Journal of hypertension. Supplement : official journal of the International Society of Hypertension最新文献

In patients with diabetes mellitus, hypertension is an important risk factor for cardiovascular and renal events, including macro and microvascular complications such as nephropathy. The risks are reduced when blood pressure is decreased, regardless of the treatment regimen, and intensive regimens have been found to offer greater protection than less intensive regimens. Reducing systolic blood pressure (SBP) and diastolic blood pressure to values less than 130/80 mmHg offers the most promising degree of protection, and antihypertensive therapy should be started in patients with diabetes with blood pressure greater than these values or at least in the high normal (>or= 130/85 mmHg) blood pressure range. This target lower blood pressure has typically been difficult to obtain, however, with clinical trials failing to achieve an SBP of less than 130 mmHg and blood pressure control rates in patients with diabetes only half those observed in those without diabetes. Combination antihypertensive therapy is superior to more conventional strategies, and is now considered necessary to achieve rapid blood pressure control in patients with diabetes and hypertension. Recent data have indicated that blood pressure control is more complex than previously believed. An individual's blood pressure can vary over time as a result of variations in biorhythms, methods of blood pressure measurement and central versus peripheral blood pressure; these factors therefore need to be taken into consideration when interpreting blood pressure results.

Many studies have shown a link between elevated glucose levels and cardiovascular disease. It is thought that elevated blood glucose levels trigger a vicious cycle of events resulting in micro and macrovascular complications. Macrovascular complications are apparent at blood glucose levels lower than those that define diabetes. Tight glucose control benefits the cardiovascular system in many ways; however, the evidence that lowering blood glucose can reduce cardiovascular risk is limited for patients with type 1 diabetes and has not yet been established for those with type 2 diabetes. Nonetheless, treating hyperglycaemia may reduce the incidence of lipid abnormalities, vascular abnormalities and hypertension. This new understanding of the pathophysiology of cardiovascular disease in patients with diabetes may help in addressing the underlying processes at an earlier stage of disease.

Hypertension and diabetes mellitus occur together frequently. There is general consensus in the literature that in patients with hypertension and diabetes, the heart and kidneys are locked in a vice, between arterial stiffening and damage to the microcirculation, with each condition feeding the other in a vicious cycle of events. Decreased glucose tolerance is associated with increased thickness and stiffness of large blood vessels, which contributes to increased blood pressure, macrovascular complications and impaired renal function. Large artery stiffness causes damage to the microvasculature, which in turn increases both capillary rarefaction, initially generated by hypertension and diabetes, and wave reflection. Systolic and pulse pressure are consequently increased, which results in completion of the cycle with more microvascular damage. In addition, macro and microvascular damage appears to increase blood pressure and impair tissue perfusion to target organs, and alterations to the vascular structure of peripheral microvessels in hypertension are related to the impairment of coronary vasodilator capacity. These mechanisms are supported by a large body of data from studies investigating the effects of diabetes and hypertension on the morphology and function of the microvasculature, some of which appear to occur in impaired glucose metabolism, preceding the development of full-blown diabetes. These changes also have important prognostic value, with direct correlations between coronary artery vasoconstriction and the incidence of cardiovascular events. Interventions to break the cycle of events are available, and regimens containing angiotensin-converting enzyme inhibitors have demonstrated good efficacy in increasing coronary reserve. Some of the mechanisms appear to be centred around the inhibition of bradykinin degradation rather than an effect on the renin-angiotensin-aldosterone system.

Objectives: ADVANCE (Action in Diabetes and Vascular Disease - PreterAx and DiamicroN MR Controlled Evaluation) is a large-scale clinical trial designed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes mellitus.

Methods and participants: ADVANCE is a 2 x 2 factorial randomized trial evaluating the benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based regimen, targeting glycosylated haemoglobin (HbA1c) levels of 6.5% or less versus standard therapy to lower blood glucose. The two primary outcomes, taken separately and jointly, are a composite macrovascular endpoint and a composite microvascular endpoint.

Results: A total of 11 140 participants were randomized between July 2001 and March 2003 from among 12 878 individuals with type 2 diabetes recruited from 215 centres in 20 countries, who entered a 6-week run-in phase. The average (SD) baseline blood pressure of 145(22)/81 (11) mmHg fell by 8/3 mmHg during the run-in phase during which participants received one tablet of open-labelled perindopril 2 mg-indapamide 0.625 mg. Only 3.6% of the 12 878 patients who entered the run-in phase withdrew because of suspected intolerance to perindopril-indapamide. With over 4 years of follow-up on average so far, over 80% of participants are still adhering to randomized therapy. Follow-up of the blood pressure arm will be completed during 2007.

Conclusion: The safety and efficacy of perindopril-indapamide in lowering blood pressure and of a gliclazide-MR-based regimen in lowering blood glucose have been established with the completion of a 6-week run-in phase and of more than 4 years of post-randomization follow-up. It is anticipated that ADVANCE will provide many new insights including: whether blood pressure lowering with perindopril-indapamide reduces the risk of both macrovascular and microvascular events irrespective of baseline blood pressure; whether more intensive blood pressure lowering with a gliclazide-MR-based regimen targeting on HbA1c levels of 6.5% or less reduces these two outcomes compared with standard guidelines therapy; and finally whether the separate benefits of these two treatment regimens are additive.

Hypertension remains uncontrolled in the majority of treated patients, especially those with multiple cardiovascular risk factors. This was demonstrated by a French study that showed that 70% of treated hypertensive patients are not controlled to the target level of 140/90 mmHg. This proportion reached 84% in hypertensive patients with diabetes (target level 130/85 mmHg). What are the reasons for this disappointing situation? Observational studies have shown that only a minority of patients with uncontrolled hypertension receive triple therapy including a diuretic. In this respect, self-measurement of blood pressure should improve the situation by allowing clinicians to base their decision to intensify hypertension treatment on more solid evidence than consultation blood pressure measurements alone. Patient-related factors may also contribute to this situation. Treated patients with uncontrolled hypertension often have multiple risk factors. This is associated with or is a source of poor treatment observance linked to patient psychological factors or a result of the increased consumption of medication. Finally, risk factors themselves may be responsible for problems with blood pressure control as a result of their detrimental effects on large arteries as well as the microvascular network. The early correction of such vascular anomalies is vital for medium and long-term blood pressure control.

Cardiovascular complications may, to a large extent, be prevented by lowering blood pressure in hypertensive patients. International recommendations currently stress the importance of reaching values of below 140/90 mmHg in each patient or even lower in the case of concomitant diabetes or renal impairment. It is currently considered crucial to control the systolic pressure as well as the diastolic pressure, in particular because the relationship between cardiovascular risk and blood pressure is closer for the systolic than the diastolic value. An increase in systolic pressure is in itself a sign of the stiffening of the arterial tree. In most patients, the target pressure may only be reached by combining several different antihypertensive agents. In the STRATHE Study, a greater antihypertensive efficacy, in particular on systolic pressure, was obtained by instituting treatment with a fixed low-dose combination of an angiotensin-converting enzyme inhibitor (perindopril) and a diuretic (indapamide), in comparison with other therapeutic strategies based on single-agent therapy. Fixed-dose antihypertensive combinations have now become a validated option for initiating antihypertensive treatment.