Transcript Pathophysiology in the Treatment of Type 2

Pathophysiology in the
Treatment of Type 2
Diabetes
Newer Agents
Part 4 of 5
Exenatide
– Exendin-4, isolated from Gila monster saliva, shares
53% of its amino acid identity with GLP-11
• Exenatide is a synthetic version of exendin-41
– In in vitro assays, exendin-4 and GLP-1 have
equivalent binding affinities for the GLP-1 receptor2-4
– In in vitro studies, the degree of GLP-1 receptor
activation by exenatide is at least equivalent to that
of native GLP-15,6
1. Nielsen LL, et al. Regul Pept. 2004;117:77-88; 2. Raufman JP. Regul Pept. 1996;61:1-18
3. Fehmann HC, et al. Peptides. 1994;15:453-456; 4. Thorens B, et al. Diabetes. 1993;42:1678-1682
5. Parkes D, et al. Drug Dev Res. 2001;53:260-267; 6. Göke R, et al. J Biol Chem. 1993;268:19650-19655
Exenatide
– Mono or Adjunctive therapy, depended on patient’s needs
or desires (not approved for combination with insulin)
– BID subcutaneous
– Start 5 mcg injected 0-60 minutes before am and pm meal for 1
month (decreased risk nausea if take with first bite)
– Or, dose with two largest meals*
– Decrease nausea risk by advising patient to stop eating when full
– Increase to 10 mcg as needed, and then tolerated
with first bite
• Don’t use if creatinine clearance < 30 ml/min
• Don’t use in gastroparesis or GI motility disorders
Exenatide: Change in A1c and
Weight
(vs Placebo)
Exenatide
10 μg bid
Add on to:
Duration
A1C
Change in
% (baseline)
Weight
change in
kg
(baseline)
Monotherapy
24 weeks
-0.7 (7.8)
-1.5 (86.2)
Metformin
30 weeks
-0.9 (8.2)
-2.4 (100.9)
Sulfonylurea
30 weeks
-1.0 (8.6)
-0.9 (95.2)
Metformin + sulfonylurea
30 weeks
-1.0 (8.5)
-0.7 (98.4)
Glitazone ± metformin
16 weeks
-0.9 (7.9)
-1.5 (97.5)
Exenatide prescribing information. Amylin Pharmaceuticals Inc; 2009.
Exenatide Lowered PPG and FPG
Concentrations in Large Phase 3 Clinical
Studies: Combined Data
Placebo
250
200
150
Difference From Placebo:
-75 to -80 mg/dL *
100
-30
0
30
60
90 120 150 180
Exenatide 10 µg BID
20
Exenatide or Placebo
Meal
Δ FPG From Baseline
(mg/dL)
Plasma Glucose (mg/dL)
300
Exenatide 5 µg BID
10
0
-10
-20
*
Difference From Placebo:
†
-20 to -23 mg/dL *
*
Time (min)
30-wk pivotal studies; Patients with T2D; Evaluable standard meal tolerance test cohorts; Placebo, n = 44 Exenatide 5 µg BID, n =
42; Exenatide 10 µg BID, n = 52; Mean ± SE; * Least squares (LS) mean difference at Wk 30, P<0.0001;
ITT population; Placebo, n = 483; Exenatide 5 µg, n = 480; Exenatide 10 µg, n = 483; Mean ± SE; *P<0.0001 vs placebo; † LS mean
difference at Wk 30. Data on file, Amylin Pharmaceuticals, Inc.
Exenatide 3-Year Completers:
A1c and Weight
PBO-Controlled
1
9
0
-1
-1.1 ±0.1%
A1C (%)
8
-1.0 ±0.1%
-2
-3
7
-4
6
-5.3 ±0.4 kg
5
-5
(Baseline Weight = 99 kg)
A1C
Weight
Change in body weight (kg)
(Baseline A1C = 8.2%)
10
Open-Label Uncontrolled
-6
54
4
0
26
46
% Achieving A1C ≤ 7%
52
78
104
130
156 Time (wk)
N = 217; Mean (- SE); P < 0.0001 from baseline to 30 weeks and baseline to 3 years.
No diet and exercise regimen was provided.
Klonoff DC, et al. Current Medical Research and Opinion. 2008;24:275–286.
-7
Changes in Glycemia and Weight in
3 Head-to-Head Studies Exenatide vs. Insulin
Added by Dr S
EXENATIDE
AND NO undue HYPOglycemia
Heine R, et al. Ann Int Med. 2005;143:559-569.
Barnett A, et al. Clin Thera. 2007;29(11):2333-2348.
Nauck M, et al. Diabetologia. 2007;50(2):259-267.
Relative differencessitagliptin vs exenatide
Exenatide: Adverse Events
• ~50% experience nausea or other GI events
– Early in course, decrease over time
– ~5% stop therapy due to nausea or vomiting
– To minimized –
• Start low dose bid for 4 weeks, then titrate to 10 μg bid
• administer exenatide just before meals until well tolerated
• SU-related hypoglycemia can be increased
–  SU dose when initiating therapy with exenatide
• Antibodies of unclear significance
• Pancreatitis – rare
• Renal failure – rare
Pancreatitis With Exenatide and Sitagliptin: Large
Database Analysis
• Analysis of data from large US commercial health insurance
database
• Active drug safety surveillance system
• June 2005 through June 2008
• No increased risk for patients treated with exenatide or sitagliptin
compared with metformin (MET) or glyburide (GLY)
Pancreatitis Occurrence
0.13% of exenatide-treated patients
EXN (n = 27,996) vs
0.12% of sitagliptin-treated patients
MET or GLY (n = 27,983)
SITA (n = 16,267) vs
MET or GLY (n = 16,281)
0.0
0.5
1.0
1.5
2.0
Relative Risk (95% confidence interval)
Dore DD, et al. Curr Med Res Opin. 2009;25:1019-1027.
2.5
Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1
Agonists: Similarities and Differences
Dr G – Needs to be redesigned/edited if kept
Properties/Effect
Glucose-dependent
secretion
insulin
Glucose-dependent
glucagon
Slows gastric emptying
Effect on body weight
Effect on A1c
Effect on fasting glucose
Effect on postprandial glucose
Effect on CVD risk factors
Side effects
Administration
Exenatide1
DPP-4 Inhibitor1
Liraglutide,
Exenatide-OW2,3
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Little or no
Weight loss
Weight neutral
Weight loss
~1%
<1%
>1%
Modest
Modest
Good
Good
Improve
(with weight loss)
Modest
No consistent
change
Modest
Nausea (?pancreatitis, CRF)
~ None observed
(pancreatitis)
Less nausea, skin,
(?pancreatitis,
?CRF, ?MTC)
Subcutaneous
Twice daily
Oral
Once daily
Subcutaneous
Daily or weekly
1. Amori RE, et al. JAMA. 2007;298:194-206.
2. Exenatide LAR (once weekly): Drucker DJ, et al. Lancet. 2008;372:1240-1250.
3. Liraglutide: Buse JB, et al. Lancet. 2009;374:39-47.
Improve