DPP 4 Inhibitors

DPP 4 inhibitors (gliptins) are oral agents that raise endogenous incretin levels. They lower glucose modestly (HbA1c by 0.5 to 0.8%), are weight neutral and carry a low hypoglycaemia risk, which suits older and frail patients.

Mechanism. They inhibit dipeptidyl peptidase 4, which degrades GLP-1 and GIP. Raised active incretin levels increase insulin release and reduce glucagon secretion only when glucose is high.

Pharmacokinetics. Well absorbed orally. Sitagliptin, saxagliptin, alogliptin and vildagliptin are cleared mainly by the kidney, so dose reduction applies. Linagliptin is cleared by the bile and gut and needs no renal adjustment. Saxagliptin is metabolised by CYP3A4.

Differences. Linagliptin suits kidney impairment. Vildagliptin carries liver enzyme monitoring. Saxagliptin and alogliptin carry a heart failure hospitalisation signal and are avoided in heart failure. Sitagliptin and linagliptin are cardiovascular neutral.

• Second-line add-on to metformin: where a sulphonylurea would pose a hypoglycaemia risk, such as older adults, kidney impairment or irregular meals.
• Monotherapy: when metformin is contraindicated or not tolerated.
• Triple therapy: with metformin and a sulphonylurea or pioglitazone.
• Not combined with GLP-1 receptor agonists, which gives no added benefit.
• Fixed dose combinations with metformin are widely used to improve adherence.

Special groups. Pregnancy: avoid; insulin is used. Breastfeeding: avoid. Children: not used. Older adults: well tolerated, low hypoglycaemia. Kidney impairment: adjust all except linagliptin. Liver impairment: avoid vildagliptin; others with caution in severe disease.

Adverse effects. Nasopharyngitis, headache, and rarely acute pancreatitis (stop permanently), severe joint pain, bullous pemphigoid (stop), angioedema (more likely with ACE inhibitors), and raised liver enzymes with vildagliptin.

Contraindications. Type 1 diabetes, ketoacidosis, pregnancy, previous pancreatitis from the drug, and heart failure for saxagliptin and alogliptin.

Interactions. Saxagliptin dose is halved with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir). Rifampicin lowers sitagliptin and linagliptin levels. Hypoglycaemia risk rises with a sulphonylurea or insulin, so reduce those doses.

Monitoring. HbA1c every 3 months, eGFR at baseline and annually, liver enzymes before vildagliptin and during the first year, and abdominal pain, skin blistering and arthralgia at review.

Referral and escalation. Suspected pancreatitis, heart failure, or failure to reach target after 3 to 6 months.