COMMENTARIES

The Metabolic Syndrome as the Cause of Hypertension: An Opportunity for Prevention

Bernard M.Y. Cheung, Ph.D., FRCP, Professor of Clinical Pharmacology and Therapeutics, Department of Clinical Pharmacology, University of Birmingham, U.K.

Please address correspondence to:
Professor Bernard M.Y. Cheung
Department of Clinical Pharmacology
University of Birmingham
Birmingham B15 2TH
U.K.
Tel: (+44) 0121 4146874
Fax: (+44) 0121 4141355
Email: b.cheung@bham.ac.uk

The metabolic syndrome is characterized by several features, including abdominal obesity, dyslipidemia (elevated triglycerides and reduced HDL-cholesterol), elevated blood glucose, and elevated blood pressure [1,2]. It is found in 34% of men and 35% of women in the United States [3,4]. Although the metabolic syndrome is a new disease entity [5,6], recognition of its importance is increasing because it is a predictor of cardiovascular disease and the development of diabetes [7,8]. The syndrome is also associated with other markers of coronary disease risk, such as increased serum levels of apolipoprotein B, small dense low-density-lipoprotein (LDL) particles, C-reactive protein, and plasminogen activator inhibitor 1 (PAI-1).

          Elevated blood pressure is a component of the metabolic syndrome in both the National Cholesterol Education Program Adult Treatment Panel III and International Diabetes Federation definitions of the syndrome [1,2]. When the characteristics of people who develop hypertension are compared with those who do not, waist circumference, plasma glucose, triglycerides, and HDL distinguish between the two groups [9]. This is because these factors cluster with hypertension in the general population and provide the rationale behind the metabolic syndrome [10]. Although there are many secondary causes of hypertension, in the majority of people with hypertension in the general population, apart from age, obesity is the major etiological factor [11]. Thus, the common form of hypertension seen in the majority of patients may in fact be part of a wider syndrome comprising also obesity, diabetes, and dyslipidemia.

          Indeed, hypertension and type 2 diabetes overlap so much that they may be regarded as different manifestations of the metabolic syndrome [12]. Other than the baseline blood pressure and glucose, there are hardly any other significant factors that predict whether the obese person is going to develop hypertension or diabetes. This is also borne out in some genetic studies; we and others have reported that there are a number of gene polymorphisms associated with hypertension that are also associated with diabetes [13,14].

          Not only is the metabolic syndrome a predictor of diabetes and cardiovascular events, it also predicts the future development of hypertension [9]. In contrast, hypertension is not a good predictor of the development of the metabolic syndrome [15]. This suggests that the metabolic syndrome may come earlier than hypertension in the chain of events, and the two are causally related. A person with obesity is prone to develop hypertension, abnormalities in glucose, and lipids, whereas a person with hypertension alone may not necessarily go on to have obesity, diabetes, and dyslipidemia. It appears that obesity develops first, followed by elevated triglycerides and/or reduced HDL; development of what we define as hypertension and diabetes comes later.

          However, we are not sure about the mechanism by which obesity raises blood pressure [11,16,17]. Generalized obesity increases oxygen and perfusion requirements, and so the cardiac output rises. Abdominal obesity can increase peripheral vascular resistance, probably through activation of the sympathetic nervous system and the renin-angiotensin system [11]. High leptin levels can activate the sympathetic nervous system via the pro-opiomelanocortin pathway [16]. Adipose tissues secrete angiotensinogen and aldosterone-releasing factors that activate the renin-angiotensin system [17]. Furthermore, compression of glomeruli and decreased response to natriuretic peptides aggravate the sodium retention and shift the pressure-natriuresis curve [11]. In time, structural changes such as endothelial proliferation, hyaline deposition, and glomerulosclerosis, occur in the kidney. When renal function starts to decline, a vicious cycle develops.

          If obesity raises blood pressure through multiple mechanisms, then the point of intervention needs to be earlier in the cardiovascular continuum [18]. Rather than viewing hypertension and diabetes as risk factors and precursors for “actual” diseases like myocardial infarction, stroke, and renal failure, hypertension and diabetes should perhaps be regarded as complications of the metabolic syndrome.

          However, apart from lifestyle changes, there is no widespread agreement on how the metabolic syndrome should be treated. A large part of the difficulty is conceptual; there are many who feel that the concept of the metabolic syndrome is redundant [19,20]. What is widely accepted is the need to initiate lifestyle changes in individuals with prehypertension and prediabetes. There are enough studies in the literature to suggest that early lifestyle intervention helps to prevent the progression to diabetes [21-23] and also helps to lower blood pressure to the extent that drugs are not required [24].

          Using drugs to treat prehypertension and prediabetes is controversial at present. The current definitions of hypertension and diabetes are based on thresholds that require treatment. This raises the question as to whether we are diagnosing them too late. There are some proof-of-concept trials in this regard, using an angiotensin receptor blocker to delay the development of hypertension [25], and using metformin, acarbose, or even insulin to prevent diabetes [21,26,27].

          Another reason to take the metabolic syndrome seriously is the recent realization that the metabolic syndrome may be less benign that previously assumed. In addition to coronary heart disease, diabetes, and hypertension, it is also associated with many of the commonest diseases in the general population. These include a nine-fold risk of sleep apnea [28], a five-fold risk of chronic renal failure [29], a three-fold risk of non-alcoholic fatty liver disease [30], a six-fold risk of colorectal cancer [31], and a three-fold risk of carcinoma of the breast [32] and uterus [33]. The metabolic syndrome is not benign and increases mortality [34,35]. Just as a breast lump or a colonic polyp cannot be met with inaction, the metabolic syndrome demands action.

          In the United States, blood pressure and cholesterol show an encouraging downward trend [36,37]. Although control of risk factors among people with diagnosed diabetes is improving [38], there is an underlying increase in obesity, the metabolic syndrome, and diabetes [3]. Furthermore, many hypertensive American women have the metabolic syndrome [39]. In the 1980s, smoking, hypertension, and hypercholesterolemia were the three leading coronary risk factors. As efforts to address those are bearing fruit, the new target is obesity and the metabolic syndrome, which come earlier in the cardiovascular continuum. Success in overcoming this new challenge would require the same magnitude of resources as those that have gone into the control of smoking, hypertension, and hypercholesterolemia.

 

Conflict of interest

 

None

References

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