When compared in a cursory manner, DPP-4 inhibitors and sulfonylureas seem to be totally different classes of drugs. However, we should be mindful of two important aspects here:

  • Both DPP-4 inhibitors and sulfonylureas are insulin secretagogues; the key difference is that DPP-4 inhibitors act indirectly on the beta cell, via the incretin pathway, while sulfonylureas act directly to increase insulin secretion.
  • Not all sulfonylureas are alike. Modern sulfonylureas, such as gliclazide modified release (MR) and glimepiride, have different molecular structures, binding sites and pharmacokinetics to the older formulations, which allow for much safer glucose control.

DPP-4 inhibitors vs modern sulfonylureas: Not so different?

When DPP-4 inhibitors are compared with modern sulfonylureas alone, multiple similarities become more obvious, as highlighted in the table below:

Characteristic DPP-4 inhibitors Modern sulfonylureas
Affected by weight Weight-neutral and cause less hypoglycemia. Weight-neutral, have low risk of hypoglycemia.
Demographic suitability Can be used in the elderly and those who fast. Can be used safely in prolonged fasting such as during Ramadan.
Cardio-renal benefit and safety Linagliptin, sitagliptin, and alogliptin have proven cardiovascular safety; however, saxagliptin is associated with an increased risk of hospitalization for heart failure. Linagliptin has been shown to have renal benefits in terms of albuminuria reduction Gliclazide MR has been shown to have cardiovascular and renal benefits in the ADVANCE and ADVANCE-ON studies.
Dose adjustment requirement Linagliptin does not require dose adjustment. Require dose titration.

From a nationwide cohort in Korea (2008–2013), 23,674 patients with type 2 diabetes treated with DPP4i plus metformin or SU plus metformin  showed that DPP4i therapy did not increase the overall risk of major cardiovascular and renal outcomes compared to SU therapy. However, the DPP4i-associated risk of hospitalization for heart failure (HHF) remained significant.

The dipeptidyl peptidase (DPP)-4 inhibitor linagliptin and the sulfonylurea glimepiride have similar cardiovascular safety profiles, show the results of the CAROLINA trial. The findings of the CAROLINA trial, which is the first cardiovascular outcomes trial to use an active comparator medication, may remove cardiovascular risk from the list of sulfonylureas’ drawbacks. The two medications produced similar glycemic control, with glycated hemoglobin levels deteriorating in both groups after initial improvements, and although bodyweight changes favored linagliptin, the difference was only modest – around 1.5 kg on average.