DPP-4 inhibitor decreases aortic pulse wave velocity in diabetic patients

Effect of linagliptin on pulse wave velocity in early type 2 diabetes (RELEASE): a randomized, double-blind, controlled 26-week trial

Literature - de Boer SA, Heerspink HJL, Juárez Orozco LE, et al. - Diabetes, Obesity and Metabolism 2017; published online ahead of print


DPP-4 inhibitors effectively reduce glycated hemoglobulin (HbA1c) levels, without inducing hypoglycaemia, and have a neutral effect on weight [1]. They inhibit the DPP-4 enzyme, which splits incretins such as glucagon-like peptide 1 (GLP-1). GLP-1 controls glucose dependent insulin secretion. DPP-4 also splits multiple substrates that influence the cardiovascular (CV) system, like the chemokine stromal cell-derived factor- 1α (SDF-1α) that is responsible for the recruitment of endothelial progenitor cells. This suggests that DPP-4 inhibition may have favourable CV effects on top of glucose lowering [2].

Arterial stiffness can be assessed by means of aortic pulse wave velocity (PWV), central systolic blood pressure (SBP) and augmentation index (AIx). PWV is a strong independent predictor of future CV events and all-cause mortality in the general population [3,4].

In the RELEASE trial, the effects on PWV, central SBP and AIx of 26 weeks treatment with the DPP-4 inhibitor linagliptin were evaluated in 44 individuals with recent type 2 diabetes mellitus (T2DM) diagnosis (so naïve to antidiabetic treatment), who were randomly assigned to receive linagliptin or placebo.

Main results

  • The median T2DM duration was 1 year (IQR: 0-3.5) and the baseline characteristics were well balanced between groups.
  • After 26 weeks of therapy, PWV was significantly lower in the linagliptin group compared with placebo, with a between group-difference of 0.91 m/s (95% CI 0.06-1.76 m/s, P=0.035).
  • PWV changed from 8.7 m/s (95% CI 8.0-9.3 m/s) at baseline to 8.3 m/s (95% CI 7.7-8.8 m/s) at 4 weeks and to 8.3 m/s (95% CI 7.8-8.9 m/s) at 26 weeks in the linagliptin group. In the placebo group PWV changed from 8.8 m/s (95% CI 8.3-9.3 m/s) at baseline to 8.8 m/s (95% CI 8.1-9.4 m/s) at 4 weeks and to 9.2 m/s (95% CI 8.6-9.8 m/s) at 26 weeks.
  • At week 30, which was after 4 weeks of washout, PWV in both groups returned to baseline.
  • Central SBP and AIx between the linagliptin and placebo groups did not differ significantly from baseline throughout treatment (week 26 ΔSBP -2.8, 95% CI -15.8 to 10.2, P=0.674 and ΔAIx -0.7, 95% CI -4.0 to 3.5, P=0.738) and at week 30 (after washout).
  • In the linagliptin group, a positive correlation was observed between the decrease of PWV from baseline to week 26 and central SBP (r=0.53, P=0.024), but no correlation was found between the decrease in PWV and AIx (r=-0.15, P=0.565).
  • PWV change from baseline to week 26 tended to correlate with change in HbA1c (%) (r=0.42, P=0.071) but not with change in glucose (r=-0.104, P=0.672) or triglycerides (r=-0.113, P=0.644).
  • After 26 weeks of linagliptin therapy, HbA1c (-0.4%, P<0.001), fasting plasma glucose (-0.7 mmol/l, P=0.002) and triglycerides (-0.49 mmol/l, P=0.019) decreased as compared to placebo.
  • Two serious adverse events were reported, both with an unlikely causal relationship between the event and the study medication. In the linagliptin group, alanine aminotransferase increased to 165 U/l after 6 weeks of study medication and subsequently decreased to 18 U/l after 10 weeks and remained normal during follow-up.


These data may confirm the hypothesis based on previous observations, that linagliptin exert favourable vascular effects beyond glucose-lowering. Compared with placebo, linagliptin decreased aortic PWV, a measure of arterial stiffness and predictor of CV events, in 44 early T2DM subjects after 26 weeks of treatment. This suggest that linagliptin has a favourable effect on arterial stiffness and further studies need to assess whether this translates to improvement of CV outcome on the long-term.


1. Scheen AJ. Cardiovascular effects of gliptins. Nat Rev Cardiol. 2013;10(2):73-84.

2. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev.


3. Cruickshank K, Riste L, Anderson SG, et al. Aortic pulse wave velocity and its relationship to mortality in diabetes and glucose intolerance: An integrated index of vascular function? Circulation. 2002;106(16):2085-2090.

4. Mitchell GF, Hwang SJ, Vasan RS, et al. Arterial stiffness and cardiovascular events: The framingham heart study. Circulation. 2010;121(4):505-511.

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