1. The Role of SGLT-2 Inhibitors
and GLP-1 Receptor Agonists and
DPP-4 Inhibitors in the
Management of Patients with
Type 2 Diabetes

2. Development and Progression of Type 2 Diabetes
and Related Complications1,a
2
aConceptual representation.
1. Reprinted from Primary Care, 26(4), Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier.
Insulin level
Insulin resistance
Hepatic glucose
production
Postprandial
glucose
Fasting plasma
glucose
Beta-cell function
Progression of Type 2 Diabetes Mellitus
Impaired Glucose Tolerance
Diabetes Diagnosis
Frank Diabetes
4–7 years
Development of Macrovascular Complications
Development of Microvascular Complications

3. 1. International Diabetes Federation. Diabetes Atlas, Fifth Edition: www.diabetesatlas.org. Accessed 25 June 2012. Estimated based on mortality data;
2. Adapted from: CDC 2011 National Diabetes Fact Sheet: http://www.cdc.gov/diabetes/pubs/estimates11.htm#12. Accessed June 2011.
Every 10 seconds, one person dies from diabetes-related complications1
137 new patients will
need dialysis2
186 new patients will
have an amputation2
62 new patients will have
severe vision loss due to
diabetes2
In the next 24 hours, 17,280 patients will develop diabetes… in USA
Heart disease by
2–4 fold2
Diabetes significantly increases the risk of
Stroke
by more than 2–4 fold2
3

4. Major Therapeutic Targets in T2DM
DeFronzo RA. Ann Intern Med. 1999;131:281-303. Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed.
WB Saunders; 2003:1427-1483.
Glucose
absorption
Hepatic glucose
overproduction
Insulin
resistance
Pancreas
Muscle and fat
Liver
Metformin
Thiazolidinediones
GLP-1 agonists
DPP-4 inhibitors
Sulfonylureas
Meglitinides
GLP-1 agonists
DPP-4 inhibitors
Thiazolidinediones
Metformin
Alpha-glucosidase inhibitors
GLP-1 agonists
Gut
Glucose
reabsorption
Kidney
Beta-cell
dysfunction
Glucose level
SGLT-2 inhibitors
Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus.

5. 5
Major Pathophysiologic
Defects in Type 2 Diabetes
Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds.
Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168;
Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Hepatic
glucose
output
Insulin
resistance
Glucose uptake
Glucagon
(α cell)
Insulin
(β cell)
Liver
Hyperglycemia
Islet-cell Dysfunction
Muscle
Adipose
tissue
Pancreas

6. Ominous Octet
DeFronzo RA. Diabetes. 2009;58:773-795.

7. Limitations of Older Agents for T2DM
Limitation Agent
Hypoglycemia Secretagogues, insulin
Weight gain Secretagogues, glitazones, insulin
Edema Glitazones, insulin
GI side effects Metformin, alpha-glucosidase
inhibitors
Lactic acidosis (rare) Metformin
Safety issues in elderly, renal-
impaired, or CHF patients Glitazones, metformin, sulfonylureas
Poor response rates All oral medications
Lack of durable effect All oral monotherapy except
glitazones
Abbreviations: CHF, congestive heart failure; GI, gastrointestinal.

8. 8
*Adapted from Saydah SH, et al. JAMA. 2004;291:335–342.
1. Dodd AH, et al. Curr Med Res Opin. 2000;291:1605–1613; 2. Oluwatowoju I, et al. Diabet Med. 2010;27:354–359; 3. ADA. Diabetes Care.
2013;36:S11–S66; 4. Inzucchi SE, et al. Diabetes Care. 2012;35:1364–1379;
The majority of patients in USA with T2D remain far above glycaemic goals
47.8% of patients
with T2D
have HbA1c >7.0%1*
10.1% have HbA1c >10%2
20.2% have HbA1c >9%1
37.2% have HbA1c >8%1
ADA/EASD target (<7%)3,4
10.0
9.0
8.0
7.0
6.0
HbA1c

9. www.diabetes.or 1-800-
ADAG Study: Correlation of AG
With HbA1c
AG(mg/dl)
HbA1c (%)
AG (mg/dl) = 28.7 x HbA1c – 46.7
R2 = 0.84
P < 0.0001

10. Development of Anti-diabetics Agents

11. Incretins (DPP-IV inhibitors):
Special Populations: Geriatrics
Pharmacology
Recommendations
•Metformin – still first line for most
• Less effective in many
• GFR - <30 – no, 30-50 reduce dose
•Glyburide – never
•DPP-IV inhibitors - recommended

12. Stomach
Islet
GI
Tract
Brain
Hypothalmus
Hind Brain
Peptide Therapeutics:
Incretins (GLP-1 and GIP)
Visceral Fat
Cell
Vagal Afferents
Leptin
Amylin
Insulin
GLP-1
GlicentinOxyntomoduli
n
Ghrelin
GIP
Adiponecti
n
Visfatin
Resistin
Glucago
n
CCK
Adapted from Badman MK and Flier JS; Science 2006: 307, 1909-1914
PYY3-36
Cardiovascu
Incretins
Exenatide – Bydureon, Byetta
Liraglutide - Victoza
DPP-IV Inhibitors
Linagliptin – Trajenta
Saxagliptin – Onglyza
Sitagliptin – Januvia
Vildagliptin - Galvus
Cardiovascular Outcome
Trials
TECOS - sitagliptin
EXSCEL – weekly exenatide
LEADER – liraglutide
ELIXA – lixisenitide
SAVOR - saxagliptin

13. 1. Wright EM, et al. Physiology. 2004;19:370–376.
2. Bakris GI, et al. Kidney Int. 2009;75:1272–1277.
Transport of glucose against a concentration gradient1,2
13
Segment S1–2
Basolateral membrane
GLUT2SGLT2
Glucose
Na+
Glucose
Na+
Glucose
Na+
K+
K+
Na+/K+ATPase
Lateral intercellular space
Glucose

14. Filtered glucose
load 180 g/day
SGLT1
SGLT2
~ 10%
~ 90%
Gerich JE. Diabet Med. 2010;27:136–142.
Renal glucose re-absorption in healthy individuals
14

15. Gerich JE. Diabet Med. 2010;27:136–142.
Renal glucose re-absorption in patients with hyperglycaemia
15
SGLT1
SGLT2
~ 10%
~ 90%
When blood
glucose increases
above the renal
threshold
(~ 10 mmol/l or 180
mg/dL), the
capacity of the
transporters is
exceeded,
resulting in urinary
glucose excretion
Filtered glucose
load > 180 g/day

16. *Loss of ~ 80 g of glucose/day (~ 240 cal/day).
Gerich JE. Diabet Med. 2010;27:136–142.
Urinary glucose excretion via SGLT2 inhibition
16
SGLT2SGLT2
inhibitor
SGLT1
SGLT2 inhibitors
reduce glucose
re-absorption
in the proximal
tubule, leading to
urinary glucose
excretion* and
osmotic diuresis
Filtered glucose
load
> 180 g/day

17. FDA Approval
March 2013 – Canagliflozin (Invokana)
January 2014 – Dapagliflozin (Farxiga)
August 2014 – Empagliflozin (Jardiance)
Contraindications: Severe renal impairment
Adverse effects: Hypotension/dehydration, genital
mycotic infections

18. Ongoing, prospective clinical trials of DPP-4 inhibitors with
cardiovascular outcomes
Scheen, A. J. (2013) Cardiovascular effects of gliptins
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2012.183

19. FDA CV safety: CI bars.
Boaz Hirshberg, and Itamar Raz Dia Care 2011;34:S101-
S106
©2011 by American Diabetes Association

20. Metformin XR
GelShield Diffusion System™
Data on File. Bristol-Myers Squibb Company.
GelShield Diffusion System is a trademark of Lipha s.a. licensed to Bristol-Myers Squibb Company.
• Provides a controlled release of metformin
• Extends drug delivery over 24 hours
• Eases absorption through the gastrointestinal tract
Please see full prescribing information, including boxed WARNING regarding Lactic Acidosis.

21. Approach to the Management of
Hyperglycemia
ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37. Figure 6.1; adapted with
permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

22. Antihyperglycemic Therapy in
Type 2 Diabetes
ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1;
adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

23. Approach To Starting and Adjusting
Insulin in Type 2 Diabetes
ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S46. Figure 7.2;
adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

24. Copyright © 2015 AACE.
May not be reprinted in any form without express written permission from AACE.
Monotherapy, Dual Therapy, and Triple
Therapy for T2D
24
How are glycemic targets achieved for T2D?
AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4
inhibitors; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; SGLT2I = sodium-glucose cotransporter 2
inhibitors; SU = sulfonylureas; TZD = thiazolidinediones.
*Intensify therapy whenever A1C exceeds individualized target. Boldface denotes little or no risk of hypoglycemia or weight
gain, few adverse events, and/or the possibility of benefits beyond glucose-lowering.
† Use with caution.
Monotherapy* Dual therapy*
Metformin (or other
first-line agent) plus
Triple therapy*
First- and second-line
agent plus
Metformin GLP1RA GLP1RA
GLP1RA SGLT2I SGLT2I
SGLT2I DPP4I TZD†
DPP4I TZD† Basal insulin†
AGI Basal insulin† DPP4I
TZD† Colesevelam Colesevelam
SU/glinide† BCR-QR BCR-QR
AGI AGI
SU/glinide† SU/glinide†

25. Copyright © 2015 AACE.
May not be reprinted in any form without express written permission from AACE.

26. Copyright © 2015 AACE.
May not be reprinted in any form without express written permission from AACE.

27. Copyright © 2015 AACE.
May not be reprinted in any form without express written permission from AACE.

28. Hypoglycaemia in type 2 diabetes
• Hypoglycaemia symptoms are common in type 2 diabetes
(38% of patients)1
• Associated with:
– Reduced quality of life
– Reduced treatment satisfaction
– Reduced therapy adherence
– More common at HbA1c < 7%
1. Diabetes, Obesity and Metabolism 2008 Jun;10 Suppl 1:25-
32.

29. Risk factors for hypoglycaemia
• Use of insulin and sulfonylureas1
• Older people2,3
• Long duration diabetes2
• Irregular eating habits3
• Exercise3
• Have lower HbA1c4
• Periods of fasting e.g. Ramadan
• Prior hypoglycemia5,6,7
• Hypoglycemia unawareness8
• Alcohol9
See notes for references.

30. Pooled hypoglycaemia results for randomized
trials, by drug comparison
Bolen S, et al. Ann Intern Med 2007;147:386-399.
Reproduced with permission

31. Hypoglycaemic events occur frequently in patients
treated with sulphonylureas
• In an observational study over 9-12 months in six UK
secondary care diabetes centres:
– 39% of patients receiving an SU described mild hypoglycaemia
– 7% of patients receiving an SU described severe hypoglycaemia
– 14% of patients receiving an SU experienced a blood glucose
<2.2 mmol/l
• The incidence of hypoglycaemia was similar in insulin-
and SU-treated patients
UK Hypoglycaemia Study Group. Diabetologia. 2007;50(6):1140-7.

32. Recent studies investigating intensive glycaemic control
have highlighted the problem of hypoglycaemia
a Conventional vs intensive
b p=0.04
CAD, coronary artery disease; CHF, congestive heart disease; CVD, cardiovascular disease; MI, myocardial infarction
Variable VADT (n=1,700) ACCORD (n=10,250) ADVANCE (n=11,140)
HbA1c (%)a 8.4 vs 6.9 7.5 vs 6.4 7.3 vs 6.5
Primary outcome MI, stroke, death from
CV causes, new or
worsening CHF,
revascularisationb and
inoperable CAD,
amputation for
ischaemic gangrene
Non-fatal MI, non-fatal
stroke, CVD death
Non-fatal MI, non-fatal
stroke, CVD death
HR (95% CI) for primary
outcome
0.87 (0.730–1.04) 0.90 (0.78–1.04) 0.94 (0.84–1.06)
HR (95% CI) for mortality 1.065 (0.801–1.416) 1.22 (1.01–1.46)b 0.93 (0.83–1.06)

33. Alternatives to sulphonylureas to reduce
hypoglycaemic risk
• UK NICE guidelines recommend adding a DPP-4 inhibitor
or glitazone to metformin instead of SU if significant risk of
hypoglycaemia and its consequences1
1. National Institute of Health and Clinical Excellence. Type 2 diabetes: newer
agents for blood glucose control in type 2 diabetes NICE clinical guideline (May
2009).

35. Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Comparison of Dipeptidyl Peptidase–4
(DPP-4) Inhibitors
Sitagliptin Linagliptin Saxagliptin Vildagliptin
Usual phase 3 dose 100 mg QD 5 mg QD 5 mg QD 50 mg BD
Half-life (t1/2), h 12.4 12.5–21.1 2.2–3.8 1.3–2.4
DPP-4 inhibition at
24 h
~80% ~80% (25 mg) ~55% (5 mg) 50% (100 mg)
Elimination Kidney
(mostly unchanged)
Bile but not kidney
(mostly unchanged)
Liver and kidney
Active metabolite
Kidney>>Liver
Inactive metabolite
Renal dose
adjustments
required
Yes No Yes None for mild
impairment; not
recommended for
moderate or severe
impairment
Selectivity for DPP-4 >2600-fold vs DPP-8
>10,000-fold vs DPP-9
>10,000-fold vs DPP-8/9 >400-fold vs DPP-8
>100-fold vs DPP-9
>90-fold vs DPP-8
Potential for drug–
drug interaction
Low Low Strong CYP3A4/5
inhibitors
Low
Food effect No No No No

36. GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Effects on HbA1c, Glucose, and
Insulin Levels

37. Liraglutide 1-Year Monotherapy
Improves Glycemic Control
Glimepiride (n = 248) Liraglutide 1.2 mg (n = 251) Liraglutide 1.8 mg (n = 246)
ΔHbA1c(%)
Garber A, et al. Lancet. 2009;373:473-481.
• 52-week phase III study in 746 T2DM patients previously on diet and exercise
or oral antidiabetic monotherapy
• Baseline HbA1c was 8.3%–8.4% in all groups
P <.0001
P = .0014
P = .0046

38. -1.4*
-1*
-0.7
-0.4
-1.5
-1
-0.5
0
HbA1cChange(%)
Liraglutide 1.8 mg†
Glimepiride
Effects of Liraglutide and Glimepiride
Monotherapy on HbA1c Over 2 Years
* P <.05 vs glimepiride; † 73% completed 2-year extension.
(n = 54)
<3 yDisease duration: ≥3 y
(n = 42)
(n = 60)
(n = 55)
Garber AJ, et al. Diabetes. 2009;58(suppl 1):162-OR.
% achieving HbA1c <7%
• 58% with liraglutide*
• 37% with glimepiride
Weight change
• -2.7 kg with liraglutide*
• 1.1 kg with glimepiride

39. Current DPP-4 Inhibitors
Sitagliptin
Vildagliptin
(approved outside
United States)
Saxagliptin
Alogliptin
Linagliptin

40. Placebo-corrected change from baseline in HbA1c - Monotherapy
Comparative Efficacies of DPP-4s
-0.1
-0.3
-0.2
-0.4
-0.8
-0.5
-0.6
-0.7
-0.9
-1.0
-1.1
-1.2
ΔHbA1c(%)
Alogliptin1
12.5 mg 25 mg
7.9% 7.9%
Linagliptin2
5 mg 5 mg
8.1% 8.0%
Saxagliptin3
5 mg 5 mg
7%-10% 8.0%
Sitagliptin4
100 mg 100 mg
8.0% 8.0%
Vildagliptin5
50 mg BID 50 mg
8.6% 8.4%
The current DPP-4s have comparative efficacy
1. DeFronzo R, et al. Diabetes Care 2008;31:2315-2317. 2. Linagliptin Prescribing Information. 3. Saxagliptin Prescribing
Information. 4. Sitagliptin Prescribing Information. 5. Vildagliptin Summary of Product Characteristics.
-0.56
-0.59 -0.6
-0.7
-0.4
-0.6 -0.6
-0.8
-0.5
-0.7

41. Alogliptin Phase III Trials: HbA1c Change
from Baseline After 26 Weeks
Abbreviations: MET, metformin; PIO, pioglitazone; SU, sulfonylurea.
*P <.001 vs control.
1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315-2317. 2. Pratley RE, et al. Diabetes Obes Metab.
2009;11:167-176. 3. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 4. Pratley RE, et al. Curr Med Res
Opin. 2009;25:2361-2371. 5. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.
Baselin
e
HbA1c
(%)
Aloglipti
n 12.5
mg
Aloglitpi
n 25 mg Control
Add-on
to SU2
8.1 -0.39* -0.53* 0.01
Add-on
to
MET3
7.9 -0.6* -0.6* -0.1
Add-on
to PIO4
8.0–8.1 -0.66* -0.80* -0.19
Add-on
to
insulin5
9.3 -0.63* -0.71* -0.13
LS Mean Change HbA1c from
Baseline (%)
Alogliptin monotherapy1 Add-on therapy
Baseline HbA1c: 8.0%

42. Linagliptin Shows Rates of Hypoglycemia
Similar to Placebo
The Majority of Hypoglycemia is Nonsevere
Investigator-defined hypoglycemia AEs at week 24 by category
All
Hypoglycemia
AEs
Severe
Placebo Linagliptin
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
Documented
Symptomatic
(≤72 mg/dL)
Documented
Symptomatic
(<54 mg/dL)

43. Study Summary:
Linagliptin as Add-On to Insulin
Efficacy and safety of linagliptin as add-on therapy to insulin in type 2 diabetes
•Linagliptin significantly reduced HbA1c after 24 weeks in patients on a stable
insulin dose (placebo-corrected reduction after 24 weeks -0.65%)
•The efficacy of linagliptin was reliable in different prespecified subgroups,
such as
– Elderly patients age ≥75 years
– Different categories of renal function
•HbA1c reductions were maintained over 52 weeks
•Linagliptin significantly reduced fasting plasma glucose after 24 weeks and
maintained it in 28-week free insulin titration period
•Linagliptin has a safety profile comparable to placebo
•Incidence of hypoglycemia with linagliptin was comparable to placebo
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

44. Both Sitagliptin and Saxagliptin Produced
Greatest Reductions in HbA1c in Patients
with High Baseline HbA1c
–1.2
–1.0
–0.8
–0.6
–0.4
–0.2
0
50 mg QD 100 mg QD
–1.15 –1.18
Hanefeld M, et al. Curr Med Res Opin. 2007;23:1329-1339. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411
Sitagliptin-Treated Subgroup
with Baseline HbA1c >9%
Open-Label Saxagliptin in 66 Patients
with Baseline HbA1c >10% to ≤12%
–0.8
–0.6
–0.4
–0.2
0
10 mg QD
–1.87
–1.0
–1.2
–1.4
–1.6
–1.8
–2.0

45. Incretin-Based Therapy Improves Glycemic
Control When Used in Combination
Abbreviation: TZD, thiazolidinedione.
*Added to thiazolidinedione plus metformin.
1. Bergenstal RM, et al. Lancet. 2010;376:431-439. 2. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100. 3. DeFronzo RA, et al. Diabetes
Care. 2010;33:951-957. 4. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 5. Buse JB, et al. Lancet. 2009;374:39-47. 6. Zinman B, et al.
Diabetes Care. 2009;32:1224-1230. 7. Marre M, et al. Diabet Med. 2009;26:268-278. 8. Pratley R, et al. ADA 2012. Abstract 1158-P. 9. Nauck MA,
et al. Int J Clin Pract. 2009;63:46-55. 10. Pratley RE, et al. Curr Med Res Opin. 2009;25:2361-2371. 11. Pratley RE, et al. Diabetes Obes Metab.
2009;11:167-176. 12. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 13. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74.
14. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661. 15. Lewin AJ, et al. Clin Ther. 2012;34:1909-1919.e15. 16. Williams-Herman D, et al.
Curr Med Res Opin. 2009;25:569-583. 17. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 18. Nauck M, et al. Diabetes Care. 2009;32:84-
90. 19. Derosa G, et al. Metabolism. 2010;59:887-895. 20. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 21. Hermansen K, et al. Diabetes
Obes Metab. 2007;9:733-745. 22. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622. 23. DeFronzo RA, et al. Diabetes Care.
2009;32:1649-1655. 24. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819. 25. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406.
With
Metformin
Initial Tx
Added to
Metformin Added to
TZD
Added to
Sulfonylurea
Exenatide ✔1,2 ✔3 ✔4
Liraglutide ✔5 ✔6* ✔5,7
Alogliptin ✔8 ✔9 ✔10 ✔11
Linagliptin ✔12 ✔13 ✔14 ✔15
Sitagliptin ✔16 ✔17,18 ✔19,20 ✔21
Saxagliptin ✔22 ✔23 ✔24 ✔25

46. Saxagliptin Together With MET Gave Medication-
Naive Adult Patients Greater Glycemic Control
Change in A1C at 6 Months*
MET + Placebo
(n=313)
Mean baseline: 9.4%
MeanChangeFromBaseline(%)
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0
–2.0%
Saxagliptin 5 mg + MET
(n=306)
Mean baseline: 9.4%
–2.5%
P<0.0001 vs MET + placebo
P<0.05 vs MET + placebo
Percentage of Patients Achieving
A1C <7% at 6 Months
PercentageofPatients(%) 0.0
20.0
40.0
60.0
Saxagliptin 5 mg + MET
(n=307)
Mean baseline: 9.4%
MET + Placebo
(n=314)
Mean baseline: 9.4%
41%
80.0
100.0
60%
*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.
Metformin was initiated at a starting dose of 500 mg daily, up-titrated to 1000 mg at Week 1, and
thereafter up-titrated as tolerated to a maximum of 2000 mg daily based on FPG through Week 5.

47. Saxagliptin With MET as Initial Combination
Delivered Statistically Significant Reductions in
FPG and PPG
Change in FPG at 6 Months* Change in 2-Hour PPG†
at 6 Months*
MET + Placebo
(n=320)
Mean baseline: 199 mg/dL
Saxagliptin 5 mg + MET
(n=315)
Mean baseline: 199 mg/dL
MET + Placebo
(n=141)
Mean baseline: 355 mg/dL
Saxagliptin 5 mg + MET
(n=146)
Mean baseline: 340 mg/dL
-120
-100
-80
-60
-40
-20
0
20
–60 mg/dL
MeanChangeFromBaseline(mg/dL)
MeanChangeFromBaseline(mg/dL)
-120
-100
-80
-60
-40
-20
0
20
–138 mg/dL
–97 mg/dL
-140
P<0.05 vs MET + placebo
-140
P<0.05 vs MET + placebo
–47 mg/dL
*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.
†As part of a 3-hour OGTT.
In addition to diet and
exercise

48. Sitagliptin Has Mixed Effects on Lipids
TC
ΔfromBaseline(mg/dL;mmol/LforFFA)
LDL-C HDL-C
Trigs FFA
Abbreviation: FFA, free fatty acids.
Hanefeld M, et al. Curr Res Med Opin. 2007;23:1329-1339.
Placebo
Sit 25 mg qd
Sit 50 mg qd
Sit 100 mg qd
Sit 50 mg BID

49. Effect of Linagliptin on Lipids in Patients
at High Risk for Renal and CVD
• Post-hoc pooled analysis of T2DM patients with hypertension and
microalbuminuria from 6 phase III linagliptin trials (N = 512)*
• No significant difference in lipid changes from baseline for linagliptin
vs placebo
*Study durations: 18–24 weeks. †Adjusted for baseline HbA1c, parameter measured, prior oral antidiabetic medications, study
and treatment.
Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.
von Eynatten M, et al. Cardiovasc Diabetol. 2013;12:60

50. GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Effects on Blood Pressure and
CVD

51. Effect of Linagliptin on Blood Pressure in
Patients at High Risk for Renal and CVD
• Post-hoc pooled analysis of T2DM patients with hypertension and
microalbuminuria from 6 phase III linagliptin trials (N = 512)*
• No significant difference in blood pressure changes from baseline
for linagliptin vs placebo
*Study durations: 18–24 weeks. †Adjusted for baseline HbA1c, parameter measured, prior oral antidiabetic medications,
study and treatment.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
von Eynatten M, et al. Cardiovasc Diabetol. 2013;12:60

52. GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Effects on the Renally Impaired

53. Dose Titration for Renally Impaired
Patients
Recommended Dose Dose Adjustment for Renal Impairment
Exenatide1 5 mcg twice daily; increase to 10 mcg
based on clinical response
Moderate: Use with caution when initiating or
escalating doses
Severe/ESRD: Not recommended
Exenatide
qwk2
2 mg once weekly Moderate: Use with caution
Severe/ESRD: Not recommended
Liraglutide3 0.6 mg once daily for 1 week, then 1.2 mg;
can be increased to 1.8 mg
Use with caution; no dose adjustment
recommended for renal impairment
Aloglitpin4 25 mg once daily Moderate: 12.5 mg once daily
Severe/ESRD: 6.25 mg once daily
Linagliptin5 5 mg once daily No dose adjustment recommended for renal
impairment
Saxagliptin6 2.5 mg or 5 mg once daily Moderate or severe/ESRD: 2.5 mg once daily
Sitagliptin7 100 mg once daily Moderate: 50 mg once daily
Severe/ESRD: 25 mg once daily
Vildagliptin8 50 mg twice daily as monotherapy; 50 mg
once daily in combination with SU
Moderate or severe/ESRD: 50 mg once daily
1. Exenatide Prescribing Information. 2. Exenatide QW Prescribing Information. 3. Liraglutide Prescribing Information.
4. Alogliptin Prescribing Information. 5. Linaglitpin Prescribing Information. 6. Saxagliptin Prescribing Information.
7. Sitagliptin Prescribing Information. 8. Vildagliptin Summary of Product Characteristics.

54. Linagliptin Added to Insulin: Renal Function vs
Linagliptin’s Efficacy at Week 24
• In a prespecified subgroup analysis, there was no
significant interaction according to patient renal function
category (P = .5784)
• The study had a high proportion of patients with renal
impairment
– Mild (EGFR 60 to <90 mL/min): 46.3% linagliptin, 44.9% placebo
– Moderate (EGFR 30 to <60 mL/min): 9.4% linagliptin, 10.8% placebo
– Severe to end-stage (EGFR <30 mL/min): 0.5% linagliptin, 0.6% placebo
Abbreviation: EGFR, estimated glomerular filtration rate.
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

55. GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Safety and Tolerability

56. Adverse Effects of GLP-1 Agonists and
DPP-4 Inhibitors
1. Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286. 2. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88: 3082-
3089. 3. Garber A, et al. Lancet. 2009;373:473-481. 4. Exenatide QW Prescribing Information. 5. Alogliptin Prescribing
Information. 6. Linagliptin Prescribing Information. 7. Hanefeld M, et al. Curr Med Res Opin. 2007;23:1329-1339.
8. Sitagliptin Prescribing Information. 9. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 10. White WB, et al.
N Engl J Med. 2013;369:1327-1335. 11. Scirica BM, et al. N Engl J Med. 2013 3;369:1317-1326.
Nausea/
Vomiting Diarrhea Hypoglycemia Pancreatitis
Exenatide1,2 ++++ + Rare
Liraglutide3 +++ + + Rare
Exenatide qwk4 ++ + + Rare
Alogliptin5 + Rare
Linagliptin6 + Rare
Sitagliptin7,8 + Rare
Saxagliptin9 +/- + Rare
• In the first long-term clinical trials (EXAMINE and SAVOR), there was no
difference in the rate of pancreatitis between the active drug and placebo10,11

57. 1. Thomas L, et al. Diabetes Obes Metab. 2012;14:94–96; 2. Komoroski B, et al. Clin Pharmacol Ther. 2009;85:520–526; 3. Komoroski B, et al.
Clin Pharmacol Ther. 2009;85:513–519; 4. Obermeier MT, et al. Drug Metab Dis. 2010;38:405–414; 5. Schwartz SS, et al. Diabetes. 2010;59
(Suppl 1)(Abstract 564-P); 6. Sha S, et al. Diabetes Obes Metab. 2011;13:669–672; 7. Nomura S, et al. J Med Chem. 2010;53:6355–6360.
PK/PD characteristics of empagliflozin, dapagliflozin and canagliflozin (1/2)
Empagliflozin1 Dapagliflozin2-4 Canagliflozin5-7
PD Clinical doses
in Phase III
10–25 mg 5–10 mg 100–300 mg
Selectivity
over SGLT1
>1:2500 1:1200 1:414
Glucose
excretion
70–90 g/day 18–62 g/day ~70 g/day
Duration of
action
T½: 10–19h T½: 17h T½: 12–15 h
PK Absorption Rapid; peak levels 1.5 h
after dosing
Rapid; peak levels 1.5 h
after dosing
Peak levels 2.75 h
(300 mg) to 4 h
(100 mg) after
dosing
Distribution Moderate volume of
distribution; GI tract,
urine and bile
Not measurable in the
central nervous system
Modest extravascular
distribution with a volume
ranging from total body water
in the dog and monkey to
~2-fold total body water in
the rat
Extensive tissue
distribution,
extensively bound
to proteins in
plasma (99%)
Competitoranalysis
57

58. 58

59. Impact of IntensiveTherapy for Diabetes:
Summaryof Major ClinicalTrials
Study Microvasc CVD Mortality
UKPDS      
DCCT /
EDIC*      
ACCORD   
ADVANCE   
VADT   
Long Term Follow-up
Initial Trial
* in T1DM
Kendall DM, Bergenstal RM. © International Diabetes Center 2009
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.
Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024)

61. HbA1c= Fasting
Glucose
Postprandial
Glucose
+
FPG influenced by:
› Hepatic glucose
production
› Hepatic sensitivity
to insulin
› Exercise during the
previous
day
› Meal from the previous
night
› Alcohol
› Obstructive sleep apnoea
› Nocturnal hypoglycaemia
PPG influenced by:
› Pre-prandial glucose
› Glucose load from meal
› Incretin level
› Insulin secretion
› Insulin sensitivity in
peripheral tissues
› Decrease in glucagon suppression
Achieving HbA1c target requires an action
on both FPG and PPG
IDF. International Diabetes Foundation. Diabetes Atlas. Third Edition.
http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 26 Jan, 2009.

62. 62
aIn patients inadequately controlled on metformin monotherapy.
bCompared with placebo plus metformin.
cLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.
dDifference from placebo.
Glycemic Efficacy for Sitagliptin Added to Patients Uncontrolled on Metformin (24-Week Placebo-
Adjusted)a
Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2632–2637.
Sitagliptin provided significant improvements in HbA1c, FPG, and 2-hr PPG vs placebo
when added to patients inadequately controlled on metformin monotherapy.
c
n=453
FPG
Mean Baseline: 170 mg/dL
(9.4 mmol/L) P <0.001
b
–25
-40
-30
-20
-10
0
ChangeinFPG(mg/dL)
c
d
n=454
c
d
n=387
(–1.4 mmo/L)
(–2.8 mmo/L)
d
HbA1c
Mean Baseline A1c: 8.0%
P<0.001
b
–0.7
-1.00
-0.75
-0.50
-0.25
0.00
ChangeinHbA1c(%)
2-hour PPG
Mean Baseline: 275
(15.3 mmol/L)P<0.001b
–51-60
-50
-40
-30
-20
-10
0
ChangeinPPG(mg/dL)

63. 63
Greater Reductions in HbA1c
Associated With Higher Baseline HbA1c
a Specifically glipizide; bSitagliptin 100 mg/day with metformin (≥1500 mg/day);
Per-protocol population; post hoc analysis.
Add-on sitagliptin with metformin vs sulfonylurea with metformin study.
Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
Baseline HbA1c CategoryChangeFromBaseline
inHbA1c(%)
n=117
<7% ≥7 to <8% ≥8 to <9% ³9%
-0.14
-0.59
-1.11
-1.76
-0.26
-0.53
-1.13
-1.68
-2.0
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Sitagliptinb + metformin
Sulfonylureaa + metformin
n=33 n=21n=82 n=82n=179 n=167n=112n=117
Mean Baseline HbA1c =
6.6% 6.7% 7.4% 7.4% 8.3%
8.3% 9.4% 9.2%

64. 64