Prior to the start of the program, please check
your syllabus to ensure you have the following
printed program materials:
• Baseline Survey
– Located at the front of your syllabus
• CME Evaluation with Post-activity Survey
– Located at the back of your syllabus
Disclosures
• The relevant financial relationships reported by faculty that they or
their spouse/partner have with commercial interests are located on
page 5 of your syllabus
• The relevant financial relationships reported by the steering
committee that they or their spouse/partner have with commercial
interests are provided on page 5 of your syllabus
• The relevant financial relationships reported by the non-faculty
content contributors and/or reviewers that they or their
spouse/partner have with commercial interests are located on page
5 of your syllabus
Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or
investigational uses of agents that are not indicated by the Food and
Drug Administration. PCME does not recommend the use of any agent
outside of the labeled indications. Please refer to the official
prescribing information for each product for discussion of approved
indications, contraindications and warnings. The opinions expressed
are those of the presenters and are not to be construed as those of the
publisher or grantors.
Educational Objectives
At the conclusion of this activity, participants should be able to
demonstrate the ability to:
• Describe the relationships between glycemia and diabetes complications
• Consider the HbA1C-lowering properties of GLP-1 agonists with their
impacts on T2DM pathophysiology, CV risk factors, and hypoglycemic risk
when individualizing treatment strategies for diabetic patients to reach
target goals
• Develop strategies to attain glycemic control throughout the life cycle of
T2DM
• Promote a collaborative approach to T2DM management, empowering the
patient through individualized patient education to address and break down
barriers for optimal outcomes, including adherence and injection-related
barriers
Polling Question
Baseline Survey
• Please take out the Baseline Survey from your packet
• Fill out the demographic information at the top of the form;
as polling questions are asked throughout the program,
please take a moment to select your answer to the
corresponding question on this form
• Your answers are important and will help us shape and
improve future CME activities
Polling Question
Baseline Survey
Please rate your confidence in managing T2DM in patients
with prevalent macro- and/or microvascular comorbidities:
A. Expert
B. Very confident
C. Confident
D. Somewhat confident
E. Not confident
Polling Question
Baseline Survey
Please rate your confidence in using GLP-1 receptor
agonists to reduce HbA1C in your T2DM patients:
A. Expert
B. Very confident
C. Confident
D. Somewhat confident
E. Not confident
Polling Question
Baseline Survey
How often do you incorporate a shared decision-making
(SDM) approach to T2DM management?
A. Always
B. Frequently
C. Sometimes
D. Never
E. I do not know the definition of SDM
Polling Question
Baseline Survey
A 42-year-old overweight man with a positive family history for MI
presents with T2DM (A1C 8.5%). He also has uncontrolled
hypertension and elevated cholesterol. He is being treated for his
hypertension and cholesterol and receives metformin 1000 mg bid and
glipizide 10 mg qd for his T2DM. He is tired of “taking so many pills.”
What do you consider?
A. Identify A1C target ~8% based on cardiovascular risk
B. Consider adding third oral agent
C. Recommend optimizing lifestyle interventions and re-evaluate
therapy in 6 months if necessary
D. Consider adding or switching to injectable therapy, such as basal
insulin and/or GLP-1 agonist
Polling Question
Baseline Survey
A 42-year-old obese woman is receiving metformin, glimepiride, and
sitagliptin. Her A1C is 8.1%. You recommend initiating a GLP-1
agonist, but the patient is afraid of needles.
What action do you take?
A. Avoid use of injectable agents in this patient
B. Tell the patient that taking shots is inevitable based on her history
of type 2 diabetes
C. Tell the patient that she needs injectable therapy because her
lifestyle interventions are insufficient
D. Show the patient needles used for GLP-1 injection and explain
the difference between intramuscular and subcutaneous
injections
Case 1: Introduction
• Marcus is a 33-year-old overweight man with 4-year history of T2DM
– Current medications: metformin 1000mg BID, glipizide 10mg QD
– He has gained 15 lbs in 11 months; current BMI: 28.3 kg/m2
• Lab evaluation
– HbA1C: 8.2%
– BP: 172/85 mm Hg
– Total cholesterol: 242 mg/dL
• Patient concerns
– Robert reveals that he has not been adherent to his T2DM medications
because he was “tired of taking so many pills every day”
– He has experienced episodes of shakiness and extreme hunger before
lunch and dinner
– He is now worried about his health because his father recently suffered a
fatal MI at age 57
I. Burden of T2DM and Its
Complications
Polling Question
Baseline Survey
Follow-up from the UKPDS study demonstrated that each
1% reduction in A1C was significantly associated with all of
the following, EXCEPT:
A. Reduced risk for myocardial infarction
B. Reduced risk for death due to diabetes
C. Reduced risk for microvascular complications
D. Reduced risk for microvascular complications, but not
macrovascular outcomes
Diabetes Prevalence in the US, 2012
National Diabetes Statistics Report, 2014
Statistics shown
are for all ages
CDC. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United
States. Atlanta, GA: US Department of Health and Human Services, 2014.
Pathophysiologic Progression of T2DM
and Its Vascular Complications
Relative function
Glucose (mg/dL)
350
300
OBESITY
IFG
IGT
T2DM
UNCONTROLLED HYPERGLYCEMIA
250
DM diagnosis
200
150
100
50
250
200
β-cell failure
150
100
MACROVASCULAR COMPLICATIONS
MICROVASCULAR COMPLICATIONS
50
0
–10
–5
0
5
10
Time (years)
Adapted from Ramlo-Halsted BA et al. Clin Diabetes. 2000;18:80-84.
15
20
25
30
IFG = impaired fasting glucose
IGT = impaired glucose tolerance
T2DM = type 2 diabetes mellitus
Relationship of HbA1C to Risk of
Microvascular Complications
15
Retinopathy
Nephropathy
Neuropathy
Microalbumin
Relative Risk
13
11
9
7
5
3
1
6
7
8
9
10
HbA1C (%)
Used with permission from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.
11
12
UKPDS: Macrovascular Complications
Increase as Glycemic Control Worsens
Fatal and nonfatal MI
Heart failure
10
10
Hazard ratio
P=0.021
Hazard ratio
P<0.0001
1
1
14% decrease per 1%
reduction in A1C
0.5
5
6
7
8
9
16% decrease per 1%
reduction in A1C
0.5
10
5
6
Updated mean A1C
concentration (%)
14%-16% reduction in cardiovascular events per 1% A1C reduction
Stratton IM et al. BMJ. 2000:321;405-412.
7
8
Updated mean A1C
concentration (%)
9
10
UKPDS Study-End and 10-year Follow-Up
Results
UKPDS original results:
intensive vs conventional treatment
10-year post-trial follow-up
(non-interventional)
1997
2007
1977–1991
Randomization
9%*
12%*
16%
Any diabetes-related endpoint
Microvascular disease
Myocardial infarction
25%*
15%*
In type 2 diabetes,
improvements in glycemic
control reduce the risk of
complications
*P<0.05; intensive vs conventional treatment
Adapted from Holman et al. N Engl J Med. 2008;359:1577-1589.
UKPDS Study Group. Lancet. 1998;352:837-853.
24%*
Implications of ACCORD, ADVANCE,
and VADT for Microvascular Risk
Microvascular disease:
• Lowering A1C to ≤7.0% reduces microvascular and neuropathic
complications in type 2 diabetes
• If achievable without causing significant hypoglycemia or other
adverse events, even lower A1C goals may be suggested for
selected individuals having:
– Short duration of diabetes
– Long life expectancy
– No significant CVD
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379.
Garber AJ et al. Endocr Pract. 2013;19:1-48.
Implications of ACCORD, ADVANCE,
and VADT for Macrovascular Risk
Macrovascular disease:
• Controversies regarding the impact of intensive glycemic control that
exceeds an A1C goal of <7.0% on CVD outcomes compared to
standard glycemic control
• Lowering A1C to a goal of ≤7.0% is a reasonable glycemic goal
until more evidence becomes available
• Long-term follow-up of the DCCT and UKPDS cohorts suggests that
treating to an A1C goal below or near 7.0% yields long-term
reductions in the risk of macrovascular disease, if instituted in the
years soon after diagnosis of diabetes
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379.
Garber AJ et al. Endocr Pract. 2013;19:1-48.
Obesity and T2D: A Common Burden
Obesity Prevalence Among US Adults, 2013
County-level Estimates of Diagnosed
T2D Among US Adults, 2011
Obesity = BMI ≥30 kg/m2 or ~30 lbs. overweight for 5’4” person
CDC Behavioral Risk Factor Surveillance Systems; CDC Diabetes Public Health Resource Center.
II. How Well Are We
Controlling T2DM?
Progress in Achieving A1C Goals: 2007-2012
HbA1C <7.0%
60%
HbA1C >9.0%
50%
43.1%
43.3%
42.1%
42.5%
42.2%
43.2%
40%
30%
29.4%
28.4%
28.2%
27.3%
28.3%
28.5%
20%
10%
0%
2007
2008
National Committee for Quality Assurance, 2013.
2009
2010
2011
2012
www.ncqa.org
Lessons from the DCCT and UKPDS
Sustained Intensification of Therapy is Difficult
HbA1C (%)
9.0
DCCT
(Type 1)
EDIC
8.1
7.9
8
UKPDS (Type 2),
Insulin Group
8
7.3
HbA1C (%)
10
7
Baseline
6
6
4
0
6.5
DCCT
+4
+ 6 yrs
Normal
0
0
2
4
6
8
10 yrs
EDIC
DCCT/EDIC Research Group. N Engl J Med. 2000;342:381-389.
Steffes et al. Diabetes. 2001 (suppl. 2) 50:A63.
UK Prospective Diabetes Study Group (UKPDS) 33.
Lancet. 1998;352:837-853.
Adherence to Prescribed Drugs in
Patients with Type 2 Diabetes
Drug class
n
% Adherent
95% CI
Oral antidiabetic drugs
66
50.0
37.9-62.1
Antihypertensive drugs
62
50.0
37.6-62.4
Lipid-lowering drugs
33
69.7
54.0-85.4
Antiplatelet drugs
40
77.5
64.6-90.4
All drugs
82
35.4
25.0-45.7
Mateo JF et al. Int J Clin Pract. 2006;60:422-428.
Clinical Inertia
Failure to Advance Therapy When Required
Percentage of Subjects advancing when HbA1C >8%
100
80
% Age of Subjects
66.6%
At Insulin Initiation, the average patient had:
• 5 years with HbA1C >8%
• 10 years with HbA1C >7%
60
44.6%
40
35.3%
18.6%
20
0
Diet
Brown JB et al. Diabetes Care. 2004;27:1535-1540.
Sulfonylurea
Metformin
Combination
Barriers to Glycemic Control
Hypoglycemia
Risk Factors
• Use of insulin or secretagogues
[e.g. sulfonylureas (SUs)]
• Drugs that affect SU levels*
• Advanced age
• Duration of diabetes
• Renal failure
• Liver failure
• Hypothyroidism, hypoadrenalism
• Missed/irregular meals
• Advanced cancer, malnutrition
• Hypoglycemia unawareness
* aspirin, allopurinol, trimethoprim, warfarin
Outcomes
•
•
•
•
•
•
•
•
Increase glucose variability
Decreased intensiveness of glucose control
Employment challenges
Loss of confidence
Loss of independence
Personal and family stress
Increased CV events
Increased rates of dementia
Barriers to Glycemic Control
Weight Gain is a Common Side Effect of Many
Oral Agents for T2DM
Oral antidiabetic agent*
Weight change (kg)
-3.8-0.5
Metformin1-3
-0.2-4.3
SUs1-4
0.9-4.6
TZDs4-6
0.3-3.0
Meglitinides4,7,8
-0.3-1.9
Metformin + SU1-3
0.8-2.1
Metformin + TZD5,6,9
*Data are not from head-to-head studies
-5
1. Bristol-Myers Squibb. Glucophage® full prescribing Information. 2004.
2. Bristol-Myers Squibb. Glucovance® full prescribing Information. 2004.
3. Bristol-Myers Squibb. Metaglip® full Prescribing Information. 2002.
4. Malone M. Ann Pharmacother. 2005;39:2046-2055.
5. Eli Lilly. Actos® full Prescribing Information. 2004.
-4
-3
-2
-1
0
1
2
3
4
5
6. GlaxoSmithKline. Avandia® full Prescribing Information. 2005.
7. Novartis. Starlix® full Prescribing Information. 2004.
8. Novo Nordisk. Prandin® full Prescribing Information. 2004.
9. GlaxoSmithKline. Avandamet® full Prescribing Information. 2005.
III. Current T2DM Treatment
Options and Their Places in
Guideline-based Care
ADA/ACC/AHA Position Statement on
HbA1C Goals Individualized for Your Patient
• Most non-pregnant adults <7%
• For selected individuals, might reasonably suggest even lower if this
can be achieved without significant hypoglycemia
- Short duration of diabetes
- Long life expectancy
- No significant CVD
• Less stringent goal for patients with:
– History of severe hypoglycemia
– Limited life expectancy
– Advanced micro- or macrovascular complications, extensive comorbid
conditions
– Longstanding diabetes in which the general goal is difficult to attain despite
diabetes self-management, etc.
American Diabetes Association. Diabetes Care. 2012;35(Suppl 1):S11-S63.
Medications for Hyperglycemia in Type 2
Diabetes: ADA 2014 Guidelines
GLP = glucagon-like peptide
American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S80.
The Pathophysiology of Type 2 Diabetes
Involves Multiple Dysfunctions
Insulin
secretion
Glucose
production
α
Glucagon
secretion
Glucose
uptake
Hyperglycemia
Incretin
effect
Lipolysis
Neurotransmitter
function
Glucose
reabsorption
DeFronzo RA. Diabetes. 2009;58:773-795..
β
Incretins
• Gut-derived hormones, secreted in response to nutrients, that
potentiate insulin secretion and suppress glucagon secretion in a
glucose dependent fashion
– Many other tissue effects
• Two predominant incretins
– Glucagon-like peptide-1 (GLP-1)
– Glucose-dependent insulinotropic peptide (GIP)
• Rapidly inactivated by dipeptidyl peptidase-4
• Incretin effect is impaired in type 2 diabetes
1. Holst JJ et al. Diabetes. 2004;53(suppl 3):s197-s204.
2. Meier JJ et al. Diabetes Metab Res Rev. 2005;21:91-117.
Incretin Effect
2.0
Oral glucose (50 g)
or isoglycemic infusion
200
100
0
0
60
120
Time (min)
IV glucose
Oral glucose
*
C-Peptide (nmol/L)
Plasma Glucose (mg/dL)
Difference in the Insulin Response to Oral vs IV Glucose
180
1.5
*
*
*
*
1.0
*
*
0.5
0.0
0
60
120
180
Time (min)
Reprinted with permission from Nauck MA et al. J Clin Endocrinol Metab. 1986;63:492-498. © 1986 The Endocrine Society.
Reduced Incretin Effect in
Type 2 Diabetes Patients
Control Subjects
80
Type 2 Diabetes Patients
80
Intravenous Glucose
Oral Glucose
60
Insulin (mU/L)
Insulin (mU/L)
60
40
*
*
*
*
*
*
*
20
30
60
90
* *
20
0
0
40
120
150 180
Time (min)
Reprinted with permission from Nauck M et al. Diabetologia. 1996;29:46-52.
0
0
30
*
60
90
120 150 180
Time (min)
Role of Incretins in Glucose Homeostasis
Pancreas2,3
Ingestion of food
GI tract
Release of gut
hormones —
Incretins1,2
Active
GLP-1 & GIP
Glucose-dependent
 Insulin from beta cells
(GLP-1 and GIP)
Blood
glucose
Beta cells
Alpha cells
DPP-4
enzyme
Inactive
GLP-1
Glucose uptake
by muscles2,4
Inactive
GIP
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876-913.
2. Ahrén B. Curr Diab Rep. 2003;2:365-372.
Glucose dependent
 Glucagon from
alpha cells
(GLP-1)
Glucose
production
by liver
DPP-4 = dipeptidyl-peptidase 4
3. Drucker DJ. Diabetes Care. 2003;26:2929-2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430-441.
Treatment Strategies Involving the
Incretin System
• GLP-1 receptor agonists
– Exenatide, liraglutide
– Long-acting exenatide QW, albiglutide, dulaglutide
– Subcutaneous injection
• DPP-4 enzyme inhibitors
–
–
–
–
–
Molecule selectivity inhibits activity of DPP-4
Sitagliptin, saxagliptin, linagliptin, alogliptin
Oral
Incretin enhancers
Lack “high” GLP-1 effects
Physician’s Desk Reference. Montvale, NJ. Thomson PDR; 2013.
GLP-1 Receptor Agonists
• Injectable
• Efficacy
–
–
–
–
Primary effect is on post-meal glucose levels
Longer duration of action, better FPG and A1C lowering
HbA1C lowering: 0.5%-2.0%
Potential for weight loss
• Safety
–
–
–
–
Major side effect: nausea/vomiting
No added hypoglycemia unless used with secretagogue or insulin
C-cell hyperplasia and medullary cancer in rodents
Pancreatitis – not seen in large database analyses
Physician’s Desk Reference. Montvale, NJ. Thomson PDR; 2013.
DPP-4 Inhibitors
• Efficacy:
– HbA1C reduction: ~0.5-0.9%
– Weight neutral
– Renal dosing adjustment – not for linagliptin
• Safety:
– No added hypoglycemia unless used with sulfonylurea
– Rare instance of Stevens-Johnson
– Evidence for no increased CV risk (saxagliptin and alogliptin)1,2
– No increased risk of pancreatitis or pancreatic cancer3
1. Scirica BM et al. New Engl J Med. 2014;369:1317-1326.
2. White WB et al. New Engl J Med. 2013;369:1327-1335.
3. Egan AG et al. New Engl J Med. 2014;370:7940797.
Short, Long, and Very Long-acting GLP-1 RA
Parameters
Short-acting
Long-acting
Very Long-acting
Compounds
Exenatide
Liraglutide
Albiglutide, Dulaglutide,
Exenatide QW
Half-life
Frequency of
administration
2-5 hours
12-14 hours
>1 week
Twice daily
Once daily
Once weekly
0.7–1.7%
0.8–1.8%
0.8-0.9% albiglutide
0.7–1.6% dulaglutide
1.3%-1.9% exenatide QW
Modest
Strong
Strong
Strong
Modest
Modest
Reduction
Reduction
Reduction
Deceleration
No effect
No effect
Reduction
Reduction
Reduction
1-5 kg
2-4 kg
0.6-2.5 kg
HbA1C reduction
FBG levels reduction
PP hyperglycemia
Glucagon secretion
Gastric emptying rate
Blood pressure
Body weight reduction
FBG = fasting blood glucose; PP = postprandial; QW = once weekly
Meier JJ. Nat Rev Endocrinol. 2012;8:728-742. Physician’s Desk Reference. Montvale, NJ. Thomson PDR; 2013.
Polling Question
Baseline Survey
The DURATION 3 trial, which compared exenatide once weekly
to insulin glargine in patients with type 2 diabetes who were
failing oral antidiabetic therapy, reported all of the following
outcomes, EXCEPT:
A. Significantly greater A1C reduction with exenatide
B. Higher rate of discontinuations due to adverse events with
exenatide
C. Similar rates of hypoglycemia in the insulin glargine and
exenatide groups
D. Weight loss with exenatide and weight gain with insulin
glargine, a significant difference
Effects of Second-Line T2D Therapies as
Add-on to Metformin
• Meta-analysis of 39 RCTs (n=17,860)
• Comparative A1C results:
– GLP1-RA achieved greater reduction vs AGIs (-0.36%), DPP-4 inhibitors
(-0.32%), glinides (-0.31%), SUs (-0.20%), and TZDs (-0.20%)
– Reduction with GLP1-RA was comparable to basal and biphasic insulin
• Other endpoints:
– Hypoglycemia was more likely associated with SUs, glinides, basal insulin,
and biphasic insulin; not with GLP1-RA
– Weight increased with SUs, glinides, TZDs, basal insulin, and biphasic insulin
– Weight reduced with AGIs and GLP-1 analogues
Liu SC et al. Diabetes Obes Metab. 2012;14:810-820.
DURATION-5: Mean A1C Reduction and
Percent at A1C Targets
• Randomized trial of once-weekly vs twice-daily exenatide in 252 patients
on metformin (71%-80%), SU (28%-31%), and/or TZD (10%-17%)
Blevins T et al. J Clin Endocrinol Metab. 2011;96:1301-1310.
Baseline HbA1C
<9.0%
≥9.0%
ExBID
72%
28%
ExQW
70%
30%
DURATION-5: Adverse Events
Adverse Event
Nausea
Diarrhea
Upper respiratory infections
Injection-site erythema
Vomiting
Headache
Dizziness
Blevins T et al. J Clin Endocrinol Metab. 2011;96:1301-1310.
Exenatide BID
(n=123)
Exenatide QW
(n=129)
35%
4.1%
4.1%
2.4%
8.9%
8.1%
6.5%
14%
9.3%
7.0%
5.4%
4.7%
4.7%
2.3%
HARMONY 7: Change in A1C Over 32 Weeks
• Randomized trial of once-weekly albiglutide vs once-daily liraglutide in
422 patients inadequately controlled on oral anti-diabetes drugs
Baseline HbA1C
Albiglutide – 8.1%
Liraglutide – 8.1%
-0.79%
-0.98%
P=0.08 for non-inferiority
Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2:289-297.
HARMONY 7: Adverse Events
Adverse Event
Diarrhea
Upper respiratory infection
Nausea
Injection-site reaction
Urinary tract infection
Headache
Vomiting
Withdrawal for AEs
Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2:289-297.
Albiglutide
(n=404)
14.9%
10.4%
9.9%
6.9%
6.2%
5.4%
5.0%
2.7%
Liraglutide
P Value
(n=408)
-0.79%
13.5%
0.57
11.0%
0.77
29.2%
1.2%
5.6%
5.4%
9.3%
0.2%
<0.0001
<0.0001
0.74
0.97
0.0154
NR
DURATION-3: Effects on A1C After 3 Years
• Randomized trial of once-weekly exenatide vs insulin glargine in 456
patients inadequately controlled on glucose-lowering drugs
Baseline HbA1C
Exenatide 8.3%
Glargine 8.3%
-0.81%
-1.01%
P=0.03
Diamant M et al. Lancet. 2014;2:464-473.
DURATION-3: Other Endpoints
+2.01 kg
-2.49 kg
P<0.001
• More GI events with exenatide vs
glargine: nausea (15% vs 2%), diarrhea
(14% vs 7%), vomiting (6% vs 3%),
constipation (5% vs 3%)
• More discontinuations due to AEs with
exenatide vs glargine: 9% vs 2%
Diamant M et al. Lancet. 2014;2:464-473.
Overall hypoglycemia rate:
Insulin glargine: 0.9 events/pt
year
Exenatide: 0.3 events/pt year
Other Adverse Effects with GLP-1 RAs
Data from Exenatide and Liraglutide Studies*
Odds ratio
(95% confidence interval)
P value
Hypoglycemia
2.92 (1.49-5.75)
0.002
With SUs
4.62 (1.89-11.21)
0.001
Without SUs
1.37 (0.72-2.63)
0.34
0.99 (0.52-1.91)
0.98
Event
Cardiovascular events
*Meta-analysis of predominantly exenatide and liraglutide studies
n=5429 receiving GLP-1 receptor agonists, n=3053 active comparators or placebo
Monami M et al. Eur J Endocrinol. 2009;160:909-917.
Incretin-related Drugs and Pancreatitis Risk
• There has been much discussion regarding the safety of incretin
agents (e.g. regarding exenatide, liraglutide, sitagliptin)
– Recent published and unpublished data report an increased risk of pancreatitis
and pancreatic duct metaplasia in T2DM patients receiving incretins
• FDA investigated potential pancreatic toxicity associated with incretins
• FDA stated that available data do not confirm recent concerns over an
increased risk for pancreatic side effects with GLP-1 therapies
• NIDDK experts also concluded that there is little evidence of
increased risk for pancreatic cancer with GLP-1 agents
• FDA study regarding pancreatitis and pancreatic cancer with incretins
is ongoing
1. FDA. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous
findings of the pancreas from incretin mimetic drugs for type 2 diabetes. 3-14-2013. Available at:
www.fda.gov/drugs/drugsafety/ucm343187.htm.
2. Brooks M. FDA sides with EMA on incretin diabetes drugs. 8-1-2013. Available at: www.medscape.com/viewarticle/808830.
Pancreatitis
Recommendations for Health Care Professionals
• Pancreatitis is more common in patients with diabetes1
• Recommendations for monitoring and management2-4
- Observe patients for symptoms of acute pancreatitis (persistent
severe abdominal pain that may be accompanied by vomiting)
- Discontinue drug if pancreatitis is suspected
- Do not restart drug if pancreatitis is confirmed
- Consider other anti-hyperglycemic therapies in patients with a
history of pancreatitis
1. Yadav D et al. Gastroenterology. 2013;144:1252-1261.
2. Byetta® fact sheet. Available at: www.byettahcp.com/pdf/BYETTA_Fact_Sheet_Safety_Update.pdf.
3. US FDA Web site; Exenatide (marketed as Byetta) – Healthcare Professional Sheet text version (8/2008). Available at:
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm.
4. Victoza [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2011.
Summary of GLP-1 Receptor Agonist
Therapy in T2D
• Incretin system is a powerful physiologic system impacting
post-meal BG control
• Defective in T2D
• Intriguing constellation of clinical effects
– Postprandial glucose control
– Weight loss
– Low risk of hypoglycemia
– Potential for weekly dosing
IV. Practical Considerations
Polling Question
Baseline Survey
A recently reported analysis of compliance data from the HARMONY
trials, which evaluated the once-weekly GLP-1 inhibitor albiglutide,
reported what finding?
A. Greater compliance with placebo injection than albiglutide
injection
B. Greater compliance with oral antidiabetic drugs compared to
albiglutide injection
C. Lower compliance with oral antidiabetic drugs compared to
placebo injection or albiglutide injection
D. No differences in compliance across all groups, including active
and placebo and oral and injectable agents
Psychosocial Predictors of Poor Adherence
to Insulin Therapy in Patients with T2D
• Survey of 1,530 adults with T2D treated with insulin
– 35% reported ≥1 days of insulin omission per month (mean: 3 days)
– Insulin omission more common in patients who were male (P<0.001),
younger (P<0.0001), and had more frequent hypoglycemia (P<0.05)
Prevalence
or Mean
Correlation
Coefficient
P Value
2.4*
-0.12
<0.001
Insulin regimen adherence perceived as “important”
99.0%
-0.05
<0.05
Injections perceived to affect lifestyle
43.3%
+0.06
<0.05
Injection difficulty (from 1 “very easy” to 4 “very difficult”)
1.8
+0.07
<0.05
Satisfaction with ability to choose when to take injections
(from 1 “very dissatisfied” to 4 “very satisfied”)
3.3
-0.07
<0.01
Psychosocial/Behavioral Correlates of Insulin Omission
Adherence to non-medication regimens
(number of succesful behaviors; range, 0-4)
Peyrot M et al. Diabetes Obes Metab. 2012;14:1081-1087.
Strategies to Improve Patient Acceptance and
Self-management with GLP-1 Agonist Therapy
Patient Barrier
Recommendations
Needle phobia
•
•
•
•
Poor motivation
• Discuss benefits such as weight loss and low hypoglycemia risk
• Encourage patients to perform SMBG for 1-2 weeks after initiating to see
reductions in FBG and PPG levels
• Involve a dietitian to help patients identify strategies to maximize the potential for
weight loss
Nausea
• Before initiation, educate patients that transient nausea is possible
• Dose-escalate exenatide BID or liraglutide, but not exenatide QW, as described in
prescribing information
• Consider lengthening the time over which the dose is escalated
• Administer exenatide BID <60 minutes before the meal
• Temporarily reduce the dose
• Counsel patients to stop eating when they feel full
• Avoid administering the medication close to a large or high-fat meal
Familiarize patients with pen devices or delivery kits
Avoid using the word “shot”
Differentiate between SC and IM injections
Have patients self-inject the first dose in the office; alternatively, just use the needle
FBG = fasting blood glucose; PPG = postprandial glucose; SMBG = self-monitoring of blood glucose.
Reid T. Clin Diabetes. 2013;31:148-157.
Compliance with T2D Medications:
Injection vs Oral Therapy
% of Patients with <80% Compliance
HARMONY 3 Trial (Week 156)
Leiter LA et al. ADA 2014 Annual Meeting. Abstract 994-P.
HARMONY 5 Trial (Week 156)
HARMONY 8 Trial (Week 52)
New Delivery Options: Exenatide Suspension
QW with Single-use Auto-injector Pen
• 28-week open-label study of exenatide twice daily (ExBID) vs
exenatide suspension given once-weekly via single-use auto-injector
pen (ExSQW) in patients with inadequately controlled T2D
ExBID (n=148)
ExSQW (n=229)
-1.02%
-1.89 kg
-1.39%*
-1.48 kg
21.2%
11.6%
6.2%
0.7%
9.6%
5.2%
3.5%
12.7%
Change in A1C
Change in body weight
Adverse events
Nausea
Diarrhea
Vomiting
Injection-site nodules
*P = 0.007 vs ExBID
Wysham CH et al. EASD 2014 Annual Meeting. Abstract 244.
Case 1: Revisited
• Marcus is a 33-year-old overweight man with 4-year history of T2DM
– Current medications: metformin 1000mg BID, glipizide 10mg QD
– He has gained 15 lbs in 11 months; current BMI: 28.3 kg/m2
• Lab evaluation
– HbA1C: 8.2%
– BP: 172/85 mm Hg
– Total cholesterol: 242 mg/dL
• Patient concerns
– Robert reveals that he has not been adherent to his T2DM medications
because he was “tired of taking so many pills every day”
– He has experienced episodes of shakiness and extreme hunger before lunch
and dinner
– He is now worried about his health because his father recently suffered a fatal
MI at age 57
Case Discussion
• Individual HbA1C goal?
• Treatment priorities
– Improved glycemic control
– Weight neutral or associated with weight loss
– Low risk of hypoglycemia
– Improved cardiovascular risk profile
Summary
• Poorly controlled hyperglycemia significantly increases the risk of
microvascular and macrovascular complications
– Despite effective therapies, <30% of patients with T2DM meet the treatment
goal of A1C <7.0%
• Patients require individualized therapy for effective glycemic control
– Consider the effects of medications on T2DM pathophysiology, body weight,
hypoglycemic risk, and other endpoints
• Utilize a collaborative approach to T2DM management
– Empower the patient through patient education on self-management strategies
– Address barriers for optimal outcomes, including poor medication adherence
and injection-related barriers
Participant CME Evaluation
• Please take out the Participant CME Post-survey and
Evaluation Form from the back of your packet.
• If you are not seeking credit, we ask that you fill out the
information pertaining to your degree and specialty, as well
as the few post-activity survey questions measuring the
knowledge and competence you have garnered from this
program. The post-survey begins on page 1 of the
evaluation form.
• Your participation will help shape future CME activities.
Thank you for joining us today!