2006 diabetes vietnam compressed 12+

Fatty liver Liver Insulin resistance increased glucose... Multi-target treatmentCentral obesity Vascular-thrombotic Complications -Cell Preservation Insulin Resistance Micro-vascular

Fatty liver Liver Insulin resistance increased glucose

Fat Poisoning

Beta-cell failure

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

Burned-out Pancreas

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

Central obesity

Vascular-thrombotic Complications

-Cell

Preservation

Insulin Resistance

Micro-vascular Complications

Insulin Secretion

Metformin + WT loss Drugs Reductil Acomplia

Once Daily Sulphonylurea Amaryl

0 0.5 1 1.5 2 2.5 3

2.5 5 10 20

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

• Glucose stimulus for 45min 3.3mM glucose (dark shade) and 16.7mM

Placebo 6 mg Glimepiride once-a-day

Sonnenberg et al Ann Pharmacother 1997;31:671.

Physiologic Glucose-M ediated Insulin Release

Throughout the Day W ith Once-Daily G lim epiride

Amaryl

8am 12 noon 6pm 10pm 2 am 24 Hours

Patients w ith 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

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

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

201

100 150 200 250 300

Insulin-stimulated glucose incorporation into glycogen:

Hep-G2 cells cultured in absence or presence of 20 mol/l glimepiride

Hribal et al Mol Pharmacol 2001;59:322

0 2 4 6 8

Placebo Glimepiride

Insulin infusion rate [U•kg -1 •min -1 ]

“Glimepiride increases peripheral insulin sensitivity …in glucos

e-tolerant, insulin- resistant offspring of patients with type 2 diabetes.”

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

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

0 10 20 30 40 50 60

Composite Endpoint of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or

Intensive Therapy

P=0.007

Hazard ratio = 0.47

(95% CI, 0.24–0.73;

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.

– 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

– The complexity of the drug regimen

– the number of dosages per day ( 34 – 36 )

medications - facilitate adherence

Once daily Treatment

Amaryl

Diamicron MR

Combination Therapy

• Avandia- Rosiglitazone

• Amaryl - glimepiride

Multi-target treatment

of the Metabolic Syndrome

Glucose Control

Central obesity

Micro-vascular Hypertension

Value of weight loss

• Risk of type 2 diabetes greatly reduced

by substantive weight loss

• Weight loss can achieve reversion to normal glucose tolerance

• Diabetes Prevention Program showed lifestyle intervention (diet + exercise)

reduced the incidence of diabetes by 58% (vs controls)

CB 1 receptors

are present in

the brain

CENTRAL NERVOUS SYSTEM

Hypothalamus Limbic system

PERIPHERAL TISSUES

CB 1 are present in adipose tissue, the

GI tract and possibly also in skeletal muscle and liver

ECS effects occur through:

1) interactions with hypothalamic and other brain circuits pathways regulating energy balance

2) peripheral effects in adipose tissue, the gut, and possibly muscle and liver

Central and Peripheral Targets of the

Endocannabinoid System (ECS)

Effects of EC system overactivity

Rimonabant : Rio-lipids Study (1 year)

% with Metabolic syndrome