© Borgis - New Medicine 2/2004, s. 52-56
Zygmunt Chodorowski, Jacek Sein Anand
Treatment of hypertension in patients with type 2 diabetes
Department of Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
Antihypertensive therapy in diabetics is highly effective in reducing cardiovascular and microvascular complications. However, many patients require three or more drugs to achieve blood pressure below 130/80 mmHg. It seems reasonable to use angiotensin-converting enzyme (ACE) inhibitors as the first-line agent in most diabetics, especially in patients with type 2 diabetes, hypertension and/or microalbuminuria. In diabetics with hypertension, proteinuria or renal insufficiency, angiotensin receptor blockers (ARBs) are considered first-line therapy. If ACE inhibitors or ARBs are not well tolerated by patients due to the renal complications, the use of â-blockers or non-dihydropyridine calcium channel blockers (non-DCCB), often with thiazide diuretics, should be considered. In patients with a recent myocardial infarction, â-blockers should also be considered. DCCBs and a-blockers can be used as second-line drugs.
There is considerable evidence that the incidence of type 2 diabetes mellitus is rising, especially in highly developed countries (1-5).
The optimal balance of glycemia prevents or retards the progress of microangiopathic changes, but it does not exert a significant inhibiting effect on the development and course of macroangiopathy. Systolic blood pressure from 130 mmHg to 139 mmHg and diastolic blood pressure from 80 mmHg to 89 mmHg or hypertension occurs in 94% of type 2 diabetics, which is one of the leading pathogenic factors accelerating the formation and progress of diabetic macro- and microangiopathy. This in turn significantly increases morbidity and mortality due to cardiovascular complications, primarily coronary artery disease (CAD), stroke, end stage renal failure, and peripheral arterial disease (6-10). Hypertension is typically part of the metabolic syndrome, along with insulin resistance, much more rarely the result of diabetic nephropathy. Hyperinsulinemia as a result of insulin resistance causes a whole range of unfavorable consequences, including hyperreactivity of the sympathetic nervous system and increased uptake of sodium ions in the kidneys. The glycation of proteins in the vascular wall and the premature development of sclerosis increase the frequency of occurrence of the isolated form of systolic hypertension, especially in persons of advanced age.
Arterial hypertension in diabetic patients is responsible for a more than two-fold greater risk of myocardial infarction and stroke, and a three-times higher frequency of occurrence of chronic congestive heart failure. The increased ferquency of cardiovascular complications is also due to left ventricular hypertrophy, the absence of nocturnal drop in blood pressure, dyslipidemia, hyperuricemia, microalbuminuria, chronic kidney failure, a tendency to thrombosis, and reduced compliance of the major arteries (11-17). The risk of cardiovascular incidents (CVIs) in diabetic patients with no history of myocardial infarction is similar to that in non-diabetic individuals who have already had a myocardial infarction. Thus one of the priorities in devising an effective therapeutic strategy for patients with diabetes and hypertension is the attempt to achieve target blood pressure (<130/80 mmHg), which significantly reduces the frequency of occurrence of such complications as macro- and microangiopathy (18-26). Achieving a maximum reduction in the danger of cardiovascular complications depends more on achieving the target blood pressure than on the choice of antihypertensive drug (24).
In cases of diabetes and hypertension, diagnostic and therapeutic procedure is conditioned by the evaluation of the presence and degree of advancement of late complications and the correction of risk factors for arteriosclerosis. All patients with hypertension and diabetes are automatically placed in the high-risk group for cardiovascular complications and should be treated intensively. According to the recommendations of the American Diabetes Association and the 7th Report of the JNC, the target blood pressure in patients with diabetes should be below 130/80 mmHg (8, 27). In patients with proteinuria over 1.0 g/24 h and/or chronic kidney failure, the limits are yet lower: blood pressure should not exceed 125/75 mmHg. These recommendations are based on the results of epidemiological research documenting the existence of a strict dependence between high blood pressure and the risk of cardiovascular complications. In research by the UKPDS, the risk of all diabetic complications and cardiovascular complications was diminished when systolic blood pressure was reduced from over 160 mmHg to under 120 mmHg (10). On this basis the conclusion was reached that the lower the systolic blood pressure, the less the risk of complications occurring.
In patients with systolic blood pressure from 130 to 139 mmHg or diastolic blood pressure from 80 to 89 mmHg, non-pharmacological methods should be used for a maximum of three months; if the desired hypotensive effect is not achieved, pharmacological treatment should be introduced (8). Non-pharmacological therapy in patients with diabetes, especially when there is co-occurring metabolic syndrome X, brings measurable benefits only when there is scrupulous observance of the regimen. Even if lifestyle modification alone reduces blood pressure only to a slight extent, it can reduce disturbances of carbohydrate and lipid metabolism. Within the framework of non-pharmacological treatment the most attention is devoted to stopping tobacco smoking, increasing physical activity, reducing body mass, limiting the consumption of alcohol, salt, saturated fats and cholesterol, and maintaining the consumption of potassium, magnesium and calcium at the proper level (8, 28). These rules apply as auxiliary treatment at all phases of pharmacotherapy.
The American Diabetes Association recommends that the treatment of diabetes include very rigorous pharmacological therapy of hypertension, hyperglycemia, and disturbances of lipid metabolism (8, 20, 29). Patients with diabetes and hypertension receive greater benefits from effective hypotensive treatment than patients without diabetes. Monotherapy can be attempted only with systolic blood pressure from 130 mmHg to 145 mmHg and diastolic blood pressure from 81 mmHg to 90 mmHg. The discussion taking place on the pages of medical journals regarding the choice of the right group of antihypertensive drugs as optimal for patients with diabetes is only partially justified, since as a general rule it becomes necessary to use from 2 to 6 hypotensive drugs at once to achieve the target blood pressure below 130/80 mmHg (6, 8, 9, 16, 22, 24). Nevertheless, the rule is always in force that one should begin therapy with small doses and gradually increase them at intervals of several weeks (8). This makes it possible, especially in elderly patients, to avoid the effects of orthostatic hypotonia. The absence of the desired hypotensive effect when using three hypotensive drugs, including a thiazide diuretic, is an indication to refer the patient to a specialist in hypotensive treatment (8).
The ideal hypotensive drug used in diabetes, in addition to metabolic neutrality, should optimize blood pressure and display cardio- and nephro-protective effects. These criteria are best met by angiotensin convertase (ACE) inhibitors, AT1 receptor blockers for angiotensin II, and some thiazide-type diuretics.
Among the hypotensive drugs, the ACE inhibitors are regarded by many authors as the drugs of choice in the treatment of diabetes with hypertension (7, 8, 25, 30, 31). These drugs display, among other things, antioxidative and antimitotic effects, and exert a protective influence on the heart and vascular system, slowing the progression of late complications in the form of macro- and microangiopathy; as a consequence, they lower the overall mortality rate (8). They do not have a negative impact on insulin secretion or glucose metabolism; in fact, quite the contrary, they even improve somewhat the metabolic equilibrium in diabetes by reducing tissue insulin resistance. ACE inhibitors markedly lower microalbuminuria, primarily due to the reduced intraglomerular pressure and permeability of the basement membrane. They also retard the proliferation of mesangial cells and slow the process of fibrosis of the renal glomerules. In the MICRO-HOPE research project, in patients with type 2 diabetes treated with ramipril, reduced volume of microalbuminuria and reduced risk of the development of nephropathy was found after even a slight reduction of blood pressure by 2/1 mm Hg (31). ACE inhibitors also act nephroprotectively and cardioprotectively, since microalbuminuria is a risk factor for both diabetic nephropathy and CAD (8, 13). The nephroprotective features of these drugs are also put to use in the treatment of patients with diabetes and normal blood pressure (26). In these patients, ACE inhibitors are recommended in gradually increasing doses, guided by the gradual reduction in microalbuminuria, until normalization is obtained or the maximum reduction of albumin secretion in urine has been achieved (17). Some data suggest that there exists a summation effect of submaximal ACE inhibitor doses and doses of angiotensin receptor blockers, in regards to lowering both blood pressure and albuminuria (14). In patients with renal insufficiency and in elderly patients with suspicion of stenosis of the renal artery, ACE inhibitor treatment requires caution and periodic monitoring of the serum concentration of creatinine. However, a small and reversible increase in the serum concentration of creatinine up to 30% of baseline in patients with creatininemia up to 3.0 mg/dl is not a sufficient reason for interrupting further treatment with ACE inhibitors (32).
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