Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 4 of 5
Jan 14, 2016
Pathophysiology in the Treatment of Type 2
Diabetes
Newer AgentsPart 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;61:1-183. Fehmann HC, et al. Peptides. 1994;15:453-456; 4. Thorens B, et al. Diabetes. 1993;42:1678-16825. 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)
Add on to: Duration
Exenatide10 μg bid
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
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.
-30 0 30 60 90 120 150 180100
150
200
250
300
Time (min)
Pla
sma
Glu
cose
(m
g/d
L)
Exenatide or PlaceboMeal
Difference From Placebo: -75 to -80 mg/dL *
Placebo Exenatide 5 µg BID Exenatide 10 µg BID
Δ F
PG
Fro
m B
asel
ine
(mg/
dL)
**
Difference From Placebo: -20 to -23 mg/dL *†
-20
-10
0
10
20
Exenatide 3-Year Completers: A1c and Weight
PBO-Controlled Open-Label Uncontrolled
N = 217; Mean (- SE); P < 0.0001 from baseline to 30 weeks and baseline to 3 years.No diet and exercise regimen was provided.
0 26 52 78 104 130 1564
5
6
7
8
9
10
Time (wk)
(Bas
elin
e A
1C
= 8
.2%
)
-1.0 ± 0.1%-1.1 ± 0.1%
% Achieving A1C ≤ 7%
A1C
(%
)
Klonoff DC, et al. Current Medical Research and Opinion. 2008;24:275–286.
-7
-6
-5
-4
-3
-2
-1
0
1
Ch
an
ge
in b
od
y w
eigh
t (kg)
(Bas
eline W
eigh
t = 9
9 kg
)
-5.3 ± 0.4 kg
A1CWeight
54 46
Changes in Glycemia and Weight in 3 Head-to-Head Studies Exenatide vs. Insulin
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.
EXENATIDEAND NO undue HYPOglycemia
Added by Dr S
Relative differences- sitagliptin vs exenatide
• ~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
Exenatide: Adverse Events
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)
Dore DD, et al. Curr Med Res Opin. 2009;25:1019-1027.
0.0 0.5 1.0 1.5 2.0 2.5
Relative Risk (95% confidence interval)
EXN (n = 27,996) vs
MET or GLY (n = 27,983)
SITA (n = 16,267) vs
MET or GLY (n = 16,281)
Pancreatitis Occurrence
0.13% of exenatide-treated patients
0.12% of sitagliptin-treated patients
Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1 Agonists: Similarities and Differences
Properties/Effect Exenatide1 DPP-4 Inhibitor1 Liraglutide, Exenatide-OW2,3
Glucose-dependent insulin secretion Yes Yes Yes
Glucose-dependent glucagon Yes Yes Yes
Slows gastric emptying Yes No Little or no
Effect on body weight Weight loss Weight neutral Weight loss
Effect on A1c ~1% <1% >1%
Effect on fasting glucose Modest Modest Good
Effect on postprandial glucose Good Modest Modest
Effect on CVD risk factors Improve (with weight loss)
No consistent change Improve
Side effects Nausea (?pancre-atitis, CRF)
~ None observed(pancreatitis)
Less nausea, skin, (?pancreatitis, ?
CRF, ?MTC)
Administration SubcutaneousTwice daily
OralOnce daily
SubcutaneousDaily 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.
Dr G – Needs to be redesigned/edited if kept