Professional Documents
Culture Documents
Obesity
Sedentary lifestyle
Aging
Genetics
Insulin
resistance
Glucotoxicity
Beta-cell
function
Blood glucose
Adequate
Euglycemia
Insulin response
Inadequate
Type 2
diabetes
FFA
Insulin resistance
Insulin production
Glucose level
Nondiabetes
Prediabetes
Type 2
diabetes
TREAT
Microvascular
and
Macrovascular
Dysmetabolic syndrome
Insulin resistance, obesity,
hyperinsulinaemia (initially),
hypertension, dyslipidaemia,
atherosclerosis, procoagulant
Mimic
Mimic insulin
insulin
action
action
Increase
Increase
-cell
-cell mass
mass
Insulin
replacement
therapy
Decrease
Decrease
obesity
obesity
Blood
Blood
Glucose
Glucose
Decrease
Decrease
countercounterregulatory
regulatory
hormones
hormones
Suppress
Suppress
glucose
glucose
production
production
Slow
Slow CHO
CHO
digestiondigestionabsorption
absorption
Slow
Slow gastric
gastric
emptying
emptying
Alter
Alter glucoseglucosefatty
acid
fatty acid cycle
cycle
Increase glucose
excretion
Stimulate
Stimulate glucose
glucose
utilization
utilization
Oral combinations
Insulin
Improved control
TZDs
Sulphonylureas
Metformin
Acarbose
Miglitol
Voglibose
-glucosidase
inhibitors
Meglitinides
Rosiglitazone
Pioglitazone
Repaglinide
Nateglinide
MOA
Agents
Insulin
secretion
Sulphonylureas
Other insulin
secretagogues
Glucose
production
Biguanides
Thiazolidinediones
Slow carbohydrate
digestion
-glucosidase
inhibitors
Peripheral insulin
sensitivity
Thiazolidinediones
(biguanides)
Treatment:
stepwise approach
+
+
3
Insulin
Oral plus
insulin
Combination of
oral medicines
2 One oral
medicine
&
1 Diet
exercise
Action
Thiazolidinediones (eg,
rosiglitazone maleate,
pioglitazone)
Insulin secretagogues
(eg,sulfonylureas [glyburide,
glipizide], repaglinide)
Sites/Mechanisms of Action of
Antihyperglycemic Agents
Decreased digestion of
complex sugars
Alpha-glucosidase
inhibitors
Sulfonylureas
Non-sulfonylurea secretagogues
Normoglycemia
Biguanides
Thiazolidinediones
Decrease in hepatic
glucose production
Increased insulin
secretion
Thiazolidinediones
Biguanides
Increase in glucose uptake
Stepwise Management of
Type 2 Diabetes
Insulin oral agents
Oral combination
Oral monotherapy
Diet & exercise
Pharmacological Intervention in
Type 2 Diabetes
Carbohydrate
Glucose
(G
e
s
o
Gluc
)I
I
G
Insulin
Sulphonylureas,
Meglitinides
(I)
G
G
I
G
Metformin
I
G
I
G
ENZYMES
DIGESTIVE
G
G
Acarbose
Biguanides
Metformin Contd
z
Metformin
Contraindications
z
z
z
z
z
z
z
Metformin Contd
z
z
z
z
z
z
z
z
Sulphonylureas
z
z
z
z
Long-acting Sulphonylureas
z
Chlorpropamide
z
z
Longest acting
No longer recommended (hyponatraemia)
Glibenclamide
z
z
z
Widely used
Long acting
Avoid in elderly
Sulphonylurea
Contraindications
Renal impairment
Use e.g. tolbutamide
Shortest acting
Metabolites not active hypoglycaemics
Pregnancy / breast-feeding
Porphyria
z
z
z
Sulphonylureas
z
z
z
Reduces HbA1C
by 1-1.5%
No lag in response
Choice of agents
available
(dependent on
onset, duration of
action &
elimination)
1st line in lean
patients
z
z
z
Hypoglycaemia
Weight gain
5-10% secondary
failure rate / year
Long-term Sulphonylurea
Side Effects
z
failure of treatment
Therefore, use
z Short-acting
versions
z Lowest effective doses
z
failure inevitable
z
z
z
z
Acarbose Contd
z
Acarbose Contd
z
Contraindications
z
z
z
Pregnancy / breast-feeding
Liver and severe renal impairment
Inflammatory bowel disease & intestinal
obstruction
In therapy
z
z
z
z
Acarbose Contd
z
z
z
z
Reduces HbA1C by
0.5%
Safe
Weight neutral
Dose coupled with
meals
z
z
z
GI intolerance
Weak potency
Monitor LFTs during
1st 6-12mths
Prandial Glucose
Regulators
Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell
Scientific Publications 1991: 7283.
Short-term
z
Medium-term
z
(Ceriello 1998)
Long-term
z
(DECODE 1999, Donahue 1987, Hanefeld 1996, Tominaga 1999, BarrettBarrett-Connor 1998, Balkau
1999 & 1998, de Vegt 1999, Shaw 1999)
An Ideal secretagogue
z
z
z
z
An Ideal secretagogue
z
z
z
z
PGRs Contd
z
z
z
Nateglinide, Repaglinide
Dose:varies per drug
Repaglinide: initially 500mcg, adjusted
according to response every 1-2weeks; up
to 4mg as a single dose, max 16mg daily
Nateglinide: initially 60mg tds, adjusted
according to response up to max 180mg
tds
Must be taken within 30 mins before a
main meal
PGRs Contd
z
Contraindications
z
z
z
z
z
z
Diabetic ketoacidosis
Pregnancy & breast feeding
Type 1 diabetes
Severe hepatic impairment (repaglinide only)
Monitoring
LFTs periodically
PGRs Contd
z
z
z
z
z
z
z
z
z
z
Complex dose
titration (repaglinide)
Limited license
(nateglinide)
Weight gain
tds dosing
No outcome data
Thiazolidinediones
Thiazolidinediones
z
z
Thiazolidinediones Contd
z
z
z
z
z
z
Pioglitazone, Rosiglitazone
Adjunct with either metformin or SU
Dose: varies per drug
Pioglitazone: 15-30mg once daily
Rosiglitazone 4 mg/day, or + metformin 8
mg/day
Contraindications
z
z
z
Pregnancy / breast-feeding
Liver impairment
Heart failure
Thiazolidinediones
z
z
z
z
z
z
Side-effects: oedema,
weight gain, GI
disturbances, headache,
dizziness
High non-response rate
Delayed effect (8weeks)
No outcome data
Thiazolidinediones
NICE guidelines
z
z
z
z
z
Thiazolidinedione Treatment
Guidelines
z
z
Combination therapy
Not licensed for
z
LIVER
Therapy:
Biguanides
Thiazolidinediones
DECREASED
INSULIN
SECRETION
INCREASED
GLUCOSE
PRODUCTION
HYPERGLYCEMIA
INTESTINE
Therapy:
Alpha-glucosidase
inhibitors
Therapy:
Sulfonylureas
Meglitinides
Insulin
DECREASED
PERIPHERAL
GLUCOSE
UPTAKE
ADIPOSE
TISSUE
INCREASE
GLUCOSE
ABSORPTION
MUSCLE
Therapy:
Thiazolidinediones
(Biguanides)
Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.
(1) Glyburide
(Diabeta, Micronase,
Glynase).
(2) Glipizide
(Glucotrol,Glucotrol XL).
(3) Glimepiride
(Amaryl).
Thiazolidinediones in Treatment of
Type 2 Diabetes
z
Thiazolidinediones: Dosing
z
Rosiglitazone:
z Starting dose: 4 mg od or 2 mg bid
z Maximum dose: 8 mg od or 4 mg bid
Pioglitazone:
z Starting dose: 15 mg od or 30 mg od
z Maximum dose: 45 mg od
+ 5 Insulin
Oral plus
insulin
ination of
3 Combmedic
ines
oral
2 One oral
medicine
&
1 Diet
exercise
Diabetes: Complications
Macrovascular
Stroke
Microvascular
Diabetic eye disease
(retinopathy and cataracts)
Neuropathy
Foot problems
Foot problems
25%
50%
Metformin
soluble matrix
75%
Glibenclamide
particle range