Summary
Introduction: Hypertension is a global public health issue. Data on the effect of Anti- hypertensive drugs on dementia, Alzheimer’s disease, cognitive impairment is limited and inconclusive.Material and Methods: It was a Prospective, randomized, open label, comparative study. Total 60 hypertensive Patients were randomized to receive either Telmisartan or Cilnidipine. Memory functions were evaluated with PGI Memory Scale, while psychomotor functions were evaluated with Six Letter Cancellation test (SLCT) and Digit Letter Substitution test (DLST) and card sorting test (CST). Student t-test was used to compare the means of test scores between and within the groups. Statistical significance was considered at P<0.05. Results: An improvement was observed in scores of memory in both the groups which was not significant. A significant improvement (p < 0.05) was shown in 3 of 10 subtests of memory in Telmisartan group compared to Cilnidipine. Both the drugs showed significant improvement in psychomotor function tests (P<0.05). SLCT score was 40.33 ± 1.58 (CI 38.8 - 42) in Cilnidipine group and 38.80 ± 1.56 (CI 37.2 - 40.4) in Telmisartan group. Cilnidipine showed significant improvement in SLCT and DLST scores compared to Telmisartan. Both the study drugs decreased BP significantly (P < 0.01).Conclusion: Both Telmisartan and Cilnidipine showed no change in memory and significant improvement in psychomotor functions in newly diagnosed Stage - I essential hypertension patients. But Telmisartan showed more improving trends in memory than Cilnidipine. Cilnidipine significantly improved psychomotor functions compared to Telmisartan. Further randomized controlled studies are needed to establish these effects.Introduction             Hypertension is a global public health issue. The prevalence of hypertension increases with age. It causes progressive pathological changes in the cardiovascular and central nervous system. The complications arising are stroke [1], vascular dementia [2] and probably Alzheimer’s disease [3]. Studies have shown that hypertension is the most important pathological factor for poor cognitive function [4,5,6]. Uncontrolled hypertension may lead to cognitive decline [7].
Several prospective studies have indicated that use of antihypertensive drugs may reduce the risk of dementia [8,9,10], whereas other studies showed no association between Hypertension and dementia [11,12]. First line treatment for hypertension according to Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC- 8) algorithm is Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin (ATII) receptor antagonists (ARBs), Diuretics and Calcium Channel Blockers (CCBs) [13].
The effect of several antihypertensive drugs on cognitive function has been studied. Clinical trials evaluating antihypertensive drugs indicated two antihypertensive drug classes in the prevention of cognition decline and dementia in patients with hypertension, independent of blood pressure (BP) decrease. They are Dihydropyridine calcium-channel blockers (CCBs) as shown in the Syst - Eur trial [14] and Angiotensin - 1 receptor blockers (AT - 1 blockers) [15,16]. Other studies have also shown better improvement in cognition with Angiotensin converting enzyme (ACE) inhibitors and Angiotensin - II (AT-II) receptor antagonists [17,18,19].
Among the ARBs, Telmisartan, Losartan, Candesartan and valsartan had shown beneficial effects on memory and psychomotor functions. Telmisartan was compared with Olmesartan [20] and losartan [21] for cognitive and psychomotor functions. In these studies, Telmisartan was found to be as effective as losartan and better than Olmesartan in improving cognitive functions. In another study, Telmisartan was compared with Atorvastatin. In this study Telmisartan showed better improvement in psychomotor function compared to atorvastatin [22].
CCBs mitigated the negative effects of the presence of APOE-4 alleles on cognitive decline. Treatment with Nifedipine led to a significant fall in levels of Aβ1-42, with no significant decrease in cell viability. CCBs (Nitrendipine, Cilnidipine and Nilvadipine) promoted Aβ1 - 42 clearance across the blood brain barrier in wild type mice.   Nilvadipine improved the cognitive functions of the animals in Morris water maze test, when treated with human Aβ1 - 42. These studies clearly suggest that DHP CCBs possess non-channelling functions that are independent of their calcium channel blocking ability, suggesting a need for thorough validation of CCBs for AD [23]. Data from these studies suggest that use of CCBs significantly diminishes the rate of progression to dementia and may minimize formation of Aβ1-42 [24]. The effect of CCBs on dementia has mainly been studied using a number of dihydropyridine molecules that have originally been developed for the treatment of hypertension. Most clinical trials focused on Nimodipine and Nilvadipine as they cross blood brain barrier effectively [25]. In one study two calcium channel blockers from the class of dihydropyridines were examined side by side: Nilvadipine and Amlodipine. Patients having mild cognitive impairment were treated with Nilvadipine and cognition did not deteriorate for 20 months. Meanwhile, amlodipine treatment did not seem to be protective. However, both treatments lowered Blood Pressure to the same extent, indicating that the protective effect was independent from the antihypertensive effect [26]. However, data on the effect of antihypertensive drugs on dementia, Alzheimer’s disease, cognitive impairment, and cognitive decline are limited and inconclusive.
Cilnidipine is a unique Ca2+ channel blocker possessing inhibitory action on the sympathetic N-type Ca2+ channels along with L-type. Cilnidipine also increases insulin sensitivity [27]. It will be more helpful to the patients with hypertension and Diabetes, if it improves cognition also. Hence, we have compared Telmisartan with Cilnidipine in this study to evaluate their effect on memory and psychomotor functions in patients with essential hypertension.
Material and Methods             The present study was conducted in the Department of Clinical Pharmacology and Therapeutics, in collaboration with Department of Medicine, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India. Study was conducted between September 2017 to October 2018. It was an open labelled, Prospective, randomized, parallel, comparative study. Sample size was 60 patients with essential hypertension, 30 in each group. Inclusion criteria were 1. Patients aged between 18 to 55 years of either gender willing to give written informed consent 2. Newly diagnosed patients with stage - I essential hypertension (systolic BP 140-159 mm of Hg or diastolic BP 90-99 mm of Hg) 3. Patients able to comprehend and perform the tests and comply with all study procedures Exclusion criteria were patients with secondary hypertension, History of hypersensitivity or drug allergy, patients with hypertensive retinopathy, patients with a history of hypertensive encephalopathy or cerebrovascular accident, patients with Type-I diabetes mellitus or patients with diabetes mellitus who are on insulin therapy, Patients with  previous or current heart failure; myocardial infarction; angina pectoris, valvulopathy or clinically relevant arrhythmias, patients with impaired hepatic or renal function, patients with clinically relevant hypo- or hyperthyroidism, patient with neuropsychiatric diseases (depression, Parkinsonism, Alzheimer’s disease), patients who are prescribed drugs that could affect cognitive functions, pregnant and lactating women.                 Approval was taken from NIMS Institutional Ethics Committee. The study was conducted according to ICH-GCP guidelines and declaration of Helsinki. Written informed consent was taken from all the study subjects. All the eligible patients were trained for psychomotor functions before study on 3 different occasions. They were asked to abstain from smoking and caffeine intake for at least 10 hours and alcohol intake for 48 hours before the study procedure.                On the study day (Day zero) vital parameters of the study subjects were measured. Baseline memory and psychomotor function tests were conducted. The patients were randomized to either Telmisartan 40 mg or Cilnidipine 10 mg once daily. Randomization was done using random tables. Patients with Type -2 Diabetes Mellitus were allowed to continue oral antidiabetic medication Metformin and Sulphonyl urea group drugs. After one month, the patients in whom, Blood Pressure (BP) did not lower satisfactorily to the study drugs, were excluded from the study. Duration of treatment was 3 months. Patients were asked for follow up visits were at 1 and 3 months.                 At each visit, body weight and sitting BP were measured and memory and psychomotor functions were assessed. Compliance was assessed by pill count method. Patients were considered compliant when more than 80% of drug used, in more than 80% of days.                Primary outcomes were changes in memory scores and psychomotor function test scores from baseline to the end of the study (3 months) in both the study groups. Secondary outcomes were 1. Change in blood pressure from the baseline to the end of the study 2. Change in body weight from the baseline to the end of the study 3. Adverse reactions reported in both the groups.            Psychomotor function tests comprise six letter cancellation test, digit letter substitution test, card sorting test. For memory testing Post Graduate Institute, Chandigarh, Memory Scale (PGIMS) was used [28,29]. It is a uniquely designed test for evaluation of memory in semi-literate people suitable for the Indian population. It comprises of 10 sub - tests to measure different components of memory (remote and recent memory, mental balance, attention and concentration, delayed and immediate recall, verbal retention of similar and dissimilar pairs, visual retention and recognition of common objects). Total score for these tests is 100.   Statistical analysis:  Data was presented as mean ± SE. Normality of distribution of data was analysed by Shapiro Wilkes test. Unpaired t-test was used to compare the means of Memory test scores between the groups and paired t test within the groups. The incidence of adverse drug reaction between the groups was analysed by Chi square test. The level of significance was 5% i.e.  P <0.05.