DPP-IV inhibitors increase GLP-1 levels in vivo by competitively binding to the DPP-IV activation site and decreasing the catalytic activity of the enzyme. Using the protein kinase (PKA)-dependent or guanine nucleotide exchange factor 4 (Epac2) pathway, intestinal-derived GLP-1 activates the glucagon-like peptide-1 receptor (GLP-1R) to increase ...
SGLT-2 inhibitors or GLP-1 receptor agonists are preferred over DPP-4 inhibitors 2, 1 For patients with BMI >35 kg/m, GLP-1 receptor agonists are recommended as second-line therapy due to their greater weight loss potential 2
In contrast with GLP-1 agonists, DPP-4 inhibitors have not been shown to reduce the occurrence of major cardiovascular events and are neutral in terms of weight loss. The difference in cardiovascular efficacy may be due to improved pharmacological activation of the GLP-1 receptor with GLP-1 agonists.
DPP-4 inhibitors and GLP-1 receptor agonists target different metabolic pathways, but combining them requires careful clinical evaluation. Understanding the evidence, mechanism overlaps, and individual biomarker context helps inform provider-guided treatment decisions.
Therapeutic Approaches to Enhance GLP-1 Activity Two pharmacological strategies are available to enhance GLP-1 signalling: DPP-4 Inhibitors Mechanism: Inhibit dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for degrading endogenous GLP-1. Effect: Modestly prolong endogenous GLP-1 activity; weight-neutral and low risk of hypoglycaemia.
GLP-1 receptor agonists also promote significantly more weight loss than DPP-4 inhibitors which are weight neutral. These observations have been made in most cases indirectly through systematic reviews and meta-analyses of incretin studies as very little data is available from direct comparisons [1, 10].
The effect produced by DPP-4 inhibitors is dependent on endogenous GLP-1 levels, and produce a modest effect on GLP-1 activity compared to giving GLP-1 receptor agonists (hence DPP-4 inhibitors do not have the same impact to produce weight loss as GLP-1 agonists).
inhibitors may also benet from weight loss (11). The cardiorenal effects of both GLP-1RA and SGLT-2 inhibitors can be summarized as follows: GLP-1RA have moderate benets on MACE.
DPP-4 inhibitors work by inhibiting the DPP-4 enzyme, which normally breaks down the incretin hormones GLP-1 and GIP. By inhibiting DPP-4, GLP-1 levels are increased for longer after meals.
