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

The relationship between arterial hypertension (AH) and type 2 diabetes mellitus (T2DM) has long been established based on the results of large-scale epidemiological and population studies. The number of patients with arterial hypertension in combination with type 2 diabetes mellitus has been steadily increasing 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 resolve them based on scientifically substantiated arguments and facts is an urgent clinical task.

An association between hypertension and type 2 diabetes mellitus has been described for men and women in all age groups. This relationship is partly due to overweight and obesity, which are prevalent in both conditions. The prevalence of hypertension in patients with type 2 diabetes mellitus is three times higher than in patients without diabetes. This association may be due to the interaction of factors such as insulin resistance (IR), long-term activation of the renin-angiotensin-aldosterone system (RAAS), and the sympathetic nervous system. The relationship between increased visceral adipose tissue and impaired adaptive changes in the heart and kidneys in patients with IR has been termed 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 storage as glycogen in the liver and muscles. In addition, insulin suppresses the formation of glucose and very low-density lipoproteins in the liver. Insulin resistance is characterized by a deterioration in the signaling response to insulin in skeletal muscles, liver, and adipose tissue. Genetic predisposition, excess weight (especially central obesity), and lack of physical activity contribute to the development of insulin resistance. In turn, insulin resistance, in the absence of an adequate beta-cell response, leads to hyperglycemia, increased formation of advanced glycation end products, increased free fatty acid content, and lipoprotein dysfunction.

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

Insulin resistance is also associated with increased activation of the RAAS and the sympathetic nervous system. Increased levels of angiotensin II and aldosterone, in turn, contribute to the deterioration of the systemic metabolic effects of insulin, which leads to the development of endothelial dysfunction and myocardial dysfunction. These two factors, decreased bioavailability of NO and activation of the RAAS, cause sodium reabsorption and vascular remodeling, contributing to the development of arterial 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.

Non-pharmacological and pharmacological strategies aimed at improving insulin secretion and metabolic signaling have been demonstrated to also reduce endothelial dysfunction and lower blood pressure (BP).

Target indicators in the treatment of patients with arterial hypertension and type 2 diabetes mellitus

Based on the results of numerous studies, in order to minimize the risk of cardiovascular complications in patients with type 2 diabetes, the American Diabetes Association and the American Association of Clinical Endocrinologists have defined target levels of indicators that represent the main factors of cardiovascular risk. Thus, the recommended target level of blood pressure is less than 130/80 mm Hg, LDL cholesterol (C) - less than 100 mg / dL, high-density lipoprotein (HDL) C - 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 presented recommendations "Prediabetes, Diabetes Mellitus and Cardiovascular Diseases", which outlined target levels of indicators representing the main cardiovascular risk factors. The target level of blood pressure for this category of patients was adopted as less than 130/80 mm Hg, and in the presence of chronic renal failure or proteinuria (more than 1 g of protein in 24 hours) - less than 125/75 mm Hg. For patients with type 2 diabetes mellitus and cardiovascular diseases, it was recommended to maintain the level of total cholesterol below 4.5 mmol/l, LDL cholesterol below 1.8 mmol/l, HDL cholesterol in men above 1 mmol/l, in women above 1.2 mmol/l, triglycerides below 1.7 mmol/l, and the ratio of total cholesterol to HDL cholesterol below 3.0. Strict smoking cessation was recommended. Regarding the degree of obesity, a body mass index below 25 kg/m2 or a weight loss of 10% of the initial body weight per year was selected, and 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 to be less than 6.5%, fasting plasma glucose - less than 6 mmol/l, postprandial plasma glucose - less than 7.5 mmol/l.

Efficacy 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 when prescribing antihypertensive therapy in patients with type 2 diabetes mellitus was the Pretereax and Diamicron MR Controlled Evaluation (ADVANCE) study, which showed that a decrease in diastolic BP (DBP) from 77 to 74.8 mm Hg and systolic BP (SBP) from 140.3 to 134.7 mm Hg provides a reliable reduction in the risk of overall mortality by 14%, major vascular complications by 9%, cardiovascular events by 14%, and renal complications by 21%. Based on the results of this study, it was concluded that additional BP reduction together with intensive glucose control have independent positive effects, and when combined, they significantly reduce cardiovascular mortality and improve renal function.

In the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint trial (ONTARGET) in patients at high cardiovascular risk, the risk of myocardial infarction was not related to or modified by changes in SBP, whereas the risk of stroke progressively increased with increasing SBP and decreased with decreasing SBP. In patients with baseline SBP <130 mmHg, cardiovascular mortality increased as SBP was further reduced. Therefore, in patients at high cardiovascular risk, the benefit of lowering SBP below 130 mmHg is determined by a reduction in stroke, while the incidence of myocardial infarction remains unchanged and cardiovascular mortality is unchanged or increased.

New data on the significance of different target SBP levels for patients with type 2 diabetes and cardiovascular disease were obtained in the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) clinical trial, which assessed the hypothesis: can a decrease in SBP to less than 120 mm Hg provide a greater reduction in the risk of cardiovascular events than a decrease in SBP to less than 140 mm Hg in patients with type 2 diabetes with a high risk of developing cardiovascular events. However, the assessment of cardiovascular events showed no significant differences between the groups in the primary endpoint (non-fatal infarction, stroke, cardiovascular death), as well as in reducing the risk of overall and cardiovascular mortality, any coronary events and the need for revascularization, and the development of chronic heart failure (CHF).

In the intensive BP control group, a decrease in the risk of all strokes and non-fatal strokes was observed. At the same time, a decrease in SBP to less than 120 mm Hg was accompanied by a significantly higher frequency of adverse events (hypotensive reactions, bradycardia, hyperkalemia, episodes of decreased glomerular filtration rate, increased macroalbuminuria). Thus, when reducing SBP to 120 mm Hg and less, there are no benefits in reducing the risk of cardiovascular events and there is even a tendency for it to increase (except for strokes).

The International Verapamil SR-Trandolapril (INVEST) trial showed that intensive BP control was associated with increased mortality compared with usual care in patients with type 2 diabetes and coronary artery disease (CAD). Patients with SBP of 130–140 mmHg had a reduced incidence of cardiovascular events compared with patients with SBP greater than 140 mmHg (12.6% versus 19.8%). Reducing SBP to less than 130 mmHg did not significantly reduce the risk of cardiovascular events, while long-term reduction increased the risk of overall mortality. At the same time, SBP less than 115 mmHg is associated with an increased risk of overall mortality even with short-term reduction.

Despite the fact that the presented studies have obtained new data on the significance of different BP levels, the question of revising the recommendations in terms of changing target BP levels in patients with type 2 diabetes mellitus remains open.

All current guidelines recommend a target BP level of less than 130/80 mmHg in patients with type 2 diabetes. The ACCORD and ONTARGET trials found no benefit in cardiovascular endpoints from lowering BP to less than 130/80 mmHg, except for reducing stroke. In the INVEST trial, lowering SBP to less than 130 mmHg was also not associated with improved cardiovascular outcomes compared with lowering SBP to less than 139 mmHg. Analysis of these trials shows that the benefit of lowering BP in reducing cardiovascular risk is lost with lowering SBP to less than 130 mmHg. In addition, there is an increase in cardiovascular events at SBP less than 120 mmHg, the so-called J-curve effect. Moreover, this effect was present in the INVEST and ONTARGET trials with lowering SBP to less than 130 mmHg. Art. in patients over 50 years of age with long-term hypertension and coronary heart disease.

Current data suggest that BP targets of 130/80 mmHg in patients with type 2 diabetes are reasonable and achievable in clinical practice. These BP levels reduce the incidence of stroke, a serious and common complication in patients with type 2 diabetes. However, caution should be exercised in older patients with coronary artery disease. In this group, reducing SBP to 120 mmHg may be associated with increased mortality. Thus, BP targets should be individualized in patients with type 2 diabetes.

To control blood pressure in patients with type 2 diabetes, the use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARBs) is recommended as first-line drugs; they 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 mellitus and stable coronary artery disease.

Previous studies have suggested that thiazide diuretics decrease insulin sensitivity. For example, the Study of Trandolapril/Verapamil and IR (STAR) investigated the hypothesis that the fixed-dose 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 renal function, and hypertension, the use of the fixed-dose combination of trandolapril and verapamil reduced the risk of new-onset diabetes compared with losartan and hydrochlorothiazide therapy. This suggests an adverse effect of diuretics on insulin secretion and/or sensitivity. Moreover, the obtained data are consistent with the observations that RAAS blockers improve insulin secretion and sensitivity and/or insulin resistance and may partially prevent some of the negative metabolic effects of thiazide diuretics.

Current guidelines recommend that if BP remains above 150/90 mmHg while taking an ACE inhibitor or ARB, 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) trial suggest that calcium antagonists, especially amlodipine, may also reduce cardiovascular events. This trial compared treatment with an ACE inhibitor plus amlodipine with treatment with an ACE inhibitor plus hydrochlorothiazide in patients with very-high-risk hypertension, half of whom had type 2 diabetes. The results showed that the combination with amlodipine was more effective than the combination with hydrochlorothiazide in reducing fatal and nonfatal cardiovascular events.

Therefore, calcium antagonists are considered preferable drugs compared to diuretics and beta-blockers due to their neutral effect on glucose levels and insulin sensitivity.

When prescribing beta-blockers, preference should be given to carvedilol due to its favorable effect on carbohydrate and lipid metabolism. The advantages of a number of drugs (atenolol, bisoprolol, carvedilol) have been demonstrated in patients with type 2 diabetes mellitus in the presence of coronary heart disease and CHF after myocardial infarction.

Use of lipid-lowering and sugar-lowering therapy in patients with hypertension in combination with type 2 diabetes mellitus

Statins are of great importance in reducing cardiovascular events and death in patients with type 2 diabetes mellitus and cardiovascular diseases. The start of therapy with them does not depend on the initial level of LDL-C, and the target level when they are prescribed 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 with type 2 diabetes, especially in the prevention of retinopathy progression. The benefits of fenofibrate were more pronounced in patients with type 2 diabetes with mixed dyslipidemia with increased triglyceride levels and low HDL-C.

To reduce the cardiovascular risk from antiplatelet drugs in patients who had type 2 diabetes mellitus, acetylsalicylic acid should be prescribed at a dose of 75-162 mg per day for both secondary and primary prevention of cardiovascular complications, and in case of its intolerance, clopidogrel at a dose of 75 mg per day or their combination is used after ischemic events.

The feasibility of twice-daily versus once-daily dosing of acetylsalicylic acid in patients with high-risk type 2 diabetes mellitus is currently being studied. The data obtained indicate an advantage of prescribing acetylsalicylic acid at a dose of 100 mg twice daily in reducing persistent cellular reactivity compared with a single dose of 100 mg per day.

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

A meta-analysis of the 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 reliable reduction in the risk of myocardial infarction. The most significant risk factor for overall mortality and cardiovascular events in patients with type 2 diabetes was the development of hypoglycemia, rather than the degree of achievement of glycemic control indicators.

Different effects of different oral hypoglycemic agents on cardiovascular risk were revealed in patients with type 2 diabetes mellitus. Metformin is a more preferable drug for treating patients with type 2 diabetes mellitus and cardiovascular diseases, as it significantly reduces the risk of myocardial infarction. Particular attention has recently been paid to the possibility of using metformin in patients with type 2 diabetes mellitus with various manifestations of atherothrombosis. Data have been obtained on a decrease in mortality among patients with type 2 diabetes mellitus and a history of atherothrombosis under the influence of metformin, which can be considered as a secondary prevention agent.

The situation with the influence of various sulfonylurea drugs on the risk of developing cardiovascular events in patients with type 2 diabetes remains controversial. For patients with type 2 diabetes of high cardiovascular risk, glimepiride is a more preferable drug from this group, and in the development of MI, only gliclazide and metformin can be drugs of choice.

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

Currently, a serious problem in reducing the frequency of cardiovascular events and death in patients who had type 2 diabetes mellitus is low adherence to recommendations and inadequate control of target indicators. The need to correct blood pressure, as well as lipid and carbohydrate metabolism indicators is considered as the main direction for reducing cardiovascular risk for patients who had type 2 diabetes mellitus.

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

Successful implementation of cardiovascular risk reduction guidelines depends on physicians providing assessment of relevant risk factors, intervention, and patient education. However, although most primary care physicians support the concept of preventive cardiovascular intervention, translation of evidence-based knowledge into clinical practice is poor.

Even when prescribed correctly, patients do not always adhere to prescribed medications. Many patients make unintentional medication errors due to forgetfulness; however, intentional non-adherence is a significant problem, especially among those requiring long-term treatment. Reasons for intentional non-adherence include the complexity of the drug regimen, the number of medications (especially among older patients), concerns about potential side effects, and a perceived lack of effectiveness (without physical evidence of a therapeutic effect). In addition, other factors, such as the patient's lack of understanding of the nature and severity of his or her disease and misunderstanding of the doctor's instructions, also play a role.

The problem is further complicated by physicians' underestimation of the patient's lack of adherence. When initiating treatment in a patient or monitoring the effectiveness of therapy, physicians should always pay attention to poor patient adherence and try to improve it. The latter can be achieved by engaging patients in dialogue and discussion of the need for treatment, especially their specific regimen, and by adapting the regimen to the patient's individual characteristics and 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 the development of macro- and microvascular complications, general and cardiovascular mortality. In the tactics of managing patients with arterial hypertension and type 2 diabetes mellitus, the main requirement is an individualized approach both in relation to the choice of antihypertensive drugs and the choice of lipid-lowering and hypoglycemic agents, with the mandatory use of non-drug interventions, which can only be achieved with high activity of both the doctor and the patient.

Prof. A. N. Korzh // International Medical Journal - No. 4 - 2012