Metformin

MetforminMetformin

• Metformin action and pharmacokinetics • Metformin and cardiac events • Metformin and pregnancy • Metformin and B12 deficiency• Metformin and lactic acidosis • Metformin and kidney • Metformin and liver • Metformin and old age • Metformin and cancer

How do insulin resistance and How do insulin resistance and -cell dysfunction -cell dysfunction combine to cause type 2 diabetes?combine to cause type 2 diabetes?

Abnormalglucose tolerance

Hyperinsulinemia,then -cell failure

Normal IGT* Type 2 diabetes

Post-prandial glucose

Insulin resistance

Increased insulinresistance

Fasting glucose Hyperglycemia

Insulinsecretion

*IGT = impaired glucose tolerance

Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.

Insulin resistance – reduced response to Insulin resistance – reduced response to circulating insulincirculating insulin

Insulinresistance

Glucose output Glucose uptake Glucose uptake

Hyperglycemia

Liver Muscle Adiposetissue

IR

Biguanides was discovered by Jean Sterne from France in 1920

Among all biguanides Sterne selected metformin for clinical development

Proposed the name Glucophage(Glucose eater) in the year 1957

During1920s biguanides were discovered from the medicinal plant Galega officinalis

CJ Bailey, C Day : Pract Diab Int April 2004 Vol. 21 No. 3

Metformin & Beta Cell Preservation

While insulin resistance lays the foundation for glucose intolerance, the progression to type 2 diabetes does not occur until a degree of beta cell dysfunction has taken place, allowing blood glucose (BG) levels to rise

Glucose Toxicity and Lipotoxicity are implicated in Beta Cell Dysfunction CANADIAN JOURNAL OF DIABETES. 2003;27(3):277-286

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Intensive (951)

Metformin (342)

Any diabetes related endpointAny diabetes related endpoint

M v Ip=0.0034

overweight patients

M v C p=0.0023

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Intensive (951)

Metformin (342)

Diabetes related deathsDiabetes related deaths

M v Ip=0.11

overweight patients

M v C p=0.017

Myocardial InfarctionMyocardial Infarction

M v Ip=0.12

overweight patients

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Metformin (342)

M v Cp=0.010

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Intensive (951)

Metformin (342)

Microvascular endpointsMicrovascular endpoints

M v Ip=0.39

overweight patients

M v Cp=0.19

Metformin in UKPDS

Mechanisms of MetforminMechanisms of Metformin

Complete mechanisms of metformin’s actions at the molecular level are not yet known

Metformin does indirectly activate AMPK (AMP-activated protein kinase) which is known as the AMPK-dependent mechanism

Activation occurs through inhibition of the mitochondrial respiration chain complex 1

Activation of AMPKActivation of AMPK

AMPK is activated by:

an increase in the intracellular AMP/ATP ratio

Inhibition of complex I results in a reduction in proton-driven synthesis of ATP from ADP and Pi and alters the AMP/ATP ratio

Activated AMPK results in:

glucose, protein, lipid synthesis

fatty acid oxidation, glucose uptake

Riddle M. Combining sulfonylureas and other oral agents. Am J of Med. 2000; 106(6A):16S-22S.

Hypertension & IHD

Metformin

PJ Grant diabetes metabolism 2003

• Stable CAD

• Acute MI

• In patients with acute coronary syndrome (MI or revascularization), metformin is associated with better short-term and long-term prognosis than other glucose-lowering agents.

• Acute coronary syndrome should not be considered a contraindication to the use of metformin in patients with T2DM provided there is no circulatory failure.

• CHF

• Metformin, earelier contraindicated in CHF, may now be used if ventricular dysfunction is not severe, if the patient's CV status is stable and if renal function is normal

• Metformin should not be withheld in diabetic patients with stable CHF who do not have other risk factors for acute decompensated CHF

• In patients with stable CHF, consistent observational data have shown that metformin is associated with a better overall prognosis than other glucose-lowering agents.

• Stable CHF should not be considered a contraindication to the use of metformin in patients with T2DM.

• diabetic patients with elevated systolic blood pressure are at increased risk of developing acute decompensated CHF, a condition that is often associated with decreased kidney function.

• During acute decompensated CHF, timely treatment may prevent the loss of kidney function to the threshold associated with an increased risk of metformin-associated lactic acidosis.

• Infants exposed to diabetes in utero have an increased incidence of childhood obesity and diabetes

• Infants of women with diabetes who were born large for gestational age have been found to have increased insulin resistance when compared with infants born of appropriate size for gestational age

• In the first follow-up of the MiG study, infants of women with GDM who had been randomized to receive either metformin or insulin during pregnancy have been examined at 2 years of age.

• the offspring exposed to metformin in utero had increased subscapular and biceps skinfolds when compared with the unexposed infants, while total body fat was similar.

• this hypothesized a possible benefit as this signal a healthier fat distribution.

• not all low plasma B12 means a “deficiency” and not all high plasma B12 mean “sufficiency”

• the possibility to measure active B12 (tHC) and the metabolic marker, methylmalonic acid (MMA), has changed the practice of diagnosing B12 deficiency in recent years.

• Serum concentrations of homocysteine (HC) as well as serum (and urinary) concentrations of methylmalonic acid (MMA) are elevated in B12 deficiency

• Low serum B12 alone without disturbances in the metabolic markers has no diagnostic value.

• When B12 is internalized and is able to maintain the B12- dependent intercellular enzyme activities (methionine synthase and methylmalonyl-CoA mutase), plasma total homocysteine (tHcy) and MMA will be within the reference range.

• Despite the obvious effect of metformin on lowering plasma B12, concentrations of tHcy were not elevated.

• Patients who were taking metformin had lower serum B12 and holotranscobalamin but normal tHcy

• the B12- dependent reactions are well functioning

in large numbers of metformin-treated patients despite low serum B12.

• In contrast, higher serum B12 in non–metformin treated patients may give the wrong impression that B12 deficiency is less common

• All available evidence suggests that with metformin therapy, lowering plasma B12 (if not associated with increased metabolites) would mean increased cellular uptake of B12.

• Metformin action and pharmacokinetics • Metformin and cardiac events • Metformin and pregnancy • Metformin and B12 defeciency• Metformin and lactic acidosis • Metformin and kidney • Metformin and liver • Metformin and old age • Metformin and cancer

What’s New?What’s New?

METFORMIN

AMPK

Indirect Effects (Insulin

Dependent)

Direct Effects (Insulin

Independent)

Metformin

Health & Medicine

Transcript of Metformin