In patients with type 2 diabetes mellitus, ARBs are especially effective for decreasing nephropathy progression rate, independent of their blood pressure–lowering effect (
Table 3). The randomized, double-blind, active-controlled, parallel-group MicroAlbuminuria Reduction with VALsartan (MARVAL) trial investigated the renoprotective effects of valsartan and amlodipine in patients with diabetes, with or without hypertension.
31 During the 24-week course of the MARVAL trial, valsartan was significantly more effective than amlodipine in reducing the urinary albumin excretion rate in the entire population with diabetes (
P < .001), in patients with diabetes and hypertension at study entry (
P < .001), and in normotensive patients with diabetes at study entry (
P < .001) with equivalent effects on blood pressure.
31
In the Reduction of Endpoints in NIDDM (non-insulin–dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) study, 1513 patients were assigned at random to receive losartan or placebo in addition to conventional antihypertensive therapy (excluding ACE inhibitors or another ARB).
46 Losartan reduced the risk of the doubling of serum creatinine concentration by 25% (
P = .006) and of ESRD by 28% (
P = .002).
46 The decreased risks of ESRD (26%;
P = .007) and of ESRD or death (19%;
P = .02)
46 remained unchanged after adjustment for blood pressure, indicating renoprotection was independent of blood pressure reduction.
46
The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) found that losartan was more effective than atenolol in preventing cardiovascular morbidity or death in hypertensive patients with and without diabetes (
P = .021),
47,48 with a 25% lower incidence of new-onset diabetes and stroke (both
P = .001) and a lower adverse event rate (
P = .001).
47 Throughout the mean 4.8 years of follow-up, blood pressure responses (systolic, diastolic, and mean arterial pressure) were virtually identical in patients randomly assigned to either drug, indicating the reduced risk for cardiovascular events with losartan was independent of its blood pressure–lowering effect.
47,48 In contrast, in a community-based study of 12,550 adults, type 2 diabetes mellitus was almost 2.5 times more likely to develop in patients with hypertension, and 28% more likely to develop in patients taking β-blockers than in those receiving no medication (relative hazard, 1.28; 95% CI, 1.04–1.57).
49 This increased risk was not seen in patients receiving thiazide diuretics, calcium channel blockers, or ACE inhibitors. In addition, risk was not influenced by the presence or absence of hypertension, weight gain, health-related behavior, level of education, or a variety of diabetes-related clinical traits and coexisting conditions.
49 Potential mechanisms for the increased incidence of diabetes with β-blockers include an attenuation of the β-receptor–mediated release of insulin from pancreatic beta cells and decreased blood flow through the microcirculation in skeletal muscle tissue leading to decreased insulin sensitivity.
50
Among patients with echocardiographic evidence of LVH at entry into the LIFE study, the urinary albumin-creatinine ratio was significantly higher in those with both eccentric and concentric LVH than in hypertensive patients with normal left ventricular geometry.
51 The correlation between urinary albumin-creatinine ratio and LVH was independent of age, race, systolic blood pressure, and presence of diabetes.
51
The Irbesartan Diabetic Nephropathy Trial (IDNT) compared irbesartan with amlodipine and placebo in diabetic hypertensive patients with macroalbuminuria (urinary protein excretion ≥900 mg/24 h).
52 Over the mean 2.6 years of follow-up, irbesartan was associated with a significantly slower increase in serum creatinine concentration compared with placebo (
P = .008) and with amlodipine (
P = .02).
52 Although the degree of blood pressure control in the irbesartan and amlodipine groups was the same, patients receiving amlodipine had worse renal outcomes (primary renal endpoint, doubling of baseline serum creatinine concentration).
52 This observation supports the concept that renoprotection provided by angiotensin-receptor blockade in patients with type 2 diabetes mellitus and nephropathy is a result of suppression of angiotensin II activity.
52
The randomized, double-blind, placebo-controlled trial IRbesartan in patients with type 2 diabetes and MicroAlbuminuria (IRMA-2) compared the effects of two doses of irbesartan and placebo on development of diabetic nephropathy.
25 This trial differed from the IDNT in that microalbuminuria, not macroalbuminuria, was an enrollment criterion. Overt nephropathy developed in significantly fewer patients taking irbesartan during the 24-month study (group treated with 150 mg of irbesartan vs group receiving placebo,
P = .05; group treated with 300 mg of irbesartan vs group receiving placebo,
P < .001).
25 Kaplan-Meier curves for the group receiving placebo and the group treated with 300 mg of irbesartan separated after 3 months of therapy and continued to diverge over the ensuing 21 months.
25 As in other studies with ARBs, the renoprotective effects of irbesartan were independent of its blood pressure effects.
25