Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes

Abstract

Introduction: Incretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from glucose-lowering, these agents exhibit pleiotropic actions that may have favourable and unfavourable clinical consequences. Incretin-based therapies have been associated with heart rate acceleration, heart failure, acute renal failure and acute pancreatitis. Conversely, these agents may reduce blood pressure, glomerular hyperfiltration, albuminuria and hepatic steatosis. While large-sized cardiovascular safety trials can potentially identify the clinical significance of some of these pleiotropic actions, small-sized mechanistic studies are important to understand the (patho)physiological rationale of these findings. The current protocol describes a mechanistic study to assess cardiovascular, renal and gastrointestinal effects, and mechanisms of incretin-based therapies in type 2 diabetes.

Methods and analyses: 60 patients with type 2 diabetes will undergo acute and prolonged randomised, double-blind, intervention studies. The acute intervention will consist of intravenous administration of the GLP-1 receptor agonist exenatide or placebo. For the prolonged intervention, patients will be randomised to 12-week treatment with the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebos. For each examined organ system, a primary end point is defined. Primary cardiovascular end point is change in resting heart rate variability assessed by beat-to-beat heart rate monitor and spectral analyses software. Primary renal end point is change in glomerular filtration rate assessed by the classic inulin clearance methodology. Primary gastrointestinal end points are change in pancreatic exocrine function assessed by MRI-techniques (acute intervention) and faecal elastase-1 levels (12-week intervention). Secondary end points include systemic haemodynamics, microvascular function, effective renal plasma flow, renal tubular function, pancreatic volume and gallbladder emptying-rate.

Medical ethics and dissemination: The study is approved by the local Ethics Review Board (VU University Medical Center, Amsterdam) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.

Trial registration number: NCT01744236.

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Figures

Figure 1

Study design: Subjects will be screened for eligibility. Included subjects will undergo a run-in period of at least 4 weeks after which the baseline end point measurements for the 12-week study and the acute intervention studies are performed*. Subsequently, subjects are randomised for the prolonged intervention. After 2 and 6 weeks, a safety visit is performed. At week 1 and 9, telephone follow-up is performed (not depicted). After 12 weeks of treatment, the end point measurements are performed. *For the acute cardiovascular and renal study, subjects are randomised to exenatide or placebo. For the acute pancreatic study, 12 patients will receive intravenous exenatide and placebo in a randomised cross-over design.

Figure 2

Flow chart of the acute and prolonged intervention study. *For the acute cardiovascular and renal intervention study, patients are randomised to receive exenatide or placebo (parallel-group design). For the acute pancreatic intervention study, patients receive exenatide and placebo, in a randomised order (cross-over design).

Figure 3

End point visit cardiovascular and renal tests. Schematic overview of the cardiovascular and renal end point visits. (A) At the baseline end point visit, the acute cardiovascular and renal intervention study is performed; (B) At the 12-week end point visit, no acute intervention study is performed. PAH, para-amino hippuric acid.