The Promise of
Genomic Drugs for Global Hypertension
1Joseph Kurantsin-Mills, Ph.D. and J. 2Kweku Laast, M.D., MPH
1Kriger
Research Group International,
Correspondence: Dr. J. Kurantsin-Mills E-mail: josephkurantsinmills@yahoo.com
J. Kurantsin-Mills is an Associate
Research Professor at the Dept of Medicine, and the Dept of Pharmacology and
Physiology, The George Washington University Medical Center, Washington, DC. He
is also in the professional clinical research program at Kriger Research
Group International,
Acknowlegements: The authors are grateful to Dr.
Nicholas Pimlott, Sunnybrook and Womens’s
Abstract
The global burden of essential hypertension and its associated cardiovascular diseases is enormous. The World Health Organization estimates that the worldwide prevalence of hypertension is approximately 600 million people and growing. The recognition that early vascular biochemical markers of hypertension are often present before a sustained elevation of blood pressure has lead to a revision of its definition, and also the promise of intervention at an earlier stage of the condition. The new definition deemphasizes the use of numerical limits of blood pressure that are the standard and useful for making treatment decisions, and recognizes hypertension as a progressive cardiovascular syndrome arising from complex and interrelated etiologies. Current antihypertensive therapy is designed to reduce the risk of end-organ damage involving the cardiovascular, cerebrovascular, heart, and renal events. This entails the use of combination therapy relating to the use of four classes of medication (usually following a thiazide diuretic): beta blockers; angiotensin-converting enzyme inhibitors; angiotensin-II receptor blockers; and calcium channel blockers. There is now ample evidence that our genetic constitution plays a role in our predisposition to hypertension. Considering that current anti-hypertensive drugs are effective in only about 50% of patients, the need for novel drugs targeted to specific populations cannot be overstated. The emergence of pharmacogenomics should lead to novel drug development which targets appropriate genes responsible for hypertension in different populations. The development of novel anti-hypertensive drugs based on pharmacogenomics would therefore require a partnership of the pharmaceutical industry with academia and government research laboratories to expedite the transfer and translation of basic molecular research into applied pharmaceutical science. Given that global antihypertensive drugs sales are forecasted to grow to $50 billion by 2009, this joint venture should eventually yield incredible profits for all partners. The potential benefits of such gene-targeted therapy would be significant worldwide.
Introduction
Hypertension is classified by etiology as either primary (essential, idiopathic) or secondary. Primary hypertension accounts for 90-95% of hypertension, while the remaining 5-10% of cases is the result of secondary hypertension. Primary hypertension is a persistent elevation in blood pressure that is considered to be higher than optimal (<120/<80) or normal (120-129/80-84). Clinically hypertension is a systolic blood pressure equal to or greater than 140 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg as recorded during two or more readings on two or more occasions (office visits). Its global prevalence rises with age, regardless of the type of blood pressure measurement and the population used for diagnosis. In both economically developed and developing countries primary hypertension affects 25% to 35% of the adult population, and up to 60–70% of adults beyond their seventh decade of life. During the past few decades, hypertension prevention programs implemented in industrialized countries have been undermined by the remarkable increase in obesity, diabetes and the associated premature cardiovascular disease in these countries. In the developing countries the increase prevalence of hypertension can be explained on the basis of current socio-demographic changes in urban centers and other interrelated cardiovascular risk factors. Furthermore, in developed countries there has been an increased prevalence of hypertension among the younger population during the past three decades due to over-consumption of unhealthy high caloric diets resulting in obesity (1). In this paper we review the global prevalence of primary hypertension and the proposed revised definition of the condition that recognizes it as a progressive cardiovascular syndrome arising from complex and interrelated etiologies. We also discuss the emergence of pharmacogenomics which will likely impact the current management and treatment of primary hypertension in different ethnic populations, by including the genotypic profile of the patient in the treatment.
Definition of hypertension
Physiologic blood pressure levels (~120/80mm Hg), as a quantitative trait, are homeostatically regulated through multifarious interactions of environmental, phenotypic and genotypic factors. Hypertension or high blood pressure may be transient or persistent. Transient rises in systolic pressure occur as normal physiologic adaptations during physical activity, emotional upset or fever. Persistent or chronic hypertension is indicative of increased peripheral resistance, homeostatic imbalance, and the emergence of a disease process. Persistent hypertension is also a major cause of heart failure, vascular disease, renal failure, and stroke. Hypertension is defined physiologically as a condition of sustained arterial blood pressure of 140/90 mm Hg or higher. The higher the blood pressure the greater the risks for serious cardiovascular complications. About 90% to 95% of hypertensive patients have essential or primary hypertension, with no underlying identifiable clinical indication making it challenging for clinicians (2). Secondary hypertension, which accounts for 5% to 10% of all cases, is due to identifiable disorders in specific organs and tissues such as the renal, endocrine, cardiovascular, neurological systems. Treatment for secondary hypertension is usually directed towards correcting the causative clinical complication (3).
Although the numerical definition of hypertension stated above is currently used in clinical practice, at the 2005 annual meeting of the American Society of Hypertension (ASH) in San Francisco, CA, a new definition for primary hypertension was unveiled by the Society (4). The new definition deemphasizes the use of numerical limits that are the standard for making treatment decisions and recognizes hypertension as a progressive cardiovascular syndrome arising from complex and interrelated etiologies. Under the new definition, patients are divided into categories of normal (normotensive) and Stages 1 to 3 hypertensives:
· Normal individuals have normal blood pressure, loosely defined as a systolic pressure of 115 mm Hg and a diastolic pressure of 75 mm Hg, no identifiable cardiovascular disease or risk factors for cardiovascular disease, no early disease markers, and no apparent end-organ damage.
· Stage 1 Hypertension involves patients with occasional or intermittent increases in blood pressure or early cardiovascular disease, several risk factors, the presence of early markers of disease, but no target-organ damage.
· Stage 2 Hypertension involves patients with sustained blood pressure elevations or progressive cardiovascular disease, many risk factors overtly present, detectable markers of disease, and early signs of target-organ disease.
· Stage 3 Hypertension involves marked and sustained blood pressure elevations or advanced cardiovascular disease, many risk factors overtly present, progressive disease markers and end-organ disease present.
The revised definition of hypertension recognizes the fact that there are detectable early biochemical markers of the syndrome that are often present before blood pressure elevation is sustained. Therefore hypertension cannot be classified solely by discrete blood pressure numerical thresholds. Progression is strongly associated with functional and structural cardiac and vascular changes and abnormalities that damage the heart, kidneys, brain, microvasculature and other organs, and can lead to premature morbidity and death. Dr. Giles, ASH president, also reported that the new definition is not a guideline for treatment. However, physicians must educate patients to understand that management and treatment of hypertension requires attention to several specific details related to the patient other than just a number (4).
This rationale supports the proposal
by Jackson and colleagues from
Etiology and Pathogenesis
Essential hypertension has no clearly defined etiology. Current evidence suggests that the disease is caused by varying combinations of many factors. Essential hypertension patients do not present any one, or a specific combination of suspected etiologic factors. The following factors are recognized as associated risks and probably all contribute significantly to the etiology and pathogenesis of hypertension (7, 8, 9, 10):
Heredity: Heredity is a predisposing factor, but the exact mechanism is unclear. Children of hypertensive parents are twice as likely to develop hypertension as children from normotensive parents. Estimates of the hereditary predisposition to hypertension are generally based on complex biometrical assumptions and Mendelian mechanisms of inheritance. Population-based studies show correlation coefficients between relatives, normally in the range 0·1–0·3. Parent-offspring correlations are smaller than those among siblings.
Diet: Dietary factors that contribute to hypertension include high sodium, saturated fat, and cholesterol consumption, and deficiencies in certain metal ions (K+, Ca2+, Mg2+).
Intracellular sodium: Elevated intracellular sodium and calcium levels in blood cells (as a result of abnormalities in sodium/potassium exchange or other sodium transport mechanisms) may possibly explain an increase in vascular smooth muscle tone seen in hypertension. Also, an inability of the kidneys to excrete normal sodium load results in an increased plasma volume.
Stress: Stressful environmental factors in modern society seem to affect genetically susceptible individuals, particularly those with labile blood pressure regulation.
Plasma renin activity: Plasma renin activity is usually normal in patients with primary hypertension but is suppressed in about 25% of patients and elevated in about 15% of them. Hypertension is more likely to be accompanied by low renin levels in people of African descent and the elderly. The accelerated (malignant) phase of hypertension is usually accompanied by elevated plasma renin activity.
Microcirculation: Deficiency of a vasodilator substance rather than excess of a vasoconstrictor (e.g., angiotensin, norepinephrine) in the microcirculation may cause hypertension. The kallikrein system, which produces the potent vasodilator bradykinin, is currently being investigated. Endothelial cells produce potent vasodilators (nitric oxide, prostacyclin) and the most potent vasoconstrictor, endothelin. Therefore, dysfunction of the endothelium could have a profound effect on blood pressure, and is currently being investigated.
The Mosaic theory: The mosaic theory states that multiple factors sustain elevated blood pressure even though an aberration of only one was initially responsible; e.g. the interaction between the sympathetic nervous system and the renin-angiotensin-aldosterone system (11, 12). Sympathetic innervation of the juxtaglomerular apparatus in the kidney releases renin; angiotensin stimulates autonomic centers in the brain to increase sympathetic discharge. Angiotensin also stimulates production of aldosterone, which leads to sodium retention; excessive intracellular sodium enhances the reactivity of vascular smooth muscle to sympathetic stimulation (12).
Global Prevalence of Essential
Hypertension
A number of published studies by the National Heart Lung and Blood Institute
(NHLBI), NIH, The British Heart Foundation (2004), The American Heart
Association (2004), and the National Health and Nutrition Examination Survey
III, (1988-94) estimate that 58 million Americans have hypertension or receive
treatment for hypertension. This represents approximately 217 per 1000 of the
total population, a prevalence rate is approximately 1 in 5 or 18.5% of the
population (NHIS95). It is estimated that another 30% (approximately 1 in 18 or
5.51% or 15 million people) are undiagnosed. Furthermore, a 2000 study reported
that 32% of non-institutionalized adults over 20 had hypertension in the
The
International Collaborative Study of Cardiovascular Disease in ASIA
(InterASIA), conducted in 2000-2001, used a multistage cluster sampling method
to examine prevalence of hypertension in a nationally representative sample of
15,540 adults, age 35 to 74 years in China (17, 18). Hypertension was defined
as a mean blood pressure ≥ 140/90 mm Hg, and/or use of antihypertensive
medications. Overall, 27.2% of the Chinese adult population age 35 to 74 years,
representing almost 130 million persons, had hypertension. Among these hypertensive
patients, only 44.7% were aware of their high blood pressure, 28.2% were taking
antihypertensive medication, and 8.1% achieved blood pressure control
(<140/90 mm Hg). Figure 1 summarizes the prevalence of undiagnosed hypertension
in the economically industrialized countries (G-8) of the world. (13, 14, 15,
16, 17). It is apparent from the figure that the
A recent
systematic review of the prevalence of hypertension from 41 cross-sectional
surveys in different regions of the world conducted by Dr. Kearney and
colleagues at
Figure 1: Estimated prevalence of diagnosed hypertension in the G-8 industrialized nations.
The review sampled representative
data from 7 world regions based on the classification of the World Bank (20, 21):
countries with established market economies; former socialist countries of
Europe; Latin America, and the Caribbean; China; India; the Middle East
crescent; other Asia and islands; and sub-Saharan Africa. The authors based their calculations on data
from 18 national and 12 regional multisite surveys of hypertension (defined as
systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg. The review found that the prevalence of
hypertension varies widely around the world, with the lowest prevalence in rural
In
economically developed countries, the prevalence of hypertension is 20% to 50%.
In the
In men,
hypertension prevalence was highest in the Latin American and
The
WHO estimates that the worldwide prevalence of hypertension is approximately
600 million people (Cardiovascular Diseases, Prevention and Control, WHO,
2001-2002). In
Figure 2: Prevalence of Hypertension (140/90 mmHg or treatment) in Populations of African and European Descent; Ages 35–64. The data have been age-adjusted for comparison. (Data from Cooper et al; BMC Medicine 2005; http://www.biomedcentral.com/1741-7015/3/2) (ref 22)
______________________________________________________________________________
Genomics of Essential
Hypertension
The heritability of hypertension supports the concept that there is a genetic basis for hypertension-associated target organ diseases. The promise of genomic drugs is indicated by candidate genes for drugs that decrease blood pressure such as those in the renin–angiotensin system, {e.g. angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1)}. Plasma AGT is significantly elevated in patients with the AGT T235 allele and serum ACE is significantly higher in subjects with the ACE D allele (23, 23a). The 17 human genes that cause Mendelian forms of either hypertension or hypotension include gene products such as α-adducin (ADD1) and 3-subunit of G-protein (GNB3). ADD1 may affect blood pressure by modulating renal tubular reabsorption of sodium through the activation of Na+, K+-ATPase with the 460W allele exhibiting higher affinity for the Na-K-ATPase (23, 23a). For example population based studies of African-Americans and Caucasians with hypertension found that the 825T allele of the gene encoding the β3-subunit of G-proteins was equally predictive in men and women for greater systolic and diastolic blood pressure responses to a standard dose of hydrochlorothiazide. The possible association of this polymorphism with differences in blood pressure response to diuretic therapy was suggested by increased frequency of the 825T allele in those subjects with low plasma renin activity. Although the 825T allele was more common among African-Americans than the Caucasians, the observed association between increasing number of 825T alleles and the progressively greater blood pressure responses to the diuretic was present in each race-gender subgroup except African-American females.
In other studies variation in the gene encoding the cytoskeletal protein α-adducin was found to be associated with essential hypertension among Italians as well as antihypertensive responses to both acute and chronic diuretic therapy with furosemide and hydrochlorothiazide, respectively. Alpha-adducin appears to play a role in the regulation of signal transduction and activity of the renal tubular sodium-potassium ATPase. In both therapeutic protocols, the average blood pressure reduction was more than two times greater in heterozygotes carrying the variant Trp460 allele of a-adducin than in homozygotes for the wild-type Gly460 allele. The study concluded that polymorphic variation in the α-adducin gene may help to identify a subset of "salt-sensitive" hypertensive patients who are more responsive to diuretic therapy, because the underlying mechanism of their hypertension may involve enhanced renal tubular sodium reabsorption and venous volume expansion. This study demonstrates the significance of genomic predictors of drug response as can be related to pathophysiologic inferences based on known mechanism of action of the drug.
Genes associated with blood pressure regulation were also identified by genome-wide scanning of chromosomal sites in African, Caucasian, and Chinese families (Table 1). All these studies emphasize the importance and potential of genome scanning studies and the opportunity for the development of novel antihypertensives based on the genetics of the population or ethnic groups (23, 24 -37).
Blood pressure levels as a quantitative trait are regulated by the complex relationship between phenotype and genotype; that is the intricate interrelated processes of different gene expressions that influence cardiac output and peripheral vascular resistance. Many genes might influence the same phenotype, or a single mutation may be associated with asymmetrically dysfunctional phenotypes. Hence hypertension as a multigenic quantitative trait may not easily fit into Mendelian models of heredity or the biometrical assumptions that reduce the variableness into genetic and environmental factors, because it differs according to race, age, dietary salt intake and tolerance, hormonal milieu, or inter-individual variability (2, 5, 6, 23a).
Table 1*: Genome-wide
scans showing chromosomes with one or more genes that influence blood pressure
regulation and suggesting evidence of gene linkage.
|
Ethnic Sample |
Chromosomes carrying genes linked to systolic blood
pressure |
Chromosomes carrying genes linked to diastolic blood
pressure |
Chromosomes carrying genes linked to hypertension |
Authors of study |
|
White families |
1, 2, 3, 4, 5, 6, 7, 8, 10,
12, 14, 15, 17, 18, 19, 21, 22, |
2, 8, 17, 18 |
1, 2, 7, 13, 15, 17, 19 |
Levy, et al. 2000, (24) Rice, et al, 2000, (25) Hsueh, et al. 2000,
(26) Atwood et al.,2001,(27) Cheng,
et al. 2001, (28) Hunt, et al., 2002, (29) Angius,et al.,2002, (30) |
|
White sibling pairs |
|
|
11 |
Sharma,et al.,2000, (31) Perola, et al., 2000, (32) |
|
Chinese sibling pairs |
2, 3, 4, 7, 11, 16, 17, 20 |
7, 10, 12, 20, 21 |
2 |
Xu et al., 1999, (33) Zhu, et al., 2001, (34) |
|
Blacks families |
2, 3, 4, 6, 7, 9, 11, 19 |
1, 2, 3, 5, 7, 8, 10, 19 |
|
Cooper et al.,2002, (35) |
*Adapted from Turner, ST and Boerwinkle E, Pharmacogenomics, 4 (1):
53-65, 2003 (ref 23). Numbers in brackets are listed in the references.
Several specific gene defects have been linked to susceptibility for hypertension, most of which control the expression of proteins involved in the renin-angiotensin-aldosterone-axis or endothelial cell function. However, the evidence is particularly strong for linkage of the angiotensinogen gene (38). This gene probably codes for a family of different proteins that participate in the regulation of the renin-angiotensin-aldosterone-axis, not simply the protein structure for angiotensinogen present in the plasma.
The inheritability
of systolic blood pressure level among 1266 individuals in 278 non-Hispanic
white pedigrees (that is, the proportion of inter-individual variation
attributable to genetic differences among individuals) was estimated to be 0.37
(39). Similar values have been reported for diastolic blood pressure level (40).
Contemporary genetics research has advanced from the general recognition of the
involvement of genes in disease processes to identifying and characterizing
specific contributing genes and gene variants. Furthermore, multiple genes
potentially influence inter-individual differences in blood pressure, and the
complexity of blood pressure regulation suggests that there is substantial
genetic heterogeneity. There is genetic linkage and association between marker
loci and candidate genes that potentially influence blood pressure level. For
example, both Jeunemaitre and colleagues (41) and Caulfield and colleagues (42)
reported positive linkage between variants at the angiotensinogen gene locus
and a gene contributing to essential hypertension. Jeunemaitre followed up this
linkage result with an association study between several variant loci in the
angiotensinogen gene and essential hypertension (41). Specifically, the
frequency of an M
T
substitution at codon 235 of angiotensinogen was associated with essential
hypertension in 2 separate samples. The associations between the
angiotensinogen gene polymorphism and essential hypertension have been verified
by some (43, 44) but not by others (45). It is generally believed that the
original association attributed to the M235T polymorphism was due to its
linkage disequilibrium with a polymorphism at position -6, which is now known
to influence transcription levels of the AGT gene (46, 47, 48, 49). These
studies suggest that epigenetic mechanisms (such as DNA methylation and histone
modification) contribute to the variability that is observed in the genetic
linkages and associations whereby trans-differentiation of specialized
cardiovascular cells can undergo changes in their function resulting in
different expression of proteins controlling the processes that cause essential
hypertension.
Antihypertensive Pharmacogenomics
Current antihypertensive therapy is designed to reduce the risk of end-organ damage involving the cardiovascular, cerebrovascular, heart, and renal events, and entails the use of combination therapy that utilize four classes of medications (usually following a thiazide diuretic): beta blockers; angiotensin-converting enzyme (ACE) inhibitors; angiotensin-II receptor blockers; and calcium channel blockers (CCBs). All antihypertensive drugs are generally safe and reasonably well tolerated, except for the poorer response of Africans or African-Americans to ACE inhibitors. However, each has specific adverse effects requiring patient monitoring (2, 50). The inherited genetic variations and mechanisms that determine and affect an individual’s pharmacokinetic and pharmacodynamic responses will eventually be used in drug design and development. Pharmacokinetic mechanisms determine the levels of the drug in the blood and ultimately at its target cell. These include drug absorption, distribution, excretion, and metabolism. Mechanisms that determine the fate of the drug itself are distinguished from pharmacodynamic mechanisms that regulate the interaction of the drug with its target cells, and the subsequent biochemical reactions and pharmacological responses that ensue. Genetic variation that alters the structure, configuration, or quantity of any of the proteins involved in any of these biochemical mechanisms may contribute to inter-individual variation in drug response (51). For example, N-acetyl transferase 2 (NAT2), is the enzyme involved in the detoxification of many carcinogens and the metabolism of many common drugs. NAT2 variants are (a) slow acetylators, and (b) rapid acetylators. Among the slow acetylators are 14% East Asians; 34% African Americans, and 54% Caucasians. Thus, the drug isoniazid used to treat tuberculosis is metabolized and inactivated by acetylation. Therefore, the capacity of individuals to metabolize the drug is dependent on their genotype at the NAT2 locus (51).
Knowledge of genes that influence the pharmacodynamic determinants of blood pressure response to antihypertensive medications has the potential to provide new insights not only into molecular mechanisms that influence drug response, but also the role that these genes may play in determining inter-individual differences in blood pressure, the occurrence of hypertension, and antihypertensive therapy. Consequently, there has been major interest in identifying genes that influence the pharmacodynamic determinants of blood pressure response (51, 52). Currently, patient compliance with anti-hypertensives in each of the four classes of drugs is as low as 38% for thiazide diuretics and 64% for angiotensin II receptor antagonists (53).
The deciphering of the human genome has presented new opportunity for fresh ideas to reexamine antihypertensive therapy (54, 55, 56, 57). One of the main aims of clinical drug testing in connection with drug development is proof of pharmacological concept. This means that clinical scientists involved in the drug design and development seek to verify that candidate drug do indeed possess the properties indicated by preclinical research. However, clinicians have known about variable response of individual patients to different types of anti-hypertensive drugs for many years. African subjects poorer response to ACE inhibitors compared to Caucasians is a case in point. However, the recent report of Dickerson et al. (58) describing 56 Caucasian patients (ages 22 to 51 years) with previously untreated essential hypertension revealed that even in this relatively homogenous cohort there was significant variability in response to the four main classes of anti-hypertensive drugs (diuretics, β-blockers, calcium antagonists and ACE inhibitors). Only 22 out of 56 (39%) individuals achieved the target blood pressure with their first drug, but this increased to 41 out of 56 (73%) when the best response was considered, supporting the concept of individual variability in anti-hypertensive response. This study illustrates the fact that common genetic variants may influence response to antihypertensive drugs but studies of polymorphisms have generally yielded conflicting results (59). Therefore the inclusion of pharmacogenomic studies in large clinical trials should clarify the potential role for genotyping in the treatment of patients with essential hypertension. In this regard, the recent announcement of novel drugs that inhibit specific proteins associated with the development and maintenance of hypertension by Speedel and Novartis (60, 61) and Myogen (62) (Table 2) is commendable.
Table 2: Novel antihypertensive drugs targeting
specific proteins associated with hypertension
|
Novel Drug |
Pharmacodynamic Target |
Clinical Trial |
Pharmaceutical Firm |
|
SPP630 and SPP635 |
Renin inhibitors; nanomolar
potency |
Human microdosing using AMS & preclinical studies with
transgenic rats that express the human genes for renin and angiotensinogen |
Speedel Experimenta ( |
|
SPP100 (Aliskiren) |
Renin inhibitor |
Phase III monotherapy in hypertension data; Phase II
combination therapy Diovan data |
Speedel & Novartis |
|
Darusentan |
Binds selectively to
endothelin A (ETA) receptor in preference to the ETB receptor |
Phase IIb trial completed. Planning Phase III with the FDA & EMEA |
Myogen, Inc. |
|
Caduet (dihydropyridine
amlodipine & atorvastatin |
The amlodipine
component inhibits the transmembrane
influx of calcium ions into vascular smooth muscle and cardiac muscle;
atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase |
Clinical studies completed;
Rx drug only |
Pfizer |
FDA:
The
Innovation: The statistics of global prevalence of hypertension summarized above, the rapidly developing understanding and insight into the genomics of hypertension provide an incredible opportunity for a fresh assessment of the approach used to design and develop antihypertensive drugs. In the future this work may help us determine the likelihood of an individual developing hypertension and target responsible genes for treatment (48, 49, 51, 52, 54). By genetically identifying the underlying cause, treatment could become more tailored to the individual, the family and even entire ethnic groups. In this regard the application of single-nucleotide polymorphisms (SNPs), and associated studies that utilize biallelic SNPs measured in biologically unrelated individuals not only are inherently more powerful but also would require fewer study subjects. Single nucleotide polymorphsims are the most common genetic variability in the human populations and they occur in both coding and noncoding regions of genes. SNPs leading to differences in coded amino acids are obvious candidates for altering protein structure and function. SNPs in the noncoding region close to the coding sequences are candidates for altering gene expression. Therefore such an approach will provide a practical study design for genetic analyses of many hypertension-related phenotypes, and also antihypertensive drug responses. In the not-too-distant future the screening and analysis of an individual’s genotype information will become a standard part of large clinical trials, especially those designed to assess novel target-specific drug for hypertension and the associated cardiovascular complications such as myocardial infarction, stroke, and progression of renal disease. Genotyping of study participants will then become a logical extension of the normal covariate information such as race, gender, age, height, and body fat, body size, etc. Such a routine clinical laboratory testing may reveal the effects of variation in known candidate genes as well as scanning the entire genome to identify loci harboring new genetic variants that influence blood pressure, development of target-organ complications, and responses to antihypertensive drug therapy (52, 54, 63, 64, 65).
Genes that influence the development and progression of hypertension, and genes that influence responses to antihypertensive therapy are therefore complimentary. New compounds in existing antihypertensive classes that are in R&D such as calcium channel blockers and angiotensin-receptor blockers together with developmental antihypertensive classes such as oral renin inhibitors, AGE crosslink breakers, endothelin antagonists, vasopeptidase inhibitors, neutral endopeptidase, and endothelin converting enzyme inhibitors, as well as new fixed-dose combination products may have to consider the genomic ramifications of the final product. This challenge would require significant investment and innovative partnership by the pharmaceutical industry with academia, government research laboratories. The effort should eventually yield incredible returns for all partners, benefit the patient, and reduce the disease burden on society.
Economics of antihypertensives: The total
world ethical pharmaceutical market grew by 7% in 1998 reaching a total of $302
billion. In 2001, the global
pharmaceutical industry was worth $364.2 billion, representing 12% growth over
2000. Furthermore, there are estimates that total pharmaceutical sales
worldwide amounted to $392 billion in 2001. The data cover approximately 90% of
all prescription drugs and certain over-the-counter products (63). Since the
growth is expected to increase at an annual rate of 8% over the next five to
ten years; the opportunity to develop novel drugs for hypertension cannot be
ignored (64, 65). The
The antihypertensive market has grown continuously as a result of increasing global prevalence of the condition and more aggressive treatment, even though treatment in most of the major markets is not optimum and requires significant improvement (69, 52) (Figure 3).
Figure 3: Percentage of patients whose hypertension (defined as <140/90 mm Hg) is controlled by various combination therapies in different countries. (Data from Wolf-Maier et al. 2004) ref 69
In 2003 antihypertensives generated $30 billion in revenue. Datamonitor forecasts that patents of the major brands will shape the future of the antihypertensives market until 2014, when the leading product, Norvasc, and the fastest growing class, the angiotensin-receptor blockers will both face challenge from generic brands. According to a recently published Datamonitor research (68) in 2005 the number of people with essential hypertension across the seven major markets reached 192 million, with this figure likely to rise to over 210 million by 2015. Meanwhile, sales of antihypertensive medications in 2005 reached $34.7 billion, an increase of 4.8% compared to 2004 sales. The angiotensin-receptor blockers lead much of the value and growth with sales of just over $11 billion, almost a third of the total.
Despite these remarkable sales, the antihypertensives market has not attracted drug developers because it is mature, with apparently poor growth prospects due, partly, to a widely used generic brands and a definite lack of innovation in research and development (R&D). A recent analysis of R&D activity within the antihypertensives market by Datamonitor revealed a common trend among pharmaceutical developers to squeeze as much profit out of existing products as possible (71, 72). As a result 40% of current R&D projects focus on fixed-dose combinations of currently marketed antihypertensives, either with other approved therapies or with various new chemical entities. This suggests that innovative strategies, based on pharmacogenomics, aimed at newer, more effective ways of treating this disease is not attractive to drug developers at the present time. It is plausible that the need to address risk factors beyond hypertension, in particular raised lipids, has led to a demand for combination therapies that can treat more than one risk factor at a time. Hence antihypertensive combinations, both with and without a statin, are likely to be common in the future. Obviously hypertension is only one link in the mosaic of cardiovascular risk chain. In this regard Pfizer’s Caduet, a combination of Lipitor (atorvastatin) and Norvasc (amlodipine) has gained significant commendations. The benefit of lipid lowering is beneficial, as is the possibility to increase overall patient compliance by offering a single-pill combination instead of an extra tablet.
Because most of the industry has resigned from novel drug development, innovation has been left to Novartis. Since 1994, when the angiotensin-receptor blockers were introduced as an innovation in the treatment of hypertension, very little originality has emerged in the field of antihypertensive R&D. However, in collaboration with Speedel Experimenta, Novartis will introduce aliskiren (Rasilez), a first-generation orally active renin inhibitor in 2007. Datamonitor projects that first year sales of Rasilez will be only $100 million rising to $1.4 billion by 2010. Global antihypertensive drugs sales are forecasted by Datamonitor to increase from $33 billion in 2004 to $50 billion by 2014 across the seven major markets, namely France, Germany, Italy, Japan, Spain, UK, and the US, with novel treatments and the market-leading angiotensin-receptor blockers delivering much of this value given the current prescription and usage rates (70, 71).
Conclusion
The etiology of essential hypertension is still elusive. The recognition that the underlying vascular biochemical dysfunction that precedes the rise in the numerical values of systolic and diastolic blood pressures must be incorporated in the management and treatment of hypertension provides new insight into the condition. Nonetheless, the current therapeutic approach to essential hypertension and its cardiovascular complications remains generic rather than specifically targeted to the patient’s genotypic profile. The present advances in pharmacogenomics will definitely result in innovative investigative methods for potential genotyping in the treatment of patients with hypertension. The enormous prevalence of hypertension on a global scale, and the opportunity to collect and analyze unprecedented amounts of genetic information through the human genome profiles will revolutionize our approaches to the evaluation, prevention, and treatment of hypertension and its associated target-organ diseases. Additionally there is need for novel drug design and development that will incorporate the known polymorphisms, or variations, in specific genes into clinical trials that measure blood pressure response to a medication or class of medications. This will allow clinicians to determine the patient’s course of therapy based on their genotypic profile.
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