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 printBackground
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.
Conclusion
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.
References
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.
2012;33(2):187-215.
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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