Features of management of patients with arterial hypertension in combination with diabetes mellitus

The interrelation of arterial hypertension (AH) and type 2 diabetes mellitus (DM2) has long been established on the basis of the results of large-scale epidemiological and population studies. The number of patients with arterial hypertension combined with type 2 diabetes mellitus has steadily increased in recent years, increasing the risk of developing both macro- and microvascular complications, which progressively worsens their prognosis. Therefore, a multilateral approach to assessing controversial issues in the tactics of managing patients with arterial hypertension and type 2 diabetes mellitus and determining ways to solve them on the basis of scientifically based arguments and facts is an actual clinical task.

The association between arterial hypertension and type 2 diabetes is described for men and women in all age groups. This relationship is partly due to overweight and obesity, which predominate in both states. The prevalence of arterial hypertension in patients who had type 2 diabetes was three times greater than in patients without diabetes. This combination may be due to the interaction of factors such as insulin resistance (IR), prolonged activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. The relationship between the increased content of visceral adipose tissue and the disturbed adaptive changes in the heart and kidneys in patients with MI was called cardiorenal metabolic syndrome.

[1], [2], [3], [4], [5]

The role of insulin resistance in the pathogenesis of arterial hypertension and type 2 diabetes mellitus

Insulin is an anabolic hormone that promotes the utilization of glucose in the liver, muscles and adipose tissue, as well as its preservation in the form of glycogen in the liver and muscles. In addition, insulin inhibits the production of glucose and very low density lipoproteins in the liver. With insulin resistance, there is a worsening of the signal response to the effect of insulin in skeletal muscle, liver and adipose tissue. The emergence of insulin resistance is facilitated by genetic predisposition, overweight (especially central obesity) and lack of physical activity. In turn, insulin resistance, in the absence of an adequate response of beta cells, leads to hyperglycemia, increased formation of final glycation products, an increase in the content of free fatty acids and impairment of lipoproteins.

These changes cause increased expression of adhesion molecules and a decrease in the bioavailability of nitric oxide (NO) in endothelial cells, as well as an increase in inflammation, migration and proliferation of smooth muscle cells. High levels of free fatty acids also have a negative effect, promoting increased oxidative stress and reduced bioavailability of NO in endothelial cells, which reduces endothelium-dependent vasorelaxation and promotes vascular stiffness.

Insulin resistance is also associated with increased activation of RAAS and the sympathetic nervous system. Increased levels of angiotensin II and aldosterone, in turn, contribute to worsening of the systemic metabolic effects of insulin, leading to the development of endothelial dysfunction and impaired myocardial function. These two factors, reduced bioavailability of NO and activation of RAAS, cause sodium reabsorption and vascular remodeling, contributing to the development of hypertension in type 2 diabetes mellitus. Moreover, the accumulation of oxidized low-density lipoproteins (LDL) in the arterial wall reduces arterial elasticity and increases peripheral vascular resistance.

The ability of non-pharmacological and pharmacological strategies aimed at improving secretion and metabolic signals of insulin, also reduce endothelial dysfunction and lower the level of arterial pressure (BP).

Targets in the treatment of patients with arterial hypertension with type 2 diabetes mellitus

Based on the results of numerous studies in order to minimize the risk of cardiovascular complications in patients who had type 2 diabetes mellitus, the recommendations of the American Diabetes Association and the American Association of Clinical Endocrinologists established target levels of indicators that represent the main factors of the cardiovascular risk. Thus, it is recommended that the target level of blood pressure is less than 130/80 mm Hg. Cholesterol (CS) LDL-less than 100 mg / dl, high-density lipoprotein (HDL) cholesterol-more than 40 mg / dL, triglycerides - less than 150 mg / dL.

The European Society of Cardiology and the European Association for the Study of Diabetes Mellitus presented recommendations "Prediabetes, diabetes mellitus and cardiovascular diseases", which indicated the target levels of indicators representing the main factors of cardiovascular risk. The target level of arterial pressure for this category of patients was taken to be less than 130/80 mm Hg. And in the presence of chronic renal failure or proteinuria (more than 1 g protein in 24 hours) - less than 125/75 mm Hg. Art. For patients with type 2 diabetes and cardiovascular diseases, the level of total cholesterol was recommended to maintain less than 4.5 mmol / l, LDL-C - less than 1.8 mmol / l, HDL cholesterol in men - more than 1 mmol / L, in women - more than 1.2 mmol / l, triglycerides - less than 1.7 mmol / l, the ratio of total cholesterol to HDL cholesterol is less than 3.0. Categorical refusal of smoking was recommended. With respect to the degree of obesity, the body mass index was chosen to be less than 25 kg / m2 or weight reduction of 10% of the initial body weight per year, a waist circumference of 80 cm for European women and 94 cm for European men respectively. The target level of glycated hemoglobin HbAlc was recommended less than 6.5%, fasting plasma glucose less than 6 mmol / l, postprandial plasma glucose less than 7.5 mmol / l.

The effectiveness of antihypertensive agents in patients with type 2 diabetes mellitus

One of the first clinical studies to provide information on the optimal threshold and target BP for the prescription of antihypertensive therapy in patients with type 2 diabetes was the Pretereax and Diamicron MR Controlled Evaluation (ADVANCE) study, which showed that a decrease in diastolic AD (DBP) from 77 to 74.8 mm Hg. Systolic blood pressure (SBP) from 140.3 to 134.7 mm Hg. Art. Provides a reliable reduction in the risk of total mortality by 14%, major vascular complications - by 9%, cardiovascular events - by 14%, renal complications - by 21%. Based on the results of this study, it was concluded that an additional reduction in blood pressure, together with intensive glucose control, had independent positive effects, and in case of combination, significantly reduced cardiovascular mortality and improved kidney function.

In a study of Ongoing Telmisartan Alone and in Combination With the Ramipril Global Endpoint trial (ONTARGET) in patients with high cardiovascular risk, the risk of myocardial infarction was not related to the level of SBP and did not change under the influence of its changes, while the risk of developing a stroke progressively increased with an increase in the SBP level and decreased with its decrease. Patients with baseline SBP less than 130 mm Hg. Art. Cardiovascular mortality increased with further decrease in SBP. Therefore, in patients with a high risk of developing cardiovascular events, the benefit of reducing the SBP below 130 mm Hg. Art. Is determined by a decrease in the development of stroke, while the incidence of myocardial infarction remains unchanged, and cardiovascular mortality does not change or increases.

New data on the significance of different target SBP levels for patients who had type 2 diabetes and cardiovascular diseases were obtained in the clinical study of the Action Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP), in which the hypothesis was assessed: SBP less than 120 mm Hg. Art. Provide a greater reduction in the risk of cardiovascular events than a decrease in SBP less than 140 mm Hg. Art. In patients with diabetes mellitus with a high risk of cardiovascular events. However, evaluation of cardiovascular events showed no significant differences between the groups at the primary endpoint (nonfatal heart attack, stroke, cardiovascular death), as well as to reduce the risk of general and cardiovascular mortality, to any coronary events and the need for revascularization, chronic development heart failure (CHF).

In the intensive blood pressure control group, there was a reduction in the risk of all strokes and nonfatal strokes. At the same time, the decrease in SBP is less than 120 mm Hg. Art. Was accompanied by a significantly higher incidence of adverse events (hypotensive reactions, bradycardia, hyperkalemia, episodes of decreased glomerular filtration rate, increased macroalbuminuria). Thus, with a decrease in SBP to 120 mm Hg. Art. And there are fewer benefits to reduce the risk of cardiovascular events and even a tendency to increase it (with the exception of strokes).

The International Verapamil SR-Trandolapril (INVEST) study showed that intensive BP control is associated with an increase in mortality in comparison with the usual management of patients who had type 2 diabetes and ischemic heart disease (CHD). In patients with SBP from 130-140 mm Hg. Art. There was a decrease in the incidence of cardiovascular events compared with patients with SBP more than 140 mm. Gt; Art. (12.6% against 19.8%). With a decrease in SBP less than 130 mm Hg. Art. There was no significant reduction in the risk of cardiovascular events, and with a prolonged decline, the risk of overall mortality increased. In this case, the SBP level is less than 115 mm Hg. Art. Is associated with an increase in the risk of overall mortality, even with a short-term decline.

Despite the fact that new data on the significance of different blood pressure levels were obtained in the presented studies, the question of revision of recommendations in terms of changing target BP levels in patients who had type 2 diabetes remained open.

All modern guidelines recommend the target level of blood pressure in patients with type 2 diabetes less than 130/80 mm Hg. Art. Studies ACCORD and ONTARGET have not revealed any benefit for cardiovascular endpoints from a decrease in blood pressure of less than 130/80 mm Hg. Art. Except for the reduction of stroke. In the INVEST study, the decrease in SBP is less than 130 mm Hg. Art. Was also not accompanied by an improvement in cardiovascular outcomes compared with SBP less than 139 mm Hg. Art. An analysis of these studies shows that the benefit of reducing blood pressure to reduce cardiovascular risk is lost with a decrease in SBP less than 130 mm Hg. Art. In addition, there is an increase in cardiovascular events with SBP less than 120 mm Hg. The so-called effect of the J-curve. Moreover, this effect was present in INVEST and ONTARGET studies with a decrease in SBP less than 130 mm Hg. Art. In patients older than 50 years with prolonged AH and IHD.

Modern data suggest that the target values of blood pressure are 130/80 mm Hg. Art. In patients with type 2 diabetes mellitus are reasonable and achievable in clinical practice. These levels of blood pressure help to reduce the development of stroke, a serious and frequent complication in patients with type 2 diabetes mellitus. However, care must be taken in the treatment of older patients with IHD. In this group, the decrease in SBP to 120 mm Hg. Can cause an increase in mortality. Thus, target blood pressure levels should be individualized in patients with type 2 diabetes mellitus.

To control the level of blood pressure in patients with diabetes, first-line drugs are recommended to use angiotensin-converting enzyme (ACE inhibitors) and angiotensin II receptor antagonists (APA), which have been shown to reduce both macro- and microvascular complications. In addition, the use of ACEI in addition to other drug therapy reduces the risk of cardiovascular events in patients with type 2 diabetes and stable coronary heart disease.

Previous studies have suggested that thiazide diuretics reduce sensitivity to insulin. For example, in the Study of Trandolapril / Verapamil and IR (STAR) study, the hypothesis was that a fixed combination of trandolapril and verapamil is superior to the combination of losartan and hydrochlorothiazide in its effect on glucose tolerance in hypertensive patients with impaired glucose tolerance. It was shown that in patients with impaired glucose tolerance, normal kidney function and AH, the use of a fixed combination of trandolapril and verapamil reduced the risk of new cases of diabetes compared with the use of losartan and hydrochlorothiazide. This indicates an adverse effect of diuretics on insulin secretion and / or sensitivity to it. Moreover, the findings are consistent with observations that RAAS blockers improve insulin secretion and sensitivity and / or insulin resistance and can partially prevent some of the negative metabolic effects of thiazide diuretics.

According to current recommendations, if the level of blood pressure remains above 150/90 mm Hg in the background of the use of the ACE inhibitor or APA, A second drug, preferably a thiazide diuretic, should be added due to its cardioprotective properties. However, recent results from the Avoiding Cardiovascular Events In Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) suggest that calcium antagonists, especially amlodipine, can also reduce cardiovascular events. This study compared treatment with a combination of ACEI plus amlodipine with therapy with ACEI plus hydrochlorothiazide in patients with high-risk arterial hypertension, half of whom had type 2 diabetes mellitus. As a result, it was shown that the combination with amlodipine was more effective than the combination with hydrochlorothiazide in reducing fatal and non-fatal cardiovascular events.

Consequently, calcium antagonists are considered to be more preferred drugs than diuretics and beta-blockers due to their neutral effect on glucose level and insulin sensitivity.

When prescribing beta-blockers, carvedilol should be given priority in connection with its beneficial effect on carbohydrate and lipid metabolism. The advantages of a number of drugs (atenolol, bisoprolol, carvedilol) in patients who had type 2 diabetes mellitus with IHD and CHF after myocardial infarction were demonstrated.

The use of lipid-lowering and hypoglycemic therapy in patients with arthritis in combination with type 2 diabetes mellitus

Important in the reduction of cardiovascular events and death in patients who had type 2 diabetes and cardiovascular diseases have statins, the initiation of therapy which does not depend on the baseline level of LDL cholesterol, and the target level for their appointment is less than 1, 8-2.0 mmol / l. To correct hypertriglyceridemia, it is recommended to increase the dose of statins or combine them with fibrates or prolonged forms of nicotinic acid.

Recently, data have been obtained on the ability of fenofibrate to reduce the risk of both macro- and microvascular complications in patients who had type 2 diabetes, especially in the prevention of progression of retinopathy. The advantages of fenofibrate were more pronounced in patients with type 2 diabetes mellitus with mixed dyslipidemia with an increase in triglyceride levels and a low level of HDL cholesterol.

To reduce the cardiovascular risk from antiplatelet agents in patients who had type 2 diabetes, acetylsalicylic acid should be administered at a dose of 75-162 mg per day for both secondary and primary prevention of cardiovascular complications, and if it is intolerant Use clopidogrel at a dose of 75 mg per day or a combination of them after the ischemic events.

At present, the feasibility of twice taking acetylsalicylic acid per day over a single dose in patients who had type 2 diabetes at high risk has been studied. The received data testify to the advantage of the appointment of acetylsalicylic acid in a dose of 100 mg twice a day in reducing persistent cellular reactivity in comparison with a single dose of the drug at a dose of 100 mg per day.

The high incidence of cardiovascular events in patients who had type 2 diabetes with concomitant cardiovascular disease, despite the use of antithrombotic drugs, may be associated with more pronounced platelet reactivity in these patients, which causes the search for new antiplatelet agents.

Meta-analysis of ACCORD, ADVANCE, VADT and UKPDS studies showed that intensive glycemic control in patients with type 2 diabetes is not accompanied by an increase in the risk of cardiovascular events and provides a significant reduction in the risk of myocardial infarction. The most significant risk factor for total mortality and cardiovascular events in patients who had type 2 diabetes was development of hypoglycemia, rather than the degree of achievement of glycemic control indicators.

A different effect on cardiovascular risk was revealed in patients who had type 2 diabetes mellitus of various oral hypoglycemic drugs. A more preferred drug for the treatment of patients who had type 2 diabetes mellitus in combination with cardiovascular disease is metformin, significantly reducing the risk of myocardial infarction. Particular attention has recently been paid to the possibility of using metformin in patients with diabetes mellitus with various manifestations of atherothrombosis. Data were obtained on the reduction in mortality among patients who had type 2 diabetes and atherothrombosis in the history under the influence of metformin, which can be considered as a means of secondary prevention.

The situation with the effect of various sulfanylurea preparations on the risk of developing cardiovascular events in patients who had type 2 diabetes remained controversial. For patients who have type 2 diabetes mellitus, a more preferred drug from this group is glimepiride, and in the development of MI only gliclazide and metformin-min can be the drugs of choice.

The problem of adherence to patients with arterial hypertension and diabetes mellitus type 2

Currently, a serious problem in reducing the incidence of cardiovascular events and death in patients who have type 2 diabetes is a low commitment to recommendations and inadequate monitoring of targets. The need for correction of blood pressure, as well as indicators of lipid and carbohydrate metabolism is considered as the main direction of reducing cardiovascular risk for patients who had type 2 diabetes mellitus.

According to a number of studies, adherence to hypoglycemic drugs among patients who have type 2 diabetes mellitus is 67 to 85%, and to antihypertensive drugs - from 30 to 90%. The problem is to ensure a long-term intake of statins.

Successful implementation of recommendations for reducing cardiovascular risk depends on physicians who provide an assessment of the relevant risk factors, the impact on them and the formation of patients. However, despite the fact that most primary care physicians support the concept of preventive cardiovascular effects, the application of proven knowledge in clinical practice is unsatisfactory.

With properly prescribed treatment, patients do not always fulfill prescribed appointments. Many patients make unintentional errors in taking medication due to forgetfulness; However, deliberate non-compliance with the recommendation is a significant problem, especially among those who require long-term treatment. The reasons for the deliberate failure to comply with the prescriptions of doctors are the complexity of the regimen of drugs, the number of medications (especially among elderly patients), concern about potential side effects and subjectively assessed lack of effectiveness (in the absence of physical evidence of therapeutic effect). In addition, other factors, such as the patient's lack of understanding of the nature and severity of his illness and a misunderstanding of the doctor's instructions, also play a role.

The problem is further complicated by the doctor's underestimation of a patient's lack of commitment. When initiating treatment in a patient or monitoring the effectiveness of therapy, doctors should always pay attention to the patient's poor adherence and try to improve it. The latter can be achieved by involving patients in the dialogue and discussing the need for treatment, especially their specific regimen and by adapting the regimen to the individual characteristics of the patient and his lifestyle.

Thus, in recent years there has been an increase in the prevalence of a combination of arterial hypertension with type 2 diabetes mellitus, characterized by an unfavorable prognosis in terms of development of macro- and microvascular complications, general and cardiovascular mortality. In the tactics of managing patients with hypertension and type 2 diabetes, the basic requirement is an individualized approach with regard to the choice of antihypertensive drugs and the choice of hypolipidemic and hypoglycemic agents, with mandatory use of non-medicamentous interventions, which can be achieved only with high activity and the doctor, and the patient himself.

Prof. AN Korzh // International Medical Journal - №4 - 2012