Transcript Diabetes Update

60
50
HbA 1c <7% (%)
Proportion of Patients With
Attaining Glycemic Goals in Type 2 Diabetes:
Diet & Exercise
40
30
20
10
0
3 Years
Turner RC et al. JAMA. 1999;281:2005-2012.
6 Years
9 Years
Treatment of Type 2 Diabetes
-glucosidase inhibitors
Thiazolidinediones
Intestine: glucose absorption
Muscle and adipose tissue:
glucose uptake
Blood glucose
GLP-1 analogs
DPP4 inhibitors
Biguanides
Liver: hepatic glucose production
Sulfonylureas
Meglitinides
Pancreas: insulin secretion
Biguanides:
Basic Characteristics of Metformin (Glucophage, Glucomin)
Mechanism of action
Depends upon
Power
Dosing
Side effects
Main risk
Decreases hepatic glucose
production
Presence of insulin
Decreases HbA1c 1% to 2%
One to three times daily
Diarrhea, nausea
Lactic acidosis
Insulin Secretagogues:
Basic Characteristics of Sulfonylureas and Meglitinides
Mechanism of action
Depends upon
Power
Dosing
Side effects
Main risk
Increase basal and postprandial
insulin secretion
Functioning -cells
Decreases HbA1c 1% to 2%
Once or twice daily (sulfonylureas);
three times daily (meglitinides)
Weight gain
Hypoglycemia
4-18
Mechanism of Sulfonylurea Induced
Insulin Secretion
Ca++
K+
Depolarization
Sulfonylureas
ATP/ADP
Carbachol
IP3
Krebs
Ca++
DAG
PKA
Glucose-6-P
Glucose
GLUT 2
GK
(sensor)
cAMP
PKC
Glucose
+
Glucagon
GLP-1
AC
-
Somatostatin
Catecholamines
INSULIN &
C-PEPTIDE
Thiazolidinedione Chemical Structures
O
CH3
N
N
N
O
S
Rosiglitazone (Avandia)
O
O
CH3
N
H3C
O
CH3
O
S
Troglitazone
O
HO
CH3
O
Et
N
N
O
S
O
Pioglitazone
Activation of PPARgamma Alters Expression of Specific
Genes
RSG
retinoic
PPARg
RXR
Regulates gene
transcription
AGGTCA X AGGTCA
PPRE (DR-1)
Gene encoding
GLUT-4, lipoprotein lipase,
PEPCK,
aP2 etc.
Sites of action of Glitazones
Carbohydrates
Gut
Digestive
enzymes
Pancreas
Blood
glucose
Insulin
Glitazones reduces
insulin resistance in
the liver, muscle and
adipose tissue
Adipose
tissue
Muscle
Liver
Oakes ND, et al. Diabetes 1994; 43:1203–1210.
Young PW, et al. Diabetes 1995; 44:1087–1092.
Rosilitazone Increases Islet Area and Density in Pancreatic Islets
of db/db Mice
Control
Rosiglitazone
Scale 100 mm (enlarged view)
Pancreatic sections were immunohistochemically stained for insulin
Lister et al, Diabetologia 1998; 41 (Supplement 1):A660.
Thiazolidinediones (Glitazones):
Basic Characteristics
Mechanism of action
Depends upon
Power
Dosing
Side effects
Main risk
Enhances muscle and adipose
tissue response to insulin
Presence of insulin and resistance
to its action
Decreases HbA1c 0.5% to 1.3%
Once or twice daily
Edema, weight gain, anemia
Liver failure (only troglitazone?)
Data from Henry. Endocrinol Metab Clin. 1997;26:553-573; Gitlin, et al. Ann Intern Med. 1998;129:36-38; Neuschwander-Tetri, et al.
Ann Intern Med. 1998;129:38-41; Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association;
1998:1-139; Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176.
Glucose Dependent Actions of GLP-1
in Patients With Type 2 Diabetes
Glucose (mmol/L)
Insulin (pmol/L)
Glucagon (pmol/L)
17.5
350
25
GLP-1/PBO infusion
15.0
300
12.5
250
10.0
7.5
*
*
*
*
*
5.0
*
*
2.5
0.0
-30 0
15
150
10
100
120
180
240
Time (min)
Data are mean ± SE.
* P <0.05
Nauck MA, et al. Diabetologia 1993; 36:741-744
0
-30 0
GLP-1/PBO infusion
20
200
50
60
GLP-1/PBO infusion
*
*
*
*
*
*
*
*
*
*
*
5
*
0
60
120
Time (min)
180
240
-30 0
60
120
Time (min)
Placebo
GLP-1
180
240
Rationale for incretin-based therapy of diabetes
"...‫ גילה‬-‫"הבה נ‬
GLP-1 analog
‫לטאת גילה‬
Gila Monster
Eng J, et al. J Biol Chem 1992; 267:7402-7405
Chen YQE and Drucker DJ, J Biol Chem 1997; 272: 4108-4115
Exendin-4
(Exenatide)
Exenatide + Met Study: Effect on A1C
Met + Placebo
Met + 5 µg exenatide
Met + 10 µg exenatide
Mean (±SE) A1C (%)
9.0
8.5
+0.1%
8.0
-0.4%*
7.5
*
-0.8%
7.0
6.5
Placebo
Lead-in
Screen
0
5
10
15
20
25
Time (wk)
ITT, N = 336 (Placebo, n = 113; 5 µg exenatide, n = 110;
10 µg exenatide, n = 113)
* P <0.0005 reductions from baseline (pairwise comparison to placebo) in both exenatide arms for Weeks 6 to 30
DeFronzo R, et al. ADA 64th Annual Scientific Sessions, June 2004
30
Dipeptidyl Peptidase 4 (DPP-4)
C
Cell membrane
Cytosol
• DPP-4 is a serine protease of the prolyl oligopeptidase enzyme family
that exists in two forms
– Membrane-bound (widely expressed)
– Soluble
Adapted from Evans DM IDrugs 2002;5:577–585; Drucker DJ Expert Opin Investig Drugs 2003;12:87–100; Rasmussen HB et al Nat Struct Biol 2003;10:19–25.
DPP-4 inhibition Increases Active
Incretin Level
Incretin
release
GLP-1 (9-36)
GIP (3-42)
DPP-4
DPP -4
Inhibitor
X
↑GLP-1 (7-36)
↑GIP (1-42)
Adapted from Deacon CF et al Diabetes 1995;44:1126–1131; Ahrén B Curr Diab Rep 2003;3:365–372;
24-week, Monotherapy, Placebo-controlled Study
Proportion of Patients
Achieving HbA1c <7.0% at Week 24
Patients (% to goal)
60
P<0.001
50
40
30
20
10
0
Placebo (n=244)
Mean baseline values: sitagliptin, 8.01%; placebo, 8.03%
All-patients-as-treated population
Adapted from Aschner et al. Diabetes Care. 2006;29:2632–2637.
Sitagliptin 100 mg/day
(n=229)
The miracle of insulin
Patient J.L., 15 December, 1922
15 February, 1923
1923: Nobel Prize to Banting and Macleod
FG Banting
JJR Macleod
CH Best
JB Collip
Pharmacodynamics of Human Insulins
Insulin
Preparation
Regular
NPH/Lente
Onset
Peak
Duration
30-60 min
2-4 h
6-10 h
1-2 h
4-8 h
10-20 h
NB: Time-course of action of any insulin may greatly vary between individuals,
or at different times in the same individual
6-22
INSULIN TACTICS
Once-daily Mixed Insulin
Insulin Effect
Regular
NPH
B
L
S
HS
B
6-23
INSULIN TACTICS
Twice-daily Mixed Insulin
Insulin Effect
Regular
NPH
B
L
S
HS
B
6-23
INSULIN THERAPY
The Basal/Bolus Insulin Concept
• Basal Insulin
– Suppresses glucose production between meals and overnight
– ~50% of daily needs
• Bolus Insulin (Mealtime or Prandial)
– Limits hyperglycemia after meals
– 10% to 20% of total daily insulin requirement at each meal
6-20
INSULIN TACTICS
Multiple Daily Injections
NPH + Regular
Insulin Effect
Regular
NPH
B
L
S
HS
B
6-24
INSULIN TACTICS
Chronic Multiple Daily Injections
Bedtime NPH + Mealtime Regular
Insulin
8 weeks
Non-DM
Serum Insulin R
R
R
N
pmol/L
300
200
100
0
0800
1200
1600
2000
2400
0400
0800
Time of Day
Lindström, et al. Diabetes Care. 1992;15:27-34.
6-50
Rapidly Acting Insulin Analogues
INSULIN TACTICS
400
Lispro
350
300
250
200
150
100
50
0
Regular
Human
0
30
Meal
SC injection
60
90 120 150 180 210 240
Time (min)
Plasma Insulin (pmol/L)
Plasma Insulin (pmol/L)
Shorter-acting Insulin Analogues:
Lispro & Aspart
500
450
400
350
300
250
200
150
100
50
0
Aspart
Regular
Human
0
50
100
150
200
Time (min)
250
300
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.
6-28
INSULIN TACTICS
Insulin Glargine:
A New Long-acting Insulin Analogue
• Modifications to human insulin chain
– Substitution of glycine at position A21
– Addition of 2 arginines at position B30
• Gradual release from injection site
• Peakless, long-lasting insulin profile
Gly
1
5
10
15
20 Asp Substitution
1
5
10
15
20
25
30
Extension
Arg Arg
6-33
INSULIN TACTICS
Glargine vs NPH Insulin in Type 1 Diabetes
Action Profiles by Glucose Clamp
Glucose Utilization Rate
(mg/kg/h)
6
5
4
NPH
3
2
Glargine
1
0
0
10
20
Time (h) After SC Injection
30
End of observation period
Lepore, et al. Diabetes. 1999;48(suppl 1):A97.
6-34
Structure of Insulin Detemir
GIR (mg/kg/min)
Pharmacodynamic action profiles for insulin detemir and NPH insulin
in subjects with
type 1 diabetes
Insulin detemir
Insulin detemir
Insulin detemir
NPH insulin 0.3
2.0
1.5
1.0
0.5
0
0
4
8
12
16
Time since insulin injection (hours)
J Plank et al. Diabetes Care 2005;28(5):1107-12
20
24
0.1 U/kg
0.2 U/kg
0.4 U/kg
IU/kg
Intention to Treat — Initiating Insulin and the 4-T Study
Graham T. McMahon, M.D., M.M.Sc., and Robert G. Dluhy, M.D.
editorial , New England journal of med., 10.1056/nejme078196
Pharmacodynamics of Native & Engineered
Human Insulin Preparations
Insulin
Preparation
Onset
Peak
Duration
Lispro/Aspart
5-15 min
1-2 h
4-6 h
Human
Regular
30-60 min
2-4 h
6-10 h
Human
NPH/Lente
1-2 h
4-8 h
10-20 h
Glargine
1-2 h
Flat
~24 h
NB: Time-course of action of any insulin may greatly vary between individuals,
or at different times in the same individual
6-22
INSULIN TACTICS
Glargine at HS + Short Acting Analogs
Insulin Effect
Immediate acting analogs
Glargine
B
L
S
HS
B
Insulin Pump
Patients reaching intensive-treatment
goals at mean 7.8 year (%)
Intensive therapy; n = 67
Conventional therapy; n = 63
P = 0.06
P < 0.001
P = 0.19
P = 0.001
P = 0.21
HbA1c
< 6.5%
Cholesterol
< 175 mg/dl
(4.5 mmol/l)
Triglycerides
< 150 mg/dl
(1.7 mmol/l)
Systolic BP
< 130 mmHg
Diastolic BP
< 80 mmHg
90
80
70
60
50
40
30
20
10
0
Multifactorial Intervention and Cardiovascular
Disease in Patients with Type 2 Diabetes
N Engl J Med 348:383-93, 2003
Islet Transplantation in Type 1 Diabetes
Robertson RP, N Engl J Med, 2004