Arterial hypertension and diabetes mellitus: what is primary, how close is the relationship and what is the optimal treatment tactics?
Post updated: July 18
It is sometimes difficult for a clinician to find unambiguous answers to questions that arise in the treatment of patients with arterial hypertension (AH) and diabetes mellitus (DM). After all, the combination of these two nosologies in one patient is often accompanied by other concomitant conditions, which significantly complicates the choice of optimal therapy with maximum effect and minimum number of side effects. With a request to understand the peculiarities of the comorbidity of hypertension and diabetes, as well as the subtleties of antihypertensive treatment of such patients, the editorial board (Journal of Health of Ukraine) turned to the head of the consultative and diagnostic department of the State Institution "Institute of Endocrinology and Metabolism named after V.P. Komissarenko NAMS of Ukraine" (Kiev), cardiologist, Ph.D. Maria Sergeevna Chersky.
Maria Sergeevna, how relevant and interrelated are the problems of hypertension and diabetes in the modern world?
In recent years, these diseases have been rapidly gaining momentum as a kind of epidemic. Thus, according to statistics, by 2030 there will be 552 million people with diabetes in the world. DM is a risk factor for many cardiovascular (SS) pathologies - coronary heart disease (CHD), stroke, heart failure (HF). However, it was only in 2015 that the results of a large-scale clinical study were published, which confirmed that DM is associated with hypertension (Connor et al., 2015). Therefore, hypertension and diabetes are kind of twin diseases that occur in one patient at the same time or develop one after the other.
It should be noted that hypertension can also cause the development of diabetes. An increase in systolic blood pressure (SBP) for every 20 mmHg increases the risk of new cases of DM by 58%, diastolic blood pressure (DBP) for every 10 mmHg - by 52% (Edmin et al., 2015). Violation of carbohydrate metabolism is found in 20-30% of patients with hypertension, and elevated blood pressure - in 50-80% of people with diabetes (Mammadov et al., 2004).
In addition, patients with diabetes and hypertension often have an increased body mass index. In order to detect diabetes in a timely manner or exclude the risk of prediabetes in people with hypertension and overweight or obesity, it is necessary to check the level of fasting blood glucose, glycated hemoglobin, C-peptide and the NOME index.
What should we focus more on at the initial stage of treatment of patients with hypertension and diabetes: lowering blood pressure or achieving normoglycemia?
Of course, the control of both blood pressure and glucose is equally important. In this case, the patient should keep a diary of blood pressure, pulse and fasting glucose. An important characteristic of AO is the variability of SAD and DAD, which is calculated as a standard deviation from the average values for the day, day and night. This indicator is 11-15 mmHg (Rogoza, 2003).
What target blood pressure levels are recommended to achieve in patients with hypertension and DM in accordance with modern treatment standards?
It should be noted that the national recommendations for the treatment of hypertension are focused specifically on the guidelines of the European Society of Cardiology (ESC) and the European Society for Hypertension (ESH) 2018 on the management of patients with hypertension, which indicate that the desired level of blood pressure in hypertension and DM should be <130/80 mm Hg. In the recommendations for the diagnosis and therapy of hypertension The National Institute of Health and Care Excellence of the United Kingdom (NICE, 2019) target blood pressure for hypertension and diabetes is <140/90 mmHg. In general, the target values of SAD and DAD in patients with hypertension differ somewhat depending on the age of the patients, if we compare the latest European and British guidelines. Thus, the target level of SAD in persons over 65 years of age should be 130-139 mm Hg, up to 65 years of age - 120-129 mm Hg.
In the British recommendations, the criteria are less stringent. Thus, in patients after 80 years of age, the desired target level of SAD is <150 mmHg, before 80 years - less than 140 mmHg. Target values of GAO also differ <80 mmHg in European and <90 mmHg in English settings.
What is the difference between a hypertensive crisis and uncontrolled hypertension?
Hypertensive crisis is a condition when very high blood pressure is accompanied by acute damage to target organs. If there is a significant symptomatic increase in blood pressure, it is always necessary to differentiate two situations: acute hypertensive lesions of target organs or uncontrolled hypertension (improperly treated hypertension when the target blood pressure level is not reached).
With a hypertensive crisis, the damage to target organs can be quite severe and manifest itself in the form of stroke, hypertensive encephalopathy, cardiogenic pulmonary edema, etc. It is important to understand that a hypertensive crisis in patients with DM is an emergency condition and requires an immediate reduction in blood pressure. So, the presence of frequent hypertensive crises (2-3 times within 10-14 days) is the basis for a change in blood pressure.
Please tell us what is the role of daily blood pressure monitoring in ensuring effective treatment of hypertension?
The use of the method of daily blood pressure monitoring is recommended for all patients with diabetes and hypertension during the first visit to the cardiologist, as well as the next scheduled visits twice a year. The results obtained help to make an adequate choice and evaluate the effectiveness of antihypertensive therapy, and in some cases, to diagnose hypertension, which may be masked in DM.
It is very important to assess the daily variability of blood pressure in DM, since this disease is characterized by the so-called autonomous diabetic neuropathy, which is characterized by hypersympathicotonia. At the same time, such unfavorable types of daily blood pressure profile as non-dipper (insufficient decrease in blood pressure at night) or night-picker (increase in blood pressure at night) are quite common.
Another manifestation of autonomous diabetic neuropathy may be orthostatic hypotension - a decrease in SAD by 20 mmHg, and DAD - by 10 mmHg in an upright position. It is also known that orthostatic hypotension is associated with an increased risk of chronic HF and SS-mortality. Therefore, it is desirable to measure blood pressure in the standing position for both primary and repeated reviews in each patient with DM, especially if orthostatic hypotension has already been diagnosed earlier (de Boer et al., 2017).
The results of a recently published study of the daily variability of blood pressure in 19,084 patients taking one or more antihypertensive drugs are interesting. It was confirmed that taking an antihypertensive agent at night was accompanied by an improvement in the circadian rhythm of blood pressure due to a significant decrease in the non-dipper profile. There was also a decrease in the number of CC events in the group of patients receiving ≥1 antihypertensive drug before bedtime (Hermida et al., 2019).
What is the optimal starting treatment for hypertension in DM, and is monotherapy appropriate at the same time?
According to the latest European recommendations for the diagnosis and treatment of hypertension, starting antihypertensive therapy should be started with a fixed combination of two drugs - ACE inhibitors (ACE inhibitors) or an angiotensin receptor blocker (ARB) and a calcium channel blocker (BCC) or a diuretic. However, there are certain difficulties associated with the use of diuretics in people with diabetes and hypertension. Firstly, there are no metabolically neutral diuretics. Secondly, thiazide and thiazide-like diuretics have limitations in prescribing to patients with reduced glomerular filtration rate (GFR), which is often observed against the background of diabetic nephropathy.
Usually, patients with DM have a high risk of SS events, so antihypertensive therapy in them should be started with fixed combinations. This will effectively control blood pressure and minimize damage to target organs. Most often, people with type 2 diabetes use a combination of two antihypertensive drugs - ACE or Sartan with BCC. In cases of real resistant hypertension, additional administration of hypotensive agents of the central mechanism of action of spironolactone or beta-blockers is recommended.
It should be emphasized that the appointment of a triple fixed combination of drugs is the second step of AD. In addition, each patient has an individual sensitivity to various drugs and a genetic predisposition to respond to a particular medication. Therefore, a quick transition from a double to a triple fixed combination of antihypertensive drugs is not always justified.
One of the most effective double fixed combinations of antihypertensive drugs, in particular in patients with diabetes, is olmesartan / amlodipine (the drug Attento). An important advantage of this drug is the possibility of use with significantly reduced GFR (up to 20 ml / min), whereas some combinations have limitations with GFR <60 ml / min / 1.73 m2.
Thus, the available results of the study of the renoprotective properties of various antihypertensive drugs (such as nifedipine, amlodipine, enalapril, losartan, candesartan, telmisartan, valsartan and olmesartan) in patients with hypertension. Against the background of long-term administration (more than one year) of these drugs, the amount of type 2 ACE (an enzyme that can promote renoprotection) in urine was evaluated. It was demonstrated that only olmesartan increased the level of APF2 in urine, which provided a potentially greater renoprotective effect (Furuhashi et al., 2014).
It is known that olmesartan reduces the level of microalbuminuria in patients with diabetes and hypertension. In a clinical study, it was shown that the use of olmesartan correlated with a decrease in the ratio of albumin / creatinine in urine in patients with hypertension, DM and early nephropathy by 28.4% more than for taking other sartans (Ikeda et al., 2009). In another clinical trial, olmesartan better reduced the level of proteinuria in individuals with hypertension and nondiabetic nephropathy compared with other Sartans (such as losartan, valsartan, candesartan), which in turn contributed to renoprotection (Ono et al., 2013).
The significant hypotensive effect of the drug Attento has been proven in numerous clinical studies. In particular, three placebo-controlled double-blind studies compared the antihypertensive effect of Attento at a dose of 40/10 mg and a combination of valsartan / amlodipine at 320/10 mg. An expressive hypotensive effect of the Attento was demonstrated - the drug reduced SAD by 10 mmHg and DAD by 6 mmHg better than the combination of valsartan / amlodipine (Ram et al., 2009).
Also, according to the results of the SEVITENSION clinical trial, therapy with Sartan (olmesartan) in combination with amlodipine was superior to perindopril / amlodipine on the effect on central SAT in patients with hypertension and high CC risk. At the same time, Atteno was associated with a large number of cases of achieving the target BP (<130/80 mmHg) compared to those patients who were prescribed a combination of perindopril / amlodipine (Ruilope et al., 2013).
In addition, olmesartan, even in monotherapy mode in clinical practice, reduces blood pressure more effectively compared to other Sartans (Venkata et al., 2011). In addition, an increase in the dose of this drug is associated with a significant dose-dependent decrease in edema associated with taking amlodipine (Chrysant et al., 2008).
How justified is the use of Attento in patients with hypertension and metabolic disorders or already diagnosed with diabetes?
The powerful hypotensive effect of this drug in people with diabetes and obesity has been proven in a large-scale clinical study SERVE. It was attended by 15 thousand. Patients with hypertension and comorbid conditions who did not reach the target BP at the initial stage of medical care. At the same time, the use of olmesartan amlodipine in such patients was accompanied by an interesting pattern: the higher the initial degree of AH, the more the AO decreased. But in patients with isolated systolic hypertension or grade 1 hypertension, there were no cases of excessive decrease in blood pressure (Bramlage et al., 2010).
Also in the study of G. Derosa et al. (2013), there was a significant achievement of the target blood pressure level during daily monitoring in individuals with hypertension, diabetes or obesity (Punzi et al., 2011). In addition, it was proved that long-term use of Attento (for a year) correlated with normalization of blood glucose levels and the NOME index.
And finally, what is the maximum time interval necessary for an adequate assessment of the effectiveness of combined antihypertensive therapy?
Usually, Sartan, subject to regular use, gradually increases the concentration in the body for 7-10 days, and the maximum effect develops on average four weeks after the start of using the drug. Of all the representatives of the sartan group, the fastest antihypertensive effect develops in olmesartan - 1-2 weeks after the start of use (Munger et al., 2011).
It is known that the maximum concentration of amlodipine in the blood is reached 6-12 hours after ingestion, and a stable balanced concentration provides a stable hypotensive effect - after 7-8 days of regular use. For amlodipine, there is an inherent long-term hypotensive effect due to a wide range of half-life (35-50 hours).
In this aspect, the results of the study are interesting, where the effectiveness of the blood pressure content was compared after skipping the next dose of fixed combinations of 20-40 mg of olmesartan with 5-10 mg of amlodipine and 4-8 mg of perindopril with 5-10 mg of amlodipine. It was shown that the combined use of olmesartan amlodipine rather reduced blood pressure during 24 weeks of follow-up and ensured its stable content in case of skipping the next dose (Redon et al., 2016).
Thus, the use of double fixed combinations of antihypertensive drugs is a fairly effective and justified step in antihypertensive therapy in patients with hypertension and DM. Thanks to this therapeutic strategy, it is possible to ensure optimal control of blood pressure and, accordingly, prevent the development of fatal SS events.
Maria Sergeevna, how relevant and interrelated are the problems of hypertension and diabetes in the modern world?
In recent years, these diseases have been rapidly gaining momentum as a kind of epidemic. Thus, according to statistics, by 2030 there will be 552 million people with diabetes in the world. DM is a risk factor for many cardiovascular (SS) pathologies - coronary heart disease (CHD), stroke, heart failure (HF). However, it was only in 2015 that the results of a large-scale clinical study were published, which confirmed that DM is associated with hypertension (Connor et al., 2015). Therefore, hypertension and diabetes are kind of twin diseases that occur in one patient at the same time or develop one after the other.
It should be noted that hypertension can also cause the development of diabetes. An increase in systolic blood pressure (SBP) for every 20 mmHg increases the risk of new cases of DM by 58%, diastolic blood pressure (DBP) for every 10 mmHg - by 52% (Edmin et al., 2015). Violation of carbohydrate metabolism is found in 20-30% of patients with hypertension, and elevated blood pressure - in 50-80% of people with diabetes (Mammadov et al., 2004).
In addition, patients with diabetes and hypertension often have an increased body mass index. In order to detect diabetes in a timely manner or exclude the risk of prediabetes in people with hypertension and overweight or obesity, it is necessary to check the level of fasting blood glucose, glycated hemoglobin, C-peptide and the NOME index.
What should we focus more on at the initial stage of treatment of patients with hypertension and diabetes: lowering blood pressure or achieving normoglycemia?
Of course, the control of both blood pressure and glucose is equally important. In this case, the patient should keep a diary of blood pressure, pulse and fasting glucose. An important characteristic of AO is the variability of SAD and DAD, which is calculated as a standard deviation from the average values for the day, day and night. This indicator is 11-15 mmHg (Rogoza, 2003).
What target blood pressure levels are recommended to achieve in patients with hypertension and DM in accordance with modern treatment standards?
It should be noted that the national recommendations for the treatment of hypertension are focused specifically on the guidelines of the European Society of Cardiology (ESC) and the European Society for Hypertension (ESH) 2018 on the management of patients with hypertension, which indicate that the desired level of blood pressure in hypertension and DM should be <130/80 mm Hg. In the recommendations for the diagnosis and therapy of hypertension The National Institute of Health and Care Excellence of the United Kingdom (NICE, 2019) target blood pressure for hypertension and diabetes is <140/90 mmHg. In general, the target values of SAD and DAD in patients with hypertension differ somewhat depending on the age of the patients, if we compare the latest European and British guidelines. Thus, the target level of SAD in persons over 65 years of age should be 130-139 mm Hg, up to 65 years of age - 120-129 mm Hg.
In the British recommendations, the criteria are less stringent. Thus, in patients after 80 years of age, the desired target level of SAD is <150 mmHg, before 80 years - less than 140 mmHg. Target values of GAO also differ <80 mmHg in European and <90 mmHg in English settings.
What is the difference between a hypertensive crisis and uncontrolled hypertension?
Hypertensive crisis is a condition when very high blood pressure is accompanied by acute damage to target organs. If there is a significant symptomatic increase in blood pressure, it is always necessary to differentiate two situations: acute hypertensive lesions of target organs or uncontrolled hypertension (improperly treated hypertension when the target blood pressure level is not reached).
With a hypertensive crisis, the damage to target organs can be quite severe and manifest itself in the form of stroke, hypertensive encephalopathy, cardiogenic pulmonary edema, etc. It is important to understand that a hypertensive crisis in patients with DM is an emergency condition and requires an immediate reduction in blood pressure. So, the presence of frequent hypertensive crises (2-3 times within 10-14 days) is the basis for a change in blood pressure.
Please tell us what is the role of daily blood pressure monitoring in ensuring effective treatment of hypertension?
The use of the method of daily blood pressure monitoring is recommended for all patients with diabetes and hypertension during the first visit to the cardiologist, as well as the next scheduled visits twice a year. The results obtained help to make an adequate choice and evaluate the effectiveness of antihypertensive therapy, and in some cases, to diagnose hypertension, which may be masked in DM.
It is very important to assess the daily variability of blood pressure in DM, since this disease is characterized by the so-called autonomous diabetic neuropathy, which is characterized by hypersympathicotonia. At the same time, such unfavorable types of daily blood pressure profile as non-dipper (insufficient decrease in blood pressure at night) or night-picker (increase in blood pressure at night) are quite common.
Another manifestation of autonomous diabetic neuropathy may be orthostatic hypotension - a decrease in SAD by 20 mmHg, and DAD - by 10 mmHg in an upright position. It is also known that orthostatic hypotension is associated with an increased risk of chronic HF and SS-mortality. Therefore, it is desirable to measure blood pressure in the standing position for both primary and repeated reviews in each patient with DM, especially if orthostatic hypotension has already been diagnosed earlier (de Boer et al., 2017).
The results of a recently published study of the daily variability of blood pressure in 19,084 patients taking one or more antihypertensive drugs are interesting. It was confirmed that taking an antihypertensive agent at night was accompanied by an improvement in the circadian rhythm of blood pressure due to a significant decrease in the non-dipper profile. There was also a decrease in the number of CC events in the group of patients receiving ≥1 antihypertensive drug before bedtime (Hermida et al., 2019).
What is the optimal starting treatment for hypertension in DM, and is monotherapy appropriate at the same time?
According to the latest European recommendations for the diagnosis and treatment of hypertension, starting antihypertensive therapy should be started with a fixed combination of two drugs - ACE inhibitors (ACE inhibitors) or an angiotensin receptor blocker (ARB) and a calcium channel blocker (BCC) or a diuretic. However, there are certain difficulties associated with the use of diuretics in people with diabetes and hypertension. Firstly, there are no metabolically neutral diuretics. Secondly, thiazide and thiazide-like diuretics have limitations in prescribing to patients with reduced glomerular filtration rate (GFR), which is often observed against the background of diabetic nephropathy.
Usually, patients with DM have a high risk of SS events, so antihypertensive therapy in them should be started with fixed combinations. This will effectively control blood pressure and minimize damage to target organs. Most often, people with type 2 diabetes use a combination of two antihypertensive drugs - ACE or Sartan with BCC. In cases of real resistant hypertension, additional administration of hypotensive agents of the central mechanism of action of spironolactone or beta-blockers is recommended.
It should be emphasized that the appointment of a triple fixed combination of drugs is the second step of AD. In addition, each patient has an individual sensitivity to various drugs and a genetic predisposition to respond to a particular medication. Therefore, a quick transition from a double to a triple fixed combination of antihypertensive drugs is not always justified.
One of the most effective double fixed combinations of antihypertensive drugs, in particular in patients with diabetes, is olmesartan / amlodipine (the drug Attento). An important advantage of this drug is the possibility of use with significantly reduced GFR (up to 20 ml / min), whereas some combinations have limitations with GFR <60 ml / min / 1.73 m2.
Thus, the available results of the study of the renoprotective properties of various antihypertensive drugs (such as nifedipine, amlodipine, enalapril, losartan, candesartan, telmisartan, valsartan and olmesartan) in patients with hypertension. Against the background of long-term administration (more than one year) of these drugs, the amount of type 2 ACE (an enzyme that can promote renoprotection) in urine was evaluated. It was demonstrated that only olmesartan increased the level of APF2 in urine, which provided a potentially greater renoprotective effect (Furuhashi et al., 2014).
It is known that olmesartan reduces the level of microalbuminuria in patients with diabetes and hypertension. In a clinical study, it was shown that the use of olmesartan correlated with a decrease in the ratio of albumin / creatinine in urine in patients with hypertension, DM and early nephropathy by 28.4% more than for taking other sartans (Ikeda et al., 2009). In another clinical trial, olmesartan better reduced the level of proteinuria in individuals with hypertension and nondiabetic nephropathy compared with other Sartans (such as losartan, valsartan, candesartan), which in turn contributed to renoprotection (Ono et al., 2013).
The significant hypotensive effect of the drug Attento has been proven in numerous clinical studies. In particular, three placebo-controlled double-blind studies compared the antihypertensive effect of Attento at a dose of 40/10 mg and a combination of valsartan / amlodipine at 320/10 mg. An expressive hypotensive effect of the Attento was demonstrated - the drug reduced SAD by 10 mmHg and DAD by 6 mmHg better than the combination of valsartan / amlodipine (Ram et al., 2009).
Also, according to the results of the SEVITENSION clinical trial, therapy with Sartan (olmesartan) in combination with amlodipine was superior to perindopril / amlodipine on the effect on central SAT in patients with hypertension and high CC risk. At the same time, Atteno was associated with a large number of cases of achieving the target BP (<130/80 mmHg) compared to those patients who were prescribed a combination of perindopril / amlodipine (Ruilope et al., 2013).
In addition, olmesartan, even in monotherapy mode in clinical practice, reduces blood pressure more effectively compared to other Sartans (Venkata et al., 2011). In addition, an increase in the dose of this drug is associated with a significant dose-dependent decrease in edema associated with taking amlodipine (Chrysant et al., 2008).
How justified is the use of Attento in patients with hypertension and metabolic disorders or already diagnosed with diabetes?
The powerful hypotensive effect of this drug in people with diabetes and obesity has been proven in a large-scale clinical study SERVE. It was attended by 15 thousand. Patients with hypertension and comorbid conditions who did not reach the target BP at the initial stage of medical care. At the same time, the use of olmesartan amlodipine in such patients was accompanied by an interesting pattern: the higher the initial degree of AH, the more the AO decreased. But in patients with isolated systolic hypertension or grade 1 hypertension, there were no cases of excessive decrease in blood pressure (Bramlage et al., 2010).
Also in the study of G. Derosa et al. (2013), there was a significant achievement of the target blood pressure level during daily monitoring in individuals with hypertension, diabetes or obesity (Punzi et al., 2011). In addition, it was proved that long-term use of Attento (for a year) correlated with normalization of blood glucose levels and the NOME index.
And finally, what is the maximum time interval necessary for an adequate assessment of the effectiveness of combined antihypertensive therapy?
Usually, Sartan, subject to regular use, gradually increases the concentration in the body for 7-10 days, and the maximum effect develops on average four weeks after the start of using the drug. Of all the representatives of the sartan group, the fastest antihypertensive effect develops in olmesartan - 1-2 weeks after the start of use (Munger et al., 2011).
It is known that the maximum concentration of amlodipine in the blood is reached 6-12 hours after ingestion, and a stable balanced concentration provides a stable hypotensive effect - after 7-8 days of regular use. For amlodipine, there is an inherent long-term hypotensive effect due to a wide range of half-life (35-50 hours).
In this aspect, the results of the study are interesting, where the effectiveness of the blood pressure content was compared after skipping the next dose of fixed combinations of 20-40 mg of olmesartan with 5-10 mg of amlodipine and 4-8 mg of perindopril with 5-10 mg of amlodipine. It was shown that the combined use of olmesartan amlodipine rather reduced blood pressure during 24 weeks of follow-up and ensured its stable content in case of skipping the next dose (Redon et al., 2016).
Thus, the use of double fixed combinations of antihypertensive drugs is a fairly effective and justified step in antihypertensive therapy in patients with hypertension and DM. Thanks to this therapeutic strategy, it is possible to ensure optimal control of blood pressure and, accordingly, prevent the development of fatal SS events.
