Metabolic Properties of Vasodilating B-Blockers: Management Considerations for Hypertensive Diabetic Patients and Patients With the Metabolic Syndrome

Stephan Jacob, MD; Erik J. Henriksen, PhD

Disclosures
In This Article

Insulin Resistance, Diabetes, and Hypertension

Resistance to the action of insulin to mediate peripheral glucose disposal is a key element in the etiology of type 2 diabetes. Insulin resistance leads to a compensatory increase in pancreatic ß-cell activity, causing hyperinsulinemia and, eventually, impaired glucose tolerance, hyperglycemia, and overt diabetes.

Hypertension is also frequently associated with reduced insulin sensitivity; insulin resistance has even been recognized in normotensive offspring and first-degree relatives of hypertensive patients, independent of obesity.[17] Although insulin ordinarily decreases BP, insulin resistance is associated with an increase in aortic stiffness and a decrease in peripheral arterial compliance.[18]

Insulin resistance often predates hypertension and has been found to predict the emergence of future hypertension in healthy, normotensive individuals. For example, in a prospective study of CVD risk factors involving 840 normotensive subjects, each measured unit of insulin sensitivity was associated with a 10% lower risk of developing hypertension over a 5-year period.[19] Figure 1 demonstrates the relationship between mean BP and insulin sensitivity found by the European Group for the Study of Insulin Resistance[20] from a data pool of nearly 1500 nondiabetic, nonhypertensive individuals.

Relationship between blood pressure and insulin resistance. Adapted with permission from Endocr Pract. 2003;9:43-49.[20]

In addition to type 2 diabetes and hypertension, insulin resistance has been associated with an overlapping cluster of interrelated clinical and laboratory features that are each CHD risk factors in themselves, including increased central obesity and atherogenic dyslipidemia; prothrombotic and proinflammatory states have recently been identified as contributing to this constellation. This cluster, referred to as the metabolic syndrome, has been closely associated with high cardiovascular risk.[1]

Although the actual pathophysiologic steps linking genetic variation and insulin resistance or hypertension are unknown, particular patterns of gene expression may influence both insulin sensitivity and peripheral vascular tone. In particular, gene products influencing the renin-angiotensin system (RAS) may have a role in both conditions. For example, the level of insulin resistance in hypertensive individuals is influenced by a common polymorphism in the ACE gene, and hypertensive (but not normotensive) subjects have been found to have significantly greater insulin resistance with the DD genotype.[21]

The relationship of RAS activity to insulin resistance may involve the lowering of insulin sensitivity due to a reduction in glucose delivery secondary to decreased peripheral blood flow. Both endothelial function (endothelium-dependent vasodilation) and insulin sensitivity were improved in a study on hypertensive subjects treated with the ACE inhibitor enalapril; improvement in the two parameters showed a significant positive correlation.[22]

Some insight into the mechanism of action of agents that modulate the RAS comes from studies using animal models of insulin resistance. Studies using the obese Zucker rat, a model of severe skeletal muscle insulin resistance and prediabetes, have demonstrated that ACE inhibitors improve skeletal muscle glucose transport and metabolism by the actions of bradykinin (acting through bradykinin B2 receptors and the associated NO production) and by a diminution of the negative metabolic effects of angiotensin II (acting through AT1 receptors).[24,25,26]

Regardless of the underlying mechanisms, clinical trials have demonstrated that interruption of the RAS by either an ACE inhibitor or an angiotensin receptor blocker can reduce the incidence of new-onset diabetes in patients at high risk for CVD.[23,24,25]

One mechanism for an acute increase in insulin-mediated glucose disposal is through the action of the hormone to increase blood flow and substrate delivery to skeletal muscle by a reduction in local vascular resistance.[26] At the same time, however, insulin activates the sympathetic nervous system (SNS), leading to an increase in peripheral vascular resistance and impaired glucose delivery to the skeletal muscle.[27]

In conditions associated with the insulin-resistant state, such as type 2 diabetes and hypertension, the normal insulin-mediated decrease in vascular resistance is blunted due to a reduction in the synthesis of endothelium-dependent NO,[26] a potent vasodilator, while the SNS pressor response is preserved.[27] An imbalance of the autonomic nervous system with an increase in sympathetic-to-parasympathetic activity has been described to be predictive of nondiabetic subjects developing diabetes. The Atherosclerosis Risk in Communities (ARIC) study[28] of over 8000 nondiabetic, middle-aged adults, at entry found that autonomic dysfunction, determined from heart rate and its variability imposed nearly twice the risk of developing diabetes over an 8-year follow-up period. Part of the beneficial effects of RAS inhibition on insulin sensitivity may be mediated through its sympathoinhibitory effects.[29]

The vascular and metabolic effects of SNS stimulation are mediated through the three major adrenergic receptors located in the peripheral resistance vessels: α1, ß1, and ß2. Through their effects on intracellular cyclic nucleotide and calcium levels, ß1-receptor stimulation results in vasoconstriction, whereas α1 and ß2 stimulation leads to vasodilatation. In addition, ß1 stimulation augments RAS activity by releasing renin from the kidney, and angiotensin II, in turn, further enhances SNS outflow. Beta1 blockade reduces renin release, and ß1-receptor stimulation can result in decreased glucose utilization; α1 or ß2 activity can lead to increased peripheral blood flow and enhanced glucose disposal.

As discussed above, ß blockers have been demonstrated to be effective in reducing CVD risk due to CHD in diabetic and nondiabetic persons. The wide variety of currently available ß blockers offer the opportunity to select individual agents for particular uses based on their desirable, as well as undesirable, pharmacologic actions. Beta blockers are indicated for the treatment of hypertension, angina, and secondary risk reduction after MI; some are approved for the management of symptomatic and asymptomatic left ventricular systolic dysfunction (LVSD). Individual agents, however can vary significantly in their propensity to promote insulin resistance and dyslipidemia, as well as in their adverse effects in patients with peripheral vascular or reactive airway disease.

Initially, ß blockers included nonselective inhibitors of ß1 and ß2 receptors, including propranolol, timolol, and pindolol. Newer, more ß1-selective, agents include atenolol, metoprolol, and bisoprolol; these agents have fewer adverse effects on the pulmonary and peripheral circulation. Selective or nonselective ß antagonists with additional pharmacologic (e.g., vasodilatory) properties have become available. Table I[30,31] displays the ß blocking and other pharmacologic properties of several current and investigational agents. Because of the different ratio of adrenergic receptor selectivity, each ß blocker produces a particular set of hemodynamic responses to acute administration (Figure 2).[32]

Comparative acute hemodynamic effects of different ß-blockers. HR=heart rate; CI=cardiac index; Ees=end systolic elastane; PWP=mean pulmonary wedge pressure; SVR=systemic vascular resistance. Adapted with permission from Am J Cardiol. 1997;80:26L-40L.[32]

The mechanisms of action of the new vasodilating ß blockers vary, as indicated in Table I .[30,31] Carvedilol possesses α1-blocking properties, whereas nebivolol increases production of nitric oxide and celiprolol and dilevalol possess ß2-agonist activity. Bucindolol has mild vasodilating properties through uncertain mechanisms.

Beta blockers are widely used for the treatment of patients at high risk for CVD due to hypertension, CHD, or LVSD. Despite varying mechanisms of increasing peripheral blood flow, most of the vasodilating ß blockers have been shown to reduce the adverse metabolic effects associated with other ß blockers in diabetic patients, such as decreased insulin sensitivity, increased plasma triglyceride levels, reduced HDL cholesterol levels, and increased relative proportions of small, dense, LDL cholesterol particles.[33] These effects may derive from the inhibition of two enzymes involved in lipoprotein metabolism, lipoprotein lipase and lecithin:cholesterol acyltransferase. Interestingly, α1 blockade increases the same enzymes.[34]

Vasodilating ß blockers with ß2 agonism include the ß1-selective celiprolol and the nonselective dilevalol. In 25 nondiabetic, hypertensive patients with baseline dyslipidemia, 6 months of celiprolol treatment increased whole-body insulin sensitivity by 35%, which was associated with increased HDL levels and decreased plasma triglycerides.[35] Dilevalol was compared with the ß1-selective blocker metoprolol in 42 hypertensive subjects. Insulin-mediated glucose disposal and insulin sensitivity were increased by 19% and 10%, respectively, in patients receiving dilevalol; metoprolol treatment was associated with 10% and 22% decreases in these parameters, respectively. Plasma triglyceride levels were likewise improved with dilevalol (-22%) but worsened with metoprolol (+10%).[36]

Carvedilol, a nonselective ß blocker, causes peripheral vasodilatation mediated by α1-receptor blockade, leading, in turn, to improved insulin sensitivity and increased HDL cholesterol.[37] The metabolic characteristics of carvedilol have been compared with both atenolol and metoprolol in hypertensive patients. In a study of 72 nondiabetic hypertensive subjects, insulin sensitivity increased by 8.5%, as compared with a 14% decrease with metoprolol. HDL cholesterol and triglyceride levels were worsened by metoprolol but were unchanged with carvedilol.[38] Compared with atenolol treatment in 45 hypertensive diabetic patients, carvedilol treatment improved insulin sensitivity by 27%, whereas atenolol decreased it by 24%. Whereas carvedilol increased HDL cholesterol and decreased plasma triglyceride levels in this study, atenolol produced the opposite effects.[37] In a study of 250 hypertensive patients with baseline dyslipidemia, carvedilol increased HDL cholesterol by 11% and lowered plasma triglycerides by 13%.[39] In a randomized, placebo-controlled trial, patients with HF and an insulin-resistant state experienced no decrease in insulin sensitivity with carvedilol.[40]

In addition to its vasodilating activity, carvedilol possesses potent antioxidant properties that may help to reduce CVD risk. Its ability to scavenge reactive oxygen species can protect endothelial cells from oxidative-stress injury and lipid peroxidation.[41] In a group of 25 hypertensive men, carvedilol enhanced the resistance of LDL to in vitro oxidation and reduced the circulating levels of autoantibodies to oxidized LDL.[42]

In addition to ACE inhibitors and lipid-lowering agents, ß blockade has demonstrated an important role in the aggressive management of patients at high risk for future major cardiovascular events due to hypertension, CHD, and LVSD. Vasodilating ß blockers, because they cause fewer adverse effects, provide an advantage over earlier ß blockers.[43] In addition, there is some evidence that these newer agents may reduce some adverse effects of ß blockade, particularly peripheral vasoconstriction,[44] but not necessarily others such as bronchospasm[45] or weight gain.[13]

Carvedilol has been found to provide significant CVD risk reduction in high-risk patient populations and has been approved for use in hypertension, HF due to LVSD, and after an MI. In a randomized clinical trial of post-MI patients with LVSD, the addition of carvedilol to the usual care significantly reduced death (23%) and recurrent infarction (41%) when compared with a regimen that did not include this agent.[46] Mortality and morbidity risks were likewise reduced in randomized trials of patients with LVSD when carvedilol was added to ACE inhibitor, diuretic, and digitalis therapy.[47] In patients with severe advanced HF, carvedilol reduced the risk of death by 35%[48]; in a comparison trial with metoprolol in patients with HF due to LVSD, carvedilol provided an additional 20% CVD mortality benefit compared with the ß1-selective agent metoprolol.[49] BP lowering with carvedilol in clinical hypertension trials is of the degree usually associated with reduced risk of major cardiovascular events.[50]

For diabetic patients at particularly high CVD risk due to concomitant hypertension, clinical trials with carvedilol have demonstrated a BP reduction without adverse metabolic effects.[51] Similarly, diabetics at increased CVD risk due to concomitant LVSD have shown improved mortality outcomes and no worsening of glucose or lipid metabolism.[40] Currently, a large, randomized clinical trial (Glycemic Effect in NIDDM: Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) comparing glycemic control in hypertensive diabetic patients treated with either carvedilol or metoprolol is being conducted.

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