Diabetes Drugs- Metaformin

Question 1

Metformin - Pharmacology

Answer 1

Biguanide

C4H11N5

Question 2

Metformin – molecular mechanism (4)

Answer 2

a weak cellular poison

1. Inhibition of complex 1 of the mitochondrial respiratory chain
2. Fall in cellular ATP (rise in ADP/ATP ratio)
3. Many consequences:
   Rise in AMP:ATP
   Activation of AMPK
   Reduction in Gluconeogenesis

Question 3

Metformin – site of action (5)

Answer 3

Metformin is hydrophilic so not readily taken up by cells

Requires active transport by Organic Cation Transporters (OCTs)

Distribution of 11C Metformin after oral dosing

Highly concentrated in the Intestines, Liver and Kidney

Excreted unchanged in the urine (i.e. Metformin is not metabolized)

Question 4

Metformin – main physiological mechanisms (2)

Answer 4

Lowers Hepatic Glucose Production
(in patients with poorly controlled diabetes)

Increases Gut glucose utilization and metabolism

Question 5

Metformin – other physiological mechanisms (4)

Answer 5

Increase intestinal GLP-1 secretion

Altered gut microbiome

Decrease Lipogenesis

Reduced inflammation

Question 6

Metformin – simply (3)

Answer 6

Lowers glucose production and increases glucose utilization

This is ‘similar’ to insulin, but It does this in an ‘insulin independent’ way

Sometimes Metformin is incorrectly termed an ‘insulin sensitizer’ – but it does not increase tissue sensitivity to insulin

Question 7

Metformin – clinical use (5)

Answer 7

Potent glucose lowering. HbA1c ~18 mmol/mol

Weight neutral or negative (weight losing)

Usual dose 500mg bd; max dose 1g bd

Once daily (M/R) preparations available – better tolerated

Cheap. £3.20 per month (for 500mg bd)

Question 8

Metformin -side effects gastrointestinal intolerance

Answer 8

~1/5 have some form of GI intolerance
~1/20 have to stop because of this

Symptoms:
Diarrhoea, Bloating, Abdominal Pain, Dyspepsia
Metallic taste in mouth

Probably reflects the high concentration of Metformin in the intestine

Question 9

Metformin- To reduce side effects GI intolerance

Answer 9

initiate slowly:
Metformin 500mg od 1 week + increase by 500mg od per week

Or

Use a modified release formulation:
Metformin M/R 1g od or 2g od.

Question 10

Metformin side effects MALA (4)

Answer 10

Metformin Associated Lactic Acidosis (MALA)

Metformin increases lactate production
(esp by the gut and liver)

Lactate is normally cleared by the liver and kidneys

In Acute Kidney Injury (often in the context of sepsis, when other sources of lactate too, and impaired liver clearance) metformin is associated with greater risk of Lactic Acidosis.

Metformin dose should be decreased as renal function falls:
-Max dose 1g daily if eGFR <45ml/min
-Contraindicated if eGFR <30ml/min
Based upon Pharmacokinetics of metformin, which is renally cleared

Question 11

WHY is metformin 1st line? (4)

Answer 11

its potent

its generally well tolerated

it is weight neutral

probably has CV benefit & very cheap