University of Groningen
Advanced vascular imaging
de Boer, Stefanie Amarens
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2017
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de Boer, S. A. (2017). Advanced vascular imaging: Technical and clinical applications in type 2 diabetes.
Rijksuniversiteit Groningen.
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Stefanie A. de Boer, Hiddo J. L. Heerspink, Joop D. Lefrandt,
Marieke C. Hovinga-de Boer, Arie M. van Roon,
Luis E. Juárez Orozco, Andor W.J.M Glaudemans
Pieter W. Kamphuisen, Riemer H.J.A. Slart, Douwe J. Mulder
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Chapter 7
LETTER TO THE EDITOR
Dipeptidyl peptidase (DPP)-4 inhibitors are a class of oral antidiabetic agents of which favorable cardiovascular effects are suggested. For example, experimental studies have shown that DPP4-inhibitors reduce atherosclerotic plaque area and macrophage accumulation.1 However, there are no randomized controlled trials investigating these
effects in humans. Arterial 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission
tomography (PET) is associated with macrophage infiltration and levels of inflammatory activity.2 Consequently, arterial 18F-FDG uptake represents a surrogate marker of arterial
inflammation and is a potential target for therapy.
In this randomized controlled trial we assessed the effect of 26 week’ treatment with the DPP-4 inhibitor lingaliptin on arterial 18F-FDG uptake in early type 2 diabetes subjects,
without cardiovascular disease and naïve to antidiabetic treatment. A total of 45 type 2 diabetes subjects (median age 63 [interquartile range (IQR): 54 to 66] years, 61% men, mean glycosylated hemoglobin 6.3±0.4%, median body mass index 30.4 [IQR: 27.5 to 35.8) kg/m2,
median high-sensitivity C-reactive protein 1.15 [IQR: 0.70 to 3.08] mg/L, use of a statin [55%]) were randomized (1:1) to once daily linagliptin 5 mg or placebo in a double-blind fashion (RELEASE study [Off taRget Effects of Linagliptin monothErapy on Arterial Stiffness in Early Diabetes]; baseline data previously published3; 40 subjects completed the study. At baseline
and at 26 weeks a whole body 18F-FDG-PET/low-dose computed tomography scan (Siemens
Biograph 64 slice, Siemens Medical Systems, Knoxville, Tennessee) was performed. Image analyses are described in detail elsewhere.3 In brief, arterial 18F-FDG uptake was quantified
as the prescan glucose-corrected maximal standardized uptake value as previously described3,4 and corrected for background activity (target-to-background ratio, [TBR]). TBRs
were calculated for the carotid arteries, ascending aorta and aortic arch, descending and abdominal aorta, and iliac and femoral arteries, and then averaged for the total aortic tree (meanTBR). Between-group differences were analyzed using a Student independent t test on thecalculated deltas.
As expected, linagliptin decreased glycosylated hemoglobin(-0.4%; P<0.001), fasting plasma glucose (-0.7 mmol/L; P=0.002), and triglycerides (-0.49 mmol/L; P=0.019) as compared to placebo. The changes in body mass index, cholesterol, and high-sensitivity C-reactive protein did not differ significantly between groups. At 26 weeks, the decrease in meanTBR under linagliptin exceeded that under placebo with 0.18 units (95% CI: 0.04 to 0.32; P=0.015) (Figure 1). No significant differences were found for the glucose-uncorrected
meanTBR (0.01 [95% CI: -0.08 to 0.09]; P=0.821).
This is the first randomized placebo-controlled trial that demonstrates that 26 weeks of treatment with linagliptin decreases arterial 18F-FDG uptake in subjects with early type
2 diabetes. Recently, 18F-FDG-PET/ computed tomography has been introduced as an
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inflammation and associated with future cardiovascular events.5 Therefore, arterial 18F-FDG
uptake may potentially be used as a surrogate marker to evaluate protective cardiovascular effects. Our results add evidence to the hypothesis that linagliptin may have potentially favorable vascular effects, supporting observations from preclinical studies.1
Despite the randomized controlled design, our study also has some limitations. First, we selected early stage diabetes subjects without cardiovascular disease and therefore our findings may not be extrapolated to subjects with longer diabetes duration or advanced atherosclerotic disease. Second, although background statin therapy was equally distributed among treatment groups and doses were stable throughout the study, it could have attenuated arterial 18F-FDG uptake, limiting the observed treatment effect. Third, our
results could be influenced by the glucose-lowering effect, as glycaemic control is associated with arterial 18F-FDG uptake.4 However, because we adjusted for prescan glucose levels, the
competitive effect of glucose and 18F-FDG is thought to be minimized.
In summary, 26 weeks of linagliptin decreases arterial 18F-FDG uptake in treatment-naive
type 2 diabetes subjects, supporting earlier observations from (pre)clinical studies that DPP4-inhibitors may have favorable effects on atherosclerosis.
2.3 2.2 2.1 2.0 1.9 0 0 26 Weeks Placebo (n=19) Linagliptin (n=21) ∆ 0.18 [95% CI, 0.04-0.32] (P=0.015) mean TBR
Figure 1 | Effect of Linagliptin on Arterial 18F-Fluorodeoxyglucose Uptake. In the linagliptin group, mean target-to-background ratio (meanTBR) changed from 2.12 (95% confidence interval [CI]: 1.99 to 2.26) to 2.00 (95% CI: 1.90 to 2.11) at 26 weeks and in the placebo group changed from 2.09 (95% CI: 1.96 to 2.21) to 2.15 (95% CI: 2.01 to 2.28), resulting in a placebo-corrected change of 0.18 units (95% CI: 0.04 to 0.32; P=0.015).
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Chapter 7
Acknowledgments
This study was supported by Boehringer Ingelheim BV, Alkmaar, the Netherlands. Boehringer Ingelheim was not involved in the design of the study, collection, management, analysis, and interpretation of the data, writing of the report, or the decision to submit the paper for publication. Parts of this study were presented at the American Heart Association Annual meeting, November 14, 2016, New Orleans, Louisiana. Dr. Heerspink has served as a consultant for Abbvie, AstraZeneca, Astellas, Boehringer Ingelheim, Fresenius, Janssen, and Merck; and has received research support from Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. (Off taRget Effects of Linagliptin monothErapy on Arterial Stiffness in Early Diabetes [RELEASE]; NCT02015299)
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18F-fluorodeoxyglucose positron emission tomography-assessed subclinical vascular inflammation in
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