2005; 353: 2643-53.
DeWitt DE, Dugdale DC. Using new insulin strategies in the outpatient treatment of diabetes.
Clinical applications. JAMA 2003; 289: 2265-9.
DCCT/EDIC Study Research Group. Sustained effect of intensive treatment of type 1 diabetes
mellitus on development and progression of diabetic nephropathy. JAMA 2003; 290: 2159-67.
DeFronzo RA, Hissa M, Blauwet MB, et. al. Saxagliptin added to metformin improves glycemic control
in patients with type 2 diabetes. Oral Presentation, 67th Scientific Session ADA 2007.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and
dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-705.
Garber AJ, Camisasca RP, Jauffret S, et. al. Efficacy and tolerability of vildagliptin added to a
sulfonylurea (SU) in patients with type 2 diabetes (T2DM). Poster Presentation, 67th Scientific
Session ADA 2007.
Goldman-Levine JD, Lee KW. Insulin detemir – a new basal insulin analog. Ann Pharmacother
2005; 39: 502-7.
Harder H, Nielsen L, Thi TD, et al. The effect of liraglutide, a long-acting glucagon-like peptide 1
derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2
diabetes. Diabetes Care 2004; 27: 1915-21.
Hirsch IB. Insulin Analogues. N Engl J Med 2005; 352: 174-83.
Hermansen K, Kipnes M, Luo E, et. al. Sitagliptin, a selective DDP-4 inhibitor, improving glycemic
control when added to a sulfonylurea or to a sulfonylurea and metformin in patients with type 2
diabetes. Poster Presentation, 67th Scientific Session ADA 2007.
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The Incretin Concept: A Case-study Approach to Glycemic Control in Type 2 Diabetes
This program is located at http://esymposia.ashp.org/cemornings
1. The percentage of patients with type 2 diabetes who have at least one serious diabetesrelated complication is estimated at:
a. 5%
b. 15%
c. 60%
d. 90%
2. Healthcare costs for people with diabetes and cardiovascular disease are:
a. Significantly higher when compared to patients without cardiovascular disease.
b. Significantly lower when compared to patients without cardiovascular disease.
c. Significantly lower in patients 55-64 years of age.
d. Expected to fall significantly within the next 10 years.
3. By the time type 2 diabetes is diagnosed, the disease typically has been present for
approximately:
a. 90 days.
b. 6 months.
c. 5 years.
d. 9 years.
4. As A1C decreases toward the target value, which of the following phenomena occurs?
a. The contribution of postprandial plasma glucose increases and the contribution of
fasting plasma glucose decreases so that the contribution of PPG exceeds that of
FPG.
b. The contribution of postprandial plasma glucose decreases and the contribution of
fasting plasma glucose increases so that the contribution of FPG exceeds that of
PPG.
c. The contribution of postprandial plasma glucose increases and the contribution of
fasting plasma glucose decreases so that the contribution becomes roughly equal.
d. The contribution of postprandial plasma glucose and fasting plasma glucose remain
the same and are roughly equal.
5. Key points to consider when selecting pharmacotherapy for patients with type 2 diabetes
include which of the following?
a. Insulin pump therapy should be evaluated as initial monotherapy for patients with
pre-diabetes.
b. Fasting glucose levels are evaluated, rather than postprandial glucose levels.
c. The duration of the disease and the degree of A1C-lowering effect required to
achieve goal.
d. Physician’s preference for route of medication administration.
6. Therapeutic inertia in patients with type 2 diabetes refers to:
a. Patient failure to adhere to the prescribed treatment regimen.
b. Patient failure to self-monitor blood glucose and adjust drug therapy accordingly.
c. Physician failure to advance therapy when required.
d. Progressive loss of β-cell function and response to drug therapy.
7. The incretin effect refers to the stimulatory effect of gut hormones known as incretins on
pancreatic secretion of insulin in response to food, and this effect is diminished in patients
with type 2 diabetes compared with healthy individuals.
a. True.
b. False.
8. Which of the following effects is exhibited by glucagon-like peptide-1 (GLP-1) but NOT by
glucose-dependent insulinotropic polypeptide (GIP)?
a. Stimulates insulin response from beta cells in a glucose-dependent manner.
b. Inhibits insulin response from beta cells in a glucose-dependent manner.
c. Inhibits glucagon secretion from alpha cells in a glucose-dependent manner.
d. Stimulates glucagon secretion from alpha cells in a glucose-dependent manner.
9. The mechanism of action of DPP-4 inhibitors includes all of the following EXCEPT:
a. Inhibition of the degradation of GLP-1 and GIP.
b. Inhibition of endogenous insulin secretion.
c. Stimulation of endogenous insulin secretion.
d. Increased levels of GLP-1 and GIP, especially in response to meals.
10. With which of the following diabetes therapies have the DPP-4 inhibitors sitagliptin and
vildagliptin been used most extensively to produce beneficial effects on A1C values?
a. Insulin and metformin.
b. Sulfonylureas and thiazolidinediones.
c. Insulin and sulfonylureas.
d. Sulfonylureas and metformin.
11. Which of the following is a consideration in dosing sitagliptin?
a. Timing with respect to meals.
b. Moderate renal impairment (CrCl ≥ 30 mL/min to <50 mL/min).
c. Moderate hepatic impairment.
d. Illness that precludes eating, resulting in hypoglycemia.