Effect of Topical Timolol and Betaxolol on Plasma Lipids in Indian Patients of Primary Open-Angle GlaucomaCorrespondence Address :
Dr Rashmi Sharma. 216-A, Last Morh Gandhi Nagar Jammu, Tawi, Pin: 180004, J&K state, India. E-mail: email@example.com
Background: The β-blockers adversely affect plasma lipids.
Aim: To evaluate the effect of topical timolol and betaxolol on plasma lipids.
Setting and Design: The present prospective randomised single-blind parallel study was conducted in Postgraduate Department of Pharmacology and Therapeutics in collaboration with Postgraduate Department of Ophthalmology of a medical college.
Materials and Methods: Sixteen (23 eyes) and 12 (20 eyes) patients of primary open-angle glaucoma with intraocular pressure (IOP) more than 26 mmHg were randomised to receive timolol maleate 0.5% and betaxolol hydrochloride 0.5%, respectively, as one drop twice a day instillation for 12 weeks. Lipid profile and IOP of each patient were recorded at 0, 6 and 12 weeks. Plasma lipids were estimated by standard method using photoelectric colorimeter.
Statistical Analysis: Effects of the individual drug on study parameters were analysed by using studentâ€™s paired t-test, and inter-group comparison was done by using unpaired t-test. P-value ≤0.05 was considered statistically significant; 95% confidence intervals (CI) were calculated according to the standard procedures laid down.
Results: In the present study, topical timolol raised total cholesterol by 17.50 Â± 2.69 mg% (p < 0.0001), LDL cholesterol by 16.27 Â± 2.48 mg% (p < 0.0001), TG cholesterol by 14.56 Â± 2.58 mg% (p = 0.0002), VLDL cholesterol by 2.91 Â± 0.51 mg% (p = 0.0002), TC:HDL by 0.56 Â± 0.07 (p < 0.0001), LDL:HDL by 0.47 Â± 0.11 (p < 0.0001) and reduced HDL cholesterol by 1.68 Â± 0.07 mg% (p = 0.035) after 12 weeks, while topical betaxolol produced insignificant effect on plasma lipids. Topical timolol and betaxolol lowered IOP by 13.05 Â± 1.53 and 7.58 Â± 0.90 mmHg, respectively, after 6 weeks and by 16.12 Â± 1.67 and 8.535 Â± 0.983 mmHg, respectively, after 12 weeks (p < 0.001).
Conclusions: In the present study, topical instillation of betaxolol was found to be superior to topical timolol with better safety profile (plasma lipids).
Plasma lipids, topical β-blockers, glaucoma therapy
The introduction of topical timolol â€“ a non-selective β-adrenergic antagonist â€“ as a treatment in open-angle glaucoma in 1978 was a milestone in the ocular pharmacology, as it has several advantages over cholinergic and adrenergic agonists. However, continued clinical experience has disclosed various potentially serious systemic effects with its topical use because of its absorption into the systemic circulation through the naso-lacrimal duct. Moreover, its plasma levels thus achieved may be equivalent to that obtained after intra-venous administration, as 50â€“70% of the drug escapes first pass metabolism (1),(2). These systemic effects after topical use of β-blockers may be of clinical significance in the elderly who commonly have undiagnosed reversible airway diseases, cardiovascular diseases and metabolic abnormalities, especially dyslipidaemia.
Advanced age, diabetes mellitus, hypertension, positive family history and obesity are known risk factors for both chronic heart disease (CHD) and increased intraocular pressure (IOP) (3),(4). Serum lipids are additionally related to the risk of atherosclerosis. However, no association has been established so far between lipid levels and IOP. Still serum lipid fractions may be important in the chronic therapy of glaucoma, as the glaucoma patients may continue ocular β-blockers during several decades of adult life and are thereby exposed to the systemic and metabolic effects of such therapy for many years. Timolol and betaxolol are commonly used drugs for the management of glaucoma in our country. Betaxolol is a cardio-selective β1-adrenergic antagonist with the theoretical advantage of better corneal penetration, fewer systemic effects and excellent lipid aqueous solubility with twice as high concentration in aqueous humor as that of timolol and much lower concentration in plasma (2),(5),(6). However, only a few studies are available demonstrating significant effect of topical timolol on serum lipids (7),(8). Moreover, no study so far has come to our notice comparing the effects of topical timolol and betaxolol on plasma lipids in the Indian patients of glaucoma, so we conducted the present study to evaluate the effect of topical timolol and betaxolol on plasma lipid in Indian patients of primary open-angle glaucoma.
This study has been described according to the CONSORT guidelines for the presentation of clinical trials. This prospective randomised single-blind parallel study was conducted in the Postgraduate Department of Pharmacology and Therapeutics in collaboration with Postgraduate Department of Ophthalmology, Government Medical College Jammu, after taking permission from the institutionâ€™s ethics committee. Sample size for the study was not definitely set before study, as it was not certain how many patients of chronic simple glaucoma attending Ophthalmology Department during the study period would be fulfilling all the inclusion criteria for the study. Total of 34 newly diagnosed patients of both sexes with 52 eyes of primary open-angle glaucoma in the age group of 40â€“80 years, having painless diminution of vision, glaucomatous optic disc damage and IOP more than 26 mmHg, attending ophthalmology OPD (out patient department) during the period from 01.04.2003 to 31.10.03, were initially enrolled for the study after taking their informed consent. All the patients were subjected to detailed medical and ophthalmic history; complete medical and ocular examination; haematological tests like Hb, BT, CT, TLC, DLC, ESR; biochemical tests â€“ LFT, RFT, blood sugar fasting, urine for routine examination; and ECG.
Only 28 patients (43 eyes)(Table/Fig 1) were included in the study after complete screening for all the exclusion criteria such as history of hypersensitivity to either oral or topical use of timolol and betaxolol; ophthalmic surgical procedures within 3 months of the study; history of bronchial asthma or chronic obstructive pulmonary disease or bronchospastic disorder; cardiac dysfunction including sick sinus syndrome, sinusbradycardia, second- or third-degree heart block, congestive heart failure and myocardial infarction within last 6 months; diabetes mellitus; dyslipidaemias; myasthenia gravis; any systemic malignancy; liver and renal diseases; psychiatric problems; and use of more than one IOP-lowering drugs or concomitant use of any other medication. During first post-registration visit at 0 week, baseline lipid profile and IOP of all the patients were recorded. Finally, 16 (23eyes) and 12 (20 eyes) patients were randomised to receive timolol maleate 0.5% and betaxolol hydrochloride 0.5%, respectively. Timolol maleate 0.5% (IotimÂ® â€“ F.D.C. Ltd) and betaxolol hydrochloride 0.5% (OptipressÂ® â€“ Cipla) for the study were purchased from the market. Both the study drugs were available in white plastic containers of equal size. Before providing drugs to the patients, the cover labels on the bottles were removed and replaced by paper slips containing study code.
Each patient was advised to instil one drop of only the dispensed drug in the affected eye twice daily after occlusion of naso-lacrimal duct and was kept under treatment for 12 weeks ((Table/Fig 2)). Each patient had to undergo two more post-registration visits, first after 6 weeks and second after 12 weeks. Patients were instructed not to change their dietary habits and life style during the study. Patientâ€™s compliance was assessed by asking the patients to maintain personal diary in which they were to note down time and date of each instillation.
IOP and lipid profile of each patient were recorded during each visit in the morning just before the instillation of the drug morning dose). Plasma lipids were estimated by photoelectric colorimeter (electronic controlled 5 filter/8 filter model).
Method of calculation
The reagents were prepared according to the manufacturerâ€™s instructions given in the kits. Three test tubes were labelled as blank (B), standard (S) and test (T). One millilitre (1000 Âµl) of reagent was taken in each of the tubes and pre-warmed at 37 C for at least 5 minutes; 0.01 ml (10 Âµl) of pati
In the present study, topical timolol and betaxolol produced insignificant change in plasma lipid levels after 6 weeks of the study. Topical timolol produced significant rise in TC (p < 0.0001), LDL cholesterol (p < 0.0001), TG cholesterol (p = 0.0002), VLDL cholesterol (p = 0.0002), TC:HDL (p < 0.0001) and LDL:HDL (p < 0.0001) and a reduction in HDL cholesterol (p = 0.035) after 12 weeks of therapy (Table/Fig 3). Whereas, topical betaxolol produced insignificant effect on plasma lipids even after 12 weeks of the therapy (Table/Fig 3).
Topical timolol and betaxolol lowered IOP by 13.05 Â± 1.53 (CI = 9.77â€“16.33) and 7.58 Â± 0.90 mmHg (CI = 5.69â€“9.47), respectively, after 6 weeks and by 16.12 Â± 1.67 (CI = 12.56â€“19.68) and 8.535 Â± 0.983 mmHg (CI = 6.48â€“10.58), respectively, after 12 weeks (p < 0.001) (Table/Fig 4). No adverse effect was reported in any of the group.
The Ăź-blockers adversely affect plasma lipids by inhibiting enzyme lipoprotein lipase; moreover, Ăź-blockade is also accompanied by increase in Ăź-adrenergic tone, which further lowers lipoprotein lipase activity (4),(9),(10),(11). However, certain Ăź-blockers also tend to reduce insulin sensitivity, which in turn lowers lipoprotein lipase activity and increases lecithin-cholesterol activity (LCAT), thereby elevating HDL cholesterol by suppressing the HDLâ€“LCAT cycle (11). In our study, topical timolol produced a rise in TC of 10%, LDL cholesterol of 16%, TG cholesterol of 10%, and VLDL cholesterol of 10% and a reduction in HDL cholesterol of 4%, after 12 weeks of study. The present study also demonstrated a significant rise in LDL:HDL and TC:HDL cholesterol ratios in timolol group after 12 weeks of the study. These findings are in conformity with the results of previous reports. Coleman and associates were first to observe an increase of 12% in TG, a decrease of 9% in HDL cholesterol and an increase of 8% in TC:HDL cholesterol after topical administration of timolol (7). Then, Freedman and associates demonstrated a reduction of 8% in HDL cholesterol and a rise of 10% in TC:HDL cholesterol with timolol after its topical use (8). Yamamoto et al. and Stewart et al. demonstrated a statistically significant fall in HDL cholesterol and a rise in TC:HDL cholesterol after topical timolol therapy (4),(12). In a study from India, topical instillation of 0.5% timolol maleate in 25 patients produced significant decrease in HDL levels after 2 months of therapy (13). In this study, levels of LDL, VLDL and TG were also increased, but the changes were not statistically significant.
However, a previously reported study demonstrated no significant change in TC, HDL cholesterol and TG levels after instillation of timolol 0.5% twice daily for 15 weeks (14). Similarly, in another population-based study from Sydney (1992â€“1994), no statistically significant differences were found in any blood lipid mean levels between 63 people who had used topical timolol for at least 1 year and 2597 nonusers (15). However, male timolol users had a mean value of HDL cholesterol 0.13 mmol/L (11%) lower then the mean value of male nonusers (15).
Topical betaxolol produced statistically non-significant effect on lipid profile in the present study. The effect of oral betaxolol on plasma lipid levels is yet unclear. One study demonstrated no effect on lipid profile, whereas another demonstrated significant increase in levels of TC, LDL cholesterol and TG after betaxolol therapy (16),(17).
As primary-angle glaucoma and atherosclerosis both are fairly common diseases among elderly persons, any adverse change in serum lipids as a result of glaucoma therapy can increase the risk of CHD many folds. It has been seen that as low as 1% fall in cholesterol results into 2â€“3% fall in the rate of CHD (1),(18). Again LDL is highly atherogenic as a result of its low binding affinity for the LDL receptors, prolonged tÂ˝ and long resistance to oxidation (19),(20). A 10% reduction in LDL can decrease the rate of CHD by 50% over 5 years, and a 10% increase in LDL can increase the risk of CHD by 20% (21),(22). However, every 1 mg/dl increase in HDL can reduce the risk of CHD by 2â€“3% (1),(23). Moreover, the ratio of LDL to HDL cholesterol provides a composite marker
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