Lixisenatide Arterial Stiffness Trial (LAST) Version 3.0
Research type
Research Study
Full title
Effect of Lixisenatide on arterial stiffness in patients with diabetic nephropathy
IRAS ID
209757
Contact name
Janaka Karalliedde
Contact email
Sponsor organisation
King's College London
Eudract number
2016-001758-17
Duration of Study in the UK
3 years, 0 months, 0 days
Research summary
Diabetic kidney disease (DKD) develops in nearly 40% of patients with type 2 diabetes (T2DM) and is the leading cause of renal disease in the UK. Patients with DKD are at higher risk of cardiovascular disease (CVD). Increased arterial stiffness due to loss of elasticity of the blood vessels and the presence of protein (albumin) in the urine can predict future risk of CVD and progression of DKD. Glucagon receptor agonists (GLP-1) are an approved treatment for T2DM. These drugs appear to have potential CVD benefits. However the exact mechanisms for these effects remain unclear. GLP-1 receptor agonists may improve the health of arteries by reducing arterial stiffness and the amount of albumin in the urine. Lixisenatide is a GLP-1 receptor agonist that is licensed for the treatment of adults with T2DM in the UK. The purpose of this study is to measure the effect of Lixisenatide on arterial stiffness in patients with diabetic kidney disease. If Lixisenatide can reduce arterial stiffness and other predictors of CVD, this work would enable us to get important information to perform a larger trial to see if this treatment reduces the risk of end stage renal disease and CVD in patients with DKD.
Lay summary of study results: We initially assessed 143 participants for eligibility, of which 42 were excluded (Supplementary Figure 1). In total, 101 participants were randomised Lixisenatide (n=51) or Placebo (n=50) of whom 90 were eligible for the final mITT analyses (Lixisenatide n=47 and placebo n=43). Of this cohort, 64.4% were males and 35.7% females with T2D, mean (standard deviation) age of 61.8 (9.3) years, 46.7% of Black heritage and 45.6% of Caucasian with remainder from Asian, other and mixed heritages. All participants were on renin-angiotensin-aldosterone system (RAAS) inhibition for their chronic kidney disease (CKD) in diabetes. The primary reasons for dropout were participant choice and inability to adhere to study visit schedule, with one participant withdrawing due health reasons unrelated to the investigational medicinal product (IMP) (placebo arm). Of those who withdrew, n=7 were in the Lixisenatide arm and n=10 in the placebo arm.
At baseline, the mean (SD) body weight was 101.1 kg (19.2) in the treatment (Lixisenatide) group, 103.0 kg (20.6) in the placebo group, and 102.0 kg (19.8) overall. Waist circumference was 118.3 cm (12.7), 119.7 cm (13.1), and 118.9 cm (12.8) in the treatment, placebo, and overall groups, respectively.
Baseline seated brachial systolic blood pressure averaged 133.8 mmHg (19.8) in the treatment group, 131.6 mmHg (14.9) in the placebo group, and 132.7 mmHg (17.6) overall. Corresponding baseline diastolic blood pressure was 78.6 mmHg (9.1), 75.2 mmHg (8.0), and 77.0 mmHg (8.7). Seated brachial pulse rate was 75.6 bpm (12.4) in the treatment group, 79.9 bpm (13.5) in the placebo group, and 77.7 bpm (13.1) overall.
The mean estimated glomerular filtration rate (eGFR) at baseline was 62.5 mL/min/1.73 m² (23.0) in the treatment group, 71.9 mL/min/1.73 m² (29.2) in the placebo group, and 67.0 mL/min/1.73 m² (26.4) overall. Baseline fasting glucose concentrations were 10.7 mmol/L (5.2), 10.2 mmol/L (3.9), and 10.5 mmol/L (4.6) in the treatment, placebo, and overall groups, respectively. Serum creatinine levels at baseline were 106.8 µmol/L (39.1) in the treatment group, 98.1 µmol/L (36.2) in the placebo group, and 102.6 µmol/L (37.8) overall.
Total cholesterol at baseline was 4.4 mmol/L (1.3) in the treatment group, 3.8 mmol/L (0.9) in the placebo group, and 4.1 mmol/L (1.2) overall. Triglyceride levels were consistent across groups at 1.7 mmol/L (1.0). High-density lipoprotein (HDL) cholesterol was 1.3 mmol/L (0.4) in the treatment group, 1.2 mmol/L (0.3) in the placebo group, and 1.2 mmol/L (0.4) overall, while LDL cholesterol was 2.4 mmol/L (1.1), 1.9 mmol/L (0.7), and 2.1 mmol/L (0.9), respectively.
With regard to baseline HbA1c level, it was 9.3% (1.7) in the treatment group and 9.0% (1.7) in the placebo group, with an overall mean of 9.2%. Baseline haemoglobin concentration was 131.9 g/L (13.8) in the treatment group, 132.9 g/L (16.1) in the placebo group, and 132.4 g/L (14.9) overall.
At baseline, the mean aortic pulse wave velocity (Ao-PWV), calculated as the average of three measurements, was similar between the two groups: 9.4 (3.0) m/s in the Lixisenatide group and 9.4 (2.3) m/s in the placebo group, with an overall mean of 9.4 (2.7) m/s across all participants.
Baseline central systolic blood pressure (SBP), also averaged over three measures, was slightly higher in the Lixisenatide group at 120 (17.4) mmHg, 116.6 (16.0) mmHg in placebo, with a total cohort mean of 118.7 (16.8) mmHg.
At baseline, central diastolic blood pressure (DBP) was 79.8 (8.8) mmHg in the Lixisenatide group 76.1 (8.4) mmHg in the placebo group (76.1 ± 8.4 mmHg), with an overall mean of 78.0 (8.8) mmHg.
The augmentation index, derived as the mean of three readings, was 18.4 (8.8) mmHg in the Lixisenatide group and 14.8 (11.2) in placebo, with a pooled mean of 16.7 (10.1) mmHg across the study population.
Over 24 weeks Ao-PWV did not differ significantly between groups. Ao-PWV (mean ±SD) did not change significantly from baseline after 24 weeks of treatment with a mean (95% confidence intervals) 9.65 m/s (9.17, 10.13) with Lixisenatide and 9.96 m/s (9.45, 10.46) with placebo, p=0.378.
We did not observe any significant changes with treatment versus placebo in a panel of cardio-renal biomarkers including sKlotho, albuminuria, central SBP, central DBP, seated brachial SBP, seated brachial DBP, weight and eGFR. HbA1c fell significantly only with Lixisenatide as expected. We also did not observe any significant changes in either group on several clinical and biochemical measures and markers.
There were no deaths during the study and overall, Lixisenatide was well tolerated with no serious adverse events (SAE) related to the drug reported.
REC name
London - Bloomsbury Research Ethics Committee
REC reference
16/LO/1947
Date of REC Opinion
14 Nov 2016
REC opinion
Favourable Opinion