Fatty liver
Liver Insulin
resistance
increased glucose
output
Fat Poisoning
Fat Poisoning
Fat + Inactivity
Fatty muscles
Muscle Insulin
resistance

Fat Poisoning
Fat Poisoning

Fat Poisoning
Fat Poisoning
Beta cell failure
Inadequate insulin
To counter Insulin resistance
Hyperglycaemia
Sugar Poisoning
Sugar Poisoning

Beta-cell failure
•
Ectopic deposition of fat in the islet cells
leads to Beta-cell failure
Burned-out Pancreas

INSULIN RESISTANCE
TIME
11
5
7.1
Plasma
Glucose
Impaired glucose tolerance
Ausdiab
10.6 % population
1.3 million Australians
NIDDM
FPG >7; 2hr >11
INSULIN
Beta cell failure
Insulin resistance combined with
beta-cell dysfunction
6.1

Treat B-cell failure & Insulin resistance

Multi-target treatment
Multi-target treatment
Central
obesity

Vascular-thrombotic
Complications
β-Cell
Preservation

Insulin
Resistance

Micro-vascular
Complications
Insulin
Secretion

+ INSULIN
+ INSULIN
+/or Glitazones
DIET+ EXERCISE
DIET+ EXERCISE
Management of Diabetes
Twice Daily
Twice Daily
Sulphonylurea
Sulphonylurea
Metformin
Metformin
+ WT loss Drugs
+ WT loss Drugs
Reductil
Acomplia
Once Daily
Once Daily
Sulphonylurea
Sulphonylurea
Amaryl


0
0.5
1
1.5
2
2.5
3
100 10 1 0
2.5
5
10
20
Glimepiride Concentration
(
µ
mol/L)
Glucose
(mmol/L)
Insulin secretion*
(
µ
U/islet/45min)
Del Guerra et al. Acta Diabetol 2000;37:139.
*Isolated human pancreatic islets
Amaryl: Physiologic Insulin Secretion
Dependent on Glucose Concentration

Responsiveness of Sulfonylureas to
Changing Glucose Concentrations
Insulin secretion

(% of cell content)
Design:
•
Incubation of human islets for 24 h with different sulfonylureas
•
Glucose stimulus for 45min 3.3mM glucose (dark shade) and 16.7mM
(light shade)
* P < .01
†
P < .05
*
Del Guerra et al. submitted to EASD 2001.
ns
Gp = Glimepiride; Gb = glibenclamide; Chl = Chlorpropamide
0
1
2
3
4
5
6
Control Gp 10?M Gb 10?M Chl 600?M

0
10
20
30
40
50
Insulin (mcU/mL)

Placebo 6 mg Glimepiride once-a-day
Sonnenberg et al. Ann Pharmacother 1997;31:671.
Physiologic Glucose-Mediated Insulin Release
Throughout the Day With Once-Daily Glimepiride
Amaryl
8am 12 noon 6pm 10pm 2 am 24 Hours
Patients with type 2 diabetes

0.43 episodes/1000 person-years vs 5.8 episodes/1000 person- years
glimepiride fewer episodes of severe* hypoglycemia than glyburide
N = 21,607 patients
Less Hypoglycaemia
Holstein et al. Diabetologia2000;43:A40.
*Defined as requiring IV glucose or glucagon
0.43
5.8
0
2
4
6
# Episodes/1000
person-years
Glimepiride Glyburide

0
0.1
0.2
Glimepiride
n=1,444
Control

n=1,002 Glyburide
n=207 Glipizide
Glimepiride Phase III clinical data showed a trend toward weight
neutrality
Bugos et al. Diabetes Res Clin Pract 2000;50 (suppl 1).
*Meta-analysis of data from 4 studies
Mean Change in Weight (kg)
P
=.05
P
= .81
Less Weight gain
0.02

Insulin-Sensitizing Action of Glimepiride
•
Enhances expression of GLUT-4 transport proteins in
cell membranes (adipocytes and myocytes)
•
Stimulates nonoxidative glucose metabolism in fat and
muscle cells
Preclinical Data:
Mueller et al. Biochim Biophys Acta 1994; Kubota et al. J Jpn Diab Soc 1995
Eckel. Horm Metab Res 1996; Mueller et al. Diab Res Clin Pract 1995; Geisen. Drug Res 1988

Improved Liver insulin sensitivity: in vitro
0 10
-10
10
-9

10
-8

10
-7
Insulin-stimulated
glucose incorporation into glycogen
(% over basal)
Insulin-stimulated glucose incorporation into glycogen:
Hep-G2 cells cultured in absence or presence of 20 µmol/l glimepiride
Hribal et al. Mol Pharmacol 2001;59:322

0
2
4
6
8
0.5 1 1.5
Placebo
Glimepiride
Insulin infusion rate [
µ
U•kg
-1
•min
-1
]
mL•
.
kg

–1 .
min
-1
“Glimepiride increases peripheral insulin sensitivity …in glucose-
tolerant, insulin-resistant offspring of patients with type 2 diabetes.”
*
P
≤
.025
*
*
Volk et al. Diabetologia2000;43(suppl 1):A39.
Glucose
Infusion Rate
[mg•kg
-1
•min
-1
]
*
P
≤
.025
Improved Liver insulin sensitivity: in Vivo

Glycaemic goals
•
Fasting plasma glucose <6.0 mmol/L
•
HbA1c levels <7%

•
New ADA 6.5%
•
HbA1c >7% 3x increased risk if infection with
sugery.

2. Glycemic goals: ADA 2006
for patients in general
Is 7%.
for the individual
close to normal (6%) as
possible without
hypoglycemia.

Conservative management of glycaemia:
traditional stepwise approach
7
6
9
8
HbA
1c
(%)
10
OAD
monotherapy
Diet OAD
combination
OAD
+ basal insulin

OAD
monotherapy
uptitration
Duration of diabetes
OAD
+ multiple daily
insulin injections

Proactive management of glycaemia: early
combination approach
OAD + basal insulin
OAD + multiple daily
insulin injections
Diet
OAD monotherapy
OAD combinations
OADs uptitration
Duration of diabetes
7
6
9
8
HbA
1c
(%)
10

Steno 2 trial
•
8 yr study of 160 diabetics + microalbuminuria -All on ACE

or ARB
•
multifactorial intervention
–
HbA1c to < 6.5% (with diet, exercise, metformin, SU, and
insulins),
–
BP < 130/80 mm Hg (agents added to the ACE-I or ARB
–
cholesterol to < 175 mg/dL (with statins)
–
triglycerides to < 150 mg/dL (with fibrates).
–
aspirin
RESULTS:
50% reduction in the risk of cardiovascular and
microvascular events
1. Solomon CG. Reducing cardiovascular risk in type 2 diabetes. N Engl J Med.
2003;348:457-459.

Composite Endpoint of Death from CV Causes,
Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or
Surgery for PAD: Steno-2
Primary Composite
Endpoint (%)
Months of Follow-up
0
24 48 60 9636 847212
Conventional
Conventional

Therapy
Therapy
Intensive
Intensive
Therapy
Therapy
P=0.007
P=0.007
Hazard ratio = 0.47
Hazard ratio = 0.47
(95% CI, 0.24–0.73;
(95% CI, 0.24–0.73;
P=0.008)
P=0.008)
Gæde P et al. N Engl J Med 2003;348:383-393.
Copyright 2003 Massachusetts Medical Society. All rights reserved.

Lesson from Steno-2
•
The clinical lesson from the Steno-2 study is
that early and continuous use of an
intensive, targeted, multifactorial approach
produces significant and persistent benefits
in diminishing diabetic complications.

Adherence to intensified treatment.
•
Patients are often need
–
1-2 pills +/- insulin for control of blood glucose,

–
1-2 pills for dyslipidaemia, and
–
3-4 pills for hypertension, +
–
low-dose aspirin each day
•
= 8+ drugs each day (+ drugs for concomitant diseases)
•
only 50–70% of the prescribed meds are taken (31,32).
•
factors influencing adherence
–
The complexity of the drug regimen
–
the number of dosages per day (34–36).
•
combinations of oral hypoglycaemic agents and of BP – lowering
medications - facilitate adherence

Once daily Treatment
Amaryl
Diamicron MR