Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors

Type 2 Diabetes Treatment: Type 2 Diabetes Treatment: Novel Therapies Novel Therapies

GLP-1 Receptor Agonists/Analogs GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitorsand DPP-4 Inhibitors

Jaime A. Davidson, MD, FACP, MACE Clinical Professor of Medicine

Division of EndocrinologyTouchstone Diabetes Center

The University of Texas Southwestern Medical CenterDallas, Texas

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 Glucose absorptionabsorption

Hepatic glucoseHepatic glucoseoverproductionoverproduction

InsulinInsulinresistanceresistance

Pancreas

Muscle and fat

Liver

MetforminThiazolidinedionesGLP-1 agonistsDPP-4 inhibitors

SulfonylureasMeglitinidesGLP-1 agonistsDPP-4 inhibitors

ThiazolidinedionesMetformin

Alpha-glucosidase inhibitorsGLP-1 agonists

GutGlucose Glucose

reabsorptionreabsorption

Kidney

Beta-cellBeta-celldysfunctiondysfunction

Glucose level

SGLT-2 inhibitors

Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus.

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.

Function of Incretins in Healthy Function of Incretins in Healthy Individuals Individuals

Role of Incretins in Glucose Role of Incretins in Glucose HomeostasisHomeostasis

Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876-913. Ahrén B. Curr Diab Rep. 2003;2:365-372. Drucker DJ. Diabetes Care. 2003;26:2929-2940. Holst JJ. Diabetes Metab Res Rev. 2002;18:430-441.

Ingestion of food

Release of gut hormones —

incretinsPancreas

Glucose-dependent Increased insulin

from beta cells(GLP-1 and GIP)

Increased glucose

uptake by muscles

Decreased glucose

production by liver

Decreased blood

glucose

Glucose-dependentDecreased glucagon

from alpha cells(GLP-1)

GI tract

ActiveGLP-1 and GIP

DPP-4 enzyme

InactiveGIP

InactiveGLP-1

Abbreviations: DPP-4, dipeptidyl peptidase-4; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1.

Actions of GLP-1Actions of GLP-1

Drucker DJ. Cell Metab. 2006;3:153-165. Grieve DJ, et al. Br J Pharmacol. 2009;157:1340-1351. Orskov C, et al. Endocrinology. 1988;123:2009-2013. Freeman JS. Cleve Clin J Med. 2009;76(suppl 5):S12-S19.

Action GLP-1Stimulation 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 √

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;368:1696-1705. 2. Kirby M, et al. Clin Sci (Lond). 2009;118:31-41. 3. Chia CW, et al. Diabetes Metab Syndr Obes. 2009;2:37.

Incretin Dysfunction in T2DMIncretin Dysfunction in T2DM

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.

Postprandial GLP-1 Levels in IGT Postprandial GLP-1 Levels in IGT and T2DMand T2DM

Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.

Abbreviations: AUC, area under the curve; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.

1927

1587

907

0

500

1000

1500

2000

2500

NGT IGT T2DM

P <.001 for T2DM vs NGT

GL

P-1

AU

C I

ncr

emen

tal

fro

m

Bas

al (

pm

ol/

L•

240

min

)2500

2000

1500

1000

0

500

1927

1587

907

2 Strategies for GLP-1 Enhancement

GLP-1 analogs• 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

DPP-4 inhibitors• 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;368:1696-1705. Gallwitz B. Pediatr Nephrol. 2010;25:1207-1217. ClinicalTrials.gov. 2013. Accessed 12/11/13 at: http://www.clinicaltrials.gov.

DPP-4 Inhibitors MOA

12

Incretin effects – Augments glucose-dependent

insulin secretion– Inhibits glucagon secretion

and hepatic glucose production– Improves hyperglycemia

MealMeal

Inactive Inactive GLP-1GLP-1

ActiveActiveGIPGIP

DPP-4DPP-4

IntestinalIntestinalGIP GIP

releaserelease

IntestinalIntestinalGLP-1 GLP-1 releaserelease

DPP-4DPP-4

DPP-4DPP-4inhibitorinhibitor

Inactive Inactive GIPGIP

DPP-4DPP-4inhibitorinhibitor

ActiveActiveGLP-1GLP-1

Selective inhibition of DPP-4 increases plasma GLP-1 levels, resulting in reduction in glycemia

DPP-4 Inhibition Improves ActiveGLP-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

Herman GA, et al. J Clin Endocrinol Metab. 2006;91:4612-4619.

Abbreviation: OGTT, oral glucose tolerance test.

Linagliptin PharmacodynamicsEffect on GLP-1 and Glucagon

Rauch T, et al. Diabetes Ther. 2012;3:10.

Statistically significant differences in postprandial intact GLP-1 (increased) and glucagon (decreased) vs placebo after 4 weeks of treatment in T2DM patients

Change from baseline in intact GLP-1 AUEC0–2h: Linagliptin: 18.5 pmol/h/LPlacebo: 0.4 pmol/h/LP <.0001

Change from baseline in glucagon AUEC0–2h: Linagliptin: -17.4 pg/h/LPlacebo: 1.3 pg/h/LP = .0452

Therapeutic Effect of GLP-1 in T2DM

GLP-1 significantly increased

• Insulin (17.4 nmol x 1-1 x min)*

• C-peptide (228 nmol x 1-1 x min)*

GLP-1 significantly reduced

• 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)

Nauck MA, et al. Diabetologia. 1993;36:741-744. Nauck MA, et al. Diabetologia. 1993;36:741-744.

10 patients with unsatisfactory control of T2DM received infusions of GLP-1 or placebo

*Decreased again after plasma glucose normalized.

GLP-1 Receptor Agonists and GLP-1 Receptor Agonists and DPP-4 InhibitorsDPP-4 Inhibitors

Effects on HbA1c, Glucose, and Insulin Levels

Exenatide Has Beneficial Effects on FPG and Insulin in T2DM

Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089.

N = 13

Mea

n F

PG

(m

g/dL

)

Pea

k M

ean

Incr

emen

tal

Ser

um I

nsul

in (

µU

/mL)

Abbreviation: FPG, fasting plasma glucose.

Exenatide Has Beneficial Effects on Postprandial Glucose and Glucagon

in T2DM

N = 24. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089.

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

Baseline

120 min (peak)

300 min

170.3 mg/dL

289.0 mg/dL

175.5 mg/dL

Postprandial glucagon, day 5 (mean)

Baseline 98.9 pg/mL

<5%–6% change over 180 min

Baseline

60 min

180 min

94.9 pg/mL

173.9 pg/mL

122.7 pg/mL

Klonoff DC, et al. Curr Med Res Opin. 2008:24:275-286.

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%

Liraglutide 1-Year Monotherapy Reduces FPG and PPG

Therapy 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


Garber A, et al. Lancet. 2009;373:473-481.

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 1.8 mg -37.5 .0038 .1319

.0223

Abbreviations: FPG, fasting plasma glucose; PPG, postprandial glucose.

Liraglutide 1-Year Monotherapy Improves Glycemic Control

Glimepiride (n = 248) Liraglutide 1.2 mg (n = 251) Liraglutide 1.8 mg (n = 246)

Δ H

bA1c

(%

)

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

-1.4*

-1*

-0.7

-0.4

-1.5

-1

-0.5

0

Hb

A1c

Ch

ang

e (%

)

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

Effects of Exenatide qwk vs Exenatide BID on Glycemic Control

Drucker DJ, et al. Lancet. 2008;372:1240-1250.

Exenatide 10 mcg BID (n = 147) Exenatide 2.0 mg qwk (n = 148)

Approximately 90% of patients completed 30 weeks of treatment.

61

77*

0

20

40

60

80

100

Hb

A1

c <

7.0

% (

% o

f P

ati

en

ts)

Similar cumulative incidences of nausea Exenatide BID, 35% of patients; Exenatide qwk, 26% of patients

Similar weight lossApproximately 4 kg in both groups

Similar rates of minor hypoglycemiaExenatide BID, 6.1% of patients; Exenatide qwk, 5.4% of patients

-1.5

-1.9*-2

-1.5

-1

-0.5

0

Hb

A1

c C

ha

ng

e (

%)

Baseline HbA1c: 8.3% 8.3%

-25

-41*-50

-40

-30

-20

-10

0

FP

G C

ha

ng

e (

mg

/dL

)

* P <.05 vs exenatide BID.

Exenatide qwk Delivered Powerful HbA1c Reductions

Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310.

Baseline HbA1c: 8.5% 8.4%

Exenatide qwk (n = 129) Exenatide BID (n = 123)

Improvements in HbA1c with Exenatide qwk Were Sustained at 1 Year

*ITT population. †52-week evaluable population. LS mean (SE).1. Bergenstal RM, et al. Lancet. 2010;376:431-439. 2. Wysham C, et al. Diabet Med. 2011;28:705-714.

DURATION-2 Open-Label Extension Completer Analysis Primary Endpoint: Change in HbA1c (%)

0.0

-0.5

-1.0

-1.5

-2.00 4 6 10 14 18 22 26 26 30 34 40 46 52

Time (wk)

Blinded period1*(N = 326)

Open-label period2†

(N = 249)

n = 130

n = 119

SitagliptinExenatide qwk

Exenatide qwk Percent to Goal Compared to Sitagliptin or Pioglitazone

• 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;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439.

Exenatide qwk1

(n = 248)Sitagliptin1

(n = 163)Pioglitazone1

(n = 163)

HbA1c <7.0% 63%* 43% 61%

HbA1c ≤6.5% 49%* 26% 42%

• Diet and exercise background

*P <.001 vs sitagliptin.

Overview of GLP-1 Receptor Agonist Safety Data

Abbreviation: SU, sulfonylurea.Monami M, et al. Eur J Endocrinol. 2009;160:909-917.

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) <.001

Liraglutide 3.48 (2.29, 5.28) <.001

Vomiting 4.23 (2.67, 6.13) <.001

Diarrhea 2.36 (1.67, 3.33) <.001

* 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.

• Meta-analysis• Predominantly exenatide and liraglutide

– n = 5429 receiving GLP-1 receptor agonists– n = 3053 receiving active comparators or placebo

Current DPP-4 Inhibitors

Sitagliptin

Vildagliptin(approved outside United States)

Saxagliptin

Alogliptin

Linagliptin

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

ΔH

bA

1c

(%)

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

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.

LS Mean Change HbA1c from Baseline (%)

Alogliptin monotherapy1 Add-on therapy

Baseline HbA1c: 8.0%

Linagliptin Significantly Reduced HbA1c After 24 Weeks in Patients on a Stable Insulin Dose

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;36:3875-3881.

Baseline HbA1c (%): 8.29 8.31

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;36:3875-3881.

• 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)

Linagliptin Reduced HbA1c After 24 Weeks (Primary Endpoint) and Maintained it in a 52-

Week Free Insulin Titration Period

Stable insulin doseBaseline to week 24

Free insulin dosestarting at week 24

Full analysis set (last observation carried forward). *Model includes treatment, baseline HbA1c, renal function, concomitant OADs. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

Linagliptin Significantly Reduced FPG After 24 Weeks and Maintained it in 28-Week Free

Insulin Titration Period

Week 24 Week 52

Change in FPG from baseline

Placebo-adjusted change with linagliptin:

-10.81 mg/dL

Placebo: -5.41 mg/dL

Linagliptin: -3.60 mg/dL

Stable insulin dosebaseline to week 24


Full analysis set (observed case set). Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

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 doseBaseline to week 24


Full analysis set, original analysis. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

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


Linagliptin, When Added to Insulin, and Its Association with 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;36:3875-3881.

Week 24 Week 52

Improved glycemic control with linagliptin added to insulindoes not appear to increase the risk of hypoglycemia

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


DocumentedSymptomatic(≤72 mg/dL)

DocumentedSymptomatic(<54 mg/dL)

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


Both Sitagliptin and Saxagliptin Produced Greatest Reductions in HbA1c in Patients

with High Baseline HbA1c

Pla

ceb

o-S

ub

trac

ted

Δ i

n H

bA

1c

(%)

fro

m B

asel

ine

to

We

ek 1

2

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

050 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 Sitagliptin-Treated Subgroup with Baseline HbA1c >9%with Baseline HbA1c >9%

Open-Label Saxagliptin in 66 PatientsOpen-Label Saxagliptin in 66 Patientswith Baseline HbA1c >10% to ≤12%with Baseline HbA1c >10% to ≤12%

Δ H

bA

1c

fro

m B

ase

lin

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W

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24 (

%) –0.8

–0.6

–0.4

–0.2

010 mg QD

–1.87

–1.0

–1.2

–1.4

–1.6

–1.8

–2.0

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

Exenatide qwk HbA1c Reduction Compared with Sitagliptin or Pioglitazone

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;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439.

8.6%8.5%

Diet and exercise background1 Metformin background2

8.5%Baseline : 8.5% 8.5%8.5%

Exenatide qwk(n = 248)


Fasting Plasma Glucose Improvement Was Greater with Exenatide qwk and Pioglitazone

LS Mean. ITT population.*P <.05 exenatide qwk vs sitagliptin.1. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439

Metformin background2Diet and exercise background1



GLP-1 Receptor Agonists and DPP-4 Inhibitors

Effects on Weight

Why Is Weight a Concern?

• Most patients with T2DM are overweight/obese• Some currently available therapies cause weight gain

– Secretagogues– Glitazones– Insulin

Klonoff DC, et al. Curr Med Res. 2008;24:275-286.

Exenatide Open-Label Extension Study Continuous Loss of Body Weight

Baseline 99.3 kg

Δ B

ody

Wei

ght f

rom

Bas

elin

e (k

g)

Δ B

ody

Wei

ght f

rom

Bas

elin

e to

W

eek

156

(kg)

Baseline BMI (kg/m2)

<30

Exenatide qwk Weight Reduction Compared with Sitagliptin or Pioglitazone

*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;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439.

Diet and exercise background1 Metformin background2

8987.5 88.7Baseline (kg) : 87 8886.1



Effect of Liraglutide vs Standard Therapy on Body Weight

*P = .0001 vs glimepiride; †P <.05 vs placebo; ‡P ≤.0001 vs placebo.Abbreviations: SU, sulfonylurea; TZD, thiazolidinedione. 1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Marre M, et al. Diabetic Med. 2009;26:268-278. 4. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 5. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

Weight Change from Baseline (kg)

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;97:258-266.

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 -0.96 kg with sitagliptin vs -3.38 kg with liraglutide 1.8 mg and -2.86 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;23:1329-1339. 2. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.

Effect of Alogliptin Monotherapy on Body Weight at 26 Weeks

DeFronzo RA, et al. Diabetes Care. 2008;31:2315-2317.

Effect of Linagliptin on Body Weight When Added to Insulin

Week 24 Week 52



Effects on Lipids

Exenatide Has Beneficial Effects on Lipids

Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

Mea

n Δ

fro

m B

asel

ine

(mg/

dL) Trigs TC

HDL-C

LDL-C

Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; Trigs, triglycerides.

Effect of Exenatide qwk and Exenatide BID on Lipids


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

Chiquette E, et al. Vasc Health Risk Manag. 2012;8:621-629.

Change from Baseline

*P <.05 from baseline.Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol.

Liraglutide Reduces Triglycerides and CVD Inflammatory Biomarkers

Difference from Placebo in Change from Baseline (%)

*P <.05.

1. Vilsbøll T, et al. Diabetes Care. 2007;30:1608-1610. 2. Courrèges JP, et al. Diabet Med. 2008;25:1129-1131.

Abbreviations: BNP, B-type natriuretic peptide; CVD, cardiovascular disease; hs-CRP, high-sensitivity C-reactive protein; PAI-1, plasminogen activator inhibitor 1.

Biomarkers of Cardiovascular Risk Were Reduced with Liraglutide vs SU

Abbreviations: BNP, B-type natriuretic peptide; FFA, free fatty acids.Kaku K, et al. J Diabetes Invest. 2011;2:441-447.

Treatment difference -0.065(95% CI -0.106 to -0.025)

Treatment difference -8.6(95% CI -13.6 to -3.6)

Sitagliptin Has Mixed Effects on Lipids

TC

Δ fr

om B

asel

ine

(mg/

dL; m

mol

/L fo

r F

FA

)

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

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;25:2401-2411.

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

GLP-1 Receptor Agonists and GLP-1 Receptor Agonists and DPP-4 InhibitorsDPP-4 Inhibitors

Effects on Blood Pressure and CVD

Exenatide Reduced Systolic Blood Pressurein Clinical Trials ≥6 Months’ Duration

• 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;23:334-339.

Pooled data from 6 trials of exenatide in T2DM; N = 2171

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

CV Events with Incretin-Based TherapiesMeta-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 8 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;10:22. 2. Marso SP, et al. Diab Vasc Dis Res. 2011;8:237-240. 3. Johansen OE, et al. Cardiovasc Diabetol. 2012;11:3. 4. Frederich R, et al. Postgrad Med. 2010;122:16-27. 5. Engel SS, et al. Cardiovasc Diabetol. 2013;12:3. 6. Monami M, et al. Diabetes Obes Metab. 2014;16:38-47. 7. Monami M, et al. Diabetes Obes Metab. 2013;15:112-120.

CV Outcomes Trials with Incretin-Based Therapies

Trial Name Comparators PopulationEstimated 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

Completed

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 T2DM with CV risk Jan 2018

CAROLINA8 Linagliptin vs glimepiride T2DM with CV risk Sep 2018

1. http://www.clinicaltrials.gov/ct2/show/NCT01107886. 2. http://www.clinicaltrials.gov/ct2/show/NCT00968708. 3. http://www.clinicaltrials.gov/ct2/show/NCT00790205. 4. http://www.clinicaltrials.gov/ct2/show/NCT01147250.5. http://www.clinicaltrials.gov/ct2/show/NCT01179048. 6. http://www.clinicaltrials.gov/ct2/show/NCT01144338. 7. http://www.clinicaltrials.gov/ct2/show/NCT01897532. 8. http://www.clinicaltrials.gov/ct2/show/NCT01243424.

Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease.

http://www.clinicaltrials.gov/ct2/show/NCT01107886




SAVOR Trial: Study Design

16,492 T2DM patients with established

CVD or multiple risk

factors

Saxagliptin 5 mg/d (2.5 mg/d if eGFR ≤50 mL/min)

Placebo

Randomized 1:1

Double-blind

Other therapy at the physician’s

discretion

Primary endpoint: composite endpoint of CV death, non-fatal MI, or non-fatal ischemic stroke

Scirica BM, et al. N Engl J Med. 2013 3;369:1317-1326.

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. 2013 3;369:1317-1326.

EXAMINE Trial: Study Design

5380 T2DM patients with recent ACS

Alogliptin (5 mg , 12.5 mg, or 6.25 mg once daily based

on renal function)

Placebo

Randomized 1:1

Double-blind

Primary endpoint: composite endpoint CV death, nonfatal Ml, or nonfatal stroke

Plus standard of care

White WB, et al. N Engl J Med. 2013;369:1327-1335.

EXAMINE Trial: Primary Endpoint

HR 0.96 (95% CI ≤1.16) P <.001 (noninferiority)P = .32 (superiority)

White WB, et al. N Engl J Med. 2013;369:1327-1335.

Placebo(n = 2679)

Study Design: SAVOR and EXAMINEStudy Design: SAVOR and EXAMINE

71

ClinicalTrials.gov. 2013. Accessed 12/31/13 at: http://www.clinicaltrials.gov.

Baseline Characteristics: SAVOR and Baseline Characteristics: SAVOR and EXAMINEEXAMINE

72

1. Scirica BM, et al. N Engl J Med. 2013 3;369:1317-1326.2. White WB, et al. N Engl J Med. 2013;369:1327-1335.

Saxagliptin (n = 8280)Mean age: 65 yMean HbA1c: 8.0%Mean BMI: 31.1 kg/m2

Median duration of diabetes: 10.3 y

Placebo (n = 8212)Mean age: 65 yMean HbA1c: 8.0%Mean BMI: 31.2 kg/m2


Alogliptin (n = 2701)Mean age: 61 yMean HbA1c: 8.0%Mean BMI: 28.7 kg/m2


Placebo (n = 2679)Mean age: 61 yMean HbA1c: 8.0%Mean BMI: 28.7 kg/m2


SAVOR Trial1

(N = 16,492)EXAMINE Trial2

(N = 5380)


Effects on the Renally Impaired

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 dosesSevere/ESRD: Not recommended

Exenatide qwk2

2 mg once weekly Moderate: Use with cautionSevere/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 dailySevere/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 dailySevere/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.

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.


Safety and Tolerability

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

Summary

GLP-1 Agonists and DPP-4 Inhibitors

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(weighted mean difference in change from baseline)

-2.37

(-3.95 to -0.78)

0.48

(0.30 to 0.66)

Incretin-Based Therapy in T2DMMeta-analysis

Amori RE, et al. JAMA. 2007;298:194-206. Slide courtesy of Dr. Jaime A. Davidson.

*The values in parentheses represent 95% CIs.†This value represents only exenatide vs placebo.

• 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

GLP-1 Receptor Agonists DPP-4 Inhibitors

HbA1c -1.10% to -1.59% -0.60% to -1.06%

FPG (mg/dL) -20.90 to -32.79 -13.15 to -28.29

Weight (kg) -2.03 to -2.41 -0.16 to -0.64

Incretin-Based Therapy in T2DMMeta-analysis

Aroda VR, et al. Clin Ther. 2012;34:1247-1258.e22.

Mean Change from Baseline

Summary: DPP-4 Inhibitors and GLP-1 Receptor Agonists

CharacteristicDPP-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 Yes

Gastrointestinal adverse events?1,2 No Yes

Improve postprandial glucose levels?1,2 Yes Yes*

Included in ADA/EASD algorithm?1 Yes Yes

Included in AACE algorithm?4 Yes Yes

*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;35:1364-1379. 2. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.3. Dicker D. Diabetes Care. 2011;34(suppl 2):S276-S278. 4. Garber AJ, et al. Endocr Pract. 2013;19:327-336.

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

Investigational Incretin-Based Therapies

• GLP-1 analogs– Albiglutide– Lixisenatide– Dulaglutide– Semaglutide

ClinicalTrials.gov. 2013. Accessed 12/11/13 at: http://www.clinicaltrials.gov.

• DPP-4 inhibitors– Vildagliptin (approved

in Europe and Latin America)

– Omarigliptin (MK-3102)

– Trelagliptin (SYR-472)

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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Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors

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