Hypertension ReninAngiotensin Aldosterone System Blockade

Hypertension frequently coexists with diabetes mellitus in adults. The prevalence is greater than 50% in persons with type 2 diabetes mellitus (54), increasing with age, and approx 25% in those with type 1 diabetes (55). As mentioned previously, the onset of hypertension in type 1 diabetes appears to be primarily a complication of DN, whereas in type 2 the hypertension is frequently present at the time of the diagnosis of diabetes with both being components of the metabolic syndrome. Despite the possible difference in pathophysiology of hypertension in the two types of diabetes, it is clear that uncontrolled hypertension increases the risk for progressive renal damage in patients with either type.

Treatment of hypertension in diabetes clearly decreases the risk of microvascular and macrovascular complications, including nephropathy. Large prospective, randomized trials (UKPDS and the Appropriate Blood Pressure Control in Diabetes trial) have shown decreased rates of progression of nephropathy with lowering of blood pressure (56,57). Based on these and other trials, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), the ADA, and the National Kidney Foundation have all redefined the goal blood pressure in individuals with diabetes as <130/80 mmHg (58-60). Although the primary goal is blood pressure lowering, the possible differential class effects above and beyond direct effects on blood pressure have been and are continuing to be addressed in large, prospective, and randomized clinical trials. As has been found in multiple clinical trials, the great majority of subjects with diabetes required at least two, and many, even three or more antihy-pertensive agents in order to reach target blood pressures (61). Most patients with diabetes on appropriately aggressive therapy, therefore, will ultimately end up taking agents from multiple drug classes.

Antihypertensive agents that block the renin-angiotensin-aldosterone system (RAAS) appear to have beneficial effects on the progression of nephropathy above and beyond their blood pressure-lowering effects. They appear to do this by decreasing intraglomerular pressure and by blocking the vasoconstrictive and trophic effects of the RAAS that are thought to be important factors in the pathogenesis of vascular injury in diabetes (62-64). Studies have shown angiotensin-converting enzyme (ACE) inhibitors to be of superior benefit in comparison with other classes of antihypertensive agents in decreasing the development of microalbuminuria and albuminuria in patients with type 1 diabetes, including those without hypertension (65,66). Currently, there are little data regarding angiotensin receptor blockers (ARBs) in type 1 diabetes and nephropathy, but the efficacy and superiority of ACE inhibitors have generally been extrapolated to ARBs.

until recently, there has been little data from large prospective trials regarding the effectiveness of ACE inhibitors for nephropathy in patients with type 2 diabetes, but again, there have been a presumed extension of their benefits to such patients. A small study of 156 normotensive, normoalbuminuric patients with type 2 diabetes treated with either enalapril or placebo for 6 yr demonstrated a significant risk reduction of 12.5% in the development of microalbuminuria with enalapril as well as a significant attenuation in decline in GFR (mean decrease of 0.025 mL/s/yr with enalapril vs 0.04 mL/s/yr with placebo, p = 0.040) (67). In the Microalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation (MICRO-HOPE) study of 3577 primarily type 2 diabetic subjects, ramipril showed a statistically significant benefit over placebo in preventing the progression from microalbuminuria to overt nephropathy (24% risk reduction), and a nonsignificant decrease in development of new microalbuminuria (68). The more recently published Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) randomized 1204 subjects with type 2 diabetes, hypertension, and no albuminuria to trandolopril, verapamil, both, or placebo. over more than 3 yr of the study, the primary endpoint of persistent microalbuminuria occurred in 5.7% of subjects receiving trandolapril and verapamil, 6% of those on tran-dolapril only, 11.9% of those on verapamil only, and 10% of those receiving placebo (69). This study confirmed the efficacy of an ACE inhibitor in type 2 diabetes as well as its superiority to verapamil.

For ARBs, more evidence of benefit in prevention of progression of nephropathy exists for type 2 than for type 1 diabetes. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study enrolled 1513 hypertensive patients with type 2 diabetes who had albuminuria and serum creatinine levels of 1.3-3 mg/dL. Patients were randomized to losartan or placebo and the blood pressure was controlled (<140/90) with other non-ACE inhibitor and non-ARB medications. Losartan use resulted in a relative risk reduction of 16% in comparison with placebo in the composite endpoint of a doubling of the serum creatinine, ESRD, or death (70). In a study of 1715 diabetic patients with similar baseline characteristics and a similar study design, the Irbesartan Diabetic Nephropathy Trial (IDNT) found that irbesartan treatment resulted in a 20% risk reduction of the same composite endpoint as was used in RENAAL, whereas no benefit was found with the dihydropyridine calcium channel blocker (CCB) amlodipine (71). In a third study of 590 patients with microalbuminuria and hypertension, irbesartan was found to decrease the rate of progression to albuminuria by 24% using a dose of 150 mg/d and by 38% using a dose of 300 mg/d (72). The Microalbuminuria Reduction with Valsartan Trial of Valsartan vs Amlodipine (MARVAL) demonstrated that valsartan decreased microalbuminuria and macroalbuminuria associated with type 2 diabetes more effectively than other antihypertensive classes (73).

Interestingly, subanalyses from the RENAAL study demonstrated that the degree of albuminuria reduction with losartan in the first 6 mo correlated positively with reduction in the renal events and ESRD; every 50% reduction in albuminuria was associated with a 36% risk reduction in renal endpoint and a 45% risk reduction for ESRD during later follow-up (74). A similar association was found for cardiovascular endpoints (75). It has thus been suggested that reduction of urinary albumin be a specific therapeutic goal, with a suggested target of less than 500 mg/d (76).

Theoretically, the idea of dual blockade of the RAAS with an ACE inhibitor plus an ARB is attractive, as neither ACE inhibition nor angiotensin subtype-1 (ATj) receptor blockade alone by pharmacological agents leads to complete RAAS blockade, and clinical trials of each drug class alone have demonstrated slowing but not arrest of nephropathy progression. Therefore, ACE inhibitor in addition to ARB therapy, blocking the RAAS at different levels and theoretically more completely, would potentially have additive effects not only on decreasing blood pressure but also vascular complications. This is supported by animal studies (77), but few human clinical studies have been published as yet. A number of small studies have provided evidence that combination therapy may be of more benefit than monotherapy in slowing progression of DN with respect to albuminuria levels (78-81). In the largest, the Candesartan and Lisinopril Microalbuminuria (CALM) study of 199 diabetic subjects, candesartan plus lisinopril therapy for 6 mo led to greater blood pressure reduction than either agent alone, as well as greater reduction in microalbuminuria; however, it was not clear whether the latter effect was owing to the greater blood pressure change or to more complete RAAS blockade (82).

The addition of a nondihydropyridine CCB to an ACE inhibitor has been shown in a small study to decrease proteinuria in patients with DN by a greater degree than either agent alone (83). There are also a couple of small studies suggesting that addition of an aldosterone antagonist to an ACE inhibitor may lead to a greater decrease in proteinuria than either alone (84,85).

A more detailed discussion of the data regarding the relative efficacy of the different antihypertensive classes in slowing the progression of DN is beyond the scope of this review. Here we provide some basic guidelines regarding the therapy of hypertension in early diabetic kidney disease: blockade of the RAAS is clearly paramount, and thus far data support the likely interchangeability of ARBs and ACE inhibitors as first-line agents. Thiazide diuretics are a valuable second-line agent particularly as many patients have a component of volume overload; CCBs and P-blockers are safe and effective in diabetic patients and represent, in most cases, useful third-line add-on therapy. a-Agonists and peripheral vasodilators are best considered as fourth- or fifth-line antihypertensive agents. A full review of contraindications and other considerations regarding the different classes of agents are not discussed here, but may be found elsewhere (e.g., Chuang and Molitch [86]). Escalation of dosage and stepwise addition of different pharmacological agents should be done in as timely a manner as possible (barring serious or intolerable side effects) so as to reach goal blood pressure as rapidly as possible. The reduction of urinary albumin to less than 500 mg/d may also be beneficial in slowing progression of nephropathy, and dual ACE inhibitor/ARB therapy or the addition of a nondihydropyridine CCB or aldosterone antagonist to RAAS blockade may assist in attaining this target.

Although management of hypertension in diabetes will often require pharmacological agents, it is important not to neglect lifestyle changes. Weight loss has been shown to decrease blood pressure (87-89). Diet composition appears to affect blood pressure as well. The Dietary Approaches to Stop Hypertension (DASH) trial found that a diet high in fruits, vegetables, and low-fat dairy products; low in red meat, sweets, and saturated fats led to blood pressure reductions, particularly in hypertensive patients (systolic blood pressure [SBP] reduction 11.4, diastolic blood pressure [DBP] reduction 5.5 mmHg) (90). The so-called DASH diet also appeared to enhance blood pressure response to the ARB losartan in a study of 55 hypertensive patients (91). In hypertensive subjects in the DASH-Sodium study, the DASH diet plus a "low" sodium intake (500-1000 mg/d) was

Table 1

Recommendations for Lifestyle Modifications in Patients With Diabetes and Hypertension

Table 1

Recommendations for Lifestyle Modifications in Patients With Diabetes and Hypertension

Modification type

Recommendations

Potential decrease in BP

Weight loss

Decrease weight by diet and/or

5-20 mm Hg reduction in SBP

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