The review outlines the main aspects of the treatment of metabolic syndrome. The approaches to the correction of overweight, arterial hypertension and disorders of carbohydrate metabolism are examined in detail.
The problem of metabolic syndrome (MS) is one of the most pressing problems of modern medicine. This symptom complex attracts the close attention of endocrinologists, cardiologists, general practitioners. This is primarily due to the widespread MS – up to 20% in the population. In addition, the isolation of MS is of great clinical importance, since, on the one hand, this condition is reversible, i.e., with appropriate treatment, it is possible to achieve the disappearance or at least reduce the severity of its main manifestations, and, on the other hand, it precedes the onset of diseases such as type 2 diabetes mellitus (DM) and atherosclerosis.
DM is one of the most acute problems of modern medicine. Currently, 146.8 million people in the world suffer from type 2 diabetes, which is 2.1% of the total population of the planet. By 2010, according to scientists, the number of people with type 2 diabetes can exceed 200 million (more than 3% of the population). According to I.I. Dedova et al. 8 million (5%) people in Russia suffer from diabetes, of which 90% are of type 2 diabetes.
As was shown in the PROCAM study, in patients with diabetes, the level of overall mortality, mortality from coronary heart disease, the incidence of coronary heart disease and stroke is significantly higher than in individuals without metabolic disorders. DM goes hand in hand with arterial hypertension (AH). An increase in blood pressure (BP) is found in 80% of patients with type 2 diabetes.
To date, there is no consensus on the root cause of metabolic disorders in the pathogenesis of metabolic syndrome. Some authors believe that a hereditary predisposition to insulin resistance and obesity in combination with low physical activity and excessive nutrition determines the development of obesity and tissue insulin resistance and, as a consequence of this, compensatory hyperinsulinemia. Hyperinsulinemia first reduces sensitivity, and then blocks insulin receptors, as a result of which glucose and fats coming from food are deposited with adipose tissue. This further enhances insulin resistance. On the other hand, hyperin-sulinemia suppresses the breakdown of fats, which contributes to the progression of obesity. A vicious circle forms. Permanent hyperinsulinemia depletes the secretory apparatus of pancreatic p-cells, which leads to impaired glucose tolerance.
There is another hypothesis that suggests that the central type of obesity is the cause of insulin resistance, hyperinsulinemia and other metabolic disorders. Adipocytes of visceral adipose tissue secrete free fatty acids directly into the portal vein of the liver. Their high concentrations inhibit the absorption of insulin by the liver, which leads to hyperinsulinemia and relative insulin resistance.
The pathogenesis of hypertension in the metabolic syndrome is based on insulin resistance and the resulting compensatory hyperinsulinemia. The main mechanisms leading to an increase in blood pressure in the metabolic syndrome are hypervolemia, caused by increased reabsorption of sodium in the proximal tubules of the kidney and causing an increase in cardiac output; activation of the sympathetic nervous system, which also causes an increase in cardiac output and leads to spasm of peripheral vessels and an increase in total peripheral vascular resistance (OPSS). Under the influence of insulin, there is an increase in the production of vasoconstrictor biologically active substances by endothelium – endothelin, thromboxane A2 and a decrease in the secretion of such powerful vasodilators as prostacyclin and nitric oxide. In addition, another theory of the pathogenesis of hypertension in obesity has recently been discussed, according to which the increase in blood pressure is due to an increase in the level of leptin in these patients. Leptin is a hormone synthesized by adipocytes of visceral adipose tissue, and its level is closely correlated with body mass index (BMI). Leptin regulates the feeling of fullness at the level of the arcuate nucleus of the hypothalamus, which is closely associated with the paraventricular nucleus, the stimulation of which leads to activation of the sympathetic nervous system. In addition, it should be borne in mind that with dyslipidemia, which is present in patients with metabolic syndrome, atherosclerotic changes in the renal arteries can occur, leading to the development of renovascular hypertension.
The main therapeutic measures in patients with metabolic syndrome are weight loss, which is achieved by non-drug methods – the use of a low-calorie diet and increased physical activity, if necessary, the use of special medications and, in extreme cases, with surgical interventions (gastroplasty).
Drug therapy for metabolic syndrome and type 2 diabetes include oral hypoglycemic agents, for example, sulfonylureas, thiazolidinedione and biguanides, the most popular of which is metformin and several others; lipid-lowering drugs – statins and fibrates and antihypertensive drugs.
Measures aimed at reducing overweight are a priority in the treatment of metabolic syndrome. The beneficial effect of weight loss on blood pressure was demonstrated in a number of large multicenter studies – TONP-1, TAIM, TOMHS.
Theoretically, it is not difficult to reduce excess weight: if you reduce food calories by 250 kcal per day and at the same time increase physical activity by 250 kcal per day, then as a result, 3500 kcal can be “missed” in a week, which is equivalent to losing one pound of excess weight. But in reality, the way to reduce excess weight is quite complicated.
The basic rule that should be followed when reducing excess weight, but is to set realistic tasks. A number of studies have shown that weight loss even by 5-10% significantly reduces the risk of cardiovascular complications and diabetes in obese patients. Therefore, it is now considered targeted just such a small decrease in body weight. But even such a task can be unattainable when using only non-drug methods. Particularly great difficulties arise after reaching the target weight loss, when you need to maintain it at the achieved level. In such cases, the question arises of joining drugs that contribute to weight loss.
The main indications for this group of drugs are the presence of a BMI in excess of 30 kg / m2 or a BMI of more than 27 kg / m2 if the patient has an abdominal type of obesity, a hereditary predisposition to type 2 diabetes or other risk factors (dyslipidemia, hypertension or type 2 diabetes )
One of the safest and most effective drugs now is orlistat (Xenical), which inhibits gastrointestinal lipases – key enzymes involved in the hydrolysis of food triglycerides, the release of fatty acids and monoglycerides. When it is used, about 30% of triglycerides are not digested and not absorbed, which creates an additional calorie deficit compared to using only a diet.
In our department, we studied the effectiveness of orlistat in patients with metabolic syndrome. The drug was prescribed for 6 months at a dose of 120 mg 3 times a day against a hypocaloric diet. All patients were on antihypertensive therapy, which remained unchanged throughout the observation period.
Orlistat treatment effectively reduced the weight of patients, which on average in the group decreased from 111.5 ± 5.4 kg to 102.7 ± 5.0 kg in 6 months, respectively, BMI in the group decreased from 36.9 ± 1.3 kg / m2 to 33.6 + 1.3 kg / m2 (p <0.05).
Weight reduction of patients was accompanied by an improvement in lipid metabolism. The level of total cholesterol (cholesterol) significantly decreased (from 6.3 ± 0.2 mmol / L to 5.7 ± 0.1 mmol / L) and triglycerides (from 1.9 + 0.1 mmol / L to 1.3 ± 0.08 mmol / L) and the level of cholesterol of high density lipoproteins increased (from 0.94 ± 0.05 mmol / L to 1.2 ± 0.07 mmol / L).
Despite the short observation period, there was a significant decrease in both systolic blood pressure (ADS) and diastolic blood pressure (ADD) at night and daytime according to daily monitoring of blood pressure (BPM), respectively, from 140.5 ± 2.9 mm RT. Art. and 90.0 ± 2.1 mmHg. Art. up to 124.0 ± 2.7 mmHg. Art. and 77.0 ± 0.9 mmHg. Art.
The high efficacy of orlistat was combined with its good tolerability. During its use, we did not register a single side effect.
Of course, the most important area of treatment for the metabolic syndrome, and primarily diabetes, is the normalization of carbohydrate metabolism. In the Department of Systemic Hypertension, a study was conducted of the efficacy and safety of glimeperide (amaryl) in patients with type 2 diabetes and hypertension.
The study involved 30 patients – 7 men and 23 women, the average age of 51.9 years.
Amaryl was prescribed in a dose of 1 to 6 mg per day for 6 months.
Against the background of the use of the drug, a significant decrease in weight was observed from 98.0 ± 16.9 kg to 94.8 ± 16.5 kg.
The level of glycated hemoglobin during treatment with glimeperid significantly decreased from 7.8 ± 0.8% to 6.0 ± 0.6%. In 16 patients with an initially elevated level of total cholesterol, its level decreased from 6.0 + 1.4 to 5.5 ± 1.3 mmol / L (p <0.05). In 15 patients with an initially elevated level of triglycerides, their level also significantly decreased from 2.8 ± 0.6 to 1.9 ± 0.8 mmol / L.
In addition, which is very important – against the background of the use of amaryl, there was a significant decrease in both ADF and ADD according to the ABPM (from 138.2 ± 12.5 mm Hg and 80.4 ± 7.4 mm Hg. respectively, up to 130.4 ± 12.2 mm Hg and 76.7 ± 7.5 mm Hg).
Unfortunately, only in isolated cases with MS and type 2 diabetes can good blood pressure control be achieved, only by reducing weight. Most patients require the use of antihypertensive drugs.
The main requirements for a hypotensive drug in patients with metabolic syndrome are: high hypotensive efficacy, “metabolic neutrality”, organoprotective properties. The main classes of modern drugs for the treatment of hypertension satisfy, to a greater or lesser extent, all of the above requirements.
Diuretics are the “oldest” antihypertensive drugs for the treatment of hypertension. They have high efficiency, organoprotective properties, in large-scale studies it has been proven that their use reduces the risk of cardiovascular complications. In patients with MS, their use is pathogenetically justified, since fluid retention plays an important role in the pathogenesis of hypertension in this condition. At the same time, the diabetic effect of diuretic drugs and their adverse effect on carbohydrate and lipid metabolism are known
. Nevertheless, the use of diuretics in patients with MS became possible after the creation of new drugs of this class that did not interfere with the exchange of glucose and lipids, for example, indapamide. When prescribed in a dose of up to 2.5 mg per day, it is metabolically neutral. An even safer in terms of the effect on carbohydrate and lipid metabolism is considered to be indapamide retard in a dose of 1.5 mg.
b-blockers have been limitedly used for a long time in patients with MS and type 2 diabetes, since when they were prescribed due to blockade of b2 receptors, there was a violation of carbohydrate metabolism. At the same time, the appointment of these drugs for the treatment of hypertension in the metabolic syndrome may be pathogenetically justified, since activation of the sympathetic nervous system plays a role in its genesis. A way out of this situation was found with the creation of highly selective b1-blockers, such as metoprolol, bisoprolol, nebivolol. The latter, in addition to super-high b1-selectivity, has a very important additional advantage: it stimulates the production of endogenous nitric oxide – a powerful vasodilator, therefore nebivolol can be considered one of the most preferred b-blockers for treating patients with metabolic syndrome.
Calcium antagonists can be safely prescribed to patients with metabolic syndrome, since these drugs do not have a negative effect on carbohydrate and lipid metabolism. Additional advantages of this class of drugs include their high antihypertensive efficacy and the absence of serious side effects. Long-acting drugs such as amlodipine, felodipine, lacidipine should be preferred, or long-acting forms of nifedipine should be used.
ACE inhibitors (ACE inhibitors) are a priority group of antihypertensive drugs in patients with metabolic syndrome. Numerous studies have shown their organoprotective effect in this category of patients, which was combined with metabolic neutrality. In addition, when they are prescribed, the risk of developing type 2 diabetes is significantly reduced, which was shown in the studies of CAPPP and HOPE.
We have studied the antihypertensive efficacy and safety of quinapril in patients with mild to moderate hypertension and concomitant type 2 diabetes.
The study involved 17 patients (10 men and 7 women) who were prescribed quinapril (Accupro) at a dose of 20 mg 2 times a day for 12 months as monotherapy. During treatment with quinapril, a significant decrease in blood pressure and blood pressure was observed, according to the ABPM (from 150.1 ± 21.1 mm Hg and 85.3 ± 10.5 mm Hg, respectively, to 131.4 ± 11.8 mmHg and 74.5 + 9.0 mmHg). At the same time, heart rate did not change significantly. Against the background of prescribing the drug, the level of glucose determined on an empty stomach significantly decreased (from 9.7 + 4.0 mmol / L to 5.7 ± 0.7 mmol / L), as well as 2 hours after the tolerance test (from 13.0+ 3.7 mmol / L to 8.6 ± 3.4 mmol \ L). The FIRI insulin resistance index significantly decreased, reaching an average of normal values in the group (from 3.8 ± 4.3 to 2.2 ± 1.0).
Long-term – up to 12 months – treatment with quinapril did not lead to a significant change in the level of total cholesterol and triglycerides, while the level of cholesterol high-density lipoproteins significantly increased (from 1.1 + 0.2 mmol / to 1.6 ± 0.3 mmol / l )
With the use of quinapril, the myocardial mass index, which was determined during cardiac MRI, significantly decreased. Before treatment, the group average was 108,
2 ± 26.0 g / m2, and after – 99.1 ± 13.8 g / m2.
Angiotensin receptor antagonists are one of the youngest groups of antihypertensive drugs. In terms of their therapeutic effect, indications and contraindications are close to ACE inhibitors. This group of drugs can also be recommended for the treatment of patients with metabolic syndrome. An active study is underway of the place of angiotensin receptor antagonists in the treatment of various forms of hypertension and, hopefully, we will soon have new data on the scope of these drugs in patients with hypertension.
Alpha-blockers, despite the undeniable advantages in terms of their effect on metabolic disorders – the ability to reduce insulin resistance, improve carbohydrate and lipid metabolism, are currently antihypertensive drugs, which should be avoided, since a number of studies have revealed an increased risk of cardiovascular complications destination.
And finally, drugs of central action. The “old” generation of these drugs, which include clonidine, methyldopa have a large number of side effects, the most dangerous of which is the “withdrawal” syndrome. Therefore, their use in patients with hypertension is undesirable. Recently created centrally acting drugs, I2-imidazoline receptor agonists, are free from these many shortcomings. The most famous representative of this group of drugs in our country is moxonidine. In addition to a sufficiently high antihypertensive activity, a number of studies have shown the ability of this drug to improve tissue sensitivity to insulin, which makes this drug one of the priorities in the treatment of metabolic syndrome.
The ability of moxonidine to increase sensitivity to insulin has been shown both in experimental studies and in a number of clinical studies, for example, in the study of N. Lithell. It included 77 patients with mild hypertension and a BMI of more than 27 kg / m2. After 3 weeks of treatment with moxonidine at a dose of 0.2 mg 2 times a day, the level of glucose infusion and the insulin sensitivity index increased by 10% and 11%, respectively, in the placebo group they remained unchanged. In the subgroup of patients with insulin resistance (with an index of insulin sensitivity less than 3.6), the level of glucose infusion and the index of insulin sensitivity against the background of the appointment of moxonidine increased by 21%.
An increase in insulin sensitivity during treatment with moxonidine was also demonstrated by V.A. Almazova et al. . It studied the effect of moxonidine (0.2-0.6 mg / day) in 30 patients with hypertension for 3 months. Comparison of the results of the glucose tolerance test before and after treatment showed that when taking moxonidine, there is a decrease in insulin levels 30, 60 and 120 minutes after oral administration of glucose.
An ALMAZ study is currently being conducted in Russia – a comparative assessment of the effect of moxonidine and metformin on glycemic control in patients with overweight, mild hypertension, insulin resistance and impaired glucose tolerance or asymptomatic diabetes, in the treatment of which only diet is used. The study included 202 patients. The study is currently completed and results are expected before the end of this year.
The objectives of the study were to study the effect of moxonidine and metformin on glycemic control, the level of triglycerides, total cholesterol an