Evaluation of safety and efficacy of Telmisartan-Amlodipine combination in treating

hypertension.

Arif A Faruqui, General Manager-Medical Services Department,

Medley Pharmaceuticals Ltd., Medley House, D-2, MIDC, Andheri (East), Mumbai
400093, India. drfaruqui@medleylab.com

Introduction
Hypertension is a cardiovascular risk factor commonly associated with insulin
resistance, the metabolic syndrome, and type II diabetes mellitus. Amongst the Indian
studies Singh et al have reported prevalence of hypertension in diabetics as 51.9% in
urban and 29.4% in rural as compared to non diabetics who had 21.9% in urban and
16.9% in rural population1. This disease is the most important modifiable risk factor for
coronary heart disease, congestive heart failure, end-stage renal disease, and peripheral
vascular disease.
Reducing blood pressure in people with hypertension and diabetes decreases both
macrovascular and microvascular complications. Clinical trials using a variety of
antihypertensive agents have demonstrated that modest reduction in blood pressure of just
9–11 mmHg systolic and 2–9 mmHg diastolic decreases cardiovascular events by 34–
69% and microvascular complications (retinopathy and nephropathy) by 26–46% within
just 2–5 years.2 Moreover the goal set by JNC VII in diabetic hypertensives is 130/80 mm
Hg that is very difficult to achieve with monotherapy. Moreover, combinations with older
antihypertensive agents such as thiazide diuretics and beta-blockers have potential
adverse effects on glucose and lipid metabolism and may even exacerbate the metabolic
syndrome and increase the risk of type II diabetes. Thus, there is a need for an
antihypertensive drug combination that can achieve the JNC VII recommended goal
without compromising the lipid profile and glycaemic control.
The safety of new antihypertensive agents or combination is of special importance
as they are likely to be used long term in considerable number of patient’s in general
medical practice. The number of subjects forming the safety database for successful
product licenses for fixed drug combinations is only limited and small compared with the

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number of patients likely to receive a new combination for a common condition such as
hypertension. The objective of this post marketing surveillance (PMS) study is to
identify, validate and quantify the safety and efficacy associated with the use of
telmisartan-amlodipine combination in hypertensive patients with or without concomitant
diabetes.

Material and Method

This was an open, non-comparative, prospective study of the fixed dose

combination of telmisartan 40mg and amlodipine 5mg .The data was collected from 72
centers from all over India during the period June 2007 to February 2008.Full prescribing
information was made available to the physicians. A total of 251 patients of either sex
were included in the study. Only those patients who were newly diagnosed stage II (JNC
VII) hypertension, or those who were uncontrolled on monotherapy with or without
diabetes mellitus were prescribed telmisartan-amlodipine combination. Blood pressure
was measured at the end of 2 weeks, 4 weeks and 8 weeks of therapy. Patients were
monitored for any adverse events reported. Overall global assessment of safety and
efficacy was recorded at the end of the treatment.

Pregnant & lactating women, women of child bearing potential not following
adequate contraceptive measures, those having history of hypersensitivity to either
telmisartan or amlodipine, those with evidence of cardiac, renal or hepatic insufficiency,
drug or alcohol abuse were excluded. Current medical history with clinical symptoms and
physical examination findings were noted. Clinical symptoms and signs were recorded on
predesigned case report forms (CRF). Clinical assessment was done at the start of the
treatment and at the end of 2 weeks, 4 weeks and 8 weeks of treatment. Concomitant
medications administered were also recorded. Primary efficacy end points were reduction
in clinical systolic BP (SBP)/ diastolic BP (DBP) from baseline to study end and number
of responders (ie, patients who achieved target SBP/ DBP <130/<80 mm Hg in diabetic
hypertensive and 140/90 mm Hg in hypertensive) at the end of study. Tolerability was
assessed by treatment-emergent adverse events. Details of any adverse event whether
considered treatment related or not, reported or noted during the treatment with
telmisartan-amlodipine combination were recorded in the appropriate section of the CRF.

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Data was analyzed with the help of Graph pad Instat Version 3.06 statistical package. All
the tests were two tailed. Results were considered statistically significant if P≤0.05.

Observations
A total of 251 patients were enrolled. At the end of 8 weeks, 208 patients had completed
the study, 42 were lost to follow-up and medication has to be stopped in 1 patient due to
dizziness and severe vertigo. The trial population included 57.7% males and 42.3%
females (Table No-01). The mean age of the patients in the study group was 54.5 ± 0.98
years for males and 52.94 ± 1.078 years for females (Table No-01). Diabetes mellitus was
seen in 64.9% of cases, dyslipidaemia in 2.88%, previous IHD in 7.2% cases and chronic
obstructive pulmonary disease (COPD) in 0.50% of cases (Table No-02, Figure-03).
Concomitant medications (Aspirin, Atorvastatin, Clopidogrel, Glimepiride,Metformin &
Pioglitazone) given to the patients were recorded and about 53.36% patients received
some medications while the rest 46.64% received no concomitant medications.
Table No-01 Gender Distribution
Male Female
Number 120 88
Percentage 57.7% 42.3%
Age (Mean ±S.D) years 54.5 ± 0.9823 52.94 ± 1.078

Table No-02 Distribution of Patients

Number of cases %
Hypertension 57 27
Hypertension with diabetes 135 64.9
Hypertension with IHD 09 4.32
Hypertension -Dyslipidemia-IHD 6 2.88
Hypertension with COPD 1 0.50

Table No-03 shows systolic blood pressure (SBP), diastolic blood pressure (DBP) and
heart rate at baseline and after 2,4 &8 weeks of treatment.
Table No-03 Effect of Telmisartan-Amlodipine (Telar-AM) on Heart Rate, Systolic
and Diastolic Blood Pressure
Parameters Baseline 2nd Week 4th Week 8th Week
(Mean±S.D) (Mean±S.D) (Mean±S.D) (Mean±S.D)
Heart Rate 86.259±0.6722 81.70±0.5474 80±0.49 80±0.4219
Systolic B.P 173.31±1.13 152.47±1.13* 140.548±1.042* 133.67±0.8448*
Diastolic B.P 99.82±0.634 89.74±0.5741* 85.293±0.5181* 82.66±0.4524*

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 *P<0.001 Versus baseline
Table No-04, Graph No-1, 2, 3 & 4 shows the changes in SBP & DBP after the
treatment. It shows that mean SBP was reduced by 20.9 mm Hg,32.8 mm Hg & 39.7mm
Hg at the end of 2,4 & 8 weeks of treatment, respectively. Similarly mean DBP was
reduced by 10.08 mm Hg,14.53 mm Hg & 17.16 mm Hg at the end of 2,4 & 8 weeks of
treatment, respectively. At the end of study the reduction in mean SBP was by 39.7mm
Hg i.e.; 22.9 % & DBP reduced by 17.16 mm Hg i.e.;17.19% from baseline which was
statistically significant (p<0.001).
Graph-01

Graph-02

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Graph-03

Graph-04

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 Table No-04 Effect of Telmisartan-Amlodipine combination on
reduction in Systolic and Diastolic Blood Pressure
Systolic B.P n (%) Diastolic B.P n (%)
2 Weeks 20.9 mm Hg (12.08%) 10.08 mm Hg (10.09%)
4 Weeks 32.8 mm Hg (18.92%) 14.53 mm Hg (14.55%)
8 Weeks 39.7 mm Hg (22.90%) 17.16 mm Hg (17.19%)

Table No-05 Effect of Telmisartan-Amlodipine combination on

Fasting and Postmeal Blood Sugar in DiabeticHypertensives.
Baseline 8 Weeks
Fasting Blood Sugar 143.54±3.4 111.059±1.518*
Postmeal Blood Sugar 214.237±5.325 151.918±2.322*
*P<0.0001 Versus baseline
Table No-05 shows the changes in fasting blood sugar (FBS) and post meal blood
sugar (PMBS) in 135 patients who were suffering from concomitant diabetes mellitus. In
this subset of patients mean baseline FBS was 143.54±3.4 mg/dl which was reduced to
111.059±1.518 at the end of 8 weeks. Similarly mean baseline PMBS was 214.237±5.325
which was reduced to 151.918±2.322 at the end of 8 weeks, both values being
statistically significant from baseline (p<0.001). All the diabetic patients were on
antidiabetic medications.

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 Table No-06, Graph No-05 mentions the adverse drug reactions (ADRs) reported
by patients receiving telmisartan-amlodipine fixed dose combination during the study.
The most common side effects reported were headache (1.92%) vertigo (1.44%), and
pharyngitis (1.44%), dizziness, nausea, gastritis, dry cough, syncope and pedal edema
(2.88%). The overall incidence of ADRs was 7.69% in the total number of patients.
Adverse drug reaction was observed in only 16 patients (7.69%) and these were not
serious.

Table No-6 Incidence of adverse drug

reactions
Adverse effects Number Percentage
Dizziness 1 0.48
Vertigo 3 1.44
Gastritis 1 0.48
Nausea 1 0.48
Headache 4 1.92
Pharyngitis 3 1.44
Pedal edema 1 0.48
Syncope 1 0.48
Dry cough 1 0.48
Graph-05

Table No-07, Graph No-06 mentions the overall assessment of efficacy of

treatment by investigators. According to physician’s assessment, 62.5% of the cases had

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 excellent response, 37.01% of the cases had good response and 0.48% had poor response.
Thus 99.5% of total cases showed good to excellent response.

Table No-07 Global assessment of efficacy of Telmisartan-Amlodipine

combination as assessed by investigator on 3-Point ranking scale.
Number %
Excellent 130 62.5
Good 77 37.01
Poor 01 0.48

Graph No-06
Table No-08, Graph No-07 mentions the overall assessment of tolerability of treatment
by the patients. It is observed that 60.57% of total cases had excellent tolerability
followed by 38.94% of cases showing good tolerability; only 2 patient ie, 0.48% of cases
had unsatisfactory tolerance.

Table No-08 Global assessment of safety of Telmisartan-Amlodipine

combination as assessed by investigator on 3-Point ranking scale.
Number %
Excellent 126 60.57%
Good 81 38.94%
Poor 01 0.48%
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 Graph No-07
At the end of the study it was found that 86.3% of the hypertensive patients and 70%
diabetic hypertensive patients achieved the JNC VII recommended goals Table-09,Graph
N0-08
Table No-09 Patients on JNC VII goals.
Achieved Percentage
goals
Diabetic 95 70.00%
Hypertensive(135)
Hypertension(73) 63 86.3%

Graph No-08

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Discussion
Compared to the general population, people with diabetes face a two- to fourfold
increased risk of cardiovascular disease (CVD).3 Concomitant hypertension triples the
already high risk of coronary artery disease (CAD), doubles total mortality and stroke
risk, and may be responsible for up to 75% of all CVD events in people with diabetes. 4
Similarly, hypertension significantly accelerates the progression of diabetic nephropathy,
retinopathy, and neuropathy. Tight BP control is cost-effective and is more rewarding
than hyperglycemic control in diabetic, hypertensive patients 5. Telmisartan and
Amlodipine are two efficacious antihypertensives with less side effects that would be
able to achieve the desired goal of maintaining greater reduction in B.P.

Telmisartan, in addition to blocking the angiotensin II type 1 receptor, activates the

peroxisome proliferator-activated receptor (PPAR)-gamma a well-known target for
treatment of the metabolic syndrome and diabetes. By contrast, other angiotensin-
receptor blockers do not have activity on PPAR-gamma. Telmisartan is a partial agonist
of PPAR-gamma and has a superior tolerability profile without causing the fluid retention
and edema associated with full agonists of PPAR-gamma such as pioglitazone and
rosiglitazone.
In addition to antidiabetic properties, PPAR-gamma activators may also provide
protection against atherosclerosis and coronary events. Calcium antagonists are
recommended as a therapeutic medicine for diabetic hypertensive patients, because they
have no adverse influence on lipid metabolism or glucose metabolism 6. The combination
thus helps in treatment of hypertension especially beneficial with those who have
concomitant diabetes or metabolic syndrome and thus prevents atherosclerotic
cardiovascular disease.
In the present study the baseline mean SBP was 173.31±1.13mm Hg which
dropped to 133.67 ± 0.8448 mm Hg at the end of the study. At the end of 8 weeks
treatment the change in mean SBP was 39.7 mm Hg i.e., 22.9% from baseline which was
statistically significant. Also the baseline mean DBP was 99.82 ± 0.634 mm Hg which
dropped to 82.66 ± 0.4524 mm Hg at the end of the study. At the end of 8 weeks
treatment the change in mean DBP was 17.16 mmHg ie, 17.19% from baseline which
was statistically significant.

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 A similar study of 203 hypertensive patients treated with telmisartan-amlodipine
combination over a period of 12 weeks done by Sharma A et al reported a reduction of
systolic BP by 27.4% and diastolic BP by 20.1%16. Response rates were 87.3%7.
In this study overall assessment of efficacy and safety by the investigators was
done on three-point scale of excellent, good and poor. It was observed that at the end of 8
weeks therapy, majority of the patients ie, 99.5% of total cases showed good to excellent
response and tolerability to study drug, and only 0.48% of cases showed unsatisfactory
response.
The present study showed that telmisartan-amlodipine is very safe and only
(7.69%) of cases i.e., 16 patients reported adverse effects, the commonest being headache
(1.92%) vertigo (1.44%), and pharyngitis (1.44%). Less than 1% patients reported
dizziness, nausea, gastritis, dry cough, syncope and pedal edema. Vertigo was severe
enough in one patient, which required discontinuation of therapy. Otherwise the drug did
not produce any life threatening adverse effect requiring hospitalization. At the end of the
study it was found that 86.3% of the hypertensive patients and 70% diabetic hypertensive
patients achieved the JNC VII recommended goals.

Conclusion

Hypertension and diabetes together considerably accelerate the development of

macrovascular and microvascular complications. Combined antihypertensive therapy
plays a crucial role in achieving targeted blood pressure reductions. Telmisartan
amlodipine combination showed good to excellent response in 99.5% of the cases with
86% patient’s achieving JNC VII recommended goals. The drug was well tolerated by the
trial population and no adverse drug reaction was reported in 92.3% of the cases and only
mild adverse drug reaction was observed in 7.69% of the cases.

Acknowledgment
We acknowledge the physicians of The Indian Telmisartan-Amlodipine Study Group
which consist of following doctors all over India.
DR. RAJENDRA DHORE – AMRAWATI, DR.SHIRISH ARDHAPURKAR – NANDED,
DR.G.B.GUPTA – RAIPUR (CHATRISGARH), DR ROHIT SHAH – NASIK,
DR.K.G.PARGAONKAR – AURANGABAD, DR.I.B.MISHRA – REWA, DR.M.A.SAMI – JALNA,

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DR.S.R.GATAGAT – LATUR, DR.MUKUND GANERIWAL – NAGPUR, DR.SANJAY JAIN –
NAGPUR, DR.J.M.SUBHEDAR – RATLAM, DR.PRASHANT POPHALKAR - AKOLA, DR.RAVI
BHATIA – INDORE, DR.O.P.JUGTAWAT – KHANDWA, DR.N.S.MORYA - SAGAR-MP, DR.
SATISH CH. GHOSH – KOLKATA, DR.S.M.ROHTAGI – PATNA, DR.S.N .MISHRA – PATNA,
DR DURGA SANKAR – MUZAFFARPUR, DR YOGESH KADAM- PUNE, DR.GOPAL
CHATTERJEE – DHANBAD, DR DILIP KUMAR – MOTIHARI, DR.SYAMAL KUNDU –
BANKURA, DR.SUBRATA KUNDU – BURDWAN, DR ANJAN GHOSH – KOLKATA, DR ASHIS
CHATTERJEE – KOLKATA, DR P.K. GHOSH – KOLKATA, DR.ASHFAQUE AHMAD -
MIDNAPORE, DR.A.K.JHA – PURNIA, DR.D.MITRA – KOLKATA, DR.H. AKTAR – KOLKATA,
DR.N.CHATTERJEE – KOLKATA, DR.ANUPAM DAS – KOLKATA, DR.DEBASIS DE –
KOLKATA, DR.INDRANIL MAITRA – KOLKATA, DR.S.K.TANDON- ALLAHABAD,
DR.SHANTANU GHOSH – BHAGALPUR, DR. A. K.TANDON- VARANASI DR ASHOK KUMAR –
LUCKNOW, DR.BRIJESH SINGH- RAIBAREILLY, DR S.P.SHRIVASTAVA – LUCKNOW,
DR.R.K.C.MISHRA- GORAKHPUR, DR.VINOD PARAMSHETTI – SANGLI, DR VINOD
CHAJED- DHULE -366, DR.DEEPAK JAWALE - BHUSAWAL(JALGAON), DR.T.S.JAGTAP-
SATARA, DR.K.RAJESH – KOLHAPUR, DR SANJAY GODBOLE- MUMBAI, DR. PRAVIN
SHINGI - MANMAD(NASIK), DR.MANGESH TIWASKAR- MUMBAI, DR.RAJESH GHAGARE –
MUMBAI, DR.SANTOSH NAGARE – MUMBAI, DR.SHIVARAJ C. PATARIA – MUMBAI,
DR.B.M.KARWA – MUMBAI, DR.C. VELANI – MUMBAI, DR.KALDANE T.G.- MUMBAI, DR
ABHAY SALVE – AHMEDNAGAR, DR.ANIL ADYA- DELHI, DR.ANIL KUMAR BHATT –
DEHRADUN, DR.AJIT SAWHNEY- BAREILLY, DR.PRADEEP KAWATRA – DELHI,
DR.RAVINDER KUMAR – DELHI, DR. SANDEEP JAIN – MEERUT, DR. ANIL GOMBER –
DELHI, DR.J.S.KOCHAR – DELHI, DR.S.K.ARORA – DELHI, DR. GUNASEKARAN – CHENNAI,
DR.R.S.JAWAHAR – KAKINADA, DR.PRAVEEN M. – VIJAYAWADA, DR.G.RAVIKANTH –
HYDERABAD, DR. R.GOPINATH – MADURAI, DR. SUNDAR – CHENNAI,
DR.S.SELVAMOORTHY – THANJAVUR, DR.V.RAJKUMAR - SALEM

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