Implications of ADVANCE in the management of blood pressure in diabetic patients



by B. Williams,United Kingdom


Bryan WILLIAMS, MD,
FRCP, FAHA
Leicester Royal Infirmary
Leicester
UNITED KINGDOM

Epidemiological studies in the 1970s established that high blood pressure (BP) is both common and a major risk factor for macrovascular and microvascular disease in people with type 2 diabetes. However, uncertainty remained about the benefits and safety of BP lowering in people with diabetes. Previous studies, such as the United Kingdom Prospective Diabetes Study (UKPDS) in the late 1990s, demonstrated that lowering BP is very effective at reducing cardiovascular disease (CVD) and microvascular disease risk and, as a consequence, mortality. Questions remained, however, about whether there was a specific threshold below which BP lowering would be ineffective at reducing risk. The Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study was designed with this key question in mind and set about lowering BP in people with diabetes, irrespective of their baseline BP, to determine whether this strategy would safely further reduce risk. The strategy employed was the addition of a combination of perindopril/indapamide, added to usual care, as part of a factorial study design that also examined the impact of “more versus less” glucose lowering. The BP-lowering arm of the ADVANCE study demonstrated that further BP lowering with perindopril/indapamide significantly reduced the risk of a combined end point of macrovascular and microvascular events and total mortality. This is a significant advance as it suggests that this treatment strategy will further reduce the risk for people with type 2 diabetes, irrespective of their prior treatment or baseline BP. This finding has important implications for people with type 2 diabetes and is a further step forward in improving treatment strategies for these patients beyond existing therapies to reduce their CVD and microvascular risk.

Medicographia. 2009;31:238-244 (see French abstract on page 244)

Some 25 years ago as a young doctor, I became interested in blood pressure (BP) in people with diabetes when I noted three things that intrigued me. Firstly, that the pathology associated with diabetes seemed to be primarily a vascular problem, and that the pathology looked remarkably similar to that seen in nondiabetic people with severe hypertension. Secondly, that people with diabetes invariably seemed to be hypertensive, often severely so. And, thirdly, that the doctors caring for patients with type 2 diabetes seemed less concerned about measuring and treating their blood pressure than I was! We now know much more, and the approach to detection and treatment of blood pressure has changed dramatically.

People with diabetes often develop hypertension. In younger people with type 1 diabetes, an increase in BP often signals the early development of diabetic nephropathy. In older patients with type 2 diabetes, hypertension—defined as a BP _140/90 mm Hg—is at least twice as common as in an agematched nondiabetic population, affecting approximately 80% of people with type 2 diabetes. It is also important to note that the characteristics of hypertension are very different in people with type 2 diabetes. In these patients, the progressive agerelated rise in systolic BP occurs earlier. This means that many people with type 2 diabetes develop systolic hypertension at least 10 years earlier than the general population, and there is an associated early widening of pulse pressure indicative of accelerated aging and stiffening of the large arteries. This arterial stiffening is important because it renders BP more resistant to treatment. Furthermore, subtle autonomic dysfunction occurs in the majority of these patients that disturbs the normal circadian rhythm of BP regulation. In particular, there is a blunting of the usual nocturnal dip in BP during sleep. This means that, for any given level of office BP, people with type 2 diabetes invariably have a higher 24-hour BP load. To compound matters, blood flow autoregulation is also impaired in people with diabetes. This means that any increase in circulatory pressures is more readily transferred to the delicate microcirculation, which thereby explains, in large part, the development of devastating microvascular disease in these patients. These observations are fundamental because they underscore why the detection and treatment of hypertension in people with diabetes is especially important in protecting both the macro- and microvasculature. Mindful of the fact that the BP load is elevated and the microcirculatory defenses are impaired, it also provides a rationale for advocating more aggressive BP lowering.

Importance of diabetes and hypertension as cardiovascular disease risk factors

We now recognize that an elevated BP is a major risk factor for macrovascular and microvascular complications in people with diabetes and a major contributor to associated premature morbidity and mortality. In 1974, the Framingham study was the first major study to highlight the fact that cardiovascular disease (CVD) risk was elevated in people with diabetes.1 This was the result of two important factors: (i) people with diabetes had a greater likelihood of abnormalities in major risk factors, such as lipids and blood pressure; and (ii) that, even when these risk factors were accounted for, their risk was magnified. Since then, there has been some controversy as to the magnitude of the excess CVD risk associated with type 2 diabetes, but no dispute about the fact that it is elevated when compared to the nondiabetic population. Moreover, elevation in CVD risk occurs at levels of glycemia below that required for the diagnosis of diabetes, suggesting that control of glycemia per se is unlikely to be a very effective strategy in reducing CVD risk. Another important observation from early epidemiological studies noted that when people with type 2 diabetes develop coronary heart disease, heart failure, or stroke, their prognosis was worse than that of the nondiabetic population. This latter point is especially important because it highlights the special importance of primary prevention in people with type 2 diabetes.

With regard to BP, it was recognized in the Framingham study that the prevalence of hypertension was higher in people with type 2 diabetes. However, hypertension at the time was defined at a higher threshold (_160/90 mm Hg). There was also a much greater focus on diastolic pressure at the time, and even though systolic pressure was commonly elevated, it was often ignored in BP classification. This means that the true prevalence of hypertension was often underestimated in the early surveys. In 1993, data from the United Kingdom Prospective Diabetes Study (UKPDS) reported a strikingly high prevalence of hypertension—defined as a systolic BP _160 mm Hg and/or a diastolic BP _90 mm Hg—in patients (40%) at the time of diagnosis of type 2 diabetes, with a higher prevalence among women and increasing prevalence with age.2-4 The thresholds for the diagnosis of hypertension used in UKPDS were much higher than current thresholds. Consequently, by modern criteria (BP _140/90 mm Hg), almost 80% would have been designated hypertensive. They also noted that hypertensive patients were more likely to be obese and that they already had almost double the risk of established cardiovascular complications at the time of diagnosis of type 2 diabetes when compared with those without hypertension.

Alarmingly, most of the hypertension was unrecognized and untreated.3 This hypertensive cohort within UKPDS became the basis of a key substudy: the Hypertension in Diabetes Study (HDS). HDS was one of the first prospective evaluations of the association between BP and clinical outcomes within a major clinical outcomes trial. Within 5 years of commencing HDS, the strong association between BP and clinical outcomes was reported by the group for patients with type 2 diabetes.3 After a median follow-up of only 4.6 years, it had become clear that hypertension was a major risk factor for cardiovascular morbidity and mortality in this population. The authors speculated that “antihypertensive therapy may provide greater benefit in this high risk group than in the general population.”3

One of the problems bedeviling treatment was a lack of clinical trial data demonstrating the safety and efficacy of BP lowering in people with diabetes. This was a key question. Today, many would regard the answer as obvious, but at the time there was concern that BP lowering might be poorly tolerated by people with diabetes and that it could lead to critical ischemia in vital organs, compounded by autonomic dysfunction. Moreover, the “presence of diabetes” was often an exclusion criteria for early BP-lowering trials, thus little data existed upon which to base treatment recommendations. Consequently, the detection and treatment of hypertension was often poor in people with diabetes and considered less important than glucose control.

The emergence of blood pressure–lowering trials in people with diabetes

The UKPDS study had originally been established to study the impact of improved glycemic control on clinical outcomes in people with type 2 diabetes. The investigators, recognizing the high prevalence of hypertension in their patients, embedded HDS within UKPDS. I recently reviewed the impact of this study on the treatment of hypertension in people with diabetes, in some detail.4 HDS addressed a key question: would more intensive versus less intensive blood pressure lowering improve clinical outcomes in people with type 2 diabetes?5 HDS started in 1987 and recruited 1148 hypertensive type 2 diabetic patients from the 4297 patients recruited into UKPDS. Of note was the fact that these patients were newly diagnosed and had not previously had BP treatment. The patients were allocated to treatment with either “less tight control of BP,” aiming for a BP <180/105 mm Hg, or “tight control of BP,” aiming for a BP of <150/85 mm Hg. The very fact that, in the early 1990s, it was considered reasonable to randomize people with diabetes to what is now considered grade III hypertension, is testimony to the lack of evidence that existed and, consequently, the low profile of BP control in the routine care of people with type 2 diabetes, at the time. After a median of 8.4 years of follow-up, the mean blood pressure during follow-up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg).5 This 10/5 mm Hg difference in BP was associated with a reduction in diabetes-related end points of a quarter, reductions in deaths related to diabetes of almost a third, a reduction in stroke of almost a half and in heart failure of more than a half, and a reduction in microvascular disease of about a third (mainly delayed progression of retinopathy). The number needed to treat (NNT) to prevent one major complication over 10 years was only 6 patients, while the NNT to prevent a diabetes-related death was only 15 patients. The treatment strategy was safe and well tolerated, and the result was unequivocal. Moreover, the treatment benefit from BP lowering was greater than anticipated from the epidemiological association between BP and risk in people with type 2 diabetes (Table I). This, perhaps, reflects the enhanced vulnerability of patients with diabetes to pressure-mediated cardiovascular disease (see below).

Table I
Table I. Relationship between predicted benefit of BP lowering and actual benefit of BP lowering in the UKPDS. Based on data from reference 5.
Abbreviations: BP, blood pressure; UKPDS, United Kingdom Prospective Diabetes Study.

Just prior to publication of UKPDS and HDS in 1998, the diabetes subgroup (n=583) from the Systolic Hypertension in the Elderly Programme (SHEP) had reported a reduction in half of cardiovascular events in an elderly population experiencing a similar improvement in BP control over 5 years of treatment.6 However, this had less impact than the UKPDS data that identified that hypertension was the norm and almost invariably present in these patients, rather than the exception. UKPDS demonstrated that hypertension was dangerous and markedly increased the risk of the premature development of diabetic complications and that, left untreated, ultimately contributed to premature mortality. It not only showed for the first time that, for BP, “lower was better” in improving the outcomes in people with type 2 diabetes, but that lower was safe. The study also showed that almost all patients require multiple drugs in combination to achieve improved BP control and better clinical outcomes.

Early indicators of the relative importance of blood pressure versus glycemic control in type 2 diabetes

Glycemic control has for many years been the main focus of treatment for people with type 2 diabetes. UKPDS allowed the relative impact of BP lowering versus intensified glycemic control on clinical outcomes to be compared prospectively. As indicated above, intensified BP control was impressive at reducing major diabetes end points, including significant reduction in diabetes-related death, stroke, and microvascular disease, and tends to be of benefit in all end points. This is despite the small size of the BP-lowering study. The benefits of BP lowering appeared more impressive than those resulting from the intensified glycemic control strategy in UKPDS, even on microvascular end points, for which the latter had been strongly advocated. I highlight this comparison not to suggest that glycemic control is unimportant, but, rather, because of its importance in changing perceptions about the importance of BP control in protecting people with type 2 diabetes from microvascular and macrovascular damage.

The ADVANCE of knowledge regarding blood pressure lowering in people with diabetes

Many questions remained after the emergence of the early evidence that BP lowering was both safe and very efficacious at reducing CVD events and microvascular disease in people with diabetes. Should BP be lowered even further than the average of 144/82 mm Hg achieved in the tight control group of HDS in UKPDS? Is the definition of hypertension, in any case, arbitrary, and would people with diabetes benefit from BP lowering, whatever their baseline BP? Moreover, does it matter what drug we use to lower BP in people with type 2 diabetes? A meta-analysis of trials that followed UKPDS concluded that BP lowering per se is the dominant means of achieving macro- and microvascular benefits, and that achieving a lower BP does appear to be better—even more so than in the nondiabetic hypertensive population.7 This, in part, relates to the fact that people with diabetes are at much higher cardiovascular risk and, thus, stand to gain more absolute benefit from BP lowering. It may also relate to the fact that people with diabetes are especially vulnerable to hypertensive injury.8 Data also suggest that blockade of the reninangiotensin system (RAS) “adds value,” over and above the BP lowering they produce, in preventing cardiovascular events in people with diabetes,9,10 although this has not been confirmed by all studies.11 One important clinical outcome where there appears to be a clear advantage of RAS blockade in people with type 2 diabetes is on renal end points (albuminuria and progression of renal disease).12-14 This has prompted international guidelines to conclude that RAS blockade should be part of the cocktail of treatments used to lower BP in people with type 2 diabetes. Thus, modern treatment strategies usually include RAS blockade, along with a calcium channel blocker and/or a thiazide-type diuretic.

However, uncertainty has remained about “how low to go?” Guidelines were making recommendations to aim for lower BP targets in people with diabetes, but evidence to support these recommendations was lacking. There was a clear need to push the boundaries beyond those explored by UKPDS and to take BP into uncharted territories and evaluate the “lower is better” hypothesis. This was the purpose of the recent Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial that tested the “lower is better” hypothesis by measuring the effect of further BP reductions (achieved with an angiotensin-converting enzyme [ACE] inhibitor [perindopril]/thiazide-type diuretic [indapamide] combination versus placebo, on top of conventional therapy) on vascular events in 11 140 people with type 2 diabetes.15 An important aspect of this study was that the BP-lowering combination therapy (perindopril/indapamide) was added: (i) irrespective of baseline blood pressure levels— that is, it was added even if patients would have been considered “normotensive” by conventional criteria; and (ii) irrespective of whether the patients were already receiving other BP-lowering drugs, including ACE inhibitors.

The mean age of the ADVANCE population was 66 years, of whom 57% were male. About a third had a prior history of major macrovascular disease and a tenth had microvascular disease. The patient profile in ADVANCE is shown in Table II (page 243). In addition, glycemic control was excellent throughout the study. A large proportion (68%) were being treated for hypertension at the time, with a baseline BP of approximately 145/81 mm Hg. Importantly, the standard deviation around this mean baseline was approximately 22/11 mm Hg, indicating that many patients had substantially lower baseline BPs. Over a mean follow-up of 4.3 years, additional perindopril/ indapamide therapy was associated with a lower BP (–5.6/–2.2 mm Hg) versus placebo treatment. This modest BP reduction reflects that fact that patients in the placebo group received additional add-on therapy for their BP (83% received additional BP-lowering drugs in the placebo group, versus 74% in the perindopril/indapamide group), as often happens in clinical trials when active BP-lowering therapy is compared to placebo treatment. The additional BP lowering associated with perindopril/indapamide was associated with a significant 9% risk reduction in major macrovascular and microvascular events (Figure 1), a significant 18% reduction in cardiovascular death, and a 14% reduction in all cause mortality (Figure 2). Importantly, there was no evidence that the benefits of additional BP-lowering therapy differed according to initial blood pressure level—in other words, even those within the lowest BP strata at baseline experienced a similar relative risk reduction to those in the highest BP strata. Moreover, the lowest BP strata included patients whose BP was already below the currently recommended treatment target for type 2 diabetes (<130/80 mm Hg). It is also noteworthy that the ADVANCE result was achieved in a population with high concomitant use of statins (almost half of patients by study end), antiplatelet drugs (more than half of patients by study end), and background ACE inhibition, and with good glycemic control, in both arms of the trial. With regard to background ACE inhibition, those already receiving ACE inhibition at baseline were standardized to treatment with perindopril, thus, by the study end, about half of all patients were receiving perindopril in addition to placebo or additional perindopril/indapamide.

Table I
Table II. Patient characteristics at baseline* in the ADVANCE study.
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; HDL, high-density lipoprotein.
Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007;370:829–840. Copyright © 2007, Elsevier Ltd.

Figure 1
Figure 1. Primary outcome in the ADVANCE trial: reduction in combined primary end point of macrovascular and microvascular events. The vertical lines indicate the 2- and 4-year time points in the trial at which data were collected for microvascular end points (albuminuria and retinal photography).
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation.
Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007; 370:829–840. Copyright © 2007, Elsevier Ltd.

Figure 2
Figure 2. Prespecified outcome of “all-cause mortality” in the ADVANCE trial.
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation.
Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007; 370:829–840. Copyright © 2007, Elsevier Ltd.

It is also worth noting that because the background use of perindopril was so extensive, one of the major differences between the treatment arms was the use of indapamide, a thiazide- like diuretic. This is important when one considers the resistance to using diuretics in people with diabetes in the past. The data from SHEP,6 the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),11 and now ADVANCE15 attest to the effectiveness of thiazide-type diuretics at reducing BP and major CVD and microvascular events in people with diabetes. In modern therapy for BP lowering in type 2 diabetes, thiazide-type diuretics are usually used alongside RAS blockade, as in the ADVANCE study.

The ADVANCE trial is very important because it extends our understanding of the importance of further BP lowering in patients with type 2 diabetes. The findings extend the original findings of UKPDS into new territories and provide strong evidence to support the safety, tolerability, and efficacy of a “lower is better” philosophy for BP control in people with diabetes. Indeed, in my recent review of key trials in hypertension, which considered the ADVANCE trial, I suggested that the modern treatment goal for hypertension in people with diabetes should be “the lowest pressure the patient will tolerate without an adverse impact on function”.16 Of course, this conclusion does warrant confirmation, and further information of the impact of a more intensive BP-lowering strategy will come from the ACCORD study (the Action to Control Cardiovascular Risk in Diabetes) in the US.17 ACCORD is testing whether lowering BP to normal (<120 mm Hg systolic) reduces stroke and heart disease risk compared with the level usually targeted in current clinical practice, ie, one below the current definition of hypertension (<140 mm Hg systolic) in people with type 2 diabetes.

Conclusions

The story of hypertension in diabetes is a young one. The first substantive epidemiological clues to its high prevalence and clinical importance first emerged less than 40 years ago. Since then, we have learned much about the pathophysiology of qualitative and quantitative BP disturbances that characterize people with type 2 diabetes. Changes in clinical practice have been driven by evidence from clinical trials, which began with UKPDS and which have continued (see the studies highlighted above) up until ADVANCE, from which the latest data come. In addition to BP, it is also clear that the high CVD risk and microvascular disease burden experienced by people with type 2 diabetes is best addressed by multifactorial intervention based on improved BP control, on better lipid management with statins, on antiplatelet drugs, and on improved glycemic control, which is best highlighted by studies from the Steno centre.18,19 Mindful of the almost obsessive focus of diabetes care on glucose control over the years, it is somewhat ironic that it is this aspect of intervention which has the less convincing evidence base and which remains the most controversial with regard to clinical outcomes. It is also clear that following the spectacular pace of change in the treatment of people with type 2 diabetes and, especially, the overall improvement in their CVD risk management, future trials will be more challenging. In this context, the data from the ADVANCE BP study are all the more remarkable in showing that we can still do more to improve the survival of an otherwise welltreated population.

References

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Keywords: blood pressure; microvascular disease; macrovascular disease; diabetes; blood glucose control; epidemiological study; Preterax; Diamicron