Reducing both microalbuminuria and cardiovascular events: how easy is it to reach this target?




José A. GARCÍA-DONAIRE
MD, PhD
Luis M. RUILOPE,MD, PhD
Hypertension Unit Hospital 12 October
Madrid, SPAIN

Reducing both microalbuminuria and cardiovascular events: how
easy is it to reach this target?
by J. A. García-Donaire and L. M. Ruilope, Spain

Microalbuminuria is an indicator of impaired renal function and an accepted risk marker for cardiovascular events and mortality. Coexistence of type 2 diabetes and arterial hypertension significantly increases the risk of cardiorenal disease and the development of cardiovascular events, and potentially augments mortality. This has led to the recommendation of use of albuminuria as a therapeutic target. Overactivity of the renin-angiotensin-aldosterone system (RAAS) has been implicated in the deterioration of renal function in patients with diabetic nephropathy. Increases in microalbuminuria are attenuated by BP reduction using inhibitors of the RAAS. In spite of a high number of well-designed controlled, randomized trials, controversies remain regarding optimal antihypertensive therapy in diabetic patients—including whether drugs acting on the RAAS have specific renal protective properties—and the relationship between renal and mortality end points. Moreover, most hypertensive diabetic patients need combinations of two or more antihypertensive drugs, which may complicate the interpretation of the evidence. Results of the published trials provide inconsistent evidence, by showing that the effects of treatment can vary widely among different renal, cardiovascular, and mortality end points. Also combinations of antihypertensive drugs differ in their ability to prevent major renal and cardiovascular events, even if they produce similar reductions in BP. And finally, simply adding further antihypertensive drugs may not improve renal and mortality outcomes, even if it produces further reductions in BP. Furthermore, in most antihypertensive treatment trials—but not all—in patients with type 2 diabetes, a reduction in microalbuminuria was consistently associated with evidence of renal protection. In this article, we review further evidence on the extent to which treatment-induced changes in proteinuria reflect cardiovascular risk modifications in patients with type 2 diabetes

Medicographia. 2012;34:48-56 (see French abstract on page 56)

Persistent microalbuminuria has been increasingly recognized not only as an early predictor of nephropathy, but also as a risk marker for cardiovascular (CV) events and CV and all-cause mortality in patients with diabetes mellitus as well as in nondiabetic patients.1-3 This has led to the recommendation ofmore widespread urine testing for microalbuminuria and the use of albuminuria as a therapeutic target.4 The presence of hypertension in patients with diabetes mellitus substantially increases the risk of renal and other organ damage, and leads to much greater incidence of cardiac events and mortality. Chronic kidney disease (CKD) is highly prevalent in people with diabetes. A recent analysis of NHANES (National Health And Nutritional Examination Survey) data found that 39.6% of people with diagnosed diabetes, 41.7% of those with undiagnosed diabetes, and 17.7% of those with prediabetes had CKD.5 A recently published collaborative meta-analysis of general population cohorts, which pooled data of all-cause and CV mortality involving more than 1 million participants, concluded that an estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2 and an albumin-tocreatinine ratio ≥1.1 mg/mmol (≥10 mg/g) were independent predictors of mortality risk in the general population. Both parameters were associated with an increased risk of mortality without any evidence of interaction. These data have confirmed that GFR 60 mL/min/1.73 m2 and the lower limit of high-normal albuminuria (1.1 mg/mmol [10 mg/g]) are adequate limits for risk assessment and for the definition and staging of CKD.6

Overactivity of the renin-angiotensin system has been implicated in the deterioration of renal function in patients with diabetic nephropathy. There is evidence that RAAS blockers may have specific renal protective properties, and such agents are preferred both for monotherapy and as components of combination therapy.7 Early detection and treatment with blood pressure (BP)–lowering drugs, especially drugs acting on the RAAS, has been shown to at least delay, and possibly even prevent, development of end-stage renal disease in patients with diabetes and macroalbuminuria/proteinuria.8,9

However, several controversial points remain regarding optimal antihypertensive therapy in diabetic patients. Evidence of simultaneous reductions in BP, microalbuminuria, renal impairment, and CV and all-cause mortality were demonstrated in the ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation).10 More recently, in the ROADMAP trial (Randomized Olmesartan And Diabetes MacroAlbuminuria Prevention11 and in ORIENT (Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial)12 reduction in BP values in patients with type 2 diabetes was associated with improved renal outcomes, while no reduction in risk of CV outcomes could be observed in active treatment groups. In this article, we review and evaluate recent evidence from landmark trials with renal end points regarding the extent to which treatment-induced changes in proteinuria reflect CV risk modification in the management of hypertension in type 2 diabetes.

Microalbuminuria as a cardiovascular risk marker

Parving et al first described the association of essential hypertension and microalbuminuria in 1974.13 They observed that the presence of elevated levels of urinary excretion of albumin in unsatisfactorily treated hypertensive patients was directly correlated with BP values and tended to be reduced if a better control of BP was obtained. These results were later confirmed by other trials.14,15

Microalbuminuria, defined as a urine albumin:creatinine ratio of 30 to 300 mg/g, is an accepted marker of CV risk,16,17 and is detectable in almost 40% of the hypertensive type 2 diabetes population, predominantly in those patients not controlled adequately on medical treatment. The prevalence of microalbuminuria is associated with the duration and severity of hypertension.18 In a large series of nondiabetic treated and nontreated hypertensive patients, the presence of microalbuminuria was significantly greater in patients with coronary artery disease, left ventricular hypertrophy, stroke, and peripheral vascular disease.18 HARVEST (Hypertension and Ambulatory Recording VEnetia STudy) examined the association between the urinary albumin-to-creatinine ratio (UACR) and office and ambulatory BP and their relationship with other recognized CV risk factors in stage I middle-aged hypertensive patients.19 An association between microalbuminuria and target- organ damage has been reported previously. Biesenbach et al described a higher prevalence of coronary artery disease and hypertensive retinopathy in a group of hypertensive patients with persistent microalbuminuria despite effective antihypertensive treatment.20

Moreover, Bigazzi et al reported an increased thickness of the intima and media layers of the common carotid artery in a group of patients with essential hypertension and microalbuminuria; this suggests a greater degree of vascular remodeling.21 Pontremoli et al reported that patients with microalbuminuria are characterized by signs of diffuse vascular and organ damage (ie, a higher incidence of major ECG abnormalities and vascular retinal changes) supporting the statement that microalbuminuria is a marker of early end-organ and CV damage in patients with essential hypertension.22

The presence of microalbuminuria in patients with essential hypertension has been systematically interpreted as a sensitive marker of intrarenal vascular dysfunction, characterized by an impairment of renal function. Several studies have shown an increased intima–media thickness (IMT) of the carotid artery in patients with microalbuminuria.23 CKD can be considered based on the finding of a decreased GFR, an elevation of serum creatinine, or an elevated urinary excretion of albumin.24 While an elevated serum creatinine concentration points to a reduced GFR, an increased rate of albumin points to a derangement in the glomerular filtration barrier. Microalbuminuria could constitute the renal expression of a generalized disorder characterized by increased endothelial permeability, abnormalities of the fibrinolytic and coagulation pathways, and activation of the inflammatory process,25 explaining the link between microalbuminuria and CV risk. In essential hypertension, microalbuminuria can be considered as a predictor of progressive deterioration of renal function.26,27 Although it has been argued that BP lowering is the primary reason for the prevention of, or decrease in, microalbuminuria, this has only been demonstrated to be the case in studies using RAAS inhibitors.28-31

RAAS inhibition in patients at cardiovascular risk and with diabetes

The first evidence of a beneficial effect of lowering BP below 150/85 mm Hg, (which was considered as “tight BP control” in the early 1990s) with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetes mellitus came from UKPDS-38 (UK Prospective Diabetes Study).2 Then came MICRO-HOPE (MIcroalbuminuria, Cardiovascular and Renal Outcomes–Heart Outcomes Prevention Evaluation), a subanalysis of a diabetic population (n=3577) from the hugely influential HOPE trial. MICRO-HOPE involved high-risk patients with a history of vascular disease or diabetes plus one other CV risk factor who were randomized to receive the ACE inhibitor ramipril or placebo for approximately 4.5 years Among patients with diabetes, reduction in BP with ramipril, relative to placebo (2.4/1.0 mm Hg) was even smaller than in the total study population (approximately 3/2 mm Hg, but the risk reductions tended to be slightly larger, with reductions in the primary outcome of 25%, CV death by 37%, and all-cause death by 24%. There was also a reduction in the incidence of overt nephropathy by 24%.33

The HOPE trial was soon followed by PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study),34 which was primarily a study in secondary prevention of stroke, but which had important implications for subsequent trial design, especially regarding combination therapies. Patients (N=6105) with a history of stroke or transient ischemic attack were randomized to active treatment with perindopril, with or without the addition of the thiazide-like diuretic indapamide, or placebo, and mean follow-up was 3.9 years. Overall, active treatment produced a reduction of 28% in stroke and 26% in major vascular events; the benefits were similar in hypertensive and nonhypertensive patients. Approximately 42% of patients were treated with perindopril alone and 58% with the perindopril+ indapamide combination. BP was reduced by 5/3mmHg by perindopril alone, and by 12/5 mm Hg by the perindopril + indapamide combination. Results in patients receiving the perindopril + indapamide combination were dramatic, with risk reductions of 43%in stroke and 40%in major vascular events. Subsequent analysis in the 761 patients with diabetes at baseline indicated a nonsignificantly larger treatment effect in diabetic compared with nondiabetic patients, with risk reductions for stroke of 38% and 28%, respectively,35 and diabetic patients who received perindopril + indapamide showed a dramatic 46% reduction in stroke risk. The results of these trials validated the benefits of ACE-inhibitor therapy, a point reinforced by subsequent guidelines, and made a strong case for their use in control groups in later trials.

Another study from the early 2000s, LIFE (Losartan Intervention For Endpoint reduction),36 compared treatment based on the angiotensin II receptor blocker (ARB) losartan and the β-blocker atenolol (addition of a thiazide diuretic was allowed in both arms) in 9193 patients with left ventricular hypertrophy and hypertension (mean baseline BP 174/98 mm Hg), with amean follow-up of 4.8 years. The risk of the primary end point was reduced by 13% in the losartan group, with a significant decrease in risk of stroke of 25%, relative to atenololbased treatment. CV and all-cause mortality were not significantly different between the treatment groups. In the subgroup of patients with diabetes at baseline, losartan was associated with a reduction of 24% in the primary end point, and significant reductions of 37% in CV and 39% in all-cause mortality.37 Albuminuria decreased more with losartan than with atenolol, and significant reductions in CV and all-cause mortality with losartan were found only among patients in the quartile of baseline microalbuminuria.38 Further robust evidence of parallel reduction in microalbuminuria and CV and all-cause mortality was prospectively demonstrated in ADVANCE, discussed below.10

RAAS inhibition and development of diabetes

The results of the LIFE trial have been the subject of considerable discussion, and a systematic review concluded that the β-blockers studied (principally atenolol) had no effect on coronary artery disease and all-cause mortality compared with placebo and had only a weak beneficial effect on stroke.27,39

In ASCOT (Anglo-ScandinavianCardiacOutcomes Trial), which enrolled 14 120 nondiabetic patients, the risk of new-onset diabetes was substantially lower with an amlodipine ± perindopril regimen than with atenolol ± thiazide (hazard ratio [HR], 0.66; 95% CI, 0.59-0.74).40 In a network meta-analysis of 22 trials, the odds ratios of new-onset diabetes with RAAS inhibitors, relative to diuretics, were 0.57 for ARBs and 0.67 for ACE inhibitors.41 Several mechanisms for “thiazide-induced dysglycemia” have been proposed, and hypokalemia has been widely implicated. In nondiabetic patients in SHEP (Systolic Hypertension in the Elderly Program), the incidence rate of diabetes was more than doubled with chlorthalidone compared with placebo, and the risk was significantly reduced, but not abolished, by adjustment for change in serum potassium.42 Hypokalemia may lead to diminished pancreatic β-cell response to glucose and reduced muscle perfusion, increased hepatic fat content, and vascular oxidative stress, all of which may impair glucose metabolism.43 Using thiazides in combination with an ACE inhibitor can minimize hypokalemia and glucose intolerance,44 although this effect was not apparent when the ARB losartan was combined with hydrochlorothiazide in the STAR study.45

And finally, the possibility of reducing the risk of diabetes and CV events through RAAS-blockade in patients with impaired glucose tolerance was investigated in the NAVIGATOR trial (NAteglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research). This study allocated 9306 patients with impaired glucose tolerance and established CV disease or CV risk factors to valsartan (up to 160 mg daily) or placebo in addition to lifestyle modification, for a median of 5.0 years. Results showed a mean systolic BP reduction greater by 2.8 mm Hg with valsartan vs placebo, and a lower cumulative incidence of diabetes of 33.1% in the valsartan group vs 36.8% in the placebo group (P<0.001). Valsartan did not significantly reduce the incidence of CV outcomes, CV or all-cause mortality compared with placebo.46

RAAS inhibitors, nephropathy, and mortality

Patients with type 1 or type 2 diabetes mellitus are at high risk for chronic kidney disease, which usually manifests with the onset of microalbuminuria, followed by nephropathy38,47 and steeply increasing risk of CV death (Figure 1).48 The complex interactions between CV disease, CKD, and diabetes are becoming more widely appreciated, if not fully understood.49

Blockade of the RAAS is widely acknowledged as beneficial in terms of renal outcomes, and a series ofmeta-analyses have indicated that ACE inhibitors can prevent new-onset microalbuminuria, progression to macroalbuminuria, and reduce allcause mortality in patients with diabetic nephropathy, and that ARBs have only renoprotective properties.50

Figure 1
Figure 1. Annual risk of cardiovascular (CV) death in patients with
type 2 diabetes mellitus and different degrees of nephropathy in
the UKPDS (United Kingdom Prospective Diabetes Study).

Abbreviations: Elev creat, elevated plasma creatinine or renal replacement
therapy; Macro, macroalbuminuria; Micro, microalbuminuria.
Based on data from reference 48: Adler AI, Stevens RJ, Manley SE; Bilous RW,
Cull CA, Holman RR; UKPDS Group. Kidney Int. 2003;63:225-232.

IDNT (Irbesartan in Diabetic Nephropathy Trial)9 and the RENAAL trial (Reduction of Endpoints in NIDDM [non–insulin dependent diabetes mellitus] with the Angiotensin II Antagonist Losartan)8 included patients with type 2 diabetes and nephropathy. In both trials, randomized treatments were given in addition to standard hypertensive therapy, which excluded ACE inhibitors, ARBs, and in the case of IDNT, calcium-channel blockers. IRMA 2 (IRbesartan in MicroAlbuminuria, type 2 diabetic nephropathy trial)51 was a smaller study that compared two doses of irbesartan with placebo in patients with type 2 diabetes and persistent microalbuminuria, who could receive other antihypertensive drugs apart fromARBs and ACE inhibitors. The level of urinary albumin excretion was reduced by 38% in the irbesartan 300-mg group compared with a reduction of 2% in the placebo group (P<0.001). Other data have concluded that ARBs offer no renal benefit in ACE-intolerant people at high vascular risk, but without macroalbuminuria.52 Evidence from the ROADMAP trial in 4500 patients with type 2 diabetes without microalbuminuria showed that target BP achievement in patients treated with olmesartan 40 mg was associated with increased time to onset of microalbuminuria. There was no significant difference in renal function between the two study groups (a doubling of the serum creatinine level occurred in approximately 1% of the patients in each study group). Although the analysis is markedly underpowered for CV end points, fatal CV events occurred in more patients in the olmesartan group than in the placebo group—15 (0.7%) vs 3 (0.1%) (P=0.01).11 This difference could be explained in part by a higher number of deaths from CV causes among patients with preexisting coronary heart disease. However, this was also discussed as a possible CV safety signal together with a similar signal from the ORIENT trial (566 patients with type 2 diabetes and overt nephropathy), despite reduction in BP values and improved renal outcomes with the same RAAS-blocking agent.12

An analysis of 19 randomized trials53 in predominantly hypertensive patients since 2000 showed that only 3 trials (ASCOTBPLA [Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure–Lowering Arm],54 ADVANCE,10 and HYVET [Hypertension in the Very Elderly Trial]55) had a significant reduction in all-cause mortality. The successful treatments in these three studies were amlodipine (± perindopril), perindopril + indapamide, and indapamide (± perindopril), respectively.

Specific combinations

Many hypertensive patients in clinical practice receive more than one antihypertensive drug, and the use of combination therapy is widely recommended in hypertension guidelines.

In the very large ONTARGET trial (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial),56 telmisartan and the combination of telmisartan and ramipril were compared with ramipril alone in patients with CV disease or diabetes with end-organ damage. There were no significant differences between the telmisartan and ramipril groups for any renal, CV, or mortality end point. However, the combination was more effective than ramipril alone in preventing newonset microalbuminuria and progression of preexisting microalbuminuria. On the other hand, the primary renal end point, the composite of doubling of serum creatinine, dialysis or death, occurred significantly more frequently with the combination than with ramipril. Declines in estimated glomerular filtration rate were greater with the combination than with ramipril (P<0.0001). Thus, addition of telmisartan to ramipril reduced the incidence of proteinuria, but caused a more rapid decline in GFR, increased the incidence of major renal events, and showed no benefit in terms of CV events or mortality. ADVANCE is the largest trial performed in diabetics, involving 11 140 patients. It compared a fixed-dose combination of perindopril and the thiazide diuretic indapamide with placebo in patients with type 2 diabetes and a history of major CV disease or at least one other CV risk factor.10,57 Combination therapy reduced the composite renal end point (new-onset microalbuminuria, new-onset nephropathy, doubling of serum creatinine, or end-stage renal disease) by 21% (HR, 0.79; P<0.0001). There were also significant reductions in new-onset microalbuminuria (21%) and progression from microalbuminuria to macroalbuminuria (31%). In contrast to the trials of ARBs described in the previous section, the renal benefits of the perindopril + indapamide combination were accompanied by significant reductions in all-cause mortality (by 14%, P=0.025), CV death (by 18%, P=0.027) and coronary events (by 14%, P=0.020). At least three further features of the ADVANCE trial are notable. Firstly, almost all other antihypertensive treatments were allowed (including RAAS inhibitors in 73% of patients of the control group, a first in these trials), except that thiazide diuretics were not permitted. Regression of albuminuria by at least one stage was observed in 50.2% of patients in the placebo group; nonetheless, active treatment provided a further benefit of 16% in the incidence of regression (P=0.0017). Secondly, significant reductions in renal events were seen in all subgroups of patients defined by baseline BP, including those with starting BP below 125/75mmHg. Indeed, the lowest risk for renal events was observed in patients with achieved BP levels below 110 mm Hg systolic or 65 mm Hg diastolic. Thirdly, a recent analysis has shown that the relative risk of all-cause mortality was reduced to a similar extent in patients with or without nephropathy, and whatever their CKD stage at baseline. One issue not resolved by ADVANCE was whether the observed benefits were independent of BP reduction, because the BP achieved was lower in the active treatment group by an average of 5.6 mm Hg systolic and 2.2 mm Hg diastolic. However, since the majority of diabetic patients with hypertension in clinical practice do not reach their target BP,58 the greater antihypertensive efficacy of the perindopril + indapamide combination could be regarded as an additional positive result.

The third trial in this group is ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension),59 which compared two fixed-dose combinations, benazepril + amlodipine and benazepril + hydrochlorothiazide, in patients with hypertension and a history of CV disease or diabetes; approximately 60% of randomized patients had diabetes. The primary end point was the composite of CV events and CV death, and the trial was halted prematurely due to a significant reduction in this end point in the benazepril + amlodipine group (HR, 0.80; P<0.001). There was a significant reduction in the compos- ite of all CV events (17%; P=0.002), but the reductions in allcause death (10%), CV death (20%), and stroke (16%) did not reach statistical significance. The primary renal end point, the composite of doubling of serum creatinine and end-stage renal disease, was almost halved in the benazepril + amlodipine group (HR, 0.52; P<0.0001), due mainly to a 49% reduction in doubling of serum creatinine (P<0.0001). As in the ADVANCE trial, dialysis was infrequent, performed in 7 patients in the benazepril + amlodipine group and 13 patients in the benazepril + hydrochlorothiazide group (NS). Despite the marked reduction in later-stage renal events with benazepril + amlodipine, the proportion of patients with baseline microalbuminuria who regressed to normoalbuminuria was substantially lower in this group (41.7%) than with benazepril + hydrochlorothiazide (68.3%, P=0.0016). The systolic BP level in the two treatment groups differed by less than 1 mm Hg.

Of note, both the perindopril + indapamide and the benazepril + amlodipine combinations have been investigated extensively in additional studies, and have shown specific beneficial actions, additional to BP lowering, that were greater with the combination than with the individual components. For example, perindopril + indapamide has been shown to improve the microcirculation in humans, with increased myocardial capillary density and improved coronary perfusion.60

Intensive therapy—more is not always better

The recent ACCORD study (Action to Control CardiOvascular Risk in Diabetes)61 evaluated the benefit of intensive BP lowering to a target of <120 mm Hg systolic compared with standard therapy with a target of <140 mm Hg in type 2 diabetics. The study treatments used in both groups were at the discretion of the individual investigators. The mean number of antihypertensive drugs taken at 1 year was 3.4 in the intensive group and 2.1 in the standard therapy group, and by the end of the study 41% of patients in the intensive group were taking drugs from ≥4 classes (including RAAS inhibitors). Achieved BPs averaged 119/64 mm Hg in the intensive group and 134/71 mm Hg with standard therapy. There was a significant reduction in the occurrence of macroalbuminuria in the intensive group (6.6% vs 8.7%, P=0.009), but elevated serum creatinine was reported more frequently with intensive (23.8%) compared with standard therapy (15.5%; P<0.001). There was no benefit from intensive therapy in the primary end point (the composite of myocardial infarction, stroke, or CV death), or in all-cause and CV mortality, or in the frequency of end-stage renal disease or the need for dialysis. On the other hand, there was a marked reduction in the frequency of stroke with intensive therapy (HR, 0.59; P=0.01). For a summary of results of trials with renal end points in patients with diabetes mellitus, see Table I.62

Table I
Table I. Summary of results of large randomized trials with renal end points including patients with diabetes mellitus.

Results should be interpreted line by line, in comparison with a control group specific to the trial. More extensive assessment is available in reference 62.
Abbreviations: * renal events; ** urinary albumin/creatinine ratio; † urinary albumin excretion rate; ‡ doubling serum creatinine; NS, not significant; RRR, relative risk
reduction.
Study acronyms: refer to the Study Acronyms box on page 49.

Conclusions

Antihypertensive drugs and combinations differ widely in their effects, particularly regarding their capacity to reduce mortality, and the differences may be especially important in diabetic patients. The near-universal use of more than one drug class to achieve target BP in diabetic patients has important implications for clinical trial design and interpretation. Beneficial and adverse effects of one drug may be accentuated or minimized by concomitant therapies, but the types and doses of background therapies are often not standardized in trials. Finally, the strategy of simply adding additional drugs to patients already receiving two or more drugs in an effort to drive BP to ever-lower levels may be counterproductive.

A lack of concordance among different renal end points and between renal and mortality end points emerged clearly from this review, and is consistent with concerns expressed over the use of proteinuria as a surrogate for kidney disease progression. Ultimately, all-cause and CV mortality are the most reliable trial end points, and so far only few and limited subgroups of trials have demonstrated simultaneous reduction of micro-albuminuria and mortality. Finally today, the ADVANCE trial (conducted with the perindopril + indapamide combination versus a control group including RAAS inhibitors) is the first main trial to have shown unequivocal renal and mortality benefits in a large population of diabetic patients. _

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Keywords: angiotensin-converting enzyme inhibitor; cardiovascular event; chronic kidney disease; hypertension; microalbuminuria; renin-angiotensin-aldosterone system inhibitor; type 2 diabetes mellitus