The Concepts of Metabolic Syndrome and Cardiometabolic Risk
Cardiometabolic risk represents a situation where the possibilities of developing atherosclerotic cardiovascular disease and diabetes are significantly enhanced as a consequence of the presence of insulin resistance and atherogenic dyslipidaemia. Dyslipidaemia is characterised by the presence of low high-density lipoprotein (HDL) cholesterol and high triglyceride levels.1,2 Clinical diagnosis of this situation is through the finding of an enhanced waist circumference (>102cm in males and >88cm in females) accompanied by the above-quoted alterations in lipid profile (HDL cholesterol <40mg/dl in males and <50mg/dl in females plus serum triglycerides >150mg/dl).
Cardiometabolic risk is particularly prevalent in patients diagnosed as having metabolic syndrome (MS). For a correct diagnosis of MS, patients need an increased waist circumference, low HDL cholesterol and elevated triglycerides, the potential presence of blood pressure (BP) values >130/85mmHg and a fasting serum glucose >100mg/dl.3,4 The International Diabetes Federation (IDF) has defined MS in those of European descent by the presence of a waist circumference >94cm in males and >80cm in females, accompanied by two out of the four criteria that remain unchanged from the Adult Treatment Panel (ATP)-III definition5 (see Table 1).
How Frequent and Relevant Is the Metabolic Syndrome in the Hypertensive Population?
The prevalence of MS in the hypertensive population is very high. In a study of more than 19,000 hypertensive patients attending primary care centres in Spain, MS was present in more than 40% of subjects using the original ATP-III definition.3 This increased to 60% when the IDF criteria5 were applied.6
MS, and consequently increased cardiometabolic risk, are therefore very prevalent in the hypertensive population and need to be incorporated into a correct risk stratification to be carried out on every hypertensive patient. In fact, the European Society of Hypertension–European Society of Cardiology7 guidelines consider the concomitant finding of arterial hypertension and MS as a situation of high added cardiovascular risk. The reason for this is based on two factors. First, MS and the accompanying cardiometabolic risk result in a significant increase in cardiovascular morbidity and mortality in several population-based studies,8 as well as in hypertensive patients.9 Second, the presence of MS is accompanied by a three- to six-fold increase in the risk of developing type 2 diabetes.10
On the other hand, the presence of MS is accompanied by a significant enhancement in the risk of developing chronic kidney disease (albuminuria and/or a diminished estimated glomerular filtration rate [GFR]). The higher the number of components used for the definition of MS, the higher the prevalence of either microalbuminuria and/or an estimated GFR value <60ml/min/1.73m2.11
How Relevant Is the Development of Diabetes in a Hypertensive Population?
The development of new-onset diabetes and its relevance in people with hypertension has been widely considered.12,13 The type of antihypertensive therapy used, alone or in combination, is relevant in accelerating the development of diabetes. A network meta-analysis14 has shown that the best protection is obtained when angiotensin-receptor blockers (ARBs) and ACE inhibitors are used, while diuretics and beta-blockers occupy the last position when used in combination.
However, some authors have denied that the development of new-onset diabetes worsens the short-term prognosis of hypertensive patients, according to data from studies such as Systolic Hypertension in the Elderly (SHEP)15 and Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).16 It seems clear that devloping diabetes must be relevant to the patient’s long-term prognosis. In fact, it was shown with 2.5 years of follow-up in ALLHAT that the risk of new-onset diabetes was equal to that of patients entering the study known to have diabetes.17
How Should a Patient with Hypertension and Metabolic Syndrome Be Treated?
The aim of intervention in patients with MS and high cardiometabolic risk is to achieve an optimal reduction of such risk. Lifestyle modifications counteract the effect of underlying risk factors (obesity, physical inactivity and atherogenic diet). Moreover, patients with hypertension also require tight BP control, a choice of antihypertensive treatment that does not produce other metabolic disturbances and, quite often, parallel drug treatment for associated metabolic risk factors (dyslipidaemia, insulin resistance, pro-thrombotic and pro-inflammatory states).
Lifestyle interventions are obviously the first step in achieving cardiometabolic risk reduction. The key lifestyle interventions are the promotion of exercise and energy expenditure and reduction in weight with a calorie-restricted diet.18 The minimal requirements for long-term effectiveness include calorie restriction in the range of 500–1,000kcal/day with 7–10% weight loss in 12 months and regular aerobic exercise of 30–45 minutes daily.
Whereas extreme calorie-restricted or element-dissociated diets have no long-term advantages, more intensive exercise programmes have additional cardiovascular benefits and help to maintain weight loss. Lifestyle interventions clearly have beneficial effects on BP and lipid profile and reduce the incidence of new-onset diabetes.19 Moreover, recent data suggest a long-term effect on reduction in cardiovascular morbidity.20
Other lifestyle changes also have a beneficial effect on specific cardiovascular risk factors and must be encouraged in specific patients. Lowering salt intake and alcohol consumption has moderate BP-lowering effects, which are enhanced in conjunction with weight loss and increased exercise.7 In addition, a diet rich in fruits, vegetables and low-fat dairy products (the Dietary Approaches to Stop Hypertension [DASH] diet) substantially lowers BP in comparison with the standard American diet.21 The Mediterranean diet, which is equally rich in fruits, vegetables, fish and olive oil, also has a favourable impact on atherogenic dyslipidaemia in MS patients.22
Maintenance of lifestyle changes requires counselling and may prove difficult in the long term. For this reason, pharmacological treatment of BP, dyslipidaemia, insulin resistance and obesity will be required in order for most patients to reduce their cardiometabolic risk.23
As mentioned above, the European Society of Hypertension– European Society of Cardiology guidelines7 emphasise the importance of MS as an indicator of high added cardiovascular risk in patients with hypertension. The guidelines indicate early antihypertensive treatment if lifestyle measures are not enough to reach BP targets.
No comparative studies are available of the different antihypertensive drug classes in people with hypertension and MS. Considering the increased risk of developing new-onset diabetes in these patients as a component of cardiometabolic risk, the choice of antihypertensive treatment must take this additional risk into account. Some international guidelines recommend diuretics as the first-step therapy for hypertensive patients, without a compelling indication for other antihypertensive drug classes. However, it has been clearly established that diuretics increase the risk of new-onset diabetes compared with placebo by 23%.14 Conversely, calcium-channel blockers and, especially, renin–angiotensin system blockers (ARBs and ACE inhibitors) decrease this risk (33% with ACE inhibitors and 43% with ARBs). These differences are probably even more pronounced in the specific subset of patients with MS. Thus, it seems reasonable that primary antihypertensive treatment in patients with hypertension, MS and high cardiometabolic risk should focus on inhibition of the renin–angiotensin system with either ACE inhibitiors or ARBs.
Additional evidence can be derived from comparative studies of antihypertensive drugs that have included an important proportion of diabetic subjects, most of them also suffering from MS. In this regard, the Appropriate Blood pressure Control in Diabetes (ABCD) study24 compared antihypertensive treatment based on the ACE inhibitor enalapril or calcium-channel blocker nisoldipine in the subset of hypertensive patients with diabetes. The study was prematurely halted due to the differences in the number of myocardial infarctions that favoured enalapril in comparison with nisoldipine.
Patients with hypertension and MS, especially those with type 2 diabetes, are often resistant to the effects of antihypertensive drugs and may require drug combinations to achieve BP control. Although some studies have demonstrated the benefits of using diuretics in combination with ACE inhibitors25 or ARBs26 in patients with diabetes, two comparative studies (Anglo Scandinavian Cardiac Outcome Trial [ASCOT] and ACE Inhibitor plus Calcium-Channel Blocker Best for Reducing Clinical Events in Hypertensive Patients [ACCOMPLISH]) suggest that combining an ARB with a calcium-channel blocker could be a better option.
ASCOT27 compared antihypertensive treatment based on the calciumchannel blocker amlodipine with the addition of the ACE inhibitor perindopril in most patients against the beta-blocker atenolol with the addition of a thiazide diuretic, also in the vast majority of patients. The study was also prematurely ended due to a consistent benefit of the former therapeutic option. More than 5,000 patients with diabetes were included in ASCOT and a particular analysis of this cohort revealed that the benefits of the combination of amlodipine and perindopril were maintained in those with diabetes.28
The ACCOMPLISH trial29 also compared two combinations of antihypertensive agents in high-risk hypertensive patients. Patients were treated with either the combination of the ACE inhibitor benazepril and calcium-channel blocker amlodipine or with benazepril combined with hydrocholothiazide. The proportion of patients with diabetes in this study reached 60%. The main results revealed a 20% reduction in the primary end-point in patients treated with benazepril amlodipine combination. The primary end-point was the composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for angina, resuscitation after sudden cardiac arrest and coronary revascularisation. Subgroup analyses did not find heterogeneity of the results in subjects with or without diabetes.
There is no evidence to support a preference for ACE inhibitors or ARBs in the treatment of MS patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET)30 compared telmisartan with ramipril in patients at risk of cardiovascular events (one-third with diabetes). It found no difference in rates of cardiovascular events between the groups.
It has been hypothesised that the fact that some ARBs act as modulators of the nuclear receptor PPAR-gamma31 could be important in conferring additional metabolic benefits of these drugs. Comparative studies of telmisartan, an ARB with a more potent ability to stimulate the PPAR-gamma receptor, against losartan,32 irbesartan33 and eprosartan34 resulted in better metabolic outcomes, as measured by fasting glucose, insulin and lipids. In the ONTARGET trial, however, rates of new-onset diabetes were no different in ramipril- or telmisartan-treated patients.30
Non-hypertensive patients with MS usually have high to normal BP (systolic 130–139mmHg and/or diastolic 85–89mmHg). Specific dietary interventions, such as sodium restriction or the adoption of the DASH diet, in addition to calorie restriction and increased exercise, could be helpful. For patients with diabetes also receiving antihypertensive treatment, ARBs are able to prevent the development of microalbuminuria in normoalbuminuric patients35 or overt proteinuria in those with microalbuminuria.36 For the remaining patients, there is no evidence for antihypertensive treatment, except that development of hypertension is prevented.37
Other Drugs that Could Add Benefit in Patients with Metabolic Syndrome
ASCOT demonstrated that treatment with 10mg atorvastatin was effective in reducing cardiovascular events when hypertension was accompanied by three or more risk factors, including most contained in the definition of MS.38 However, typical dyslipidaemia in patients with hypertension and MS is characterised by low HDL cholesterol and increased triglycerides. Two classes of drugs reduce triglycerides and increase HDL cholesterol. These are nicotinic acid and fibrates. Although limited evidence is available, some post hoc analyses suggest a beneficial effect of these drugs in patients with MS.39,40 Other apparently promising alternatives, such as cholesteryl ester transfer protein inhibition, have recently been associated with increased mortality.41
In addition to lifestyle changes, treatment with metformin,19 acarbose42 and thiazolidindiones43 decreases the risk of new-onset diabetes in patients with impaired glucose tolerance. However, the long-term benefits of these drugs and a cost–benefit analysis have not been adequately addressed.
Abdominal obesity is one of the main components of MS and increased cardiometabolic risk. In addition to a calorie-restricted diet and increased exercise, two different pharmacological approaches are available for weight loss: sibutramine and orlistat. Sibutramine has demonstrated its superiority with respect to placebo in reducing weight and waist circumference. In patients with hypertension, sibutramine slightly increases BP and heart rate and should be used with caution.44 However, another trial suggests that the effects of sibutramine in patients receiving antihypertensive treatment largely depend on the type of antihypertensive drug used.45 Orlistat is an inhibitor of gastrointestinal lipases, especially pancreatic lipase. Its efficacy has been also proved, although the weight loss is usually less than that obtained with sibutramine. Orlistat has a favourable influence on lipids and glycaemic control, especially in patients with diabetes, although gastrointestinal tolerance is poor.46
More antiobesity drugs will be available in the very near future for incorporation in the treatment of patients with abdominal obesity. However, recent experience with the endocannabinoid receptor antagonist rimonabant has served as a lesson on the need to be cautious of the possible effects of potential new drugs.
A key feature of MS that explains increased cardiometabolic risk is an enhanced pro-thrombotic state, especially in the presence of insulin resistance. Post-prandial hyperglycaemia, increased free fatty acids and elevated triglyceride levels may all have adverse effects on platelets, coagulation and fibrinolysis.
Pharmacological interventions targeting these abnormalities have the potential to reduce thrombosis. Antiplatelet drugs, such as low-dose aspirin, have proved beneficial in patients with previous cardiovascular disease, but extension to other groups, including those with diabetes, is controversial.47 Efforts to control BP should be reinforced before the introduction of aspirin.
Although there are several areas of uncertainty with respect to the definition, usefulness and pathogenesis of MS, simple clinical tools exist that identify subjects at a higher risk of developing both type 2 diabetes and cardiovascular disease, and thus high cardiometabolic risk. The management of these patients is based principally on lifestyle measures, but various antihypertensive, lipid-lowering, insulin-sensitising, antiobesity and antiplatelet drugs could be helpful in reducing cardiometabolic risk.
This is particularly important in the hypertensive population. The presence of MS identifies individuals with high cardiometabolic risk who require an integrated therapeutic approach. Clinicians should consider the earlier use of antihypertensive drugs that do not increase the risk of type 2 diabetes, as well as other therapies that counteract the associated metabolic alterations present in every single patient.
Population-based strategies are clearly necessary to reduce the impact of underlying risk factors on cardiometabolic disease (obesity, physical inactivity and atherogenic diet). However, there is general agreement that earlier and more aggressive therapy is required to further reduce the risk of new-onset diabetes and cardiovascular disease, although evidence is scarce. Prospective, randomised trials addressing the effect of potentially beneficial treatments on cardiometabolic outcomes should be strongly encouraged.