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.