Update on DPP-4 Inhibition in T2DM: Implications from Recent and Ongoing Trials Richard Pratley, M.D. Samuel Crockett Chair in Diabetes Research Director , Florida Hospital Diabetes Institute Senior Investigator, Translational Research Institute Adjunct Professor, Sanford Burnham Prebys Medical Discovery Institute Orlando, Florida
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Update on DPP-4 Inhibition in T2DM:
Implications from Recent and Ongoing Trials
Richard Pratley, M.D.
Samuel Crockett Chair in Diabetes Research
Director , Florida Hospital Diabetes Institute
Senior Investigator, Translational Research Institute
Adjunct Professor, Sanford Burnham Prebys Medical
Discovery Institute
Orlando, Florida
Disclosures
Advisory Board / Consultant: Boehringer-
Ingleheim, GSK, Lilly, Merck, Novo Nordisk,
Takeda
Research Support: Lilly, Merck, Novo Nordisk,
Sanofi, Takeda
All honoraria directed toward a non-profit
which supports education and research
Outline
Rationale for incretin therapy in T2DM
Pharmacology of DPP-4 inhibitors
Efficacy of DPP-4 inhibitors
DPP-4 inhibitor use in special populations
Elderly
CKD
Multiple Metabolic Defects Contribute to
Hyperglycemia in T2DM
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Islet a-cell
Increased
Glucagon Secretion
Increased Glucose
Reabsorption
Increased
HGP
DeFronzo, Diabetes. 2009
Islet b-cell
Impaired
Insulin Secretion
DecreasedIncretin Effect
IncreasedLipolysis
Nauck et al. Diabetologia. 1986;29:46-52.
The Incretin Effect Is Diminished
in Type 2 Diabetes
Normal Glucose Tolerance Type 2 Diabetes
(n=8) (n=14)
IV Glucose
Oral Glucose
0 60 120 180
240
Pla
sm
a G
luc
os
e (
mg
/dL
)
180
90
0
0 60 120 180
Pla
sm
a G
luc
os
e (
mg
/dL
) 240
180
90
0
**
* **
* * *
0 60 120 180
C-P
ep
tid
e (
nm
ol/L
)
Time (min)
30
20
10
00 60 120 180
C-p
ep
tid
e (
nm
ol/
L)
Time (min)
30
20
10
0
*P≤.05
GLP-1 and GIP Augment Insulin Secretion by
the b-Cell in a Glucose-Dependent Manner
Ca2+
KATP channel subunits:
SUR 1=regulatory subunit;
Kir 6.2=inward rectifying channel
Glucose entry
GLUT2
Glucokinase
ADP/ATP
Potassium (KATP)
channel closes
K+
Ca2+
Calcium channel
SUR 1
Glucose metabolism
ADP/ATP
K+Ca2+
Ca2+
Kir 6.2
Insulin secretory granules
opens
Ca2+
Insulin secretion
K+
ATP cAMP
ACG
GLP-1/GIP
PKA
EPAC
No Significant Reduction in GLP-1
Secretion in Patients with Type 2 Diabetes
*P<0.05 compared with control.
Nauck MA et al. Diabetologia. 2011;54:10-18.
Inte
gra
te G
LP
-1 (
% o
f C
on
tro
l)
Individual Studies of Patients with Type 2 Diabetes andWeight-Matched, Non-Diabetic Controls
Adapted from Vilsbøll T, et al. Diabetologia. 2002; 45: 1111–1119.
GLP-1 but not GIP Enhances Insulin
Secretion in Patients with T2DM
GLP-1
GIP
Saline
−15 −10 0 5 10 15 20 30 45 60 75 90 105 120 150
Hyperglycemic Clamp
Saline or GIP or GLP-1
Hyperglycemia Downregulates Incretin
Receptor Expression
Xu G, et al. Diabetes. 2007;56:1551-1558.
GIP
receptor
GLP-1
receptor
Sham Px Px + Phlorizin
A B C
FED
Insulin Response to Physiologic Levels of
GLP-1 Is Impaired in Type 2 Diabetes
1Modified from Højberg PV et al. Diabetologia. 2009;52:199-207.
Physiologic GLP-1 levels1
(0.5 pmol/kg/min)
Plasma GLP-1:46 pmol/LHealthy
Plasma GLP-1:41 pmol/LType 2 diabetes
0
0 30 60 90 120
Time (min)
1000
2000
3000
4000
5000
Ins
uli
n (
pm
ol/
L)
150
Pharmacologic GLP-1 levels2
(1.0 pmol/kg/min)
0
Time (min)
1000
2000
3000
4000
5000
Ins
uli
n (
pm
ol/
L)
0 30 60 90 120 150
Plasma GLP-1:126 pmol/LType 2 diabetes
2Modified from Vilsbøll T et al. Diabetologia. 2002;45:1111–1119.
*P<0.05.
GLP-1 = glucagon-like peptide–1.Adapted from Nauck et al. Diabetologia. 1993;36:741-44.
Glucose Dependent Effects of GLP-1 in T2DM
–30 0 30 60 90 120 150 180 210 240
Time (min)
0
5
10
15
20
25
30
**
* *
GLP-1 infusion
Glucagon (pmol/L)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
**
*
* **
**
–30 0 30 60 90 120 150 180 210 240
Time (min)
GLP-1 infusion
C-Peptide (nmol/L)
0
50
100
150
200
250
300
**
**
**
*
–30 0 30 60 90 120 150 180 210 240
Time (min)
GLP-1 infusion
Glucose (mg/dL)(n=10)
GLP-1 Saline
GLP-1 Addresses Multiple Metabolic
Defects in T2DM
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Islet a-cell
Increased
Glucagon Secretion
Increased Glucose
Reabsorption
Increased
HGP
DeFronzo. Diabetes. 2009
Islet b-cell
Impaired
Insulin Secretion
DecreasedIncretin Effect
IncreasedLipolysis
GLP-1
The Incretin Defect in T2DM
Substantial impairment – 40% of normal response
Not due to impaired secretion of GLP-1 or GIP
Absent insulinotropic response to GIP
Beta-cell GIP receptor down-regulation
Decreased response to GLP-1
Can be overcome by achieving higher than physiologic GLP-1 levels
GLP-1 infusions that achieve higher levels effective at enhancing insulin secretion and suppressing glucagon in a glucose-dependent manner
Nauck et al. Diabetologia. 1986;29:46–52. Laakso et al. Diabetologia. 2008;51:502-11. Nauck et al. Diabetologia. 2011;54:10-8.Højberg et al. Diabetologia. 2009;52:199-207. Vilsbøll et al. Diabetologia. 2002;45:1111–19. Nauck et al. Diabetologia. 1993;36:741–44.
Rationale for Using Incretin Therapies in the
Treatment of Type 2 Diabetes
● Incretins play a key and early role in
maintaining glucose homeostasis
● Incretin effects are diminished in patients with
type 2 diabetes
● Incretin-based therapies
Target multiple defects of type 2 diabetes, including
those not addressed by traditional medications
Do not cause hypoglycemia
Have favorable effects on weight
ADA/EASD Position Statement:
Managing Hyperglycemia in Type 2 Diabetes
Monotherapy
Efficacy ( A1C): HighHypoglycemia: Low risk
Lifestyle Changes
METFORMIN
2-drugcombinationsEfficacy ( A1C)
Hypoglycemia
Weight
Side effects
Costs
3-drugcombinations
More complexinsulin strategies Insulin
(multiple daily doses)
Weight: Neutral/loss Side effects: GI/lactic acidosisCosts: Low
Proceed after 3 mo. if needed Order does not indicate preference
METFORMIN +
Proceed after 3 mo. if needed Order does not indicate preference
METFORMIN +
SU +
TZD
DPP4-I
GLP-1-RA
Insulin
or
TZD +
SU
DPP4-I
GLP-1-RA
Insulin
or
DPP4-I +
SU
TZD
Insulinor
GLP-1-RA +
SU
TZD
Insulinor
Insulin +
TZD
DPP4-I
GLP-1-RA
or
SUHigh
Moderate risk
Gain
Hypoglycemia
Low
Proceed after 3-6 mo. if needed Insulin usually in combination with1-2 noninsulin agents
TZDHigh
Low risk
Gain
Edema, HF, Fx
High
DPP4-IIntermediate
Low risk
Neutral
Rare
High
GLP-1-RAHigh
Low risk
Loss
GI
High
Insulin
Highest
High risk
Gain
Hypoglycemia
Variable
Inzucchi et al. Diabetologia. doi: 10.1007/s00125-012-2534-0. Best of the Cardiometabolic Health Congress Regional Conference Series
Matikainen N, et al. Diabetologia 2006; 49: 2049-2057.
Before vilda, week 0 (n=13)
Vilda 50 mg twice daily,
week 4 (n=15)
0.8
0.6
0.4
0.2
0.0−1 0 1 2 3 4 5 6 7 8
Time (h)
0.08
0.06
0.04
0.02
0.00−1 0 1 2 3 4 5 6 7 8
Time (h)
0.50
0.40
0.30
0.20
0.10
0.00−1 0 1 2 3 4 5 6 7 8
Time (h)
4.0
3.5
3.0
2.5
2.0
1.5
1.0−1 0 1 2 3 4 5 6 7 8
Time (h)
Plasma TG Chylomicron TG
Chylomicron apo B-48 Chylomicron cholesterol
mm
ol/L
mm
ol/L
mm
ol/L
mg
/L
Outline
Rationale for incretin therapy in T2DM
Pharmacology of DPP-4 inhibitors
Efficacy of DPP-4 inhibitors
DPP-4 inhibitor use in special populations
Elderly
CKD
Efficacy of DPP-4 Inhibitor Therapy Added
to Metformin
26
1. Charbonnel. Diabetes Care. 2006;29:2638-43. 2. Raz et al. Curr Med Res Opin. 2008;24:537-50.3. Scott et al. Diabetes Obes Metab. 2008;10:959-69. 4. DeFronzo et al. Diabetes Care. 2009;32:1649-55.5. Taskinen et al. Diabetes Obes Metab. 2011;13:65-74. 6. Nauck et al. Int J Clin Pract. 2009;63:46-55.
a ALO: 26-wk trial, BL A1C 9.3%, 55 units insulin median TDD at BL.b LINA: 24-wk trial, BL A1C 8.3%. 40-42 units insulin mean TDD at BL.c SAXA: 24-wk trial, BL A1C 8.7%, 53-55 units insulin mean TDD at BL. intermediate, long-acting, or premixed INS only.d SITA: 24-wk trial, BL A1C 8.6-8.7%. 42-45 units insulin median TDD at BL, intermediate, long-acting, or premixed INS only. 1. Drugs@FDA.
1. Del Prato S, et al. Study 305 2-year data. Poster presented at ADA 2013. 2. Seck T, et al. Int J Clin Pract 2010;64:562–576. 3. Göke B, et al. Int J Clin Pract
2013;67:307–316. 4. Gallwitz B, et al. Lancet 2012;380:475–483
Long-term Studies of DPP-4 Inhibitors
vs. Sulfonylureas
Alogliptin + metformin vs glipizide1
104 weeks (PPS)
Sitagliptin + metformin vs glipizide2
104 weeks (PPS)
Saxagliptin + metformin vs glipizide3
52-week extension of 52-week study (FAS)
Linagliptin + metformin vs glimepiride4
104 weeks (PPS)
1. Del Prato S, et al. Study 305 2-year data. Poster presented at ADA 2013. 2. Seck T, et al. Int J Clin Pract 2010;64:562–576. 3. Göke B, et al. Int
Hypoglycemia is an important limiting factor in glycemic management.
It may be a significant barrier in terms of treatment adherence and achievement of a lifelong goal of attaining normal glycemic levels.
Fear of hypoglycemia is an additional barrier to control.
A study in patients with type 2 diabetes showed increased fear of hypoglycemia as the number of mild/moderate and severe hypoglycemic events increased.
Amiel SA et al. Diabet Med. 2008;25(3):245–254.
1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267. 2. Gomis R, et al. Diabetes Obes Metab. 2011;Mar 15. Epub ahead of
print. 3. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 4. Owens DR, et al. Diabetes. 2010;59(suppl 2): Abstr. 548-P.
Hypoglycemia With Linagliptin:
Mono and Combination Therapy
0,6 02,3
14,8
0,3 1,2 0,4
22,7
0
5
10
15
20
25
Monotherapy
24 Weeks1
Initial Combo
w/ Pioglitazone
24 Weeks2
Add-on to Metformin
24 Weeks3
Add-on to Metformin
+ SU
24 Weeks4
N 503 389 700 1055
Treatment PBO Lin Pio Lin +
Pio
Met Lin +
Met
Met + SU Lin +
Met + SU
Patients
Report
ing
Hypogly
cem
ia (
%)
Canadian Journal of Diabetes 2016 40, 50-57DOI: (10.1016/j.jcjd.2015.06.010)
Hypoglycemia in Patients with T2DM on Basal
Insulin Treated With Linagliptin vs. Placebo
Common – 40% of all patients with diabetes
Optimal glycemic targets unknown
Optimal therapeutic approaches unknown
Clinical heterogeneous population
Variable life expectancies
Variable comorbidities and functional status
Polypharmacy and geriatric syndromes
Lack of Grade A evidence
Exclusion from large RCTs
Individualize Goals for DM management
The Problem of Diabetes in Older Adults
-0,8
-0,6
-0,4
-0,2
0,0
0,2
Baseline Week 6 Week 12 Week 18 Week 24
Linagliptin Reduced A1C vs Placebo at 24
Weeks in Patients Aged ≥70 Years
1. Boehringer Ingelheim. Data on file. 2. Barnett AH, et al. Lancet. 2013;382:1413-1423.
*P<0.0001. †Placebo corrected.
Baseline A1C: 7.8% for linagliptin-treated group and 7.7% for placebo group; full analysis set; last observation carried forward.
Placebo (n=78) Linagliptin 5 mg (n=160)
Clinical experience with TRADJENTA has not identified differences in response between the elderly and younger patients;
however, greater sensitivity of some older individuals cannot be ruled out.
SE=standard error.
Difference
-0.6%*
0.04
-0.6
Primary Endpoint: Placebo-Adjusted Mean Difference in
1. Linagliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf
2. Sitagliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021995s007lbl.pdf
3. Saxagliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022350lbl.pdf.
4. Alogliptin full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022271s000lbl.pdf
Linagliptin Lowers HbA1c Over 52 weeks in
Patients with Renal Impairment
Janet B McGill et al. Diabetes and Vascular Disease Research 2015;12:249-257
Mild RI Moderate RI
Severe RI
Incidence of Renal Adverse Events in T2DM
Patients Treated with Linagliptin vs. Control
Janet B McGill et al. Diabetes and Vascular Disease Research 2015;12:249-257
Safety of Linagliptin in T2DM Patients
with CKD
Janet B McGill et al. Diabetes and Vascular Disease Research 2015;12:249-257
Pancreatitis Risk With DPP-4 Inhibitors
The available evidence suggests that incretin-based therapies do
not themselves increase the risk of pancreatitis in patients with
T2DM1
But other factors may increase the risk of pancreatitis with use of
DPP-4 inhibitors2:
Obesity
Hypertriglyceridemia
Gallstones
Biliary/pancreatic cancer, or neoplasm
Alcohol and/or tobacco use
Current prescribing recommendations3
Educate patients—ask about pancreatitis history/risk factors
Monitor for pancreatitis signs and symptoms—discontinue promptly if they occur
1. Li L, et al. BMJ. 2014;348:g2366.2. Singh S, et al. JAMA Intern Med. 2013;173:534-539.3. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/ cder/DrugsatFDA.
Oral therapy, once daily
Endogenous GLP-1 and GIP levels are increased in response to meals and are transient
Clinically significant A1c reductions
Comparable efficacy to SUs
Complementary mechanism of action with many drugs
Don’t use with GLP-1 receptor agonists
Very well tolerated
No GI sx, no weight gain, low hypoglycemia, no edema