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European Journal of Heart Failure 2002 4(4):445-453; doi:10.1016/S1388-9842(02)00035-1
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© 2002 European Society of Cardiology

Carvedilol does not alter the insulin sensitivity in patients with congestive heart failure

Jens Refsgaarda,b,*, Claus Thomsenc, Frederik Andreasenb and Ole Gøtzschea

a Department of Cardiology and Medicine, Aarhus Amtssygehus Aarhus University Hospital, Tage Hansensgade 2, DK-8000 Aarhus C, Denmark
b Center of Clinical Pharmacology University of Aarhus, DK-8000 Aarhus C, Denmark
c Department of Endocrinology Aarhus Amtssygehus, Aarhus University Hospital, DK-8000 Aarhus C, Denmark

* Corresponding author. Department of Cardiology and Medicine, Aarhus Amtssygehus, Aarhus University Hospital, Tage Hansensgade 2, DK-8000 Aarhus C, Denmark. Tel.: +45-8949-7601; fax: +45-8949-7619 E-mail address: jensrefsgaard{at}post.tele.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Congestive heart failure (CHF) has previously been shown to be associated with insulin resistance and hyperinsulinemia. A beneficial effect of the non-selective β-blocker carvedilol has been demonstrated in patients with CHF. However, whether the drug affects the insulin sensitivity (Si) is unknown.

Aims: To investigate whether treatment with carvedilol alters the Si in patients with CHF during a prospective, double-blinded, placebo-controlled study. Methods and results: The patients were randomized to receive either carvedilol (n=29) or matched placebo (n=17). Insulin and glucose responses were measured during a 0.3 g/kg intravenous glucose tolerance test, and Si was calculated according to Bergman's Minimal Model. Baseline Si values correlated significantly with body mass index (r=–0.42, P=0.002), plasma urate (r=–0.42, P=0.002), plasma HDL-cholesterol (r=0.39, P=0.003), maximal oxygen uptake (r=0.35, P=0.009), plasma triglycerides (r=–0.34, P=0.01) and weight (r=–0.29, P=0.03). During the study the insulin sensitivity was unchanged in the carvedilol group compared with placebo (2.63±1.45 to 2.38±1.64 vs. 2.81±2.36 to 2.48±1.84x10–4 min–1/mU1–1, P=0.83).

Conclusion: Additional treatment with carvedilol is neutral with regard to influence the insulin sensitivity in patients with mild to moderate CHF.

Key Words: Congestive heart failure • Insulin resistance • Beta-blockade • Minimal model

Received March 27, 2001; Revised November 9, 2001; Accepted February 4, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Conditions with impaired insulin sensitivity and hyperinsulinism e.g. type-2 diabetes mellitus, hypertension and dyslipidemia are strongly associated with ischemic heart disease (IHD) [1]. Furthermore, in heart failure reduced insulin sensitivity and hyperinsulinism have been described [2,3]. Various neurohormonal factors participate in the pathophysiology of congestive heart failure (CHF) [4]. The activation of the sympathetic nervous system has a negative influence on the prognosis of heart failure [5] and could possibly contribute to hyperinsulinism [6]. The activation of the sympathetic nervous system is the target for treatment with β-blockers in CHF, which have been shown to have beneficial effect with marked reductions in mortality and morbidity [7,8].

The pharmacological profile of carvedilol includes both β-adrenoreceptor and {alpha}1-adrenoreceptor blockade [9]. The combination may protect the myocardium against injury from high levels of catecholamines (β-blocker effect) and increase the blood flow in the striated musculature ({alpha}1-blocker effect). Due to this pharmacological profile, carvedilol might thus alter the insulin sensitivity in patients with CHF.

The aims of the present study were (I) to correlate hormonal and hemodynamic variables with the insulin sensitivity (Si) in patients with CHF, and (II) to investigate the insulin sensitivity in patients with CHF during treatment with carvedilol.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study protocol
The study was prospective, randomized, double-blinded and placebo-controlled. Sixty patients were recruited from our out patient clinic, and randomized to receive either carvedilol or matched placebo in a ratio 2:1 without an open run-in period. All participants provided information on medical history, physical activities, concomitant medication, and had dietary instructions according to NCEP step 1 [10]. They were not allowed to change dietary habits during the study period. Body height and weight were measured in light clothing, and body mass index computed (kg/m2). Resting blood pressure was measured three times and the average was used for the study.

The patients were studied on their standard medication. After randomization, the initial dose of carvedilol was 3.125 mg b.i.d. with a dosage increase every second week up to 25 mg b.i.d. or maximal tolerated dose. The up-titration was followed by a maintenance period of 17 weeks. At the final visit after 23 weeks of double-blinded treatment, baseline measurements were repeated. The treatment code was not broken until all analyses had been performed.

Each patient gave written informed consent for participation in the study according to the protocol, which was approved by the Regional Committee of Ethics, the National Board of Health, and the Danish Registry Board. The study was performed in accordance with the principles of the Declaration of Helsinki.

2.2. Study population
All patients were Caucasians and had symptomatic mild to moderate heart failure (NYHA class II or III) caused by IHD or idiopathic dilated cardiomyopathy (DCM). The diagnosis of IHD was based on documentation of previous myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), coronary by pass grafting (CABG), or coronary angiography (CAG), and DCM on left ventricular dysfunction without a specific etiology and with normal coronary arteries verified by CAG. Further inclusion criteria were (1) stable regime without changes in concomitant medicine during the last month; (2) left ventricular ejection fraction (LVEF) <45%; and (3) age 40–80 years.

Exclusion criteria were (1) NYHA group I and IV; (2) known diabetes mellitus; (3) angina pectoris; (4) atrial fibrillation; (5) episodes of acute heart failure during the last 3 months; (6) acute myocardial infarction within the last 3 months; (7) CABG and/or PTCA within the last 3 months; (8) hypotension (systolic blood pressure <100 mmHg and/or diastolic blood pressure <50 mmHg; (9) bradycardia (<50 beats/min); (10) sick sinus node syndrome; (11) SA-block grade 2–3 and/or AV-block grade 2–3; (12) history of sustained (above 15 s) ventricular tachycardia; (13) symptomatic non-sustained tachycardia; (14) active myocarditis; (15) chronic airways disease; (16) claudicatio intermittens; (17) collagen vascular diseases; (18) Raynaud's phenomenon; (19) chronic renal impairment (serum creatinine >300 µmol/l); haematological diseases and hepatic disease (serum transaminase >3 times upper normal limit); (20) known alcohol or drug abuse; (21) fertile women who were not using contraception; (22) current treatment with beta-blockers, beta-agonist agents or calcium channel blockers; (23) other diseases apart from heart failure with expected survival less than 6 months and (24) suspected low compliance. None of the patients included in the study had significant heart valve disease.

2.3. Measurement of the insulin sensitivity
The patients were given dietary advice and refrained from systematic physical exercise during the 4 days before the intravenous glucose tolerance test (IVGTT). Patients arrived between 08.00 h and 09.00 h, 12 h after the last drug intake, (to avoid acute metabolic effect of the medicine), and an overnight fast, including no smoking. After placement of two intravenous catheters, one in each antecubital vein, the patients rested in sitting position for 30 min, then basal blood samples were taken for analysis of catecholamines, lipids and urate. The IVGTT test was then initiated by four basal samples collected over 20 min from one of the catheters. At the time t=0 a 300 mg/kg body weight i.v. glucose load was given in the opposite catheter over 1 min as a 50% solution. Blood samples for glucose and insulin assay were collected at the following times: at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, 22, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 160 and 180 min. At time 20 min a bolus of insulin 0.03 IU/kg body weight (Actrapid Human, Novo Nordisk, Copenhagen, Denmark) was given intravenously. The patients remained seated during the whole test.

The analysis of the IVGTT data was based on Bergman's Minimal Model of glucose disappearance and insulin kinetics [11]. The minimal model of glucose disappearance yields two parameters: the insulin sensitivity index, Si, and the glucose effectiveness, Sg [12]. The Si represents the increase in net fractional glucose clearance rate per unit change in plasma insulin concentration following the intravenous glucose load and is highly correlated to the insulin sensitivity as assessed by the clamp method [11]. The Sg represents the net fractional glucose clearance rate simply due to the increase in glucose itself in the absence of any increase in insulin concentration above baseline [11]. Plasma glucose was analyzed by the hexokinase method [13] and plasma insulin by an ELISA method with minor cross-reactivity with proinsulin [14]. Four baseline blood samples from each participant were used to determine the coefficient of variation (CV) of plasma insulin and plasma glucose, which was 8.2 and 2.1%, respectively.

2.4. Measurement of catecholamines
After 30 min rest, 9 ml blood were drawn from an antecubital vein through the intravenous cannula, into pre-chilled tubes containing 15 mg EGTA (ethylene-glycol-tetraacetic-acid) and 12 mg glutathione. The tubes were kept on ice before and after blood sampling, and were immediately centrifuged at 4 °C and 3000 rpm for 15 min, and then stored at –80 °C until analysis by high-performance liquid chromatography [15]. Blood samples were double tested each day on two consecutive days, and the average of the four tests at baseline and the end of the study were used for statistical analysis. All blood samples from the same patient were analyzed within the same set up. The within-assay CV of plasma norepinephrine and epinephrine was 4.4 and 6.3%, and the day-to-day CV 11.3 and 13.2%, respectively.

2.5. Measurement of lipids
Plasma total cholesterol, high-density lipoprotein cholesterol, triglycerides, glycated hemoglobin and urate were analyzed by normal laboratory routine. Low-density lipoprotein cholesterol was estimated according to the formula of Friedewald et al. [16].

2.6. Echocardiography
The equipment used was an ALOKA (SSD 2200) with a 2.5 MHz transducer. All scans were performed by the same experienced investigator, and were recorded on super VHS video, and analyzed later by one observer blinded to the identity of the patient and stage of the study. LVEF, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and cardiac output (CO) were calculated with an apical four- and two-chamber approach according to Simpson's modified biplane method [17] from an average of three cycles. LVEDV and LVESV were adjusted for body surface area. CV was 5.9, 3.4, 3.8 and 6.3%, respectively.

2.7. Maximal oxygen uptake
After an overnight sleep followed by a light meal, and before intake of project medicine to avoid acute hemodynamic effects, the participants underwent a maximal bicycle exercise test. Initial workload was 25 W, increasing progressively by 25 W every second minute until dyspnoea or fatigue terminated exercise. A standard ECG was monitored continuously, and blood pressure measured via a mercury sphygmomanometer every second minute during the test. Maximal oxygen uptake (MVO2) was calculated from the maximal bicycle test as described in details by Åstrand [18].

2.8. Statistical analyses
Baseline characteristics and study variables are given as means with their respective standard deviations (S.D.). The SPSS for Windows 8.0 computer package was used for statistical analysis. Baseline characteristics between the two groups were compared by the Mann–Whitney test for continuous variables. Changes in measured variables within each treatment group were tested by ANOVA or the Wilcoxon signed rank test. Treatment effects between the two groups were compared by an ANOVA procedure used for the normally distributed data, and the Mann–Whitney U-test used for the non-normally distributed data. Non-parametric correlation analysis (Spearman) was used to assess the association between insulin sensitivity and hormonal and hemodynamic variables. Spearman correlation coefficients ({rho}) and corresponding P-values are given. A priori, we decided to exclude negative Si values or Si values above 10x10–4 min–1/mU l–1 [19]. All analyses were two-sided, and results were considered statistically significant at the level of P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Baseline characteristics are depicted in Table 1. For correlation analysis of baseline data, Si values from 55 patients were used. In 3 patients the minimal model test was not performed because of cannula problems, and further 2 patients were excluded because of Si values >10x10–4 min–1/mU l–1. Out of 36 patients enrolled in the carvedilol group, 5 patients left the study because of side effects, and 2 patients were excluded because of negative Si values. The placebo group contained 19 patients at baseline. One patient stopped during the study period because of side effects, and 1 patient was excluded because of Si value >10x10–4 min–1/mU l–1.


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  		Table 1 Baseline characteristics of the whole study group and the patients in the treatment groups who completed the study

 
At baseline there were 7 women in the carvedilol group and 1 in the placebo group (P=0.08). All women were postmenopausal, and because of the unequal randomization, we tested differences of major variables at baseline between genders. The men had significantly higher weight (83.7 vs. 68.4 kg, P=0.004), waist–hip-ratio (0.99 vs. 0.86, P<0.001), fasting plasma insulin (66 vs. 39 pmol/l, P=0.02), plasma urate (0.47 vs. 0.36 mmol/l, P=0.008), and alcohol consumption (9.4 vs. 2.3 units per week, P=0.02) compared with the women.

None of the included patients had previously been treated with a β-blocker. At baseline there were some differences (non-significant) in concomitant medication, smoking and alcohol consumption between the two groups. However, during the study no changes in these parameters were observed. At each visit, the remaining project medicine was counted. A high level of compliance was found, with 1.5±2.4 unused tablets in the carvedilol and 1.2±1.2 in the placebo group (P=0.63). Mean dose of carvedilol was 49.0 mg daily (one patient in the carvedilol group was unable to tolerate the full dose and maintained on 12.5 mg b.i.d.).

3.1. Correlation between Si and main study variables at baseline
Coefficients of correlation are listed in Table 2. Inverse correlations between Si and fasting plasma insulin levels, plasma triglycerides, fasting plasma glucose levels, BMI, and plasma urate were observed. A positive correlation between Si and plasma HDL cholesterol and MVO2 were found. Insulin sensitivity correlated neither with NYHA class, W/H ratio, age, LVEF, nor plasma catecholamines levels.


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  		Table 2 Correlation (Spearman correlation coefficient, rho) between insulin sensitivity, and metabolic and hemodynamic variables at baseline

 
3.2. Metabolic results in the treatment groups
Fig. 1 illustrates that no significant changes in Si occurred in any of the groups. Table 3 summarizes the metabolic findings. Within the carvedilol group, we observed a 0.6% increase in body weight (P=0.04). Plasma epinephrine increased in the carvedilol group (P=0.004), and there were minor (but significant) increases in waist-hip ratio, glycated hemoglobin (HbA1C), plasma urate and a trend to a decrease of plasma LDL cholesterol (P=0.06) within the carvedilol group. None of these parameters changed significantly in the placebo group. No significant differences between the groups were observed, although we observed a trend towards differential changes of plasma LDL-cholesterol (–0.2 vs. +0.4 mmol/l, P=0.07), between the carvedilol and placebo group.


Figure 1
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  		Fig. 1 The insulin sensitivity index (Si) in the placebo and carvedilol groups at baseline and at the end of the study. NS: non-significant. *P value is within the group between baseline and week 23; **P value is difference between the groups during the study.

 


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  		Table 3 Metabolic variables obtained in the treatment groups

 
3.3. Hemodynamics and maximal oxygen uptake
Results are listed in Table 4. Carvedilol treated patients had a significant increase in LVEF (Fig. 2). Significant decreases in left ventricular end systolic volume index, systolic and diastolic blood pressure and heart rate were observed in the carvedilol group compared to placebo.


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  		Table 4 Hemodynamic and function variables obtained during the study in the treatment groups

 


Figure 2
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  		Fig. 2 Ejection fraction (EF, %) in the placebo group and the carvedilol groups at baseline and at the end of the study. Other details are explained under Fig. 1.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the present study we found that additional treatment with the combined {alpha}1/β1/β2-blocker carvedilol did not alter the insulin sensitivity in patients with mild to moderate CHF.

In recent years there has been focus on insulin sensitivity in cardiovascular disease. This interest has been stimulated by epidemiological studies showing an association between insulin resistance and cardiovascular disease [20]. The associations between insulin resistance and hypertension [21], and IHD [22] are well established, and moreover, insulin resistance has been associated with CHF [2,3,23]. We did not have a matched control group without CHF in the present study, but our population apparently had impaired insulin sensitivity when compared with other populations in previous studies [3,11].

The pathophysiological mechanisms of insulin resistance in patients with CHF are not fully understood. However, they seem to include both metabolic and vascular components. Overactivation of the sympathetic nervous system in patients with CHF is believed to contribute to the hyperinsulinism and the insulin resistance [6]. A moderate increase in plasma norepinephrine concentration has been observed to reduce the glucose tolerance and insulin sensitivity with 35%, an effect that may be mediated by an increased lipolysis and free fatty acid levels [24]. Moreover, small increases in plasma norepinephrine have been shown to increase fasting blood glucose through a transient stimulation of basal hepatic glucose output without changing basal glucose utilization, insulin or glucagon secretion [25]. Activation of the sympathetic nervous system has a considerable impact on insulin sensitivity. However, insulin does also stimulate the sympathetic nervous system. From animal and human studies it has been observed, that short-term infusion of insulin [26] and carbohydrate ingestion [27], stimulate the sympathetic nerve activity. It is known that acute physiological and pharmacological euglycemic hyperinsulinemia increases plasma catecholamine concentration [28]. Furthermore, it is generally agreed that hypertensive patients show an enhanced sympathetic activity in response to insulin [29]. Hyperinsulinemia may therefore also influence adrenergic activity, contributing to further deterioration of the insulin resistance.

The putative effect of vasoconstriction on insulin resistance may help to explain the decreased insulin sensitivity in patients with CHF. Insulin is known to act as a vasodilator, which may improve the blood flow to the skeletal muscles. Besides a direct vasodilating effect, insulin counteracts the vasoconstriction response to norepinephrine in forearm vasculature and peripheral veins [30]. The potential role of blood flow as an independent determinant of insulin stimulated muscle glucose up-take in patients with CHF seems to be an interesting approach for future studies.

In the present study, we did not register any correlation between the insulin sensitivity and the level of the plasma catecholamines, and it is still uncertain which factor could start the vicious circle. Previously, there have been conflicting results with no correlation [3] or high inverse correlation [23] between plasma norepinephrine and insulin sensitivity in patients with CHF. However, several clinical pathological states associated with sympathetic stimulation in skeletal muscle, like obesity [29], liver cirrhosis [31], and CHF [32] seem characterized by compromised insulin sensitivity. It should be stressed, however, that plasma norepinephrine levels do not necessarily reflect the level of sympathetic activation in skeletal muscle. Furthermore, it is difficult to discriminate the neurohormonal changes due to heart failure from changes mediated by concomitant therapy.

It is known that drugs widely used in cardiovascular diseases may alter insulin sensitivity. Thus, ACE-inhibitors and {alpha}1-blockers are neutral or improve insulin sensitivity [33–35], whereas high doses of thiazides and β-blockers decrease insulin sensitivity [34,36]. Treatment with celiprolol and dilevalol (β1-selective beta-blockers with β2-agonist properties) has been shown to improve the insulin sensitivity in hypertensive patients [37,38]. In randomly designed studies, carvedilol has been shown to increase the insulin sensitivity more than the β1-selective beta-blockers metoprolol [39] and atenolol [40] in hypertensive patients by improving glucose metabolism. An improvement was also observed by Lithell and Andersson [41] in a single blind study in patients with essential hypertension, and the {alpha}1-adrenoreceptor blocking properties of carvedilol might explain the changes compared with the selective beta-blockers. In CHF patients, Wallhaus et al. [42] recently demonstrated, that treatment with carvedilol decreases myocardial free fatty acids (FFA) without changing the glucose use, potentially contributing to improved energy efficiency which have been observed. Unfortunately, FFA was not measured in our study.

Patients with diabetes and CHF have a worse prognosis than non-diabetic patients with heart failure [43]. Although beta-blockade has been shown to be beneficial [44] and well-tolerated [45] in diabetic patients, the proportion of diabetics receiving beta-blockers are lower compared with non-diabetics [44,46]. Presumably, some beta-blockers decrease the insulin sensitivity [36,39] potentially creating a long-term problem. In our study, treatment with the vasodilating β-blocker carvedilol was neutral concerning changes in the insulin sensitivity in patients with mild to moderate CHF. This finding might open the way for using carvedilol in diabetic CHF patients. However, to clarify this hypothesis well-designed studies with diabetic CHF patients have to be performed rather than extrapolating the results from the present study to diabetic CHF patients. Further prospective studies focusing on the importance of insulin resistance in patients with CHF are mandatory.

4.1. Study limitations
The hyperinsulinemic, euglycemic clamp method is considered the ‘gold standard’ to measure insulin sensitivity. However, a highly significant correlation (r=0.92) between results from the minimal model and the clamp method has been demonstrated in patients with CHF [47]. We chose the minimal model in this study, because it requires less fluid loading and is less invasive compared with the clamp method.

This study was a prospective randomized, double-blinded and placebo-controlled study with duration of 23 weeks. The duration of the study might be too short to detect minor changes of insulin sensitivity between the groups. However, Jacob et al. [39] were able to detect a beneficial effect of carvedilol treated hypertensive patients after 12 weeks treatment.

We did not control the dietary habits of the patients during the study period. Prior to the study, however, they had instructions concerning the preferred diet. Furthermore, the importance of a stable diet throughout the study was emphasized before and during the study. Finally, relatively stable body weight and unchanged levels of plasma lipids and lipoproteins indicate that no major changes in dietary habits took place during the study.


   Acknowledgements
 
Bioanalysts Birthe Baumgarten, Jainamah Dolberg, Kirsten Eriksen, Anne Wood Ibsen, Dorthe Olesen Wehner and Pia Buchtrup Hornbek are thanked for excellent technical assistance. The study was supported by The Danish Medical Research Council, Roche A/S (Denmark), SmithKline Beecham (Denmark), and The Foundation of Lily Benthine Lund.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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R. J. Shelton, P. Velavan, N. P. Nikitin, A. P. Coletta, A. L. Clark, A. S. Rigby, N. Freemantle, and J. G.F. Cleland
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