Renal Benefit of ACE Inhibitors
Renal Benefit of ACE Inhibitors
Is there any significant study evidence of type 2 normotensive diabetics with microalbuminuria benefiting renally from angiotensin-converting enzyme (ACE) inhibitors that has not been extrapolated from studies done on type 1 diabetics?
Daniel Moore, MBChB, MRCGP
There are no large studies specifically addressing the question of ACE inhibitor use in normotensive type 2 diabetic patients, but this is partly because the definition of normotension has changed over the years. It has long been recognized that blood pressure increases in type 1 diabetes patients as albuminuria rises from the normal to the microalbuminuric range. This rise in pressure is well within even today's definition of normotension. By the time persistent microalbuminuria has developed, around 50% of type 1 patients have a blood pressure of > 140/90 mmHg.
In type 2 diabetes, the data are not so complete, but at least in the Pima Indians baseline mean arterial pressure was closely related to development of microalbuminuria over 15 years of diabetes duration. In the intervention trials in type 1 diabetes summarized in a meta-analysis, normotension was defined as < 160/95 mmHg in some studies, which is overt hypertension by today's definition. Thus the evidence of efficacy of therapy in "normotension" is perhaps more apparent than real, although adjustment for baseline blood pressure did not significantly diminish the magnitude of the effect. The important messages from this analysis are that ACE inhibitor therapy reduces the albumin excretion rate; this reduction is sustained for at least 4 years; statistically fewer patients develop overt proteinuria; and more regress to normoalbuminuria.
In type 2 diabetes, all of the data suggest a similar magnitude of effect. There are 3 studies of ACE inhibitor therapy of over 4 years' duration specifically in "normotensive" type 2 diabetes patients with microalbuminuria. These studies took place in Israel, India, and Japan, and all had a similar protocol using enalapril. It is important to note that the patients were relatively young (mean age < 50 years in the Israeli and Indian studies, and < 64 years in the Japanese study), slim (BMI < 25 kg/m), and had a blood pressure < 140/90 mmHg. Thus they were not typical of the white Europid type 2 diabetes population.
More recently, investigators have explored the use of the angiotensin II receptor blockers (ARBs). The MicroAlbuminuria Reduction With VALsartan (MARVAL) study in 332 largely white, Europid microalbuminuric patients looked at the effect of valsartan vs amlodipine on albuminuria over a 24-week study period. Around one third were "normotensive," defined as < 140/90 mmHg. The magnitude of reduction in albuminuria was similar for the normo- and hypertensive patients.
Thus it is probably fair to say that patients with both type 1 and type 2 diabetes who have microalbuminuria respond in a similar fashion to renin-angiotensin system blockade using ACE inhibitors or ARBs, irrespective of whether they are classified as normo- or hypertensive. I would therefore recommend therapy on the basis of the presence of microalbuminuria alone, aiming for a target blood pressure of < 130/80 mmHg in line with the latest JNC VII recommendations.
Is there any significant study evidence of type 2 normotensive diabetics with microalbuminuria benefiting renally from angiotensin-converting enzyme (ACE) inhibitors that has not been extrapolated from studies done on type 1 diabetics?
Daniel Moore, MBChB, MRCGP
There are no large studies specifically addressing the question of ACE inhibitor use in normotensive type 2 diabetic patients, but this is partly because the definition of normotension has changed over the years. It has long been recognized that blood pressure increases in type 1 diabetes patients as albuminuria rises from the normal to the microalbuminuric range. This rise in pressure is well within even today's definition of normotension. By the time persistent microalbuminuria has developed, around 50% of type 1 patients have a blood pressure of > 140/90 mmHg.
In type 2 diabetes, the data are not so complete, but at least in the Pima Indians baseline mean arterial pressure was closely related to development of microalbuminuria over 15 years of diabetes duration. In the intervention trials in type 1 diabetes summarized in a meta-analysis, normotension was defined as < 160/95 mmHg in some studies, which is overt hypertension by today's definition. Thus the evidence of efficacy of therapy in "normotension" is perhaps more apparent than real, although adjustment for baseline blood pressure did not significantly diminish the magnitude of the effect. The important messages from this analysis are that ACE inhibitor therapy reduces the albumin excretion rate; this reduction is sustained for at least 4 years; statistically fewer patients develop overt proteinuria; and more regress to normoalbuminuria.
In type 2 diabetes, all of the data suggest a similar magnitude of effect. There are 3 studies of ACE inhibitor therapy of over 4 years' duration specifically in "normotensive" type 2 diabetes patients with microalbuminuria. These studies took place in Israel, India, and Japan, and all had a similar protocol using enalapril. It is important to note that the patients were relatively young (mean age < 50 years in the Israeli and Indian studies, and < 64 years in the Japanese study), slim (BMI < 25 kg/m), and had a blood pressure < 140/90 mmHg. Thus they were not typical of the white Europid type 2 diabetes population.
More recently, investigators have explored the use of the angiotensin II receptor blockers (ARBs). The MicroAlbuminuria Reduction With VALsartan (MARVAL) study in 332 largely white, Europid microalbuminuric patients looked at the effect of valsartan vs amlodipine on albuminuria over a 24-week study period. Around one third were "normotensive," defined as < 140/90 mmHg. The magnitude of reduction in albuminuria was similar for the normo- and hypertensive patients.
Thus it is probably fair to say that patients with both type 1 and type 2 diabetes who have microalbuminuria respond in a similar fashion to renin-angiotensin system blockade using ACE inhibitors or ARBs, irrespective of whether they are classified as normo- or hypertensive. I would therefore recommend therapy on the basis of the presence of microalbuminuria alone, aiming for a target blood pressure of < 130/80 mmHg in line with the latest JNC VII recommendations.
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