Management of Type 2 Diabetes

Should metformin
be at the core
of treatment
guidelines?

IDF Global Guidelines 2005

Glucose Control

Lifestyle modification
Initiative: Prof P Home
Newcastle

Pharmacological agents
Metformin
Sulfonylureas
Thiazolidinediones
Glucosidase inhibitors
Insulin
Diabet Med 2006; 23: 579-93

Members of the Guideline Group

Countries Represented

37 Members

Cochrane Database of Systematic Reviews

Efficacy

Safety

Unsurpassed benefit for glycaemic control,

body weight and favourable lipid changes

Risk of lactic acidosis is zero if

prescribed as recommended

Galagine

Galega Officinalis

Metformin

Standard care should begin with metformin

unless there is evidence of contraindications

ADA/EASD Consensus Statement on

Management of T2DM (August 2006)

Diabetes Care
2006; 29: 1963-1972

Diabetologia
2006; 49: 1711-1721

ADA-EASD Consensus Algorithm for T2DM

Lifestyle + metformin
HbA1c > 7%
Add
SU

Add
basal insulin

Add
TZD

HbA1c > 7%
Add
TZD

Add
basal insulin

Intensify
insulin

Add
basal insulin

Add
SU

HbA1c > 7%
Further intensify insulin or add
basal insulin + metformin + TZD*

Metformin

Nathan. Diabetes Care 2006; 29: 1963-1972

Metformin - Therapeutic Diversity

NH

CH3
N
CH3

NH
NH

NH2

In type 2 diabetes
Counters insulin resistance
- by insulin-dependent and insulin-independent effects
Antihyperglycaemic (Not cause hypos)
Not cause weight gain
CV protection (improves vascular parameters, MI, survival)
Can improve some lipid parameters
Antihyperinsulinaemic (slightly basal insulin)
Possible further benefits (eg cancer risk)

Limitations

GI intolerance
Contraindications (renal, hepatic, any predisposition to hypoxaemia)
Risk (rare) of lactic acidosis
Monitoring (Hb and possibly vit B12, folate)
Administration of multiple large tablets

Metformin and Body Weight Regulation

Meta-analysis: Net difference (+) 4 kg
for sulphonylureas

ll
pb
e

Bo
yd

C
am

n
an
H
er
m

an
H
er
m

ry
N
ou

ut
ty
Jk

r
C
ol
lie

R
ai
ns

C
la
r

ke

* p>0.05 ** p<0.01 *** p<0.001

Campbell & Howlett. Diabetes/Metabolism Review 1995; 11: S57-S62

Metformin-Induced Alterations in Body Composition

Selective loss of visceral fat
Mean change (%)

*
*
**

**

Data are means. Duration of treatment: 6

months
*p<0.05; **p<0.01 vs. baseline
Kurukulasuriya R et al. Diabetes

Lipid Response in Diabetics

* Significant versus glibenclamide

*
*

*
*
*

DeFronzo RA, N Engl J Med 1995; 333: 541-549

Lipid Response in Non-Diabetics

with Heart Disease

**

*
*

* p<0.05 ** p<0.001
n=30 Controls, n=30 Metformin
Carlsen. J Intern Med 1996; 239: 227-233

Vascular Effects of Metformin

Anti-atherogenic actions
cholesterol deposition
lipid peroxidation
endothelial function
oxidative stress
Antithrombotic actions
platelet activation
blood flow
PAI-1 and fibrin breakdown
Metformin: Intrinsic Vascular Protective Properties
Diabetes Technology and Therapeutics 2000; 2: 259-272

Characteristics of
Vulnerable and Stable Plaques
Large lipid core with thin
fibrous cap, macrophages
interacting with thrombus

Reduced lipid core with thick

fibrous cap reinforced with
increased smooth muscle cells
Thrombus
Lumen
Endothelium

Smooth
muscle cell
Lipid rich core
Thin
fibrous cap

Platelets

Vulnerable Plaque

Thick
fibrous cap

Macrophage

Stable Plaque

Metformin Effect on
Monocyte Differentiation to Macrophages
Control

Metformin 0.5g/mL

Metformin 0.1g/mL

Metformin 1g/mL

Human monocytes cultured for 9 days metformin.

Formation of macrophages (control) reduced by metformin
Mamputu et al. Br J Diabetes Vasc Dis 2003; 3: 302-310

Metformin and Endothelial Function

Structural Similarities
CH3
N
CH3

NH

NH

NH2

NH

Metformin

COOH
NH2

NH

NH2

NH

CH
NH2

(CH)3

NH

C
NH

Aminoquanidine

Arginine

Potent inhibitor of Advanced

Glycation End products (AGE)

Potent precursor of
Nitric oxide

NH2

Metformin Counters Oxidative Stress

Hyperglycaemia

Metformin Type 2 Patients

8 Weeks

Age formation
Oxidative stress

Nitric Oxide

Angiopathy

Arginine Infusion Test

Arterial compliance
Blood filterability
Platelet aggregation
Blood viscosity

p<0.05
p<0.05
p<0.05
p<0.05

Marfella R. Diabetes Care 1996; 19: 934-939

Postulated Mechanisms of Altered

Fibrinolysis in Diabetes

Cytokines
Insulin
Proinsulin
High glucose
Modified LDL
Modified VLDL

Fibrin
deposits

Activated
platelets

Plasmin

Glycation
PAI-1
(-) tPA

PAI-1

(-)

Plasminogen
tPA

Collagenase
Colwell JA. Diabetes Rev. 1994;2:277-291

Effects of Metformin on PAI-1 Levels in

Patients With Type 2 Diabetes
PAI-1 activity (U/mL)

35
30

25
20
15
10
5
0

Basal

Placebo

Metformin

Results at 12 weeks
* P<0.001 compared with placebo.
Nagi DK, Yudkin JS. Diabetes Care. 1993;16:621-629.

Effect of Metformin on Fibrin Clots

Control

Metformin

Results: Polymerisation with thinner fibres and smaller pores

easier to lyse and therefore associated with reduced
antithrombotic risk.

Standeven. Diabetes 2002; 51: 189-97

Metformin - Therapeutic Diversity

NH

CH3
N
CH3

NH
NH

NH2

In type 2 diabetes
Counters insulin resistance
- by insulin-dependent and insulin-independent effects
Antihyperglycaemic (Not cause hypos)
Not cause weight gain
CV protection (improves vascular parameters, MI, survival)
Can improve some lipid parameters
Antihyperinsulinaemic (slightly basal insulin)
Possible further benefits (eg cancer risk)

Limitations

GI intolerance
Contraindications (renal, hepatic, any predisposition to hypoxaemia)
Risk (rare) of lactic acidosis
Monitoring (Hb and possibly vit B12, folate)
Administration of multiple large tablets

Limitations of Standard Metformin

Dosing Schedule

GI Side Effects

Side Effects of Oral Monotherapy Agents

Effect

Acarbose

Metformin

SUs

TZD

Flatulence
Diarrhoea
Abdominal pain

Diarrhoea

Hypoglycaemia

Oedema *
Mild GI

Long term

Transient

Transient

* Long term

Dose related

Yes

Yes

Yes

Yes

Discontinuation

15%

<5%

<5%

<5%

Elevated liver
enzymes

Rare 1

Yes?

Severe
hypoglycaemia

Rare 3

Lactic acidosis

Rare 2

Side effects

Duration

0.038

0.03

0.190 cases per 1000 patient years

Drug Related Adverse Events

Patients with adverse events (%)
Metformin dose (mg)

Any adverse event*

Digestive disturbances*

Placebo 500
1000
(n=79) (n=73) (n=73)
15
25
30
13
16
29

1500
(n=76)
26
24

2000
(n=73)
27
23

2500
(n=77)
30
29

* p <.05 for metformin (all doses) vs placebo

Digestive disturbances include diarrhoea, nausea, dyspepsia
Only 5% discontinued metformin due to treatment-related adverse events
Digestive disturbances were not dose related
Garber AJ. Am J Med 1997; 102: 491-7

Metformin Dosing:
Empirical Approach
Start with low dosage
Follow an incremental dosage plan
Allow 7-14 days between dosage levels
Establish a maintenance dose (max 3.0 grams)
Take with food using a divided dosage schedule

Incidence of Lactic Acidosis

Country

UK
Switzerland
Sweden

France
USA

Years

1976-1986
1972-1977
1972-1981
1987-1991
1987-1997
1984-1992
1993-1997
1995-1996
1995-1997

Patient Years of
Treatment

Total Incidence
(Cases per 1000
patient years of
treatment)

400 000
29 800
83 500
100 100
227 644
2 476 061
1 928 486
1 000 000
2 893 900

0.027
0.067
0.084
0.029
0.053
0.029
0.035
0.047
0.032

Howlett & Bailey. Drug Safety 1999; 20(6): 489-503

Predisposing Factors to Lactic Acidosis

Yes

No

Renal failure
Impaired liver funtion
Hypoxia
Alcoholism

Duration of treatment
Dosage
Age
Sex

Metformin Contraindications
-

Renal dysfunction
Severe liver disease
Use of iv contrast media
Major surgical procedures
Congestive heart failure
Acute myocardial infarction
History of lactic acidosis
History of alcohol abuse

Contraindications Can Damage Your Health

Is Metformin a Case in Point?

Benefits
Contraindications

Patients needlessly denied metformin

Withdrawal means replacement
Hypos, wt gain, heart failure

Diabetologia 2005; 48: 2454-9

Revisions to Metformin Prescribing

Specific Recommendations
Age per se should not be a contraindication.
Renal impairment okay if GFR >40 ml/min.
Stable heart failure (NHYA I & II)
General Recommendations
Prescribing information should be
harmonised worldwide
Diabetologia 2005; 48: 2454-9

Improved clinical outcomes associated with

metformin in patients with diabetes and heart
failure
DT Eurich, SR Majumdar, FA McAlister, RT Tsuyuki, JA Johnson

Metformin (+ Su)

Sulfonylureas

Diabetes Care 2005; 28: 2345-2351

Incidence of Heart Failure

TZD

Subjects (%)

TZD Present = 8.8%

TZD Absent = 5.3%

No TZD

12

18

24

30

36

Months
Delea TE. Diabetes Care 2003; 26: 2983-2989

Historic Milestones in T2DM

1957

First entry into clinical medicine in Europe

1970s

Biguanides lactic acidosis fears

1980s

Favourable comparative risk benefit analysis for metformin

but not phenformin or buformin

1995

Enters clinical practice in USA

1998

UKPDS (20 year trial) reports improved survival with metformin

2001

EU prescribing information recognises UKPDS findings

2003

US and EU prescription information recommends use in children

2005

IDF global guidelines recommends metformin as No. 1 agent

2006

ADA/EASD treatment recommendations state metformin should

be co-prescribed with lifestyle advice at diagnosis

Conclusions
International guidelines support metformin as
foundation therapy for T2DM.
Evidence base for metformin is 50 years young but
new data gives insight into how the drug reduces
mortality from all causes, not just of cardiovascular
origin.
Contraindications need to be liberalised to stop
patients being denied metformin.
Prolonged exposure to metformin increases
survival.

Metformin A Preventative Medicine

UKPDS

Primary Prevention
CV Complications

Chicago

Secondary Prevention
CV Complications

Washington

Prevention of
Non-CV Deaths

Prevention
of Diabetes

Guidelines
Metformin
Improves
Survival