Blood Pressure Outcomes With Liraglutide Therapy

Type 2 Diabetes Clinical Trial

— BOLT  

Official title:

Hormonal Regulation of Systolic Blood Pressure in Response to the GLP-1 (Glucagon-Like Peptide-1) Receptor Agonist, Liraglutide.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01755572
• Other study ID #: MSH-12-0020-A
• Status: Completed
• Phase: Phase 4
• First received: December 19, 2012
• Last updated: March 23, 2015
• Start date: January 2013
• Est. completion date: March 2014

Study information

• Verified date: March 2015
• Source: Mount Sinai Hospital, Canada
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: March 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Hypertension
• Systolic Hypertension
• Type 2 Diabetes

Intervention

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.
• 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.

Locations

Country	Name	City	State
Canada	Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Canada	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Mount Sinai Hospital, Canada	Novo Nordisk A/S

Country where clinical trial is conducted

Canada, 

References & Publications (1)

Lovshin JA, Barnie A, DeAlmeida A, Logan A, Zinman B, Drucker DJ. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes. Diabetes Care. 2015 Jan;38(1):132-9. d — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in HbA1c%	-0.7%, p=0.005; least squares mean difference, liraglutide compared placebo	21 days
Other	Change in Fasting Blood Glucose	-3.4 mmol/L, p=0.0004; least squares mean difference, liraglutide compared to crossover with placebo, p-value	21 days
Other	Change in Total Cholesterol	-0.63 mmol/L, p=0.002; least squares mean difference, liraglutide compared to crossover with placebo, p-value	21 days
Other	Change in LDL Cholesterol	-0.37 mmol/L, p=0.04; least squares mean difference, liraglutide compared to crossover with placebo, p-value	21 days
Other	Change in eGFR (estimated Glomerular Filtration Rate)	-5.76 ml/min/1.73m2 (2.60), p=0.04; least squares mean difference, liraglutide compared to crossover with placebo, (SE), p-value	21 days
Other	Change in Body Weight	+1.35 Kg (0.46), p=0.009; least squares mean difference (SE), p-value, liraglutide compared to crossover with placebo	21 days
Other	Change in BMI (Body Mass Index)	-0.42 Kg/cm2 (0.18), p=0.03; least squares mean difference (SE), p-value, liraglutide compared to crossover with placebo	21 days
Other	Change in Plasma Angiotensin II	-0.97 pmol/L (0.86), p=0.28; least squares mean difference (SE), p-value, liraglutide compared to placebo	21 days
Other	Change in Plasma CRP	0.09 mg/L (0.80), p=0.91; least squares mean difference (SE), p-value, liarglutide compared to placebo	21 days
Other	Change in Triglycerides	-0.2 mmol/L (0.18), p=0.28;least squares mean difference (SE), p-value, liarglutide compared to placebo	21 days
Other	Change in HDL	+0.083 mmol/L (0.03), p=0.02;least squares mean difference (SE), p-value, liarglutide compared to placebo	21 days
Primary	Change in plasma ANP level at 1 Day	+16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 hours	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
Primary	Change in plasma ANP level at 21 Days	-17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 hours	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
Secondary	Change in mean 24-Hr urinary sodium excretion rate following 21 days of liraglutide (titrated 1.8mg) compared to crossover with placebo (baseline-subtracted)	median change +14.18 mmol/L liraglutide vs. placebo (statistically significant, Wilcoxon rank sum)	21 days
Secondary	Change in mean Nighttime urinary sodium excretion rate following 21 days of liraglutide (titrated 1.8mg) compared to crossover with placebo (baseline-subtracted)	median change +4.24 mmol/L nighttime, liraglutide vs. placebo (statistically significant, Wilcoxon Rank Sum)	21 days
Secondary	Change in mean 24-Hr systolic BP, liraglutide compared to crossover with placebo (baseline-subtracted)	+2.33 ± 1.67, p=0.18;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value	21 days
Secondary	Change in mean 24-hr diastolic BP, liraglutide compared to crossover with placebo (baseline-subtracted)	+3.78 ± 1.34, p=0.01;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value	21 days
Secondary	Change in mean 24-hr HR, liraglutide compared to crossover with placebo (baseline-subtracted)	+5.21 ± 2.42, p=0.05; Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value	21 days
Secondary	Office-measured systolic BP; Treatment difference for liraglutide compared to crossover with placebo	-2.35 mmHg (3.49), p=0.51;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value	21 days
Secondary	Office-measured diastolic BP;Treatment difference for liraglutide compared to crossover with placebo	+3.6 mmHg (2.33), p=0.14;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value	21 days
Secondary	Office-measured heart rate;Treatment difference for liraglutide compared to crossover with placebo	+9.25 (3.51), p=0.02;Treatment difference liraglutide (1.8 mg) vs. placebo LSMD (±SE), p value	21 days