DPP-4 inhibitors (gliptins): mechanism of action
Gliptins (DPP-4 inhibitors) block the enzyme DPP-4, so the body's own incretins (gut hormones released after eating) last longer and insulin release rises mainly when blood glucose is high.
Remember
Think of a gliptin as an enzyme inhibitor, not a receptor agonist: it keeps the body's own incretins active for longer, so insulin rises mainly when glucose is high.
Memory aid
gliptins protect, tides copy
The '-gliptin' drugs protect the incretins the body already makes, whereas the '-tide' drugs copy them.
Incretins are gut hormones that the body releases after eating, and they boost insulin release. The two that matter here are GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). An enzyme called DPP-4 (dipeptidyl peptidase-4) normally breaks the incretins down.
A gliptin such as sitagliptin is a DPP-4 inhibitor, so it blocks that enzyme. With less breakdown, the body's own GLP-1 and GIP last longer. The pancreas then releases more insulin and less glucagon (the hormone that raises blood glucose).
The effect is glucose-dependent, which means it is seen mainly when blood glucose is high. That explains the profile of these drugs: a modest fall in HbA1c (the blood test of average glucose control over recent weeks to months), weight neutral, which means neither weight gain nor weight loss is expected, and a low risk of hypoglycaemia (abnormally low blood glucose) when used on its own. Hypoglycaemia may occur if sitagliptin is taken alongside other diabetes medicines.
A gliptin protects the incretins that the body already makes, whereas the '-tide' drugs (GLP-1 receptor agonists) copy them. GLP-1 receptor agonists (the '-tide' drugs, such as liraglutide) activate the GLP-1 receptor directly, whereas a gliptin does not act on the receptor itself. Sulphonylureas (drugs such as gliclazide) force the beta cells, the pancreatic cells that release insulin, to release it regardless of the glucose level. SGLT2 inhibitors (the '-flozins', such as dapagliflozin) act in the kidney, so that glucose is lost in the urine.
Key facts
- Target
- the enzyme DPP-4, which breaks down GLP-1 and GIP.
- Effect
- the body's own GLP-1 and GIP last longer, so the pancreas releases more insulin and less glucagon, mainly when blood glucose is raised.
- Glucose-dependent
- insulin release rises mainly when glucose is high, so hypoglycaemia is uncommon when a gliptin is used on its own.
- HbA1c
- the fall is modest.
- Weight
- gliptins are weight neutral.
- Type of drug
- an enzyme inhibitor, not a receptor agonist, so a gliptin does not activate the GLP-1 receptor itself.
Exam traps
- Releasing insulin whatever the blood glucose level is how sulphonylureas work, and it is why they carry a real risk of hypoglycaemia; a gliptin only amplifies the glucose-driven signal, so its risk is low when it is used on its own.
- The major effect of metformin is reducing glucose production by the liver; its main action is not on the incretin system, whereas gliptins prevent incretin breakdown.
- Glucose being lost in the urine is the action of SGLT2 inhibitors, which act in the kidney, whereas gliptins act through gut hormones that influence the pancreas.
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