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Transcript of 1 New therapies in diabetes mellitus (or how to keep your friendly diabetologist busy) Melissa...
1
New therapies in diabetes mellitus
(or how to keep your friendly diabetologist busy)
Melissa Meredith, M.D.Mar. 7, 2007
2
New Available Therapies
Incretin agents
Incretin agonists
– Exenatide (Byetta)
DPP-IV inhibitors
– Sitagliptin (Januvia)
– Vildagliptin (Galvus)
Insulin
Insulin detemir (Levemir)
Inhaled insulin- Exubera
Pramlintide (Amylin)
3
Patterns of Glucose, Insulin, and Glucagon in Type 2 Diabetes
400
Type 2 diabetes
Normal
0
120
240
360
-60 0 60 120 180 240 300
Delayed and reduced
Postprandial hyperglycemia
Minutes
300
200
100
Mitrakou A et al. Diabetes. 1990;39:1381-1390
pm
ol/
L m
g/d
L
Glucose
Insulin
-60 0 60 120 180 240 300
60
30
45
High and not suppressed
Minutes
fmo
l/L
Glucagon
4
Time, min
IR In
sulin
, mU
/L nm
ol/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 1200
The Incretin Effect in Subjects Without and With Type 2 Diabetes
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
Time, min
IR In
sulin
, mU
/L nm
ol / L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 120 0
Oral glucose load
Intravenous (IV) glucose infusion
Incretin Effect
The incretin effect is diminished
in type 2 diabetes.
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.Permission pending.
5
GLP-1 Effects in HumansUnderstanding the Natural Role of Incretins
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553Adapted from Drucker DJ. Diabetes. 1998;47:159-169
Stomach:Stomach: Helps regulate Helps regulate
gastric emptyinggastric emptying
Promotes satiety and Promotes satiety and reduces appetitereduces appetite
Liver:Liver: Glucagon reduces Glucagon reduces
hepatic glucose outputhepatic glucose outputBeta cells:Beta cells:Enhances glucose-Enhances glucose-
dependent insulin secretiondependent insulin secretionDecreased apoptosisDecreased apoptosisBeta cell regenerationBeta cell regeneration
Alpha cells:Alpha cells: PostprandialPostprandial
glucagon secretionglucagon secretion
GLP-1 secreted upon the ingestion of food
Beta-cellworkload
Beta-cellworkload
Beta-cellresponse
Beta-cellresponse
GLP-1 levels are decreased in DM 2
6
Glucose-Dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in Patients With Type 2 Diabetes
Glucose
Glucagon When glucose levels approach normal values, glucagon levels rebound.
When glucose levels approach normal values,insulin levels decrease.
*P <0.05Patients with type 2 diabetes (N=10)
mm
ol/
L
15.012.510.0
7.55.0
25020015010050
mg
/dL*
* * * * * *p
mo
l/L 250
200150100
50
40
30
20
10
0
mU
/L
* ** ** * * *
Infusion
Minutes
pm
ol/
L 20
15
10
5
0 60 120 180 240
* * * *
pm
ol/L
20
15
10
5
Placebo
GLP-1
Insulin
2.50
0
0 0
0
Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.Permission pending
–30
7
Effect of Exenatide on A1C
SFU
See Important Safety Information included in this presentationMean (SE); *P<0.005Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100Data from Buse JB, et al. Diabetes Care. 2004;27:2628-2635Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091
Placebo BID Exenatide 5 mcg BID Exenatide 10 mcg BID
MET + SFU
0.2
-0.6*
*-0.8
247 245 241
8.5 8.5 8.5
0.1
-0.5*
*-0.9
123 125 129
8.7 8.5 8.6
MET
-0.4*
- 0.8*-1
-0.5
0
0.5
Baseline
n 113 110 113
8.2 8.3 8.2
A1C (%) 0.1
8N = 283; Mean (± SE); P<0.05.Henry R, et al. Diabetes 2006; 55:A116.
Exenatide Sustained A1C Reduction2-Year Completers
0 10 20 30 40 50 60 70 80 90 100 1106.5
7.0
7.5
8.0
8.5
Time (wk)
Placebo-Controlled Open-Label Extensions
Baseline A1C8.3%
-1.1 0.1%
A
1C (
%)
9
No diet and exercise regimen was provided.N = 283; Mean (± SE); P<0.05.Henry R, et al. Diabetes 2006; 55:A116.
Exenatide Continued to Reduce Weight 2-Year Completers
0 10 20 30 40 50 60 70 80 90 100 110-7
-6
-5
-4
-3
-2
-1
0
1Placebo-Controlled Open-Label Extensions
Baseline Weight100 kg
-4.7 0.3 kg
Time (wk)
W
eig
ht
(kg
)
10
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal GIP and GLP-1 release
GIP and GLP-1 Actions
DPP-4Enzyme
GIP-(1–42)GLP-1(7–36)
Intact
GIP-(3–42)GLP-1(9–36)Metabolites
Rapid Inactivation
Half-life*GLP-1 ~ 2 minutes
GIP ~ 5 minutes
Deacon CF et al. Diabetes. 1995;44:1126–1131.*Meier JJ et al. Diabetes. 2004;53:654–662.
11
Mean Baseline: 8.0% P <0.001*
–0.8-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Ch
an
ge
in
A1
C,
%
†
‡
A1C
(95% CI: –1.0, –0.6)
A1C, FPG, and 2-Hour PPG Placebo-Adjusted Resultsin a 24-Week Study of Sitagliptin Phosphate(Januvia)
*Compared with placebo.†Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
‡Difference from placebo.
• Sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared with placebo.
• A1C lowering appears to be related to the degree of A1C baseline level.
Section
14.1
n=229
Mean Baseline: 170 mg/dL P <0.001*
–17
-25
-20
-15
-10
-5
0
Ch
ang
e in
FP
G, m
g/d
L
†
‡
FPG
(95% CI: –24, –10)
n=234
Mean Baseline: 257 mg/dL P<0.001*
–47-60
-50
-40
-30
-20
-10
0
Ch
ang
e in
2-h
r P
PG
, m
g/d
L
†
‡
2-hr PPG
(95% CI: –59, –34)
n=201
12
Pooled Analysis*
–1.4
–0.7–0.6
–0.7
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Reduction of A1C Overall and Stratified by Baseline A1C in aPrespecified Pooled Analysis of 2 Monotherapy Studies of sitagliptin
Reductions are placebo-subtracted. * P<0.001 overall and for treatment by subgroup interactions.+ Combined number of patients on sitagliptin or placebo
Inclusion Criteria: 7%–10%
Monotherapy Studies: Mean Response of A1c to Sitagliptin Appears to Be Related to the Degree of A1C Elevation at Baseline
Overall <8 ≥8–<9 ≥9
Baseline A1C
(%)
Ch
an
ge in
A1
C,
%
n=411+
n=239+
n=119+
n=769+
The magnitude of A1C lowering by strata varied by study.
Section
14.1
13
Comparison of incretin agents
Exenatide DPP-IV inhibitor
FDA indications Combo with SU, metformin or TZD
Mono; combo with metformin or TZD
Mode of administration
Injected BID Oral; once daily
Weight effects Average loss 10# Weight neutral
Side effects 30% nausea Virtually none
Renal insufficiency Not recommended Dose adjustment necessary
14
Summary- incretin agents
Incretin agonists and DPP-4 inhibitors appear to have similar ability to lower blood glucose and A1c
Both agents are most suitable for patients with diabetes for <10 years duration (need to be able to secrete adequate insulin)
Consider when patient has reasonable FPG, but post-prandial hyperglycemia
Both agents are costly ($130-179/month range)
ADA recommends metformin as first-line agent for virtually all patients with DM 2 (unless contraindicated or not tolerated) and these agents currently are best suited for second or third line therapy
.
15
Modification of isoelectric point - precipitation at pH 7.4
Insulin glargine
Strengthening of hexamer association, e.g., Co(III)-hexamer (substituting Zn ions with Cobalt at high
insulin concentration)
Acylation with hydrophobic residues, e.g.,
Insulin detemir
Strategies for engineering basal insulins
16
Insulin detemir: Mode of protraction
Self-association (hexameric)
Fatty acid side chains bind to albumin in injection depot
Albumin binding in circulation
Protracted absorption
‘Buffering’ effect and minor contribution to protraction
17
PD profiles in patients with type 1 DM
Plank et al. Diabetes Car.e. 2005;28(5):1107-12
GIR
(m
g/k
g/m
in)
Levemir 0.4 U/kgLevemir 0.2 U/kg
3.0
0
1.0
2.0
Time since Injection (hrs)0 4 8 12 16 20 24
4.0
5.0
6.0
Pharmacodynamic Parameters for LEVEMIR and NPH
LEVEMIR NPH
0.2 U/kg 0.4 U/kg 0.3 U/kg
AUCGIR (mg/kg) 419 1184 743
GIRmax (mg/kg/min) 1.1 1.7 1.6
NPH 0.3U/kg
GIR: Glucose infusion rate
18
PD profiles in patients with type 2 DM
0.4 U/kg 0.8 U/kgLevemir
glargine
0 2 4 6 8 10 12 14 16 18 20 22 240
0.5
1.0
1.5
2.0
2.5
3.0
Glu
cose
infu
sion r
ate
(mg/k
g/m
in)
Time (h)
Mean GIR profiles (smoothed with a local regression technique)for 0.4 and 0.8 U/kg Levemir and glargine*
*An additional dose of 1.4 U/kg was tested. No significant difference in pharmacodynamics was observed.
Klein et al. Diabetes. 2006;55(suppl 1):A76, 325-OR
19
Individual GIR profiles
GIR
(m
g/k
g/m
in)
GIR
(m
g/k
g/m
in)
GIR
(m
g/k
g/m
in)
6
0
3
6
0
3
8 16 240 8 16 240 8 16 240
8 16 240248 160
6
0
3
6
3
00 8 16 24
8 16 240248 160
6
0
3
6
3
00 8 16 24
Elapsed Time (hours)
Levemir
NPH-insulin
Insulin glargine
Heise et al. Diabetes. 2004;53:1614-1620
Each panel = 4 injections of the indicated formulation in an individual study subject.
20
Protracted time-action profile similar to insulin glargine
Comparable glycemic results as NPH insulin and insulin glargine
Lower risk of nocturnal hypoglycemia as compared with NPH-insulin
Less weight gain than NPH insulin and insulin glargine
Best results with BID (AM and HS)
Cost similar to glargine
Summary- insulin detemir
21
Pfizer / Aventis / Nektar Exubera® Pulmonary Insulin Delivery System
22
0
20
40
60
80
100
0 60 120 180 240 300 360 420 480 540 600
Me
an
Glu
cos
e In
fus
ion
Ra
te
(% o
f M
ax
imu
m)
Time (min)
INH 6 mgInsulin lispro 18 URegular insulin 18 U
INH Absorbed More Rapidly than SC Regular; as Rapidly as SC Lispro - Study 017
Diabetologia 2000;43(Suppl 1):A46.
23
Summary of INH therapy in Type 1DM
Similar level of glycemic control over 12-24 week time periods as SC NPH/regular insulin regimens
Short-term decreases in DLCO and increases in insulin antibody binding noted without apparent clinical consequences
Studies comparing to insulin analogs and real efficacy studies are on-going
Pts on INH therapy still require at least 1 SC injection/day of basal insulin
24
Summary of INH Therapy in DM2
Achieves similar glycemic control compared to SC NPH/regular insulin regimens over 12-24 weeks
Achieves better glycemic control than failing OHA regimens over 12-24 weeks
Patient satisfaction scores and quality of life scores higher with inhaled insulin
Patients report higher likelihood of using insulin if able to use inhaled insulin
25
Safety of inhaled insulin
Adverse events: increased cough; no increased SAEs or deaths
Hypoglycemia- similar rates of hypoglycemia (vs. Regular); no difference in severe hypoglycemia
Pulmonary safety• Small decreases in FEV1 and DLCO were observed• Changes were not progressive or apparently clinically
significant, but did resolve with discontinuation
Insulin antibodies• Increased production of IgG antibodies, esp in DM 1
(30%)• Clinical significance unknown
26
Using Exubera
Available in 1 mg (approx. 3 units) and 3 mg (approx. 8 units) blisters
Initial pre-meal dosing determined by weight
Take no more than 10 minutes before the meal
Take in one breath and hold for 5 seconds
Clean the inhaler weekly
Replace release unit every 2 weeks
Store insulin at room temperature
27
Using Exubera
Get baseline spirometry (FEV1) and recheck in 6 months and then yearly
Do not use in smokers (need to have quit for 6 months prior to using)
Not recommended for people with COPD or asthma
Probably safe to use with upper respiratory illness; unclear with pneumonia
28
Conclusions- inhaled insulin
Inhaled insulin generally well-tolerated and as efficacious as Regular insulin in controlling blood glucose
Best use will probably be in adding to oral agents in type 2 patients
Studies comparing to insulin analogs are underway
Need longer duration studies for safety
Cost is about 30% higher than current insulins
29
Pramlintide (Symlin)
Analog of a beta-cell protein named amylin (islet-associated polypeptide)
Physiologic actions• Delayed gastric emptying• Reduced post-prandial glucose excursion• Neuroendocrine effects on appetite and satiety
FDA approved for use in type 1 and type 2 diabetes who are not controlled on insulin therapy
Injected with each meal
Trend to weight loss (or no gain with improved A1c)
30
36
Effect of Pramlintide on PostprandialGlucose Excursions When Added to Regular
Insulin or Insulin Lispro
Type 1 Diabetes, Insulin Lispro Type 1 Diabetes, Regular Insulin
Inc
rem
en
tal
Pla
sm
a
Glu
co
se
(m
g/d
L)
-50
-25
0
25
50
75
100
0 30 60 90 120 150 180 210 240
Time Relative to Meal (min)
-30-50
-25
0
25
50
75
100
0 30 60 90 120 150 180 210 240
Time Relative to Meal (min)
Inc
rem
en
tal
Pla
sm
a
Glu
co
se
(m
g/d
L)
-30
Weyer C, et al. Diabetes Care 2003; 26:3074-3079
Mean ±SEInsulin Lispro (n=21)Regular Insulin (n=19)
Placebo (-15 min)60 µg Pramlintide (0 min)
Placebo (-15 min)60 µg Pramlintide (0 min)
Mixed Meal, Lispro Mixed Meal
Insulin
31
Change in A1C in Type 1 and Type 2 Pivotal Phase 3 Trials (ITT Population)
-0.8
-0.6
-0.4
-0.2
0
**
** **
* *
** **
A
1C
(%
)
Time (wk)
0 13 26 39 52
-0.6
-0.4
-0.2
0
Time (wk)
0 13 26 39 52
-0.8 **
Type 1 Type 2Placebo + Insulin
120 µg Pramlintide + InsulinPlacebo + Insulin
30 µg/60 µg Pramlintide + Insulin
Data from Whitehouse F, et al. Diabetes Care 2002; 25:724-730Data from Hollander PA, et al. Diabetes Care 2003; 26:784-790
Type1: Placebo (n=237), Pramlintide (n=243)Type 2: Placebo (n=161), Pramlintide (n=166)*P <0.05, **P <0.001; Mean ± SE (change from baseline)
A
1C
(%
)
32
Pramlintide (Symlin)
Is injected with each meal containing at least 30 gms of carbohydrate
Cannot mix with insulin
Should not be used in patients who are non-compliant, have an A1c>9.0%, gastroparesis, severe hypoglycemia, children
Start with low dose to minimize GI effects
Need to decrease bolus insulin dose
Strongly encourage using this medication with a diabetes educator who is experienced in insulin dose adjustment