type 2 diabetes treatment: novel therapies glp-1 receptor agonists/analogs and dpp-4 inhibitors...
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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
Liraglutide 1.8 mg -25.6 .0001
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 1.2 mg -30.8 .1616
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
Free insulin dosestarting at 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
Free insulin dosestarting at 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
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
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
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
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
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
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
e to
W
eek
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)
Exenatide qwk(n = 160)
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
Exenatide qwk(n = 248)
Exenatide qwk(n = 160)
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
Exenatide qwk(n = 160)
Exenatide qwk(n = 248)
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
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
GLP-1 Receptor Agonists and DPP-4 Inhibitors
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 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
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.
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
Median duration of diabetes: 10.3 y
Alogliptin (n = 2701)Mean age: 61 yMean HbA1c: 8.0%Mean BMI: 28.7 kg/m2
Median duration of diabetes: 7.1 y
Placebo (n = 2679)Mean age: 61 yMean HbA1c: 8.0%Mean BMI: 28.7 kg/m2
Median duration of diabetes: 7.3 y
SAVOR Trial1
(N = 16,492)EXAMINE Trial2
(N = 5380)
GLP-1 Receptor Agonists and DPP-4 Inhibitors
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.
GLP-1 Receptor Agonists and DPP-4 Inhibitors
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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