attaining glycemic goals in type 2 diabetes: diet & exercise
DESCRIPTION
Attaining Glycemic Goals in Type 2 Diabetes: Diet & Exercise. 6. 0. 5. 0. 4. 0.TRANSCRIPT
Attaining Glycemic Goals in Type 2 Diabetes:Diet & Exercise
Turner RC et al. JAMA. 1999;281:2005-2012.
0
10
20
30
40
50
60
3 Years 6 Years 9 Years
Pro
port
ion
of P
atie
nts
With
HbA
1c <
7% (
%)
Blood glucose
Intestine: glucose absorption
Thiazolidinediones -glucosidase inhibitors
Treatment of Type 2 Diabetes
SulfonylureasMeglitinidesBiguanides
Pancreas: insulin secretionLiver: hepatic glucose production
Muscle and adipose tissue:glucose uptake
GLP-1 analogs DPP4 inhibitors
Biguanides:Basic Characteristics of Metformin (Glucophage, Glucomin)
Mechanism of action Decreases hepatic glucoseproduction
Depends upon Presence of insulin
Power Decreases HbA1c 1% to 2%
Dosing One to three times daily
Side effects Diarrhea, nausea
Main risk Lactic acidosis
Insulin Secretagogues:Basic Characteristics of Sulfonylureas and Meglitinides
Mechanism of action Increase basal and postprandialinsulin secretion
Depends upon Functioning -cells
Power Decreases HbA1c 1% to 2%
Dosing Once or twice daily (sulfonylureas);three times daily (meglitinides)
Side effects Weight gain
Main risk Hypoglycemia
4-18
Mechanism of Sulfonylurea Induced Insulin Secretion
Glucose
K+
DepolarizationCa++
INSULIN & C-PEPTIDE
Sulfonylureas
ATP/ADP
Ca++
Carbachol
PKC
DAG
IP3
AC+ -
cAMP
PKA
GlucagonGLP-1
SomatostatinCatecholamines
GLUT 2
Glucose
Glucose-6-P GK(sensor)
Krebs
Thiazolidinedione Chemical Structures
Rosiglitazone (Avandia)
Pioglitazone
Troglitazone
O
CH3
O
NS
N N O
O
NS
N O
Et
O
CH3
O
NSO
O
HO
H3C
CH3
CH3 O
Activation of PPARgamma Alters Expression of Specific Genes
Gene encoding GLUT-4, lipoprotein lipase,
PEPCK, aP2 etc.
PPRE (DR-1)
PPAR RXR
AGGTCA X AGGTCA
Regulates gene transcription
RSG retinoic
Sites of action of Glitazones
Oakes ND, et al. Diabetes 1994; 43:1203–1210.Young PW, et al. Diabetes 1995; 44:1087–1092.
Digestiveenzymes
AdiposetissueAdiposetissue
Blood glucoseBlood
glucose
GutGut
MuscleMuscleLiverLiver
InsulinInsulin
Carbohydrates
Glitazones reduces insulin resistance in the liver, muscle and adipose tissue
PancreasPancreas
Rosilitazone Increases Islet Area and Density in Pancreatic Islets of db/db Mice
Pancreatic sections were immunohistochemically stained for insulin
Control Rosiglitazone
Scale 100 m (enlarged view)
Lister et al, Diabetologia 1998; 41 (Supplement 1):A660.
Thiazolidinediones (Glitazones):Basic Characteristics
Mechanism of action Enhances muscle and adiposetissue response to insulin
Depends upon Presence of insulin and resistanceto its action
Power Decreases HbA1c 0.5% to 1.3%
Dosing Once or twice daily
Side effects Edema, weight gain, anemia
Main risk 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-1in Patients With Type 2 Diabetes
Nauck MA, et al. Diabetologia 1993; 36:741-744
Data are mean ± SE.* P <0.05
25
20
15
10
5
0
Glucagon (pmol/L)
Time (min)
-30 0 60 120 180 240
**
* *
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
*
Glucose (mmol/L)
GLP-1/PBO infusion
***
**
*
-30 0 60 120 180 240
350
300
250
200
150
100
50
0
Insulin (pmol/L)
GLP-1/PBO infusion
Time (min)
* **
* ** * *
GLP-1/PBO infusion
Time (min)
-30 0 60 120 180 240
PlaceboGLP-1
Rationale for incretin-based therapy of Rationale for incretin-based therapy of diabetesdiabetes
"... - גילה" נ הבה
Eng J, et al. J Biol Chem 1992; 267:7402-7405 Chen YQE and Drucker DJ, J Biol Chem 1997; 272: 4108-4115
לטאת גילהGila Monster
GLP-1 analog
Exendin-4
(Exenatide)
Exenatide + Met Study: Effect on A1C
PlaceboLead-in
5 10 15 20 25 30Screen 0
6.5
7.0
7.5
8.0
8.5
9.0M
ean
(±S
E)
A1C
(%
)
Time (wk)
+0.1%
-0.4%
-0.8%
DeFronzo R, et al. ADA 64th Annual Scientific Sessions, June 2004
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
Met + PlaceboMet + 5 µg exenatide
Met + 10 µg exenatide
*
*
Dipeptidyl Peptidase 4 (DPP-4)Dipeptidyl Peptidase 4 (DPP-4)
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 is a serine protease of the prolyl oligopeptidase enzyme family that exists in two forms– Membrane-bound (widely expressed)– Soluble
Cell membraneCytosol
N N
C C
DPP-4 inhibition Increases Active Incretin Level
↑GLP-1 (7-36)
↑GIP (1-42)
DPP-4
DPP -4 Inhibitor
Incretinrelease GLP-1 (9-36)
GIP (3-42)
X
Adapted from Deacon CF et al Diabetes 1995;44:1126–1131; Ahrén B Curr Diab Rep 2003;3:365–372; Deacon CF et al J Clin Endocrinol Metab 1995; 80:952–957; Weber AE J Med Chem 2004;47:4135–4141.
24-week, Monotherapy, Placebo-controlled Study
Proportion of Patients Achieving HbA1c <7.0% at Week 24
Mean baseline values: sitagliptin, 8.01%; placebo, 8.03%All-patients-as-treated populationAdapted from Aschner et al. Diabetes Care. 2006;29:2632–2637.
P<0.001
0
10
20
30
40
50
60
Placebo (n=244) Sitagliptin 100 mg/day(n=229)
Pati
en
ts (
% t
o g
oal)
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 Onset Peak Duration Preparation
Regular 30-60 min 2-4 h 6-10 h
NPH/Lente 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
Regular
NPH
B SL HS
Insu
lin
Eff
ect
B
6-23
INSULIN TACTICS
Twice-daily Mixed Insulin
Regular
NPH
B SL HS
Insu
lin
Eff
ect
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 InjectionsNPH + Regular
Insu
lin
Eff
ect
B SL HS B
Regular NPH
6-24
INSULIN TACTICSINSULIN TACTICSChronic Multiple Daily InjectionsChronic Multiple Daily Injections
Bedtime NPH + Mealtime RegularBedtime NPH + Mealtime Regular
Lindström, et al. Diabetes Care. 1992;15:27-34.
Non-DM Insulin8 weeks
0800 1200 1600 2000 2400 0400 0800
Time of Day
Serum Insulin R NR R
0
300
200
100
pm
ol/L
6-50
Rapidly Acting Insulin AnaloguesRapidly Acting Insulin Analogues
INSULIN TACTICS
Shorter-acting Insulin Analogues: Lispro & Aspart
400
350
300
250
200
150
100
MealSC injection
50
00 30 60
Time (min)90 120 180 210150 240
Lispro
Regular Human
500450400350300250
150
50
200
100
00 50 100
Time (min)150 200 300250
Aspart
Regular HumanP
lasm
a In
suli
n (
pm
ol/L
)
Pla
sma
Insu
lin
(p
mol
/L)
MealSC 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
1 5 10 15 20 25 30
1 5 10 15 20 Asp
Gly
ArgExtension
Substitution
Arg
6-33
INSULIN TACTICS
Glargine vs NPH Insulin in Type 1 DiabetesAction Profiles by Glucose Clamp
Lepore, et al. Diabetes. 1999;48(suppl 1):A97.
6
5
4
3
2
1
00 10
Time (h) After SC Injection
End of observation period
20 30
Glargine
NPH
Glu
cose
Uti
liza
tion
Rat
e(m
g/k
g/h
)
6-34
Structure of Insulin Structure of Insulin DetemirDetemir
Pharmacodynamic action profiles for insulin detemir and NPH insulin in subjects with type 1 diabetes
Insulin detemir 0.1 U/kgInsulin detemir 0.2 U/kgInsulin detemir 0.4 U/kgNPH insulin 0.3 IU/kg
2.0
1.5
1.0
0.5
00 4 8 16 20 2412
Time since insulin injection (hours)
GIR
(m
g/k
g/m
in)
J Plank et al. Diabetes Care 2005;28(5):1107-12
Intention to Treat — Initiating Insulin and the 4-T StudyGraham 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 Onset Peak Duration
Preparation
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
B SL HS B
Immediate acting analogs Glargine
Insu
lin E
ffec
t
INSULIN TACTICSINSULIN TACTICSGlargine at HS + Short Acting AnalogsGlargine at HS + Short Acting Analogs
Insulin Pump
HbA1c < 6.5%
Pati
ents
reach
ing inte
nsi
ve-
treatm
en
t goals
at
mean
7.8
year
(%)
Cholesterol< 175 mg/dl(4.5 mmol/l)
Triglycerides< 150 mg/dl(1.7 mmol/l)
Systolic BP< 130 mmHg
Diastolic BP< 80 mmHg
Intensive therapy; n = 67 Conventional therapy; n = 63
P = 0.06 P < 0.001 P = 0.19 P = 0.001
P = 0.21
0
10
20
30
40
50
60
70
80
90
Multifactorial Intervention and Cardiovascular Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 DiabetesDisease in Patients with Type 2 Diabetes
N Engl J Med 348:383-93, 2003
Islet Transplantation in Type 1 DiabetesIslet Transplantation in Type 1 Diabetes
Robertson RP, N Engl J Med, 2004