Carvedilollisinopril combination therapy and endothelial function in obese individuals with hypertension

Carvedilol-Lisinopril Combination Therapy and Endothelial Function in Aaron S. Kelly, PhD;1 J. Michael Gonzalez-Campoy, MD, PhD;2 Kyle D. Rudser, PhD;3 Harold Katz, MD;4 Andrea M. Metzig, MA;1 From the Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN;1 Minnesota Center for Obesity, Metabolism andEndocrinology, Eagan, MN;2 the Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN;3 Allina Hospitals andClinics, St. Paul, MN;4 and the Department of Research, St. Paul Heart Clinic, St. Paul, MN5 The authors hypothesized that carvedilol controlled-release adjusted for baseline measurements by analysis of covari- plus lisinopril combination therapy (C+L) would increase ance, with robust variance estimation for confidence inter- endothelial function and decrease oxidative stress to a vals and P values. C+L treatment compared to H+L greater extent than hydrochlorothiazide plus lisinopril com- treatment significantly improved RHI (0.74, 95% confi- bination therapy (H+L) in obese patients with hypertension.
dence interval, 0.31–1.19, P =.001). This difference per- Twenty-five abdominally obese patients (aged 54.4Æ7.3 sisted after adjustment for the change in systolic blood years; 14 women) with hypertension ⁄ prehypertension were enrolled in a 7-month (two 3-month treatment periods sep- observed for oxLDL, 8-isoprostane, or ADMA. These data arated by a 1-month washout), randomized, double-blind, provide evidence that independent of blood pressure–low- controlled, crossover clinical trial comparing C+L vs H+L.
ering, C+L therapy improves endothelial function to a Endothelial function, measured by digital reactive hyper- greater extent than H+L therapy. Levels of oxidative stress emic index (RHI), circulating oxidized low-density lipo- were not significantly different between treatments, sug- gesting that other mechanisms may be responsible for the dimethylarginine (ADMA) were obtained at baseline, post- improvement in endothelial function. J Clin Hypertens period 1, post-washout, and post-period 2. Analyses were (Greenwich). 2012;14:85–91. Ó2011 Wiley Periodicals, Inc.
Obesity and hypertension often coexist and each studies have shown that angiotensin-converting enzyme condition is independently associated with endothelial (ACE) inhibitors improve endothelial function,11–13 dysfunction. Endothelial dysfunction is thought to be probably by increasing bradykinin in the arterial wall14 one of the earliest detectable signs of atherosclerosis.
The presence of endothelial dysfunction independently b-adrenergic receptor blockers (b-blockers) have not predicts the development of atherosclerosis and future been favored as first-line antihypertensive agents in cardiovascular events.1–3 Healthy vascular endothelial obese patients, especially in those with type 2 diabetes cells control arterial tone by producing vasodilating or prediabetes since first- and second-generation agents factors such as nitric oxide, a free radical that signals have been shown to worsen glycemic control.16,17 How- underlying smooth muscle cells to relax.4 Nitric oxide ever, evidence is accumulating that third-generation helps to prevent atherosclerosis by interfering with b-blockers such as carvedilol and nebivolol do not nega- monocyte adhesion to the arterial wall, inhibiting tively affect glucose metabolism.18,19 Moreover, studies smooth muscle cell proliferation and decreasing plate- have reported beneficial effects of these medications on let aggregation.5–7 Impaired bioavailability of nitric endothelial function,20–28 with reduction of oxidative oxide (decreased production and ⁄ or increased inactiva- tion) often manifests as endothelial dysfunction.8 In Since third-generation b-blockers and ACE inhibi- the context of hypertension and obesity, oxidative tors independently reduce oxidative stress and aug- stress has been implicated as a primary cause of ment endothelial function, it is possible that when reduced nitric oxide bioavailability and impaired endo- used together as combination antihypertensive therapy, these drugs may act in a complimentary fashion to When considering antihypertensive medication for improve vascular health. Therefore, we conducted a obese individuals, agents that have the potential to randomized, controlled, crossover (all participants improve endothelial function may be desirable. Multiple received both therapies) clinical trial and hypothesizedthat carvedilol controlled-release plus lisinopril combi-nation therapy (C+L) would increase endothelial func- Address for correspondence: Aaron S. Kelly, PhD, Division of Epidemi-ology and Clinical Research, Department of Pediatrics, University of Min- tion and decrease oxidative stress to a greater extent nesota Medical School, 420 Delaware St. S.E., MMC 715, Minneapolis, than hydrochlorothiazide plus lisinopril combination therapy (H+L) in obese patients with hyperten- sion ⁄ prehypertension. We chose to compare these Manuscript received: July 22, 2011; Revised: September 20, 2011; specific pairs of medications because they are com- Accepted: October 4, 2011DOI: 10.1111/j.1751-7176.2011.00569.x monly used antihypertensive medication combinations.
Official Journal of the American Society of Hypertension, Inc.
Hydrochlorothiazide was selected as the main compar- ment assignments. Study medications were withheld ator (in essence, this was the case because lisinopril on the mornings of all study visits.
was used in both arms) because of its neutral vasculareffects.11,23 Measurement of Clinical VariablesHeight and weight were obtained using a standard sta- diometer and electronic scale, respectively. Body massindex (BMI) was calculated as weight in kilograms divided by height in meters squared. Waist circumfer- Twenty-five hypertensive ⁄ prehypertensive patients (sys- ence was obtained at end-expiration and measured tolic blood pressure [SBP] !130 mm Hg and ⁄ or dia- midway between the base of the rib cage and the supe- stolic blood pressure [DBP] !85 mm Hg or currently rior iliac crest. Sitting blood pressure measurements taking antihypertensive medication) with abdominal were obtained manually on the same arm using the obesity (waist circumference !102 cm for men and same cuff size and equipment after the patient had !88 cm for women) were enrolled. The blood pressure been resting quietly for 10 minutes. The final 2 of 3 criteria were based on values corresponding with the consecutive measurements, separated by 3 minutes, hypertension component of the metabolic syndrome.37 were averaged and used for analysis. Fasting lipid pro- Patients were excluded if they were not on a stable file, glucose, and insulin assays were conducted with (!1 month) cardiovascular medication regimen, cur- standard procedures by Quest Diagnostics (Minneapo- rently (<1 month) using antihypertensive medications, lis, MN). Homeostasis model assessment of insulin had contraindications for b-blocker or ACE inhibitor resistance (HOMA-IR), a surrogate measure of insulin therapy, or had a history of myocardial infarction, resistance, was calculated using previously described angina, or heart failure. Patients were recruited from local medical clinics and through advertisements. Thestudy protocol was approved by an institutional review board and consent was obtained from all Blood plasma for biomarker analysis was stored at )80°C until the end of the study, at which time all samples were assayed together. Circulating oxidized We performed a 7-month, randomized, double-blind, Winston-Salem, NC), 8-isoprostane (Cayman Chemi- active-control, crossover (participants received both cal Company, Ann Arbor, MI), and asymmetric dime- combination therapies, one in each period) clinical thylarginine (ADMA) (ALPCO, Salem, NH) were trial. Patients were treated for 3 months each with measured in duplicate by enzyme-linked immunosor- C+L and H+L in a randomized order. Study periods bent assay in the University of Minnesota Cytokine were separated by a 1-month washout period during Reference Laboratory (CLIA licensed).
which all antihypertensive therapy was discontinued.
Measurements of study variables were made at base- line (immediately prior to randomization), month 3 Endothelial function was measured noninvasively by (post-period 1), month 4 (post-washout), and month 7 digital reactive hyperemia (EndoPAT 2000; Itamar (post-period 2). All testing was performed in the Medical, Caesarea, Israel). Digital reactive hyperemia morning after patients had been fasting for at least is nitric oxide–dependent,39 associated with coronary artery blood flow40 and multiple cardiovascular riskfactors,41 and independently predicts future cardio- vascular events.3 Following 10 minutes of quiet rest Patients who were taking antihypertensive medica- in the supine position, finger probes were placed on tion(s) at the time of screening underwent a 1-month the index fingers of both hands to measure baseline washout period prior to randomization during which and reactive hyperemic pulse amplitude. Inside the all antihypertensive therapy was discontinued. C+L probes, a uniform pressure (10 mm Hg < DBP) was combination therapy was initiated at 20 mg and placed on the fingers, which allowed for the detection 10 mg (low dose), respectively. Patients returned of small pulse volume changes throughout the cardiac 1 week later and doses of carvedilol CR and lisinopril cycle. Following the collection of 5 minutes of base- were increased to 40 mg and 20 mg (high dose), line data, a blood pressure cuff on the upper arm was respectively, if SBP was !130 mm Hg or DBP was inflated to a suprasystolic level for 5 minutes. Follow- !85 mm Hg. H+L combination therapy was initiated ing cuff release, the change in pulse amplitude during at 12.5 mg and 10 mg (low dose), respectively.
reactive hyperemia was measured for 5 minutes. The Patients returned 1 week later and doses of hydrochlo- ratio of the hyperemic to the baseline pulse amplitude rothiazide and lisinopril were increased to 25 mg and (corrected for the same ratio on the control finger) 20 mg (high dose), respectively, if SBP was !130 mm was calculated and expressed as the reactive hyper- Hg or DBP was !85 mm Hg. Patients and investiga- emic index (RHI). Endothelium-independent hyper- tors ⁄ study staff members were blinded to the treat- emic index (EIHI) was quantified by calculating the Official Journal of the American Society of Hypertension, Inc.
ratio of the hyperemic to the baseline (immediately pre-nitroglycerin) pulse amplitude in the control finger(arm not previously occluded for RHI measurement) following the administration of 0.4 mg sublingual Baseline characteristics were tabulated with respect to randomized order of C+L and H+L. Outcomes were evaluated at baseline, end of period 1, end of washout, and end of period 2. Treatment effects for period 1 used the difference from baseline while effects for per- iod 2 were based on the difference from the end of washout. SBP was selected a priori as a variable that may influence results and was adjusted for in second- ary analyses. Generalized estimating equations were used with exchangeable working correlation structure and robust variance estimation was used for confi- dence intervals and P values. All statistical analyses were performed using R v2.9.2 with the ‘‘gee’’ library v4.13–14 to account for correlated responses.
(SBP, 138Æ13 mm Hg; DBP, 85Æ11 mm Hg) were enrolled. None of the patients had type 1or type 2 dia- betes mellitus. Two of the 25 patients who were ran- domized did not have any follow-up, and one was Abbreviations: ADMA, asymmetric dimethylarginine; BMI, body mass evaluated after the first period only. Across both first index; DBP, diastolic blood pressure; EIHI, endothelium-independent and second periods, 12 of 23 (52%) required the high hyperemic index; HDL, high-density lipoprotein; HOMA-IR, homeo-stasis model assessment of insulin resistance; LDL, low-density lipo- dose of C+L, while 9 of 22 (41%) required the high protein; oxLDL, oxidized low-density lipoprotein; RHI, reactive dose of H+L. There were no significant differences in hyperemic index; SBP, systolic blood pressure. Data are shown as any of the variables at baseline by treatment order mean (standard deviation) and No. (%) where indicated. aFivepatients missing data. bOne patient missing the value at the end of group (Table I). One patient had a missing value for the primary outcome of RHI at the end of washout.
The trajectories of patients’ RHI values from base- line across period 1, washout, and period 2 are dis- the end of the first period was carried forward and played in the Figure. At the conclusion of the washout used to calculate the change over period 2, the treat- period, the changes observed over period 1 appeared ment effect was attenuated to 0.56 (95% CI, 0.05– to have persisted somewhat, suggesting a potential 1.07) although it remained statistically significant carry-over effect and raising the possibility that the data from period 2 may be challenging to interpret.
As mentioned previously, evaluation of treatment Therefore, a follow-up analysis examining the data differences in RHI (adjusting for baseline RHI and from the first period only (data with no concerns SBP) at the end of washout suggested a significant dif- about reliability) was conducted with adjustment for ference between the two treatment groups of 0.72 baseline measurements. There was one patient with a (95% CI, 0.26–1.17) as period 2 began (P=.002). As missing value at the end of washout but not the end of such, a follow-up analysis was performed after remov- ing the potentially unreliable data from the second Compared with H+L, C+L was found to have sig- period with adjustment for baseline measurements of nificantly higher RHI of 0.67 (95% confidence inter- RHI and SBP. The results were similar, with a signifi- val [CI], 0.17–1.16) after adjusting for period and cant difference of 0.75 (95% CI, 0.31–1.19) with baseline SBP (P=.008). Due to the missing data at the end of washout, the experience for 1 of the 9 patients Since blood pressure can directly influence endothe- randomized to C+L ⁄ H+L only contributed informa- lial function and we observed a nonstatistically signifi- tion from the first period. This patient’s value at the cant difference (P=.20) in SBP by period in favor of end of period 2 was the largest observed RHI at any H+L, a secondary analysis, adjusting for the change in time point in the study. When that patient’s RHI at SBP, was also conducted. Although attenuated, a Official Journal of the American Society of Hypertension, Inc.
FIGURE. Change in RHI by period according to treatment order grouping. Open circle represents the patient who was missing data from washoutand the measurement from the end of period 1 carried forward.
meaningful effect persisted of 0.62 (95% CI, 0.12– our measures of oxidative stress were primarily systemic (blood plasma) and not specific to the vascular wall, it is There were no significant differences by treatment still possible that carvedilol acts directly on the arterial for BMI, SBP, DBP, heart rate, total cholesterol, LDL wall to reduce the oxidative burden. Alternatively, other cholesterol, high-density lipoprotein cholesterol, trigly- mechanisms, such as decreased peripheral vascular cerides, glucose, insulin, HOMA-IR, EIHI, oxLDL, resistance, may be at least partially responsible for improvements in endothelial function with carvedilol.
Unlike other b-blockers, which generally do not reduce peripheral vascular resistance, carvedilol possesses Our findings are in line with previous studies that a1-adrenergic receptor–blocking effects42,43 favoring have reported beneficial effects of third-generation increased nitric oxide bioavailability and peripheral function.11–13,20–28 In a previous study in patients with Improvements in endothelial function with C+L type 2 diabetes mellitus, we demonstrated that com- therapy persisted somewhat after withdrawal in the washout period. The study was designed on the pre- improved brachial artery flow-mediated dilation, a mise that any beneficial effects as a result of treatment measure of conduit artery endothelial function.20 The would disappear within 1 month after discontinuation current study extends these observations by showing of therapy. Interestingly, however, it appears that the that C+L combination therapy improves endothelial improvement in endothelial function with C+L may be function in resistance arteries (digital reactive hyper- durable up to at least 1 month after withdrawal of emia), suggesting a systemic vascular effect in an obese therapy. This finding suggests that the beneficial effects hypertensive ⁄ prehypertensive population. Endothelial of C+L on the vasculature may involve changes in improvements were observed with C+L despite the fact structural and ⁄ or mechanical effects of the arteries that this drug combination lowered blood pressure to since it persisted longer than expected after the drugs a lesser degree compared with H+L and that as a were out of the system. Although noteworthy in a sci- group, average baseline blood pressure was relatively entific sense, the clinical relevance of this finding may low in this patient population (136 ⁄ 84 mm Hg).
be somewhat limited since most patients use antihy- The current data suggest that reduction in level of sys- pertensive medications indefinitely.
temic oxidative stress is not the mechanism responsiblefor improvement in endothelial function with C+L. This finding is in agreement with our earlier study, which did Study limitations included the fact that 2 participants not show reductions of oxidative stress with carvedilol dropped out of the trial following randomization, one therapy in patients with type 2 diabetes mellitus.20 Since did not complete period 2 and one did not have a use- Official Journal of the American Society of Hypertension, Inc.
TABLE II. Changes From Baseline Across Period 1, Washout, and Period 2 Abbreviations: ADMA, asymmetric dimethylarginine; CI, confidence interval; C+L, carvedilol controlled-release plus lisinopril combination therapy;EIHI, endothelium-independent hyperemic index; HDL, high-density lipoprotein; H+L, hydrochlorothiazide plus lisinopril combination therapy; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein; RHI, reactive hyperemic index; SBP, systolic blood pressure.
able RHI evaluation at the end of washout. In addi- tive, treatment of hypertension with third-generation tion, we did not obtain information on the dietary and b-blockers and ACE inhibitors may be a preferred physical activity patterns of the participants.
first-line strategy since accumulating evidence suggeststhat these agents are associated with beneficial vascu- lar effects. Future research in this area should attempt Results of this study provide evidence that combina- to clarify whether reduction in oxidative stress (mea- tion antihypertensive therapy with carvedilol CR and suring biomarkers specific to arterial oxidative stress) lisinopril significantly improves resistance artery endo- with carvedilol and other third-generation b-blockers thelial function in abdominally obese individuals with is the primary mechanism of endothelial function hypertension ⁄ prehypertension. From a clinical perspec- Official Journal of the American Society of Hypertension, Inc.
antihypertensive medications offer the most beneficial Atherosclerosis Risk in Communities Study. N Engl J Med.
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Bank is a member of the speakers’ bureau for Forest Pharmaceuticals and receives research grant support from GlaxoSmithKline and Amylin ⁄ Eli Lilly.
Third-generation beta-blockers stimulate nitric oxide release from Dr Rudser, Ms Metzig, and Ms Thalin have no disclosures.
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