|Year : 2016 | Volume
| Issue : 2 | Page : 80-86
Effect of losartan and atenolol on insulin sensitivity in nondiabetic hypertensive patients
Sandesh Madhukar Bharati1, Nishith Singh2
1 Department of Pharmacology, SMBT Institute of Medical Sciences and Research Centre, Dhamangaon, Nashik, Maharashtra, India
2 Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||03-Oct-2015|
|Date of Decision||10-Dec-2015|
|Date of Acceptance||03-Jan-2016|
|Date of Web Publication||28-Jun-2016|
Sandesh Madhukar Bharati
Department of Pharmacology, SMBT Institute of Medical Sciences and Research Centre, Nandi Hills, Dhamangaon-Ghoti, Igatpuri, Nashik - 422 403, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: To study the effects of losartan and atenolol on glucometabolic parameters in nondiabetic hypertensive patients. Materials and Methods: In a prospective, open-label, parallel group study, nondiabetic patients with mild to moderate hypertension were randomized to either losartan (titrated from 50 to 100 mg/day, n = 20) or atenolol (titrated from 25 mg to 100 mg/day, n = 20) for period of 24 weeks. At baseline, 12 and 24 weeks fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment for insulin resistance (HOMA-IR) apart from lipid parameters, mean systolic, and diastolic blood pressures levels were determined. Results: At the end of study, losartan significantly (P < 0.05) reduced FPG, FPI, and HOMA-IR compared to atenolol and baseline. While atenolol increased the HOMA-IR levels significantly compared to the baseline. Conclusions: Losartan improved the insulin sensitivity while atenolol worsened it. Losartan is better than atenolol for its effects on the glucose-insulin metabolism.
Keywords: Atenolol, hypertension, insulin resistance, losartan
|How to cite this article:|
Bharati SM, Singh N. Effect of losartan and atenolol on insulin sensitivity in nondiabetic hypertensive patients. J Pharmacol Pharmacother 2016;7:80-6
|How to cite this URL:|
Bharati SM, Singh N. Effect of losartan and atenolol on insulin sensitivity in nondiabetic hypertensive patients. J Pharmacol Pharmacother [serial online] 2016 [cited 2017 Oct 17];7:80-6. Available from: http://www.jpharmacol.com/text.asp?2016/7/2/80/184771
| Introduction|| |
Different studies have shown that lowering blood pressure in patients of hypertension decreases the risk of death due to cardiovascular complications irrespective of the antihypertensive drug used for the treatment.  Various antihypertensive drug groups are used for the management of hypertension, including angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), thiazide diuretics, and calcium channel blockers (CCBs).  Irrespective of the identical benefits of lowering cardiovascular mortality, antihypertensive agents differ in terms of their adverse effects. Some antihypertensive drug groups may adversely affect the metabolic parameters including glucose-insulin metabolic parameters and lipid levels differently.  Hypertension itself induces a state of insulin resistance and impaired glucose tolerance culminating in the development of diabetes mellitus (DM) in hypertensive patients.  The occurrence of diabetes with hypertension increases the hazard of cardiovascular diseases by manifold.  Therefore, choosing antihypertensive medications that do not adversely affect the metabolic outcome and worsen the already insulin resistant state in hypertensive patients, instead prevent the new-onset of DM is important in nondiabetic patients with hypertension.  Different studies have shown the insulin sensitizing effects of ARBs especially that of telmisartan. Telmisartan is a mono-carboxylic acid, nontetrazole lipid soluble compound unlike other losartan such as ARBs with large tetrazole ring. Telmisartan is believed to have thiazolidinedione like agonistic activity at peroxisome proliferator-activated receptor, gamma (PPAR-γ) which explains its effects on glucose-insulin metabolism.  However, it remains unknown whether this is a class-effect or not. A metabolite of losartan, EXP-3174 can also have partial agonistic activity at PPAR-γ receptor. 
Regarding the effects of losartan on insulin resistance results have been conflicting. Recently, a few studies have demonstrated the favorable effects of losartan on the glucose-insulin metabolism.  A study demonstrated that losartan lowered the relative risk of incidence of type 2 DM by 25% compared to atenolol.  However, other studies have failed to demonstrate the insulin resistance lowering effect of losartan. ,
The present study was undertaken with the aim of studying the influence of commonly used antihypertensive drugs losartan and atenolol on glucometabolic parameters in nondiabetic hypertensive patients.
| Materials and Methods|| |
Forty nondiabetic patients of mild (systolic blood pressure [SBP]: 140-159 mmHg and/or diastolic blood pressure [DBP]: 90-99 mmHg) to moderate hypertension (SBP: 160-179 mmHg and/or DBP: 100-109 mmHg) between 18 and 75 years, male or female subjects attending medicine out-patient department of a tertiary care hospital and consenting to participate were enrolled in the study. The exclusion criteria were as follows: Type 1 or type 2 DM, secondary hypertension, history of hypersensitivity to ARBs/BB, one or both sided renal artery stenosis, acute or chronic renal failure, serum creatinine ≥2.5 mg/dl, serum potassium >5.5 mEq/l, patients who are known case of chronic obstructive pulmonary disease or bronchial asthma, smokers, patients with significant electrocardiogram abnormality, significant cardiovascular disease, history of hypertensive encephalopathy/stroke/transient ischemic attack (TIA) within last 6 months, pregnant/lactating women, or women intending for pregnancy.
Participants of the study were made aware of the nature and purpose of this study and written informed consent was obtained. The study was conducted after obtaining approval from the Institutional Ethical Committee. This study was done in Unison with the Declaration of Helsinki.
This was a prospective, randomized controlled, open-label, parallel group study conducted in a tertiary care teaching hospital. The patients included in the study were randomized, using lottery method into two groups of 20 each to receive following treatments orally: Group I: Losartan titrated from 50 to 100 mg daily, Group II: Atenolol titrated from 25 to 100 mg daily. Titration of the doses was done similar to the study by Reneland et al.  A rescue therapy of indapamide was given to patients in whom the blood pressure was not controlled on titration to the highest possible doses of individual drugs. Patients received the medicines for 24 weeks and were followed at 12 and 24 weeks to study the effects on SBP, DBP, and heart rate (HR) and following metabolic parameters:
- Fasting plasma glucose (FPG) and fasting plasma insulin (FPI) were measured using standard techniques on samples obtained from the subjects after overnight fasting. Insulin was estimated by enzyme-linked immunosorbent assay technique. The homeostasis model assessment for insulin resistance(HOMA-IR) was computed as:
HOMA-IR = FPI (μU/ml) × FPG (mmol/L)/22.5
HOMA-IR: It is a computer model of glucose-insulin interactions proposed by Matthews et al. based on the supposition that is averagely weighing healthy persons under 35 years had 100% β-cell function and labeled having insulin resistance of one.  Various studies have correlated the insulin resistance obtained from HOMA-IR with that from the gold standard hyperinsulinemic-euglycemic glucose clamp technique. 
- Lipid parameters namely serum high-density lipoprotein cholesterol, serum triglycerides, and total cholesterol were measured using standard methods. Low-density lipoprotein cholesterol levels were calculated using Friedewald's formula.
Blood pressure measurement
Mercury sphygmomanometer with appropriate sized cuff, i.e., to encircle at least 80% of the arm was used to record the blood pressure. Each patient was made to sit for at least 5 min in a chair with feet touching the floor and arm supported at heart level in a private, quiet setting with a comfortable room temperature. The auscultatory method of blood pressure measurement was used. Mean of the two recordings was noted.
Body mass index
Also called as Quetelet index was calculated using formula:
BMI = Weight (kg)/height (m 2 )
Sample size calculation
The sample size was computed based on earlier studies of Yavuz et al. of the effect of losartan on insulin sensitivity in essential hypertensive patients.  The HOMA-IR (mean ± standard deviation [SD]) levels before and after 6 months of losartan treatment in hypertensive patients were 2.3 ± 0.6 and 1.5 ± 0.7, respectively. Assuming alpha risk 5%, power 95%, and ratio of sample size (n2/n1) 1, and then the total sample size required is 18 patients.
Data were analyzed using GraphPad Instat ® version 3.10, 32 bit for Windows, GraphPad Software, Inc. 7825 Fay Avenue, Suite 230, La Jolla, CA 92037 USA. Data are stated as means ± SD for data following a normal distribution and expressed as median (range) for the skewed data. After testing the data for normality (Kolmogorov-Smirnov test), intergroup analyses between losartan and atenolol groups for the data at baseline, at 12 weeks and 24 weeks and percent change from baseline till 12 weeks and till 24 weeks were assessed using the unpaired Student's t-test for Gaussian data with or without Welch correction and using Mann-Whitney test for non-Gaussian data.
For intragroup (or within-group) comparison, repeated measure analysis of variance (RM-ANOVA) was applied for comparing different parameters with normal distribution in the same group at different time points. For non-Gaussian data, Kruskal-Wallis test was used. Tukey Kramer test and Dunn's test were used as a posttest with multiple comparisons to detect the group responsible for the difference for the Gaussian and non-Gaussian data, respectively. The results were evaluated at a significance level of P < 0.05 and with 95% confidence intervals.
| Results|| |
A total of 40 patients were enrolled, with 20 randomized to each treatment group, baseline clinical characteristics of study patients are shown in [Table 1], and no significant differences were noted between groups for different variables.
Systolic blood pressure, diastolic blood pressure, and heart rate
Intergroup analysis [Table 2] shows no significant difference in the SBP and DBP levels at different times points of follow-up. Intragroup analysis [Table 3] shows that both groups had significant reductions in SBP and DBP levels at the 12 and 24 weeks follow-up (P < 0.0001, vs. baseline). At the end of study, atenolol decreased the HR significantly as compared to losartan (P < 0.0001).
|Table 2: Effect of atenolol versus losartan on different variables: Intergroup analysis|
Click here to view
|Table 3: Effects of atenolol and losartan on different variables at different time points of follow-up: Intragroup analysis|
Click here to view
Fasting plasma glucose, fasting plasma insulin, and homeostasis model assessment for insulin resistance
Intergroup analysis [Table 2] shows the FPG and FPI levels in the two groups are statistically significant at the end of treatment (P = 0.0018 and P < 0.0001). The HOMA-IR levels in study groups were significantly different at 12 and 24 weeks (P = 0.0144 and P < 0.0001). Groups were also compared in terms of percent change from baseline to the end of 12 and 24 weeks. Effect of losartan versus atenolol on percent change in HOMA-IR is significant at 12 weeks (P = 0.0386) and 24 weeks (P < 0.0001) as shown in [Figure 1] and [Figure 2]. Intragroup analysis at 12 and 24 weeks follow-up shows that atenolol increased whereas losartan decreased FPG, FPI, and HOMA-IR levels. The statistical significance levels for these changes compared to baseline are shown in [Table 3].
|Figure 1: Effect of atenolol versus losartan on glucometabolic factors after 12 weeks. FPG: Fasting plasma glucose, FPI = Fasting plasma insulin, HOMA-IR = Homeostasis model assessment index-insulin resistance, NS = Not significant, * = Significant|
Click here to view
|Figure 2: Effect of atenolol versus losartan on glucometabolic factors after 24 weeks. FPG: Fasting plasma glucose, FPI = Fasting plasma insulin, HOMA-IR = Homeostasis model assessment index-insulin resistance, NS = Not significant, * = Significant, *** = Extremely significant|
Click here to view
Lipid metabolic parameters
There was no significant difference between the losartan and atenolol groups at 12 and 24 weeks follow-up in the lipid metabolic parameters [Table 2]. Intragroup analysis [Table 3] showed no difference in the levels of different lipid metabolic variables at 12 and 24 weeks follow-up compared to baseline.
| Discussion|| |
The present study provides evidence that losartan has an insulin-sensitizing effect in nondiabetic hypertensive patients. Furthermore, the antihypertensive drugs losartan and atenolol have distinct metabolic effects despite similar antihypertensive efficacy.
The results of this study showed that in nondiabetic hypertensive patients, losartan reduced the insulin resistance index, HOMA-IR more than atenolol. Different studies support that ARBs including losartan decrease the insulin resistance. ,, In a study by Jin and Pan Losartan (100 mg daily) was compared with amlodipine (10 mg daily) administered for a period of 3 months in patients of type 2 diabetes with nephropathy. Insulin resistance was measured using HOMA-IR. Significant reductions of FPI concentrations and HOMA-IR were also observed at the end of treatment for the losartan group when compared with the baseline. However, reductions were not statistically significant in comparison to the amlodipine group.  In a study by Aksnes et al., insulin resistance was studied by glucose clamp technique in patients of hypertension. Glucose disposal rate were found to be significantly higher after treatment with losartan 100 mg + amlodipine 5 mg compared to amlodipine 10 mg (4.97 ± 0.4 vs. 4.27 ± 0.5 mg/kg/min, P = 0.039). HOMA-IR levels in the losartan + amlodipine group significantly reduced after 8 weeks compared to the baseline (4.4 ± 0.8 vs. 3.1 ± 0.6, P = 0.007).  Nishimura et al. studied the effects of losartan (50-100 mg/day) versus a CCB administered for 3 months in patients of impaired glucose tolerance. Losartan caused a significant reduction in HOMA-IR (23.9%). 
Renin angiotensin system plays a role in the development of insulin resistance. Angiotensin II induced vasoconstriction may impair the tissue blood flow thereby impairing glucose utilization.  In addition, angiotensin II through its AT1 receptor-associated jannus kinase 2 (JAK2) phosphorylates insulin receptor substrate (IRS)-1 which further decreases the activation of phosphatidylinositol (PI) 3-kinase. This action of angiotensin II is implicated to affect the insulin signaling and induce a state of insulin resistance.  Angiotensin II is also implicated in upregulation of oxidative stress, which in turn affects insulin sensitivity. Renin angiotensin system is involved in upregulating tumor necrosis factors, TNF-α in skeletal muscle which decreases translocation of glucose transporter (GLUT) thus play a role in inducing insulin resistance. Angiotensin II through its AT1 and AT2 receptors induces adipose tissue hypertrophy and preadipocyte differentiation, respectively. Hypertrophied adipose tissue, in turn, secrete cytokines which are involved in the development of insulin resistance.  ARBs may exert beneficial effects on glycemic control through a variety of mechanisms related to the inhibition of angiotensin-II. 
Our study is in contrast to the studies which show that losartan does not improve the insulin sensitivity. ,,, Bahadir et al. investigated the effect of telmisartan (80 mg/day) versus Losartan (50 mg/day) given for 8 weeks on insulin resistance in hypertensive patients with metabolic syndrome where insulin resistance was evaluated by using HOMA-IR. Mean HOMA-IR levels at baseline and at the end of the study, in losartan group were 1.8 ± 0.6 and 1.8 ± 0.6 (P > 0.05).  Yavuz et al. compared the effects of enalapril (5-40 mg/day) with losartan (50-100 mg/day) administered for 6 months on insulin resistance and endothelial function. HOMA-IR levels for the losartan group decreased from 2.3 + 0.6 to 1.5 + 0.7 at the end of 6 months but this change was not significant (P > 0.05).  Huang et al. studied the effects of telmisartan against losartan given for 16 weeks on body fat distribution and insulin sensitivity in Chinese patients with hypertension and obesity. HOMA-IR levels showed no improvement in the losartan group.  Perl et al. studied the vascular, antihypertensive, and metabolic effects of 12 weeks treatment of telmisartan or losartan in patients of hypertension with impaired glucose tolerance. Insulin resistance was assessed by HOMA-IR. Losartan did not show improvement in insulin sensitivity (baseline: 3.04 ± 0.60, after losartan treatment: 3.38 ± 0.84, P > 0.05). 
In a study by Moan et al., losartan was administered at a dose of 50-100 mg/day for 4 weeks in patients of mild hypertension. Euglycemic glucose clamp technique was used to evaluate the effects on glucose insulin metabolism. Losartan did not significantly alter insulin sensitivity.  Same author found that losartan significantly improved the insulin sensitivity in severe hypertensive patients.  The discrepancy between these studies and our study might because of differences in the dose of losartan, duration of the treatment, severity of hypertension, or other unknown variables.
Our study shows that insulin sensitivity is decreased in atenolol group. Results of this study in relation to the effects of atenolol on glucose-insulin metabolism match with that of previous studies. , BB may affect insulin sensitivity and glycemic control in different ways. Antagonism at the pancreatic β2 receptors reduces the insulin release. This effect is more pronounced with nonselective BBs but can also be seen with higher doses of β1 selective blockers. Insulin sensitivity is further impaired by weight gain associated with the use of BBs. In normal people, vasodilatation induced by insulin increases blood flow to the skeletal muscles. Nonselective BBs decrease blood flows to muscles because of unrestricted α1-activity mediated vasoconstriction. This compromises insulin-stimulated glucose uptake and leads to a state of insulin resistance.  BBs affect the first phase of insulin secretion by reducing β2-mediated insulin release. Attenuation of the early phase of insulin secretion is an important predictor of the development of type 2 DM. 
This study emphasizes the importance of choosing an antihypertensive drug that does not increase the risk of developing DM in patients of hypertension.
| Conclusion|| |
The findings of this study showed that irrespective of the similar antihypertensive efficacy, losartan improved while atenolol worsened insulin resistance in nondiabetic hypertensive patients. Losartan appears to be superior to atenolol as far as the effects on the glucometabolic parameters are concerned. Further studies are needed to elucidate the mechanisms by which losartan improves insulin sensitivity.
We thank the participants of this study and the Department of Internal Medicine and Biochemistry, Armed Forces Medical College, Pune, for their invaluable contribution
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Blackburn DF, Wilson TW. Antihypertensive medications and blood sugar: Theories and implications. Can J Cardiol 2006;22:229-33.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr., et al.
Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206-52.
Taylor EN, Hu FB, Curhan GC. Antihypertensive medications and the risk of incident type 2 diabetes. Diabetes Care 2006;29:1065-70.
Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: An update. Hypertension 2001;37:1053-9.
Fukao K, Shimada K, Hiki M, Kiyanagi T, Hirose K, Kume A, et al.
Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: A comparative study between azelnidipine and amlodipine on glucose tolerance and endothelial function - A crossover trial (AGENT). Cardiovasc Diabetol 2011;10:79.
Kurtz TW, Pravenec M. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: Beyond the renin-angiotensin system. J Hypertens 2004;22:2253-61.
Igarashi M, Hirata A, Kadomoto Y, Tominaga M. Dual blockade of angiotensin II with enalapril and losartan reduces proteinuria in hypertensive patients with type 2 diabetes. Endocr J 2006;53:493-501.
Aksnes TA, Reims HM, Guptha S, Moan A, Os I, Kjeldsen SE. Improved insulin sensitivity with the angiotensin II-receptor blocker losartan in patients with hypertension and other cardiovascular risk factors. J Hum Hypertens 2006;20:860-6.
Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlöf B, et al.
Risk of new-onset diabetes in the losartan intervention for endpoint reduction in hypertension study. J Hypertens 2002;20:1879-86.
Bahadir O, Uzunlulu M, Oguz A, Bahadir MA. Effects of telmisartan and losartan on insulin resistance in hypertensive patients with metabolic syndrome. Hypertens Res 2007;30:49-53.
Fogari R, Zoppi A, Lazzari P, Preti P, Mugellini A, Corradi L, et al.
ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients. J Cardiovasc Pharmacol 1998;32:616-20.
Reneland R, Alvarez E, Andersson PE, Haenni A, Byberg L, Lithell H. Induction of insulin resistance by beta-blockade but not ACE-inhibition: Long-term treatment with atenolol or trandolapril. J Hum Hypertens 2000;14:175-80.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9.
Radikova Z. Assessment of insulin sensitivity/resistance in epidemiological studies. Endocr Regul 2003;37:189-94.
Yavuz D, Koç M, Toprak A, Akpinar I, Velioglu A, Deyneli O, Haklar G, Akalin S. Effects of ACE inhibition and AT1-receptor antagonism on endothelial function and insulin sensitivity in essential hypertensive patients. J Renin Angiotensin Aldosterone Syst 2003;4:197-203.
Jin HM, Pan Y. Angiotensin type-1 receptor blockade with losartan increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetes and nephropathy. Nephrol Dial Transplant 2007;22:1943-9.
Aksnes TA, Seljeflot I, Torjesen PA, Hoieggen A, Moan A, Kjeldsen SE. Improved insulin sensitivity by the angiotensin II-receptor blocker losartan is not explained by adipokines inflammatory markers, or whole blood viscosity. Metab Clin Exper 2007;56:1470-7.
Nishimura H, Sanaka T, Tanihata Y, Naito T, Higuchi C, Otsuka K. Losartan elevates the serum high-molecular weight-adiponectin isoform and concurrently improves insulin sensitivity in patients with impaired glucose metabolism. Hypertens Res 2008;31:1611-8.
Morisco C, Trimarco B. Insulin resistance and hypertension: The link. Hot Top Hypertens 2008;2:7-20.
Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A 1996;93:12490-5.
Shiuchi T, Iwai M, Li HS, Wu L, Min LJ, Li JM, et al.
Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension 2004;43:1003-10.
Siegel D, Swislocki AL. Effects of antihypertensives on glucose metabolism. Metab Syndr Relat Disord 2007;5:211-9.
Huang GZ, Tang YH, Wang BY, Zhang B, Hu TJ, Zhang L, et al.
Effects of telmisartan on insulin resistance and visceral fat distribution in Chinese hypertensive patients with obesity. Saudi Med J 2011;32:1017-21.
Perl S, Schmölzer I, Sourij H, Pressl H, Eder M, Zweiker R, et al.
Telmisartan improves vascular function independently of metabolic and antihypertensive effects in hypertensive subjects with impaired glucose tolerance. Int J Cardiol 2010;139:289-96.
Moan A, Høieggen A, Seljeflot I, Risanger T, Arnesen H, Kjeldsen SE. The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity. J Hypertens 1996;14:1093-7.
Moan A, Høieggen A, Nordby G, Eide IK, Kjeldsen SE. Effects of losartan on insulin sensitivity in severe hypertension: Connections through sympathetic nervous system activity? J Hum Hypertens 1995;9 Suppl 5:S45-50.
Kuperstein R, Sasson Z. Effects of antihypertensive therapy on glucose and insulin metabolism and on left ventricular mass: A randomized, double-blind, controlled study of 21 obese hypertensives. Circulation 2000;102:1802-6.
Kraus D, Jäger J, Meier B, Fasshauer M, Klein J. Aldosterone inhibits uncoupling protein-1, induces insulin resistance, and stimulates proinflammatory adipokines in adipocytes. Horm Metab Res 2005;37:455-9.
Sarafidis PA, Bakris GL. Antihypertensive treatment with beta-blockers and the spectrum of glycaemic control. QJM 2006;99:431-6.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]