QJM Advance Access originally published online on June 9, 2006
QJM 2006 99(7):431-436; doi:10.1093/qjmed/hcl059
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Review |
Antihypertensive treatment with beta-blockers and the spectrum of glycaemic control
From the Hypertension/Clinical Research Center, Departments of Preventive and Internal Medicine, Rush University Medical Center, Chicago, USA
Address correspondence to Dr P.A. Sarafidis, Hypertension/Clinical Research Center, Department of Preventive Medicine, Rush University Medical Center, 1700 West Van Buren, Suite 470, Chicago, IL 60612, USA. email: psarafidis11{at}yahoo.gr
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Summary |
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 Top Summary IntroductionEffects of conventional...Potential mechanisms of the...Effects of vasodilating...Potential mechanisms of the...ConclusionsReferences |
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Hypertension and type 2 diabetes mellitus (DM) are major cardiovascular risk factors, and often cluster in the same individual in the context of the metabolic syndrome. Management of hypertension in the diabetic patient is extremely important, and agents from all major antihypertensive classes are effective towards this goal. Conventional ß-blockers are associated with detrimental effects on insulin sensitivity, glycaemic control, and the incidence of type 2 DM and thus are less often used in hypertensive patients with DM. In contrast, the newer vasodilating ß-blockers appear to be free of adverse effects on the above metabolic parameters, and could be a valuable tool for hypertension treatment in patients with DM or the metabolic syndrome. This review summarizes the evidence on the effects of antihypertensive treatment with both traditional and vasodilating ß-blockers on parameters related to carbohydrate metabolism, and discuss the pathophysiological mechanisms that may be responsible.
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Introduction |
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TopSummaryIntroductionEffects of conventional...Potential mechanisms of the...Effects of vasodilating...Potential mechanisms of the...ConclusionsReferences |
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Hypertension and diabetes mellitus (DM) represent two of the major risk factors for cardiovascular disease (CVD).1 In many individuals, hypertension and type 2 DM accompany other CVD risk factors such as visceral adiposity and dyslipidaemia, in the so-called Metabolic or Insulin Resistance Syndrome, for which insulin resistance and compensatory hyperinsulinaemia have been proposed as the underlying disorders.2 This combination appears to accelerate the development of atherosclerosis, adding substantial cardiovascular risk beyond that of the individual risk factors.3
Treatment of CVD risk factors such as hypertension aims primarily to reduce cardiovascular morbidity and mortality.4,5 In diabetic patients, management of hypertension is of great importance,6 and current guidelines recommend that to achieve a goal of 130/80 mmHg, agents from all antihypertensive classes can be used, usually in combination.4,5 However, previous studies have suggested that antihypertensive agents from different classes may exert different effects on glucose tolerance. In general, angiotensin-converting-enzyme (ACE) inhibitors and calcium-channel blockers (CCBs) were associated with neutral or beneficial effects on carbohydrate and lipid metabolism, but thiazide diuretics and ß-blockers with adverse effects.7,8 Therefore, although conventional ß-blockers reduce cardiovascular risk in diabetic individuals,6,9 they are not recommended as first-line antihypertensive therapy in patients with DM.4,5 However, there are data suggesting that newer ß-blockers with vasodilating properties have a different metabolic profile from traditional ones,10–13 and could therefore be of particular benefit for patients with type 2 DM.
This review summarizes the clinical evidence on the effects of antihypertensive treatment with both conventional and vasodilating ß-blockers on parameters related to carbohydrate metabolism, such as glycaemic control, insulin sensitivity and type 2 DM incidence, providing also some potential pathophysiological explanations for these effects. For this purpose, a systematic literature search of MEDLINE/PubMed database was performed to identify English-language articles published until October 2005 that reported data on the effects of antihypertensive treatment with ß-blockers on glycaemic control, insulin sensitivity and incidence of DM. Search terms used were: 'ß-blocker', 'antihypertensive treatment', 'diabetes', 'glucose', 'glycated hemoglobin', 'glycemic control', 'insulin sensitivity' and 'insulin resistance'. Reference lists of identified articles were also evaluated for additional relevant papers and information. Clinical studies providing adequate information on effects of ß-blockers on the above parameters, as well as background studies providing mechanistic explanations for these effects, were included.
The text that follows is divided in four sections: the effects of conventional ß-blockers on insulin sensitivity and the risk of new onset type 2 DM; potential mechanisms for these effects of conventional ß-blockers; the effects of vasodilating ß-blockers on insulin sensitivity and glycaemic control; and potential mechanisms for these effects of vasodilating ß-blockers.
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Effects of conventional ß-blockers on insulin sensitivity and the risk of new-onset type 2 diabetes mellitus |
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TopSummaryIntroductionEffects of conventional...Potential mechanisms of the...Effects of vasodilating...Potential mechanisms of the...ConclusionsReferences |
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In clinical studies that used the euglycaemic hyperinsulinaemic clamp technique (the most reliable available method of estimating insulin sensitivity), treatment with conventional ß-blockers (either non-selective, e.g. propranolol,14 or ß1-selective, e.g. atenolol,15,16 metoprolol,11,16) significantly decreased insulin sensitivity in hypertensive patients. This deterioration of insulin sensitivity with ß-blockers is expected to have a direct negative effect on glycaemic control in patients with both hypertension and type 2 DM. On the other hand, in patients without type 2 DM, the concept of the metabolic syndrome suggests that a decrease in insulin sensitivity would not result in elevation of blood glucose levels, as long as the pancreatic ß-cells could secrete the necessary amounts of insulin. However, after a certain period of time, ß-cells would no longer be able to compensate for the increasing insulin resistance and type 2 DM would appear.17
The importance of this detrimental effect of ß-blockers on insulin sensitivity can be seen from studies examining their effect on the incidence of DM, which represents a more definite outcome. Most of these data suggest that use of conventional ß-blockers, such as atenolol or metoprolol, increases the propensity of patients with hypertension to develop type 2 DM. For example, in the large prospective Atherosclerosis Risk in Communities (ARIC) cohort study, of 3804 hypertensive subjects, representing a subgroup of the original study cohort, after appropriate adjustment for all potentially important confounders those treated with ß-blockers had a 28% higher risk of type 2 DM, compared to those taking no medication (RR 1.28, 95%CI 1.04–1.57), whereas users of thiazide diuretics, ACE inhibitors or CCBs were not at significantly higher or lower risk for subsequent type 2 DM than untreated hypertensives.18
In the Captopril Prevention Project (CAPPP) trial, in which 10 985 hypertensive subjects were randomized to captopril or conventional treatment consisting of a diuretic, ß-blockers or both, the captopril-based regimen was associated with a lower incidence of type 2 DM compared to the conventional regimen, in both intention-to-treat (RR 0.86, 95%CI 0.74–0.99) and on-treatment (RR 0.79, 95%CI 0.67–0.94) analyses.19 In the Losartan Intervention For Endpoint reduction (LIFE) study, 9193 patients with hypertension and left ventricular hypertrophy were randomized to losartan-based or atenolol-based antihypertensive treatment for at least 4 years. In patients without diabetes in randomization, the risk of subsequent DM was 25% lower for those on losartan-based compared with those on atenolol-based therapy (RR 0.75, 95%CI 0.63–0.88).20
In the International Verapamil-Trandorapril Study (INVEST) trial, 22 576 patients with hypertension and coronary artery disease were randomized to verapamil-based or atenolol-based antihypertensive therapy. Among patients without DM at entry, those in the verapamil group had a 15% lower incidence of new onset diabetes than subjects in the atenolol group (RR 0.85, 95%CI 0.77–0.95).21 In contrast to the above data, in the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension 2) study, there was no difference in diabetes incidence between conventional treatment (ß-blockers or diuretics) and either ACE-inhibitor based or CCB-based treatment.22
Most of the above studies suggest that type 2 DM incidence is increased in subjects receiving ß-blockers. However, a number of methodological issues limit the conclusions that can be drawn from these studies. For example, none of those studies,18–22 nor any randomized controlled trial with antihypertensive agents published so far, examined diabetes incidence as a primary end-point. In some of the above mentioned randomized trials, a large proportion of patients in the various groups were receiving second-line agents that could influence glycaemic control in the opposite direction from the main agent.19,21,22 In some of these studies, an ACE inhibitor19,22 or a CCB22 was compared to conventional treatment consisting of diuretics or ß-blockers in various combinations, and thus the net effect of the latter cannot be easily assessed. Moreover, as these trials compared active regimens, the observed differences19–21 could be attributed either to a negative effect of ß-blockers or to a beneficial effect of the other treatment compared, a fact not allowing firm conclusions to be drawn. Detection bias could have occurred in those of the above studies that were open-label with blinded end-point evaluation,19,21,22 as diabetes may have been more intensively sought in patients receiving ß-blockers. Therefore to have a definite answer in this field, it seems that we still need randomized, double-blind controlled trials examining diabetes incidence as a primary end-point, preferably comparing a ß-blocker to placebo and having the same proportion of second-line agents in the groups compared.
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Potential mechanisms of the effects of conventional ß-blockers on insulin sensitivity and glycaemic control |
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TopSummaryIntroductionEffects of conventional...Potential mechanisms of the...Effects of vasodilating...Potential mechanisms of the...ConclusionsReferences |
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Although the actions through which conventional ß-blocking agents influence insulin sensitivity and glycaemic control are not fully clarified, several mechanisms have been described that may be responsible. The most important are the haemodynamic effects of these agents. Under normal conditions, insulin promotes vasodilatation and increases blood flow in the skeletal muscles, an action tightly coupled with an increase of glucose disposal in the same tissue.23 In contrast, in insulin-resistant states such as type 2 DM and obesity, endothelium-dependent insulin-mediated vasodilatation is seriously impaired, and it is considered an important cause of reduction of insulin-stimulated glucose uptake in the periphery.23,24 On the other hand, acute sympathetic nervous system (SNS) stimulation in normal individuals lowers insulin-stimulated glucose uptake in muscles through vasoconstriction and blood flow reduction.25,26 This effect is mediated via
1-adrenergic pathways, as evident from studies with direct - and ß-blockade,27 and further supported by the vasodilatating and insulin-sensitizing properties of -adrenergic blockers.28 During treatment with conventional ß-blockers, unopposed 1-activity would cause vasoconstriction and decreased blood flow to muscles.29,30 According to the above logic, this effect will result in reduced insulin-stimulated glucose uptake: in other words, insulin resistance. Treatment with ß-blockers can also interfere with insulin secretion from pancreatic ß cells. In particular, ß-blockers may decrease the first phase of insulin secretion, possibly through an impairment of ß2-mediated insulin release.14–16,31 In general, attenuation of the first phase of insulin secretion represents a crucial step in the natural history of type 2 DM, and has been suggested as an important predictor of this disease.32 Thus, this action of ß-blockers could be another important contributor towards the development of type 2 DM.
Weight gain is another proposed mechanism of insulin sensitivity deterioration with ß-blockers, as those agents have been associated with an important increase in body weight in various studies9,33 and weight gain is closely connected to insulin sensitivity reduction.34 However, this mechanism does not seem to be of primary importance, since in the above mentioned studies decreased insulin sensitivity was also observed in subjects without weight gain,14–16 and in the ARIC study, weight increase in patients treated with ß-blockers was identical to that of participants receiving no medication.18
In addition to the above, in insulin-resistant states, one of the main problems at the level of the liver is the inability of insulin to suppress hepatic glucose production, which leads to elevated hepatic glucose production after meals, a disorder also contributing to loss of glycaemic control.32,35 Sympathetic activation stimulates glyconeogenesis and glycogenolysis and inhibits glycogen synthesis in the liver. Although the relative importance of - and ß-adrenergic receptors in mediating catecholamine-induced hepatic glucose production in humans in vivo remains to be resolved, in rats 2-receptors are involved.36 If -receptors play the major role in humans, unopposed -activity in the presence of ß-blockade, as in the case of haemodynamic effects, could result in enhanced hepatic glucose output, increasing the risk for type 2 DM. Other mechanisms responsible for this detrimental effect of ß-blockers on glycaemic control have been also speculated upon, but not extensively studied, such as changes in the capacity of aerobic exercise, or changes in the cellular actions of insulin.8
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Effects of vasodilating ß-blockers on insulin sensitivity and glycaemic control |
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TopSummaryIntroductionEffects of conventional...Potential mechanisms of the...Effects of vasodilating...Potential mechanisms of the...ConclusionsReferences |
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In contrast to the effect described above, some studies suggest that newer ß-blockers with vasodilating properties can have beneficial effects on parameters such as glycaemic control and insulin sensitivity. Several years ago, delivalol, a ß1-selective ß-blocker with a ß2-agonistic action was found to improve insulin sensitivity by about 10% in hypertensive patients,37 but was withdrawn from the market due to side-effects. In a subsequent study, another ß1-blocker with ß2-agonistic effects, celiprolol, was associated with a 35% increase in insulin sensitivity after a treatment period of 12 months.10
Carvedilol, a non-selective ß-blocker with 1-blocking properties has been also found to improve insulin sensitivity. Jacob et al. compared the effects of carvedilol and metoprolol in 72 hypertensive patients without DM, and observed a 14% increase in insulin sensitivity estimated with the clamp with carvedilol after 12 weeks of treatment, whereas metoprolol was associated with a reduction in this parameter.11 In another study, Giuglano et al. compared the effects of carvedilol and atenolol in 45 patients with both hypertension and type 2 DM. After 24 weeks of treatment, fasting plasma glucose and HbA1c were decreased and insulin sensitivity measured with the clamp was increased with carvedilol, whereas atenolol had the opposite results.12
Some months ago, the results of the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial were published.13 In this multicentre trial, 1235 subjects with hypertension and type 2 DM who were already receiving an ACE inhibitor or an angiotensin-receptor blocker (ARB) were randomized to receive 6.25–25 mg of carvedilol or 50–200 mg of metoprolol twice daily, to compare the effects of these ß-blockers on glycaemic and metabolic control. After 5 months of maintenance therapy, although both drugs were well-tolerated and blood pressure control was similar in the two groups, HbA1c increased in the metoprolol (mean ± SD 0.15% ± 0.04%, p < 0.001) but not in the carvedilol group (0.02% ± 0.04%, p = 0.65), resulting in a difference between the two groups of 0.13% ± 0.05% (95%CI –0.22% to –0.04%, p = 0.004) in the modified intention-to-treat analysis. Insulin resistance, as assessed by the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) index was significantly decreased with carvedilol (–9.1%, p = 0.004) but not metoprolol (–2.0%, p = 0.48) and the between-group difference was –7.2% (95%CI –13.8% to –0.2%; p = 0.04). In addition, among patients with normal urine albumin excretion in baseline, fewer progressed to microalbuminuria in the carvedilol than in the metoprolol group (6.4% vs. 10.3%, respectively; OR 0.60, 95%CI 0.36–0.97, = 0.04). These findings support a less detrimental effect of vasodilating compared to older ß-blockers on glycaemic control and insulin sensitivity and suggest that among ß-blockers, vasodilating agents should be preferred in subjects with type 2 DM or the metabolic syndrome.
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Potential mechanisms of the effects of vasodilating ß-blockers on insulin sensitivity and glycaemic control |
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TopSummaryIntroductionEffects of conventional...Potential mechanisms of the...Effects of vasodilating...Potential mechanisms of the...ConclusionsReferences |
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These beneficial or at least neutral effects of newer ß-blocking agents on glycaemic control and insulin sensitivity could be explained in terms of pathophysiology from positive actions on some of the above adverse mechanisms of the conventional ß-blockers. For example, as far as the haemodynamic effects are concerned, stimulation of ß2-receptors causes vasodilatation,38 therefore non-selective ß-blockade will also stop this ß2-mediated increase in blood flow. This is probably why insulin sensitivity is relatively more decreased with propranolol than with ß1-selective blockers.14–16 In addition, in a patient receiving a ß-blocker that combines ß1-selective and ß2-agonistic action, vasodilatation will predominate and peripheral blood flow will increase.38 Thus, the observed increases of insulin sensitivity with delivalol37 and celiprolol10 could be attributed to the vasodilatation they cause. Moreover, it seems unlikely these compounds impair first-phase insulin secretion, which is ß2-mediated31 and therefore they are not implicated in another important mechanism of deterioration in glycaemic control.
In the case of carvedilol, the 1-blocking property would be expected to oppose to the 1-mediated vasoconstriction. Indeed, carvedilol has been known for several years to cause vasodilatation and increase peripheral blood flow.39 Therefore, the beneficial effects of carvedilol on glycaemic parameters could be also explained by its haemodynamic properties, at least in part. Further, carvedilol has an - to ß-blockade ratio of 1:7.6 and has fewer side-effects associated with vasodilatation, such as postural hypotension and dizziness, than for example labetalol, an older combined - and ß-blocker with an - to ß-blockade ratio of 1:4.9.40 This could be of particular importance for patients with DM, which is often complicated by autonomic neuropathy.
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Conclusions |
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TopSummaryIntroductionEffects of conventional...Potential mechanisms of the...Effects of vasodilating...Potential mechanisms of the...ConclusionsReferences |
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Although antihypertensive treatment with traditional ß-blockers reduces cardiovascular risk in diabetic individuals,6,9 these agents are underused in patients with type 2 DM and the metabolic syndrome, as several studies suggested they exert detrimental effects on insulin sensitivity11,14–16 and the incidence of type 2 diabetes.18–21 Studies comparing newer vasodilating to conventional ß-blocking agents showed positive or at least neutral effects of the former on glycaemic control and insulin sensitivity,10–13,37 suggesting that they could be used in subjects with hypertension with or without DM, without the fear of deterioration in these parameters. For a definite answer on the possible benefits of vasodilating over conventional ß-blockers we need studies not only on these surrogate metabolic parameters but also on outcomes such as the incidence of new-onset type 2 DM, cardiovascular events and mortality. The available evidence suggests, however, that vasodilating ß-blockers could be a valuable tool in managing hypertension in patients with type 2 DM or the metabolic syndrome.
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References |
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