1. Jaime A. Davidson, MD, FACP, MACE
Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors
Jaime A. Davidson, MD, FACP, MACE
Clinical Professor of Medicine
Division of Endocrinology
Touchstone Diabetes Center
The University of Texas Southwestern Medical Center
Dallas, Texas 1

2. Major Therapeutic Targets in T2DM
4/8/2017 4:58 AM
Glucose absorption
Hepatic glucose overproduction
Insulin resistance
Pancreas
Muscle and fat
Liver
Metformin
Thiazolidinediones
GLP-1 agonists
DPP-4 inhibitors
Sulfonylureas
Meglitinides
Alpha-glucosidase inhibitors
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.
DeFronzo RA. Ann Intern Med. 1999;131: Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. WB Saunders; 2003:
References:
1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.
2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004.
3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
4. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
5. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619.

3. Limitations of Older Agents for T2DM
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.

4. Function of Incretins in Healthy Individuals4

5. Role of Incretins in Glucose Homeostasis
Ingestion of food
Glucose-dependent Increased insulin from beta cells
(GLP-1 and GIP)
Increased glucose uptake by muscles
Release of gut hormones — incretins
GI tract
Decreased blood glucose
Pancreas
Active
GLP-1 and GIP
Glucose-dependent
Decreased glucagon from alpha cells
(GLP-1)
DPP-4 enzyme
Decreased glucose production by liver
Inactive GLP-1
Inactive GIP
Abbreviations: DPP-4, dipeptidyl peptidase-4; GIP, gastric inhibitory polypeptide;
GLP-1, glucagon-like peptide-1.
Kieffer TJ, Habener JF. Endocr Rev. 1999;20: Ahrén B. Curr Diab Rep. 2003;2: Drucker DJ. Diabetes Care. 2003;26: Holst JJ. Diabetes Metab Res Rev. 2002;18: 5

6. Actions of GLP-1 Action GLP-1 √ Stimulation of insulin secretion
Inhibition of glucagon secretion
Reduction in circulating glucose
Delayed gastric emptying
Induction of satiety/reduction of food intake
Potentially improved myocardial and endothelial function
Possible neuroprotection
Drucker DJ. Cell Metab. 2006;3: Grieve DJ, et al. Br J Pharmacol. 2009;157: Orskov C, et al. Endocrinology. 1988;123: Freeman JS. Cleve Clin J Med. 2009;76(suppl 5):S12-S19.

7. DPP-4
Transmembrane cell surface aminopeptidase expressed in liver, lungs, kidneys, intestines, lymphocytes, and endothelial cells1
Active extracellular domain also circulates as free soluble DPP-4 in plasma1
Active site is in a large “pocket”2
Access limited to substrates with small side chains (eg, proline, alanine)2
Active site cleaves to proline or alanine from 2nd aminoterminal position, inactivating its substrates1
Key substrates: GLP-1 and GIP2
Rapid and efficient metabolism by DPP-4 = short half-lives (~2 minutes for GLP-1)3
1. Drucker DJ, et al. Lancet. 2006;368: Kirby M, et al. Clin Sci (Lond). 2009;118: Chia CW, et al. Diabetes Metab Syndr Obes. 2009;2:37.

8. Incretin Dysfunction in T2DM

9. The Incretin Effect
Oral glucose vs IV glucose infusion: differences in insulin secretion
Insulin secretion is significantly higher with oral glucose vs IV glucose infusion (“incretin effect”)
Incretin effect is diminished in T2DM patients
Failure of insulin secretion
Nauck M, et al. Diabetologia. 1986;29:46-52.

10. Postprandial GLP-1 Levels in IGT and T2DM
2500
1927
2000
1587
1500
P <.001 for T2DM vs NGT
GLP-1 AUC Incremental from Basal (pmol/L• 240 min)
907
1000
500
NGT
IGT
T2DM
Abbreviations: AUC, area under the curve; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.
Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86: 10

11. 2 Strategies for GLP-1 Enhancement
GLP-1 analogs
DPP-4 inhibitors
Chemically modified GLP-1, not susceptible to DPP-4 metabolism
Longer half-lives
FDA approved: exenatide BID and qwk and liraglutide
Investigational
Albiglutide
Lixisenatide
Dulaglutide
Subcutaneous injection
Block DPP-4 so that it blunts breakdown of GLP-1
Raise endogenous GLP-1 levels; should also raise GIP
FDA approved: alogliptin, linagliptin, saxagliptin, and sitagliptin
Vildagliptin (approved outside United States)
Oral administration
Drucker DJ, et al. Lancet. 2006;368: Gallwitz B. Pediatr Nephrol. 2010;25:
ClinicalTrials.gov Accessed 12/11/13 at:

12. DPP-4 Inhibitors MOA Meal Active GLP-1 Active GIP Incretin effects
Augments glucose-dependent insulin secretion
Inhibits glucagon secretion and hepatic glucose production
Improves hyperglycemia
Meal
Inactive GLP-1
Active GIP
DPP-4
Intestinal
GIP
release
GLP-1
DPP-4 inhibitor
Inactive GIP
Active GLP-1
Selective inhibition of DPP-4 increases plasma GLP-1
levels, resulting in reduction in glycemia 12 12

13. DPP-4 Inhibition Improves Active GLP-1 Levels Single-Dose OGTT Study
3 arms (N = 58)
Placebo
Sitagliptin 25 mg
Sitagliptin 200 mg
Increase in active GLP-1 with sitagliptin compared with placebo
Placebo: active GLP-1 increases to ~7 pM at 2−3 h
Sitagliptin: active GLP-1 increases to ~15−20 pM and remains higher than placebo for ~6 h
Abbreviation: OGTT, oral glucose tolerance test.
Herman GA, et al. J Clin Endocrinol Metab. 2006;91:

14. Linagliptin Pharmacodynamics Effect on GLP-1 and Glucagon
Change from baseline in intact GLP-1 AUEC0–2h:
Linagliptin: 18.5 pmol/h/L
Placebo: 0.4 pmol/h/L
P <.0001
Change from baseline in glucagon AUEC0–2h:
Linagliptin: pg/h/L
Placebo: 1.3 pg/h/L
P = .0452
Statistically significant differences in postprandial intact GLP-1 (increased) and glucagon (decreased) vs placebo after 4 weeks of treatment in T2DM patients
Rauch T, et al. Diabetes Ther. 2012;3:10.

15. Therapeutic Effect of GLP-1 in T2DM
10 patients with unsatisfactory control of T2DM received infusions of GLP-1 or placebo
GLP-1 significantly increased
GLP-1 significantly reduced
Insulin (17.4 nmol x 1-1 x min)*
C-peptide (228 nmol x 1-1 x min)*
Fasting plasma glucose (normal levels reached in all patients)
Pancreatic glucagon secretion (-1418 pmol x 1-1 x min)
Plasma nonesterified fatty acids (-26.3 mmol x 1-1 x min)
*Decreased again after plasma glucose normalized.
Nauck MA, et al. Diabetologia. 1993;36: 15

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

17. Exenatide Has Beneficial Effects on FPG and Insulin in T2DM
Mean FPG (mg/dL)
Peak Mean Incremental Serum Insulin (µU/mL)
Abbreviation: FPG, fasting plasma glucose.
Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:

18. Exenatide Has Beneficial Effects on Postprandial Glucose and Glucagon in T2DM
Exenatide 0.1 μg/kg
Placebo
Postprandial glucose, day 5 (mean)
Baseline
180 min (nadir)
300 min
15.9 mg/dL
126.4 mg/dL
177.8 mg/dL
120 min (peak)
170.3 mg/dL
289.0 mg/dL
175.5 mg/dL
Postprandial glucagon, day 5 (mean)
98.9 pg/mL
<5%–6% change over 180 min
60 min
180 min
94.9 pg/mL
173.9 pg/mL
122.7 pg/mL
N = 24.
Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:

19. Exenatide at 3 Years of Therapy Provides Sustained Effects on HbA1c
217 patients randomized to placebo, 5 µg exenatide, or 10 µg exenatide during prior 30-week placebo-controlled studies were transitioned to open-label exenatide treatment
All patients had a minimum of 3 years of exenatide exposure for this analysis
By week 12, exenatide reduced HbA1c by 1.1%
Reduction in HbA1c was sustained throughout 156 weeks of treatment
Change from baseline to week 156 = -1.0% (95% CI, -1.1 to -0.8); P <.0001
46% of patients achieved HbA1c ≤7%; 30% achieved HbA1c ≤6.5%
Klonoff DC, et al. Curr Med Res Opin. 2008:24:

20. Liraglutide 1-Year Monotherapy Reduces FPG and PPG
Δ FPG (mg/dL)
P Value for Liraglutide vs Glimepiride
P Value for Liraglutide 1.8 vs 1.2 mg
Glimepiride
-5.2
Liraglutide 1.2 mg
-15.1
.027
Liraglutide 1.8 mg
-25.6
.0001
.0223
Therapy
Δ PPG (mg/dL)
P Value for Liraglutide vs Glimepiride
P Value for Liraglutide 1.8 vs 1.2 mg
Glimepiride
-24.5
Liraglutide 1.2 mg
-30.8
.1616
Liraglutide 1.8 mg
-37.5
.0038
.1319
Abbreviations: FPG, fasting plasma glucose; PPG, postprandial glucose.
Garber A, et al. Lancet. 2009;373: 20

21. Liraglutide 1-Year Monotherapy Improves Glycemic Control
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
Glimepiride (n = 248) Liraglutide 1.2 mg (n = 251) Liraglutide 1.8 mg (n = 246)
Δ HbA1c (%)
P = .0014
P = .0046
P <.0001
Garber A, et al. Lancet. 2009;373: 21

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

23. Effects of Exenatide qwk vs Exenatide BID on Glycemic Control
Exenatide 10 mcg BID (n = 147) Exenatide 2.0 mg qwk (n = 148)
Baseline HbA1c:
8.3%
-25
-41*
-50
-40
-30
-20
-10
FPG Change (mg/dL)
-0.5
HbA1c Change (%) -1
-1.5
-1.5 -2
-1.9*
100
Similar cumulative incidences of nausea
Exenatide BID, 35% of patients;
Exenatide qwk, 26% of patients
Similar weight loss
Approximately 4 kg in both groups
Similar rates of minor hypoglycemia
Exenatide BID, 6.1% of patients;
Exenatide qwk, 5.4% of patients
77* 80 61 60
HbA1c < 7.0% (% of Patients) 40 20
Approximately 90% of patients completed 30 weeks of treatment.
* P <.05 vs exenatide BID.
Drucker DJ, et al. Lancet. 2008;372: 23

24. Exenatide qwk Delivered Powerful HbA1c Reductions
Baseline HbA1c:
8.5%
8.4%
Exenatide qwk (n = 129)
Exenatide BID (n = 123)
Blevins T, et al. J Clin Endocrinol Metab. 2011;96: 24

25. Improvements in HbA1c with Exenatide qwk Were Sustained at 1 Year
DURATION-2 Open-Label Extension Completer Analysis Primary Endpoint: Change in HbA1c (%)
0.0
Blinded period1*
(N = 326)
Open-label period2†
(N = 249)
-0.5
-1.0
n = 130
-1.5
n = 119
-2.0 4 6 10 14 18 22 26 26 30 34 40 46 52
Time (wk)
Exenatide qwk
Sitagliptin
*ITT population. †52-week evaluable population. LS mean (SE).
1. Bergenstal RM, et al. Lancet. 2010;376:
2. Wysham C, et al. Diabet Med. 2011;28: 25

26. Exenatide qwk Percent to Goal Compared to Sitagliptin or Pioglitazone
Diet and exercise background
Exenatide qwk1
(n = 248)
Sitagliptin1
(n = 163)
Pioglitazone1
HbA1c <7.0%
63%*
43%
61%
HbA1c ≤6.5%
49%*
26%
42%
*P <.001 vs sitagliptin.
Metformin background
A significantly greater percentage of patients achieved HbA1c <7.0% and HbA1c ≤6.5% with exenatide qwk than with sitagliptin (P <.0001) or pioglitazone (P <.05)2
1. Russell-Jones D, et al. Diabetes Care. 2012;35:
2. Bergenstal RM, et al. Lancet. 2010;376: 26

27. Overview of GLP-1 Receptor Agonist Safety Data
Event
Odds Ratio
(95% confidence interval)
P Value
Hypoglycemia*†
2.92 (1.49, 5.75)
.002
With SUs
4.62 (1.89, 11.21)
.001
Without SUs
1.37 (0.72, 2.63)
.34
Cardiovascular events
0.99 (0.52, 1.91)
.98
Nausea
3.88 (2.79, 5.42)
<.001
Exenatide BID
8.38 (4.27, 16.48)
Liraglutide
3.48 (2.29, 5.28)
Vomiting
4.23 (2.67, 6.13)
Diarrhea
2.36 (1.67, 3.33)
Meta-analysis
Predominantly exenatide and liraglutide
n = 5429 receiving GLP-1 receptor agonists
n = 3053 receiving active comparators or placebo
* Odds ratio based on analysis of exenatide bid trials.
† Severe hypoglycemia reported for 19 patients in exenatide BID trials and 1 patient in liraglutide trials.
Abbreviation: SU, sulfonylurea.
Monami M, et al. Eur J Endocrinol. 2009;160:

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

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

30. Alogliptin Phase III Trials: HbA1c Change from Baseline After 26 Weeks
Alogliptin monotherapy1
Add-on therapy
LS Mean Change HbA1c from Baseline (%)
Baseline HbA1c: 8.0%
Baseline
HbA1c (%)
Alogliptin 12.5 mg
Aloglitpin 25 mg
Control
Add-on to SU2
8.1
-0.39*
-0.53*
0.01
Add-on to MET3
7.9
-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
Abbreviations: MET, metformin; PIO, pioglitazone; SU, sulfonylurea.
*P <.001 vs control.
1. DeFronzo RA, et al. Diabetes Care. 2008;31: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Curr Med Res Opin. 2009;25: Rosenstock J, et al. Diabetes Obes Metab. 2009;11: 30

31. Linagliptin Significantly Reduced HbA1c After 24 Weeks in Patients on a Stable Insulin Dose
Baseline HbA1c (%):
8.29
8.31
Full analysis set (last observation carried forward). Change-from-baseline HbA1c at Week 24 is the primary endpoint.
*Model includes treatment, baseline HbA1c, renal function, concomitant OADs. †Sensitivity analyses (FAS OC and PPS) revealed similar results.
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

32. HbA1c Reduction with Linagliptin in Elderly Patients Over 75 Years
In a prespecified subgroup analysis, there was no significant interaction according to patient age group (P = .1000)
The study had a high proportion of elderly patients
65−74 years: 26.1% linagliptin, 28.7% placebo
≥75 years: 5.5% linagliptin, 6.5% placebo
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

33. Linagliptin Reduced HbA1c After 24 Weeks (Primary Endpoint) and Maintained it in a 52- Week Free Insulin Titration Period
Stable insulin dose
Baseline to week 24
Free insulin dose
starting at week 24
The difference in HbA1c reduction between linagliptin and placebo was maintained during a 52-week free insulin titration period starting at week 24 (out to week 76)
Full analysis set (last observation carried forward).
*Model includes treatment, baseline HbA1c, renal function, concomitant OADs.
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

34. Placebo-adjusted change with linagliptin:
Linagliptin Significantly Reduced FPG After 24 Weeks and Maintained it in 28-Week Free Insulin Titration Period
Stable insulin dose
baseline to week 24
Free insulin dose
starting at week 24
Week 24
Week 52
Change in FPG from baseline
Placebo-adjusted change with linagliptin:
mg/dL
Placebo: mg/dL
Linagliptin: mg/dL
Full analysis set (observed case set).
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

35. Insulin Dose Stabilized in 1st 24 Weeks and Increased in Both Groups in 2nd 28-Week Free-Titration Period, but With Greater Extent in Placebo Group
Stable insulin dose
Baseline to week 24
Free insulin dose
starting at week 24
Full analysis set, original analysis.
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

36. Safety Profile of Linagliptin Compared with Placebo After 52 Weeks
The overall risk of adverse events (AEs) with linagliptin (n = 631) vs placebo (n = 630):
Patients with any AEs
78.4% with linagliptin vs 81.4% with placebo
Patients with investigator-defined drug-related AEs
18.7% with linagliptin vs 22.2% with placebo
Patients with AEs leading to discontinuation of trial drug
3.3% with linagliptin vs 4.4% with placebo
Patients with serious AEs
13.8% with linagliptin vs 13.2% with placebo
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

37. Linagliptin, When Added to Insulin, and Its Association with the Risk of Hypoglycemia
Week 24
Week 52
Improved glycemic control with linagliptin added to insulin
does not appear to increase the risk of hypoglycemia
Treated set (all patients who were treated with at least 1 dose of study medication).
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

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

39. 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:

40. Both Sitagliptin and Saxagliptin Produced Greatest Reductions in HbA1c in Patients with High Baseline HbA1c
Sitagliptin-Treated Subgroup with Baseline HbA1c >9%
Open-Label Saxagliptin in 66 Patients with Baseline HbA1c >10% to ≤12%
Placebo-Subtracted Δ in HbA1c (%) from Baseline to Week 12
–1.2
–1.0
–0.8
–0.6
–0.4
–0.2
50 mg QD
100 mg QD
–1.15
–1.18
Δ HbA1c from Baseline to Week 24 (%)
–0.8
–0.6
–0.4
–0.2
10 mg QD
–1.87
–1.0
–1.2
–1.4
–1.6
–1.8
–2.0
Hanefeld M, et al. Curr Med Res Opin. 2007;23: Rosenstock J, et al. Curr Med Res Opin. 2009;25:

41. With Metformin Initial Tx
Incretin-Based Therapy Improves Glycemic Control When Used in Combination
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
Abbreviation: TZD, thiazolidinedione.
*Added to thiazolidinedione plus metformin.
1. Bergenstal RM, et al. Lancet. 2010;376: DeFronzo RA, et al. Diabetes Care. 2005;28: DeFronzo RA, et al. Diabetes Care. 2010;33: Buse JB, et al. Diabetes Care. 2004;27: Buse JB, et al. Lancet. 2009;374: Zinman B, et al. Diabetes Care. 2009;32: Marre M, et al. Diabet Med. 2009;26: Pratley R, et al. ADA Abstract 1158-P. 9. Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Curr Med Res Opin. 2009;25: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Haak T, et al. Diabetes Obes Metab. 2012;14: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: Gomis R, et al. Diabetes Obes Metab. 2011;13: Lewin AJ, et al. Clin Ther. 2012;34: e Williams-Herman D, et al. Curr Med Res Opin. 2009;25: Charbonnel B, et al. Diabetes Care. 2006;29: Nauck M, et al. Diabetes Care. 2009;32: Derosa G, et al. Metabolism. 2010;59: Rosenstock J, et al. Clin Ther. 2006;28: Hermansen K, et al. Diabetes Obes Metab. 2007;9: Jadzinsky M, et al. Diabetes Obes Metab. 2009;11: DeFronzo RA, et al. Diabetes Care. 2009;32: Hollander P, et al. J Clin Endocrinol Metab. 2009;94: Chacra AR, et al. Int J Clin Pract. 2009;63:

42. Diet and exercise background1
Exenatide qwk HbA1c Reduction Compared with Sitagliptin or Pioglitazone
Diet and exercise background1
Metformin background2
Baseline :
8.5%
8.5%
8.5%
8.6%
8.5%
8.5%
Exenatide qwk
(n = 248)
Exenatide qwk
(n = 160)
LS Mean. ITT population.
*P <.001 vs sitagliptin. †P <.0001 vs sitagliptin ‡P <.05 vs pioglitazone.
1. Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: 42

43. Diet and exercise background1
Fasting Plasma Glucose Improvement Was Greater with Exenatide qwk and Pioglitazone
Diet and exercise background1
Metformin background2
Exenatide qwk
(n = 248)
Exenatide qwk
(n = 160)
LS Mean. ITT population.
*P <.05 exenatide qwk vs sitagliptin.
1. Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376:

44. GLP-1 Receptor Agonists and DPP-4 Inhibitors
Effects on Weight

45. Why Is Weight a Concern? Most patients with T2DM are overweight/obese
Some currently available therapies cause weight gain
Secretagogues
Glitazones
Insulin

46. Exenatide Open-Label Extension Study Continuous Loss of Body Weight
Baseline 99.3 kg
Baseline BMI (kg/m2)
<30
Δ Body Weight from Baseline to Week 156 (kg)
Δ Body Weight from Baseline (kg)
Klonoff DC, et al. Curr Med Res. 2008;24: 46

47. Diet and exercise background1
Exenatide qwk Weight Reduction Compared with Sitagliptin or Pioglitazone
Diet and exercise background1
Metformin background2
Baseline (kg) :
87.5
88.7
86.1 89 87 88
Exenatide qwk
(n = 248)
Exenatide qwk
(n = 160)
*P <.001 vs sitagliptin. †P <.001 vs pioglitazone. ‡P = .002 vs sitagliptin. §P <.0001 vs pioglitazone.
1. Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: 47

48. Effect of Liraglutide vs Standard Therapy on Body Weight
Weight Change from Baseline (kg)
Liraglutide
1.2 mg
1.8 mg
Comparator(s)
Monotherapy1
-2 to -3* (approximate)
1−2 with glimepiride (approximate)
Add-on to metformin2
-2.6†
-2.8†
-1.5 with placebo
1.0 with glimepiride
Add-on to SU3
0.3†
-0.2†
-0.1 with placebo
2.1 with rosiglitazone
Add-on to metformin + TZD4
-1‡
-2‡
0.6 with glimepiride
Add-on to metformin + SU5
-1.8‡
-0.42 with placebo
1.6 with glargine
*P = vs glimepiride; †P <.05 vs placebo; ‡P ≤.0001 vs placebo.
Abbreviations: SU, sulfonylurea; TZD, thiazolidinedione.
1. Garber A, et al. Lancet. 2009;373: Nauck M, et al. Diabetes Care. 2009;32: Marre M, et al. Diabetic Med. 2009;26: Zinman B, et al. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetologia. 2009;52:

49. Liraglutide Delayed Gastric Emptying
Comparative trial: liraglutide, glimepiride, placebo in T2DM patients (N = 46)
Gastric emptying was slowed with liraglutide, mainly during the first postprandial hour
Mean estimated acetaminophen AUC0-60 min ratios
0.62 with liraglutide vs placebo (P <.001)
0.67 with liraglutide vs glimepiride (P <.001)
Mean estimated percentage of acetaminophen exposure during the first postprandial hour (AUC0-60 min/AUC0-300 min)
30% less with liraglutide compared with placebo (P <.001)
29% less with liraglutide compared with glimepiride (P <.001)
Acetominophen Cmax
20% lower with liraglutide compared with placebo (P ≤.006)
15% lower with liraglutide compared with glimepiride (P ≤.006)
Horowitz M, et al. Diabetes Res Clin Pract. 2012;97:

50. Neutral Effect of DPP-4 Inhibitors on Body Weight
Sitagliptin produced statistically significant (P <.05) decreases of 0.5–0.8 kg in body weight from baseline at week 12 at all doses1
Not significantly different from weight loss seen with placebo (-0.5 kg)
Saxagliptin reduced body weight by -0.1 to -1.2 kg at week 24 compared with baseline2
Weight loss was -1.4 kg with placebo
In a comparative trial, mean weight loss after 26 weeks was kg with sitagliptin vs kg with liraglutide 1.8 mg and kg with liraglutide 1.2 mg3
Linagliptin produced no significant difference in body weight from baseline4
No significant difference in body weight from baseline with placebo
1. Hanefeld M, et al. Curr Res Med Opin. 2007;23: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Pratley RE, et al. Lancet. 2010;375: Del Prato S, et al. Diabetes Obes Metab. 2011;13:

51. Effect of Alogliptin Monotherapy on Body Weight at 26 Weeks
DeFronzo RA, et al. Diabetes Care. 2008;31:

52. Effect of Linagliptin on Body Weight When Added to Insulin
Week 24
Week 52
Yki-Järvinen H, et al. Diabetes Care. 2013;36:

53. GLP-1 Receptor Agonists and DPP-4 Inhibitors
Effects on Lipids

54. Exenatide Has Beneficial Effects on Lipids
Trigs TC
LDL-C
HDL-C
Mean Δ from Baseline (mg/dL)
Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; Trigs, triglycerides.
Klonoff DC, et al. Curr Med Res Opin. 2008;24: 54

55. Effect of Exenatide qwk and Exenatide BID on Lipids
Change from Baseline
Exenatide qwk
(n = 106)
Exenatide BID
(n = 105)
LDL-C (mg/dL)
-2.70
0.39
HDL-C (mg/dL)
1.24
0.19
Triglycerides (mg/dL)
-31.86*
-30.09*
VLDL-C (mg/dL)
-12.74*
-13.13*
Non-HDL-C (mg/dL)
-3.32
0.58
*P <.05 from baseline.
Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol.
Chiquette E, et al. Vasc Health Risk Manag. 2012;8:

56. Liraglutide Reduces Triglycerides and CVD Inflammatory Biomarkers
Difference from Placebo in Change from Baseline (%)
Liraglutide mg
Liraglutide mg
Liraglutide mg
Triglycerides1
-19*
-15
-22*
PAI-12
-14
-29*
-25*
BNP2
-26
-30*
-38*
hs-CRP2 -3
-12
-20
*P <.05.
Abbreviations: BNP, B-type natriuretic peptide; CVD, cardiovascular disease; hs-CRP, high-sensitivity C-reactive protein; PAI-1, plasminogen activator inhibitor 1.
1. Vilsbøll T, et al. Diabetes Care. 2007;30: Courrèges JP, et al. Diabet Med. 2008;25:

57. Biomarkers of Cardiovascular Risk Were Reduced with Liraglutide vs SU
Treatment difference -8.6
(95% CI to -3.6)
Treatment difference
(95% CI to )
Abbreviations: BNP, B-type natriuretic peptide; FFA, free fatty acids.
Kaku K, et al. J Diabetes Invest. 2011;2: 57

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

59. Saxagliptin’s Effects on Lipids
Specific data were not provided in the published phase III trial
“Modest numerical improvements from baseline to week 24 in total cholesterol were demonstrated in the saxagliptin treatment groups.”
“There were no clear effects of saxagliptin on fasting lipid concentrations.”
Rosenstock J, et al. Curr Med Res Opin. 2009;25:

60. 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

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

62. Exenatide Reduced Systolic Blood Pressure in Clinical Trials ≥6 Months’ Duration
Pooled data from 6 trials of exenatide in T2DM; N = 2171
Mean Change in Systolic Blood Pressure (mmHg)
P Value
Mean Change in Diastolic Blood Pressure (mmHg)
Exenatide
-2.2
.0002
-0.7
.21
Placebo
+0.6
-0.2
-4.5
<.0001
-1.6
.16
Insulin
-0.9
-0.8
No differences between treatments in proportion of patients reducing number, type, or intensity of antihypertensive therapy
Reduction in blood pressure correlated only weakly with weight loss in exenatide-treated patients (r = 0.09; P = .002)
Okerson T, et al. Am J Hypertens. 2010;23:

64. 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

65. CV Events with Incretin-Based Therapies Meta-analyses/Pooled Analyses
Drug Name/Class
Number of Studies Analyzed N
CV Events
Exenatide BID1 12
3945
(2316 exenatide BID; 1629 comparator)
Risk ratio 0.70
(95% CI 0.38−1.31)
Liraglutide2 15
6638
(4257 liraglutide; 2381 comparator)
Incidence ratio 0.73
(95% CI 0.38−1.41)
Linagliptin3 8
5239
(3319 linagliptin; 1920 comparator)
Hazard ratio 0.34
(95% CI 0.16−0.70)
Saxagliptin4
4607
(3356 saxagliptin; 1251 comparator)
Relative risk 0.43
(95% CI 0.23−0.80)
Sitagliptin5 25
14,611
(7726 sitagliptin; 6885 comparator)
Incidence ratio 0.83
(95% CI 0.53−1.30)
GLP-1 receptor agonists6
37*
15,398
(8619 GLP-1 RA; 6779 comparator)
Odds ratio 0.78
(95% CI 0.54−1.13)
DPP-4 inhibitors7
70†
41,959
Odds ratio 0.71
(95% CI 0.59−0.86)
*25 trials reported ≥1 CV event and were included in the main analysis.
†63 trials reported ≥1 CV event and were included in the main analysis.
1. Ratner R, et al. Cardiovasc Diabetol. 2011;10: Marso SP, et al. Diab Vasc Dis Res. 2011;8: Johansen OE, et al. Cardiovasc Diabetol. 2012;11:3. 4. Frederich R, et al. Postgrad Med. 2010;122: Engel SS, et al. Cardiovasc Diabetol. 2013;12:3. 6. Monami M, et al. Diabetes Obes Metab. 2014;16: Monami M, et al. Diabetes Obes Metab. 2013;15:

66. CV Outcomes Trials with Incretin-Based Therapies
Trial Name
Comparators
Population
Estimated Primary Completion Date
SAVOR-TIMI 531
Saxagliptin vs placebo
T2DM with history of CVD or CV risk
Completed
EXAMINE2
Alogliptin vs placebo
T2DM with recent ACS
TECOS3
Sitagliptin vs placebo
T2DM with pre-existing CVD
Dec 2014
ELIXA4
Lixisenatide vs placebo
T2DM with ACS
Jan 2015
LEADER5
Liraglutide vs placebo
T2DM with CV risk
Oct 2015
EXSCEL6
Exenatide ER vs placebo
T2DM
Dec 2017
CARMELINA7
Linagliptin vs placebo
Jan 2018
CAROLINA8
Linagliptin vs glimepiride
Sep 2018
Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease.

67. SAVOR Trial: Study Design
16,492 T2DM patients with established CVD or multiple risk factors
Randomized 1:1
Double-blind
Saxagliptin 5 mg/d (2.5 mg/d if eGFR ≤50 mL/min)
Other therapy at the physician’s discretion
Placebo
Primary endpoint: composite endpoint of CV death, non-fatal MI, or non-fatal ischemic stroke
Scirica BM, et al. N Engl J Med ;369:

68. SAVOR Trial: Primary Endpoint
HR 1.00 (95% CI 0.80−1.12)
P <.001 (noninferiority)
P = .99 (superiority)
Scirica BM, et al. N Engl J Med ;369:

69. EXAMINE Trial: Study Design
5380 T2DM patients with recent ACS
Randomized 1:1
Double-blind
Alogliptin (5 mg , 12.5 mg, or 6.25 mg once daily based on renal function)
Plus standard of care
Placebo
Primary endpoint: composite endpoint CV death, nonfatal Ml, or nonfatal stroke
White WB, et al. N Engl J Med. 2013;369:

70. EXAMINE Trial: Primary Endpoint
HR 0.96 (95% CI ≤1.16)
P <.001 (noninferiority)
P = .32 (superiority)
Placebo (n = 2679)
White WB, et al. N Engl J Med. 2013;369:

71. Study Design: SAVOR and EXAMINE
SAVOR (N = 16,492)
EXAMINE (N = 5380)
Planned duration
Event-driven until the occurrence of 1040 primary events
Event driven with interim analyses after 80, 100, 125, 150, 550, 600, and 650 events (~5 yrs)
Analysis
Noninferiority/superiority
Prevention
1° or 2° 2°
Primary outcomes
Efficacy and safety: time to confirmed CV event (composite of death, nonfatal MI, nonfatal ischemic stroke)
Time to CV event (composite of CV death, nonfatal MI, nonfatal stroke)
Secondary outcomes
Time to first occurrence of primary outcome + hospitalization for HF, unstable angina, or coronary revascularization
All-cause mortality
Time to occurrence of any event in the secondary MACE composite of CV death, nonfatal MI, nonfatal stroke, and urgent revascularization for unstable angina
Key inclusion
≥40 years, A1C ≥6.5% and ≤12.5% within 6 months
Pre-existing CVD or high risk for CV or multiple CV risk factors
≥18 years, A1C 6.5%−11.0% while receiving monotherapy or combination antihyperglycemic therapy, or from 7.0%−11.0% if the regimen includes insulin
Key exclusion
Acute vascular event <2 months prior to randomization
Treatment with DPP-4i or GLP-1 RA within 6 months
Type 1 diabetes
Treatment with GLP-1 RA at screening
Treatment with DPP-4i within 3 months of screening or more than 14 days total
ClinicalTrials.gov Accessed 12/31/13 at: 71 71

72. Baseline Characteristics: SAVOR and EXAMINE
SAVOR Trial1
(N = 16,492)
EXAMINE Trial2
(N = 5380)
Saxagliptin (n = 8280)
Mean age: 65 y
Mean HbA1c: 8.0%
Mean BMI: 31.1 kg/m2
Median duration of diabetes: 10.3 y
Placebo (n = 8212)
Mean BMI: 31.2 kg/m2
Alogliptin (n = 2701)
Mean age: 61 y
Mean HbA1c: 8.0%
Mean BMI: 28.7 kg/m2
Median duration of diabetes: 7.1 y
Placebo (n = 2679)
Median duration of diabetes: 7.3 y
1. Scirica BM, et al. N Engl J Med ;369:
2. White WB, et al. N Engl J Med. 2013;369: 72 72

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

74. 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
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.

75. 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:

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

77. Adverse Effects of GLP-1 Agonists and DPP-4 Inhibitors
Nausea/ Vomiting
Diarrhea
Hypoglycemia
Pancreatitis
Exenatide1,2
++++ +
Rare
Liraglutide3
+++
Exenatide qwk4 ++
Alogliptin5
Linagliptin6
Sitagliptin7,8
Saxagliptin9
+/-
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
1. Klonoff DC, et al. Curr Med Res Opin. 2008;24: Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88: Garber A, et al. Lancet. 2009;373: Exenatide QW Prescribing Information. 5. Alogliptin Prescribing Information. 6. Linagliptin Prescribing Information. 7. Hanefeld M, et al. Curr Med Res Opin. 2007;23: Sitagliptin Prescribing Information. 9. Rosenstock J, et al. Curr Med Res Opin. 2009;25: White WB, et al. N Engl J Med. 2013;369: Scirica BM, et al. N Engl J Med ;369:

78. GLP-1 Agonists and DPP-4 Inhibitors
Summary
GLP-1 Agonists and DPP-4 Inhibitors

79. Incretin-Based Therapy in T2DM Meta-analysis
GLP-1 Analogs vs Placebo*†
DPP-4 Inhibitors vs Placebo*
Achieved HbA1c <7%
(risk ratio)
4.19†
(3.17 to 5.53)
2.47
(2.14 to 2.84)
HbA1c reduction
(weighted mean difference in change in HbA1c percentage)
-0.97%
(-1.13% to -0.81%)
-0.74%
(-0.85% to -0.62%)
FPG level, mg/dL
(weighted mean difference in change from baseline)
-27
(-33 to -21)
-18
(-22 to -14)
Weight, kg
-2.37
(-3.95 to -0.78)
0.48
(0.30 to 0.66)
*The values in parentheses represent 95% CIs.
†This value represents only exenatide vs placebo.
Amori RE, et al. JAMA. 2007;298: Slide courtesy of Dr. Jaime A. Davidson.

80. Incretin-Based Therapy in T2DM Meta-analysis
Mean Change from Baseline
GLP-1 Receptor Agonists
DPP-4 Inhibitors
HbA1c
-1.10% to -1.59%
-0.60% to -1.06%
FPG (mg/dL) to to
Weight (kg)
-2.03 to -2.41
-0.16 to -0.64
Meta-analysis
GLP-1 receptor agonists
19 studies with exenatide BID, 7 studies with exenatide qwk, 11 studies with liraglutide
DPP-4 inhibitors
5 studies with alogliptin, 9 studies with linagliptin, 7 studies with saxagliptin, 23 studies with sitagliptin, 6 studies with vildagliptin
Aroda VR, et al. Clin Ther. 2012;34: e22.

81. Summary: DPP-4 Inhibitors and GLP-1 Receptor Agonists
Characteristic
DPP-4 Inhibitors
GLP-1 Receptor Agonists
Expected HbA1c decrease1,2
0.5%−1.0%
0.8%−1.9%
How administered1
Orally
Injected
Weight effect1,2
Neutral
Weight loss
Common adverse events1-3
Headache, infection
Nausea, vomiting
Rare serious adverse events1-3
Hypersensitivity/ allergic reactions
Symptoms of pancreatitis
Low risk of hypoglycemia?1,2
Yes
Gastrointestinal adverse events?1,2 No
Improve postprandial glucose levels?1,2
Yes*
Included in ADA/EASD algorithm?1
Included in AACE algorithm?4
What is your opinion about initial combination therapy?
What are your thoughts on candidates for DPP-4 inhibitors vs GLP-1 agonists or mimetics (injections vs pills, weight loss vs weight neutral, etc)?
*Greater effect for this class.
Abbreviations: AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes.
1. Inzucchi SE, et al. Diabetes Care. 2012;35: Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.
3. Dicker D. Diabetes Care. 2011;34(suppl 2):S276-S Garber AJ, et al. Endocr Pract. 2013;19: 81

82. Benefits and Advantages of Incretin-Based Therapies
GLP-1 analogs
Lower HbA1c ~0.8%-1.1% from baseline
Promote satiety and weight loss
Beneficial effects on lipids
Beneficial effects on systolic blood pressure
DPP-4 inhibitors
Lower HbA1c ~0.4%–0.9% from baseline
Weight neutral (do not promote weight gain)
Once-daily oral therapy
vs once daily, twice daily, or once weekly injections with GLP-1 analogs
Minimal GI side effects

83. Investigational Incretin-Based Therapies
GLP-1 analogs
Albiglutide
Lixisenatide
Dulaglutide
Semaglutide
DPP-4 inhibitors
Vildagliptin (approved in Europe and Latin America)
Omarigliptin (MK-3102)
Trelagliptin (SYR-472)
ClinicalTrials.gov Accessed 12/11/13 at:

84. Conclusion
Incretin-based therapies are welcome additions to treatment of T2DM
Both improve glycemic control
GLP-1 agonists have beneficial effects on lipids, blood pressure, and weight
DPP-4 inhibitors are convenient once-daily oral therapies with a good safety and tolerability profile
The first 2 long-term trials with DPP-4 inhibitors—SAVOR and EXAMINE—showed these therapies to be safe in T2DM patients at a high risk for cardiovascular disease

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