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

BackgroundStudies 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.MethodsThis 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.ResultsBaseline 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%).ConclusionsLinagliptin 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, 2012Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0493-3) contains supplementary material, which is available to authorized users.

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

“…The glomerular hyperfiltration that characterizes early diabetic nephropathy is associated with increased basal nitric oxide activity [154,155]. Another mechanistic, randomized clinical study found that 4 weeks of linagliptin treatment improved microvascular endothelial function compared with both placebo and the sulphonylurea, glimepiride [156]. In this crossover study in 42 patients with early type 2 diabetes, there was no significant change in macrovascular endothelial function measured by brachial flow-mediated vasodilation.…”

“…In this crossover study in 42 patients with early type 2 diabetes, there was no significant change in macrovascular endothelial function measured by brachial flow-mediated vasodilation. However, there were significant improvements in fasting microvascular function, as measured by changes in blood flow on the dorsal thenar site of the right hand recorded with laser-Doppler flowmetry [156].…”

Linagliptin and cardiovascular outcomes in type 2 diabetes after acute coronary syndrome or acute ischemic stroke

“…In clinical studies, the initial combination of linagliptin and metformin substantially enhanced glycemic control without weight gain and with infrequent hypoglycemia [ 43 ] and also significantly improved microvascular function in the fasting state [ 44 ]. Besides, the special issues of linagliptin is about neuroprotective effects based on some evidences showing that patients treated with linagliptin were significantly associated with fewer events of stroke [ 25 , 26 ].…”

DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho−/− mice

“…It has been shown that DPP-4 inhibitor-treated type 2 diabetic patients had lower risks for cardiovascular disease as compared to those for non-DPP-4 inhibitor users, except metformin users [ 36 ], and its use did not increase the risk of heart failure compared with sulfonylurea [ 37 ]. The initial combination of linagliptin and metformin substantially improved glycemic control without weight gain and with infrequent hypoglycemia [ 38 ] and also significantly improved microvascular function in the fasting state [ 39 ]. Very importantly, type 2 diabetes is known to significantly accelerate premature aging of systemic organs.…”