A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes

Abstract

Background: Studies of dipeptidyl peptidase (DPP)-4 inhibitors report heterogeneous effects on endothelial function in patients with type 2 diabetes (T2D). This study assessed the effects of the DPP-4 inhibitor linagliptin versus the sulphonylurea glimepiride and placebo on measures of macro- and microvascular endothelial function in patients with T2D who represented a primary cardiovascular disease prevention population.

Methods: This crossover study randomised T2D patients (n = 42) with glycated haemoglobin (HbA1c) ≤7.5%, no diagnosed macro- or microvascular disease and on stable metformin background to linagliptin 5 mg qd, glimepiride 1-4 mg qd or placebo for 28 days. Fasting and postprandial macrovascular endothelial function, measured using brachial flow-mediated vasodilation, and microvascular function, measured using laser-Doppler on the dorsal thenar site of the right hand, were analysed after 28 days.

Results: Baseline mean (standard deviation) age, body mass index and HbA1c were 60.3 (6.0) years, 30.3 (3.0) kg/m2 and 7.41 (0.61)%, respectively. After 28 days, changes in fasting flow-mediated vasodilation were similar between the three study arms (treatment ratio, gMean [90% confidence interval]: linagliptin vs glimepiride, 0.884 [0.633-1.235]; linagliptin vs placebo, 0.884 [0.632-1.235]; glimepiride vs placebo, 1.000 [0.715-1.397]; P = not significant for all comparisons). Similarly, no differences were seen in postprandial flow-mediated vasodilation. However, under fasting conditions, linagliptin significantly improved microvascular function as shown by a 34% increase in hyperaemia area (P = 0.045 vs glimepiride), a 34% increase in resting blow flow (P = 0.011 vs glimepiride, P = 0.003 vs placebo), and a 25% increase in peak blood flow (P = 0.009 vs glimepiride, P = 0.003 vs placebo). There were no significant differences between treatments in postprandial changes. Linagliptin had no effect on heart rate or blood pressure. Rates of overall adverse events with linagliptin, glimepiride and placebo were 27.5, 61.0 and 35.0%, respectively. Fewer hypoglycaemic events were seen with linagliptin (5.0%) and placebo (2.5%) than with glimepiride (39.0%).

Conclusions: Linagliptin had no effect on macrovascular function in T2D, but significantly improved microvascular function in the fasting state. Trial registration ClinicalTrials.gov identifier-NCT01703286; registered October 1, 2012.

Keywords: Dipeptidyl peptidase-4 inhibitor; Endothelial function; Flow-mediated vasodilation; Linagliptin; Macrovascular; Microvascular; Sulphonylurea; Type 2 diabetes.

Figures

Fig. 1

a Study design. b Vascular assessments on day 1 and day 28 of the 4-week treatment periods. FMD flow-mediated vasodilation, NMD nitroglycerin-mediated vasodilation. *Glimepiride dose uptitration protocol: initial daily dose of 1 mg for 1 week, uptitrated to 2 mg from week 2; further uptitration to maximum daily dose of 4 mg was allowed if fasting glucose levels were >110 mg/dL (>6.1 mmol/L) at days 14 and 21, and at the investigator’s discretion. †2-h postprandial

Fig. 2

Change from baseline after 28 days between the three treatment groups in brachial endothelial-dependent macrocirculatory function using flow-mediated vasodilation (efficacy set). a Fasting. b 2-h postprandial. *Ratio of flow-mediated vasodilation on day 28 to flow-mediated vasodilation at baseline. †n = 40 at baseline. CI confidence interval, FMD flow-mediated vasodilation

Fig. 3

Change from baseline after 28 days between the three treatment groups in endothelial-dependent microcirculatory function using laser-Doppler—hyperaemia area (efficacy set). a Fasting. b 2-h postprandial. *Ratio of hyperaemia on day 28 to hyperaemia at baseline. †n = 40 at baseline. ‡n = 38 at baseline. CI confidence interval

Fig. 4

Change from baseline after 28 days between the three treatment groups in endothelial-dependent microcirculatory function using laser-Doppler—resting blood flow (efficacy set). a Fasting. b 2-h postprandial. *Ratio of resting blood flow on day 28 to resting blood flow at baseline. †n = 40 at baseline. ‡n = 38 at baseline. CI confidence interval

Fig. 5

Change from baseline after 28 days between the three treatment groups in endothelial-dependent microcirculatory function using laser-Doppler—peak blood flow (efficacy set). a Fasting. b 2-h postprandial. *Ratio of peak blood flow on day 28 to peak blood flow at baseline. †n = 40 at baseline. ‡n = 38 at baseline. CI confidence interval

Fig. 6

Frequency of patients with investigator-reported hypoglycaemia (treated set). BG blood glucose