Pathology of Type 2 Diabetes

Obesity

Sedentary lifestyle

Aging

Genetics

Insulin
resistance

Glucotoxicity

Beta-cell
function
Blood glucose

Adequate

Euglycemia

Insulin response

Inadequate

Type 2
diabetes

FFA

Progression of Insulin Resistance

Time

Insulin resistance
Insulin production
Glucose level

Nondiabetes

Prediabetes

Type 2
diabetes

Treating type 2 diabetes

hyperglycaemia and metabolic
syndrome
Good glycaemic control

TREAT

Microvascular
and
Macrovascular
Dysmetabolic syndrome
Insulin resistance, obesity,
hyperinsulinaemia (initially),
hypertension, dyslipidaemia,
atherosclerosis, procoagulant

Approaches to blood glucose

lowering
Improve
Improve insulin
insulin
action
action
Increase
Increase insulin
insulin
secretion
secretion

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

Treatment algorithm for type 2

diabetes
Aim

Diet, exercise, health education

Sulphonylurea, metformin
Glucosidase Inhibitors
Glitinides
Thiazolidinediones

Oral combinations
Insulin
Improved control

Insulin plus oral agents

Choice of agents in current use

Glipizide
Gliclazide
Glimepiride
Glibenclamide

TZDs

Sulphonylureas

Metformin

Acarbose
Miglitol
Voglibose

-glucosidase
inhibitors

Meglitinides
Rosiglitazone
Pioglitazone

Repaglinide
Nateglinide

Site and mode of action of oral

antidiabetic medications
Site of action

MOA

Agents

Insulin
secretion

Sulphonylureas
Other insulin
secretagogues

Glucose
production

Biguanides
Thiazolidinediones

Slow carbohydrate
digestion

-glucosidase
inhibitors

Peripheral insulin
sensitivity

Thiazolidinediones
(biguanides)

DeFronzo. Ann Intern Med 1999;131:281-303

Treatment:
stepwise approach
+
+
3

Insulin

Oral plus
insulin

Combination of
oral medicines

2 One oral

medicine

&
1 Diet
exercise

Pharmacologic classes of agents to control hyperglycemia in type 2 diabetes

Class

Action

Thiazolidinediones (eg,
rosiglitazone maleate,
pioglitazone)

Bind to peroxisome proliferator-activated

receptor-gamma (PPAR-gamma) in muscle, fat,
and liver to decrease insulin resistance

Insulin secretagogues
(eg,sulfonylureas [glyburide,
glipizide], repaglinide)

Stimulate pancreatic beta cells to increase insulin

output

Biguanides (eg, metformin

HCl)

Target liver to decrease glucose production

Alpha-glucosidase and lipase

inhibitors (eg, acarbose and
miglitol, orlistat)

Inhibit intestinal enzymes that break down

carbohydrates, thus delaying carbohydrate
absorption

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

Oral Hypoglycaemic Agents

Biguanides
z Sulphonylureas
z Alpha glucosidase inhibitors
z Guar gum
z Post prandial regulators
z Thiazolidinediones
z

Biguanides

Metformin - only one available in UK

z Drug of choice in obese patients only?
z Monotherapy or adjunct
z Decreases gluconeogenesis
z Increases peripheral uptake of glucose
into cells
z

Metformin Contd
z

Dose: 500mg daily increasing gradually

to 500mg three times a day
Max dose 3g most only tolerate 2g
daily
Side effects
Nausea, vomiting, diarrhoea, abdominal
discomfort, impaired B12 absorption

Metformin
Contraindications
z
z

z
z
z
z
z

May provoke lactic acidosis

Contraindicated with
Renal impairment
Any condition predisposing to lactic acidosis
Liver failure
Heart failure
Severe dehydration
Check renal & liver function periodically
Avoid in pregnancy, alcohol dependence and
breast-feeding

Metformin Contd
z
z
z
z
z
z
z
z

Reduces HbA1C by 1-2%

Safe
Reduces Basal & post prandial glucose
levels
Outcome data (UKPDS), microvascular &
macrovascular end points
Weight neutral
No hypoglycaemia
Increased insulin sensitivity
Beneficial effect on plasma lipid profile

Sulphonylureas
z
z
z
z

Gliclazide, glipizide, glimepiride + others

Stimulate beta cells to release insulin (assumes
there is residual beta cell activity)
Dose: varies per drug (see BNF)
Side effects: weight gain, GI disturbances,
headache

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

Severe liver impairment

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

Beta cell exhaustion

z Secondary

failure of treatment

Therefore, use
z Short-acting

versions
z Lowest effective doses
z

After many years of treatment

z Secondary

failure inevitable

Alpha Glucosidase Inhibitors

z
z
z
z

Acarbose - only one available in UK

Monotherapy or adjunct
Reduces glucose absorption from the gut
Inhibits intestinal enzyme, specific activity
on sucrase, delaying digestion of starch and
sucrose into absorbable monosaccharides
such as glucose

Acarbose Contd
z

Dose: 50mg daily increasing gradually to

three times a day, if necessary up to
200mg three times a day

Take with or just prior to meal

Treat hypo with glucose

Side effects: flatulence, diarrhoea,

abdominal distension & pain

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

Add-on to treatment with metformin or

sulphonylureas
Part of triple therapy
Monotherapy
With insulin in Type 1 diabetes

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

The Biphasic Insulin Response

Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell
Scientific Publications 1991: 7283.

Postprandial glucose spikes

the potential impact
z

Short-term
z

Increased atheromatous factors

z
z
z

Oxidative stress( Ceriello 1998)

Hypertriglyceridemia (Ceriello 2000)
endothelial dysfunction (Ceriello 2000)

Medium-term
z

(Ceriello 1998)

Glucose is toxic to the -cell, therefore hyperglycemia impairs

-cell responsiveness, which may accelerate the deterioration
Yki-Jrvinen 1992)
of -cells( Yki-

Long-term
z

PPG spikes* are an independent indicator of cardiovascular

risk

(DECODE 1999, Donahue 1987, Hanefeld 1996, Tominaga 1999, BarrettBarrett-Connor 1998, Balkau
1999 & 1998, de Vegt 1999, Shaw 1999)

*as measured by an OGTT.

An Ideal secretagogue
z
z
z
z

Rapid restoration of early-phase insulin release

to reduce post-prandial glucose spikes
Minimal risk of hyperinsulinaemia / between
meal hypoglycaemia
Plasma insulin should be returned to preprandial
levels as soon as possible
Suitable for use in combination with a treatment
for insulin resistance

An Ideal secretagogue
z
z
z
z

Rapid restoration of early-phase insulin release

to reduce post-prandial glucose spikes
Minimal risk of hyperinsulinaemia / between
meal hypoglycaemia
Plasma insulin should be returned to preprandial
levels as soon as possible
Suitable for use in combination with a treatment
for insulin resistance

Prandial Glucose Regulators

z
z
z
z

Stimulate beta cells to release insulin,

response however is glucose dependent
Following meals there is an early phase
insulin release
In Type 2 diabetes, this is lost causing post
prandial spikes
PGR mimic release of physiological insulin,
as they are short acting and do not
stimulate the beta cells constantly

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

Quickly lowers post

prandial glucose
levels (no lag before
response)
HbA1C 0.5-2%
Short half life
Meal time flexibility
Risk of weight gain

z
z
z
z
z

Complex dose
titration (repaglinide)
Limited license
(nateglinide)
Weight gain
tds dosing
No outcome data

PGR Treatment Guidelines

z
z

Not yet widely adopted into treatment guidelines

Recent evidence may alter this
z

Repaglinide/glitazone and nateglinide/metformin

combinations = synergistic effect on glycaemic control

Thiazolidinediones

Thiazolidinediones
z
z

Counteract insulin resistance

Bind to PPAR-gamma (receptor), forming
a complex promoting transcription of
genes sensitive to insulin
Receptors are present in skeletal muscle,
adipose tissue & liver, thereby promoting
uptake of fatty acids & glucose at these
sites

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

Reduces HbA1C by 1-2%

? Alternative to insulin
Beneficial effect on lipids

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

Effective when added to metformin or SU

Offer metformin and SU 1st if monotherapy
ineffective
If intolerant, contraindicated or persistent high
glucose, glitazone may be offered with
metformin or SU as insulin alternative
Glitazone +metformin is preferred in obese,
unless contraindicated
On treatment, patients to be monitored against
treatment targets for glucose,CV risks including
lipid profile

Thiazolidinedione Treatment
Guidelines

z
z

Combination therapy
Not licensed for
z

Use with insulin

? Early use to preserve beta cell function

Sites of Action by Therapeutic

Options
PANCREAS

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).

(4) Repaglinide (Prandin),

(5) Nateglinide (Starlix),

(6) Metformin hydrochloride

(Glucophage),

(9) Acarbose (Precose,

Glucobay),
(10) Miglitol (Glyset)

(7) Pioglitazone hydrochloride

(Actos).

(8) Rosiglitazone malate

(Avandia).

Thiazolidinediones in Treatment of
Type 2 Diabetes
z

Rosiglitazone indications (type 2):

z

monotherapy + diet + exercise

combination with sulfonylurea when diet + exercise +

sulfonylurea are inadequate

combination with metformin when diet + exercise +

metformin are inadequate

add to (do not substitute for) sulfonylurea or metformin

Pioglitazone indications (type 2):

z

monotherapy + diet + exercise

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

Treatment: Step-wise Approach

+

+ 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)

Heart disease and

hypertension
Renal disease
Peripheral
vascular disease

Neuropathy
Foot problems

Foot problems

Glucovance tablet technology:

engineered to optimise drug delivery

25%

50%

Metformin
soluble matrix

75%
Glibenclamide
particle range

Donahue et al. Clin Pharmacokinet 2002;41:1301-1309