Download Therapeutic Advances T2DM 2008

Therapeutic Advances for
Type 2 Diabetes Mellitus
Meredith Hawkins, MD
Diabetes Research Center
Albert Einstein College of Medicine
Evidence that Improving Glycemic
Control Reduces Complications
DCCT
Kumamoto
UKPDS
9  7%
9  7%
8  7%
Retinopathy
76%
69%
17-21%
Nephropathy
54%
70%
24-33%
Neuropathy
60%
-
-
Macrovascular
disease
41%*
-
16%*
HbA1c
* not statistically significant
Glycosylated Hemoglobin
(HbA1c)
12
HbA1c
11
10
HbA1c 9
8
(%)
7
“Normal
range”
6
5
4
100
200
300
Mean daily plasma glucose (mg/dl)
Diet and Exercise
are the
Cornerstones of
Diabetes Management!!
Long-term Success Stories:
1. Self-monitoring:
Diet: record food intake
daily, limit certain foods
or food quantity
Weight: check body
weight 1 x/wk
2. Lower calorie, fat intake
3. Eat breakfast daily
4. Regular physical activity: 2500–3000 kcal/wk
(eg, walk 4 miles/d)
5. Behavior strategies: eg. Cognitive restructuring,
spiritual
Relationship of walking to mortality
among US adults with diabetes
•
•
•
•
DESIGN: Prospective cohort study
SUBJECTS: 2896 adults 1990 and 1991 National Health Interview Survey
RESULTS:
Mortality
Inactive
2 hours/wk 3-4 hrs/wk
All Cause
Ref 1.0
39%
54%
CV
Ref 1.0
34%
53%
CONCLUSIONS: Walking was associated with lower mortality across a
diverse spectrum of adults with diabetes. One death per year may be
preventable for every 61 people who could be persuaded to walk at least 2
h/wk.
Arch Intern Med. 2003 Jun 23;163(12):1440-7
Physical Activity: Caloric
Expenditure per hour
• Bicycling 6 mph
240 kcal/hr
• Jogging 5.5 mph
740 kcal/hr
• Walking 3 mph
320 kcal/hr
• Swimming 25 yards/min
275 kcal/hr
DPP: Results
Sites of Action of Oral Antidiabetic
Agents
Liver: Glucose
production
METFORMIN
Muscle and adipose tissue:
Peripheral glucose uptake
THIAZOLIDINEDIONES
Pancreas: Insulin
secretion
SULFONYLUREAS
INCRETINS
Intestine: Digestion and
absorption of carbohydrates
a-GLUCOSIDASE
INHIBITORS
Metformin
Advantages
• Improves insulin
resistance
• Low risk of
hypoglycemia
• Effective in > 80% of
patients
• Advantageous lipid
effects
• Long record of relative
safety
• Favorable effects on
weight
• Decreased
macrovascular
complications (UKPDS)
• Prevents Diabetes (DPP)
Disadvantages
• Contraindicated in
organ failure
• Lactic acidosis
(1:30-90,000)
• Slow titration
• GI side effects
.
Metformin Dose-Response Study
Mean HbA1c Reductions
0.5
0
Mean Difference -0.5
in HbA1c (%)
vs. Placebo at
-1
End of Study
-0.9
*
-1.5
-1.2
*
-2
*
-2.0
*
*
-2.5
*P<0.001
-1.6
-1.7
500 mg
(n=73)
1000
mg
(n=73)
1500
mg
(n=76)
2000
mg
(n=73)
2500
mg
(n=77)
UKPDS: Effects of Intensive
(Metformin) Treatment*
0
% Risk
Reduction
-10
-20
-30
-40
-32 †
-36
§
-42 ‡
-50
Any DiabetesRelated
Endpoint
DiabetesRelated
Mortality
* Compared with conventional treatment;
† P=0.0023; ‡ P=0.017; §P=0.011;
¶ P=0.01
All-Cause
Mortality
-39 ¶
MI
American Diabetes Association. Diabetes Care.
1999;22(suppl 1):S27-S31.
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
Sites of Action of Oral Antidiabetic
Agents
Liver: Glucose
production
METFORMIN
Muscle and adipose tissue:
Peripheral glucose uptake
THIAZOLIDINEDIONES
Pancreas: Insulin
secretion
SULFONYLUREAS
INCRETINS
Intestine: Digestion and
absorption of carbohydrates
a-GLUCOSIDASE
INHIBITORS
K+
Sulfonylurea
Ca++
Glucose
Amino
Acids
METABOLISM
SUR
K+
Ca++
ATP
ADP
Insulin
Sulfonylureas
Advantages
Disadvantages
• Improves insulin
secretion
• Long history of use
• Once-daily dosing
• Dose flexibility
• Effective
• Fast response
• Well tolerated
• Low cost
• Weight gain
• Hypoglycemia
• Caution in the elderly and
with organ failure
• Hyperinsulinemia
• Drug interactions
• No response (20%) or
response lost over time
• Increased risk of
cardiovascular disease ?
Insulin Secretagogues:
Sulfonylureas
Drug
Tolbutamide
Daily Dose # Doses
(mg)
per day
Duration of
Action
500-3000 2-3
6-10
Chlorpropamide 100-500
1
24-72
Glyburide
1.25-20
1-2
16-24
Glipizide
2.5-20
1-2
12-16
Glimepiride
1-8
1
24
Sites of Action of Oral Antidiabetic
Agents
Liver: Glucose
production
METFORMIN
Muscle and adipose tissue:
Peripheral glucose uptake
THIAZOLIDINEDIONES
Pancreas: Insulin
secretion
SULFONYLUREAS
INCRETINS
Intestine: Digestion and
absorption of carbohydrates
a-GLUCOSIDASE
INHIBITORS
Insulin and Glucagon in Normal
Glucose Tolerance
Glucagon
a-Cells
+
HGO
Glucose
-Cells
Insulin
HGO= hepatic glucose output
Adapted from Unger RH. Metabolism. 1974;23:581.
+
Glucose
uptake
The Incretin Effect in Healthy
Subjects
Oral Glucose
Intravenous (IV) Glucose
*
2.0
*
C-peptide (nmol/L)
Plasma Glucose (mg/dL)
200
100
0
*
1.5
*
Incretin Effect
*
*
1.0
*
0.5
0.0
0
60
120
180
Time (min)
N = 6; Mean (SE); *P0.05
Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498
0
60
120
Time (min)
180
Role of Incretins in Glucose
Homeostasis
Ingestion of food
Pancreas2,3
GI tract
Glucose-dependent
 Insulin from beta cells
(GLP-1 and GIP)
Release of gut
hormones —
Incretins1,2
Active
GLP-1 & GIP
Blood
glucose
Beta cells
Alpha cells
DPP-4
enzyme
Inactive
GLP-1
Glucose
uptake
by
muscles2,4
Glucose dependent
 Glucagon from
alpha cells
(GLP-1)
Inactive
GIP
DPP-4 = dipeptidyl-peptidase 4
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
Glucose
production
by liver
GLP-1 Modulates Numerous
Functions in Humans
GLP-1: Secreted upon
the ingestion of food
Promotes satiety and
reduces appetite
Alpha cells:
 Postprandial
glucagon secretion
Liver:
Beta cells:
 Glucagon reduces
hepatic glucose output
Enhances glucose-dependent
insulin secretion
Stomach:
Helps regulate
gastric emptying
Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422
Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169
Incretins
eg. GLP-1, Exenatide (Byetta), DPP-IV inhibitors (Januvia)
Advantages
Disadvantages
• Promote satiety
• Weight loss (Byetta)
• Improve postprandial
insulin secretion
• Reduce glucagon levels
• Delayed nutrient
absorption
•
•
•
•
•
Duration (GLP-1)
Nausea
Other GI side effects
Require injection
Lack of long-term
safety data
• Cost
Sites of Action of Oral Antidiabetic
Agents
Liver: Glucose
production
METFORMIN
Muscle and adipose tissue:
Peripheral glucose uptake
THIAZOLIDINEDIONES
Pancreas: Insulin
secretion
SULFONYLUREAS
INCRETINS
Intestine: Digestion and
absorption of carbohydrates
a-GLUCOSIDASE
INHIBITORS
Thiazolidinediones: PPAR-gamma
agonists
TZD
TZD
TZD
insulin-mediated
glucose uptake
Thiazolidinediones
Advantages
Disadvantages
• Target insulin
resistance
• +/- lipid profile
• Use in renal
insufficiency
• Preserve b-cell
function
• Prevent progression
from IGT to type 2
diabetes
•
•
•
•
•
•
Hepatotoxicity
Weight gain
Fluid retention
Congestive Heart Failure
Delayed onset of action
Lack of long-term safety
data
• Cost
• Cardiovascular
outcomes???
Currently Available TZDs
Agent
Dosage Range
Pioglitazone
15–45 mg once daily
Rosiglitazone
4–8 mg daily (in 1 or 2 doses)
+ Hepatic metabolism
Renal and liver excretion
Sites of Action of Oral Antidiabetic
Agents
Liver: Glucose
production
METFORMIN
Muscle and adipose tissue:
Peripheral glucose uptake
THIAZOLIDINEDIONES
Pancreas: Insulin
secretion
SULFONYLUREAS
INCRETINS
Intestine: Digestion and
absorption of carbohydrates
a-GLUCOSIDASE
INHIBITORS
Acarbose
Miglitol
a-Glucosidase Inhibitors
Advantages
• Long history of use
• Good safety profile
• No weight gain
• Mild stool softening
• No substantial
systemic drug-drug
interaction
• Good adjunctive
therapy
Disadvantages
• Require highcarbohydrate diet
• Most be taken
before every meal
• Modest efficacy
• Flatulence and GI
side effects
• Elevated LFT’s
have been
reported
Physiologic Insulin Secretion
75
Breakfast
Lunch
Dinner
Plasma
Insulin 50
(U/mL)
25
0
4:00
8:00
12:00
16:00
20:00
Time
24:00
28:00
32:00
Insulin Preparations
• These preparations target insulin-sensitive tissue
to increase glucose uptake and decrease hepatic
glucose production
Rapid-Acting
– Insulin lispro (analogue)
– Insulin aspart (analogue)
– Insulin glulisine (analogue)
Short-Acting
– Regular (soluble)
Intermediate-Acting
– NPH (isophane)
– Lente (insulin zinc suspension)
Long-Acting
– Ultralente (no longer on market)
– Insulin glargine and detemir (analogue)*
Pharmacokinetic Profiles of Human
Insulin and Insulin Analogues
Dissociation of Insulin Analogues:
Lispro/Aspartate
Insulin
10-3 M
10-3 M
10-5 M
f f f f ff
f ff
ff
f f f ff f f
10-8 M
peak time
2–4 hr
formulation
capillary membrane
Monomeric Insulin Analogues
10-3 M
ff f f
f f
f
f
f
ff
f f ff fff
formulation
10-3 M
[ ]
transient
10-3 M
peak time
1 hr
Glargine: Mechanism of Action
Injection of an acidic
solution (pH 4.0)
Clear Solution
pH4

Precipitation of
glargine in
subcutaneous
tissue (pH 7.4)
pH
7.4
Precipitation
Dissolution
Hexamers
Dimers
10-3 M
Monomers
10-5M
10-8 M

Slow dissolution of free
glargine hexamers from
precipitated glargine
(stabilized aggregates)
Capillary Membrane
Insulin in Blood
Adapted from: Kramer W. Exp Clin Endocrinol Diabetes. 1999; 107: Suppl 2.

Protracted action
Insulin Effect
Basal-Bolus Insulin: Insulin Glargine
at HS and Mealtime Lispro or Aspart
B
L
Insulin lispro or aspart
D
HS
Insulin glargine
Starting Basal Insulin: Type 2 DM
• Continue oral agent(s) at same dosage (d/c TZD)
• Add single, evening insulin dose (around 10 U)*
– NPH (bedtime)
• Treat to target fasting glucose (usually 80-120
mg/dL)
• Increase insulin dose weekly as needed
– Increase 4 U if FBG >140 mg/dL
– Increase 2 U if FBG = 120 to 140 mg/dL
• Next step: add short-acting insulin before meals
* It will usually take 40-60 units to get to target
5-18
ADA Treatment Guidelines 2007
Cost of pharmacological therapy
for Type 2 DM for glucose control
Drug
Sulfonylureas
Repaglinide
Metformin
Acarbose/Miglitol
Rosi-/Pioglitazone
Sitagliptin (Januvia)
Insulin
Analogue insulin
Exenatide/Pramlintide
Cost per month
$30-45*
$40-60
$50-65*
$45-55
$75-125
$145-150*
$14-20/bottle
$18-58/bottle
$121-269/bottle
IGT
Type 2 diabetes
HYPERGLYCEMIA
MICROVASCULOPATHY
MACROVASCULOPATHY
METFORMIN
T H I A Z O L I D I N ED I O N E S
SULFONYLUREAS/Incretins
INSULIN
Hyperglycemia: The Tip of the
Iceberg of Insulin Resistance
Syndrome
Hyperglycemia
Clinical Manifestations:
Central obesity,
Hypertension,
Polycystic ovarian syndrome,
Accelerated atherosclerosis
Lipid:
Carbohydrate:
Insulin resistance
Hyperinsulinemia
IGT
FFA
TG
 HDL
Dense LDL
Coagulation:
 PAI-1
 Fibrinogen
 Platelet adhesion
Goal Recommendations in Type 2
Diabetes
Goal
Average preprandial glucose (mg/dL) 90–130
Average postprandial glucose (mg/dL) <180
HbA1c (%)
<7
LDL-Cholesterol (mg/dL)
<100
Triglycerides (mg/dL)
<150
HDL-Cholesterol (mg/dL)
>40
Blood pressure (mm Hg)
<130/80
American Diabetes Association: Clinical Practice Recommendations. Diabetes Care Vol. 30, Suppl. 1, 2007
Avoiding microvascular complications!
•Screening annually: dilated retinal exams
• Urine for microalbuminuria
• Microfilament exam for neuropathy
• Optimal blood
pressure control
• ACE inhibitors if
microalbuminuria
• Careful foot care
• Smoking cessation
• TIGHT glycemic
control!!!!!
Future Targets
BRAIN
LIVER
• Central insulin
• PTP-1B inhib.
• CPT-1 inhib.
• IKK2 inhibitors
• Adiponectin
agonists
• Sirt-1 agonists
• PTP-1B inhib.
• PPAR-α agonists
• Selective thyroid
agonists
MUSCLE, FAT
• Sirt-1 agonists
• AMP Kinase
activators
• HSD-1
inhibitors
PANCREAS
• Incretins
• SUR-1
agonists
• Glucokinase
agonists