Epidemiological and economic burden of metabolic syndrome and its consequences in patients with hypertension in Germany, Spain and Italy; a prevalence-based model

High blood pressure is a leading cause of death and disability causing 13.5% of the world's premature death and 6% of its disability. Half of all strokes and ischemic heart disease can be attributed to high blood pressure[1]. This situation shows no sign of abating. Obesity, a major risk factor for hypertension, has reached pandemic proportions [2] and research shows that around two thirds of the prevalence of hypertension is directly attributable to obesity[3]. Along with obesity, other independent cardiometabolic abnormalities, such as dyslipidaemia, hypertriglyceridaemia and glucose metabolism disturbances have also been found to cluster together. Such groupings of risk factors for cardiovascular disease in the same hypertensive individual occur together more often than would be expected by chance alone, giving rise to a clinical entity that has been termed metabolic syndrome (MetS)[4]. The syndrome has been shown to significantly increase the risk of cardiovascular disease, type 2 diabetes and mortality[5‐8]. In patients with hypertension it doubles the relative risk of cardiovascular disease[9‐11] and triples the relative risk of type 2 diabetes[12]. Moreover, the risk increases with the number of MetS components present[10, 13]. As there are 16 different conceivable combinations of risk factors that could be diagnosed as MetS not all can be weighted equally in terms of their impact on risk and for some combinations this increase in risk is controversial. However, what is known for sure is that the coexistence of hypertension disproportionately increases the risk of cardiovascular disease[14].

However, there is much debate as to whether MetS should be treated as a clinical entity in general practice or whether physicians should concentrate on treating individual risk factors. The primary purpose for diagnosing MetS in general practice is to identify patients who are at high long-term risk of developing cardiovascular disease and type 2 diabetes and who require lifestyle and/or pharmacological therapies to reduce this risk. Recent European guidelines on the management of patients with arterial hypertension consider those with hypertension and MetS as a special condition suggesting a different therapeutic approach compared to patients with hypertension alone[15]. Such recommendations are based on a number of evidence-based observations. In a position statement the European Society of Hypertension pointed out that in patients with hypertension and MetS the overall cardiovascular risk may be greater than the sum of its identifiable components and that MetS components are often defined by values lower than those defined in various individual risk factor guidelines which may lead to many patients with high cardiovascular risk not being identified[16]. They also point out that MetS risk factors are relatively easily identified in clinical practice.

The clinical utility of diagnosing MetS in general practice has been hampered by the inconsistency of the diagnostic criteria available. Some definitions appear to be better than others at identifying high risk patients in Europe. In studies using both the International Diabetes Federation criteria and those developed by the United States Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) a much higher prevalence of MetS was identified by the International Diabetes Federation criteria[17, 18] but these criteria led to much lower predictive power for coronary events than the ATP III criteria[19]. This suggests that currently the ATP III criteria are the most appropriate for European populations given that excessive over-diagnosing of the syndrome would subject the health service to unnecessary budget pressures.

Relatively little is known about the epidemiological burden of MetS in patients with hypertension in the general population in Europe. Using ATP III criteria, European population studies suggest that the prevalence is around 8% to 13%[20‐22]. The reported proportion of hypertensive patients that have MetS is wide-ranging. Population-based studies suggest the proportion is around 20% to 40%[20‐23]. Primary care studies report that a fifth and up to just over a half of hypertension patients can be diagnosed with MetS[13, 17, 24‐27].

No studies have assessed the economic burden of MetS in patients with hypertension. In order to fill this gap this study aims to model the health care costs of hypertension in three European countries (Germany, Spain and Italy) in 2008 and 2020 and to assess how the consequences of MetS in terms of associated type 2 diabetes and the increase in cardiovascular events impacts on this economic burden.

The results of this modelling study suggest that the presence of MetS in patients with hypertension significantly inflates the cost of illness due to the increase in cardiovascular events and cases of type 2 diabetes. These costs rise incrementally with the additional number of MetS components present. In Germany hypertensive patients with MetS account for over 60% of all hypertensive patients and contribute to 80% of the costs. In Spain and Italy they account for nearly a quarter of the hypertensive population and contribute to nearly half of the costs. The much higher prevalence in Germany can be explained by the country having one of the highest rates of abdominal obesity in Europe[47]. Mean annual costs per patient for those with MetS are two to three times higher than for those without. Antihypertensive drug costs make up less than 10% of overall costs of care in this high risk patient group with the management and treatment of cardiovascular events and type 2 diabetes accounting for the majority of costs.

These costs are set to rise in the future as the proportion of the population over the age of 50 years grows and the prevalence of the components of MetS increases. The most prevalent component of MetS in patients with hypertension is abdominal obesity which has reached epidemic proportions in Europe and currently shows no sign of slowing down[48].

This study used a prevalence-based modelling approach to estimate cost-of-illness and therefore is subject to a number of assumptions. Although efforts were made to ensure the best sources of data available to date were used in the model, as the published literature in this area is still relatively limited and national databases do not provide all appropriate data required to estimate epidemiological burden [49], there were a number of data gaps. As with all models that require some assumptions to be made an element of caution is required when interpreting the results. The assumptions used in this model are described in detail elsewhere[28]. For example we used a United States database to develop our conditional probability matrix which provided data on the probability of hypertensive subjects having no other MetS components, one, two, three or four and the probability of each combination occurring in each age and sex group. These probabilities were applied to country-specific prevalence data to break-down individuals into each risk group. We have no reason to assume that such conditional structures would be different between the U.S. and the three European countries as the clustering of individual MetS risk factors is unlikely to be significantly different.

Our estimates of the economic burden of MetS in patients with hypertension are on the conservative side for a number of reasons. First, no data were available to distribute costs of antihypertensive medications across risk groups and therefore costs have been distributed evenly across each of the five risk groups. Data suggest that the quantity and type of antihypertensive medication does differ between those with and without MetS. Those with MetS use significantly more ACE-inhibitors and ARBs and in general use antihypertensive drugs significantly more frequently than those without the syndrome[17, 50]. A redistribution of costs accounting for this would not increase the overall drug costs, but would increase the proportion of drug costs that are attributable to MetS. Second, the number of cardiovascular events occurring in the population was predicted using data derived from a population initially free of cardiovascular disease (a proportion of the population had type 2 diabetes). The model therefore does not take into account the costs attributable to those hypertensive subjects with MetS and established cardiovascular disease, which would increase the total cost of illness. Finally, we only included healthcare costs in our model. Including costs relating to the loss in productivity due to morbidity or premature mortality would inflate cost-of-illness estimates by between 1.28 fold[51] and 10 fold[52]. Such wide estimates reflect the different methodologies used to calculate productivity losses.

Future prevalence estimates and costs are based on projected changes in the demographics of each country and the increase in prevalence of MetS components based on historical data trends. However, such forecasts do not take into account the potential impact of policy directives aimed at reducing the risk of developing one of the five MetS components. Future public health incentives will have an impact on future prevalence and costs however, these policies will be working against an increase in prevalence brought about by the aging population. The burden of illness in the future will therefore be dependent on how effective public health policies and guidelines are at preventing and treating MetS.

A handful of studies have assessed the prevalence of hypertension in patients with MetS, but none to date have assessed its economic impact. Previous population studies using ATP III criteria have shown that approximately 20% to 40% of the hypertensive population has MetS [20‐23] giving rise to a prevalence in the general population of hypertension and MetS of 8% to 14% [20‐22]. These estimates are similar to our estimates for Spain and Italy. Much higher estimates of the proportion of hypertensive subjects that have MetS are reported in primary care studies where the variation can be explained in part by the different sub-populations studied[13, 17, 24, 25, 27, 53].

This study has highlighted the additional resource implications of hypertensive patients with MetS and the need to manage these patients effectively according to European guidelines to reduce the risk of cardiovascular disease and type 2 diabetes. However, a previous European study reported that fewer than 30% of treated hypertensive patients had their blood pressure controlled to levels recommended by European guidelines and that uncontrolled hypertension was strongly associated with MetS[27]. Not achieving recommended target levels of blood pressure control leaves these patients with elevated levels of risk. The study highlighted the importance of considering the patient's entire cardiometabolic profile when considering appropriate treatment rather than focusing solely on blood pressure targets alone[27].

European guidelines advocate that appropriate management of patients with hypertension should be based on their blood pressure level and overall cardiovascular risk profile. Guidelines recognise that due to the different mode of action of these classes, some drug groups are likely to offer greater benefits to different subgroups of patients [15, 54, 55]. In a recent reappraisal of guidelines on hypertension management, they suggest that drug choice should take into account contraindications as well as favourable effects in specific clinic settings. The guidelines do not recommend specific drugs for the treatment of hypertensive patients with metabolic syndrome, but do point out that 'there is no doubt that beta-blockers and diuretics (especially when combined together) have adverse metabolic effects and facilitate new onset diabetes in predisposed patients such as those with metabolic syndrome or impaired glucose tolerance.' They go on to point out that there is still controversy over whether drug-induced new onset diabetes carries the same negative prognosis as naturally occurring diabetes [55]. In patients with diabetes the guidelines suggest that combination treatment is usually required and that 'a renin-angiotensin receptor blocker should always be included because of the evidence of its superior protective effect against initiation or progression of nephropathy.'

Evidence suggests that newer antihypertensive medications are associated with a reduced risk of incident diabetes[39] and that they are also associated with better adherence to therapy[38, 56, 57]. Although meta-analyses suggest antihypertensive drugs have a similar effect on reducing cardiovascular events [58], there is some evidence to suggest that newer antihypertensive medications may lead to a greater reduction in the risk of first hypertension-related cardiovascular or diabetic event [57]. In addition, it has been recently demonstrated that obese hypertensive patients under drug-based weight loss therapy show significantly better weight reduction and improvement of insulin resistance when treated with newer antihypertensive medications compared to the older blood pressure lowering drugs (beta blocker, diuretics)[59]. Of the newer antihypertensive treatments ARBs have been found to be associated with the highest level of adherence[38, 56, 57] and the lowest association with incident diabetes[39]. Furthermore specific ARBs have also demonstrated favourable metabolic effects not present in other ARBs or ACE-inhibitors[60].

Following such guidelines which recommend the aggressive management of these high risk patients with a combination of lifestyle interventions to treat the MetS components present in the hypertensive individual and to prevent the onset of additional components is likely to lead to a significant reduction in costs of care. Newer antihypertensives lead to better control of blood pressure in part brought about by better adherence, thereby reducing the risk of cardiovascular disease. They also reduce the risk of new onset type 2 diabetes. Such outcomes are associated with significant associated costs. Therefore, in patients with hypertension and MetS, some of the drug costs of newer antihypertensive medications will be balanced by costs saved from reducing these negative outcomes. The magnitude of these savings is likely to depend on risk group. Patients with hypertension and four other components of MetS will demonstrate greater reductions in the incidence of cardiovascular events and new cases of type 2 diabetes and their associated costs as a result of treatment with newer antihypertensives compared to patients with hypertension only. Cost-effectiveness studies, assessing long-term costs and outcomes, will be required to demonstrate the incremental costs and benefits of new versus old antihypertensives for patients with hypertension and MetS. Studies have already demonstrated the cost-effectiveness of ARBs and ACE-inhibitors in patients at increased risk of diabetes and heart failure[54].

The results of this study show that hypertensive patients with MetS are associated with higher costs of care compared to those without due to the increase in incident cardiovascular events and prevalent cases of type 2 diabetes. The resource implications of MetS rise linearly with each additional MetS component. This burden is forecast to rise in the future as a result of the aging population and an increase in the components of the syndrome. Prevention and appropriate treatment of MetS is likely to lead to a reduction in costs of care. Newer antihypertensive medications provide better control of blood pressure leading to reduced incidence of cardiovascular disease and type 2 diabetes. These benefits will be more marked in those hypertensive subjects who have a high number of MetS components clustered together. Following guidelines set out for this special group of patients, which advocate the use of newer antihypertensives, are likely to lead to longer-term economic benefits for the health service and quality of life improvement for patients.