Research is ongoing into several new drugs for high blood pressure.
Blood pressure is a measure of the force with which blood is circulating in the arteries. Two pressures are measured – systolic (when the heart is contracting) and diastolic (when the heart relaxes). Blood pressure must be adequate to deliver oxygen and nutrients to vital body organs, and it changes in different situations – for example, blood pressure temporarily increases during exercise, and then returns to a resting level. A complex interaction of nerve and hormone feedback systems throughout the body control and adjust blood pressure levels as needed. Medical guidelines advise that resting blood pressure should be below 120/80 mmHg. Research has shown that higher resting pressures, although producing no symptoms in the short-term, increase the risk of heart disease, stroke, and kidney failure long-term.
High blood pressure affects around one-third of the global adult population
High blood pressure, or hypertension, affects around one-third of the global adult population and is a leading cause of premature death. In the majority of cases, there is no known underlying cause for hypertension. However, risk factors include family history, high-salt diet, sedentary lifestyle, obesity, smoking, or older age. Modifying risk factors where possible can reduce blood pressure to healthy levels, but many people who have hypertension will also need drug therapy.
Antihypertensive drugs target the body’s blood pressure control pathways to lower pressure. A diverse range of antihypertensive drugs are available, but hypertension remains poorly controlled worldwide. This may be partly due to patients not taking drugs correctly and regularly, but it may also be that the underlying mechanisms of hypertension are not fully controlled. Innovative therapies targeting different blood pressure control pathways are needed. Experts from the University of Paris, France, recently reviewed some new developments in antihypertensive drugs in the journal Hypertension.
Drugs for heart failure and diabetic kidney disease have antihypertensive effects
Developing unique antihypertensive therapies is difficult and costly, as these drugs need long-term testing. However, some drugs that have been developed to treat other conditions including heart failure and diabetic kidney disease have blood pressure-lowering effects, and these are being investigated for treating hypertensive patients.
Neprilysin inhibitors act on hormonal feedback systems to increase vasodilation (relaxing the blood vessels) and sodium excretion in the kidney. These drugs were developed for the treatment of heart failure, but when combined with angiotensin receptor inhibitors, which act on another target for blood pressure control, also have potential as antihypertensives. One such combination drug, sacubitril/valsartan, has undergone preliminary clinical trials, which show that it is safe and effective in the treatment of hypertension in the short-term. No long-term clinical outcome trial in hypertensive patients is currently planned, but ongoing trials in heart failure patients may give some insight into sacubitril/valsartan’s long-term safety and efficacy in treating blood pressure.
Soluble guanylate cyclase (sGC) stimulators promote various important cell and tissue functions in the cardiovascular system. One of the most potent effects is the stimulation of vasodilation. sGC stimulators are currently undergoing clinical trials in the treatment of heart failure. In animal studies, sGC stimulators reduced blood pressure, but so far there have been no trials in hypertensive patients. Whilst studies in healthy volunteers showed a reduction in blood pressure, trials in heart failure patients did not show any significant change in blood pressure – although these trials were not specifically designed to assess blood-pressure-lowering effects. Overall, data suggest that sGC stimulators may be effective antihypertensive drugs, but this requires further investigation.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase the excretion of glucose in the urine and are used to treat type 2 diabetes. These drugs have also been shown to have beneficial cardiovascular effects in diabetic patients, especially in reducing heart failure. The mechanism of action of SGLT2 inhibitors on the cardiovascular system is not fully understood, but may include a modest diuretic effect (increase in fluid excretion from the kidneys), weight loss, and reducing “stiffness” of the arteries. These drugs have been shown to have a blood pressure-lowering effect in diabetic patients, and may be particularly helpful in hypertensive diabetic patients to improve their cardiovascular prognosis.
Other new approaches to antihypertensive treatment
There is a growing understanding of some of the cardiovascular control pathways within the brain and this has allowed the development of innovative antihypertensives. Centrally acting aminopeptidase A inhibitors act within the brain to inhibit nerve and hormonal pathways and decrease blood pressure. Results of preliminary studies in hypertensive patients with the centrally acting aminopeptidase inhibitor firabastat have been encouraging, although further larger scale and comparative trials are required.
Hormones called endothelins are produced by the arterial lining cells. Endothelins constrict blood vessels and raise blood pressure. Endothelin overproduction has been implicated in hypertension and blood vessel disease of the heart, lungs, kidney, and brain. Endothelin receptor antagonists (ERAs), which block endothelin effects, have been investigated for treatment of hypertension, but unfortunately were linked to some severe side effects including liver injury. ERAs have been used in the treatment of pulmonary hypertension (a serious condition of high blood pressure in the lung blood vessels). More selective versions of ERAs are being investigated for the treatment of patients with resistant hypertension that cannot be controlled by other drugs. Assessing the long-term benefit/risk balance of ERAs will be key in future trials.
Personalized treatment program and improving adherence is important
Whilst there are many promising developments in antihypertensive drugs, evaluation of the efficacy and safety of new therapies is likely to take a long time. In the meantime, using existing drugs to develop a patient-personalized treatment program, improving treatment adherence, increasing access to healthcare, and reducing drug costs are all important issues in the challenge to lower the incidence of poorly-controlled and resistant hypertension.
Written by Julie McShane, MA MB BS
Reference: Azizi M., Rossignol P., Hulot J-S. Emerging drug classes and their potential use in hypertension. Hypertension 2019:74:1075-1083.
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