Effect of Beta-Blockers on I suli Resistance in Patients with Hypertension and Metabolic Syndrome after 6 Months of Treatment

Participants in this study came from a single clinic in Kiev, Ukraine attending a specialized hypertension clinic. This report includes 131 patients with mild to moderate hypertension and metabolic syndrome according to ATP III criteria without diabetes. There were 71 (54%) males and 60 females. All patients had office and ambulatory blood pressure measurements, fasting blood glucose and lipid levels. Glucose and insulin levels were assessed during a glucose tolerance test (PGTT) at baseline and after 6 months. The HOMA index was calculated. For 7 days before all medications was stopped. Hydrochlorothiazide was added if needed for BP control.


Background
For years the use of beta-blockers in patients with metabolic syndrome has been limited due to the negative impact of non-selective beta -blockers on carbohydrate and lipid metabolism.Despite these possible adverse metabolic effects administration of beta -blockers in patients with type 2 diabetes had a similar impact on reducing the incidence of diabetic complications as the ACE inhibitor captopril (ref UKPDS 39).
Carvedilol, a third generation beta-blocker, is a nonselective drug with vasodylating facilities.This property (vasodylating effect) has differing effects on the metabolism of glucose and lipids.The highly selective beta -blocker bisoprolol may positively affect insulin sensitivity and reduces insulin resistance.Improvement of beta -blockers (Generation III) led to the creation of non-selective beta -blocker carvedilol, which has vasodylatating facilities and may be due to that affects the metabolism of glucose and lipids in another way.Some studies have shown that carvedilol increases insulin sensitivity, that reduces insulin resistance.This ability of carvedilol is associated with alpha 1 -adrenoblocade that may be particularly pronounced in combination with blockade of beta 2 -adrenergic receptors.
Nebivolol is a highly selective beta -blocker.Its selectivity is almost an order of magnitude greater than bisoprolol.In addition nebivolol has vasodilatating properties due to its impact on the production of NO, a major endogenous vasodilator [2,5,19,21].
Our group studied antihypertensive therapy with different beta -blockers over 6 months on the impact on insulin resistance, lipid metabolism and blood pressure in patients with mild to moderate hypertension and metabolic syndrome.

Materials and Methods
Patients met the following inclusion criteria:

•
Men and women aged 18 to 65 years; • Mild to moderate arterial hypertension essential by WHO classification (1999) (International Society for the Study of hypertension) and Ukrainian Society of Cardiology (2004).One of the important conditions was the mean levels of blood pressure (BP) measured in the morning in a sitting position -office systolic blood pressure (SBP) was greater than 140 mmhg and diastolic blood pressure (DBP) greater than 90 mmhg at the end of the seven-day washout period;

•
Antihypertensive drugs during the seven-day washout period were canceled; • Metabolic syndrome according to ATP III criteria.
The study did not include patients with: • Existing diabetes types I and II; • Verified symptomatic hypertension; • Level of office systolic (SBP) greater than 180 mmhg or diastolic (DBP) blood pressure greater than 110 mm Hg (Severe hypertension);

•
Acute myocardial infarction or cerebrovascular accidents in history; • Acute or chronic renal failure (serum creatinine levels more than200 mmol/l)

•
Decompensate liver disease (level of AST, ALT above 3 times upper limit of normal);

•
Pregnancy or lactation; • Heart failure; • Clinical signs of coronary heart disease.
Participants in this study came from a single clinic in Kiev, Ukraine attending a specialized hypertension clinic.This report includes 131 patients with mild to moderate hypertension and metabolic syndrome according to ATP III criteria without diabetes (ref for ATII) [8].There were 71 (54%) males and 60 females.All patients had office and ambulatory blood pressure measurements, fasting blood glucose and lipid levels.Also glucose and insulin levels were assessed during a glucose tolerance test at baseline and after 6 months [18].The HOMA index was calculated.Baseline data are found in (Table 1).For 7 days before all medications was stopped.Hydrochlorothiazide was added if needed for BP control.ABPM Meditech_04 every 15 minutes during day and 30 minutes at night was measurement BP method of doing 24 hour BP.This study was carried out with ethical approval from the study Institute of Cardiology, Kiev, Ukraine.
The proportion of patients treated with mono-or combination therapy in groups of observation was the same.

Initial examination, clarification of criteria for inclusion in
the study and the distribution of the patients (using envelopes) into three groups, depending on the intended antihypertensive therapy: Group 1 -atenolol therapy (Tenolol, IPKA, India) 50 -100 mg daily in two divided doses.
When during the first month of treatment target levels of office blood pressure (<140/90 mm Hg) were not achieved hydrochlorothiazide at a dose of 12.5 mg once daily was added to the administered therapy.Repeated full examination was performed after 6 month at the end of observation.
In 1998 it was recommended by in 6's recommendations of the U.S. National Committee for diagnosis and treatment of hypertension tat the normal values of blood pressure are: for average daily SBP -135 mm Hg, for average daily DBP -85 mmhg.In 1999, experts from WHO and the International Society of Hypertension recommended to consider as a normal blood pressure an average daily SBP -125 mmhg and average daily DBP -80 mmhg.
Based on the data in creating a database system in SPSS.Statistical analysis of the results was performed using the analysis

Results
We examined 131 patients.The mean follow-up was  BP was equivalent in all four groups.Office BP decreased equally in all groups.
During treatment with atenolol, carvedilol, bisoprolol and nebivolol blood pressure reduction over 24 hours did not differ between the groups.There was a decrease in the average systolic pressure of 16.86, 15.40, 16.26 and 17.00mm Hg respectively (p <0.05 for all values) and the average DBP decreased by 10.67, 9.00, 12.72 and 10.03 mmhg respectively (p <0.05 for all values).(Figure 1, figure 2).Treatment with atenolol carvedilol, bisoprolol and nebivolol significantly decreased the average heart rate by 4.00, 3.92, 3.82 and 3.54 beats / min respectively (p<0,05 for all).

Effect of Beta -Blockers on Insulin Resistance in Patients with Hypertension and Metabolic Syndrome after 6 Months of Treatment
Significant office blood pressure control (< 140/90 mmhg) was achieved in 78.1% of patients in the atenolol group, 75% of patients in the carvedilol group, 81.3% in the bisoprolol group and 80% in the nebivolol group, (p>0,05) = non significant between groups).Significant (ambulatory blood pressure control) (less than 125/80 mm Hg) was achieved in 71.9% in the atenolol group,in 62.5% of patients in the carvedilol group, in 78% of patients in the bisoprolol group and 74.3% in the nebivolol group (p>0,05 )= non -significant between groups).
Carvedilol treatment reduced levels of total cholesterol, triglycerides, LDL cholesterol, VLDL cholesterol, IA; the level of HDL cholesterol was unchanged.Triglyceride levels decreased from 1.86 ± 0.14 to 1.44 ± 0.15 mmol/l (p<0.05) and total serum cholesterol from 6.29 ± 0.14 to 5.86 ± 0.25 mmol/l but not statistical significant (Table 3).In the bisoprolol treatment group triglyceride levels decreased from 1.67 ± 0.13 mmol/l to 1.58 ± 0.15 mmol/l, (p>0,05) and serum total cholesterol decreased from 6.35 ± 0.19 mmol/l to 5.78 ± 0.18 mmol/l (p=0,02).In the nebivolol group triglyceride levels decreased from 1.74 ± 0.15 mmol/l to 1.23 ± 0.06 mmol/l, and total cholesterol decreased from 6.12 ± 0.25 mmol/l to 5.44 ± 0.20 mmol/l (p <0.01 for both values).In the atenolol group TG and total cholesterol changed not statistical significant.The levels of TG and VLDL in nebivolol group decreased from 29.4% and 25% respectively.Reduction of these parameters in the carvedilol group was slightly lower about 21.0% and 12.5% respectively.Reduction of TG and VLDL in the bisoprolol group was the lowest only 5.9% and 12.5%, respectively.(Table 3).Glucose levels in the atenolol group increased at all three points of PHTT.Increased fasting insulin level is a sign of the progression of insulin resistance in group of atenolol.The percentage of patients with identified insulin resistance (HOMA> 3) increased from 34.4% to 71.9% (p <0.05) six months following treatment.According to PHTT Score there were 6 (18.7%) cases of onset diabetes.Carvedilol therapy contributed to a significant, reduction in fasting insulin.In comparison to baseline data fasting insulin levels decreased by 22.8% (p <0.05), HOMA index by 21.7% (p <0.05), and serum glucose levels did not change significantly.The percentage of patients whose HOMA index was 3 and above decreased from 31.3% to 18.8%.In the carvedilol group, there were 2 with onset diabetes (6.3%).Bisoprolol based treatment significantly decreased HOMA index by 17.4% (p <0.05), fasting insulin by 10.7% (p <0.05), fasting glucose by 10% (p <0.05).This group also demonstrated a positive trend toward HOMA index > 3 (at baseline -34.4% of patients at the end of the study -12.5%).There was also one case of the onset diabetes (3.2%).In the nebivolol group the HOMA index decreased from 2.3 ± 0.3 to 1.76± 0.1 mmol/l (p <0.05), and fasting glucose decreased by 7.4% (p<0.05);no cases of onset diabetes were recorded.The proportion of patients with manifest insulin resistance decreased from 34.3% to 2.9% (p <0.05).This finding suggests that nebivolol may improve insulin sensitivity (Table 4).

Effect of Beta -Blockers on Insulin Resistance in Patients with Hypertension and Metabolic Syndrome after 6 Months of Treatment
Copyright: © 2017 Yuriy Sirenko, et.al.we can conclude that adherence to HCTZ monotherapy with atenolol is accurate negative impact on carbohydrate metabolism and the use of such combinations may be considered undesirable in patients with hypertension and clinical signs of metabolic syndrome.We noticed a significant difference in the incidence of cases of diabetes in the two groups of patients.All cases of diabetes were in the group with HCTZ.Diabetes appeared in 5 patients, predominantly in patients with diagnosed insulin resistance at baseline or in violation of tolerance to carbohydrates.That is to say that diabetes develops in patients with insulin resistance mainly due to hyperinsulinemia.Due to the impact on insulin resistance we can help to reduce onset of diabetes.
After analyzing the effects of carvedilol on carbohydrate metabolism depending with the addition of hydrochlorothiazide, we found that in group carvedilol alone, most of the glucose and insulin oral glucose tolerance test level significantly improved, while as adding HCTZ.Thus, fasting glucose alone in the carvedilol subgroup did not change (5,6 ± 0,2 to 5,5 ± 0,2 mmol / l ,p >0.05), while adding HCTZ decreased it more (5,9 ± 0, 3 to 5,6 ± 0,2 mmol/l, p <0.05), the difference between subgroups was significant, p <0.05.Fasting insulin levels were significantly decreased in subgroup of carvedilol monotherapy 9,2 ± 0,9 to 6,9 ± 0,8 mked/ml (p <0.05), and the addition of HCTZ 9,4 ± 1,8 to 7,5 ± 1,6, mked/ml, (p <0.05), this difference between subgroups was significant, p <0.05.HOMA index was significantly decreased in both carvedilol monotherapy and the addition of HCTZ subgroups.So, HOMA index in subgroup of carvedilol monotherapy decreased from 2,2 ± 0,2 to 1,7 ± 0,2 U, (p <0.05) and in the subgroup with HCTZ from 2,6 ± 0,6 to 1,9 ± 0,4 U (P> 0.05) difference between subgroups was significant, p <0.05.Thus, we can conclude that monotherapy with carvedilol has statistically significant effects on carbohydrate metabolism, and addicting HCTZ had not significantly impaired carbohydrate metabolism, so the use of this combination may be considered appropriate in patients with hypertension and clinical signs of metabolic syndrome.We noted significant negative impact of the addition of HCTZ incidence of cases of diabetes in these two groups of patients.In the group with diagnosed diabetes HCTZ not occurred in the subgroup without diabetes HCTZ appeared in two patients diagnosed with insulin resistance at baseline.In other words, we can say that the addition of HCTZ monotherapy to carvedilol did not contribute to the onset of diabetes and its appearance is connected, likely with the matter of disease itself.
Combination therapy with HCTZ in contrast had a negative effect on carbohydrate metabolism.We found one case of onset diabetes in subgroup of bisoprolol with HCTZ.Therefore, the use of such combinations may be considered inappropriate in patients with hypertension and clinical signs of metabolic syndrome.
After analyzing the effect of nebivolol on parameters of carbohydrate metabolism depending on the addition of hydrochlorothiazide, we found that with the nebivolol monotherapy all indicators of glucose and insulin in oral glucose tolerance test significantly improved, while adding HCTZ this positive trend was less pronounced.Thus, fasting glucose levels in the nebivolol monotherapy group decreased from 5,5 ± 0,2 to 5,1 ± 0,1 mmol/l (p <0.05), and in case of adding HCTZ this figure has not changed, the difference between groups significant, p < 0,001.Fasting insulin was significantly decreased in patients in nebivolol monotherapy group 9,7 ± 0,4 to 7,8 ± 0,8 mked/ml (p <0.05), but not significantly increased when HCTZ was added, the difference between groups was significant, p < 0.05.HOMA index was significantly decreased in the nebivolol monotherapy group, while adding HCTZ did not change it.So, HOMA index in the nebivolol monotherapy group decreased from 2,5 ± 0,4 to 1,8 ± 0,2 U, (p <0.05) difference between groups is significant, p <0.05.Thus, we can conclude that nebivolol monotherapy has statistically significant effects on carbohydrate metabolism, and the addition of HCTZ does not significantly impair carbohydrate metabolism, so the use of this combination may be considered appropriate in patients with hypertension and clinical signs of metabolic syndrome.Onset diabetes did not appear in any groups.
HCTZ in combination with atenolol led to significantly worsened glycemic profiles and increased insulin resistance compared to the subgroup without HCTZ.Administration of HCTZ with nebivolol and carvedilol had no negative impact on the state of insulin resistance.In the carvedilol group the adverse metabolic effect of adding HCTZ neutralized the positive impact of carvedilol (HOMA were not significantly changed).Nebivolol therapy with or without HCTZ decreased HOMA index consistently.Monotherapy with bisoprolol had a significant impact on carbohydrate metabolism.Combination therapy with HCTZ conversely negatively impacted carbohydrate metabolism.There was one case of onset diabetes in the bisoprolol with HCTZ group.Therefore, the use of such combinations may be considered inappropriate in patients with hypertension and clinical signs of metabolic syndrome.

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Copyright: © 2016 Houldsworth, et al.
We analyzed in the subgroup of patients depended of HOMA level.Results presents in (Table 5), In the atenolol subgroup with HOMA >3 was significant worsening fasting insulin and HOMA index, (p<0,05).In the atenolol subgroup with HOMA <3, all indicators significant demonstrated worsening of glycemic profile.(Table 5).
During treatment with carvedilol significant decreased in patients with levels of HOMA> 3 fasting insulin level, (p <0.05) and HOMA index.In the carvedilol subgroup with HOMA <3 was the decreased fasting insulin and HOMA index, (p< 0.05) (Table 5).

Discussion
We can conclude that during atenolol based treatment risk of developing type 2 diabetes increased significantly, while nebivolol and carvedilol therapy significantly improved glycemic profile, which may improve prognosis.Thus, nebivolol and carvedilol may be recommending as a drug of choice in patients with hypertension and metabolic syndrome with signs of impaired carbohydrate metabolism.
Administration of nebivolol as monotherapy or combination with diuretics may be rational in patients with mild to moderate hypertension, clinical signs of metabolic syndrome and manifestations of insulin resistance without diabetes.Bisoprolol can be used as metabolically neutral drugs in patients with mild to moderate hypertension, clinical signs of metabolic syndrome and manifestations of insulin resistance without diabetes.Administration of atenolol is undesirable in patients with hypertension, clinical signs of metabolic syndrome without diabetes despite of the presence or absence manifestations of insulin resistance because it appears to facilitate the development of diabetes.
The LIFE trial (Lozartan Intervention For Endpoint reduction in hypertension) long-term use of selective betablocker atenolol (over 4 years) in patients with hypertension has led to the development of type 2 diabetes de novo only in 8% of patients, it is 3.5 times lower than in ARIC study (28%), in which first generation nonselective beta-blocker without vasodilating activity(propranolol) was used, since research began in the 80s when the range of selective beta-blockers was not so great [12].
It was found that the pro diabetic effect of beta-blockers in most cases is present due to the properties of non-selective beta-blockers amplify tissue insulin resistance.At the same time, according to the purpose of the analysis Jasob et al (1998), which combines a number of studies on treatment of hypertension with the use of beta-blockers, it appears that some of them may even increase the sensitivity of peripheral tissues to insulin [6].
Among the drugs that significantly improved insulin sensitivity (which was assessed by HOMA index), beta-blockers appeared, including not selective to β -adrenergic receptors, but which had a vasodilator activity and property to block α1-and α2 -adrenergic receptors ( Carvedilol, celiprolol, dilevalol).Perhaps vasodilatation and related simplified insulin delivery to the tissues is of great importance in elimination of insulin resistance than β -selectivity of beta-blockers [1].
Nebivolol not only affects the β-2 adrenergic receptors, but also able to modulate the release endoteliy relaxation factor -nitric oxide (NO) causing a decrease in peripheral resistance.Nebivolol therapy almost does not effect on glucose metabolism.In the placebo controlled study therapy 5 mg nebivolol, which was administered for 4-8 weeks did not lead to changes in plasma glucose levels in patients with hypertension and without diabetes.In patients with impaired glucose tolerance nebivolol (2.5 and 5 mg) did not change it, and atenolol (50 and 100 mg) resulted in a significant decrease in sensitivity to insulin, compared with placebo.It was significantly decreased glucose clearance value in the atenolol group.In 30 patients suffering from hypertension and insulinfree diabetes, for 24 weeks nither nebivolol (5 mg), nor atenolol (50 mg) did not affect the utilization of glucose and insulin sensitivity [10,14,15,20].
In most studies, including a 6-month follow-up of patients with insulin free diabetes in patients with hypertension nebivolol had no effect on total cholesterol, high and low density lipoproteins, triglycerides, apolipoproteins A1 and B.Moreover, Y. Lacourciere and co-authors showed that total cholesterol levels and low density lipoprotein with the nebivolol had even decreased [9].
In the mid-80s in the global pharmaceutical market was Carvedilol -a new drug for the treatment of hypertension.The results of numerous studies suggest that this drug used in therapeutic doses acts as a nonselective b-blocker and a-adrenergic receptors blocker.The benefit of carvedilol in that it does not cause severe bradycardia, which is inherent in selective blocker b -blockers, and tachycardia, which is typical of vasodilators.Since the mid-90th the new perspectives of effective clinical use of carvedilol appeared [16,17] .
The main mechanisms of action of carvedilol should be noted: blocking the renin -angiotensin system, sympathetic division of the autonomic nervous system, endothelin system; reducing the total peripheral vascular resistance and reduction of preload; reduce myocardial oxygen demand; lack of reflex tachycardia; inhibition of cardiac arrhythmias; inhibition of cardiomyocyte apoptosis; inhibition of proliferation of smooth muscle cells; inhibition of the formation of free radicals; slowing the progression of heart failure.
In the recent literature there are many reports of the obtained clinical evidence that have shown the positive metabolic effects of carvedilol.Thus, within 24 weeks of observation carvedilol 50 mg daily had a positive effect on blood glucose and fasting insulin levels compared with atenolol 100 mg daily in patients with obesity, hypertension and type II diabetes, while body weight of these patients remained constant.Lipid spectrum, especially triglycerides, cholesterol and high density lipoprotein levels have also been upgraded by the end of the observation [1,3].
GEMINI trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives).In this randomized, double-blind study (G.Bakris et al, 2004) it was made a comparison of two beta -blockers in the treatment regimen of patients with hypertension and type 2 diabetes: metoprolol -β1 -selective beta -blocker and carvedilol -nonselective betablocker, which has an additional feature to block α 1 -adrenergic receptors [1].
Researchers believed that due to the α1 -adrenergic receptors blockade carvedilol may have advantages over metoprolol not only due to its already proven vasodilating activity, but perhaps due to more favorable effects on metabolic parameters (dyslipidemia, insulin resistance), due to that the α1 -adrenergic receptors blockade promotes increased activity of lipoprotein lipase, which breaks down triglycerides.The study included 1235 patients with hypertension and diabetes mellitus type 2. One group (n = 737) received metoprolol tartrat 50-200 mg twice a day, the second one (n = 498) -carvedilol 6,25-25 mg twice a day for 35 weeks.Moreover, all patients continued to receive previously prescribed therapy.Comparing data of glycemic control it was recorded that during carvedilol treatment mean level of hba1c in this group did not change, and in metoprolol group it increased by 0.15%, insulin sensitivity (which is determined by the HOMA index) improved in carvedilol group, but did not changed in metoprolol group (decreased by 9.1 and 2.0%, respectively).The risk of microalbuminuria was significantly lower in carvedilol group than in metoprolol group (6.4 and 10.3%, respectively) [4,7,11].
Thus, this study dispelled the "myth" about the dangers of beta -blockers in treatment patients with diabetes and proved that carvedilol not only worsens metabolic control in this case, but even improves insulin sensitivity.Of course, the results of this study cannot be transferred to the whole group of beta-blockers because carvedilol has additional properties of α1 -blocker, which explains these obtained metabolic effects.
In numerous clinical studies the effectiveness of bisoprolol without any adverse effects on insulin sensitivity and glucose metabolism during long-term treatment of patients with hypertension and diabetes was confirmed.Thus, the usage of bisoprolol 5-10 mg daily for 24 weeks did not significantly differedcompared with previous figures according to the levels of plasma glucose, gly cosylated hemoglobin and plasma insulin after glucose load, at the same time the levels of systolic, diastolic and mean blood pressure decreased significantly.HU Janka et al.Had investigated the effect of bisoprolol on blood glucose levels in patients with type 2 diabetes.After 2 weeks of bisoprolol therapy blood glucose levels 2 hours after taking the drug or placebo were evaluated, it was found a significant difference in this glucose levels between bisoprolol and placebo groups.These data allowed the authors to conclude that there were no episodes of hypoglycemia observed during bisoprolol treatment of patients with diabetes so there is no need of dose adjustment of oral antidiabetic drugs [7].
So the representatives of only a one class of antihypertensive drugs potentially may have different effects on glycemia in patients with metabolic syndrome.

Conclusions
This study showed that all four beta-blockers had similar BP lowering but different metabolic effects.There was a significant worsening of insulin resistance in patients receiving atenolol.Bisoprolol can be used as metabolically neutral drugs in patients with mild to moderate hypertension, clinical signs of metabolic syndrome and manifestations of insulin resistance without diabetes.Patients treated with nebivolol and carvedilol had a trend toward more improvement in insulin sensitivity and glucose tolerance.Nebivolol and carvedilol therapy significantly improved glycemic profile, which may improve prognosis.Nebivolol and carvedilol may be recommend as a drug of choice in patients with hypertension and metabolic syndrome with signs of impaired carbohydrate metabolism.

Table 1 :
19seline Data package in SPSS system and computer software package SPSS.19.ANOVA to calculate the following parameters: the arithmetic mean value -M, the SD from the arithmetic mean value of -m; coefficient of reability -p.The difference was considered reliable at a value of p < 0.05.

Table 3 :
Dynamics of lipid level during treatment in groups

Table 4 :
Dynamics of HOMA, insulin and glucose level during treatment in groups

Table 5 :
Dynamics glucose and insulin level depends HOMA index

Table 6 :
Properties of beta-blockers