Description of the condition

Hypertension is a worldwide health problem and has become a heavy burden on the health care system. Hypertension is associated with cardiovascular mortality and morbidity such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Blood pressure (BP) is elevated in many people with type 2 diabetes, which is a major health problem worldwide, and the increased prevalence of diabetes mellitus (DM) is primarily due to the increase in type 2 diabetes mellitus (T2DM) (Inzucchi 2005). Among U.S. adults with diabetes, 71.0% had elevated BP (i.e., BP ≥130/85 mm Hg or current use of prescription medication for hypertension) (Geiss 2002). Elevated BP is associated with a spectrum of later health problems in people with diabetes, notably cardiovascular disease and kidney damage. Elevated BP has been identified as a major risk factor in progression of diabetic nephropathy (Aurell 1992). The risk of cardiovascular morbidity and mortality is also doubled in hypertensive patients when diabetes is present (DeStefano 1993). Review of the evidence‐base on this topic is distributed among guidelines primarily addressing diabetes (CPG 2008) or hypertension (JNC‐VII 2003). Antihypertensive agents used include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), beta‐blockers and diuretics.

Description of the intervention

In the past 10 years, antagonism of the renin‐angiotensin system (RAS) has become a focus of therapeutic interventions for hypertension. The guidelines (ADA 2005, JNC‐VII 2003) that recommend the use of ACE inhibitors or ARBs in diabetics with renal disease base their recommendations on the results of placebo‐controlled trials, which have been interpreted to show that ACE inhibitors and ARBs have specific renoprotective effects beyond those resulting from lowering blood pressure alone. Blood‐pressure‐independent beneficial effects of ACE inhibitors and ARBs on cardiovascular outcomes have also been proposed, based on the results of several large multicentre placebo‐controlled trials, especially HOPE 2000, PROGRESS 2001 and RENAAL 2001 studies. A recent meta‐analysis (Saha 2008) indicated that in patients with DM treatment with tissue ACE inhibitors (ramipril 1.25 or 10 mg/day; perindopril 4 or 8 mg/day) when compared to placebo significantly reduced the risk of cardiovascular mortality by 14.9% (p=0.022), myocardial infarction (MI) by 20.8% (p=0.002) and the need for invasive coronary revascularization by 14% (p= 0.015) ; the risk of all‐cause mortality also tended to be lower (RR 0.913, 95% confidence intervals (CI) 0.825‐1.011) among patients randomized to tissue ACE inhibitors. A Cochrane systematic review (Strippoli 2006) from 13 randomised controlled trials (RCTs) in 10070 patients showed a significant reduction in the risk of end‐stage renal disease (ESRD) with ACE inhibitors or ARBs compared to placebo/no treatment (RR 0.60, 95% CI 0.39 to 0.93; RR 0.78, 95% CI 0.67 to 0.91, respectively), and ACE inhibitors at the maximum tolerable dose were found from 10 studies in 2034 patients to significantly reduce the risk of all‐cause mortality in placebo controlled studies (RR 0.78, 95% CI 0.61 to 0.98, ARR 0.04, NNT 24.56).

The evidence of benefit in terms of mortality and morbidity using ACE inhibitors or ARBs versus other antihypertensive agents is not clear. Some studies suggested that RAS inhibitors might prevent or delay cardiovascular events in some subgroups, but their role in the broader group of people with hypertension remains unknown (CAPPP 2001, LIFE 2002). Some trials provide evidence of benefit of RAS inhibitors on renal function over other antihypertensive drugs (ABCD‐HT 2000, LIFE 2002, MARVAL 2002). However, clinically relevant outcomes or hard endpoints such as combined renal dysfunction or renal failure were not examined.

Other systematic reviews related to this review are summarized below in chronological order by date of publication.

A systematic review and meta‐analysis by Casas et al assessed the effect of RAS inhibitors and other antihypertensive drugs on renal outcomes (Casas 2005). In this review, the effects of ACE inhibitors or ARBs in placebo‐controlled trials were indirectly compared to the effects of other antihypertensive drug in patients with type 1 or 2 diabetes or without diabetes. In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine, ESRD, glomerular filtration rate (GFR), or creatinine levels. Placebo‐controlled trials of ACE inhibitors or ARBs decreased all renal outcomes, but also reduced blood pressure.

A Cochrane systematic review (Strippoli 2005) of RCTs comparing any antihypertensive agent with placebo or another agent in hypertensive or normotensive patients with diabetes and no kidney disease was published. This review assessed the renal outcomes and all‐cause and cardiovascular mortality. It showed that compared to placebo, ACE inhibitors significantly reduced the development of microalbuminuria (six trials, 3840 patients: RR 0.60, 95% CI 0.43 to 0.84, ARR 0.03 and NNT 33.81) but not doubling of creatinine or ESRD or all‐cause mortality. Compared to CCBs, ACE inhibitors significantly reduced progression to microalbuminuria (four trials,1210 patients: RR 0.58, 95% CI 0.40 to 0.84, ARR 0.05 and NNT 20).

A meta‐analysis of double‐blinded RCTs by Siebenhofer et al compared ARBs to placebo or standard anti‐hypertensive treatment in T2DM (3 trials, 4423 patients included) and examined clinical endpoints (all‐cause mortality, cardiovascular morbidity and mortality, and ESRD) (Siebenhofer 2004). The only statistical significant benefit of ARBs was the reduction of ESRD compared with placebo (OR 0.73, 95% CI 0.60 to 0.89, ARR 0.05 and NNT 20). ARBs failed to show superiority to standard anti‐hypertensive treatment (CCB, beta‐blockers) in total mortality and cardiovascular morbidity and mortality. However, ACEI were not included in this meta‐analysis.

A systematic review and meta‐analysis by Pahor et al assessed therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with T2DM and hypertension (Pahor 2000). This meta‐analysis showed a significant benefit of ACE inhibitors compared with alternative treatments (CCB, beta‐blockers, diuretics) on acute MI (63% reduction, P<0.001, ARR 0.06 and NNT 17), cardiovascular events (51% reduction, P<0.001, ARR 0.08 and NNT 13), and all‐cause mortality (62% reduction, P = 0.010, ARR 0.02 and NNT 40) but not stroke. However, ARBs were not included in this review. Renal outcomes (ESRD, GFR, serum creatinine or albuminuria) were not reported.

A meta‐analysis of 100 controlled and uncontrolled trials in 2494 subjects with diabetes assessed the effect on proteinuria of different classes of antihypertensive agents (ACEI inhibitors, CCBs, beta‐blockers and control) (Kasiske 1993). This review showed that ACE inhibitors produced the greatest reductions in urine albumin and protein excretion compared with other antihypertensive agents (P<0.05 vs calcium channel blockers; P<0.05 vs control). ACE inhibitors achieved these beneficial effects on renal function independent of changes in blood pressure. This meta‐analysis examined surrogate markers rather than clinically relevant endpoints (such as end‐stage renal failure, all‐cause mortality).

How the intervention might work

The RAS is a potential pathophysiologic mechanism causing diabetic heart disease. Angiotensin II (Ang II) is thought to play an important role in the pathogenesis of cardiovascular complications (Dzau 2001). The role of the RAS on diabetic nephropathy has also been extensively studied (Kocks 2002).

Drugs inhibiting the RAS include: renin inhibitors, ACE inhibitors and ARBs. These drugs inhibit the enzymatic action of renin, the conversion of Ang I to Ang II or blocking the Ang II receptors, respectively.

ACE inhibitors and ARBs block the RAS further downstream, whereas renin inhibitors prevent the formation of renin, which is responsible for all "downstream" events leading to production of Ang II and subsequently stimulation of its receptors. It has been proposed that renin inhibitors might provide more effective means of blockade of the RAS than ACE inhibitors or ARBs (Duprez 2006).

Why it is important to do this review

RAS inhibitors are widely prescribed for treatment of hypertension. Furthermore for people with diabetes, the JNC‐VII treatment guidelines recommended that anti‐hypertensive drug therapy be initiated for blood pressure >130/85 mm Hg, ACE inhibitors and ARBs are specifically promoted for diabetic patients on the basis of postulated advantages with regard to the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of ACE inhibitors and ARBs for diabetes, the efficacy compared to other antihypertensive drugs is still unclear. A systematic review is needed in order to establish the benefits and harms in terms of clinically relevant outcomes (especially all‐cause mortality and morbidity, renal and cardiovascular outcomes) of RAS inhibitors compared to other antihypertensive drugs in patients with elevated blood pressure.