Prevention of Hypertension Incidence and Diabetes Italian Assessment Study. Therapeutic Strategies of Prevention of Diabetes and Hypertension in Subjects With Metabolic Syndrome and High-Normal Blood Pressure.

1. Background and rationale

2. Evidence available Data obtained from observational studies have shown that subjects with hypertension have an increased prevalence of type II diabetes mellitus compared to normotensives, and that the association between diabetes and hypertension represents a markedly increased risk of cardiovascular disease (1). Also the recent overview of the Blood Pressure Lowering Treatment Trialists' Collaboration indicates that the risks for stroke, coronary events, heart failure, and cardiovascular death are about twice as large in hypertensives with diabetes than in hypertensives without diabetes, independently of absence of treatment or use of different antihypertensive regimens (2). On the other hand, a number of observational and randomised intervention trials has shown that antihypertensive therapy may increase the risk of developing new diabetes mellitus in hypertensives patients. This evidence has been reviewed and meta-analysed in several recent papers (3,4). In brief, of 13 large randomised trials of antihypertensive therapy, 12 have shown a greater incidence of new diabetes mellitus in the treatment arms using thiazide diuretics or beta-blockers (and often the two types of agent in association) than in the treatment arms based on angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) or calcium antagonists (CAs) (often with addition of thiazides and sometimes of beta-blockers) (3). Furthermore, a recent review analysed 48 groups of subjects without diabetes mellitus at the time of randomization in 22 clinical trials. 17 of such trials enrolled patients with hypertension, 3 enrolled high risk patients, and only 1 enrolled patients with heart failure. The primary outcome was represented by incident diabetes mellitus. Overall, the antihypertensive classes that were found to be associated with newly developed diabetes mellitus were, in increasing order, ACEIs, ARBs, followed by CAs and placebo (4). It is debated whether thiazide diuretics and beta-blockers are really diabetogenic, by exaggerating or accelerating the time-dependent tendency to develop diabetes, and whether ACEIs and ARBs are antidiabetogenic by retarding this normal trend, or simply lack the diabetogenic effect of thiazides/beta-blockers. The issue, of obvious clinical importance, can only be solved by placebo-controlled studies, but placebo-controlled studies are ethically difficult to be conducted nowadays when evidence favouring active treatment of hypertension and cardiovascular risk is overwhelming.

Nonetheless, data from a small number of placebo-controlled studies are available. The diuretic chlorthalidone, often associated with a beta-blocker, has been compared with placebo in elderly patients with isolated systolic hypertension in the Systolic Hypertension in the Elderly Program (SHEP) trial: when the current definition of diabetes was used (fasting glucose, FG, >=126 mg/dl), a significant higher incidence of diabetes was found in the actively treated group (13 vs 8.7%, p<0.0001) (5), a finding which substantiates the hypothesis that diuretic and beta-blocker therapy exaggerates the trend towards developing diabetes, i.e. has a diabetogenic effect. Placebo-controlled studies are also available concerning the effects of ACEIs and ARBs on diabetes onset. Unfortunately, in all these trials placebo groups were contaminated by administration of multiple therapies required for the control of the cardiovascular pathologies of the patients under study. In the Study on Cognition and Prognosis in the Elderly (SCOPE), concerning elderly patients with hypertension, the use of hydrochlothiazide and beta-blockers was more extensive in the so called "placebo" arm than in the active (candesartan) treatment arm, and may explain the higher incidence of diabetes in the placebo than the candesartan group (6). Likewise, in four large trials in which an ACEI or ARB were compared to placebo in patients at high cardiovascular risk because of coronary heart disease or heart failure, both the ACEI or the ARB and the placebo were given on top of multiple background therapies required by the severity of the diseases being investigated. Furthermore, little information is available from publications of these trials as to what extent background therapies were modified during the trials and whether these changes were balanced between the placebo and active treatment arms of the trials (see 3). Therefore the issue whether ACEIs and ARBs have an active antidiabetogenic action or simply lack the diabetogenic action of thiazides and beta-blockers remains undecided, and any claim that agents blocking the renin-angiotensin system exert an antidiabetogenic action appears unjustified. Prevention of the onset of diabetes, as well as of hypertension, and even more of the ominous association of diabetes and hypertension, remains, however, of primary public health concern, because of the morbidity burden represented by these ailments and the health care cost involved. Prevention must obviously be exerted before a disease develops, and is most effective in those subjects in whom the risk of developing the disease is high. Conditions predisposing to both hypertension and diabetes are well known. Individuals with so-called high-normal blood pressure (i.e., systolic blood pressure, SBP, 130-139,or diastolic blood pressure, DBP, 85-89 mmHg) have a 40% chance of becoming hypertensives (i.e.,SBP>=140 or DBP>=90 mmHg) over 4 years according to the Framingham Heart Study (7)and the initial findings of the Trial Of Preventing Hypertension (TROPHY, 8). High-normal BP together with impaired glucose tolerance (as indicated by fasting glucose, FG, >=100 mg/dl), abdominal obesity, a low HDL-cholesterol and high triglycerides are often found clustered in a large portion of populations both in USA and Europe, the cluster being commonly referred to as the metabolic syndrome (MS) (9). Independently of the current debate whether all manifestations of MS are due to a common pathophysiological mechanism (i.e., insulin resistance), it is undisputed that coexistence of high-normal BP, a raised FG and an elevated BMI is a very strong predictor of both hypertension and diabetes mellitus. 2. Knowledge effect Lifestyle changes (suitable diet and physical exercise) are known to be effective in preventing both hypertension (10) and diabetes (10-12), but whether addition of an ACEI or ARB may further reduce both conditions is unknown. Individuals with MS are ideal subjects for investigating whether agents blocking the renin-angiotensin system exert a real antidiabetogenic effect in addition to what can be achieved by non-pharmacologic measures, as there are no compelling medical indications for treating these subjects with other drugs that may confound interpretation of the findings. Therefore the PHIDIAS trial plans to study a large cohort of individuals with high-normal BP, high FG (but below cut-off values of diabetes) and abdominal obesity, all instructed to lifestyle changes. They will be randomly and double-blindly assigned to placebo, or an ACEI or an ARB over a period of approximately 3 years, in order to investigate whether blockade of the renin-angiotensin system on top of lifestyle advise can further reduce onset of diabetes, a hypothesis so far based only on animal studies suggesting that some ARBs may be partial agonists of peroxisome proliferator-activated receptor gamma (PPAR-gamma) involved in regulating insulin sensitivity (13). Furthermore, the subject will be followed up for additional 6 months after withdrawal of randomised medications to investigate whether the preventive actions are enduring and survive medication. 3. Implication for AIFA and the NHS Both the conduct and the results of PHIDIAS are expected to have favourable implications both for the Italian Agency for Medicinal Products (AIFA) and the Italian National Health System (NHS). The conduct of a trial such as PHIDIAS that is committed to general practitioners and involve individuals at high risk of cardiovascular disease, will effectively promote education to healthier lifestyle measures and help prevention of cardiovascular disease and diabetes. The results of the trial will also have considerable impact both on AIFA and the NHS: 1) if addition of an ACEI or ARB to lifestyle measures is shown not to have any further preventive effect on diabetes, the claim of an antidiabetogenic action of these agents will be disproved, and their use in diabetes prevention discouraged; 2) if both an ACEI and an ARB are found to prevent hypertension and/or diabetes, but their effects are not significantly different or an ACEI is found more effective than an ARB, the use of a generic ACEI- such as the one to be administered in PHIDIAS- will represent a benefit for the subjects combined with considerable savings for the NHS; 3) if an ARB is found to be significantly more effective than an ACEI in preventing diabetes, this will implicate temporarily increased costs for the NHS, largely compensated on the long term by the decreased or delayed onset of diabetes and hypertension, as well as their complications. 4. Differences from other current trials PHIDIAS substantially differs from a few ongoing trials of diabetes prevention. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial (14-15) and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial (16) are only directed to diabetes prevention. Both of them intend to test an ACEI (DREAM) or an ARB (NAVIGATOR) versus an antidiabetic agent (rosiglitazone in DREAM, nateglinide in NAVIGATOR ) versus placebo with a factorial design, in individuals selected primarily on the basis of impaired glucose tolerance, so that other cardiovascular conditions are not excluded: in DREAM 43% of recruited subjects are hypertensives and 35% are dyslipidemic, and in NAVIGATOR previous cardiovascular disease or risk factors are criteria for eligibility. Therefore in both studies the investigation of the possible antidiabetogenic effect of the ACEI or ARB is likely to be confounded to some extent by concomitant therapies for hypertension and cardiovascular disease. Finally the TROPHY trial (8) is only planned for prevention of hypertension (by the ARB candesartan) and is not exploring the equally important issue of diabetes prevention by blockade of the renin-angiotensin system. 2. Objectives of the study

1. Primary objectives. In a group of individuals with high-normal blood pressure (SBP 130-139, or DBP 85-89 mmHg), FG in the high but nondiabetic range (100-125 mg/dl), and abdominal obesity (abdominal circumference >= 102 cm in men and >= 88 cm in women), i.e. with those characteristics of the so called MS that are major predictors of DM and HT, the trial will explore whether addition of an agent blocking the renin-angiotensin system (either an ACEI or an ARB) over periodically reinforced instructions for suitable lifestyle changes reduces: 1) onset of diabetes (defined as FG >= 126 mg/dl or need for antidiabetic therapy) or 2) onset of hypertension (defined as SBP >= 140 or DBP >= 90 mmHg, or need for antihypertensive therapy) to a significantly greater extent than addition of a placebo.

2. Secondary objectives. In the same group of individuals, the trial will also investigate whether 1) the diabetes preventing effects of an ACEI and ARB significantly differ, because of the different blocking mechanisms on the renin-angiotensin system, and the additional action on bradykinin and, respectively, on PPAR gamma of the two agents, 2) the effects of the ACEI and ARB on the onset of diabetes and hypertension are enduring, persisting 3 to 6 months after substitution of the active drugs with placebo. Obviously, preventive effects substantially surviving medication would strengthen the therapeutic role of these agents, whereas disappearance of the effects after a short period would suggest a masking effect only.

3. Study design

4. Study population