Blood Pressure Outcomes With Liraglutide Therapy (BOLT)

This study has been completed.
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
Mount Sinai Hospital, Canada
ClinicalTrials.gov Identifier:
NCT01755572
First received: December 19, 2012
Last updated: March 23, 2015
Last verified: March 2015
  Purpose

Purpose:

The purpose of this study is to further study the mechanism by which liraglutide, a relatively new anti-hyperglycemic medication, might lower blood pressure in patients with Type 2 diabetes and high blood pressure.


Condition Intervention Phase
Type 2 Diabetes
Systolic Hypertension
Drug: Liraglutide
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Hormonal Regulation of Systolic Blood Pressure in Response to the GLP-1 (Glucagon-Like Peptide-1) Receptor Agonist, Liraglutide.

Resource links provided by NLM:


Further study details as provided by Mount Sinai Hospital, Canada:

Primary Outcome Measures:
  • Change in plasma ANP level at 1 Day [ Time Frame: Change from Baseline compared in plasma ANP following 1 dose of liraglutide (0.6 mg) compared to crossover treatment with placebo at the 2-hour timepoint ] [ Designated as safety issue: No ]
    +16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 hours

  • Change in plasma ANP level at 21 Days [ Time Frame: Change from Baseline in plasma ANP following 21 days of liraglutide (titrated to 1.8 mg) compared to crossover treatment with placebo at the 2-hour timepoint ] [ Designated as safety issue: No ]
    -17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 hours


Secondary Outcome Measures:
  • Change in mean 24-Hr urinary sodium excretion rate following 21 days of liraglutide (titrated 1.8mg) compared to crossover with placebo (baseline-subtracted) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    median change +14.18 mmol/L liraglutide vs. placebo (statistically significant, Wilcoxon rank sum)

  • Change in mean Nighttime urinary sodium excretion rate following 21 days of liraglutide (titrated 1.8mg) compared to crossover with placebo (baseline-subtracted) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    median change +4.24 mmol/L nighttime, liraglutide vs. placebo (statistically significant, Wilcoxon Rank Sum)

  • Change in mean 24-Hr systolic BP, liraglutide compared to crossover with placebo (baseline-subtracted) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    +2.33 ± 1.67, p=0.18;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value

  • Change in mean 24-hr diastolic BP, liraglutide compared to crossover with placebo (baseline-subtracted) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    +3.78 ± 1.34, p=0.01;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value

  • Change in mean 24-hr HR, liraglutide compared to crossover with placebo (baseline-subtracted) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    +5.21 ± 2.42, p=0.05; Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value

  • Office-measured systolic BP; Treatment difference for liraglutide compared to crossover with placebo [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    -2.35 mmHg (3.49), p=0.51;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value

  • Office-measured diastolic BP;Treatment difference for liraglutide compared to crossover with placebo [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    +3.6 mmHg (2.33), p=0.14;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value

  • Office-measured heart rate;Treatment difference for liraglutide compared to crossover with placebo [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    +9.25 (3.51), p=0.02;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value


Other Outcome Measures:
  • Change in HbA1c% [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    −0.7%, p=0.005; least squares mean difference, liraglutide compared placebo

  • Change in Fasting Blood Glucose [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    −3.4 mmol/L, p=0.0004; least squares mean difference, liraglutide compared to crossover with placebo, p-value

  • Change in Total Cholesterol [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    -0.63 mmol/L, p=0.002; least squares mean difference, liraglutide compared to crossover with placebo, p-value

  • Change in LDL Cholesterol [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    −0.37 mmol/L, p=0.04; least squares mean difference, liraglutide compared to crossover with placebo, p-value

  • Change in eGFR (estimated Glomerular Filtration Rate) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    -5.76 ml/min/1.73m2 (2.60), p=0.04; least squares mean difference, liraglutide compared to crossover with placebo, (SE), p-value

  • Change in Body Weight [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    +1.35 Kg (0.46), p=0.009; least squares mean difference (SE), p-value, liraglutide compared to crossover with placebo

  • Change in BMI (Body Mass Index) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    -0.42 Kg/cm2 (0.18), p=0.03; least squares mean difference (SE), p-value, liraglutide compared to crossover with placebo

  • Change in Plasma Angiotensin II [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    -0.97 pmol/L (0.86), p=0.28; least squares mean difference (SE), p-value, liraglutide compared to placebo

  • Change in Plasma CRP [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    0.09 mg/L (0.80), p=0.91; least squares mean difference (SE), p-value, liarglutide compared to placebo

  • Change in Triglycerides [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    -0.2 mmol/L (0.18), p=0.28;least squares mean difference (SE), p-value, liarglutide compared to placebo

  • Change in HDL [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    +0.083 mmol/L (0.03), p=0.02;least squares mean difference (SE), p-value, liarglutide compared to placebo


Enrollment: 22
Study Start Date: January 2013
Study Completion Date: March 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Liraglutide
Liraglutide 0.6mg for 7 days, liraglutide 1.2mg for 7 days, liraglutide 1.8mg for 7 days
Drug: Liraglutide
Single cross-over study, 1 arm starting with liraglutide for 3 weeks crossed-over to placebo for 3 weeks, and 1 arm starting with placebo with cross-over to liraglutide for 3 weeks.
Other Name: Victoza
Drug: Placebo
Single cross-over study, 1 arm starting with liraglutide for 3 weeks crossed-over to placebo for 3 weeks, and 1 arm starting with placebo with cross-over to liraglutide for 3 weeks.
Other Name: Placebo
Placebo Comparator: Placebo
Placebo 0.6mg sc for 3 weeks, Placebo 1.2mg sc for 3 weeks, Placebo 1.8mg for 3 weeks.
Drug: Liraglutide
Single cross-over study, 1 arm starting with liraglutide for 3 weeks crossed-over to placebo for 3 weeks, and 1 arm starting with placebo with cross-over to liraglutide for 3 weeks.
Other Name: Victoza
Drug: Placebo
Single cross-over study, 1 arm starting with liraglutide for 3 weeks crossed-over to placebo for 3 weeks, and 1 arm starting with placebo with cross-over to liraglutide for 3 weeks.
Other Name: Placebo

Detailed Description:

Background: Type 2 diabetes is a worldwide health problem. As the reduction in blood pressure has been coupled to improvements in overall cardiovascular outcomes, the control of hypertension has become an important modifiable risk factor in the overall care of the patient with Type 2 Diabetes, in addition to glycemic control. Recently, several large-scale clinical trials evaluating the glucose-lowering effects of the anti-hyperglycemic agent, liraglutide (a glucagon-like peptide-1 receptor agonist), have demonstrated a modest yet persistent anti-hypertensive effect in patients with Type 2 diabetes.

Study Objectives: Accordingly, the goal of this small study is to understand whether the blood pressure lowering effect of liraglutide is coupled to the release of vasoactive mediators which may stimulate natriuresis and/or diuresis and lower systolic blood pressure.

Study Design: Randomized, double-masked, cross-over study with treatment of liraglutide or placebo for 3 weeks, with an intervening washout period for 3 weeks, and cross-over to identical treatment with placebo or liraglutide for 3 weeks.

Study Patients: 20 patients with Type 2 Diabetes and Systolic Hypertension

Endpoints: Change in vasoactive hormones, 24-hour ambulatory blood pressure, urinary sodium excretion patterns.

  Eligibility

Ages Eligible for Study:   30 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women between the ages of 30-70.
  2. Patients with Type 2 Diabetes [diagnosed by their physician] with a serum HbA1c ≥ 6.5% and ≤ 10%.
  3. Patients currently prescribed 0-2 oral hypoglycemic agents by their physician.
  4. Patients with systolic blood pressure ≥ 130 mmHg and ≤ 180 mmHg measured by an automated oscillometric blood pressure device [BPTru® or DinaMAP®].

Exclusion Criteria:

  1. Individuals with Type 1 Diabetes, [or secondary forms of diabetes including gestational diabetes, transplant-associated, glucocorticoid-associated, latent-onset diabetes of the adult, or known monogenic forms of diabetes].
  2. Elevated LVEDP (left ventricular end-diastolic pressure) including congestive heart failure, cardiomyopathy, atrial fibrillation, any valvular heart disease (rated by echocardiography and/or clinically by a cardiologist as moderate or severe in nature), and or elevated RVEDP (right ventricular end-diastolic pressure) including pulmonary hypertension.
  3. Moderate renal failure or dysfunction as indicated by a serum creatinine >150 μmol/l, and/or an estimated GFR (Glomerular Filtration Rate) less than 59 ml/min per 1.73m2.
  4. Individuals with secondary forms of hypertension including primary hyperaldosteronism, renal artery stenosis, obstructive sleep apnea, pheochromocytoma, hyperthyroidism, acromegaly, exogenous systemic glucocorticoid use, hypercortisolism.
  5. Current pregnancy, or recent pregnancy within the last 3 months, or current breast-feeding. Female patients of child bearing potential [premenopausal, or not surgically sterile] who are unwillingly to have a baseline serum pregnancy test, and/or who are unwillingly to use active contraception throughout the duration of the study.
  6. Use within the last 3 months of any DPP-IV (Dipeptidyl Peptidase) inhibitor, GLP-1 receptor agonist [liraglutide, exenatide (ExBID, or Ex QW)], or insulin [bolus, pre-mixed, or prandial].
  7. Liver failure, including liver cirrhosis or non-alcoholic fatty liver disease.
  8. Dependence upon alcohol, >14 servings per week if male, >9 servings per week if female.
  9. Prior history of any clinical presentation consistent with pancreatitis [acute or chronic], or a history of medullary thyroid cancer, c-cell hyperplasia or history of multiple endocrine neoplasia syndromes which predisposes to medullary thyroid cancer [Multiple Endocrine Neoplasia Type 2].
  10. Individuals with severe systolic hypertension, SBP (systolic blood pressure) ≥ 181 mmHg measured by an automated oscillometric blood pressure device [BPTru® or DinaMAP®].
  11. Individuals with severe diastolic hypertension, DBP (diastolic blood pressure) ≥ 100 mmHg measured by an automated oscillometric blood pressure device [BPTru® or DinaMAP®].
  12. Individuals currently prescribed an insulin secretagogue [sulphonylurea] unwillingly to decrease their dose by 50% prior to the start of, and for the duration of the study.
  13. Individuals with resting tachycardia of >100 bpm or individuals who have a prior history of known conduction abnormalities associated with tachycardia including atrial fibrillation, atrial flutter, prolongation of PR interval, or ventricular tachycardias.
  14. Current involvement, or any recent involvement [within 3 months] in any other clinical trial involving an investigational product.
  15. Unwillingness to perform daily sc injection with study drug therapy for duration of 21 days throughout 2 treatment phases.
  16. Individuals who are currently taking or who have taken diuretic therapy in the past 3 months.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01755572

Locations
Canada, Ontario
Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Canada
Toronto, Ontario, Canada
Sponsors and Collaborators
Mount Sinai Hospital, Canada
Novo Nordisk A/S
Investigators
Principal Investigator: Dr. Daniel J. Drucker, MD Samuel Lunenfeld Research Institute
Study Director: Dr. Julie A. Lovshin, MD, PhD Samuel Lunenfeld Research Institute
Study Director: Dr. Bernard Zinman, MD Leadership Sinai Centre for Diabetes
Study Director: Dr. Alexander A. Logan, MD Samuel Lunenfeld Research Institute
  More Information

Publications:
Responsible Party: Mount Sinai Hospital, Canada
ClinicalTrials.gov Identifier: NCT01755572     History of Changes
Other Study ID Numbers: MSH-12-0020-A
Study First Received: December 19, 2012
Last Updated: March 23, 2015
Health Authority: Canada: Health Canada

Keywords provided by Mount Sinai Hospital, Canada:
Type 2 Diabetes
Hypertension
Liraglutide
GLP-1

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Hypertension
Cardiovascular Diseases
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Vascular Diseases
Glucagon-Like Peptide 1
Liraglutide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 29, 2015