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Optimizing Treatment of Diabetes and Cardiovascular Disease With Combined [Alpha],[Beta]-Blockade

Posted on: Tuesday, 11 October 2005, 03:00 CDT

By Bell, David S H

Key words: β-Blockers - Cardiovascular disease - Carvedilol - Diabetes

ABSTRACT

Background: Cardiovascular risk factors of the diabetic patient should be treated as aggressively as those of the nondiabetic patient who has had a myocardial infarction. β-Blockers are established to reduce cardiovascular risk in patients with hypertension, coronary heart disease, and heart failure. Despite this benefit of β-blockers, physicians have been reluctant to use them in patients with diabetes, in whom they are even more effective, because of the negative effects on carbohydrate and lipid metabolism.

Objective: This paper reviews (based on a Medline literature search to December 2004) the relationship between diabetes and cardiovascular risk factors, describes the metabolic consequences of insulin resistance, and discusses the impact of different β- blockers on the treatment of cardiovascular disease in patients with diabetes.

Results: There is a large cardioprotective benefit with the use of β-blockers in patients with diabetes; however, metabolic risks are associated with some β-blockers. Newer, vasodilating, nonselective β-blockers do not have the same adverse metabolic consequences observed with earlier β-blockers. Recent evidence has shown that they have a neutral effect on metabolic parameters and lipid profile. They do not promote insulin resistance and can be used safely in heart failure patients with diabetes.

Conclusions: Nonselective vasodilating β-blockers, such as carvedilol, may be used in patients with cardiovascular disease and diabetes without the same negative metabolic consequences seen with the use of earlier generation β-blockers.

Introduction

Diabetes or impaired glucose tolerance is present in a large proportion of patients with cardiovascular disease (CVD) and increases their risk for adverse outcomes. β-Blocker therapy is a well-established intervention for reducing the risk of CVD in patients with hypertension, coronary heart disease (CHD), and heart failure (HF). Nevertheless, there is a longstanding reluctance on the part of physicians to use β-blockers in patients with diabetes due to the recognized detrimental effects of this class of drug on carbohydrate and lipid metabolism1.

The detrimental metabolic effects of β-blockade occur because β^sub 1^-selective blockers increase insulin resistance and worsen glycemic control, increasing triglyceride levels and decreasing high-density lipoprotein (HDL) cholesterol levels1-3. Unfortunately, not only insulin resistance, but the resistance of clinicians to use to β-blockers, deprives diabetic patients of the cardioprotective effects of β-blockade, which may be even greater in the diabetic than in the nondiabetic patient4,5. However, not all β-blockers affect carbohydrate metabolism to the same degree. Newer vasodilating nonselective β-blockers are generally not associated with metabolic side effects and should circumvent the resistance to their utilization23. This paper reviews the relationship between diabetes

and CVD risk, describes the metabolic consequences of insulin resistance, and discusses the variable impact of different β- blocker therapies on the treatment of hypertension, CHD, and HF in the diabetic subject. Relevant articles were identified through a Medline search (to December 2004) using the following terms: β- blockers, diabetes, heart failure, hypertension, myocardial infarction, cardiovascular disease, coronary heart disease, insulin resistance, metabolic effects, and clinical guidelines. Both large clinical trial and community study data on these topics were selected for inclusion.

Cardiovascular disease in diabetes

The risk of cardiovascular disease is 2 to 3 times greater in diabetic patients than in nondiabetic patients6,7. Even impaired glucose tolerance without overt diabetes increases the risk of cardiovascular disease8. Diabetes is also more likely to develop in patients who are hypertensive9. In the Atherosclerosis Risk in Communities (ARIC)9 study, newonset diabetes was more than twice as likely to develop in patients with hypertension as in those with normal blood pressure (BP). Furthermore, over 70% of older patients (ages 65-74 years) with established diabetes concomitantly receive treatment for hypertension1". There is a robust association between diabetes and CHD and evidence suggests that there is a large increase in risk of future myocardial infarction (MI) in type 2 diabetic patients11,12. This has led to the recognition that diabetes is a cardiac risk factor; the National Cholesterol Education Project places diabetic patients in the highest-risk category (> 20% 10-year risk) for a cardiovascular event, which is equivalent to a patient with cerebrovascular disease, peripheral vascular disease, or abdominal aortic aneurysm and those who already have coronary heart disease13. The American College of Cardiology/ American Heart Association HF guidelines consider diabetes to be Stage A (preclinical) HF even in the absence of structural or functional cardiac abnormalities14.

Metabolic consequences of insulin resistance

Carbohydrate metabolism

Hypertension, CHD, and HF are all associated with decreased sensitivity to the metabolic actions of insulin. Genetics account for 50% of insulin resistance (IR)15 and muscle biopsy of insulin- resistant subjects shows small mitochondria and the accumulation of fat. Decreased mitochondrial function leads not only to impaired glucose oxidation but also to decreased fatty acid oxidation16. Mitochondrial function decreases with aging, which adds to the genetic defect and further decreases mitochondrial function. The defect in mitochondrial function has now been identified as a lack of activity of peroxisome proliferator-activated receptors gamma PPAR-γ-1 coactivator-1 (PGC1), which leads to reduced oxidative phosphorylation16,17. Since mitochondria are inherited maternally, this defect is in keeping with the usual family history of type 2 diabetes, i.e. a predominance and preponderance on the maternal side of the family16. About 50% of hypertensive patients demonstrate some degree of IR, as do many normotensive first-degree relatives of patients with hypertension18. Patients with HF and CHD have a 58% and 32% lower insulin sensitivity, respectively, than normal control subjects19.

The inflammatory state produced by IR leads to endothelial dysfunction20. The vasoconstriction associated with endothelial dysfunction leads to a decreased surface area for exchange of glucose in the muscle leading to the hyperinsulinemia, which stimulates the sympathetic nervous system (SNS)21,22. If HF is present, there is an even greater stimulation of the SNS and worsened IR2325. Diabetes mellitus, hypertension, and atherosclerosis are all conditions that result in endothelial dysfunction, increased peripheral vascular resistance, and decreased insulin sensitivity due to oxidative stress24,25.

Chronic hyperglycemia through the formation of advanced glycosylated end products (AGEs) leads to collagen cross-linking and myocardial fibrosis, which can promote or exacerbate HF. In addition, hyperinsulinemia is associated with left ventricular hypertrophy even in the absence of hypertension26,27. Intracellular myocardial glycation also alters calcium homeostasis leading to myocardial dysfunction28. Activation of protein kinase C beta (PKC- β) activity by hyperglycemia results in myocardial necrosis and fibrosis and ventricular dysfunction, which can be improved with an inhibition of PKC-β29. Hyperglycemia also increases the myocardial content of free radicals and oxidants which decreases nitric oxide levels, worsens endothelial function, and induces myocardial inflammation through stimulation of poly (ADP-ribose) polymerase-1 (PARP-I). PARP-1 inhibition prevents and reverses these effects30. The elevation of free fatty acids (FFAs) associated with hyperglycemia and/or insulin resistance causes lipotoxicity. FFAs and their oxidation products may be toxic to the myocardium and contribute to the development of cardiomyopathy31.

Lipid metabolism

Normal insulin action facilitates FFA uptake by the adipocyte by translocating fatty acid transport protein (FATP) from a perinuclear compartment to the plasma membrane32. Resistance to insulin action directly increases serum FFA levels by interfering with adipocyte uptake and indirectly by promoting lipolysis. Norepinephrine (NE) is elevated in the insulin-resistant state and is a potent stimulator of hormone-sensitive lipase (HSL), which, by increasing lipolysis of adipocyte triglyceride, results in increased FFA release into the circulation33,34.

FFA, via carrier proteins, is transported to the liver where it is re-esterified into triglyceride and incorporated with cholesterol into very low-density lipoprotein (VLDL) particles, which are released into the systemic circulation via the hepatic vein. Triglyceride is gradually removed from the VLDL particles by the action of capillary-bound lipoprotein lipase (LPL) and by hepatic lipase (HL), forming the LDL particle which in the oxidized form is the principle constituent of the atheromatous plaque in the arterial wall35. Lecithin cholesterol acyltransferase (LCAT) is responsible for the esterification of cholesterol wit\h fatty acids, and along with LPL is responsible for one of the major pathways to HDL synthesis. LCAT removes cholesterol from the tissue and is necessary for the production of HDL. LCAT activity is suppressed by β- adrenergic blocking drugs, but enhanced by α-adrenergic blockade35. LPL activity is decreased by P^sub 2^-adrenergic blockade and stimulated by α-adrenergic blockade35.

Insulin-resistant states are associated with a distinctive 'atherogenic dyslipidemia' or 'atherogenic triad' of elevated triglycride levels, decreased HDL levels, and particularly small, dense, and atherogenic LDL and small, dense, less cardioprotective HDL particles36. Small, dense LDL particles easily penetrate the arterial wall where they quickly become oxidized and are more readily taken up by the scavenger receptor on the macrophage to form a foam cell and initiate the atherogenic process. Small, dense HDL particles (HDL3) are more easily metabolized by the liver, which accounts for the low total HDL levels seen with IR. Furthermore, only the larger HDL particle (HDL2) takes part in reverse cholesterol transportation. Small, dense LDL and HDL particles are the result of the increased activity of hepatic lipase on the triglyceride-rich LDL and HDL particles37. Increased triglyceride content of the LDL and HDL particles and increased hepatic lipase activity are both features of the IR syndrome.

LDL particles mature by gaining cholesterol and losing triglycride through exchange with triglyceride-rich lipoprotein particles due to the activity of cholesterol ester transfer protein (CETP), which is enhanced by adrenergic stimulation3738. This exchange may be reversed in the insulin resistance syndrome, where both LDL and HDL particles become triglyceride rich. Chronic hyperglycemia causes glycation of lipoproteins, which further enhances the atherogenicity of the small, dense LDL particles. Glycated LDL particles are more easily oxidized33, which makes them more likely to be recognized and picked up by the scavenger receptor on the arterial wall macrophages to form atherosclerotic foam cells39,40.

A further cardiovascular consequence of IR is the shift from glucose to FFA as a substrate for metabolism. Use of FFAs increases myocardial oxygen consumption by increasing mitochondrial uncoupling protein activity and dissipating energy in the form of heat and by inhibiting membrane ATP. The resultant increased cardiac workload worsens myocardial ischemia, extending myocardial damage post-Mi, reducing ventricular function, and increasing the frequency of cardiac arrhythmias41.

β-Blocker effects

Due to the fear of worsening an insulin-resistant state, many physicians do not use β-blockers in diabetic patients. In patients with diabetes controlled without the use of insulin, the addition of a β-blocker will decrease insulin release from the pancreatic β cell and increase insulin resistance, β- blockers, by increasing insulin resistance, increase the triglyceride, LDL, and total cholesterol levels and decrease the HDL level. However, the cardioprotective effects of β-blockers in this high risk population trump the adverse metabolic effects and the choice of a vasodilating β-blocker may reduce or eliminate the adverse effects.

Cardiovascular risk reduction with β-blockers

β-Blockers are an established effective therapy for treating CVD and reducing mortality and morbidity in patients with hypertension, CHD, and HF42,43. β-Blockade has also been long recognized as standard therapy for angina and is now recommended for almost all patients following an MI44,45. Likewise, strong mortality and morbidity benefits have been demonstrated for β-blocker therapy in patients with HF, especially in the presence of severe left ventricular dysfunction46-48.

β-Blockers have a number of mechanisms by which they provide cardioprotection. β-Blockers reduce sympathetic activity and increase cardiac vagal tone. They decrease heart rate and blood pressure, which reduces cardiac workload and stress on the myocardial wall. This results in less myocardial ischemia and damage and improved myocardial function. β-Blockers prolong diastole, reduce oxygen consumption, and increase blood flow through the myocardium. They also produce an anti-atherosclerotic effect by decreasing wall stress, altering LDL structure (which reduces its potential to bind to the arterial wall), and increasing synthesis of prostacyclin47. β-Blockers also have an anti-inflammatory effect which serves to stabilize plaque and lower the rate of plaque rupture. This anti-inflammatory effect is especially important in the patient with diabetes who is insulin-resistant. Prevention and reversal of myocardial remodeling also contribute to the cardioprotective role of β-blockers in the diabetic patient50.

There is evidence that the benefits of β-blockade are even greater in diabetic patients with cardiovascular diseases. Both β-blockade and angiotensin-converting enzyme (ACE) inhibition lowered systolic BP by an average of 10mmHg and equally reduced the risk of death, stroke, and MI for hypertensive diabetic patients in the UK Prospective Diabetes Study (UKPDS)51. Furthermore, the Hypertension Optimal Treatment (hot) study showed that only a 4 mmHg decrease in systolic BP reduced cardiac events by 51 % in hypertensive diabetic patients, whereas the similar reduction in the nondiabetic group led to an insignificant decrease in cardiac events52. Therefore, the diabetic patient is exquisitely sensitive to BP lowering and even more sensitive to BP lowering than the nondiabetic patient.

The Beta-Blocker Heart Attack Trial (BHAT)53, the Norwegian Timolol Trial54, and the Cooperative Cardiovascular Project all found that β-blocker use after MI reduced mortality in diabetic patients to a comparable or greater extent than in nondiabetic patients55. The Benzafibrate Infarction Prevention56 study enrolled diabetic subjects with known coronary artery disease. There was a 44% decrease in mortality after 3 years in patients who were on β-blockers compared with those who were not, and this difference increased with time. In HF the diabetic patient has a higher mortality, which is important since 44% of patients admitted to the hospital in the United States for HF have diabetes57. In addition, the higher mortality burden imposed by diabetes in CVD can make the absolute risk reduction even greater in diabetic than in nondiabetic patients58. In a meta-analysis by Hass et al.4, diabetic patients with HF had a 25% increased mortality risk, which was negated by the use of β-blockers.

The safety and efficacy of β-blockade in HF patients with diabetes has been confirmed in a number of studies. Long-term carvedilol administration was associated with an improvement in left ventricular function, clinical symptoms, and resting and exercise hemodynamic parameters compared to baseline, with no significant difference between the diabetic and nondiabetic patients. The incidence of adverse effects was similar in the diabetic and nondiabetic groups59. In meta-analyses of HF trials, β- blockers have been reported to reduce mortality in the diabetic patient, although to a lesser extent than in the nondiabetic patient58. Other authors have noted that while the relative reduction in mortality may be less for patients with diabetes than for those without diabetes, because the absolute risk of mortality is greater in diabetic patients, the absolute risk reduction is equal or greater for diabetic than for nondiabetic HF patients treated with β-blockers4. These meta-analyses combined pooled data from studies of β-blockers with different pharmacologie properties (both β^sub 1^-selective and nonselective blockers), which may have mitigated the effect that carvedilol has in HF patients with diabetes. Data from the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial demonstrate that carvedilol use in severe HF patients with diabetes was safe (no excess risk of hypoglycemia or renal dysfunction) and resulted in a comparable reduction in all-cause mortality as in nondiabetic patients in COPERNICUS60. An analysis of the diabetic subgroup in the Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) trial, the dose-ranging study component of the US Carvedilol Trials, demonstrated that carvedilol increased LVEF and reduced mortality similarly in this group as in the nondiabetic patients. In MOCHA, there was evidence of a comparable dose-reponse relationship61. A recent analysis of seven carvedilol HF trials alone showed that carvedilol was just as effective in the diabetic population as in the nondiabetic HF population, with only 18 diabetic patients needed to be treated for 1 year to save one life; however, this was not statistically superior to the 40 nondiabetic patients needed to be treated for 1 year to save one life. (Bell, 2005, unpublished data). The benefit of vasodilating β-blockers, such as carvedilol, in the HF patients with diabetes may derive from the mediation of vasodilation, improved renal blood flow, and a reduction in peripheral resistance. Carvedilol also reduces microalbuminuria, a marker of inflammation and cardiovascular risk62.

Metabolic risk associated with β-blocker use

While observational and clinical studies have shown that BP reduction in patients with hypertension significantly reduces the risk of stroke, its effect is notably smaller in reducing the risk of CHD, possibly because of the metabolic side effects of some antihypertensives (β-blockers and thiazide diuretics) that promote insulin resistance, hyperglycemia, and dyslipidemia63,64. High-dose, but not low-dose, thiazides increase insulin resistance. For instance in the Antihypertensives and Lipid Lowering Treatment to Prevent Heart Attack Trial (\ALLHAT), the chlorthalidone utilized in a dose equivalent to 50 mg of hydrochlorothiazide increased the rate of new-onset diabetes by 28% versus a calcium channel blocker and 34% versus an ACE inhibitor65,66. The ARIC study found a 28% increase in the risk of developing diabetes associated with the use of β-blockers to lower BP, independent of the effect of hypertension; however, thiazide use did not increase diabetes risk9. In the Losartan Intervention for Endpoint Reduction (LIFE) study, a 25% increase in diabetes was seen with atenolol versus losartan, which neither increases nor decreases IR67,68. In the Carvedilol or Metoprolol European Trial (COMET), a 22% increase in the new-onset of diabetes-related adverse events was seen with metoprolol tartrate versus carvedilol, which does not increase IR (see below)69.

Likewise, β-blocker use in CHD has been associated with increased blood glucose levels. β-Blockade is known to increase insulin resistance and hyperglycemia, as well as promote a more atherogenic lipid profile by elevating the serum triglycerides while lowering the HDL cholesterol levels. The vasoconstriction caused by most β-blockers resulting in reduced blood flow to skeletal muscle is one reason for the negative effect on insulin sensitivity. Glucose uptake by the muscle is decreased with decreased peripheral blood flow70. In the Norwegian Timolol Trial71 of MI survivors, hyperglycemia was 40% more common with β-blockers than with placebo. In addition, because of an increase in IR, β-blockade has generally been associated with proatherogenic changes in blood lipids marked by elevated triglyceride levels and decreased HDL levels72. This is likely due to the effects of β^sub 2^- antagonism and unopposed a-stimulation on LPL, HL, and LCAT activity, as reviewed above, and possibly an inhibitory effect on CETP35. Unopposed α-sympathetic stimulation, especially in the insulin-resistant state and in HF patients receiving β-blocker therapy, can result in marked peripheral vasoconstriction due to α-adrenergic activation unopposed by concurrent β^sub 2^- mediated vasodilation. Peripheral vascular disease (PVD) is more prevalent in the diabetic subject (20%-40%), and worsening of PVD due to vasoconstriction can result in vascular insufficiency and worsening intermittent claudication, impaired healing of foot ulcers73, and gangrene74-77. β-Blockers also have the potential to increase the severity and frequency of hypoglycemia as well as interfere with its clinical recognition78. Since hepatic glucose production is stimulated through the activation of β,- sympathetic receptors, β-blockade may worsen and prolong hypoglycemia. Since many of the clinical signs of hypoglycemia are mediated by β-stimulation (palpitations, tremors), they may go unrecognized by patients, thus delaying appropriate treatment. Diaphoresis and neuroglycopenic symptoms, however, are not affected. The incidence of serious hypoglycemia, however, is reduced with β^sub 1^selective blockers compared with nonselective β- blockers79,80.

Table 1. Effect of β-blockers on glucose and lipid metabolism [adapted from Jacob et al.23)

While hypoglycemia is a major problem in type 1 diabetic patients, it is less so in type 2 diabetic patients who still have endogenous insulin production that can be 'turned off and a preserved ability to stimulate production of counter-regulatory hormones81. Hypoglycemia is unusual even in the type 2 subject with long-standing diabetes although it commonly afflicts type 1 diabetic patients, especially those with long-standing diabetes and autonomie neuropathy. In a sample study of my own practice of type 2 diabetic patients receiving monotherapy (90 on sulfonylurea, 172 on insulin) only 5/262 (1.9% compared with 60% of type 1 subjects) reported multiple bouts of severe hypoglycemia. These patients were shown to have no endogenous insulin production and were, effectively, type 1 patients81.

Third-generation β-blockers are not associated with adverse metabolic effects

Unfortunately, despite the advantages in tolerability promised by β-receptor selectivity, both the firstgeneration nonselective β-blockers, such as propranolol, and the second-generation β^sub 1^-selective blockers, such as metoprolol and atenolol, have been associated with significant reductions in insulin sensitivity and increases in the incidence of new-onset diabetes and dyslipidemia1,72,82,83. Insulin sensitivity is reduced by 20% with metoprolol treatment and 13% with atenolol treatment82, while propranolol increases triglycerides by 24% and reduces HDL by 13%84. The metabolic effects of first-, second-, and third-generation β-blockers are summarized in Table 1(23).

The third-generation β-blockers were developed to have vasodilating properties so that the cardiac workload lowered by β-blocker-induced decrease in cardiac output would not be compromised by a β-blocker-induced increase in vasoconstriction and increased afterload. The combined decrease in cardiac output and decreased afterload makes the vasodilating β-blockers particularly suitable for treatment of HF. An important by-product of vasodilatation is an increased surface area for glucose exchange in the muscle that improves insulin resistance and carbohydrate and lipid metabolism, rather than the deterioration seen with first- and second-generation β-blockers.

Dilevalol, a nonselective β-blocker with a β,-agonist effect, was associated with a 19% increase in glucose uptake and a 10% increase in insulin sensitivity compared with 10% and 22% respective decreases with metoprolol in nondiabetic patients with hypertension. In addition, VLDL triglycerides fell 29% with dilevalol but rose 14% with metoprolol after 6 months of treatment85. However, dilevalol was never approved for use in the United States due to its hepatotoxicity86. In a study of nondiabetic hypertensive patients treated for 12 months, celiprolol, a β^sub 1^selective blocker that also acts as a β^sub 2^- agonist, increased insulin sensitivity by 35%, decreased triglyceride levels by 15%, and increased HDL levels by 5%87. However, while available in Europe, celiprolol has not been approved in the United States.

Labetalol is an FDA approved β-blocker for use in hypertension. It combines β, and β2-blockade with α- blocking properties. In a comparison of labetalol and propranolol in 140 mild-moderate hypertensive patients, an increase in serum triglycrides was observed with propranolol treatment, which became significant when hydrochlorothiazide was added at 24 weeks. Labetalol had superior effects on BP lowering, especially in the black cohort of patients, as evidenced by the need to add a diuretic at 30 weeks instead of 24 weeks88.

Carvedilol, a nonselective β-blocker with β^sub 2^- blocking and antioxidant properties, is the only third-generation vasodilating β-blocker approved in the United States for use in HF and systolic dysfunction post-Mi. When carvedilol was compared with metoprolol for 3 months in a randomized trial of nondiabetic, insulinresistant, hypertensive patients3, metoprolol further decreased insulin sensitivity by 14% compared with a 9% improvement with carvedilol. Triglycride levels rose and HDL levels fell with metoprolol treatment but remained unchanged with carvedilol.

The same metabolic responses that occur in nondiabetic subjects also occur with a Pj-selective blocker in diabetic subjects. A 24- week randomized, double-blind study of diabetic hypertensive patients compared treatments with carvedilol and atenolol. Total glucose disposal was improved by 20% with carvedilol treatment, whereas it decreased by 16% with atenolol. Triglycerides fell by 20% and HDL levels rose by 7% with carvedilol while triglycrides increased by 12% and HDL decreased by 5% with atenolol2.

Hyperglycemia can be a problem with advanced HF, where insulin resistance is highly prevalent due to the increased catecholamine levels associated with HF19. In the COPERNICUS60 trial, a large placebo-controlled, randomized, blinded trial, in which both diabetic and nondiabetic patients with severe left ventricular dysfunction experienced a similar improvement in outcome with carvedilol treatment, there was no change in glucose levels in either group.

Most recently, a randomized, double-blind clinical trial, Glycemic Effect in NIDDM: CarvedilolMetoprolol Comparison in Hypertensives (GEMINI), was completed in 1235 diabetic hypertensive patients. Prior to the study all patients were treated with an ACE inhibitor or angiotensin receptor blocker (ARB) and, after removing antihypertensives other than ACE inhibitors or ARBs and becoming hypertensive, these subjects were randomly assigned to receive escalating doses of carvedilol or metoprolol tartrate. Included were patients with systolic BP 130-179 mmHg and diastolic BP 80-109 mmHg as well as a glycosylated hemoglobin (HbA^sub 1c^) level 6.5%-8.5% (the study's primary outcome). Carvedilol and metoprolol tartrate doses were gradually increased in three stages over 2-7 weeks to achieve a target BP goal. A similar percentage of patients in both groups received baseline antihypertensive treatment with hydrochlorothiazide, dihydropyridine calcium channel blockers, and α-blockers. After 5 months of subsequent maintenance therapy, which was supplemented by hydrochlorothiazide in 44% of patients, a dihydropyridine calcium channel blocker in 24%, and an oc-blocker in 2% of patients, there was a significant difference favoring carvedilol between the 2 treatment groups in the change from baseline HbAk (0.12%, p = 0.006) (Figure 1)89.

This is a clinically significant difference considering that results from UKPDS found that each 1% decrease in HbA1 was associated with a significant 16%reduction in HF, a 21% reduction in diabetes-related death, and a 14% reduction in myocardial reinfarction among other end points90. Recent data from the European Prospective Investigation of Cancer (EPIC)-Norfolk study indicate that even a 0.1% decrease in HbA]c is associated with a 12% reduction in the risk of mortality91. Increases of over 0.5% and 1% in HbA|c were more frequent with metoprolol, as were dropouts due to glycemic control. IR was significantly reduced by carvedilol and nonsignificantly increased by metoprolol.

Compared with the metoprolol tartrate group, the carvedilol group had no increase in triglycerides (p > 0.001) and a significant lowering of total cholesterol (p = 0.001) levels. No differences in HDL or LDL levels were observed, probably due to more subjects in the metoprolol group being started on statins during the study89. Most significantly, carvedilol-treated patients also showed less new- onset microalbuminuria and a significant 14% reduction in existing albumin: creatinine ratio. Microalbuminuria is a well-recognized marker of endothelial dysfunction and has been shown to be a powerful risk predictor for CHD in diabetic as well as nondiabetic patients. The effects on microalbuminuria and improvement in endothelial function seen with carvedilol are most likely due to its antioxidant effect rather than to β- or α-blockade92-94. Fewer subjects completed the study with metoprolol tartrate and those on metoprolol tartrate had more hyperglycemia and hypoglycemia than subjects treated with carvedilol. Weight was significantly increased with metoprolol tartrate but not with carvedilol. While the weight gain in the metoprolol tartrate group was significant the gain was only 1.2 kg (1 kg more than carvedilol), which is not enough to account for the changes in metabolic effects. The GEMINI investigators recently tested this with pairwise correlation analyses of weight vs. HbAk, HOMA-IR, SBP, and DBP and no significant associations were seen between the change from baseline in any of these parameters and weight change95. The dose of carvedilol needed to reduce BP to target (37.5mg) was a dose that is often used in practice while the metoprolol dose that was needed to achieve target BP levels (256mg) was higher than what HTN-DM patients commonly achieve in real life89.

Figure 1. GEMINI: glycosylated hemoglobin (HbA^sub 1c^) at baseline and each maintenance month. Change from baseline to maintenance month 5 (primary outcome) was significant (standard deviation [SD]: 0.13% [0.05%]; 95% confidence interval: -0.22% to - 0.04%; p = 0.004). Error bars indicate SD from mean. (Adapted from Bakris et al.89, with permission)

Conclusions

Although β-blockers can reduce the risk of mortality and morbidity in diabetic patients with or without cardiovascular disease, their protective effect may be ameliorated by adverse metabolic effects. Traditional β-blockers, whether nonselective or β^sub 1^-selective, have repeatedly been shown to reduce insulin sensitivity, worsen glucose tolerance, increase the frequency of new-onset diabetes, and promote an atherogenic lipid profile.

Recent evidence has shown that vasodilating β-blockers have a neutral effect on metabolic parameters and lipid profile. They do not promote insulin resistance and can be used safely in HF patients with diabetes. A recent clinical trial with carvedilol in the diabetic hypertensive patient has not only confirmed these findings but has also shown improvement in albumin:creatinine ratio, which may indicate an improvement in endothelial function previously compromised by the inflammatory state of insulin resistance.

Acknowledgment

Declaration of interest: Editorial support was provided by a technical grant from GlaxoSmithKline, Philadelphia, PA.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3036_4, Accepted for publication: 31 May 2005

Published Online: 24 June 2005

doi:10.1185/030079905X53306

David S. H. Bell

Division of Endocrinology, Department of Medicine, University of Alabama Medical School, Birmingham, AL, USA

Address for correspondence: David S. H. Bell, MB, Department of Medicine, The University of Alabama Medical School, Room 702, Faculty Office Tower, 570 20th Street South, Birmingham, AL 35294, USA. Tel.: +1 205 975 2404; Fax: +1 205 975 9304; email: dshbell@uab.edu

Copyright Librapharm Aug 2005

Source: Current Medical Research and Opinion

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