Treatment of Diabetes

Question 1

Describe NICE guidance for adults who can take metformin

Answer 1

1. If HbA1c rises to 48mmol/mol on lifestyle intervention: Offer standard release metformin (oral 500mg/day) and aim to maintain level of 48mmol/L
2. If HbA1c rises to 58mmol/mol: Consider dual therapy of metformin with DPP-4 inhibitor (sitagliptin 100mg daily), pioglitazone (oral 15-45mg daily), SU (oral gliclazide 40-80mg daily), SGLT-2 inhibitor (dapagliflozin oral 5mg daily). Aim for 53mmol/mol.
3. Second intensification if HbA1c rises to 58mmol/mol: Consider insulin therapy or triple therapy with metformin.
   Metformin + DPP-4 + SU
   Metformin + Pioglitazone + SU
   Metformin + Pioglitazone + SU/SGLT-2

Question 2

Describe pharmacokinetics of metformin

Answer 2

Metformin has a pKa of 12.4 and hence is a highly polar molecule. Remains charged even in the most alkaline tissue. Metformin is transported by OCT-1 (organic cation transporter-1)

Question 3

Describe how metformin is transported after ingestion

Answer 3

After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios.6 These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism.

Question 4

Where is OCT-1 expressed?

Answer 4

Expressed in hepatocytes (liver), enterocytes (small bowel) and proximal tubules (kidney). Small bowel OCT-1 allows it to be absorbed. Hepatocyte OCT-1 allows it to be distributed to the site of action. Proximal tubule OCT-1 helps excretion.

Question 5

What are key side effects of the drugs used in diabetes treatment?

Answer 5

DPP-4 inhibitor: Upper respiratory tract infections
Pioglitazone: Heart failure
Sulphonylurea: Weight gain
SGLT-2 inhibitor: Urogenital infections

Question 6

How does eGFR influence metformin dose?

Answer 6

If below 30, contraindicated. If at lower end of 30-45, do not newly initiate. If at higher end, if already taking metformin consider 50% dose reduction. If 45-60, monitor eGFR every 3-6 months. If above 60, no adjustment needed.