The Effect of Extended‐Release Metoprolol Succinate on C‐Reactive Protein Levels in Persons With Hypertension

Abstract

The objective of this study was to determine whether 3 months of treatment with extended‐release metoprolol succinate would reduce C‐reactive protein (CRP) levels. Seventy‐five patients aged 30–65 years with uncontrolled hypertension were treated with extended‐release metoprolol at 25–50 mg, titrated up to 100–200 mg daily. CRP was evaluated at baseline and at 1 and 3 months. In the 61 hypertensive patients who completed the study, CRP decreased from 6.2±7.5 mg/L at baseline to 5.4±7.0 mg/L (p=0.03) at 1 month and showed no further change at 3 months (5.6±6.5 mg/L; p=0.13). The 13 patients who received 200 mg of extended‐release metoprolol had a 32% decline in CRP from 7.0±9.0 mg/L to 4.8±6.6 mg/L (−2.2 mg/L) (p=0.005) over the 3‐month period, whereas lower doses did not reduce CRP (p>0.05). Age, race, sex, and change in blood pressure were not related to the reduction in CRP in multivariate analysis. If CRP evolves into a confirmed modifiable risk factor, a β blocker such as metoprolol may be a useful addition to pharmacotherapy options.

Recent evidence strongly supports a significant role for inflammation in the development of cardiovascular disease. Higher levels of inflammatory markers such as C‐reactive protein (CRP) are associated with increased cardiovascular risk. ¹ , ² , ³ , ⁴ , ⁵ CRP levels are also higher in persons with hypertension and prehypertension. ⁶ , ⁷ Because of the possibility of compounded cardiovascular disease risk in individuals with both hypertension and elevated CRP, ⁸ , ⁹ lowering CRP levels might provide risk amelioration in patients with hypertension, over and above the benefits of blood pressure (BP) lowering.

Whether treatment with β blockers in persons with hypertension could lower CRP levels has not been fully investigated. A recent cross‐sectional study in a population of patients with stable angina who underwent coronary angiography found that patients prescribed β blockers had significantly lower mean CRP concentrations than patients in whom β blockers were not prescribed (by 1.2 mg/L, or 40% difference in geometric mean concentration; p<0.001). ¹⁰ This association remained significant (p=0.03) after excluding patients with a contraindication to β blockers and adjusting for the probability of β‐blocker therapy (propensity score) and other clinical predictors of CRP concentration, including body mass index (BMI), high‐density lipoprotein cholesterol (HDL‐C) level, family history of coronary artery disease, and angiographic severity. No differences among types or dosages of β blockers were evident. A study in Japan examined the effect of two different β blockers on CRP levels in patients with hypertension. ¹¹ Sixty hypertensive patients were randomly assigned to carvedilol (20 mg; n=30) or propranolol (60 mg; n=30) for 6 months. Thirty normotensive subjects served as controls. Carvedilol decreased CRP significantly, by a median of 0.073 mg/dL (interquartile range, 0.034–0.112 mg/dL; p<0.001), whereas propranolol decreased levels by 0.012 mg/dL (interquartile range, 0.009–0.032 mg/dL; p=0.26; p=0.003 for difference between treatments).

Other β blockers have not been fully investigated. The purpose of this study was to determine whether 3 months of treatment with extended‐release (ER) metoprolol succinate would reduce CRP levels in patients with hypertension.

METHODS

This was a prospective, nonrandomized, open‐label study. Seventy‐five hypertensive patients between the ages of 30 and 65 from the campus and clinics of the Medical University of South Carolina (MUSC) in Charleston, SC volunteered for the study. The study was approved by the MUSC Institutional Review Board. Written informed consent was obtained from all participants.

Included were patients who had hypertension by physician diagnosis, self‐report, or were taking antihypertensive medication and had a BP >120/80 mm Hg. Participants could be taking non–β‐blocker medication but had to be on stable medical therapy for at least the past 60 days. Patients were excluded for a history of asthma, inflammatory diseases, bradycardia <50 bpm, history of serious adverse or allergic reaction to any form of metoprolol or any β blocker, or if they were active in a weight loss program. Participants were allowed to continue taking nonsteroidal anti‐inflammatory drugs, vitamin E, or antioxidants, as long as their regimen had been stable for at least 2 months prior to the study.

After an initial history, physical examination, and electrocardiography were performed at the university's General Clinical Research Center, participants were started on 50 mg of ER metoprolol succinate (25 mg for patients with heart failure), administered orally for 3 months in a prospective, open‐label fashion. The dose was titrated (doubled) at 2 weeks and again at the 1‐month visit to the maximum dose tolerated or until BP was <120 mm Hg systolic. Fasting blood samples were collected at baseline and at 1 and 3 months. Venous blood was used for measurement of plasma glucose, plasma cholesterol, triglyceride, and HDL‐C levels. Serum CRP levels were measured using a high‐sensitivity latex‐enhanced immunoneph‐elometric IMMAGE system (Beckman Coulter, Fullerton, CA). A total of 63 patients completed at least 75% of the medication and were included in the analysis.

Statistical analyses were done using SAS version 9.1 (SAS Institute, Cary, NC). Descriptive statistics were performed using t tests or chi‐square tests as appropriate. Comparisons of CRP measurements at baseline and 1 and 3 months were made using paired t tests. Paired t tests and chi‐square tests were also used to determine whether age, race, gender, ER metoprolol dose, or BP response were associated with change in CRP from baseline to 3 months. ¹² , ¹³ CRP changes in the high‐dose (200 mg) group were compared with the lower‐dose group (<200 mg) using chi‐square to determine whether treatment group was related to reduction in CRP level. Multivariate analyses were conducted to examine changes in CRP while controlling for age, race, sex, and changes in BMI, BP, and total cholesterol. Statistical significance was defined as ≤0.05 for all analyses.

RESULTS

Of the 75 patients enrolled in the study, 61 completed the study and were compliant with the medical regimen. In this compliant group, the average age was 50 years, 30% were men, and 59% were African American. Further baseline characteristics of the study population are shown in Table I.

Table I.

Baseline Characteristics of Study Participants: Likelihood of a Random Distribution Between Dosage Groups

	Dose <200 mg	Dose 200 mg	p Value
Sample number	48	13
Mean age (yr)	49.8	50.7	0.73
Male sex (%)	27	38	0.42
African‐American race (%)	54	77	0.14
Mean body mass index (kg/m2)	34.2	33.3	0.69
Mean total cholesterol (mg/dL)	211	192	0.12
Mean systolic blood pressure (mm Hg)	141	152	0.04
Diagnosed diabetes (%)	10.4	30.8	0.07
Current smoker (%)	12.5	23.1	0.34

Overall, CRP decreased from 6.2±7.5 mg/L at baseline to 5.4±7.0 mg/L (p=0.03) at 1 month but showed no further change and no change from baseline at 3 months (5.6±6.5 mg/L; p=0.13). Age, race, sex, and change in BP were not associated with changes in CRP from baseline to 3 months. However, a final titrated dose of 200 mg for 2 months or more was associated with a 32% decrease in CRP from baseline to 3 months (7.0 mg/L to 4.8 mg/L; p=0.005), whereas lower doses did not reduce CRP (p>0.05) (Table II). Lower doses had no consistent effect on CRP (p>0.05). Twelve of 13 participants taking 200 mg had lower CRP levels at 3 months, compared with only 23 of 48 participants at lower doses.

Table II.

Mean C‐Reactive Protein (mg/L) (± SD) at Baseline, 1 Month, and 3 Months by Dosage Group

Group	Baseline	1 Month	3 Months
Overall	6.2±7.5	5.4±7.0	5.6±6.5
Dose <200 mg	5.9±7.1	5.5±7.2	5.8±6.6
Dose 200 mg	7.0±9.0	5.1±6.5	4.8±6.6

In multivariate analysis, after adjusting for age, sex, race, change in BMI, change in cholesterol, and change in systolic BP, taking 200 mg of ER metoprolol remained significantly associated with a decrease in CRP (β coefficient=−0.207; t test β=0; p=0.015). In this analysis, changes in systolic BP, BMI, and total cholesterol were not associated with the change in CRP (p>0.30).

DISCUSSION

Therapy for hypertensive patients with ER metoprolol succinate resulted in a 10% reduction from baseline in CRP levels at 1 month in all subjects, but no change was found in the overall group at 3 months. The only subgroup that encountered a significant reduction at 3 months was the group receiving 200 mg daily, which experienced a 32% reduction in CRP at 3 months. Age, race, sex, and changes in BMI, BP, and total cholesterol were not associated with the change in CRP during the study period. Lower doses of ER metoprolol had an inconsistent effect on CRP.

These results provide new information and help explain previous research findings. Previous research studying the effect of the β blockers carvedilol and propranolol on oxidative stress markers found that treatment with carvedilol was associated with a reduction in CRP but propranolol was not. ¹¹ While these results may be due to different drugs of the same class having a different effect on CRP, the differences could also be dose‐related. In our study, the higher dose of ER metoprolol succinate (200 mg) had a more consistent effect on CRP levels. This raises the possibility that the findings of Yasunari and colleagues ¹¹ could be due to the relatively low dose of propranolol used in that study (60 mg daily) rather than a specific drug effect.

Our findings also extend the results of Jenkins and associates, ¹⁰ who found that CRP levels in patients with stable angina were 40% lower in patients taking β blockers. However, there were no differences by type or dose evident in that cross‐sectional study. Our study expands on those results by demonstrating a dose‐related effect and by showing that the reduction in CRP was maintained over 3 months with the higher dose of the β blocker.

The 32% reduction in CRP levels seen in this study is substantial. The most effective pharmacologic treatment to reduce CRP levels to date has been using 3‐hydroxy‐3‐methylglutaryl coenzyme‐reductase inhibitors (statins). A recent study reported that, compared with placebo, pravastatin reduced median CRP levels by 16.9% at 24 weeks. This effect was seen as early as 12 weeks (median reduction in CRP with pravastatin, 14.7%; p<0.001). ¹⁴ Changes of this magnitude have been calculated to reduce myocardial infarction and cardiovascular death by as much as 45% over and above benefits from reduction of LDL. ¹⁵ Exercise and weight loss together have also been shown to reduce CRP by as much as 30% in a study by Esposito and colleagues. ¹⁶ These are similar to the results of the current study with a higher‐dose β blocker. However, the level of intense diet instruction, exercise, and regular reinforcement in the Esposito study may not be achievable outside of a clinical trial.

The results of the current study suggest a possible new option for cardiovascular risk reduction in patients with hypertension if CRP is confirmed as a risk factor and not just a marker of risk. ¹⁷ Pharmacotherapy that treats both the elevated BP and the elevated CRP with which hypertension is often associated may be beneficial in reducing cardiovascular disease risk more than therapy that reduces BP alone. Combining therapy with a drug like ER metoprolol, statins, or diet/exercise regimens may further enhance results. The current study was not able to investigate longer‐term outcomes or combination therapy to test this concept.

Our study was limited by the relatively small proportion of participants (13 of 61) who took 200 mg of ER metoprolol succinate to reduce their BP to goal levels. The comparatively small number of subjects receiving 200 mg limits the opportunity to conduct further analysis regarding associated or confounding factors that might skew the results. The study was powered to detect an overall effect of ER metoprolol, but was not powered in advance to investigate a possible relationship between the dose of ER metoprolol succinate and the change in CRP level.

The mechanism by which some β blockers may lower CRP is unknown. The CRP‐lowering effects may be related to effects of β blockers on the renin–angiotensin axis or may be the result of an undiscovered effect on vascular endothelium or oxidative processes thought to be an integral part of CRP metabolism. ¹⁸

In summary, treatment with ER metoprolol suc‐cinate at 200 mg daily lowers CRP in hypertensive patients. CRP levels are elevated in many hypertensive patients and may contribute to excess cardiovascular risk. Therapies that lower both BP and CRP may afford greater cardiovascular risk reduction than treatments that reduce BP only. Clinical trials to evaluate this possibility may lead to more effective strategies for cardiovascular protection in high‐risk patients.

Disclosure:

This study was supported by a grant from the Investigator Sponsored Studies Program of AstraZeneca and the General Clinical Research Center at the Medical University of South Carolina (Grant #RR0107).