1. Pharmacological Treatment
of
f
Type 2 Diabetes
Vivian Fonseca, MD

2. Clinical Pearls
♦ Prevention of type 2 diabetes is possible
yp p
♦ Cardiovascular and microvascular
complications of type 2 diabetes begin prior to
y g
its clinical diagnosis
♦ Monotherapy fails in the majority of patients
with type 2 diabetes
ih di b
♦ Effective treatment strategies should include
reduction in A1C, blood pressure, and
d ti i A1C bl d d
cholesterol levels
♦ Improvement in cardiovascular outcomes in
patients with type 2 diabetes remains a
challenge

3. DPP: Incidence of Type 2 Diabetes
40
Placebo
30
Metformin
ative incidence
Lifestyle
of diabetes (%)
20
Cumula
10
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Year
*P<0.001 compared with each group
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

4. DPP: Baseline Predictors
of Response to Metformin
Lifestyle Metformin Placebo
25 25 25
on-years
20 20 20
15 15
Cases/100 perso
15
10 10 10
5 5 5
0 0 0
95-109 110-125 25-44 45-59 ≥ 60 22 to < 30 30 to < 35 ≥ 35
(n = 2174) (n = 1060) (n = 1000) (n = 1586) (n = 648) (n = 1045) (n = 995) (n = 1194)
FPG Age BMI
(mg/dL) (years) (kg/m2)
• Lifestyle is more effective generally than metformin or placebo
• Metformin is more effective if FPG > 110 mg/dL, age < 60 years, and BMI > 30 kg/m2
• Gender, ethnicity, and 2-hour glucose were NOT predictive
2-
DPP = Diabetes Prevention Program
Knowler WC, et al. N Engl J Med. 2002;346:393-403.

5. ACT NOW: Islet-Cell Preservation
May D l Onset of Type 2 Diabetes
M Delay O t fT Di b t
0.30 Placebo
Hazard ratio (HR) = 0.19
( )
(95% CI, 0.09-0.39)
0.09-
0.25 P < 0.00001 6.8%
per year
0.20
ard
umulative haza
0.15
0.10 Pioglitazone
Pi lit
Cu
0.05 1.5%
per year
0
0 10 20 30 40 50
Time (months)
n = 602 patients (95 mg/dL ≥ FPG ≤ 125 mg/dL)
Mean follow-up p
p period of 2.6 y
years
The number needed to treat to prevent 1 case of type 2 diabetes was 3.5 patients for 1 year (development of type 2 diabetes defined as FPG > 126 mg/dL,
confirmed with an OGTT)
DeFronzo RA. Presented at: ADA 68th Scientific Sessions; June 2008; San Francisco, CA.

6. DREAM
Primary Outcome:Rosiglitazone
Primary Outcome Rosiglitazone
.6
0.
0.1 0.2 0.3 0.4 0.5
HR = 0.40 (0.35-0.46); P<0.0001
mulative Hazard
Placebo
Cum
Rosiglitazone
0.0
Year
0 1 2 3 4
Placebo
No. at Risk 2634 2470 2150 1148 177
Placebo 2634 2470 2150 1148 177
Rosiglitazone 2635 2538 2414 1310 217
Rosiglita 2635 2538 2414 1310 217

7. NAVIGATOR
G O
2 x 2 Factorial Design
Valsartan comparison
Valsartan/Nateglinide Placebo/Nateglinide
(n = 2,288) (n = 2,288) Nateglinide
comparison
Valsartan/Placebo Placebo/Placebo
(n = 2,288) (n = 2,288)
Dosages
Nateglinide 60 mg PO ac
Valsartan 160 mg PO qd
All subjects will receive a lifestyle advice program

8. Primary End Points: Results of Intensive
Treatment in ACCORD and ADVANCE
ACCORD: Primary Outcome ADVANCE: Primary Outcome
25 25
Intensive Therapy Intensive Therapy
20 20 Standard Therapy
Standard Therapy
Cumulative incidence (%)
15
Patients with events (%)
15
10 10
5 5
0 0
0 1 2 3 4 5 6 0 6 12 18 24 30 36 42 48 54 60 66
Years Months of Follow-up
Number at Risk Number at Risk
Intensive 5128 4843 4390 2839 1337 475 448 Intensive 5570 5369 5100 4867 4599 1883
Standard 5123 4827 4262 2702 1186 440 395 Standard 5569 5342 5056 4808 4545 1921
Primary
Primar composite o tcome nonfatal myocardial infarction, nonfatal
outcome: m ocardial infarction Primary
Primar composite end point: nonfatal myocardial infarction, nonfatal
point m ocardial infarction
stroke, or death from cardiovascular causes stroke, death from cardiovascular causes, new or worsening
Glycemia intervention stopped early for excess deaths in the intensive nephropathy, or retinopathy
therapy group The hazard ratio was 0.90 (P = 0.01) for intensive compared to
The hazard ratio was 0.90 (P = 0.16) for intensive compared to standard treatment.
standard treatment.
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.
ACCORD: Action to Control Cardiovascular Risk in Diabetes ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

9. Main Findings From the ACCORD and
ADVANCE Studies
ACCORD ADVANCE
10,251 participants 11,140 participants
Mean age: 62 years Mean age: 66 years
Median duration of diabetes Mean duration of diabetes
mellitus: 10 years mellitus: 8 years
Mean A1C at entry: 8.3% Mean A1C at entry: 7.48%
Known heart disease History of major CV event
or at least 2 risk factors or at least 1 risk factor
Standard: Intensive: Standard: Intensive:
A1C 7.0%-7.9% A1C < 6.0% A1C, usual care A1C ≤ 6.5%
Conclusion: intensive glucose lowering may Conclusion: intensive glucose lowering in
cause harm in high-risk patients with type 2 high-risk patients reduces renal complications
diabetes and high A1C levels by 21% (95% CI, 7%-34%)
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

10. VADT1 ACCORD2 ADVANCE3
(n=1700) (n=10250) (n=11140)
HbA1c – Std vs.
8.4 vs. 6.9 7.5 vs. 6.5 7.3 vs. 6.5
Intensive
Non-fatal MI
Non-fatal stroke Non-fatal MI Non-fatal MI
Primary outcome CVD death Non fatal
Non-fatal stroke Non fatal
Non-fatal stroke
Hospitalization for CHF CVD death CVD death
Revascularization
Hazard Ratio for
0.87
0 87 0.90
0 90 0.94
0 94
primary outcome
(0.730 – 1.04) (0.78 – 1.04) (0.84 – 1.06)
(95% CI)
Hazard Ratio for *
1.065 (0.801 – 1.416) 1.22 (1.01 – 1.46) 0.93 (0.83 – 1.06)
mortality (95% CI)
%
*P=0.04
1W. Duckworth et al presented at EASD Annual Meeting, 2008; 2The ACCORD Study Group NEJM 2008;358:2545;
3The ADVANCE Collaborative Group NEJM 2008,358:2560

11. ACCORD VADT ADVANCE
p
p<0.001 p
p< 0.01 p
p<0.001

12. The VADT Trial
Relationship of DM Duration and Hazard Ratio for CVD Events
1.4
1.2
1
HR for CVD
0.8
f
Intensive Therapy
0.6
(p<0.0001)
0.4
04
0 3 6 9 12 15 18 21 24
DM Duration (years)
Duckworth W, ADA Scientific Sessions, Symposia. June 8, 2008
.

13. Kaplan-Meier Curves for Four Prespecified Aggregate Clinical Outcomes
Holman R et al. N Engl J Med 2008;10.1056/NEJMoa0806470

14. Recommendations for Adults
with Diabetes Mellitus
• Goals should be individualized
• Certain populations (children, pregnant females,
elderly) require special considerations
• Set less intensive goals in patients with severe or
frequent hypoglycemia (especially if ‘hypoglycemia
q yp g y ( p y yp g y
unawareness’ is present.)
• More stringent goals (i.e. a normal A1C ≤6.0-6.5%)
6.0 6.5%)
may further reduce microvascular outcomes (renal),
but do not effect macrovascular outcomes
(ACCORD, ADVANCE, VADT).
(ACCORD ADVANCE VADT)

15. The ABCs of Diabetes Care
A1C
• ADA recommends < 7% = average glucose of 150 mg/dL
mg/dL
• AACE/IDF recommend ≤ 6.5% = average glucose of 135 mg/dL
mg/dL
Blood pressure
p
• < 130/80 mm Hg
Cholesterol
• LDL-C: < 100 mg/dL ( 70 mg/dL in very high-risk patients)
LDL- mg/dL (< mg/dL high-
• HDL-C: > 40 mg/dL in men and > 50 mg/dL in women
HDL- mg/dL mg/dL
• Non-HDL-C: ≤ 130 mg/dL (< 100 mg/dL in high-risk patients)
Non-HDL- mg/dL mg/dL high-
• TGs: < 150 mg/dL
mg/dL
g
Don’t forget aspirin!
ADA Standards of Medical Care in Diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36.
American Association of Clinical Endocrinologists. Endocr Pract. 2002;8(suppl 1):S5-S11.
International Diabetes Federation. Diabetes Med. 1999;16:716-730.

16. Therapy for Type 2 Diabetes:
Sites of Action
Secretagogues
Alpha-glucosidase inhibitors
Stimulate
insulin secretion
Inhibit
carbohydrate Incretins
breakdown ↑ insulin secretion
↓ glucagon secretion
Incretins
Slow gastric emptying
Metformin
Thiazolidinediones
Thiazolidinediones
↑ glucose
metabolism
↑ glucose intake
↓ FFA output
Metformin
Thiazolidinediones
Suppress glucose
production
Adapted from Saltiel AR, Olefsky JM. Diabetes. 1996:45:1661-1669. Physicians' Desk Reference®. 59th ed.
Montvale, NJ:Thomson PDR; 2005. Drucker DJ. Mol Endocrinol 2003;17:161-171.

17. Updated ADA/EASD Consensus Algorithm
STEP 1 STEP 2 STEP 3
Tier 1: Well-validated therapies
Lifestyle + Metformin Lifestyle + Metformin
+ +
Basal Insulin Intensive Insulin
At Diagnosis:
Lifestyle
+
Metformin
Lifestyle + Metformin
+
Sulfonylureaa
Tier 2: Less well-validated therapies
Lifestyle + Metformin
Lifestyle + Metformin
+
+ Pioglitazone
Pioglitazone +
Sulfonylureaa
Lifestyle + Metformin Lifestyle + Metformin
+ +
GLP-
GLP-1 agonistb Basal Insulin
Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is < 7 0% then at least every 6 months thereafter Change interventions
7.0%, thereafter.
whenever A1C is ≥ 7.0%. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.
Nathan DM, et al. Diabetes Care. 2008;31:1-11.

18. Changing Treatment Paradigm
Diet Combinations
& Monotherapy of oral Insulin
exercise agents
Problems
Glycemic targets often not met
Monotherapy not effective long-term
long-
Treatment fails to address multiple impairments
Step-
Step
S -wise approach tends to perpetuate “failure”
f
Glucose toxicity interferes with treatment response
Harris, MI et al. Diabetes Care. 1999; 22: 403-408.
Harris, MI et al. Diabetes Care. 1998; 21: 518-524.

19. Primary Objectives of Effective
Management
Diagnosis
A1C %
9
8
7
Reduction
SBP of both
mm Hg micro- and macro-
vascular event
145 rates
…by 75%!
y
130
LDL
mg/dL
140
100
45 50 55 60 65 70 75 80 85 90
Patient’s age
American Diabetes Association. Diabetes Care. 2003:26(suppl 1):S28-S32.
Gæde P et al. N Engl J Med. 2003;348:383-393.

20. Primary endpoint: Kaplan-Meier Estimates of the
Cumulative Incidence of Monotherapy Failure
Hazard ratio (95% CI)
Rosiglitazone vs metformin, 0.68 (0.55–0.85); P<0.001
40 Rosiglitazone vs glyburide, 0.37 (0.30–0.45); P<0.001
Glyburide
notherapy Failure
30
Cumulative Incidence of Mon
Metformin
20
(%)
Rosiglitazone
10
0
0 1 2 3 4 5
Years
No. at risk
Rosiglitazone 1393 1207 1078 957 844 324
Metformin
M tf i 1397 1205 1076 950 818 311
Glyburide 1337 1114 958 781 617 218
20
Kahn SE, et al. N Engl J Med 2006;355:2427–2443.

21. Thiazolidinediones (TZD’s):
Pioglitazone and Rosiglitazone
•Mechanism of action
– Enhance insulin sensitivity in muscle, adipose tissue
– Inhibit hepatic gluconeogenesis
– Reduced rate of beta cell dysfunction
y
•Safety and efficacy
– Decrease A1C 1-2%
– Adverse effects: edema, weight gain, anemia; peripheral
fractures in women, macular edema, (MIs - rosiglitazone*)
•Dosing
D i
– Initial dose (monotherapy): 1/2 to 2/3 maximum;
dosing,1-2 x/day
–M i
Maximum effective dose: maximum d
ff ti d i dose
– Titration frequency: weeks to month(s)
* Use no longer endorsed by ADA

22. PROactive: Reduction in Main
Secondary E d P i t
S d End Point
Main primary composite end point: all-cause mortality, nonfatal myocardial infarction
point: all- Main secondary composite end point: all-cause mortality, nonfatal
point: all-
(including silent MI), stroke, acute coronary syndrome, endovascular or surgical intervention in myocardial infarction, and stroke
y ,
coronary or leg arteries, above-ankle amputation
above-
No. of 3-yr No. of 3-yr
events estimate ARR events estimate ARR
25 Pioglitazone 514/2605
Pi lit 21.0%
21 0% 2.5%
2 5% 25 Pioglitazone 301/2605 12 3% 2 1%
Pi lit 12.3% 2.1%
Placebo 572/2633 23.5% Placebo 358/2633 14.4%
20 20
HR 0.90 (95% CI, 0.80-1.02) HR 0.84 (95% CI, 0.72-0.98)
P = 0.095 P = 0.027
15 15
oportion of events (%)
oportion of events (%)
(
(
10 10
5 5
Pro
0 Pro 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Time from randomization (mo) Time from randomization (mo)
No. at Risk: No. at Risk:
Pioglitazone 2488 2373 2302 2218 2146 348 Pioglitazone 2536 2487 2435 2381 2336 396
Placebo 2530 2413 2317 2215 2122 345 Placebo 2566 2504 2442 2371 2315 390
ARR = average risk ratio
PROactive = Prospective Pioglitazone Clinical Trial in Macrovascular Events
Dormandy JA, et al. Lancet. 2005;366:1279-1289.

23. Major Pathophysiologic Defects in Type 2 Diabetes1,2
Islet-cell d f
I l t ll dysfunction
ti
Glucagon
(alpha cell)
Pancreas
Insulin Insulin
(beta cell) resistance
Hepatic
glucose
output Glucose uptake
Hyperglycemia
Muscle
Liver
Adipose
tissue
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
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. 23

24. Role of Incretins in Glucose Homeostasis
Ingestion of food
Pancreas2,3
Glucose-dependent
Glucose dependent
Insulin from beta cells
Glucose
Release of gut (GLP-1 and GIP) uptake
hormones — by
Incretins1,2 muscles2,4
GI tract Blood
Beta cells
Active Alpha cells glucose
GLP-1 & GIP Glucose
production
DPP-4 Glucose dependent by liver
enzyme Glucagon from
alpha cells
(GLP-1)
Inactive Inactive
GLP-1 GIP
DPP-4 = dipeptidyl-peptidase 4
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. 24

25. Physiological Actions of GLP-1 and GIP
Neuroprotection
Cardioprotection
Appetite Cardiac output
Gastric emptying
GLP-1 Glucagon secretion
Insulin secretion
Insulin biosynthesis
β cell proliferation
GIP β cell apoptosis
Glucose production
Osteoblast Glucose Disposal
Lipogenesis
25 Pratley/Cardiometabolic/16Oct08

26. GLP–
GLP–1 Replacement Therapy in T2DM
The Players
• Short-acting GLP–1 receptor agonists
Short- GLP–
Exenatide (Amylin/Lilly)
Liraglutide (Novo Nordisk)
AVE0010 ( (sanofi–
(sanofi–aventis)
fi ti )
MKC253 Inhaled (MannKind)
• Long-Acting GLP–1 receptor agonists
Long- GLP–
LAR–
LAR–exenatide (Amylin/Lilly)
Taspoglutide (R1583–Roche)
(R1583–
Albiglutide (Syncria®–GSK)
(Syncria®–
Lilly compound
Conjuchem compound

27. Exenatide + Oral Agents
Summary of A1C Changes
Placebo
“THE 3 AMIGOS TRIALS”
TRIALS” Exenatide 5 μg
30-
30-Week, Randomized, Placebo-Controlled
Placebo-
Exenatide 10 μg
0.5%
0.23%
0.12%
0.08%
0 08%
8.6% 8.2% 8.5%
0%
0 5%
-0.5% -0.40%
Δ A1C
-0.46%
* * -0.55%
*
-0.78% -0.77%
-1% -0.86%
* *
*
Exenatide + SU Exenatide + Met (n=336) Exenatide + SU + Met
-1.5% (n=377) (n=733)
*P<0.01 vs placebo
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 27

28. Exenatide + Oral Agents
Summary of Weight Changes
Placebo
“THE 3 AMIGOS TRIALS”
TRIALS” Exenatide 5 μg
30-
30-Week, Randomized, Placebo-Controlled
Placebo-
Exenatide 10 μg
0.0
-0.3
-0.5
-0.6
-1.0 -0.9
-0.9
-1 5
1.5
Δ weight
t
(kg)
-1.6 -1.6 -1.6 -1.6
-2.0 * * * *
-2.5
-3.0 -2.8
*
Exenatide + SU Exenatide + Met (n=336) Exenatide + SU + Met
(n=377) (n=733)
*P<0.05 vs placebo
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 28

29. Exenatide:
Potential for Type 2 Diabetes
Benefits
B fit Limitations
Li it ti
• Beta Cell Effect • Nausea
– Restored first-phase insulin – Mild-Moderate ~40%
• Tend to subside over time
• Three AMIGOs Endpoints – Severe ~5%
– A1C ↓ of ~ 0.8-0.9%
f – Causing Withdrawal ~3%
aus ng W th rawa
– A1C ≤7% in ~35-45% • Vomiting
– Weight Loss 1.6-2.8 kg – 13%
• Ongoing Open Label Study
g g p y – Causing Withdrawal ~1%
in Completers/Responders • Twice Daily Injections
– Sustained A1C reductions ~1% • Cost
– Sustained Weigh Loss ~3 kg
• No Long-Term Controlled Study
g y
29

30. Exenatide Added to Ongoing
Therapy Improves Risk Factors
P Value
Parameter Change From Baseline (n = 151)
Body Weight (kg) – 5.3 ± 0.5 < 0.0001
A1C (%) –08±01
0.8 0.1 < 0.0001
0 0001
Total Cholesterol (mg/dL) – 10.8 ± 3.1 0.0007
Triglycerides (mg/dL) – 44.4 ± 12.1 0.0003
LDL-C (mg/dL) – 11.8 ± 2.9 < 0.0001
HDL-
HDL-C (mg/dL) + 8.5 ± 0.6 < 0.0001
Systolic Blood Pressure (
y (mm Hg)
g) – 3.5 ± 1.2 0.0063
Diastolic Blood Pressure (mm Hg) – 3.3 ± 0.8 < 0.0001
Open-
Open-label extension study; 527 patients using metformin and/or sulfonylurea added exenatide 5 µg BID for 4 weeks
followed by 10 µg BID thereafter; 151 subjects with baseline lipid measurements completed 3.5 years of treatment
Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

31. Glycemic Efficacy for JANUVIA™ (sitagliptin phosphate)
Added to Patients Uncontrolled on Metformin
(24-week Placebo-Adjusted)*
A1C FPG 2-Hour PPG
Mean Baseline A1C: 8.0% Mean Baseline: 170 mg/dL Mean Baseline: 275 mg/dL
†
P <0 001
<0.001 †
P <0 001
<0.001 P <0 001†
<0.001
0.00 0 0
§
§
-10
g/dL
Change in A1C, % §
dL
-0.25
-0 25
Change in FPG, mg/d
10
-10
Change in PPG, mg
n=453 n=454 -20 n=387
-0.50 -30
-20
-40
40
e
‡
-0.75 –0.7 ‡ –25
-30 -50
‡
(95% CI: –0.8, –0.5) (95% CI: –31, –20)
–51
(95% CI: –61, –41)
-1.00 -60
-40
JANUVIA provided significant improvements in A1C, FPG, and 2-hr PPG vs placebo
when added to patients inadequately controlled on metformin monotherapy.
*In patients inadequately controlled on metformin monotherapy.
†Compared with placebo plus metformin.
‡Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
§Difference from placebo.
31

32. Emerging Therapies: Glucose-
Lowering T i l With DPP 4 I hibit
L i Trials DPP-4 Inhibitors
Change from Baseline
Prior A1C FPG Weight
Dose Duration Study
Treatment (%) (mg/dL) (lbs)
50 mg BID 24 wk –0.8 –14.4 –0.3 ± 0.4
Drug naive 50 mg BID 24 wk –1.1
11 –23.4
23 4 –0.3 ± 0 2
0 3 0.2
50 mg BID 24 wk –1.4 –21.6 –0.4 ± 0.1
Vildagliptin 1
Add-on to
50 mg BID 24 wk –1.0 ± 0.1 –19.8 ± 3.6 –
pioglitazone
Add-on to
50 mg BID 24 wk –0.6 ± 0.1 –7.2 ± 3.6 –
sulfonylurea
Newly
25 mg QD 26 wk –0.59 –16.4 –0.48 2
diagnosed
Alogliptin
g p
Add-on t
Add to
25 mg QD 26 wk –0.8 –19.9 – 3
pioglitazone
Conclusions4:
• No definite data, especially on cardiovascular outcomes, are still needed
Long-term
conclusions can be drawn from measurements of DPP-4 inhibitor effects on islet-cell function
•
1Chia CW, et al. J Clin Endocrinol Metab. 2008;93:3703-3016.
2DeFronzo RA, et al. Presented at: ADA 68th Scientific Sessions; June 2008; San Francisco, CA. Abstract 446-P.
3Pratley R, et al. Presented at: ADA 68th Scientific Sessions; June 2008; San Francisco, CA. Abstract 478-P.
4Richter B, et al. Cochrane Database Syst Rev. 2008;2:CD006739.

33. Taspoglutide Dose Finding Study
Summary
8 weeks study PBO vs Taspoglutide dose finding:
weekly 5-10-20 mg and every 2 weeks 10-20 mg
n=306 T2 DM on Metformin
Baseline HbA1c 7.9%
BMI 33 k / 2
kg/m2
Placeb 5 mg 10 mg 20 mg 10 mg 20 mg
o QW QW QW Q2W Q2W
∆HbA1c -0.2% -1.0%* -1.2%* -1.2%* -1.0%* -1.0%*
HbA1c 17% 59% 79% 81% 44% 63%
≤7%
∆Body - - -2.0kg* -2.8kg* - -1.9kg*
weight
(kg)
*significant vs placebo
Balena R et al, Diabetes 2008

34. Welchol™ Consistently Lowers A1C* by An
Additional Mean 0.5%
Welchol Plus Welchol Plus Welchol Plus
Metformin-Based Sulfonylurea-Based Insulin-Based
Therapy Therapy Therapy
(n = 148) (n = 218) (n = 144)
Baseline A1C = 8.1% Baseline A1C = 8.2% Baseline A1C = 8.3%
0
-0.1
-0.2
-0.3
Mean
Change in
g -0.4
A1C (%)
-0.5
-0.50
-0.6 -0.54 -0.54 P <0.001
P <0.001 P <0.001
07
-0.7
-0.8
*From baseline, placebo-adjusted. Data on file, Daiichi Sankyo, Inc.
ITT P
Population, L
l i Last Ob
Observation C i d F
i Carried Forward (LOCF) patients on b k
d (LOCF), i background monotherapy and combination therapy.
d h d bi i h

35. FXR: Metabolic Modulator of Post-prandial
Hepatic Lipid and Glucose Metabolism
Lipids
BA BA synthesis Cholesterol
Cyp7a1
VLDL
FFA
production
esis
Glucose
e
Lipogene
FAS VLDL
BA FXR ACC-1
Ac-CoA
LPK
NTESTINE
Glucose Glycolysis Pyruvate
BLOOD
YMPH
LIVER
MIT
Glycogenesis Glycogen
LY
IN
B
L
Duran-Sandoval D. et al. J Biol Chem 2005.

36. JUPITER Ridker et al NEJM 2008
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
HR 0.56, 95% CI 0.46-0.69 Placebo
P < 0.00001 251 / 8901
0.08
Number Needed to Treat (NNT ) = 25
5
- 44 %
0.06
mulative Incidence
0.04
Cum
Rosuvastatin 20 mg QD
142 / 8901
0.02
0.00
0 1 2 3 4
Follow-up (years)
N=17,802
(No DM, LDL < 130 mg/dL, hsCRP > 2 mg/L)

37. Chronic Subclinical Inflammation:
Part f the I
P t of th Insulin Resistance Syndrome
li R i t S d
1.6
16
1.4
1.2
1.0
0.8
0.6
Mean values
(SE), log CRP 0.4
0.2
0
0 1 2 3 4
Number of metabolic disorders
Festa. Circulation. 2000.

38. Chronic Inflammation Precedes Onset of
Type 2 Diabetes: IRAS
P=0.013 P=0.0001 P=0.0001
288 3
300 275 30
2.4 24
200 2 1.7 20
16
100 1 10
0 0 0
Fibrinogen (mg/dL) CRP (mg/L) PAI-1 (ng/mL)
Diabetes No diabetes
Festa A et al. Diabetes. 2002;51:1131-1137.

39. Two Week Trial: Salsalate (Disalcid) 4.5 g/day
Baseline 2 Wk Rx Δ, %
Salicylate (mg/dl) 0 19 / 28 Trough/Peak
Weight (kg) 88.6 ± 22 88.4 ± 22 -0.2 NS
FBG (mg/dl) 112 ± 43 91 ± 19 -19 P = 0.03
Cholesterol (mg/dl) 201 ± 49 177 ± 36 -12 P = 0.03
Triglycerides (mg/dl) 174 ± 97 105 ± 53 -40 P = 0.007
FFA (μM) 0.68 ± 0.05 0.35 ± 0.02 -49 P = 0.0006
CRP (
(mg/dl)
/dl) 0.6 0.72
0 6 ± 0 72 0.31 0.46
0 31 ± 0 46 -48
48 P = 0 02
0.02
Adiponectin (mg/l) 15.5 ± 0.19 22.7 ± 0.25 +46 P < 0.01
Goldfine & Shoelson, in Press

40. TINSAL-
TINSAL-T2D Trial Design
Stage I: 14-week multicenter, double-masked, placebo-controlled
dose ranging study in inadequately controlled T2D (7.0 ≤ HbA1c ≤ 9.5)
Screen n=240, Randomize n=108
n=240
Placebo 3.0g 3.5g 4.0g
n=27 n=27 n=27 n=27
52
Stage II: 26-week multicenter, double-masked,
placebo-controlled phase III trial
Screen n=564, Randomize n=282
Placebo Salsalate 3.5 g/d
n=141 randomized n=141 randomized
Placebo Salsalate
n=113 complete n=113 complete

41. β
β-Cell Deficiency in Diabetes:
y
Insulin and Amylin
• Amylin
– Reported in 1987
– 37-amino acid peptide
– Colocated and
Amylin Insulin
T
A
T A
T
Q
A
cosecreted with insulin
L N L
C R F V
N
H
C
from pancreatic Amide
Y
T
K
L A F N
S
S
β cells
ll
S S I G N
N
T
S V N
G
Unger R, et al. In: Williams Textbook of Endocrinology. 8th ed. 1992:1273-1275.

42. Amylin: Cosecreted With Insulin and
y
Deficient in Diabetes
Insulin
Amylin Meal
Meal Meal Meal
20
30
600 Without
25 Diabetes
15
Plasm Amylin (pM)
Plasm Amylin (pM)
Plasm Insulin (pM)
20 400
10
15 Insulin-Using
ma
ma
ma
Type 2
200 5
10 Type 1
0 0
5
30
-30 0 30 60 90 120 150 180
7 am 12 noon 5 pm Midnight
Time Time After Sustacal® meal (min)
Left graph: n=6 healthy subjects
Right graph: n=27 without diabetes, Type 2 n=12, Type 1 n=190
g g p , yp , yp
Kruger D, et al. Diabetes Educ 1999;25:389-397.
Copyright © 1999 Sage Publications.

43. SUMMARY
TYPE 2 DIABETES IS A COMPLEX DISEASE
MULTIPLE NEW TARGETS FOR TYPE 2 DIABETES
WHICH TREATMENT WILL PROVIDE VALUE?