© 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
Summary
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.
INTRODUCTION
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).
THERAPEUTIC STRATEGY
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.
ACE INHIBITORS
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).
Achieving the target blood pressure below 130/80 mmHg using ACE inhibitors in monotherapy is rarely possible in practice, and in most cases it is necessary to add other hypotensive drugs, especially thiazide diuretics and/or calcium antagonists. The use of compound preparations including an ACE inhibitor and hypotensive drugs from another group (a calcium antagonist or a diuretic) can support the observance of the treatment regimen by the patient and limit the costs (15). In the PREMIER program (Preterax in Albuminuria Regression), 480 hypertensive diabetic patients received a preparation composed of small doses of perindopril and indapamide as a first-line treatment, which caused a greater reduction of albuminuria than monotherapy with enalapril (15).
AT1 RECEPTOR BLOCKERS FOR ANGIOTENSIN II
In the event that undesirable side effects occur with ACE inhibitors (cough, hyperkaliemia, angioedema edema, skin lesions), many authors recommend replacing them with AT1 receptor blockers for angiotensin II (18, 33, 34). Virtually all the counterindications for ACE inhibitors include also angiotensin receptor antagonists. In the ALLHAT research project, involving type 2 diabetes patients treated with ACE inhibitors, thiazide diuretics, or calcium channel blockers, a similar number of CAD-related deaths and non-fatal myocardial infarctions was found, and a similar all cause mortality rate (35). Chlortalidon significantly exceeded the other drugs to which it was compared, lisinopril and amlodipine, in terms of preventing the occurrence of heart failure (35).
Angiotensin receptor antagonists are characterized by good tolerance and nephroprotective action, reducing microalbuminuria or proteinuria, and cardioprotective action, correcting left ventricular hypertrophy (LVH) (18, 19, 23, 33, 34). One preparation from this group, losartan, has found a permanent place in the treatment of diabetes with hypertension and nephropathy. An additional advantage is the beneficial influence on cognitive function, especially in elderly patients (36). The results of multi-center, randomized trials indicate a highly positive effect of AT1 receptor antagonists for angiotensin II on lowering the volume of microalbuminuria and slowing the progress of diabetic nephropathy and end-stage renal disease (17, 18, 34). In the LIFE program (Losartan Intervention For Endpoint reduction), a comparison of outcome with losartan and atenolol in the entire study population and in the group of patients with hypertension and diabetes showed an advantage for losartan in respect to regression of late complications, with lower frequency of cardiovascular episodes and mortality and total mortality (23). In the IDNT research project (Irbesartan Diabetic Nephropathy Trial), among 1715 patients with diabetes, hypertension, and chronic nephropathy, irbesartan proved to be more effective than amlodipine in inhibiting the doubling of the level of serum creatinine and the progress of end-stage renal disease, and in lowering the mortality rate (33).
CALCIUM CHANNEL BLOCKERS
Non-dihydropyridine derivatives of free calcium channel antagonists (verapamil, diltiazem) reduce the frequency of occurrence of coronary events and reduce the volume of microalbuminuria, and also act synergistically with ACE inhibitors. In the NORDIL research project (Nordic Diltiazem), in a subgroup of 727 patients with diabetes and hypertension, no difference was seen in the cardiovascular endpoints (myocardial infarction, stroke, cardiovascular mortality) among patients treated with diltiazem, a b-adrenolytic and/or a thiazide diuretic (21). Presently, dihydropyridine calcium blockers continue to be recommended for the treatment of combined diabetes and hypertension, especially in the case of simultaneous occurrence of microalbuminuria, diabetic nephropathy, and/or chronic kidney failure (creatinine content in plasma>3.0 mg/dl, glomerular filtration rate <30 ml/min), but they cannot constitute first-line drugs in this patient population (8, 32).
One disadvantage of the use of beta-adrenolytic drugs is the possibility of deterioration of glycemia control, which as a consequence compels the intensification of anti-diabetic treatment. In persons with impaired glucose tolerance they can promote the development of new cases of diabetes (37, 38). These potential drawbacks to beta-blockers should not be an obstacle, however, to the use of these drugs if they are necessary to achieve the target blood pressure, or to treat arrhythmia or co-occurring myocardial ischemia, including especially contractile dysfunction of the left ventricle after myocardial infarction, or chronic congestive heart failure (39). Patients after myocardial infarction derive considerable benefits from the use of some beta-blockers (carvedilol, bisoprolol, metoprolol) which lower the risk of repeat cardiac episode and the cardiac mortality rate. Bisoprolol is characterized by neutrality in respect to carbohydrate and lipid metabolism, and is thus an especially safe preparation in the therapy of diabetes and hypertension. Due to the undesirable metabolic effects of beta-blockers, including masking hypoglycemia, reducing tissue sensitivity to insulin, and evoking hypertriglyceridemia, they cannot constitute a group of first-choice drugs for patients with diabetes and hypertension (39). In elderly persons, there are many more counterindications to the administration of b-adrenolytic drugs. In the STOP-2 research project, a comparison was made of the hypotensive effectiveness of three groups of drugs in elderly patients with hypertension: a b-blocker (including a thiazide diuretic), a calcium channel antagonist, and an ACE inhibitor. Nevertheless, despite all the cautions listed above, the results obtained in the sub-population of patients with diabetes showed approximately similar values in decreased blood pressure in all the study groups; the figures for risk of CVI and total mortality rate were also similar (40).
DIURETICS
Diuretics still constitute an important group in the treatment of hypertension in patients with diabetes, especially in view of the frequent occurrence in these patients of hypervolemia and excessive sensitivity to sodium. Many authors treat thiazide and thiazide-type diuretics as being on the same level as the main hypotensive drugs in terms of effectiveness (35), with a particularly selective indication of indapamide, in view of its metabolic neutrality and insignificant effect on the electrolyte balance (16, 22). It also reduces albuminuria and the degree of LVH (12, 27). In the LIVE research project (left ventricular hypertrophy regression, indapamide versus enalapril) indapamide caused greater regression of LVH than did enalapril (12). In the event that noticeable impairment of kidney function occurs, or congestive heart failure, loop diuretics are recommended. The combination of low doses of diuretics and ACE-inhibitors causes a synergistic hypotensive action, especially in elderly persons, with no significant impact on glucose metabolism. In the ARIC research project (Atherosclerosis Risk for Communities Study), the use of thiazide diuretics in patients treated hypotensively was not associated with an increased risk of developing diabetes (37).
ALPHA1-ADRENERGIC RECEPTOR BLOCKERS
Alpha1-adrenergic receptor blockers do not reduce microalbuminuria, but they do have a positive effect on lipid metabolism in the course of dyslipidemia, and improve tissue sensitivity to insulin. However, in the ALLHAT research project it was observed that cardiovascular complications occurred more frequently, especially heart failure in patients receiving doxasozine in comparison to patients treated with chlorthalidone (8, 35). This phenomenon requires further expanded comparative research, but at present alpha1 – adrenergic blockers can still be used only as a component in multidrug therapy, especially in patients with benign prostate hypertrophy (8).
IMIDAZOL RECEPTOR BLOCKERS
Imidazol receptor blockers in the central nervous system are metabolically neutral, and can even improve glucose metabolism (41). They cause regression of LVH and improve its diastolic function, and also increase the compliance of the arterial walls due to the inhibition of their reconstruction under the influence of catecholamines and angiotensin II. The results of a multi-center, randomized trial indicated that the hypotensive and nephroprotective effectiveness of rilmenidine is similar to that of captopril (42).
THE FUTURE
The programs now being conducted have taken on the goal of specifying yet more optimal values for blood pressure and the lipid profile parameters at which there is a potential for further reduction of cardiovascular threats and late complications of diabetes (8). This research will also make it possible to determine whether reducing the value of the diastolic blood pressure below 70 mmHg, and even more below 60 mmHg, can become a reason for a less favorable prognosis in patients with diabetes and isolated systolic hypertension.
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