22 januari 2009

Metformin:

• effective glucose lowering agent

• lack of weight gain

• low / no risk of hypoglycaemia

• increases insulin sensitivity

• anti-atherosclerotic and cardioprotective properties

Metformin:

• gastrointestinal intolerability

• traditional contra-indications with respect to lactic acidosis

• old age (>70 years?)• liver dysfunction

• myocardial insufficiency, respiratory insufficiency

• RENAL insufficiency

A. Holstein and M. Strumvoll

Diabetologia 2005

“There is no evidence from prospective comparative trials or from observational studies that metformin is associated with an

increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments”

Conclusion (Cochrane analyses):

Metformin-associated

lactic acidosis

SU-induced

hypoglycaemia

Insulin-induced

hypoglycaemia

Incidence of lactic acidosis or severe hypoglycaemia in type 2 DM (number per 100.000 pt years)

6.4 1000 1800

Mortality (percentage; most pessimistic available figure) 50% 4.3% 4.3%

Predicted absolute no. of death (number

per 100.000 pt years 3 43 77.4

WG Herrington and JB Levy

Int Urol Nephrol 2008

Predicted absolute number of deaths caused by the life-threatening complications of metformin and sulphonylureas

JAMC 2005

What is the case with metformin?

Mechanisms of metformin action on hepatic glucose production andmuscle glucose consumption

Kirpichnikov, D. et. al. Ann Intern Med 2002;137:25-33

Metformin and fatty acids

Kirpichnikov, D. et. al. Ann Intern Med 2002;137:25-33

P. Smits and C. Tack. Neth J Med 2002;60:228-230

• biguanides (metformin)

pyruvate

pyruvate

citrate

isocitrate

αααα-ketoglutarate

suc-CoA

succinate

fumarate

malate

oxaloacetate

FADH2

FAD

NADNADH

pyruvate

pyruvate

citrate

isocitrate

αααα-ketoglutarate

suc-CoA

succinate

fumarate

malate

oxaloacetate

FADH2

FAD

NADNADH

lactate

carbohydrates

Amino acids

acetylCoAFatty Acids

Ketones

lactate

Hutchinson DS et al. Pharmacol Ther 2008;119:291-310

Mechanisms utilized by insulin and AMPK to increase glucose uptake in skeletal muscle and adipocytes. Insulin increases GLUT4

translocation and glucose uptake through the well characterized IRS-PI3K-Akt-PKC pathway. Metformin, glitazones, exercise and contraction

act through AMPK and are independent of the insulin-signaling pathway, making AMPK an attractive therapeutic target for the treatment of

type 2 diabetes and obesity. The role of AMPK activation on whole body energy metabolism. Activation of AMPK causes both activation of catabolic pathways

(pathways generating energy) and inhibition of anabolic pathways (pathways consuming energy).

Hutchinson DS et al. Pharmacol Ther 2008;119:291-310

Proposed cellular mechanisms of metformin action in the vascular smooth-muscle cells and cardiomyocytes

Kirpichnikov, D. et. al. Ann Intern Med 2002;137:25-33

CJ Bailey. Cardiovasc Drugs Ther 2008;22:215-224

0.5

0.0

“There is no evidence from prospective comparative trials or from observational studies that metformin is associated with an

increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments”

Conclusion (Cochrane analyses):

Almirall, J. et al. Nephrol. Dial. Transplant. 2008 23:2436-2438

A. Evolution of metformin consumption (DHD) in the general population during the period 2001-2005 (2001: 4.8; 2002: 6.6; 2003: 8.8; 2004: 10.8; 2005: 13.1)

B. Case distribution of lactic acidosis throughout the same time period. The increase runs in parallel with administered DHD. Corresponding incidence for years 2004 and 2005: 1.8 and 1.01 x 1000 patients/year, respectively.

Possible trigger factors for lactic acidosis due to metformin use

in 13 pt’s (10 women / 3 men)

Dehydration 85%

Overt congestive heart failure

15%

Significant renal insuff. 100%

Almirall, J. et al. Nephrol. Dial. Transplant. 2008 23:2436-2438

Pre-existing contra-indications for metformin

Pre-existing renal insuff.

(GFR<60ml/min)

70%

Congestive heart failure 38%

> 1 risk factor 31%

Almirall, J. et al. Nephrol. Dial. Transplant. 2008 23:2436-2438

Possible trigger factors for lactic acidosis due to metformin use in 3 pt’s (2 women / 1 men)

Dehydration 66-100%

Overt congestive heart failure

33%

Significant renal insuff. 100%

Pre-existing contra-indications for metformin

Pre-existing renal insuff.

(GFR<60ml/min)

0%

Congestive heart failure 66%

> 1 risk factor 66%

Pharmacokinetics of metformin

• peak 2.5 hr after oral intake

• t1/2 6.5h (normal renal function)

• protein binding negligible

• volume distribution 63-276 L

• >90% unchanged excreted by kidneys

• tubular secretion• glomerular filtration

1000/Screat

time

Conclusion

• The risk of lactic acidosis on metformin is (very) low

• conscientious adherence to current guidelines protects pt’s from SAE

• current contra-indications of metformin deprive many pt’s of the benefits of this drug

• (withdrawal of metformin is not a neutral one since

alternatives predispose to weight gain, heart failureand hypoglycaemia)

Metformin’s effectivity and safety in renal disease. Recommendations 2

• in situations of suspected acute deterioration of renal

function metformin should be stopped

• contrast imaging studies: stop metformin???

• (metformin is contra-indicated in liver dysfunction and

NYHA 3-4)