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. Author manuscript; available in PMC: 2014 Nov 14.
Published in final edited form as: J Diabetes Complications. 2014 Jan 21;28(3):399–405. doi: 10.1016/j.jdiacomp.2014.01.009

Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: Insights from a patient-level pooled analysis of six randomized clinical trials☆

Vivian A Fonseca a,*, J Hans DeVries b, Robert R Henry c, Morten Donsmark d, Henrik F Thomsen e, Jorge Plutzky f
PMCID: PMC4231710  NIHMSID: NIHMS618958  PMID: 24561125

Abstract

Aims

To quantify the effect of liraglutide on systolic blood pressure (SBP) and pulse in patients with type 2 diabetes (T2D), and assess the influence of covariates on observed SBP reductions.

Methods

A patient-level pooled analysis of six phase 3, randomized trials was conducted.

Results

The analysis included 2792 randomized patients. In the intention-to-treat population (n = 2783), mean [±SE] SBP reductions from baseline with liraglutide 1.2 mg (2.7 [0.8] mmHg) and 1.8 mg (2.9 [0.7] mmHg) once daily were significantly greater than with placebo (0.5 [0.9] mmHg; P = 0.0029 and P = 0.0004, respectively) after 26 weeks, and were evident after 2 weeks. Liraglutide was also associated with significantly greater SBP reductions than glimepiride and, at a dose of 1.8 mg, insulin glargine and rosiglitazone. SBP reductions with liraglutide weakly correlated with weight loss (Pearson’s correlation coefficient: 0.08–0.12; P ≤ 0.0148). No dependence of these reductions on concomitant antihypertensive medications was detected (P = 0.1304). Liraglutide 1.2 and 1.8 mg were associated with mean increases in pulse of 3 beats per minute (bpm), versus a 1 bpm increase with placebo (P < 0.0001 for each dose versus placebo).

Conclusions

Liraglutide reduces SBP in patients with T2D, including those receiving concomitant antihypertensive medication.

Keywords: Type 2 diabetes, Hypertension, Blood pressure, Liraglutide

1. Introduction

Approximately 20%–60% of patients with type 1 or type 2 diabetes have hypertension, varying as a function of obesity, ethnicity, and age (Arauz-Pacheco, Parrott, & Raskin, 2003). Hypertension substantially increases the risk of both microvascular and macrovascular diabetic complications, including stroke, coronary artery disease, peripheral vascular disease, retinopathy, nephropathy, and possibly neuropathy (Adler, Stratton, Neil, et al., 2000; UK Prospective Diabetes Study Group, 1998). In recent years, data from well-designed randomized clinical trials have demonstrated the effectiveness of treating hypertension, lipids, and glycemia in reducing vascular complications of diabetes, albeit with varying benefit (Gaede, Lund-Andersen, Parving, & Pedersen, 2008; Holman, Paul, Bethel, Matthews, & Neil, 2008; Kearney, Blackwell, Collins, et al., 2008; Turnbull, Neal, Algert, et al., 2005). Among these interventions, control of blood pressure (BP) is one of the most effective strategies for improving long-term cardiovascular (CV) outcomes for patients with diabetes (Arauz-Pacheco et al., 2003).

The American Diabetes Association (ADA) and the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommend a target BP of <140/80 mmHg or <130/80 mmHg for individuals with type 2 diabetes (American Diabetes Association, 2013; Chobanian, Bakris, Black, et al., 2003; Gaede et al., 2008). Meanwhile, the European Association for the Study of Diabetes (EASD) recommend a BP target of <130/80 mmHg, or <125/75 mmHg in those with renal impairment (Ryden, Standl, Bartnik, et al., 2007). The latter recommendation is supported by the American Association of Clinical Endocrinologists (AACE) Hypertension Task Force, who reasoned that the more stringent BP target of <120/75 mmHg may be even more effective in slowing the progression of CV and renal complications, particularly in the presence of proteinuria (Torre, Bloomgarden, Dickey, et al., 2006). Achieving this BP target is challenging, often requiring multiple antihypertensive medications, which can lead to problems with adherence, side effects, and drug–drug interactions. Patients with type 2 diabetes often need combination antidiabetic therapy to achieve appropriate glucose control, which may have little or no effect on BP. Furthermore, these individuals are frequently treated with multiple additional medications to treat dyslipidemia and prior CV events.

In addition to their well-appreciated effects to reduce hyperglycemia, glucagon-like peptide (GLP)-1 receptor agonists have effects on the CV system, including BP lowering – perhaps due to associated weight loss (Vilsbøll, Christensen, Junker, Knop, & Gluud, 2012), natriuresis (Kim, Platt, Shibasaki, et al., 2013; Thomson, Kashkouli, & Singh, 2013), vasodilation (Gaspari, Liu, Welungoda, et al., 2011; Kim et al., 2013), or a combination of these mechanisms. While the detection of GLP-1 receptors using immunological techniques is technically challenging (Pyke & Knudsen, 2013), GLP-1 receptors have been detected in human CV tissues using reverse transcription polymerase chain reaction (RT-PCR) (Wei & Mojsov, 1995), and GLP-1 receptors have been located to the myocardium (predominantly to the atria Kim et al., 2013), microvascular endothelium, and coronary smooth muscle cells in mice (Ban et al., 2008; Kim et al., 2013). Both direct and indirect effects of GLP-1 receptor agonists on the CV system have been proposed (Ban et al., 2008; Gaspari et al., 2011; Kim et al., 2013).

The ‘Liraglutide Effect and Action in Diabetes’ (LEAD) clinical development program, comprising six randomized clinical trials, evaluated the efficacy and safety of the GLP-1 analogue liraglutide in different type 2 diabetes populations: from drug-naïve patients to those for whom single or multiple oral antidiabetic drugs (OADs) had failed (Buse, Rosenstock, Sesti, et al., 2009; Garber, Henry, Ratner, et al., 2009; Marre, Shaw, Brandle, et al., 2009; Nauck, Frid, Hermansen, et al., 2009; Russell-Jones, Vaag, Schmitz, et al., 2009; Zinman, Gerich, Buse, et al., 2009). Active comparators in these trials included glimepiride, rosiglitazone, insulin glargine, and the GLP-1 receptor agonist exenatide. Across the LEAD trials, liraglutide improved glycosylated hemoglobin (HbA1c) by 1.0%–1.5%, and was associated with sustained body weight reductions of 2.0–3.4 kg (Buse et al., 2009; Garber et al., 2009; Marre et al., 2009; Nauck et al., 2009; Russell-Jones et al., 2009; Zinman et al., 2009). BP was a pre-specified secondary endpoint in all six randomized LEAD trials. Although the trials were not statistically powered to assess BP lowering, consistent reductions in systolic BP (SBP) with liraglutide (1.8 mg or 1.2 mg once daily) were observed, with reductions ranging from 2.1 to 6.7 mmHg from baseline to the end of the treatment period under evaluation (26–52 weeks) (Buse et al., 2009; Garber et al., 2009; Marre et al., 2009; Nauck et al., 2009; Russell-Jones et al., 2009; Zinman et al., 2009). Small, non-significant reductions in diastolic BP from baseline were observed with liraglutide in most of these trials (Buse et al., 2009; Garber et al., 2009; Marre et al., 2009; Nauck et al., 2009; Russell-Jones et al., 2009; Zinman et al., 2009).

In this study, we used patient-level data to carry out a pooled analysis of the effects of liraglutide versus comparators on SBP in a large patient population (almost 2800 individuals) to gain more definitive evidence of a change in SBP following treatment with liraglutide, to quantify the change, and to investigate its determinants.

2. Materials and methods

2.1. Study design and patients

A database was compiled including 26-week clinical data from five randomized controlled trials, LEAD-1, -2, -4, -5 and -6, and 28-week clinical data from LEAD-3. These trials were sponsored by Novo Nordisk A/S (Copenhagen, Denmark). Study designs, entry criteria, and primary efficacy and safety results have been published previously for all six trials (Buse et al., 2009; Garber et al., 2009; Marre et al., 2009; Nauck et al., 2009; Russell-Jones et al., 2009; Zinman et al., 2009). All trials followed protocols approved by institutional review boards or ethics committees, and were conducted in accordance with the Declaration of Helsinki (World Medical Association General Assembly, 2008).

Some heterogeneity of trial design was present. Four of the trials were placebo-controlled (LEAD-1, -2, -4 and -5) (Marre et al., 2009; Nauck et al., 2009; Russell-Jones et al., 2009; Zinman et al., 2009), while the remaining two trials compared liraglutide with either exenatide twice daily (LEAD-6) (Buse et al., 2009), or glimepiride (LEAD-3) (Garber et al., 2009). While four of the trials were completely double-blinded, one trial was open-label (LEAD-6) (Buse et al., 2009) and the LEAD-5 study had an open-label arm (Russell-Jones et al., 2009). Patients from two trials received liraglutide 1.8 mg once daily (Buse et al., 2009; Russell-Jones et al., 2009); the remaining four trials included liraglutide 1.2 and 1.8 mg once daily arms (Garber et al., 2009; Marre et al., 2009; Nauck et al., 2009; Zinman et al., 2009).

Enrolled patients continued their baseline antihypertensive and lipid-lowering therapies, as the protocols did not make any recommendations to change these existing therapies. Patients randomly assigned to the liraglutide groups received liraglutide subcutaneously once daily. Liraglutide doses were escalated to the target dose (1.2 or 1.8 mg) in weekly increments of 0.6 mg, from an initial dose of 0.6 mg. Since the purpose of the analysis was to evaluate the effects of approved maintenance doses of liraglutide (1.2 and 1.8 mg once daily) (Victoza (Liraglutide) Summary of Product Characteristics, 2012; Victoza (liraglutide) (liraglutide), 2013), patients randomized to a final dose of liraglutide 0.6 mg were not included in this analysis.

2.2. BP and pulse measurements

BP was measured according to American Heart Association (AHA) recommendations using a standardized auscultatory method (Pickering, Hall, Appel, et al., 2005). Patients were instructed to avoid caffeine, smoking and exercise ≥30 min before BP measurement, and were sitting for ≥5 min prior to the first reading. Mercury sphygmomanometers were used, with the use of aneroid or hybrid sphygmomanometers restricted to circumstances where mercury devices were banned due to environmental concerns. The size of the cuff was selected so that the bladder of the cuff encircled at least 80% of the arm circumference, and the width of the cuff was at least 40% of the arm circumference. The measurements were taken with precision to the nearest 2 mmHg. BP was checked on both arms at the first visit: in case of an inter-arm difference, the arm with the higher reading was used for all subsequent measurements. At least two measurements at intervals of at least 2 min were performed at baseline and follow-up visits. In the event of a >5 mmHg difference between the first and the second diastolic BP readings, one additional reading was obtained. The average of these readings was used to represent the patient’s BP. Resting pulse data were also captured.

2.3. Statistical methods

Baseline data, 26-week data from LEAD-1, -2, -4, -5 and -6, and 28-week data from LEAD-3 were collected and analyzed. Missing post-baseline data were imputed using the last observation carried forward (LOCF) method for all studies. Changes in SBP and pulse from baseline were compared between treatment groups using a linear mixed effect model that included treatment, trial, and previous OAD treatment as fixed effects, baseline value of the dependent variable as a covariate, country as a random effect and trial-specific residual variance. Individual patient data were also analyzed by subgroup of patients either using or not using antihypertensive therapy at randomization by adding a treatment*antihypertensive drug interaction. Analyses of mean arterial pressure (MAP) and pulse pressure (PP) were conducted as per the method used for changes in SBP and pulse, except the baseline and endpoint values were log-transformed.

A Pearson correlation coefficient for the potential relationship between weight loss and reduction in SBP for liraglutide-treated patients was also calculated. Inferential statistical tests were performed using a 2-sided test, and statistical significance was defined as P < 0.05. Change-from-baseline values are presented as least squares mean change ± standard error of mean (SEM). Statistical analyses were performed using SAS 9.3 (SAS Institute Inc., Cary, NC, USA).

3. Results

3.1. Demographics and baseline characteristics

Pooled patient demographics and baseline characteristics from individuals randomized in LEAD-1–6 (n = 2792; n = 898 receiving liraglutide 1.2 mg, n = 1366 receiving liraglutide 1.8 mg, and n = 528 receiving placebo) are presented in Table 1. Demographics and baseline characteristics were well matched between the liraglutide and placebo groups, perhaps with the exception of diabetes duration. Of note, mean baseline SBP was 133 mmHg in the liraglutide 1.2 mg group, 134 mmHg in the liraglutide 1.8 mg group, and 135 mmHg in the placebo group.

Table 1. Demographics and baseline characteristics.

Randomization ratios for each of the LEAD studies: LEAD-1 – 2:2:2:1:2 (0.6 mg liraglutide + glimepiride, 1.2 mg liraglutide + glimepiride, 1.8 mg liraglutide + glimepiride, glimepiride monotherapy, glimepiride + rosiglitazone); LEAD-2 – 2:2:2:1:2 (0.6 mg liraglutide + metformin, 1.2 mg liraglutide + metformin, 1.8 mg liraglutide + metformin, metformin monotherapy, metformin + glimepiride); LEAD-3 – 1:1:1 (1.2 mg liraglutide, 1.8 mg liraglutide, glimepiride); LEAD-4 – 1:1:1 (1.2 mg liraglutide + rosiglitazone + metformin, 1.8 mg liraglutide + rosiglitazone + metformin, rosiglitazone + metformin); LEAD-5 – 2:1:2 (1.8 mg liraglutide + glimepiride + metformin, glimepiride + metformin, glargine + glimepiride + metformin); LEAD-6 – 1:1 (1.8 mg liraglutide + metformin/sulfonylurea, exenatide + metformin/sulfonylurea). HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose.

Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
Patients randomized 898 1366 528
Male/female 450/448 720/646 291/237
Age (years) 56 56 56
BMI (kg/m2) 32 32 32
Duration of diabetes (years) 7 8 9
Body weight (kg) 89 90 91
HbA1c (%) 8.3 8.4 8.4
FPG (mmol/L) 9.8 9.7 9.8
Blood pressure (mmHg)
Systolic 133 134 135
Diastolic 80 81 81
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3.2. Changes in systolic blood pressure (SBP)

In pooled analyses, mean SBP reductions after 26 weeks were significantly greater with liraglutide 1.2 mg (2.7 [0.8] mmHg) and 1.8 mg (2.9 [0.7] mmHg) than with placebo (0.5 [0.9] mmHg); P = 0.0029 and P = 0.0004, respectively (Fig. 1). SBP reductions were also significantly greater with liraglutide than with the active comparators that were evaluated, except when comparing exenatide with liraglutide 1.8 mg (1.2 mg dose not evaluated) and liraglutide 1.2 mg with rosiglitazone (Fig. 1).

Fig. 1. Change in systolic blood pressure (SBP) with liraglutide versus placebo and active comparators.

Fig. 1

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Diamonds indicate liraglutide–placebo or liraglutide–active comparator estimated treatment differences in change in SBP from baseline (analysis of covariance models) for pooled data from LEAD-1–6. The width of the horizontal lines indicates 95% confidence intervals for each estimated treatment difference. LS, least squares; SBP, systolic blood pressure.

Rapid reductions in SBP with liraglutide were evident, which were sustained over 26 weeks (Fig. 2). Within 2 weeks, SBP had decreased by 2.6 and 3.3 mmHg with liraglutide 1.2 and 1.8 mg, respectively, compared with a reduction of 1.4 mmHg with placebo (Fig. 2).

Fig. 2. Change in systolic blood pressure (SBP) over time.

Fig. 2

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Data are last observation carried forward for the intention-to-treat population, and expressed as least squares means ± 95% confidence interval.

3.3. Relationship between SBP reductions and weight loss

Consistent with the established effects of GLP-1 receptor agonists, liraglutide 1.2 mg and 1.8 mg were associated with mean weight losses of 1.2 kg and 1.8 kg, respectively, after 26 weeks (versus a mean reduction of 0.5 kg with placebo). There was a weak, although statistically significant, correlation between weight loss and SBP changes in liraglutide-treated patients at 2 and 26 weeks, and in placebo-treated patients at 26 weeks (Table 2).

Table 2. Pearson’s correlation coefficient showing relationship between decreases in systolic blood pressure (SBP) and body weight.

Data are last observation carried forward for the intention-to-treat population.

Treatment Week Least squares means of change in SBP (mmHg) Least squares means of change in body weight (kg) Pearson’s correlation between change in SBP and change in body weight P value of Pearson’s correlation between change in SBP and change in body weight
Liraglutide 1.2 mg 2 −3.11 −0.94 0.0823 0.0148
26 −2.67 −1.19 0.0920 0.0063
Liraglutide 1.8 mg 2 −2.97 −0.96 0.1084 0.0001
26 −2.91 −1.78 0.1208 <0.0001
Placebo 2 −0.63 −0.19 0.0428 0.3305
26 −0.53 −0.52 0.0923 0.0355
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3.4. Relationship between SBP reductions and antihypertensive therapy

At randomization, 63.6% and 65.4% of the populations receiving liraglutide 1.2 and 1.8 mg, respectively, were receiving concomitant antihypertensive medication. Similarly, 68.8% of patients in the placebo intention-to-treat group were receiving concomitant antihypertensive medication. Very few patients (≤3%) initiated or discontinued antihypertensive therapy over the 26–28-week period of interest.

Reductions in SBP with liraglutide appeared to be independent of concomitant antihypertensive medications: no dependence of the observed SBP reductions with liraglutide on concomitant antihypertensive medications was detected (P = 0.1304; test for treatment*antihypertensive drug interaction). The estimated treatment differences between liraglutide (1.2 and 1.8 mg) and placebo were similar in those who were receiving concomitant antihypertensive medication to control BP, and those who were not (Table 3), although placebo-adjusted SBP reductions did not reach significance in the latter group, possibly due to insufficient statistical power.

Table 3. Changes in systolic blood pressure (SBP) with liraglutide versus placebo at the end of 26 weeks by concomitant antihypertensive medication status.

Data are last observation carried forward for the intention-to-treat population.

n Least squares mean change (mmHg) Standard error P value
Patients receiving concomitant antihypertensive medications
Treatment Liraglutide 1.2 mg 560 −1.44 0.87 0.0989
Liraglutide 1.8 mg 884 −2.02 0.78 0.0105
Placebo 358 +0.61 0.95 0.5187
Estimated treatment differences Liraglutide 1.2 mg – Placebo −2.05 0.86 0.0171
Liraglutide 1.8 mg – Placebo −2.63 0.80 0.0010
Patients not receiving concomitant antihypertensive medications
Treatment Liraglutide 1.2 mg 320 −4.42 0.97 <0.0001
Liraglutide 1.8 mg 467 −4.06 0.86 <0.0001
Placebo 162 −2.21 1.18 0.0612
Estimated treatment differences Liraglutide 1.2 mg – Placebo −2.21 1.21 0.0680
Liraglutide 1.8 mg – Placebo −1.85 1.15 0.1058
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3.5. Change in pulse

At Week 26, patients injecting liraglutide 1.2 mg or 1.8 mg had pulse elevations of 3.22 ± 0.45 bpm and 3.46 ± 0.39 bpm (both P < 0.0001 versus baseline), while mean pulse had increased by 0.89 ± 0.50 bpm in those receiving placebo (P = 0.08 versus baseline). The corresponding placebo-adjusted changes with liraglutide 1.2 mg and 1.8 mg were 2.33 ± 0.49 bpm and 2.57 ± 0.45 bpm, respectively (both P < 0.0001).

No correlation was observed between change in SBP and change in pulse in patients receiving liraglutide 1.2 mg and 1.8 mg (Pearson’s correlation coefficient at Week 26: 0.045 [P = 0.1856] and 0.003 [P = 0.9152], respectively), and placebo (0.055 [P = 0.2079]).

3.6. Changes in mean arterial pressure (MAP) and pulse pressure (PP)

While liraglutide 1.2 mg and 1.8 mg reduced MAP from baseline after 26 weeks of treatment (−1.56 mmHg and −1.41 mmHg, respectively; P = 0.0077 and P = 0.0091), the corresponding placebo-adjusted changes were not statistically significant (−0.95 mmHg and −0.80 mmHg, respectively; P = 0.0561 and P = 0.0823). With regard to active comparators, greater reductions in MAP were observed with liraglutide than with glimepiride (vs. liraglutide 1.2 mg, P = 0.071; vs. liraglutide 1.8 mg, P = 0.0154) and insulin glargine (vs. liraglutide 1.8 mg, P = 0.0154), but not with rosiglitazone or exenatide.

In terms of PP, significantly greater reductions from baseline were observed with liraglutide 1.2 mg and 1.8 mg compared with placebo (placebo-adjusted decreases of 3.31 mmHg and 4.51 mmHg, respectively; P = 0.0049 and P < 0.0001). Moreover, both liraglutide doses resulted in significantly greater reductions in PP compared with all active treatments (P ≤ 0.0072) with the exception of liraglutide 1.8 mg vs. exenatide.

4. Discussion

In this patient-level pooled analysis, the administration of liraglutide (1.2 or 1.8 mg subcutaneously, once daily) was associated with significantly greater reductions in SBP from baseline to 26 weeks, compared with placebo. Liraglutide was also associated with significantly greater SBP reductions than glimepiride and, at a dose of 1.8 mg, insulin glargine and rosiglitazone. There were significant reductions in MAP with liraglutide compared with glimepiride and insulin glargine (but not placebo, rosiglitazone or exenatide), accompanied by a significant fall in PP (compared with placebo and all active comparators, with the exception of exenatide). These results add to the pool of knowledge obtained from the individual LEAD trials, which showed reductions in SBP of 2.1–6.7 mmHg, although with insufficient power to fully establish the effect of liraglutide on SBP (Buse et al., 2009; Garber et al., 2009; Marre et al., 2009; Nauck et al., 2009; Russell-Jones et al., 2009; Zinman et al., 2009).

The reductions in SBP were observed within 2 weeks of initiating treatment with liraglutide, in agreement with a previous study of the onset of the effects of liraglutide (Gallwitz, Vaag, Falahati, & Madsbad, 2010), which showed that the addition of liraglutide to OADs led to rapid improvements in SBP versus placebo. Exenatide has a similar effect on SBP (Okerson, Yan, Stonehouse, & Brodows, 2010), and lixisenatide was also associated with small BP reductions in phase 3 clinical trials (Lyxumia (Lixisenatide) (Lixisenatide), 2013), suggesting that the SBP-lowering effect may be a drug class phenomenon. Indeed, two recent meta-analyses independently reported SBP reductions of 1–5 mmHg with liraglutide and exenatide (Robinson, Holt, Rees, Randeva, & O’Hare, 2013; Wang, Zhong, Lin, et al., 2013). Here, we utilized individual patient data to investigate factors affecting reductions in SBP with liraglutide, including weight.

The SBP reductions observed in liraglutide-treated patients correlated weakly with weight loss, suggesting that SBP reductions with liraglutide are mediated at least in part by a mechanism involving weight loss. There was no correlation between change in HbA1c with liraglutide treatment and SBP (Data on file), indicating a mechanism independent of mid- to long-term glycemic control. Other mechanistic hypotheses have been proposed to explain the BP-lowering effects of GLP-1 receptor agonists, including GLP-1 receptor-mediated increases in renal Na+ excretion and vasodilatation (Basu et al., 2007; Gutzwiller, Tschopp, Bock, et al., 2004; Kim et al., 2013). Most recently, a preclinical study linked GLP-1 receptor activation by liraglutide to the release of atrial natriuretic peptide (ANP; well-established as a physiological regulator of vasodilation, natriuresis and diuresis) and BP reduction in mice, via a cAMP/Epac2-dependent pathway (Kim et al., 2013). Two clinical studies are currently ongoing/in recruitment to further investigate the time course and mechanisms of the SBP reductions observed with liraglutide (Blood Pressure Outcomes with Liraglutide Therapy [BOLT], NCT01755572; Time Course of the Blood Pressure Lowering Effect of Liraglutide Therapy in Type 2 Diabetes [Liratime], NCT01499108) (Mount Sinai Hospital, 2013; Rossing, 2013).

Clinicians monitoring patients in the LEAD trials had unrestricted use and dosing of concomitant antihypertensive medications, as hypertension was not the primary outcome of these studies. We addressed this possible limitation and utilized this information, by examining the effects of liraglutide in the presence and absence of concomitant antihypertensive medications. No significant dependence of these reductions on concomitant antihypertensive medications was detected (P = 0.1304). Interestingly, the SBP reductions associated with liraglutide were observed in both the presence and absence of concomitant antihypertensive medication (with sufficient statistical power to detect significance versus placebo in the group receiving antihypertensive medications). Thus, the effects of liraglutide and concomitant antihypertensive medications on SBP appear to be additive, which is likely to be a welcome outcome in the many patients who have type 2 diabetes complicated by hypertension. Prior studies have demonstrated clinical benefits from SBP reductions in hypertensive patients with type 2 diabetes (Adler et al., 2000; Kearney et al., 2008; UK Prospective Diabetes Study Group, 1998).

The clinical consequences of the dose-independent increase in pulse of 3 bpm noted with liraglutide are unclear. The exact mechanisms underlying this increase are also yet to be elucidated. Although a compensatory increase in heart rate in response to the decrease in BP has been suggested, there was no correlation between change in SBP and change in pulse. A resting heart rate elevation in excess of 10 bpm has been positively correlated with CV and all-cause mortality (Jensen, Marott, Allin, Nordestgaard, & Jensen, 2012), hence caution is warranted for drugs that substantially increase heart rate. The mean increases in pulse observed with GLP-1 receptor agonists reported here and elsewhere (Robinson et al., 2013) were below 4 bpm. Furthermore, the major adverse CV events (MACE) analysis for liraglutide conducted as part of the Food and Drug Administration (FDA) regulatory review did not indicate any increase in CV risk with liraglutide (Marso, Lindsey, Stolker, et al., 2011).

The long-term CV safety of liraglutide is being prospectively studied in 9340 patients with type 2 diabetes and a high CV risk profile in the ‘Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation’ (LEADER; NCT01179048) trial (Bergenstal, Daniels, Mann, et al., 2011; Novo Nordisk, 2013a). This study will provide valuable insights as to whether reductions in SBP with liraglutide therapy (coupled with improvements in other risk factors, such as body weight and glucose control) might translate into a beneficial effect on CV morbidity and mortality. Long-term outcome trials are also ongoing for the GLP-1 receptor agonists exenatide (Exenatide Study of Cardiovascular Event Lowering Trial [EXSCEL]: NCT01144338) (Amylin Pharmaceuticals, LLC, 2012), lixisenatide (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) [ELIXA]: NCT01147250) (Sanofi, 2013), dulaglutide (Researching Cardiovascular Events With a Weekly Incretin in Diabetes [REWIND]: NCT01394952) (Eli Lilly and Company, 2013) and semaglutide (SUSTAIN 6; NCT01720446) (Novo Nordisk, 2013b).

In conclusion, this patient-level pooled analysis showed that, in patients with type 2 diabetes, liraglutide 1.2 and 1.8 mg produced statistically significant SBP reductions that were evident within 2 weeks and sustained to 26 weeks. The reductions in SBP were weakly correlated with weight loss and observed in the presence and absence of antihypertensive therapy. Together, these findings raise the possibility of beneficial effects of liraglutide on CV risk in patients with type 2 diabetes.

Acknowledgments

The authors would like to thank all the investigators, patients, and study coordinators involved in the LEAD studies; Charlotte Thim Hansen, a medical doctor employed by the sponsor, Novo Nordisk, for supporting the coding and analysis related to concomitant antihypertensive medication; Ashwini Dhume, a medical writer employed by Novo Nordisk and Laura Elson of Watermeadow Medical, UK (supported by Novo Nordisk), for providing medical writing and editorial assistance to the authors during the preparation of this manuscript.

Footnotes

☆

Clinical trial registration: This patient-level pooled analysis is based on data from the following six clinical trials, registered at ClinicalTrials.gov: NCT00318422, NCT00318461, NCT00294723, NCT00333151, NCT00331851, NCT00518882.

This is an open access article under the CC BY-NC-ND license

Part of the data contained herein was presented at the American Diabetes Association 69th Scientific Sessions, 2009, New Orleans, Louisiana (Fonseca, Madsbad, Falahati, et al., 2009) and at the 45th Annual Meeting of the European Association for the Study of Diabetes, 2009, Vienna, Austria (Fonseca, Falahati, Zychma, et al., 2009).

Conflicts of interest: V.F. has received advisory board honoraria and speakers’ bureau honoraria from Novo Nordisk, and his institution has received research funding from Novo Nordisk; V.F. is currently Editor-in-Chief of this journal. J.H.D. or his institution has received advisory board honoraria and speakers’ bureau honoraria from Novo Nordisk, and his institution has received research funding from Novo Nordisk. R.H.’s institution has received research funding from Novo Nordisk. J.P. has received consultancy fees from Novo Nordisk. M.D. and H.T. are currently employed by and own shares in Novo Nordisk A/S. These analyses were sponsored by Novo Nordisk A/S, Copenhagen, Denmark. All authors discussed the data, edited the manuscript for important intellectual content, and approved the version for publication. H.T carried out the statistical analyses.

References

  1. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. BMJ. 2000;321:412–419. doi: 10.1136/bmj.321.7258.412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. American Diabetes Association. Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36(Suppl 1):S11–S66. doi: 10.2337/dc13-S011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Amylin Pharmaceuticals, LLC. [accessed 8 Aug 2013];Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A trial to evaluate cardiovascular outcomes after treatment with exenatide once weekly in patients with type 2 diabetes mellitus. 2012 Available at: http://clinicaltrials.gov/show/NCT01144338.
  4. Arauz-Pacheco C, Parrott MA, Raskin P American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(Suppl 1):S80–S82. doi: 10.2337/diacare.26.2007.s80. [DOI] [PubMed] [Google Scholar]
  5. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117:2340–2350. doi: 10.1161/CIRCULATIONAHA.107.739938. [DOI] [PubMed] [Google Scholar]
  6. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Beneficial effects of GLP-1 on endothelial function in humans: Dampening by glyburide but not by glimepiride. American Journal of Physiology. Endocrinology and Metabolism. 2007;293:E1289–E1295. doi: 10.1152/ajpendo.00373.2007. [DOI] [PubMed] [Google Scholar]
  7. Bergenstal R, Daniels G, Mann J, Nissen S, Pocock S, Zinman B, et al. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER™) Trial: Rationale and study design. Diabetes. 2011;59(Suppl 1):2303-PO. [Google Scholar]
  8. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6) Lancet. 2009;374:39–47. doi: 10.1016/S0140-6736(09)60659-0. [DOI] [PubMed] [Google Scholar]
  9. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252. doi: 10.1161/01.HYP.0000107251.49515.c2. [DOI] [PubMed] [Google Scholar]
  10. Data on file, Novo Nordisk.
  11. Eli Lilly and Company. [accessed 8 Aug 2013];Researching cardiovascular events with a weekly incretin in diabetes (REWIND) 2013 Available at: http://clinicaltrials.gov/show/NCT01394952.
  12. Fonseca V, Falahati A, Zychma M, Madsbad S, Plutzky J. A meta-analysis of six clinical trials demonstrates that the once-daily human GLP-1 analogue liraglutide reduces systolic blood pressure. Diabetologia. 2009;52(Suppl 1):S299. [Google Scholar]
  13. Fonseca V, Madsbad S, Falahati, Zychma MJ, Plutzky J. Once-daily human GLP-1 analog liraglutide reduces systolic BP – A meta-analysis of 6 Clinical Trials. Diabetes. 2009;58(Suppl 1):A146. [Google Scholar]
  14. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. New England Journal of Medicine. 2008;358:580–591. doi: 10.1056/NEJMoa0706245. [DOI] [PubMed] [Google Scholar]
  15. Gallwitz B, Vaag A, Falahati A, Madsbad S. Adding liraglutide to oral antidiabetic drug therapy: Onset of treatment effects over time. International Journal of Clinical Practice. 2010;64:267–276. doi: 10.1111/j.1742-1241.2009.02265.x. [DOI] [PubMed] [Google Scholar]
  16. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): A randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473–481. doi: 10.1016/S0140-6736(08)61246-5. [DOI] [PubMed] [Google Scholar]
  17. Gaspari T, Liu H, Welungoda I, Hu Y, Widdop RE, Knudsen LB, et al. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE−/− mouse model. Diabetes & Vascular Disease Research. 2011;8:117–124. doi: 10.1177/1479164111404257. [DOI] [PubMed] [Google Scholar]
  18. Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. Journal of Clinical Endocrinology and Metabolism. 2004;89:3055–3061. doi: 10.1210/jc.2003-031403. [DOI] [PubMed] [Google Scholar]
  19. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine. 2008;359:1577–1589. doi: 10.1056/NEJMoa0806470. [DOI] [PubMed] [Google Scholar]
  20. Jensen MT, Marott JL, Allin KH, Nordestgaard BG, Jensen GB. Resting heart rate is associated with cardiovascular and all-cause mortality after adjusting for inflammatory markers: The Copenhagen City Heart Study. European Journal of Preventive Cardiology. 2012;19:102–108. doi: 10.1177/1741826710394274. [DOI] [PubMed] [Google Scholar]
  21. Cholesterol Treatment Trialists’ (CTT) Collaborators. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: A meta-analysis. Lancet. 2008;371:117–125. doi: 10.1016/S0140-6736(08)60104-X. [DOI] [PubMed] [Google Scholar]
  22. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nature Medicine. 2013;19:567–575. doi: 10.1038/nm.3128. [DOI] [PubMed] [Google Scholar]
  23. Lyxumia (lixisenatide) [accessed 8 Aug 2013];Summary of product characteristics. 2013 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002445/WC500140401.pdf.
  24. Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU) Diabetic Medicine. 2009;26:268–278. doi: 10.1111/j.1464-5491.2009.02666.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Marso SP, Lindsey JB, Stolker JM, House JA, Martinez Ravn G, Kennedy KF, et al. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Diabetes & Vascular Disease Research. 2011;8:237–240. doi: 10.1177/1479164111408937. [DOI] [PubMed] [Google Scholar]
  26. Mount Sinai Hospital. [accessed 8 Aug 2013];Blood pressure outcomes with liraglutide therapy (BOLT) 2013 Available at: http://clinicaltrials.gov/ct2/show/NCT01755572.
  27. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care. 2009;32:84–90. doi: 10.2337/dc08-1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Novo Nordisk. [accessed 8 Aug 2013];Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A long term evaluation (LEADER) 2013a Available at: http://clinicaltrials.gov/show/NCT01179048.
  29. Novo Nordisk. [accessed 8 Aug 2013];Trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes (SUSTAIN™ 6) 2013b Available at: http://clinicaltrials.gov/ct2/show/NCT01720446.
  30. Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. American Journal of Hypertension. 2010;23:334–339. doi: 10.1038/ajh.2009.245. [DOI] [PubMed] [Google Scholar]
  31. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: Blood pressure measurement in humans: A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation. 2005;111:697–716. doi: 10.1161/01.CIR.0000154900.76284.F6. [DOI] [PubMed] [Google Scholar]
  32. Pyke C, Knudsen LB. The glucagon-like peptide-1 receptor–or not? Endocrinology. 2013;154:4–8. doi: 10.1210/en.2012-2124. [DOI] [PubMed] [Google Scholar]
  33. Robinson LE, Holt TA, Rees K, Randeva HS, O’Hare JP. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: Systematic review and meta-analysis. BMJ Open. 2013:3. doi: 10.1136/bmjopen-2012-001986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rossing P. [accessed 8 Aug 2013];Time course of the blood pressure lowering effect of liraglutide therapy in type 2 diabetes (Liratime) 2013 Available at: http://clinicaltrials.gov/ct2/show/NCT01499108.
  35. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met + SU): A randomised controlled trial. Diabetologia. 2009;52:2046–2055. doi: 10.1007/s00125-009-1472-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ryden L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: Executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD) European Heart Journal. 2007;28:88–136. doi: 10.1093/eurheartj/ehl260. [DOI] [PubMed] [Google Scholar]
  37. Sanofi. [accessed 8 Aug 2013];Evaluation of cardiovascular outcomes in patients with type 2 diabetes after acute coronary syndrome during treatment with AVE0010 (lixisenatide) (ELIXA) 2013 Available at: http://clinicaltrials.gov/show/NCT01147250.
  38. Thomson SC, Kashkouli A, Singh P. Glucagon-like peptide-1 receptor stimulation increases GFR and suppresses proximal reabsorption in the rat. American Journal of Physiology. Renal Physiology. 2013;304:F137–F144. doi: 10.1152/ajprenal.00064.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Torre JJ, Bloomgarden ZT, Dickey RA, Hogan MJ, Janick JJ, Jyothinagaram SG, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of hypertension. Endocrine Practice. 2006;12:193–222. [PubMed] [Google Scholar]
  40. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: Results of prospectively designed overviews of randomized trials. Archives of Internal Medicine. 2005;165:1410–1419. doi: 10.1001/archinte.165.12.1410. [DOI] [PubMed] [Google Scholar]
  41. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703–713. [PMC free article] [PubMed] [Google Scholar]
  42. Prescribing information highlights. FDA; 2013. [accessed 8 Aug 2013]. Victoza (liraglutide) Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. [Google Scholar]
  43. [accessed 8 Aug 2013];Victoza (liraglutide) summary of product characteristics. 2012 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001026/WC500050017.pdf.
  44. Vilsbøll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: Systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771. doi: 10.1136/bmj.d7771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wang B, Zhong J, Lin H, Zhao Z, Yan Z, He H, et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: A meta-analysis of clinical trials. Diabetes, Obesity & Metabolism. 2013;15:737–749. doi: 10.1111/dom.12085. [DOI] [PubMed] [Google Scholar]
  46. Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: Brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Letters. 1995;358:219–224. doi: 10.1016/0014-5793(94)01430-9. [DOI] [PubMed] [Google Scholar]
  47. World Medical Association General Assembly. [accessed 8 Aug 2013];World Medical Association Declaration of Helsinki – ethical principles for medical research involving human subjects. 2008 doi: 10.1001/jama.2013.281053. Available at: http://www.wma.net/en/30publications/10policies/b3/ [DOI] [PubMed]
  48. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met + TZD) Diabetes Care. 2009;32:1224–1230. doi: 10.2337/dc08-2124. [DOI] [PMC free article] [PubMed] [Google Scholar]

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