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
Major Therapeutic Targets in T2DM
Liver
Hepatic glucose
overproduction
Pancreas
Sulfonylureas
Meglitinides
Beta-cell
dysfunction
GLP-1 agonists
DPP-4 inhibitors
Muscle and fat
Metformin
Thiazolidinediones
GLP-1 agonists
DPP-4 inhibitors
Kidney
Glucose
reabsorption
Glucose level
Gut
Glucose
absorption
Insulin
resistance
Thiazolidinediones
Metformin
Alpha-glucosidase inhibitors
GLP-1 agonists
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;131:281-303. Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed.
WB Saunders; 2003:1427-1483.
Limitations of Older Agents for T2DM
Agent
Limitation
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, renalimpaired, 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
Individuals
Role of Incretins in Glucose
Homeostasis
Ingestion of food
GI tract
Glucose-dependent
Increased insulin
from beta cells
(GLP-1 and GIP)
Release of gut
hormones —
incretins
Pancreas
Active
GLP-1 and GIP
DPP-4
enzyme
Glucose-dependent
Decreased glucagon
from alpha cells
(GLP-1)
Inactive Inactive
GLP-1
GIP
Abbreviations: DPP-4, dipeptidyl peptidase-4; GIP, gastric inhibitory polypeptide;
GLP-1, glucagon-like peptide-1.
Increased
glucose
uptake by
muscles
Decreased
blood
glucose
Decreased
glucose
production
by liver
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.
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;3:153-165. 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.
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 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
and T2DM
GLP-1 AUC Incremental from
Basal (pmol/L• 240 min)
2500
2500
2000
2000
1927
1587
1587
1500
1500
P <.001 for T2DM vs NGT
907
1000
1000
500
500
00
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;86:3717-3723.
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
• 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
• Subcutaneous injection
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
Meal
Intestinal
GLP-1
release
Intestinal
GIP
release
Active
GIP
Active
GLP-1
DPP-4
inhibitor
DPP-4
Inactive
GLP-1
Incretin effects
– Augments glucose-dependent
insulin secretion
– Inhibits glucagon secretion
and hepatic glucose production
– Improves hyperglycemia
DPP-4
inhibitor
DPP-4
Inactive
GIP
Selective inhibition of DPP-4 increases plasma GLP-1
levels, resulting in reduction in glycemia
12
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;91:4612-4619.
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: -17.4 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.
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)*
•
*Decreased again after plasma glucose normalized.
Nauck MA, et al. Diabetologia. 1993;36:741-744.
•
•
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)
GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Effects on HbA1c, Glucose, and
Insulin Levels
Exenatide Has Beneficial Effects on
FPG and Insulin in T2DM
Abbreviation: FPG, fasting plasma glucose.
Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089.
Peak Mean Incremental
Serum Insulin (µU/mL)
Mean FPG (mg/dL)
N = 13
Exenatide Has Beneficial Effects on
Postprandial Glucose and Glucagon
in T2DM
Exenatide 0.1 μg/kg
Placebo
Postprandial
glucose, day 5
(mean)
Baseline
15.9 mg/dL
Baseline
170.3 mg/dL
180 min (nadir)
126.4 mg/dL
120 min (peak)
289.0 mg/dL
300 min
177.8 mg/dL
300 min
175.5 mg/dL
Postprandial
glucagon, day 5
(mean)
Baseline
98.9 pg/mL
Baseline
94.9 pg/mL
<5%–6%
change over
180 min
60 min
173.9 pg/mL
180 min
122.7 pg/mL
N = 24.
Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089.
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. 2008:24:275-286.
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
.0223
Δ PPG (mg/dL)
P Value for
Liraglutide vs
Glimepiride
P Value for
Liraglutide 1.8
vs 1.2 mg
Therapy
Glimepiride
-24.5
Liraglutide 1.2 mg
-30.8
.1616
Liraglutide 1.8 mg
-37.5
.0038
Abbreviations: FPG, fasting plasma glucose; PPG, postprandial glucose.
Garber A, et al. Lancet. 2009;373:473-481.
.1319
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
Liraglutide 1.2 mg (n = 251)
Δ HbA1c (%)
Glimepiride (n = 248)
P = .0014
P = .0046
P <.0001
Garber A, et al. Lancet. 2009;373:473-481.
Liraglutide 1.8 mg (n = 246)
Effects of Liraglutide and Glimepiride
Monotherapy on HbA1c Over 2 Years
HbA1c Change (%)
Disease duration:
0
≥3 y
<3 y
-0.4
-0.5
(n = 55)
Liraglutide 1.8 mg†
Glimepiride
-0.7
(n = 42)
-1
-1*
(n = 60)
-1.5
-1.4*
% achieving HbA1c <7%
• 58% with liraglutide*
• 37% with glimepiride
(n = 54)
*
P <.05 vs glimepiride; † 73% completed 2-year extension.
Garber AJ, et al. Diabetes. 2009;58(suppl 1):162-OR.
Weight change
• -2.7 kg with liraglutide*
• 1.1 kg with glimepiride
Effects of Exenatide qwk vs Exenatide BID
on Glycemic Control
Exenatide 10 mcg BID (n = 147)
Baseline HbA1c:
8.3%
8.3%
-0.5
-1
-1.5
-2
HbA1c < 7.0% (% of Patients)
FPG Change (mg/dL)
HbA1c Change (%)
0
-1.5
-1.9*
100
77*
80
61
0
-10
-20
-30
-25
-40
-50
-41*
Similar cumulative incidences of nausea
Exenatide BID, 35% of patients;
Exenatide qwk, 26% of patients
60
40
Similar weight loss
Approximately 4 kg in both groups
20
0
Approximately 90% of patients completed 30 weeks of treatment.
*
Exenatide 2.0 mg qwk (n = 148)
P <.05 vs exenatide BID.
Drucker DJ, et al. Lancet. 2008;372:1240-1250.
Similar rates of minor hypoglycemia
Exenatide BID, 6.1% of patients;
Exenatide qwk, 5.4% of patients
Exenatide qwk Delivered
Powerful HbA1c Reductions
Baseline HbA1c:
8.5%
Exenatide qwk (n = 129)
Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310.
8.4%
Exenatide BID (n = 123)
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
Open-label period2†
(N = 249)
Blinded period1*
(N = 326)
-0.5
-1.0
n = 130
-1.5
n = 119
-2.0
0
4
6
10
14
18
22
26 26
30
34
Time (wk)
Exenatide qwk
*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.
Sitagliptin
40
46
52
Exenatide qwk Percent to Goal
Compared to Sitagliptin or Pioglitazone
• Diet and exercise background
Exenatide qwk1
(n = 248)
Sitagliptin1
(n = 163)
Pioglitazone1
(n = 163)
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;35:252-258.
2. Bergenstal RM, et al. Lancet. 2010;376:431-439.
Overview of GLP-1 Receptor Agonist
Safety Data
Odds Ratio
(95% confidence interval)
P Value
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
Event
Hypoglycemia*†
• 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;160:909-917.
Current DPP-4 Inhibitors
Sitagliptin
Vildagliptin
(approved outside
United States)
Alogliptin
Linagliptin
Saxagliptin
Comparative Efficacies of DPP-4s
Placebo-corrected change from baseline in HbA1c - Monotherapy
Alogliptin1
12.5 mg
7.9%
25 mg
7.9%
Linagliptin2
5 mg
8.1%
5 mg
8.0%
Saxagliptin3
5 mg
7%-10%
5 mg
8.0%
Sitagliptin4
100 mg
100 mg
8.0%
8.0%
Vildagliptin5
50 mg BID 50 mg
8.6%
8.4%
-0.1
-0.2
-0.3
ΔHbA1c (%)
-0.4
-0.4
-0.5
-0.6
-0.7
-0.56
-0.5
-0.59
-0.6
-0.6
-0.6
-0.7
-0.8
-0.7
-0.8
-0.9
-1.0
-1.1
The current DPP-4s have comparative efficacy
-1.2
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.
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*
-0.6*
-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;31:2315-2317. 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.
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;36:3875-3881.
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.
Linagliptin Reduced HbA1c After 24 Weeks
(Primary Endpoint) and Maintained it in a 52Week 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;36:3875-3881.
Linagliptin Significantly Reduced FPG After
24 Weeks and Maintained it in 28-Week Free
Insulin Titration Period
Change in FPG
from baseline
Stable insulin dose
baseline to week 24
Free insulin dose
starting at week 24
Week 24
Week 52
Placebo-adjusted
change with linagliptin:
-10.81 mg/dL
Placebo: -5.41 mg/dL
Full analysis set (observed case set).
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
Linagliptin: -3.60 mg/dL
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
Full analysis set, original analysis.
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
Free insulin dose
starting at week 24
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
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;36:3875-3881.
Linagliptin Shows Rates of Hypoglycemia
Similar to Placebo
The Majority of Hypoglycemia is Nonsevere
Investigator-defined hypoglycemia AEs at week 24 by category
Placebo
All
Hypoglycemia
AEs
Documented
Symptomatic
(≤72 mg/dL)
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
Linagliptin
Documented
Symptomatic
(<54 mg/dL)
Severe
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
Sitagliptin-Treated Subgroup
with Baseline HbA1c >9%
50 mg QD
100 mg QD
0
Open-Label Saxagliptin in 66 Patients
with Baseline HbA1c >10% to ≤12%
10 mg QD
0
–0.2
–0.2
–0.4
–0.4
–0.6
–0.6
–0.8
–0.8
–1.0
–1.0
–1.2
–1.2
–1.15
–1.18
–1.4
–1.6
–1.8
–2.0
–1.87
Hanefeld M, et al. Curr Med Res Opin. 2007;23:1329-1339. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411
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;376:431-439. 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;32:8490. 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.
Exenatide qwk HbA1c Reduction
Compared with Sitagliptin or Pioglitazone
Diet and exercise background1
Baseline :
8.5%
Exenatide qwk
(n = 248)
8.5%
8.5%
Metformin background2
8.6%
8.5%
8.5%
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;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439.
Fasting Plasma Glucose Improvement Was
Greater with Exenatide qwk and Pioglitazone
Diet and exercise background1
Exenatide qwk
(n = 248)
Metformin background2
Exenatide qwk
(n = 160)
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
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
Exenatide Open-Label Extension Study
Continuous Loss of Body Weight
Baseline BMI (kg/m2)
Baseline 99.3 kg
Klonoff DC, et al. Curr Med Res. 2008;24:275-286.
Δ Body Weight from Baseline to
Week 156 (kg)
Δ Body Weight from Baseline (kg)
<30
Exenatide qwk Weight Reduction
Compared with Sitagliptin or Pioglitazone
Diet and exercise background1
Baseline (kg) :
87.5
Exenatide qwk
(n = 248)
88.7
86.1
Metformin background2
89
87
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;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439.
88
Effect of Liraglutide vs Standard
Therapy on Body Weight
Weight Change from Baseline (kg)
Liraglutide
1.2 mg
Liraglutide
1.8 mg
Comparator(s)
-2 to -3*
(approximate)
-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‡
Monotherapy1
-0.42 with placebo
1.6 with glargine
*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.
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
Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.
Week 52
GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Effects on Lipids
Mean Δ from Baseline (mg/dL)
Exenatide Has Beneficial Effects on
Lipids
Trigs
TC
LDL-C
HDL-C
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;24:275-286.
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*
-3.32
0.58
Non-HDL-C (mg/dL)
*P <.05 from baseline.
Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very lowdensity lipoprotein cholesterol.
Chiquette E, et al. Vasc Health Risk Manag. 2012;8:621-629.
Liraglutide Reduces Triglycerides and
CVD Inflammatory Biomarkers
Difference from Placebo in Change from Baseline (%)
Liraglutide
0.65 mg
Liraglutide
1.25 mg
Liraglutide
1.90 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;30:1608-1610. 2. Courrèges JP, et al. Diabet Med. 2008;25:1129-1131.
Biomarkers of Cardiovascular Risk
Were Reduced with Liraglutide vs SU
Treatment difference -8.6
(95% CI -13.6 to -3.6)
Treatment difference -0.065
(95% CI -0.106 to -0.025)
Abbreviations: BNP, B-type natriuretic peptide; FFA, free fatty acids.
Kaku K, et al. J Diabetes Invest. 2011;2:441-447.
Δ from Baseline (mg/dL; mmol/L for FFA)
Sitagliptin Has Mixed Effects on Lipids
Trigs
FFA
Placebo
Sit 25 mg qd
Sit 50 mg qd
Sit 100 mg qd
TC
LDL-C
HDL-C
Abbreviation: FFA, free fatty acids.
Hanefeld M, et al. Curr Res Med Opin. 2007;23:1329-1339.
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
DPP-4 Inhibitors
Effects on Blood Pressure and
CVD
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)
Exenatide
-2.2
Placebo
+0.6
Exenatide
-4.5
Insulin
-0.9
P
Value
.0002
<.0001
Mean Change in
Diastolic Blood
Pressure (mmHg)
-0.7
-0.2
-1.6
-0.8
P
Value
.21
.16
• 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.
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 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
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
Estimated Primary
Completion Date
Comparators
Population
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 preexisting 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
Linagliptin vs placebo
T2DM with CV risk
Jan 2018
Linagliptin vs glimepiride
T2DM with CV risk
Sep 2018
SAVOR-TIMI 531
CARMELINA7
CAROLINA8
Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease.
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.
SAVOR Trial: Study Design
16,492 T2DM
patients with
established
CVD or
multiple risk
factors
Randomized
1:1
Saxagliptin 5 mg/d (2.5 mg/d
if eGFR ≤50 mL/min)
Other therapy at
the physician’s
discretion
Double-blind
Placebo
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
Randomized
1:1
Alogliptin (5 mg , 12.5 mg,
or 6.25 mg once daily
based on renal function)
Plus standard
of care
Double-blind
Placebo
Primary endpoint: composite endpoint CV death,
nonfatal Ml, or nonfatal stroke
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)
Placebo
(n = 2679)
White WB, et al. N Engl J Med. 2013;369:1327-1335.
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
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. 2013. Accessed 12/31/13 at: http://www.clinicaltrials.gov.
71
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
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 = 8212)
Mean age: 65 y
Mean HbA1c: 8.0%
Mean BMI: 31.2 kg/m2
Median duration of diabetes: 10.3 y
Placebo (n = 2679)
Mean age: 61 y
Mean HbA1c: 8.0%
Mean BMI: 28.7 kg/m2
Median duration of diabetes: 7.3 y
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.
72
GLP-1 Receptor Agonists and
DPP-4 Inhibitors
Effects on the Renally Impaired
Dose Titration for Renally Impaired
Patients
Recommended Dose
Exenatide1
5 mcg twice daily; increase to 10 mcg
based on clinical response
Exenatide
qwk2
2 mg once weekly
Dose Adjustment for Renal Impairment
Moderate: Use with caution when initiating or
escalating doses
Severe/ESRD: Not recommended
Moderate: Use with caution
Severe/ESRD: Not recommended
Liraglutide3
0.6 mg once daily for 1 week, then 1.2 mg;
can be increased to 1.8 mg
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
Sitagliptin7
100 mg once daily
Vildagliptin8
50 mg twice daily as monotherapy; 50 mg
once daily in combination with SU
Use with caution; no dose adjustment
recommended for renal impairment
Moderate or severe/ESRD: 2.5 mg once daily
Moderate: 50 mg once daily
Severe/ESRD: 25 mg once daily
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
Nausea/
Vomiting
Diarrhea
Hypoglycemia
Pancreatitis
+
Rare
Exenatide1,2
++++
Liraglutide3
+++
+
+
Rare
Exenatide qwk4
++
+
+
Rare
Alogliptin5
+
Rare
Linagliptin6
+
Rare
Sitagliptin7,8
+
Rare
+
Rare
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;24:275-286. 2. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88: 30823089. 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.
Summary
GLP-1 Agonists and DPP-4
Inhibitors
Incretin-Based Therapy in T2DM
Meta-analysis
Achieved HbA1c <7%
(risk ratio)
HbA1c reduction
(weighted mean difference in
change in HbA1c percentage)
FPG level, mg/dL
(weighted mean difference in
change from baseline)
Weight, kg
(weighted mean difference in
change from baseline)
GLP-1 Analogs vs
Placebo*†
DPP-4 Inhibitors vs
Placebo*
4.19†
(3.17 to 5.53)
2.47
(2.14 to 2.84)
-0.97%
(-1.13% to -0.81%)
-0.74%
(-0.85% to -0.62%)
-27
(-33 to -21)
-18
(-22 to -14)
-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;298:194-206. Slide courtesy of Dr. Jaime A. Davidson.
Incretin-Based Therapy in T2DM
Meta-analysis
Mean Change from Baseline
GLP-1 Receptor Agonists
DPP-4 Inhibitors
-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
HbA1c
• 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;34:1247-1258.e22.
Summary:
DPP-4 Inhibitors and GLP-1 Receptor Agonists
DPP-4
Inhibitors
GLP-1
Receptor
Agonists
0.5%−1.0%
0.8%−1.9%
Orally
Injected
Neutral
Weight loss
Headache, infection
Nausea, vomiting
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
Characteristic
Expected HbA1c decrease1,2
How administered1
Weight effect1,2
Common adverse events1-3
Rare serious adverse events1-3
*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
• DPP-4 inhibitors
– Vildagliptin (approved
in Europe and Latin
America)
– Omarigliptin (MK3102)
– Trelagliptin (SYR-472)
ClinicalTrials.gov. 2013. Accessed 12/11/13 at: http://www.clinicaltrials.gov.
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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