Role of a1-blocker in
hypertensive patients with metabolic syndrome
Hing-Chung Lam M.D.,F.A.C.E.
林興中醫師 高雄榮總新陳代謝科
Diabetes Mellitus is a vascular disease. The goals of treating diabetes are to alleviate its symptoms and to prevent its chronic complications. Atherosclerosis is the major killer of patients with diabetes, causing death in 75% of patients and resulting in myocardial infarction (MI), stroke, and peripheral vascular disease, all of which are increased by 2- to 5-fold in patients with diabetes. Coronary heart disease (CHD) remains the leading cause of mortality in the USA and is responsible for 1.5 million MI per year. Indeed evidence of CHD is already present in 50% of Type 2 Diabetes Mellitus (T2DM) patients at the time of diagnosis and a significant number of patients have unrecognized silent ischemia.
Insulin resistance is said to be present when the ability of insulin to stimulate the uptake and disposal of glucose by muscle is impaired. In 1988, Dr. Reaven first addressed that individuals who are insulin resistant and hyperinsulinemic are more likely to be hypertensive, glucose intolerant or diabetic, and to have a dyslipidemia characterized by a high plasma concentration of triglycerides (TG) and a low plasma concentration of high-density lipoprotein (HDL) cholesterol. All of these changes have also been shown to increase the risk of CHD and these relationships were designated as the components of “Syndrome X”, “The Insulin Resistance Syndrome”, or “The Metabolic Syndrome”. The underlying pathophysiology and relationship between the various components of this syndrome have been obscure, but Landsberg et al. suggest that both insulin and the sympathetic nervous system (SNS) may be involved. More recently, several other abnormalities have been linked to insulin resistance and/or compensatory hyperinsulinemia and CHD. These include an increase in small density low-density lipoprotein (LDL), an enhanced postprandial lipemia, salt sensitivity, hyperuricemia, increased plasma concentrations of fibrinogen and plasminogen activator inhibitor type 1 (PAI-1), enhanced sympathetic nervous system (SNS), upper body obesity, and microalbuminuria. These characteristics coexist together such that patients with one of the conditions are likely to have the other components as well, and this clustering of pathophysiological alterations conveys considerable cardiovascular risk. However, insulin resistance need not be global and it has been known that not all tissues respond similarly to insulin within the same individual. For example, insulin-stimulated glucose disposal in muscle can be decreased, while other effects of insulin are normal. This intraindividual difference of tissue responses to insulin together with insulin resistance are the main mechanism for the components of Syndrome X to develop. The number of manifestations of insulin resistance that exist in a given individual will vary as a function of the cutpoints chosen to identify an abnormality (for example, TG³ 150 or ³200 mg/dl), or, will vary primarily as a function of the severity of the defect in insulin action and the magnitude of the compensatory hyperinsulinemia. The consequences of insulin resistance/compensatory hyperinsulinemia will also depend upon the individual response to the processes initiated by the abnormalities in insulin metabolism.
The occurrence of hypertension in association with T2DM constitutes one of the most rapidly increasing disorders in the world. There are substantive data suggesting that the vascular complications associated with T2DM are amplified in the presence of hypertension. Mortality, cardiovascular disease, renal disease, retinopathy, and neuropathy are all significantly increased when hypertension is combined with T2DM. The achievement of good blood pressure (BP) control is considered almost as important as the achievement of good glycemic control. Actually, the “tight” blood pressure control study embedded in the UKPDS demonstrated that lowering the blood pressure below 150/85 mm Hg was associated with a significant reduction in the risk of microvascular and macrovascular complications, and clinically important reductions in the risk of deaths related to diabetes. However, since diabetic hypertensive patients have several metabolic risk factors which are themselves multiplicative in terms of cardiovascular risk, treatment used to achieve goal BP should not further worsen (and preferably improve) concomitant cardiovascular risk factors. This suggests that in treating diabetic hypertensive patients, nonpharmacologic interventions that increase sensitivity to insulin, including weight reduction, low-fat diet, and increased physical activity, have a primary role. When pharmacologic treatment is required, a case can be made for drugs that improve insulin sensitivity, lower circulating insulin levels, and improve the attendant profile of risk factors for cardiovascular disease, as well as lower blood pressure.
Specific antihypertensive agents confer different effects, both detrimental and beneficial, on metabolic risk factors for cardiovascular disease. It is clear that the incidence of new cases of diabetes is greater in patients treated with diuretics or β-blockers. Although captopril increases insulin sensitivity, angiotensin converting enzyme inhibitors as a class (and probably those of angiotensin II receptor blockers) do not seem to have this effect. Except short-acting nifedipine which decreases insulin sensitivity, calcium channel blockers as a class also show neutral effects on insulin sensitivity. On the other hand, selective α1 blockers such as doxazosin, beyond blood pressure lowering, also have a potentially important role in the management of insulin resistance syndrome, due to their action to reduce insulin levels, improve insulin sensitivity and lipid profile(such as a reduction in total cholesterol, LDL cholesterol and triglycerides, and an increase in HDL cholesterol), and suppress sympathetic activity. The lipid-lowering effect of doxazosin has been shown to be accompanied by an increase in plasma lipoprotein lipase (LPL) activity as well as a dose-dependent increase in LDL receptor activity. The mechanism underlying the effects of doxazosin on insulin sensitivity and lipid-lowering may probably due to the relaxation of peripheral arterioles as well as capillary recruitment, which increases the blood flow and prolongs the transit time for the blood over the muscle bed, thereby improves tissue responses to glucose and insulin and increases LPL activity. In addition, doxazosin treatment has been shown to reduce significantly the pressor response to smoking, thus it may be useful in hypertensive smokers who are unwilling or unable to stop smoking. Furthermore, the incidence of reported male erectile dysfunction by treatment assignment in the Treatment Of Mild Hypertension Study (TOMHS) is the lowest in the doxazosin-treated group. Since the risk of sexual dysfunction is greatly exacerbated by ancillary factors such as smoking and diabetes mellitus and as sexual dysfunction acts as an obstacle to compliance with antihypertensive therapy, the use of α1 blockers may have an additional benefit in the treatment of hypertensive diabetic patients. Finally, doxazosin has been shown to increase nitric oxide production by the stimulation of nitric oxide synthase activity in the rat kidney, and this may have a role in the prevention of glomerulosclerosis.
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