Supplementary Figure 1. Flowchart for the screening, enrolment and follow-up of the study population.
Supplementary tables
Supplementary Table S1. Effect of liraglutide vs. placebo on mean 24-h BP at four intervals of the day
Treatment effect Difference 95% CI p-value
Liraglutide Placebo 24-h blood pressure parameters
Morning systolic BP (7-12) -4.8 (11.5) -3.3 (15.6) -1.5 (17.5) -9.0 to 6.1 0.686
Afternoon systolic BP (13-18) -0.6 (12.9) -3.4 (17.6) 2.8 (25.7) -8.1 to 13.6 0.602
Evening systolic BP (19-24) 4.3 (15.3) -4.8 (11.9) 9.2 (19.1) 1.1 to 17.2 0.028
Late Night systolic BP (01-06) 0.5 (18.4) -1.0 (14.9) 1.5 (26.7) -10.0 to 13.0 0.790
Morning diastolic BP (7-12) 2.4 (8.3) -0.4 (12.5) 2.8 (16.0) -4.1 to 9.7 0.406
Afternoon diastolic BP (13-18) 2.1 (10.4) -2.4 (11.7) 4.4 (17.0) -2.8 to 11.6 0.215
Evening diastolic BP (19-24) 5.2 (9.3) -4.5 (9.2) 9.7 (13.8) 3.9 to 15.5 0.002
Late Night diastolic BP (01-06) 1.9 (8.5) 0.1 (10.3) 1.8 (12.9) -3.8 to 7.3 0.523
Data are expressed as mean (SD) unless stated otherwise. BP, blood pressure
Supplementary Table S2. Treatment Effect by Subgroup
Subgroup Measurement Treatment effect Differenc
e 95% CI p-value N
Liragluti
de Placebo Baseline visit 1
mean 24-h systolic BP
<133.9 mmHg Mean 24-h Systolic BP,
mmHg -2.1
(4.6) 1.0
(11.6) -3.1
(14.4) -12.2 to
6.1 0.477 12
≥ 133.9 mmHg Mean 24-h Systolic BP, mmHg
-0.7 (10.8)
-7.4
(9.2) 6.7 (13.5) -1.9 to
15.2 0.116 12
Baseline visit 1 mean 24-h diastolic BP
<77.7 mmHg Mean 24-h Diastolic BP, mmHg
-2.2 (4.5)
-1.4 (10.9)
-0.8 (13.5)
-9.4 to
7.8 0.842 12
≥ 77.7 mmHg Mean 24-h Diastolic BP,
mmHg 2.0 (8.4) -2.7
(8.2) 4.7 (13.0) -3.6 to
13.0 0.240 12
Data are expressed as mean (SD) unless stated otherwise. BP, blood pressure
Supplementary Table S3. List of Total Adverse Events in Study.
Group Event Liraglutide
period Placebo period Washout period Abnormal blood
test Amylase increased 1 (1.1) 0 (0) 0 (0)
Abnormal blood
test Anemia 1 (1.1) 0 (0) 0 (0)
Abnormal blood
test Creatinine Increased 1 (1.1) 0 (0) 1 (7.7)
Abnormal blood
test PSA Elevated 1 (1.1) 1 (2.6) 0 (0)
Cardiac Atrial Fibrillation 0 (0) 1 (2.6) 1 (7.7)
Cardiac Non Cardiac Chest Pain 0 (0) 0 (0) 2 (15.4)
Cardiac Chest Pain Cardiac 2 (2.2) 3 (7.9) 1 (7.7)
Cardiac Dyspnea 1 (1.1) 1 (2.6) 0 (0)
Cardiac Myocardial Infarction 2 (2.2) 0 (0) 0 (0)
Cardiac Palpitations 1 (1.1) 1 (2.6) 0 (0)
Cardiac Sinus Tachycardia 2 (2.2) 0 (0) 0 (0)
Gastrointestinal Anorexia 12 (13.2) 1 (2.6) 0 (0)
Gastrointestinal Bloating 1 (1.1) 0 (0) 0 (0)
Gastrointestinal Constipation 5 (5.5) 2 (5.3) 0 (0)
Gastrointestinal Dehydration 0 (0) 1 (2.6) 0 (0)
Gastrointestinal Diarrhea 7 (7.7) 4 (10.5) 1 (7.7)
Gastrointestinal Gastroesophageal Reflux
Disease 8 (8.8) 1 (2.6) 0 (0)
Gastrointestinal Gastroenteritis 0 (0) 1 (2.6) 1 (7.7)
Gastrointestinal Nausea 18 (19.8) 3 (7.9) 0 (0)
Gastrointestinal Stomach Pain 1 (1.1) 2 (5.3) 0 (0)
Gastrointestinal Vomiting 4 (4.4) 0 (0) 0 (0)
Infection Chills 1 (1.1) 0 (0) 0 (0)
Infection Infection eye 0 (0) 1 (2.6) 0 (0)
Infection Infections Other Cold 1 (1.1) 3 (7.9) 1 (7.7)
Infection Sinusitis 2 (2.2) 1 (2.6) 0 (0)
Infection Skin Infection 0 (0) 0 (0) 2 (15.4)
Muscle Myalgia 0 (0) 1 (2.6) 1 (7.7)
Neurological Dizziness 5 (5.5) 3 (7.9) 2 (15.4)
Neurological Erectile Dysfunction 0 (0) 1 (2.6) 0 (0)
Neurological Headache 2 (2.2) 0 (0) 0 (0)
Neurological Insomnia 0 (0) 2 (5.3) 0 (0)
Neurological Libido Decreased 1 (1.1) 0 (0) 0 (0)
Neurological Concussion 1 (1.1) 0 (0) 0 (0)
Neurological Somnolence 2 (2.2) 0 (0) 0 (0)
Other Fat Biopsy Related
Complication 2 (2.2) 0 (0) 0 (0)
Renal, urine Proteinuria 1 (1.1) 0 (0) 0 (0)
Renal, urine Discoloration of Urine 0 (0) 1 (2.6) 0 (0)
Skin Pruritus 2 (2.2) 0 (0) 0 (0)
Skin Maculopapular Rash 1 (1.1) 1 (2.6) 0 (0)
Vascular Allergic reaction 0 (0) 1 (2.6) 0 (0)
Vascular Hot flash 1 (1.1) 1 (2.6) 0 (0)
Vascular Vascular Disorders -
Hypotension 1 (1.1) 0 (0) 0 (0)
Total events 91 38 13
Supplementary Table S4. Period, sequence and carry over effects for primary and secondary outcomes
Parameter
P-value for period effect
P-value for sequence effect
P-value for carry over effect
Weight 0.415 0.528 0.519
Waist 0.599 0.813 0.934
HbA1C 0.007 0.058 0.041
Resting Heart rate 0.729 0.452 0.426
24-h systolic BP 0.236 0.264 0.371
24-h diastolic BP 0.286 0.444 0.618
24-h HR 0.778 0.999 1.000
Data are expressed as p-values for period, sequence and carry over effects. Analysis of variance for 2x2 crossover study was used (pkcross command in Stata 13.1).
HbA1C, glycated hemoglobin; BP, blood pressure; HR, heart rate
Supplementary Table S5. Main characteristics of the studies included in the meta-analysis Study Design Liraglutide
subcutaneo us dosage
Subjects Duration Age, years Mean BMI HbA1C, %
Scholten,
2014 Non-
randomized , no
placebo- control
Titrated to
1.8 mg n=31;
T2D 7 weeks Median
age 64 (range: 37- 78)
31.9±4.4 7.7±1.3 %
Meier, 2015 Randomize d, no- placebo control
1.2 mg arm;
1.8 mg arm 1.2 mg arm (n=44) and 1.8 mg arm (n=46);
T2D
8 weeks 1.2 mg arm:
61.4±7.9 1.8 mg arm:
62.6±9.4
1.2 mg arm:30.5±
4.0 1.8 mg arm:
31.2±4.3
1.2 mg arm:
7.8±0.8%
1.8 mg arm:
7.9±0.8%
Lovshin, 2015
Randomize d, placebo- controlled, cross-over
Titrated to 1.8 mg
n=17;
T2D
3 weeks Median age 62 years
29.5 7%
Present study
Randomize d, placebo- controlled, cross-over
Titrated to 1.8 mg
n=24;
T2D
12 weeks 62.5±7.2 30.9±3.9 6.5±0.5%
BMI, body mass index; HbA1C, glycated hemoglobin; T2D, type 2 diabetes