Current Advances in
Diabetes Management
John B. Buse, MD, PhD
Associate Professor of Medicine
Chief, Division of General Medicine and Clinical Epidemiology
Director, Diabetes Care Center
University of North Carolina
Chapel Hill, NC
jbuse@med.unc.edu
Change in Age-Adjusted
Mortality Rates
50
40
% Change
in AgeAdjusted
Mortality
Rate Since
1979
Diabetes Mortality
30
20
Cancer Mortality
10
0
-10
-20
-30
All-Cause Mortality
Major CVD Mortality
-40
-50
Year
B Sobel et al., Circ 2003; 107:636 (CDC, PMD)
ABC’s of Diabetes Management
Glycemic control
A1C
<7.0%
Preprandial plasma glucose
90-130 mg/dL (5.0-7.2 mmol/L)
Postprandial plasma glucose
<180 mg/dL (<10.0 mmol/L)
Blood pressure
<130/80 mm Hg
Lipids
LDL-cholesterol
<100 mg/dL (<2.6 mmol/L)
Triglycerides
<150 mg/dL (<1.7 mmol/L)
HDL-cholesterol
>40 mg/dL (>1.1 mmol/L)
Antiplatelet therapy
Everyone over 40 or with risk factors
Smoking cessation
Everyone
American Diabetes Association. Diabetes Care. 2004;27:s19.
63% of Patients With Diabetes
are Not At ADA A1C Goal <7%
Adults aged 20-74 years with previously diagnosed diabetes who participated in the interview
and examination components of the National Health Examination Survey (NHANES), 1999-2000.
100
80
% of
Subjects
n = 404
60
12.4%
7.8%
63%
7%
17.0%
25.8%
>10%
>9%
>8%
7-8%
40
20
37.2%
>8%
A1C
37.0%
<7%
0
Only 7% of adults with diabetes in NHANES 1999-2000 attained:
• A1C level <7%
• Blood pressure <130/80 mm Hg
• Total cholesterol <200 mg/dL
Saydah SH et al. JAMA. 2004;291:335-342.
Difficulties in Achieving
Target A1C Values

What is the appropriate A1C target

Challenges
– Late diagnosis and initiation of therapy
– Therapeutic inertia
– Lack of effective lifestyle intervention
– Secondary failure
– Adverse events associated with antihyperglycemic
therapies
– Complexity of care
– Role of postprandial glucose in failure
Glycemic Goals of Therapy
Goal
ADA
Premeal plasma glucose (mg/dl) 90-130
2-h postprandial plasma glucose <180*
HbA1c
<7%**
ACE
<110
<140
<6.5%
Verbal Target
~100
<<200
As low as
possible w/o
unacceptable AE
* Evaluation and treatment of postprandial glucose may be useful in the
setting of suspected postprandial hyperglycemia, with the use of agents
targeting postprandial hyperglycemia and for suspected hypoglycemia.
** More stringent glycemic goals (i.e. a normal A1C, <6%) may further
reduce complications at the cost of increased risk of hypoglycemia
Diabetes Care 28:s4-36, 2005
http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php
Effect of Early TZD Use on A1C
6.8 -
Rosiglitazone (n=39)
6.6 -
Pioglitazone (n=62)
6.4 -
Control (n=71)
†
*
†
6.2 -
A1C (%)
6.0 -
*
5.8 -
*
5.6 -
*
5.4 5.2 -
*
*
*
* P<0.001 vs. baseline; † P<0.001 vs. rosiglitazone and pioglitazone
5.0 -
Baseline
Switch
Durbin RJ Diabetes, Obesity & Metabolism 6:280-285, 2004
2-yr check
3-yr final
Patients Remain on Monotherapy
>1 Year After First A1c >8.0%*
Length of time that the patient’s A1c remained above 8.0%
before a switch/addition in therapy*
25
20 months
20
Months
15
14 months
10
5
0
Metformin Only
(n=354)
Sulfonylurea Only
(n=2517)
*May include up-titration. Length of time between first A1c >8.0% and switch/addition in therapy could include periods where patients
had subsequent A1c test values below 8%. Based on nonrandomized retrospective database analysis. Data from Kaiser Permanente
Northwest 1994-2002. Patients had to be continuously enrolled for 12 months with A1c lab values.
Brown et al. Diabetes. 2003;52(suppl 1):A61-A62. Abstract 264-OR.
Effectiveness of Medical Nutrition
Therapy in Management of Type 2 Diabetes
A1C (%)

Emphasize
blood glucose control,
8.4
8.2
8.0
 Focus
on carbohydrate foods,
7.8
7.6
number
of servings per meal.
7.4
7.2
7.0
 Encourage
physical activity.
6.8
6.6
Initial
6 week
3 month
No nutrition education
1 visit with dietitian
with dietitian
not3 visits
weight
loss.
*
†
portions, and
†
6 month
Use
food
records
with
blood
glucose monitoring
for 3-visit
and 1-visit
groups vs
no nutrition
education
No significant
data. difference between 3-visit and 1-visit groups:

*P<0.05
†
P<0.001 significantly less than at entry
Franz MJ et al. J Am Diet Assoc. 1995;95:1009-1017.
Progressive Hyperglycemia Despite Insulin,
Sulfonylurea, or Metformin
Median HbA1c (%)
9
Conventional
Glibenclamide
Metformin
Chlorpropamide
Insulin
8
7
6
0
UKPDS 34, Lancet 1998.
2
4
6
8
Years from randomization
10
As Patients Get Closer to A1c Goal, the
Need to Manage PPG Increases
100
30%
80
%
60
Contribution
40
20
70%
55%
60%
50%
FPG
PPG
70%
30%
40%
45%
50%
9.2-8.5
8.4-7.3
0
>10.2
10.2-9.3
A1C Range (%)
Monnier L, et al. Diabetes Care. 2003;26:881-885.
<7.3
Anti-Hyperglycemic Agents in Type 2 Diabetes
Class
Insulin
Sulfonylureas, particularly
glimepiride and glipizide GITS
Fast acting secretagogue
("glinides"):
Biguanides (metformin)
Thiazolidinediones
("glitazones")
Alpha-glucosidase inhibitors
Amylin-mimetics (pramlintide)
Incretins (exenatide)
Advantages
Efficacy
Titratability
Inexpensive
Titratability
Flexibility
Fast on - Fast off
No weight gain
?CVD reduction
?CVD reduction
Preserve β-cell
No hypoglycemia
No weight gain
Weight loss
No hypoglycemia
Weight loss
No hypoglycemia
?preserve β-cell
Disadvatages
Weight gain
Hypoglycemia
Min. hypoglycemia
Minimal wt gain
TID
Expense
BID - GI complaints
Contraindications
Expensive - Slow onset
Weight gain - Fluid retention
GI complaints
Expensive
Injected
Expensive
Injected
Expensive
Glycemic
Control
Treatment Algorithm - Glucose
Diagnosis
by screening or with symptoms
Lifestyle Intervention
nutrition, exercise, education
Quarterly to
semi-annual
follow-up
Are A1c/FPG Targets Achieved?
Yes
Monthly to
quarterly
follow-up
No
FPG > 200 mg/dL
Target Insulin
Deficiency
*
Target Insulin
Resistance
FPG < 130 mg/dL
Target PPG
*Keep adding agents until target is reached. Self-titration at home when possible.
Metformin, glitazone
Exenatide, nateglinide, α-glucosidase inhibitors, rapid-acting insulin, pramlintide
SFUs/glinide, insulin, exenatide
Diabetes-related Deaths:
UKPDS Overweight Subgroup
40%
30%
Proportion of
Patients With
Events
20%
Conventional
(n=411)
MvC
P=.017
Insulin or SFU
(n=951)
Metformin
(n=342)
10%
MvI
P=0.11
0%
0
Lancet. 1998;352:837.
3
6
9
Years from randomization
12
15
Insulin Resistance:
Cardiovascular
Correlates
Glitazone Effects
Accelerated
Atherosclerosis
Improves
Type 2 diabetes
glycemic control
Modulates
Inflammation
adipocytokines
and
inflammatory markers
Reverses of
Coagulation/Fibrinolytic
coagulation and
defects
fibrinolytic defects
X
Insulin
Resistance
TZD
Improves
Endothelial
endothelial
dysfunction
dysfunction
Adapted from Diabetes Care 21:310-314, 1998.
Reduces
blood
Hypertension
pressure
Decreases TG (P)
DyslipidemiaHDL
Increases
Improves LDL size
Reduces
central(central)
Obesity
obesity
Ongoing Clinical Trials
Charbonnel B, et al. Diabetes Care 27:1647–1653, 2004
RECORD (Rosiglitazone Evaluated for CVD Outcomes & Regulation of Glucose in Diabetes)

6,000 patients (add Rosi to exisiting Rx) – 6 year follow-up

1° Endpoint = combined cardiovascular events
BARI 2D (Bypass Angioplasy Revascularization Inverstigation – Type 2 Diabetes)

Medical management vs. revascularization – of early CAD

Comparison of insulin sensitizing vs. insulin providing therapies
Pioglitazone Comparator Studies – Europe
Durability
R. Urquhart. IDF 2003.
Glitazones:
Minimizing Adverse Effects



Warn patients about the possible (liver) and expected
adverse effects (edema and weight gain); develop
prospectively a plan for home evaluation & management
ALT measurements prior to initiating therapy and
intermittently thereafter; avoid use in active liver disease.
Start with a low dose in high risk patients (pre-existing
edema, insulin treated or known heart disease)
– Pioglitazone 15 mg po qd or rosiglitazone 2-4 mg po qd
– At 1-2 month follow-up visit, increase dose as needed
– If edema develops, salt restriction ± low-dose thiazide diuretic ±
loop diuretic ± dose reduction
– Consider role of ACE inhibition, CCB’s, NSAID’s
Buse JB. Circulation. 108(8):e57, 2003. Nesto RW. Circulation. 108(23):2941-8, 2003.
Intensive Management Strategy: Step 1
Insulin Effect
Met + Glitazone
Brfst

Lunch
Supper
Bed
Insulin sensitization
– Diet/exercise + glitazone + metformin (if FPG > 110 mg/dl)
– Minimal risk of hypoglycemia
– Minimize weight gain
Multiple Sites of Action of
Exenatide
CNS:
Promotes satiety and
reduction of appetite
Liver:
Reduces hepatic glucose
output by inhibiting glucagon
release
Alpha cell:
Inhibits glucagon secretion
in a glucose dependent
fashion
Beta cell:
Stimulates glucosedependent insulin
secretion
Increases beta cell
mass
Stomach:
Slows gastric
emptying
A1C and Body Weight Reductions:
Preliminary Analysis for Subjects Treated for 2 Years
2 yr data for 82-wk cohort (N = 146)
Mean ± SE
Δ A1C (%)
Placebo
Controlled
Δ Body Weight (kg)
Open-Label Extensions
0.0
1.2±0.1%
-1.5
0.0
Open-Label Extensions
-2
-0.5
-1.0
Placebo
0 Controlled
5.5±0.5 kg
-4
-6
0.5
1.0
1.5
2.0
Duration of Treatment (Years)
Baseline A1C 8.2%
0.0
0.5
1.0
1.5
Duration of Treatment (Years)
Baseline weight: 100 kg
2.0
General Prescribing Considerations:
Dosing
Stable Dose
10 mcg BID
Stable Dose
5 mcg BID
Initiation
1 Mo
• Evaluate need for SFU dose reduction to minimize risk of hypoglycemia
• No dosage adjustments based on meal size or exercise
• No additional glucose monitoring required
Exenatide Prescribing Information, 2005.
General Prescribing Considerations:
Administration and Storage

SC injection
– Administer BID within 60 minutes before morning and
evening meals (do not give after meal)
– Abdomen, thighs, and arms

Missed dose
– Wait until the next scheduled dose

Refrigeration
– Refrigerate (36°-46° F) between injections
– Do not freeze
– Discard 30 days after first use
Exenatide Prescribing Information, 2005.
Intensive Management Strategy: Step 2
Insulin Effect
Metformin + Glitazone + Secretagogue
Brfst

Lunch
Supper
Bed
Insulin sensitizers + secretagogue
– Glitazone +/- metformin
– + exenatide (or sulfonylurea or “glinide”)
Glargine vs. Exenatide
Exenatide
Insulin Glargine
1.5
1.0
 HbA1c8.5
(%)
8.0
8.0
6
7.5
7.5
2
0.5
 Body Weight (lbs)
4
7.0
7.0
6.5
6.5
0.0
-0.5
0
-2
-4
-1.0
0.0
0.0
-1.5
0
12
Weeks
**
* *
*
-6
0 26
0
Heine RJ, et al. ADA Scientific Sessions, June 2005
12
12
Weeks
Weeks
8 12
0 2 4 26
18
26
Weeks
*
26
ITT patient sample
Mean ± SE shown
* p<0.0001, exenatide vs insulin glargine at same time point
Options to Individualize Therapy in Patients
Failing Oral Anti-Hyperglycemic Therapy
1 shot
basal
OAH’s
Ready for
injected
therapy
MDI lite
2-3 shots
MDI
4 shots
Coverage:
Only FPG
Coverage:
FPG
PPG x 1-2
Premix
QD
Premix
BID
Analog
premix
TID
Coverage:
FPG
PPG x 1
Coverage:
FPG
PPG x 2
Coverage:
FPG
PPG x 3
Exenatide
BID
Coverage:
FPG
PPG x 3
???
Coverage:
FPG
PPG x 3
Insulin Pens
Lilly
Novo
Others
Intensive Management Strategy
Monomeric Insulin
Analog
Insulin Effect
Glargine
Met + Glitazone (+ Secretagogue)
Brfst
Lunch
Dinner
Bed
Insulin sensitizer(s) + secretagogue (SFU or “glinide”)
Add glargine or NPH QHS; titrate to
normalize fasting glucose
Add monomeric insulin analog QAC; titrate to normalize
postprandial glucose (generally discontinue secretagogue)
Amylin: The Second -Cell Hormone
• First reported in 1987
• Important regulator of glucose influx into bloodstream
• 37–amino acid neuroendocrine hormone
• Co-located and co-secreted with insulin from pancreatic -cells
• Not synonymous with “amyloid deposits”
Amylin
Insulin
Unger. Williams Textbook of Endocrinology. 1992.
Amylin Is Deficient in Diabetes
Sustacal®
20
No diabetes
15
Plasma
Amylin
(pM)
10
Insulin-treated type 2 diabetes
5
Type 1 diabetes
0
-30
0
30
60
90
120
150
180
Minutes After Sustacal®
Fineman. Diabetologia. 1996;39(suppl 1):A149.
Kruger. Diabetes Educ. 1999;25:389.
Multiple Sites of Action of
Pramlintide
CNS:
Promotes satiety and
reduction of appetite
Liver:
Reduces hepatic glucose
output by inhibiting glucagon
release
Beta cell:
None
Alpha cell:
Inhibits glucagon secretion
Stomach:
Slows gastric
emptying
Pramlintide Clinical Effects
TYPE 2 DIABETES COMBINED PIVOTALS
Placebo + Insulin
120 g Pramlintide BID + Insulin
 Insulin Use (%)
 A1C (%)
Week 4
Week 13
Week 26
Week 4
Week 13
 Weight (kg)
Week 26
Week 13
Week 26
1
8
0
Week 4
6
-0.2
4
-0.4
0
2
**
0
-1
-0.6
**
-0.8
**
-2
*
-4
Placebo + insulin (n=284), Baseline A1C = 9.3%
Pramlintide + insulin (n=292), Baseline A1C = 9.1%
*P <0.01, **P <0.0001; ITT population; Mean (SE) change from baseline
Pramlintide Prescribing Information, 2005. Data on file, Amylin Pharmaceuticals, Inc.
Hollander P, et al. Diabetes Care 2003; 26:784-790
Ratner RE, et al. Diabetes Technol Ther 2002; 4:51-61
**
**
**
-2
**
Pramlintide + Insulin:
General Considerations
Administration

SC injection into abdomen or thigh

Do not mix with insulin

Pramlintide and insulin should
always be given as separate
injections and at separate sites at
least 2 inches apart

Administer using U-100 insulin
syringe

Inject before each major meal
(and snack 250 kcal or 30 g CHO)
Pramlintide Prescribing Information, 2005
Dose
Units
15 µg
2.5 U
30 µg
5U
45 µg
7.5 U
60 µg
10 U
120 µg
20 U
Lipids
Statins:
Effective Agents to Reduce CVD
4S
25
% With
CAD
Event
20
LIPID
CARE
15
HPS
PROVE-IT
10
WOSCOPS
TNT
5
TNT
HPS
(estimated)
AFCAPS
0
50
70
90
110
130
150
170
190
210
LDL-C (mg/dL)
Adapted from Illingworth. Med Clin North Am. 2000;84:23. Available at: http://www.hpsinfo.org.
VA-HIT: Effects of Gemfibrozil on CVD
Events in CHD Patients With Low HDL-C
10
6.0*
5
% Change From Baseline
Subjects: 2531 men
Age: ≤74 (avg 64) yr
Mean baseline LDL-C:
111 mg/dL
Mean baseline HDL-C:
32 mg/dL
Mean baseline TG:
161 mg/dL
Duration of Type 2 DM:
7 yr
Intervention:
Gemfibrozil 600 mg BID
4
TG
0
-5
Nonfatal
MI/CHD
Death
CHD
Death
All-Cause
Stroke Mortality
LDL-C HDL-C
-10
-11
-15
-20
-25
-22†
-22‡
-25
-30
-31*
*P<0.001; †P=0.006; ‡P=0.07.
Rubins HB, et al. N Engl J Med. 1999;341:410-418.
Comprehensive Management
of Dyslipidemia
Increased

Triglycerides

VLDL

Small dense LDL

LDL

Apo B
Decreased
DM Rx
Fibrates
Niacin
Fish oil

HDL

Apo A-I
Statins
Bile acid sequestrants
Chol. absorption inhibitors
Stanol esters
Blood Pressure
HOT Trial
Effect of Diastolic Target on CVD Events - 4 Years
30
20
48%
24.4
Events/
1000
Pt-Yrs
18.6
Risk
Reduction
10
11.9
9.9
10.0
<90
<85
9.3
0
<90
<85
Diabetic Patients
n=1,501, P=0.016
Lancet 351: 1755-1762, 1998
<80
<80
Non-Diabetic Patients
n=18,790, P=NS
Number of Medications to Achieve Goal
BP in 5 Trials of DM &/or Renal Disease
UKPDS (<150/85 MM Hg)
2.7
ABCD (< 75 mm Hg DBP)
2.8
MDRD (<92 mm Hg MAP)
3.6
HOT (<80 mm Hg DBP)
3.3
AASK (<92 mm Hg MAP)
3.8
0
1
2
3
Number of BP Meds
Bakris. J Clin Hypertens 1999;1:141-7
4
Treatment Algorithm—Hypertension
BP > 130/80 mm Hg
Lifestyle Intervention
Diet (FFV, low-fat dairy, low Na, modest E to H)
Weight loss
Exercise (30 minutes most days of the week)
Smoking cessation
Quarterly to
semi-annual
follow-up
SBP <130 and DBP <80?
Yes
No
Albuminuria/CVD Risk Factors
Coronary Disease
-blocker
•
•
•
•
Monthly to
quarterly
follow-up
Thiazide
ACE/ARB
Virtually all two-drug combinations should include a thiazide diuretic
The third drug could (should) be a calcium channel blocker
In the setting of kidney or heart disease, consider adding a furosemide BID or torsemide
In the setting of kidney disease and significant proteinuria, consider combined ACE/ARB therapy
Multifactorial Intervention for
Type 2 DM: Steno-2 Study
160 Patients With Type 2 Diabetes and Albuminuria
Mean baseline characteristics
Age: 55 yr
BMI: 30
Duration of DM: ~5.8 yr
A1c: 8.6%
Randomized to conventional or intensive therapy
Mean follow-up: 7.8 yr
Gaede P, et al. Lancet. 1999;353:617-622.
Gaede P, et al. N Eng J Med. 2003;348:383-393.
Multifactorial Intervention for
Type 2 DM: Steno-2 Study (cont)
Physiologic Measures at End of Study
A1c, %
Systolic BP
mm Hg
LDL chol
mg/dL
TG
mg/dL
Gaede P, et al. Lancet. 1999;353:617-622.
Gaede P, et al. N Eng J Med. 2003;348:383-393.
Conventional
Intensive
~9.0
~7.8
~148
~132
~130
~75
~260
~150
Multifactorial Intervention for
Type 2 DM: Steno-2 Study (cont)
60
P=0.007
Conventional Therapy
50
Hazard Ratio=0.47
(95% CI, 0.24-0.73; P=0.008)
40
Primary
Composite
End Point
(%)
53%
30
20
Intensive Therapy
10
0
0
12
24
36
48
60
Months of Follow-up
Gaede P, et al. N Engl J Med. 2003;348:383-393.
72
84
96