OHA series - Metformin

Metformin is the prototype oral hypoglycemic agent (OHA). It’s is often reflexively used by physicians in newly diagnosed diabetics. This confidence is inspired by its many positive effects and relatively few adverse effects.

Metformin belongs to a class of drugs called biguanides.

Where did Biguanides come from?

In medieval times the plant Galega officinalis was prescribed for patients with polyuria and excessive thirst. G. officinalis, is also called Goat’s rue, French lilac or Italian fitch, was recognised to have an active ingredient called guanidine which lowered blood glucose.

Once guanidine was identified as the active ingredient with blood sugar lowering properties, the next step was the make synthetic guanidine. However, synthetic guanidine itself was not great for treating diabetes mellitus due to its toxicity.

But two guanidine molecules put together did the trick! And voila, we had biguanides (Two guanidines side by side).

There were three biguanides that were initially introduced in the 1950s - Phenformin, buformin and metformin. However, Phenformin and Buformin were discontinued because of their tendency to cause lactic acidosis and cardiac disturbances.

Mechanism of Action - How does Metformin work?

There are two things about metformin’s mechanism of action that you need to understand.

1. It does not lower blood glucose if the blood glucose is not elevated. This means that it does not cause hypoglycemia.

2. It does not increase serum insulin levels. This means that it does not cause weight gain.

The main mechanism of action of metformin is activation of AMP activated protein kinase in hepatocytes and skeletal muscles. This leads to increased utilisation of blood glucose. It also reduces hepatic gluconeogenesis and lipogenesis.

Metformin also slightly promotes insulin mediated uptake of blood glucose by the skeletal muscles.

As an added bonus, Metformin also results in a more desirable lipid profile because it reduces lipogenesis.

Indications of Metformin - When should it be used?

1. Newly diagnosed diabetes mellitus type 2

2. Obese patients with diabetes mellitus

How effective is Metformin?

Typically after a single dose, the blood glucose levels reduce by approximately 20%.

What are the adverse effects of Metformin?

1. GI disturbances - nausea, vomiting, flatuance

2. Chest pain, palpitations

3. Taste abnormalities

4. Vitamin B12 deficiency

5. Lactic acidosis - seen in <1% of patients

What conditions predispose to lactic acidosis during Metformin use?

• Renal failure

• Liver failure

• Heart failures

• Past history of lactic acidosis

• Sepsis with shock

• Hypoxia / hypotension

What is the dose of Metformin used?

Initial dose is 500 mg daily. Dose escalation should be done every 1-2 weeks.

Maximum dose is 2000mg daily.

Contraindications - When should you not give Metformin?

• eGFR < 45ml/min/ sq. M.

• Acidosis

• Congestive heart failure

• Cirrhosis

• Hypoxia or shock.

Author:
Narendran Sairam

Sources and citations

1. Ganesan, Kavitha, et al. “Oral Hypoglycemic Medications - Statpearls - NCBI Bookshelf.” National Library of Medicine, 8 May 2022, https://www.ncbi.nlm.nih.gov/books/NBK482386/.
   
2. Stephens, Julia. “Oral Hypoglycemic Drugs.” Boulder Medical Center, 13 Sept. 2018, https://www.bouldermedicalcenter.com/oral-hypoglycemic-drugs/.
   
3. Witters, Lee A. “The Blooming of the French Lilac.” Journal of Clinical Investigation, vol. 108, no. 8, 2001, pp. 1105–1107., https://doi.org/10.1172/jci14178.