Transcript Cards 2000 - Kansas Academy of Physician Assistants

Sponsored by
Supported by an educational grant from
Amylin Pharmaceuticals, Inc., and Eli Lilly and Company
Produced by
KAPA Annual Conference
October 14, 2010
Ellen D. Mandel, DMH, MS, PA-C, RD, CDE
Associate Professor, Seton Hall University
South Orange, NJ
Physician Assistant, Evening Practice
Summit Medical Group, Berkeley Heights, NJ
Faculty Disclosures
Ellen D. Mandel, DMH, MS, PA-C, RD, CDE

Nothing to disclose

Does not intend to discuss any unapproved/
investigational use of a commercial product
Learning Objectives
Upon completion of this activity, PAs should be better able to:

Explain the relationship between excess body fat and cardiovascular disease (CVD) with type 2 diabetes mellitus (T2DM).

Recognize the need for early and individualized management
of T2DM, given the progressive loss of beta-cell function that
occurs years before diagnosis.

Differentiate among pharmacologic therapies for T2DM that
target specific glycemic patterns and/or metabolic defects to
achieve and maintain optimal glycemic control.

Integrate current guidelines into daily clinical practice.

Implement strategies to achieve postprandial glucose control
with a goal to reduce risk for CVD.
Agenda

Snapshot: Type 2 Diabetes Today

Clinical Implications of Lack of Glycemic Control

Typical Management of Type 2 Diabetes

Early Intervention for Optimal Glycemic Control
The State of Diabetes in America

8% of
US population
has diabetes
Who is affected?
– An estimated 24 million Americans—~8% of the population
– Most have type 2 diabetes
– About 40 million people 20 years old have IFG or IGT (pre-diabetes)

What is the impact?
– 3 of 5 patients suffer from a complication of the disease
– $174 billion in 2007 for direct ($116 billion) and indirect
($58 billion) costs

2 of 3 patients with type 2 diabetes do not meet HbA1C
treatment targets
IFG = impaired fasting glucose; IGT = impaired glucose tolerance
AACE. Available at: www.aace.com/public/
awareness/stateofdiabetes. Accessed May 7, 2009.
CDC. Available at: http://apps.nccd.cdc.gov/DDTSTRS. Accessed May 7, 2009.
Cowie CC et al. Diabetes Care. 2009;32:287-294.
Both FPG and 2-h PPG Predict Mortality
in Persons Not Known to Have Diabetes
All Subjects (N ≈ 25,000)
Subjects With FPG <110 mg/dL
Adjusted HR for Mortality
2.5
2.5
2.0
1.76
1.86
2.00
2.0
1.59
1.5
1.5
1.21
1.00
1.00
1.0
1.0
0.5
0.5
0.0
0.0
< 110
110 - 125
126 - 140
FPG (mg/dL)
> 140
< 140
> 200
2-h PPG (mg/dL)
FPG = fasting plasma glucose; PPG = postprandial glucose; HR = hazard ratio
DECODE Study Group. Lancet. 1999;354:617-621.
140 - 200
HbA1C as a Predictor of CHD
in Type 2 Diabetes
Low (<6.0%)
Middle (6.0%-7.9%)
High (>7.9%)
Incidence in 3.5 Years (%)
25
20
†
15
*
10
5
0
CHD Mortality
*P<0.01 vs lowest tertile; †P<0.05 vs lowest tertile
CHD = coronary heart disease
Kuusisto J et al. Diabetes. 1994;43:960-967.
All CHD Events
Diabetes Has an Adverse Impact
on Quality of Life

Macrovascular and microvascular consequences =
long-term complications of diabetes

Toll of diabetes-related complications in US:
– 71,000 nontraumatic lower-limb amputations (2004)
– 12,000 to 24,000 new cases of blindness each year
– Causes 44% of new cases of kidney failure (2005)
– 233,619 deaths from complications of diabetes (2005)
CDC. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed May 7, 2009.
Prevalences of Obesity and Diabetes
Continue to Rise: NHANES Data
Obesity (BMI 30 kg/m2)
8
40
Percentage of Population
Physician-diagnosed Diabetes
35
6
30
25
4
20
15
2
10
5
0
0
1988-1994
1999-2002
2003-2006
1988-1994
1999-2002
BMI = body mass index; NHANES = National Health and Nutrition Examination Survey
CDC. Health, United States, 2008. Available at: http://www.cdc.gov/nchs/data/hus/hus/08.pdf.
2003-2006
Are We Achieving Glycemic Control?
NHANES 1999-2004
1999-2000
2001-2002
2003-2004
(N = 403)
(N = 448)
(N = 482)
Mean HbA1C
7.82
7.47
7.18
Patients with
HbA1C <7%
36.9%
49.4%
56.8%
More than 40% of patients with diabetes
do not have adequate glycemic control
Hoerger TJ et al. Diabetes Care. 2008;31:81-86.
How Does HbA1C Translate
to Glucose Levels?
HbA1C Level (%)
Blood Glucose Level (mg/dL)
5
97
6
126
7
154
8
183
9
212
10
240
11
269
12
298
Average Estimated Glucose (mg/dL) = 28.7 x HbA1C – 46.7
Nathan DM et al. Diabetes Care. 2008; 31:1473-1478.
Agenda

Type 2 Diabetes Today

Clinical Implications From Lack of Glycemic Control

Typical Management of Type 2 Diabetes

Early Intervention for Optimal Glycemic Control
Glucose (mg/dL
Natural History of Type 2 Diabetes
Post-meal Glucose
350
Obesity – Inactivity
Genetics
300
250
Fasting Glucose
200
350
100
Relative Function
50
Insulin Resistance
350
300
250
200
350
Diabetes
Diagnosis
Pre-diabetes (IFG, IGT)
Metabolic Syndrome
Insulin Response
100
-15
-10
-5
0
ONSET
5
10
15
20
25
Years
DeFronzo RA. Pathogenesis of type 2 diabetes: implications for metformin. Drugs. 1999;58(suppl 1):29-30.
30
Can Type 2 Diabetes Be Prevented or Delayed?
Diabetes Prevention Program (DPP)
Placebo
Metformin
Lifestyle
10
-31% vs
placebo
-58% vs
placebo
5
0
Placebo
Metformin
Lifestyle
40
Cumulative Incidence of Diabetes (%)
Overall Incidence of Diabetes (%)
15
Placebo
Metformin
Lifestyle
30
20
10
0
0
0.5
1
1.5
2
Year
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346(6):393-403.
2.5
3
3.5
4
Type 2 Diabetes Characterized by a
Progressive Decline in -Cell Function
100
-Cell function (%)
•
75
•
•
•
50
IGT
25
Postprandial
Hyperglycemia
Type 2
Diabetes
Phase I
Type 2
Diabetes
Phase II
Causes of β-cell Failure
Reduction of β-cell mass
– Apoptosis
– Decreased
proliferation
– Amyloid deposition
Glucotoxicity
Lipotoxicity
Decreased incretin effect
Type 2 Diabetes
Phase III
0
-12
-10
-6
-2
0
2
6
Years From Diagnosis
Lebovitz H. Diabetes Rev. 1999;7:139-153.
•UKPDS Extrapolation
10
14
Recommended Standard-of-Care Targets
for Patients With Type 2 Diabetes
ADA
AACE
<7.0%
6.5%
Preprandial plasma glucose
90–130 mg/dL
<110 mg/dL
Peak postprandial glucose
<180 mg/dL
<140 mg/dL
HbA1C
Blood pressure
<130/80 mm Hg
LDL-C
<100 mg/dL
Triglycerides
<150 mg/dL
HDL-C
>40 mg/dL (male)
>50 mg/dL (female)
ADA = American Diabetes Association; AACE = American Association of Clinical Endocrinologists;
LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol
ADA. Diabetes Care. 2009;32(suppl 1):S13-S61; AACE. Endocr Pract. 2007;13(suppl 1):4-68.
Are Patients With Diabetes Meeting
ADA Clinical Practice Guidelines?
Meeting Recommended Goals (%)
NHANES 1999-2002 (N = 998)
100
80
60
49.8 +3.68
39.6 +2.7
36.0 +4.06
40
27.4 +2.0
20
0
HbA1C <7%
LDL-C
<100 mg/dL
BP = blood pressure
Resnick HE et al. Diabetes Care. 2006;29:531-537.
HDL-C
BP
<130/80 mm Hg
>45 mg/dL (men)
>55 mg/dL (women)
Does Glycemic Control Reduce Risk for
Diabetes-Related Complications? UKPDS
Every 1% reduction in HbA1C translates to:
Risk
Reduction
Complication
P Value
43%
Amputation or death from PVD
<0.0001
37%
Microvascular
<0.0001
21%
Any diabetes-related end point
<0.0001
21%
Diabetes-related death
<0.0001
14%
Fatal or nonfatal MI
<0.0001
UKPDS = United Kingdom Prospective Diabetes Study; MI = myocardial infarction; PVD = peripheral
vascular disease
Stratton IM et al. BMJ. 2000;321:405-412.
Microvascular Complications Increase
as HbA1C Increases: DCCT
15
Retinopathy
Relative Risk
13
Nephropathy
11
Neuropathy
Microalbuminuria
9
7
5
3
1
6
7
8
9
10
11
12
HbA1C (%)
DCCT = Diabetes Control and Complications Trial
Skyler J. Endocrinol Metab Clin North Am. 1996;25:243; DCCT Research Group. N Engl J Med. 1993;329:977.
Younger Patients With Type 2 Diabetes Have
Increased Risk for Morbidity
Patients with diabetes 18 to 44 years old are:

14 times more likely to have MI

30 times more likely to have STROKE

80% more likely to need insulin 2 years of diagnosis
Hillier TA, Pedula KL. Diabetes Care. 2003;26:2999-3005.
•N=7800 newly diagnosed DM
Patients With Type 2 Diabetes
Have Reduced Life Expectancy
Age at Diagnosis (y)
Men
0
20
30
40
60
20
Women
30
40
60
-5
-7.3
Years
-10
-9.5
-11.6
-15
-11.1
-16.5
-17.2
-17.9
-18.6
-20
-22
-23.1
-25
-26.1
-30
-13.8
-14.3
-14.5
-27.4
QALY = quality-adjusted life years
Life Years Lost
QALYs Lost
Venkat Narayan KM et al. JAMA. 2003;290:1884-1890.
-29.6
NHANES 1984-2002
Agenda

Type 2 Diabetes Today

Clinical Implications From Lack of Glycemic Control

Typical Management of Type 2 Diabetes

Early Intervention for Optimal Glycemic Control
Therapeutic Options in Type 2 Diabetes

Therapeutic lifestyle
changes (TLCs)

Metformin

Sulfonylureas
(secretagogues)

Glinides

α-glucosidase
inhibitors

TZDs

Insulin

GLP-1 agonists
(exenatide)

DPP-IV inhibitors
(sitagliptin, saxagliptin)

Amylin agonists
(pramlintide)*
TZD = thiazolidinedione, GLP = glycoprotein, DPP = dipeptidyl peptidase
*Approved in US only for use in combination with insulin
Nathan DM et al. Diabetes Care. 2009;32:193-203.
Conventional Management
of Type 2 Diabetes
Diet + Exercise
+
One OAD
Add Second OAD
Three OADs
Two OADs + Insulin
Add Insulin
Basal and Preprandial Insulin
OAD = oral antidiabetic drug
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
ADA/EASD Consensus
Treatment Algorithm
Tier 1: Well-validated core therapies
At diagnosis:
TLCs
+
Metformin
TLCs + Metformin
+
Basal insulin
TLCs + Metformin
+
Intensive insulin
TLCs + Metformin
+
Sulfonylurea
STEP 1
STEP 2
STEP 3
Tier 2: Less well-validated therapies
TLCs + Metformin
+
Pioglitazone
No hypoglycemia
Edema/CHF
Bone loss
TLCs + Metformin
+
GLP-1 agonist
No hypoglycemia
Weight loss
Nausea/vomiting
EASD = European Association for the Study of Diabetes
Nathan DM et al. Diabetes Care. 2009;32:193-203.
TLCs + Metformin
+
Pioglitazone
+
Sulfonylurea
TLCs + Metformin
+
Basal insulin
Scientific Evidence: Treatment Is Beneficial
to Reduce Complications

UKPDS and DCCT: reducing HbA1C lowers risk for
complications

Meta-analysis (before ACCORD):
– Intensified glycemic control = 19% reduced macrovascular risk
– Effect due to reductions in stroke and PVD events (42% each)
– 9% reduction in cardiac events

ACCORD and ADVANCE
– Early intervention is better
– Not sufficiently powered for CV end points
– ACCORD: higher mortality with intensive treatment
ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and
Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation
UKPDS 33. Lancet. 1998;352:837-853; DCCT. N Engl J Med. 1993;329:977-986; Stettler C et al. Am Heart J.
2006;152:27-38; ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group.
N Engl J Med. 2008;358:2560-2572.
ACCORD vs ADVANCE:
Studies of Intensive Glycemic Control
ACCORD
ADVANCE
(N = 10,251)
(N = 11,140)
Mean age
62 y
66 y
Mean duration of diabetes
10 y
8y
Median HbA1C at entry
8.1%
7.2%
Target HbA1C
<6%
<6.5%
Duration of treatment
3.5 y
5y
6.4% vs 7.5%
6.4% vs 7.0%
HR 1.22
HR 0.93
(P = 0.04)
(P = 0.28)
Median HbA1C at study end
(intensive vs conventional treatment)
Outcome risk for all-cause mortality
ACCORD. N Engl J Med. 2008;358:2545-2559; ADVANCE. N Engl J Med. 2008;358:2560-2572.
Type 2 Diabetes and CVD Risk Reduction: Lessons
From ADVANCE, ACCORD, VADT, and UKPDS
 Prevent early microvascular complications through better
glycemic control
 Individualize glucose goals for patients with advanced CVD
– Close to 7%, not necessarily <7%, in high-risk elderly
 For early type 2 diabetes without advanced CVD:
– Use more intense glycemic control to modestly reduce CVD risk
– An HbA1C target 6.5% may be appropriate
TREAT TYPE 2 DIABETES EARLY
VADT = Veterans Affairs Diabetes Trial
ACCORD. N Engl J Med. 2008;358:2545-2559; ADVANCE. N Engl J Med. 2008;358:2560-2572; Duckworth W et al.
N Engl J Med. 2009;360:129-139; UKPDS 33. Lancet. 1998;352:837-853.
Type 2 Diabetes and CVD Risk Reduction: Lessons
From ADVANCE, ACCORD, VADT, and UKPDS (cont’d)
 Avoid hypoglycemia, especially in known/suspected CVD
 Focus on other CVD risk factors through:
– Lipid-lowering
– BP reduction
– Anti-platelet therapy
– Smoking cessation
– Antihyperglycemic agents
TREAT TYPE 2 DIABETES EARLY
BP = blood pressure
ACCORD. N Engl J Med. 2008;358:2545-2559; ADVANCE. N Engl J Med. 2008;358:2560-2572; Duckworth W et al.
N Engl J Med. 2009;360:129-139; UKPDS 33. Lancet. 1998;352:837-853.
Agenda

Type 2 Diabetes Today

Clinical Implications From Lack of Glycemic Control

Typical Management of Type 2 Diabetes

Early Intervention for Optimal Glycemic Control
Case in Point: Isabel

Latina, age 30

History of gestational diabetes mellitus

“Social” smoker

BMI: 29 kg/m2 (overweight)

BP: 140/80 mm Hg

Lipids:
– Total cholesterol = 204 mg/dL
– HDL-C = 30 mg/dL
– LDL-C = 138 mg/dL
– Triglycerides: 180 mg/dL

FPG: 118 mg/dL

Order 2-h OGTT and HbA1C
OGTT = oral glucose tolerance test
Does Isabel have
pre-diabetes?
ADA Pre-Diabetes Decision Tree
Identify patients at high risk for pre-diabetes
Obtain FPG or OGTT for all high-risk patients
FPG
100-125 mg/dL
Pre-diabetes
OGTT
>126 mg/dL
Diabetes
ADA. Diabetes Care. 2009;32(Suppl 1):S13-S61.
140-199 mg/dL
Pre-diabetes
>200 mg/dL
Diabetes
ADA Recommended Standard of Care
for Pre-Diabetes

Monitor for development of diabetes annually

Individualized medical nutrition therapy

Weight loss of 5% to 10%

Moderate physical activity (~30 min/day for
5 days/wk)
ADA. Diabetes Care. 2007;30(suppl 1):S4-S41.
ADA Recommended Standard of Care
for Pre-Diabetes (cont’d)

Consider metformin treatment for:
– Patients at very high risk for developing diabetes
 Combined IFG and IGT
 HbA1C >6%
 Hypertension
 Low HDL-C
 Elevated triglycerides
 Family history in 1° relative
– Obese patients
– Patients <60 years old
ADA. Diabetes Care. 2007;30(suppl 1):S4-S41.
Lifestyle Modification Can Reduce Incidence
of Type 2 Diabetes by >50%
Incidence of Type 2 Diabetes
(cases/100 person-years)
Diabetes Prevention Program (N = 3234)
15
10
5
↓31%*
↓58%*†
11.0
7.8
4.8
0
Placebo
*P<0.001 vs placebo
†P<0.001 vs metformin
DPP. N Engl J Med. 2002;346:393-403.
Metformin
(850 mg BID)
Lifestyle
Modification
(>7% weight loss,
>150 min activity/wk)
Isabel: Follow-up Laboratory Tests

Repeat FPG: 122 mg/dL

2-h 75-g OGTT results:
– Fasting glucose level = 120 mg/dL
– 2-h glucose level = 233 mg/dL

HbA1C = 7.3%
Isabel has
clinical diabetes
Isabel: Treatment Decisions

Therapeutic lifestyle
changes (TLCs)

Metformin

Sulfonylureas
(secretagogues)

Glinides

α-glucosidase
inhibitors

TZDs

Insulin

GLP-1 agonists
(exenatide, liraglutide)

DPP-IV inhibitors
(sitagliptin, saxagliptin)

Amylin agonists
(pramlintide)*
*Approved in US only for use in combination with insulin
Nathan DM et al. Diabetes Care. 2009;32:193-203.
Major Organ Systems Contribute
to Hyperglycemia
Pancreas
Adipose tissue
 Insulin
secretion
 Glucose
uptake
Gut
 FFA
output
Glucose
absorption
Hyperglycemia
Liver
 HGO*
Muscle
 Glucose
uptake
HGO = hepatic glucose output
DeFronzo RA. Diabetes Rev. 1997;5:177-269; Rosenstock J, Wyne K. In: Rosenstock J et al, eds. Textbook of Type
2 Diabetes. 2003:131-154.
Why Focus on Postprandial Glucose
at Levels Close to Goal?
PPG
FPG
Contribution to Overall
Hyperglycemia (%)
100
80
60
40
20
0
<7.3
7.3-8.4
8.5-9.2
HbA1C (%)
Monnier L et al. Diabetes Care. 2003;26:881-885.
9.3-10.2
>10.2
The Role of the Incretin System in
Maintaining Blood Glucose Homeostasis
GI tract
Pancreas
Insulin
from ß-cells
Ingestion
of food
Release of
GLP-1
and GIP
(Glucose
dependent)
-cells
a-cells
Glucagon
from a-cells
(Glucose
dependent)
Drucker DJ. Diabetes Care. 2003;26:2929-2940.
 Glucose
uptake by
adipose and
muscle tissue
 Glucose
production
by liver
Blood
glucose
homeostasis
Postprandial Hyperglycemia: The Result of
Increased Glucagon and Poor Insulin Secretion
Carbohydrate Meal
Healthy Subjects (n = 14)
Type 2 Diabetes (n = 12)
120
Insulin (µU/mL)
60
0
140
Glucagon (pg/mL)
120
100
360
300
Glucose (mg/dL)
240
140
80
-60
0
60
120
Time (min)
Müller WA et al. N Engl J Med. 1970;283:109-115.
180
240
Insulin
(pmol/L)
*
250
200
150
100
50
*
*
*
*
*
*
•* *
•*
*
*
*
40
30
20
•* 10
0
Effect declines as
glucose reaches
normal levels
20
Placebo
GLP-1
15
10
*
*
*
*
5
0
*P <0.05
250
200
150
* 100
50
mIU/L
Glucagon
(pmol/L)
15.0
12.5
10.0
7.5
5.0
Glucose
(mg/dL)
Glucose
(mmol/L)
Glucose-Dependent Effects of GLP-1:
Patients With Type 2 Diabetes
60
120
180
Minutes
Nauck MA et al. Diabetologia. 1993;36:741-744.
240
Metabolism of GLP-1
Mixed Meal
Intestinal
Release of GLP-1
GLP-1
Inactive
DPP-IV
GLP-1
Active
Rapid inactivation
(>80% of pool)
Plasma
GLP-1 Actions
Excreted by kidneys
DPP-IV = dipeptidyl peptidase-VI
Drucker DJ. Diabetes Care. 2003;26:2929-2940; Holst JJ, Ørskov C. Diabetes. 2004;53(suppl 3):S197-S204.
Inhibiting DPP-IV Augments GLP-1 Levels
Mixed Meal
Intestinal
Release of GLP-1
X
GLP-1
Inactive
DPP-IV
GLP-1
Active
Rapid inactivation
(>80% of pool)
Plasma
GLP-1 Actions
Excreted by kidneys
Drucker DJ. Diabetes Care. 2003;26:2929-2940; Holst JJ, Ørskov C. Diabetes. 2004;53(suppl 3):S197-S204.
Treatment Strategies That Target
the Incretin System
GLP-1 Analogs
DPP-IV Inhibitors
GLP-1 receptor agonist
resistant to inactivation
by DPP-IV
Highly selective for DPP-IV
Stimulates glucosedependent insulin secretion
Activity dependent on
incretin action
Injectable
Oral
Longer acting: days to weeks
Short- vs long-acting
Drucker DJ. Diabetes Care. 2003;26:2929-2940.
Exenatide Mimics Many Properties of GLP-1
GLP-1
Exenatide
 Glucose-dependent insulin secretion


 Glucagon secretion ( hepatic glucose output)


Regulates gastric emptying ( rate of nutrient
absorption)


 Food intake


 Plasma glucose acutely to near-normal levels



Resistant to DPP-IV degradation
Duration in plasma following SC injection
SC = subcutaneous
Drucker DJ. Diabetes Care. 2003;26:2929-2940.
Short
Long
GLP-1: Liraglutide
 SQ Injectable (0.6 mg, 1.2 mg or 1.8 mg once daily), independent
of meals
 Balck Box: Risk of Thyroid C-Cell Tumors in rodents.
Contraindicatd with FH or personal Hx of medullary thyroid
cancer of MEN type 2
 No studies combined with insulin
 Monotherapy
–Dose-related ↓ in HbA1C of 0.98% to 1.45% as monotherapy
for 14 wk
–Significantly greater ↓ in HbA1C than glimepiride over 52 wk
Vilbøll T et al. Diabetes Care. 2007;30:1608-1610; Garber A et al. Lancet. 2009;373:473-81; Freeman JS. Available
at: http://www.medscape.com/viewarticle/585162.
http://www.victoza.com/ Accessed 2010Jan28
GLP-1: Liraglutide
 Combination therapy (26 wk): significantly greater ↓ in HbA1C
when added to:
–Glimepiride vs rosiglitazone + glimepiride
–Metformin + glimepiride vs insulin glargine added to
metformin + glimepiride
–Metformin + rosiglitazone vs placebo added to metformin +
rosiglitazone
–Metformin, SU, or both vs exenatide added to metformin, SU,
or both
 Significant decrease in body weight vs placebo or glimepiride
 Increased risk of hypoglycemia in combination with insulin
secretagogue
Vilbøll T et al. Diabetes Care. 2007;30:1608-1610; Garber A et al. Lancet. 2009;373:473-81; Freeman JS. Available
at: http://www.medscape.com/viewarticle/585162.
http://www.victoza.com/ Accessed 2010Jan28
Features of DPP-IV Inhibitors
Sitagliptin & Saxagliptin

Antidiabetic effects of DPP-IV inhibitors in animals
– Delay in progression from IGT to type 2 diabetes
– Improved glucose tolerance and insulin secretion
– Progressive improvement in glycemic control
– Improved β-cell function
– Increased hepatic and peripheral insulin sensitivity

Indicated as monotherapy or in combination with
other oral agents

Once daily oral dosing, independent of meals
Chahal H, Chowdhury TA. Q J Med. 2007;100:671-677; Drucker DJ. Diabetes Care. 2003;26:2929-2940;
Nicolucci A, Rossi MC. Acta Biomed. 2008;79:184-191.
Saxagliptin (FDA Approved July 2009)
Saxagliptin monotherapy (vs placebo in
drug-naïve patients)
–Dose-related decreases in HbA1C (0.7% to 1.1%),
FPG, and PPG over 12 or 24 wk
–No confirmed hypoglycemic episodes
–Headache most common adverse effect (16%)
Joins Sitagliptin
as DPP IV agent
How Do Glucose-Lowering
Agents Compare?
Class/
Drug
HbA1C
Reduction (%)
Advantages
Disadvantages
Metformin
1.5
• Weight neutral
• GI side effects
• Contraindicated in renal
insufficiency
SU
1.5
• Rapidly effective
• Weight gain
• Hypoglycemia
TZDs
α-glucosidase
inhibitors
0.5 to 1.4
1 to 1.5
• Improved lipid profile
• Potential  in MI
(pioglitazone)
• Weight neutral
•
•
•
•
•
Fluid retention
CHF
Weight gain
Bone fractures
Potential  in MI
(rosiglitazone)
• Frequent GI side effects
TID dosing
Cost
$
$
$$$
$$$
SU = sulfonylureas; GI = gastrointestinal; MI = myocardial infarction;
CHF = congestive heart failure
Nathan DM et al. Diabetes Care. 2009;32:193-203.
(cont’d)
How Do Glucose-Lowering
Agents Compare? (cont’d)
Class/
Drug
Glinides
HbA1C
Reduction (%)
0.5 to 0.8
Advantages
Disadvantages
• Rapidly effective
• Weight gain
• TID dosing
• Hypoglycemia
$$$
$$$
$$$
Exenatide
0.5 to 1.0
• Weight loss
• 2 daily injections
• Frequent GI side effects
• Long-term safety not
established
Sitagliptin
0.6 to 0.8
• Weight neutral
• Long-term safety not
established
1.5 to 3.5
• No dose limit
• Rapidly effective
• Improved lipid profile
•
•
•
•
Insulin
Cost
TID = three times a day
Nathan DM et al. Diabetes Care. 2009;32:193-203.
1 to 4 daily injections
Monitoring
Potential weight gain
Potential hypoglycemia
$$$
AACE Guidelines: Patients Naïve to
Pharmacologic Therapy
HbA1C
Level
Guideline
Pharmacologic Options
6% to 7%
• Initiate monotherapy
• Monitor and titrate for 2-3 mo
• Consider combination therapy
if goals not met after 2-3 mo
•
•
•
•
•
Metformin
TZD
SU
DPP-IV inhibitor
α-glucosidase inhibitor
7% to 8%
• Initiate combination therapy
• Rapid-acting or premixed
insulin analogs for special
situations
• All oral medications may be
combined with insulin, based
on SMBG levels
•
•
•
•
•
•
Metformin + SU or TZD or DPP-IV inhibitor
SU + TZD or α-glucosidase inhibitor
DPP-IV inhibitor + TZD
Metformin + SU + TZD
Fixed-dose TZD + metformin or glimepiride
Fixed-dose metformin + glyburide
SMBG = self-monitored blood glucose
AACE. Endocr Pract. 2007;13(Suppl 1):4-68.
(cont’d)
AACE Guidelines: Patients Naïve to
Pharmacologic Therapy (cont’d)
HbA1C
Level
8% to 10%
>10%
Guideline
Pharmacologic Options
• Initiate/intensify combination
therapy to address fasting and
postprandial glucose levels
• Same as for HbA1c levels 7% to 8%
• Initiate/intensify insulin
therapy
• Rapid-acting + long-acting insulin analogs
• Premixed insulin analogs
SMBG = self-monitored blood glucose
AACE. Endocr Pract. 2007;13(Suppl 1):4-68.
In Addition to TLCs, Which Would Be
Appropriate Initial Therapy for Isabel?

Isabel’s treatment plan:
– Individualized weight loss and exercise program
– Begin metformin 1000 mg BID
– Self-monitor blood glucose once a day at various times
Preferred
• Metformin
• Low-dose SU
BID = twice a day
AACE. Endocr Pract. 2007;13(Suppl 1):4-68.
Alternatives
• TZD
• α-glucosidase inhibitor
• Exenatide (monotherapy
10/2009)
• DPP-IV inhibitor
• Glinides
• Prandial insulin
Isabel: Two-Year Follow-up
Previous 2 Years
Lifestyle change
• Walking 30 min 4 x per wk
• Lost 15 lb
– Reduced calories
– Reduced fat intake
This Visit
• Walking only 1 or 2 x per wk
• Gained back 20 lb
• Concerned about:
– “Gaining weight”
– “Swollen ankles”
– “Low blood sugar”
Medication
• Metformin 1000 mg BID
• Metformin 1000 mg BID
SMBG
• Up to 3 times daily
• Once daily
• HbA1C: 6.2%-6.7%
• Fasting: 110-130 mg/dL
• Postprandial: 190-230 mg/dL
• HbA1C: 7.8%
Glucose levels
AACE Guidelines That Apply to Isabel

HbA1C between 7% and 8%

Guideline: Initiate combination therapy

Two oral-agent options
– Metformin + SU or TZD or
DPP-IV inhibitor
– Fixed-dose TZD + metformin or
glimepiride
– SU + TZD or α-glucosidase
inhibitor
– Fixed-dose metformin + glyburide
– DPP-IV inhibitor + TZD

Triple oral-agent options
– Metformin + SU + TZD
– Exenatide + SU + metformin

Pramlintide + prandial insulin
AACE. Endocr Pract. 2007;13(Suppl 1):4-68.
– Exenatide + SU or metformin or TZD
What Will Influence Treatment
Modification for Isabel?
HbA1C
Reduction (%)
Hypoglycemia
Weight
Change
Fluid
Retention
Metformin
1.5
No
Neutral
No
SU
1.5
Yes
Gain
No
TZDs
0.5 to 1.4
No
Gain
Yes
Exenatide
0.5 to 1.0
No
Loss
No
α-glucosidase inhibitors
0.5 to 0.8
No
Neutral
No
1 to 1.5
Yes
Gain
No
Pramlintide
0.5 to 1.0
No
Loss
No
Sitagliptin
0.6 to 0.8
No
Neutral
No
Insulin
1.5 to 3.5
Yes
Gain
No
Class/Drug
Glinides
Nathan DM et al. Diabetes Care. 2009;32:193-203.
Which of the Following Anti-Hyperglycemic
Agents Address Isabel’s Concerns?

An α-glucosidase inhibitor, exenatide, or sitagliptin acceptable
– Not likely to cause hypoglycemia
– Not likely to induce weight gain
– Not associated with fluid retention

Isabel chose a trial of exenatide based on her concerns about
weight gain and hypoglycemia
– Initial dosage: 5 mcg SC before breakfast and dinner
– Continue metformin 1000 mg twice a day
– Intensify TLCs

Do you agree with the patient’s decision?
We will discuss this during the Q&A
AACE. Endocr Pract. 2007;13(Suppl 1):4-68; Hoogwerf BJ. Curr Drug Ther. 2006;73:477-484.
Exenatide Dosing

5 mcg SC 0-60 min generally before breakfast and
dinner

Titrate up to 10 mcg BID after 1 mo, if no significant
nausea or vomiting

Dose of SU may need to be reduced to avoid
hypoglycemia

Dose reduction of metformin or TZD not likely
Hoogwerf BJ. Curr Drug Ther. 2006;73:477-484.
Effect of Addition of Exenatide to Oral
Antidiabetic Agents on Weight: AMIGO Trials
Sulfonylurea
(N = 377)
Change From Baseline (lb)
0
Metformin
(N = 336)
-1
-2
-3
Metformin + Sulfonylurea
(N= 733)
-0.7
-1.3
-2.0
-4
-2.0
-3.6*
-3.6†
-3.6†
-3.6†
-5
-6
-6.2†
-7
-8
Baseline
Weight:
Exenatide 5 mcg BID
209.4-218.3 lb
Exenatide 10 mcg BID
220.5 lb
Placebo
213.8-218.3 lb
*P<0.05; †P<0.001
AMIGO = AC 2993: Diabetes Management for Improving Glucose Outcomes
Buse JB et al. 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.
Proportion of Patients Achieving HbA1C
<7% at 30 Weeks: AMIGO Trials
Change From Baseline (lb)
50
46†
41*
40
33*
34‡
32†
30
27‡
20
13
0
Sulfonylurea
(N = 377)
Exenatide 5 mcg BID
Baseline
HbA1C:
9
9
10
8.5%-8.7%
Metformin
(N = 336)
Exenatide 10 mcg BID
8.2%-8.3%
Metformin + Sulfonylurea
(N= 733)
Placebo
8.5%
*P<0.001; †P<0.01; ‡P<0.0001
Buse JB et al. 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.
Sitagliptin Added to Metformin Reduces HbA1C
in Patients With Inadequate Glycemic Control
Patients Achieving HbA1C <7% After 24 Weeks
Change in HbA1C After 24 Weeks
P<0.001
-0.02%
47
8
40
30
18
20
10
0
Baseline
HbA1C:
HbA1C (%)
Percentage of Patients
50
8.2
7.8
Sitagliptin +
Metformin (n=453)
7.6
Placebo (n=224)
7.4
7.2
Sitagliptin +
Metformin
(n=453)
7.96%
Placebo
(n=224)
8.03%
Charbonnel B et al. Diabetes Care. 2006;29:2638-2643.
7
-0.67%
(P<0.001)
0
6
12
Week
18
24
Effectiveness of Initial Combination
Therapy With Sitagliptin and Metformin
Baseline HbA1C:
8.68%
8.87%
8.90%
8.68%
8.79%
8.76%
11.2%
Change From Baseline (%)
1.00
0.50
0.17
0.00
-0.50
-1.00
-0.66*
-0.82*
-1.50
-2.00
-1.13*
-1.40*
-1.90*
-2.50
-3.00
Placebo Sitagliptin Metformin Metformin Sitagliptin Sitagliptin
100 mg QD 500 mg
1000 mg
50 mg +
50 mg +
BID
BID
Metformin Metformin
500 mg
1000 mg
BID
BID
*P0.001 vs placebo at 24 weeks
-2.90
Open
Label
Open Label = Patients with baseline HbA1C >11% or FPG >280 mg/dL treated with sitagliptin 50 mg
+ metformin 1000 mg BID for 24 wk
Goldstein BJ et al. Diabetes Care. 2007;30:1979-1987.
Adverse-Event Profiles of Exenatide
and Sitagliptin
Exenatide
5 mcg BID
Hypoglycemia
With metformin
With SU
With metformin + SU
Sitagliptin
10 mcg BID
4.5%
14.4%
19.2%
5.3%
35.7%
27.8%
100 mg/day
1.2%
Nasopharyngitis
5.2%
URTI
6.3%
Headache
9%
Dizziness
9%
Abdominal pain
5.1%
2.3%
Nausea
44%
Vomiting
13%
Diarrhea
13%
Dyspepsia
6%
1.4%
3.0%
URTI = upper respiratory tract infection
Byetta® (exenatide injection) prescribing information; Januvia (sitagliptin tablets) prescribing information.
Isabel: Follow-up on Combination Therapy

1 month
– Had lost 3 lb
– FBG: 110-130 mg/dL
– PPG: 160-190 mg/dL

3 months
– Patient pleased with weight loss (now a total of 6 to 7 lb)
– FBG: 105-115 mg/dL
– PPG: 130-160 mg/dL
– HbA1C: 6.9%

Improved glycemic control + weight loss = reduced risk
for macrovascular/microvascular complications
Summary

Type 2 diabetes affects nearly 8 million Americans

Early and intensive treatment to lower HbA1C reduces risk
for macrovascular and microvascular complications

Postprandial hyperglycemia should be a focus of diabetes
management

GLP-1 analogs and DPP-IV inhibitors
– Maintain normal blood glucose by regulating postprandial
glucose
– Are recommended as combination therapy with other OADs
– Induce weight loss or weight neutral
– Significantly reduce HbA1C vs metformin or SU monotherapy
Summary (cont’d)

Exenatide (GLP-1 analog)
– Twice-daily injectable
– Risk for hypoglycemia with SU

Sitagliptin & Saxagliptin (DPP-IV inhibitor)
– Once-daily oral
– Risk for hypoglycemia with SU

New agents in development with less frequent dosing

Addition of GLP-1 analog or DPP-IV inhibitor
– Can help reduce HbA1C to recommended target
– May contribute to weight loss
– Together, risk for diabetes-related complications may be reduced