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Targeted antihypertensives: Individualising treatment by patient profile
In 2019, 1.3 billion people were living with hypertension, defined by systolic blood pressure (SBP) ≥140 mmHg and diastolic blood pressure (DBP) ≥90 mmHg. SBP is often referred to as a ‘silent killer’ and causes >10 million deaths annually, making it the leading global health risk.1
Globally, about 33% of adults between 30- and 79-years have hypertension, but only 54% are diagnosed, 42% receive treatment, and just 21% have it under control. In Africa, hypertension affects 36% of adults, with 43% diagnosed, 27% receiving treatment, and only 12% having it under control. If countries can achieve a 50% hypertension control rate by 2050, the World Health Organization (WHO) estimates that 76 million cardiovascular (CV) deaths and 450 million disability-adjusted life years could be prevented.1
Common triggers
Three common triggers for hypertension are high sodium intake, alcohol consumption, and tobacco use. In Africa, sodium intake averages 2687mg/day, exceeding the recommended <2000mg/day. Alcohol, while temporarily lowering BP, often leads to a rebound increase and chronic hypertension, making its reduction crucial for mitigating hypertension-related health issues. Tobacco use was responsible for 8.7 million deaths globally in 2019, with acute effects on BP due to sympathetic nervous system stimulation, although the long-term impact on chronic hypertension is less clear.1
Effective interventions
Pharmacological treatment for hypertension has been around since the 1950s, contributing to ~20% of the decline in CV mortality in high-income countries over the past four decades.1
The WHO sets treatment goals of BP <140mmHg/90mmHg for patients without comorbidities, while for those with CV disease (CVD) or high CV risk, including diabetes or chronic kidney disease (CKD), the target is SBP <130mmHg.1
The 2024 European Society of Hypertension (ESH) guidelines support these targets, recommending a target SBP of <130mmHg and DBP <80mmHg for most patients up to 79-years. Lifestyle interventions have also proven effective in reducing blood pressure, including adopting a healthy diet, regular physical activity, weight reduction, sodium restriction to <5g/day, increasing potassium intake, limiting alcohol intake, quitting smoking, and managing stress.2
When to add anti-hypertensives
The WHO recommends starting anti-hypertensive medication for individuals who have an SBP of ≥140mmHg, or a DBP of ≥90mmHg. For those with existing CVD and an SBP between 130mmHg-139mmHg, treatment is also recommended. Additionally, individuals without CVD but with high CV risk factors such as diabetes or CKD, and an SBP in the 130mmHg-139mmHg range, should also begin treatment.1
When starting anti-hypertensive therapy, the WHO suggests conducting laboratory tests to screen for comorbidities and secondary hypertension, provided these tests do not delay the initiation of treatment. CVD risk assessment should be carried out if feasible but should not hinder treatment initiation.1
For first-line pharmacological treatment, the WHO recommends using drugs from one of three classes:1
Thiazide and thiazide-like diuretics.
Angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis).
Long-acting dihydropyridine calcium channel blockers (CCBs).
Anti-hypertensives: Who and what?
According to the ESH guidelines, the pharmacological treatment of hypertension involves a stepwise approach, starting with combination therapy for most patients. The initial combination typically includes an ACEi or ARB with a CCB or a thiazide/thiazide-like diuretic. If well tolerated, the dosage can be increased to achieve up to 60% control of BP.2
For patients requiring further control, a triple combination therapy is recommended, adding another agent to the initial combination, potentially achieving up to 90% control.2
Monotherapy should be reserved for selected patients, such as those with low-risk hypertension, high-normal BP with very high CV risk, or frail and elderly patients. Beta-blockers (BBs) can be used as monotherapy or at any step of combination therapy.2
In cases of true resistant hypertension, where BP remains uncontrolled despite the use of three anti-hypertensive agents, additional therapies such as spironolactone or other mineralocorticoid receptor antagonists can be considered. Renal denervation may be an option for patients with an estimated glomerular filtration rate >40ml/min/1.73 m².2
Comparative efficacy and safety of ACEis and ARBs
Peresuodei et al conducted a systematic review comparing the safety and efficacy of ARBs and ACEis in the management of hypertension. The review included 10 studies and data of >1.6 million patients.3
ARBs work by competitively binding to angiotensin-2 receptors, preventing its activation, while ACEis block the conversion of angiotensin (AT)-1 into the active form, AT-2.3
The team found that ARBs and ACEis are equally safe and effective in managing hypertension. However, in terms of tolerability, the review noted that ARBs were better tolerated than ACEis.3
Patients on ACEis were more likely to experience dry cough and angioedema compared to those on ARBs. Overall, ARBs had a lower rate of adverse effects (AEs).3
Choosing the right ARB for the right patient
According to Dézsi, the introduction of ARBs represents a significant milestone in the management of hypertension, expanding personalised treatment options, particularly for patients intolerant to ACEis.4
International guidelines recommend ARBs or ACEis as first-line therapies for patients with various comorbidities, including microalbuminuria, renal dysfunction, CKD, metabolic syndrome, diabetes, atherosclerosis, stable angina, a history of myocardial infarction (MI), atrial fibrillation (AFib), and heart failure (HF).4
A large-scale observational study involving >3 million patients commencing anti-hypertensive treatment with either an ARB or ACEi found no significant difference in effectiveness between the two classes in preventing acute MI, HF, stroke, or composite CV events. However, ARBs demonstrated a better safety profile, with lower risks of acute pancreatitis, angioedema, cough, and gastrointestinal bleeding.5
Currently, guidelines do not specify which ARB should be used for patients with various comorbidities, although several studies have indicated that certain ARBs can provide additional beneficial effects.4
Among ARBs, telmisartan is unique, as it is the only ARB approved for reducing CV morbidity in patients with atherothrombotic CV disease. This approval is based on findings from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, which demonstrated that telmisartan offers similar reductions in composite endpoints of CV death, MI, stroke, or HF hospitalisations compared to ramipril. Additionally, the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease reported that telmisartan was linked to reduced CV hospitalisations, lower left ventricular hypertrophy, and decreased incidence of both macrovascular and microvascular events, including microalbuminuria. A combined analysis with data from the Prevention Regimen for Effectively Avoiding Second Strokes study also revealed telmisartan’s significant benefits in reducing CV death, MI, and stroke. Furthermore, telmisartan has been shown to significantly reduce the recurrence of AFib compared to carvedilol, amlodipine, and ramipril.4
A meta-analysis of eight trials found that telmisartan outperformed other ARBs in reducing fasting plasma glucose and increasing adiponectin levels. At an 80mg dose, telmisartan lowered fasting plasma insulin levels and improved insulin resistance, measured by the homeostasis model assessment, and was associated with a 16% reduction in the risk of new-onset diabetes compared to placebo.4
The Angiotensin II Receptor Blockade in Obese Patients with Hypertension and Insulin Resistance study demonstrated that telmisartan significantly improved the hyperinsulin response to glucose loading in obese patients with hypertension and insulin resistance, along with improvements in vascular inflammation, reductions in visceral fat, and increases in serum adiponectin.4
Telmisartan also shows promise in improving proteinuria and preventing progression to end-stage renal disease (ESRD). It significantly reduced urinary albumin/protein excretion and the urinary albumin/protein to creatinine ratio by 20% and 14%, respectively, compared to other ARBs and ACEis, resulting in an overall reduction of 40%.4
Furthermore, telmisartan appears to protect against hypertension-related cognitive decline through angiotensin 1 receptor blockade and partial activation of PPAR-γ in the hippocampus, significantly restoring cognitive functions impaired by chronic stress and reducing forgetfulness.4
Effective antihypertensive treatment must sustain BP control, particularly in the last six hours of the dosing period or following a missed dose. Early morning BP surges and 24-hour mean BP are associated with CV events and target-organ damage.6
A key advantage of telmisartan is its long half-life, providing 24-hour protection. Lacourcière et al compared telmisartan’s long half-life with the shorter half-life valsartan during the last six hours of treatment and after a missed dose.6,8
In their study, participants received once-daily telmisartan (40mg-80mg) or valsartan (80mg-160mg) for eight weeks. Results showed that during the last six hours of treatment, telmisartan reduced DBP by 7.6mmHg compared to 5.8mmHg with valsartan, with SBP reductions of 11.1mmHg for telmisartan versus 9.1mmHg for valsartan.6
After a missed dose, telmisartan reduced 24-hour mean DBP by 7.2mmHg versus 5.5mmHg with valsartan, and SBP reductions were 10.7mmHg with telmisartan compared to 8.7mmHg with valsartan. The authors concluded that telmisartan consistently provided greater BP reductions, especially in the last hours of the dosing interval, making it particularly beneficial for patients with poor adherence to treatment.6
In the Study of Micardis (telmisartan) in Overweight/Obese Patients with Type 2 Diabetes and Hypertension, 840 patients were randomised to receive telmisartan 80mg or valsartan 160mg daily for four weeks, followed by HCTZ 12.5mg for six weeks.7
Results showed that telmisartan/HCTZ significantly reduced mean BP in the last six hours of the dosing interval compared to valsartan/HCTZ, with greater reductions in SBP and DBP.7
Overall, telmisartan combined with HCTZ provided more significant BP reductions, particularly during early morning hours, making it a more effective option for managing high-risk patients with hypertension and type 2 diabetes.7
Fixed-dose combination of telmisartan/HCTZ
The fixed-dose combination of telmisartan and hydrochlorothiazide (HCTZ) is used for adults whose BP is inadequately controlled with telmisartan alone. Studies demonstrate that adding HCTZ to telmisartan significantly improves BP control, with reductions in ambulatory SBP and diastolic DBP of 21.5/14.6mmHg over 24-hours, 21.8/14.9mmHg during the day, and 20.4/13.7mmHg at night.8,9,10,11
Concerns have been raised regarding the metabolic side effects of thiazide diuretics, particularly their impact on glucose tolerance. Combining ARBs with HCTZ can mitigate some of the metabolic effects associated with thiazide diuretics. For instance, ARBs reduce the risk of hypokalaemia, and their use may also counterbalance the tendency of thiazides to cause hyperglycaemia and new-onset diabetes. Studies have shown that ARBs are linked to fewer cases of new-onset diabetes compared to certain other agents.12
Losartan
Losartan has demonstrated benefits in reducing the relative risk of the composite endpoint of death, MI, or stroke by 13% in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. Greater benefits were observed in diabetic patients, where mortality was reduced by 39%.4
The Evaluation of Losartan in the Elderly (ELITE) I and II trials showed that, in elderly patients living with HF, treatment with losartan provided similar outcomes to captopril regarding all-cause mortality, sudden death, and resuscitated arrests. In the ELITE I study, losartan also showed a lower mortality rate, primarily due to a greater reduction in sudden cardiac death. Additionally, using a 150mg dose of losartan provided further benefits compared to the 50mg dose, reducing the rate of death or HF hospitalisation and improving left ventricular ejection fraction.4
Post-hoc analyses indicate that losartan, valsartan, and candesartan are associated with a 20%-35% reduction in the incidence of new-onset AFib. Losartan also effectively reduced the maximum and total duration of paroxysmal AFib in patients with sick sinus syndrome, without causing significant haemodynamic changes.4
Studies have shown that losartan reduces the risk of ESRD by 28% and lowers urinary protein excretion by 35% in patients with diabetic nephropathy, compared to placebo.4
Treatment with losartan has also been shown to enhance erectile function, sexual satisfaction, and frequency of sexual activity in hypertensive patients. In diabetic patients, losartan alone or in combination with tadalafil significantly improved erectile dysfunction (ED), with the greatest benefit observed in those with mild to moderate ED.4
Additionally, losartan uniquely lowers serum uric acid (SUA) levels, which are associated with an increased risk of gout. Compared with a low dose (50mg), high-dose losartan (150mg) reduced SUA by -0.27mg/dl. High-dose losartan reduced the incidence of hyperuricaemia.13
A real-world study assessed the effectiveness of combining losartan 50mg with HCTZ 12.5mg in managing isolated systolic hypertension among patients with various comorbidities. The analysis included 15 846 patients diagnosed with SBP >140mmHg and DBP <90mmHg, excluding those with diabetes or CKD. The most prevalent CV risk factor was hypercholesterolaemia (48.1%), followed by obesity (16.3%). Other conditions included cerebrovascular diseases (9.6%), ischaemic heart disease (7.9%), and left ventricular hypertrophy (4.6%). The proportion of patients with complications varied by age: 62% for ≤64 years, 69% for 65-74 years, and 67% for ≥75 years. Mean BP improved from 156/78mmHg initially to 140/72 mmHg at one month and 134/72mmHg at six months.14
Laboratory values for total cholesterol, uric acid, haemoglobin A1c, and serum potassium remained stable. Adverse effects such as orthostatic hypotension and significant BP drops were rare. This combination therapy proved effective and safe in achieving the recommended BP target of <140mmHg.14
Role of CCBs and BBs
Amlodipine is a widely used CCB that effectively lowers blood pressure by inhibiting calcium influx into vascular smooth muscle cells, leading to vasodilation. It is particularly beneficial for patients with isolated systolic hypertension, a common condition in the elderly. Amlodipine has a favorable side effect profile and is well-tolerated by most patients. Additionally, it has been shown to reduce the risk of CV events, including stroke and MI.15
According to the 2024 European Society of Cardiology (ESC), combination therapy including a CCB combined with either a thiazide diuretic or a renin-angiotensin system blockers (ACEis or ARBs) should be considered in patients of African descent who require BP-lowering treatment.16
The ESC recommends BBs in specific situations, such as managing angina, HF, or post-MI, and for controlling heart rate, where they play a crucial role in therapy. In these cases, second-generation (cardio-selective) and third-generation (vasodilating) BBs are recommended. However, BBs are generally less effective than ACEis, ARBs, CCBs, or diuretics in preventing stroke and have a higher discontinuation rate due to side effects. Additionally, the use of BBs and diuretics, particularly in combination, is linked to an increased risk of new-onset diabetes in susceptible patients.1
Conclusion
In conclusion, patient selection is crucial in hypertension management, and telmisartan offers significant advantages, particularly for those with comorbidities such as atherosclerosis, diabetes, and CKD. Its long half-life ensures sustained BP control, particularly in the last hours of the dosing interval, making it beneficial for patients with adherence challenges.
Telmisartan also provides additional CV protection, reducing the risk of MI, stroke, and HF hospitalisations, while improving insulin resistance and reducing proteinuria.
Patients with hypertension who struggle with early morning BP surges or those who require better 24-hour BP control may particularly benefit from telmisartan. Furthermore, its fixed-dose combination with HCTZ enhances blood pressure control while minimizing metabolic side effects at lower doses. Overall, telmisartan is an excellent option for high-risk patients requiring both BP management and CV protection.
Losartan is beneficial for patients with diabetes and CVD, while CCBs are effective in reducing BP by relaxing blood vessels, and BBs are often used for patients with HF or arrhythmias.
References
World Health Organization. Global report on hypertension: the race against a silent killer. 2023 [Internet]. Available at https://www.who.int/publications/i/item/9789240081062
European Society of Hypertension. 2024 European Society of Hypertension clinical practice guidelines for the management of arterial hypertension. European Journal of Internal Medicine, 2024.
Peresuodei TS, et al. A Comparative Study of the Safety and Efficacy Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on the Management of Hypertension: A Systematic Review. Cureus, 2024.
Dézsi CA. The Different Therapeutic Choices with ARBs. Which One to Give? When? Why? Am J Cardiovasc Drugs, 2016.
Chen RJ, et al. Comparative First-Line Effectiveness and Safety of ACE (Angiotensin-Converting Enzyme) Inhibitors and Angiotensin Receptor Blockers. A Multinational Cohort Study. Hypertension, 2021.
Lacourcière Y, Krzesinskib J-M, Whitec WB, et al. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Pressure Monitoring, 2004.
Sharma AM, Davidson J, Koval S, Lacourcière Y. Telmisartan/hydrochlorothiazide versus valsartan/hydrochlorothiazide in obese hypertensive patients with type 2 diabetes: the SMOOTH study. Cardiovascular Diabetology, 2007.
Gosse P. A review of telmisartan in the treatment of hypertension: blood pressure control in the early morning hours. Vasc Health Risk Manag, 2006.
Professional Information. Telmisartan/Hydrochlorothiazide 40 mg/12.5 mg tablets. 2023 [Internet]. Available at: www.hpra.ie/img/uploaded/swedocuments/Licence_PA2315-107-001_12042023131159.pdf
Fogari R, et al. Effectiveness of hydrochlorothiazide in combination with telmisartan and olmesartan in adults with moderate hypertension not controlled with monotherapy: a prospective, randomized, open-label, blinded end point (PROBE), parallel-arm study. Curr Ther Res Clin Exp, 2008.
Kjeldsen SE, et al. Telmisartan and hydrochlorothiazide combination therapy for the treatment of hypertension. Curr Med Res Opin, 2010.
Weir MR, Bakris GL. Combination therapy with Renin-Angiotensin-aldosterone receptor blockers for hypertension: how far have we come? J Clin Hypertens (Greenwich), 2008.
Ferreira JP, Zannad F, Kiernan MS, Konstam MA. High- versus low-dose losartan and uric acid: An analysis from HEAAL. Journal of Cardiology, 2023.
Suzuki H, et al. Antihypertensive effectiveness of combination therapy with losartan/hydrochlorothiazide for ‘real world’ management of isolated systolic hypertension. Therapeutic Advances in Cardiovascular Disease, 2015.
Bulsara KG, et al. Amlodipine. [Updated 2024 Apr 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519508/
McEvoy JW, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. European Heart Journal, 2024.
