Treating Diabetic Nephropathy — Are There Only Economic Issues?
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《新英格兰医药杂志》
Economic issues sometimes seem to be the primary considerations in discussions of treatment for nephropathy in patients with type 2 diabetes. But in the end, the economics of treatment are driven by clinical issues, many of which have yet to be resolved. For example, in the United States, type 2 diabetes is the leading cause of end-stage renal disease; it accounted for approximately 40 percent of cases in patients who began dialysis between 1994 and 1999. Worse yet, the worldwide incidence of end-stage renal disease among patients with type 2 diabetes is expected to double by 2010. These depressing data are compounded by estimates that 11 percent of adults in the United States have chronic kidney disease. Consequently, Medicare costs associated with end-stage renal disease are projected to increase from $12.7 billion in 1999 to $28.0 billion in 2010. Regardless of the exact dollar figures, the increase in the rate of diabetic nephropathy will undoubtedly strain the economies of all countries.
In addition to the macroeconomic impact, we must contend with the costs of drugs that are used to limit kidney damage caused by diabetes. As reported in this issue of the Journal, Barnett et al. (pages 1952–1961) compared an angiotensin II–receptor blocker, telmisartan, to an angiotensin-converting–enzyme (ACE) inhibitor, enalapril, in terms of stemming the loss of kidney function in patients with diabetes. Whichever type of agent is used, treatment costs are likely to be substantial. On the basis of the estimated number of diabetic adults with microalbuminuria, extrapolated from data from the third National Health and Nutrition Examination Survey (NHANES III), the yearly cost of treating these patients with enalapril or telmisartan would be about $327 million or $398 million, respectively, given the average wholesale costs of the drugs.
Are there effective treatments that could prevent or slow the damage from diabetic nephropathy? On the basis of the observation that diabetic rats that were given ACE inhibitors had substantially less kidney damage than control rats treated with other agents, despite similar blood-pressure levels in the two groups, the answer appears to be yes. When ACE inhibitors were used to treat patients with type 1 diabetes and established nephropathy, the loss of kidney function was reduced, so the answer was clearly yes.
These results also suggested that ACE inhibitors would benefit patients with nephropathy due to type 1 diabetes by mechanisms that go beyond treatment of their hypertension. Obvious questions are whether blocking the renin system would be beneficial in persons with type 2 diabetes and nephropathy and, if so, when therapy should begin and which drug or drugs should be used. In this issue of the Journal, Ruggenenti et al. (pages 1941–1951) report that ACE-inhibitor therapy significantly reduces the likelihood that microalbuminuria (overnight albumin excretion, 20 to 200 μg per minute) — which is generally accepted as the first sign of progressive kidney damage — will develop in a patient with type 2 diabetes and hypertension. Angiotensin-receptor blockers also reduce the frequency of progression from microalbuminuria to macroalbuminuria (albumin excretion of more than 200 μg per minute) in hypertensive patients with type 2 diabetes.
Barnett et al. studied patients with similar characteristics and found that both an ACE inhibitor and an angiotensin-receptor blocker slow the decrease in the glomerular filtration rate. They used a term that seems unusual to many of us — "noninferior" — in interpreting their outcomes. This term is used when a comparison is designed to demonstrate equivalence rather than the superiority of one therapy over the other. Such an analysis depends heavily on the clinical relevance of the expected outcome and therefore affects the sample size. The difference the investigators found in the decrease in the glomerular filtration rate (–3 ml per minute per 1.73 m2 of body-surface area) reveals the equivalence of the two agents, at least in patients who were predominantly microalbuminuric and who had an average glomerular filtration rate of more than 90 ml per minute per 1.73 m2.
The reason the angiotensin-receptor blocker was not found to be superior to the ACE inhibitor is unexplained but relevant, because the influence of angiotensin II may persist during prolonged therapy with an ACE inhibitor, since angiotensin II can be produced in blood vessels and other organs through a chymase-mediated pathway. Possible explanations include the use of an inadequate dose of the angiotensin-receptor blocker or increased bradykinin levels (an effect of ACE inhibition). An understanding of the mechanism could improve therapy, since the combination of ACE inhibition and angiotensin-receptor blockade is reportedly more effective in protecting the kidney than the use of either type of drug alone.
Is it necessary to conduct another trial comparing an ACE inhibitor with an angiotensin-receptor blocker in patients with type 2 diabetes? It would be of great interest to know whether the severity of diabetic complications is reduced to an equivalent degree by these two classes of drugs. Both types of drugs suppress albuminuria, and albuminuria, like hypertension, is not just a marker of the degree of kidney damage, but also a harbinger of cardiovascular disease. The reports by Ruggenenti et al. and Barnett et al. cannot answer the question about a reduced severity of diabetic complications, because cardiovascular events are infrequent among hypertensive patients with type 2 diabetes and microalbuminuria. However, they are not rare among patients with macroalbuminuria.1,2
The good news is that if an angiotensin-receptor blocker does suppress albuminuria when chronic kidney disease is advancing, the risk of end-stage renal disease or cardiovascular events is decreased.3,4 There is abundant evidence that ACE-inhibitor therapy suppresses albuminuria.5 Consequently, it is possible but not proven that ACE inhibition will be noninferior (equivalent) to angiotensin-receptor blockade in decreasing albuminuria along with the risk of kidney damage and cardiovascular events in hypertensive patients with type 2 diabetes and macroalbuminuria. In this case, the difference in cost between the two drugs becomes much more important. Second, clinicians are clamoring for such a trial because type 2 diabetes is so prevalent.5 Finally, there is the example of the Evaluation of Losartan in the Elderly (ELITE) trial: an initial analysis suggested that angiotensin-receptor blockade unexpectedly benefited older patients with heart failure, although this finding was not confirmed on formal testing.
Which drug should be used for treating people with type 2 diabetes? In the absence of ACE-inhibitor–associated cough or angioedema, clinical trials indicate that either an ACE inhibitor or an angiotensin-receptor blocker is effective in hypertensive patients who have type 2 diabetes with or without microalbuminuria (see Figure). For patients with macroalbuminuria, the results reported by Barnett et al., based largely on patients with microalbuminuria, are not conclusive, and there is more evidence supporting the use of angiotensin-receptor blocker therapy. However, the care of patients with type 2 diabetes involves much more than giving an ACE inhibitor or an angiotensin-receptor blocker. Monitoring of the blood pressure, albuminuria, and blood glucose levels is required; excess weight should be lost; and regular exercise is needed. Important goals are to lower the blood pressure to less than 130/80 mm Hg and to eliminate albuminuria. Controlling hypertension invariably requires dietary salt restriction and the use of diuretics, but controlling hypertension while blocking the renin–angiotensin system can have an important effect on nephropathy and possibly other complications of type 2 diabetes.
Figure. ACE Inhibition versus Angiotensin-Receptor Blockade in Progressive Nephropathy Associated with Type 2 Diabetes.
Clinical trials indicate that drugs that interrupt the renin–angiotensin system can suppress progressive kidney damage in type 2 diabetes. Angiotensin-converting–enzyme (ACE) inhibitors and angiotensin II–receptor blockers have similar benefits, but they have not been adequately compared in patients in whom macroalbuminuria has been detected. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
Source Information
From the Renal Division, University of Texas Medical Branch, Galveston.
References
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.
de Zeeuw D, Remuzzi G, Parving H-H, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004;110:921-927.
de Zeeuw D, Remuzzi G, Parving H-H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309-2320.
Lewis EJ, Lewis JB. ACE inhibitors versus angiotensin receptor blockers in diabetic nephropathy: is there a winner? J Am Soc Nephrol 2004;15:1358-1360.(William E. Mitch, M.D.)
In addition to the macroeconomic impact, we must contend with the costs of drugs that are used to limit kidney damage caused by diabetes. As reported in this issue of the Journal, Barnett et al. (pages 1952–1961) compared an angiotensin II–receptor blocker, telmisartan, to an angiotensin-converting–enzyme (ACE) inhibitor, enalapril, in terms of stemming the loss of kidney function in patients with diabetes. Whichever type of agent is used, treatment costs are likely to be substantial. On the basis of the estimated number of diabetic adults with microalbuminuria, extrapolated from data from the third National Health and Nutrition Examination Survey (NHANES III), the yearly cost of treating these patients with enalapril or telmisartan would be about $327 million or $398 million, respectively, given the average wholesale costs of the drugs.
Are there effective treatments that could prevent or slow the damage from diabetic nephropathy? On the basis of the observation that diabetic rats that were given ACE inhibitors had substantially less kidney damage than control rats treated with other agents, despite similar blood-pressure levels in the two groups, the answer appears to be yes. When ACE inhibitors were used to treat patients with type 1 diabetes and established nephropathy, the loss of kidney function was reduced, so the answer was clearly yes.
These results also suggested that ACE inhibitors would benefit patients with nephropathy due to type 1 diabetes by mechanisms that go beyond treatment of their hypertension. Obvious questions are whether blocking the renin system would be beneficial in persons with type 2 diabetes and nephropathy and, if so, when therapy should begin and which drug or drugs should be used. In this issue of the Journal, Ruggenenti et al. (pages 1941–1951) report that ACE-inhibitor therapy significantly reduces the likelihood that microalbuminuria (overnight albumin excretion, 20 to 200 μg per minute) — which is generally accepted as the first sign of progressive kidney damage — will develop in a patient with type 2 diabetes and hypertension. Angiotensin-receptor blockers also reduce the frequency of progression from microalbuminuria to macroalbuminuria (albumin excretion of more than 200 μg per minute) in hypertensive patients with type 2 diabetes.
Barnett et al. studied patients with similar characteristics and found that both an ACE inhibitor and an angiotensin-receptor blocker slow the decrease in the glomerular filtration rate. They used a term that seems unusual to many of us — "noninferior" — in interpreting their outcomes. This term is used when a comparison is designed to demonstrate equivalence rather than the superiority of one therapy over the other. Such an analysis depends heavily on the clinical relevance of the expected outcome and therefore affects the sample size. The difference the investigators found in the decrease in the glomerular filtration rate (–3 ml per minute per 1.73 m2 of body-surface area) reveals the equivalence of the two agents, at least in patients who were predominantly microalbuminuric and who had an average glomerular filtration rate of more than 90 ml per minute per 1.73 m2.
The reason the angiotensin-receptor blocker was not found to be superior to the ACE inhibitor is unexplained but relevant, because the influence of angiotensin II may persist during prolonged therapy with an ACE inhibitor, since angiotensin II can be produced in blood vessels and other organs through a chymase-mediated pathway. Possible explanations include the use of an inadequate dose of the angiotensin-receptor blocker or increased bradykinin levels (an effect of ACE inhibition). An understanding of the mechanism could improve therapy, since the combination of ACE inhibition and angiotensin-receptor blockade is reportedly more effective in protecting the kidney than the use of either type of drug alone.
Is it necessary to conduct another trial comparing an ACE inhibitor with an angiotensin-receptor blocker in patients with type 2 diabetes? It would be of great interest to know whether the severity of diabetic complications is reduced to an equivalent degree by these two classes of drugs. Both types of drugs suppress albuminuria, and albuminuria, like hypertension, is not just a marker of the degree of kidney damage, but also a harbinger of cardiovascular disease. The reports by Ruggenenti et al. and Barnett et al. cannot answer the question about a reduced severity of diabetic complications, because cardiovascular events are infrequent among hypertensive patients with type 2 diabetes and microalbuminuria. However, they are not rare among patients with macroalbuminuria.1,2
The good news is that if an angiotensin-receptor blocker does suppress albuminuria when chronic kidney disease is advancing, the risk of end-stage renal disease or cardiovascular events is decreased.3,4 There is abundant evidence that ACE-inhibitor therapy suppresses albuminuria.5 Consequently, it is possible but not proven that ACE inhibition will be noninferior (equivalent) to angiotensin-receptor blockade in decreasing albuminuria along with the risk of kidney damage and cardiovascular events in hypertensive patients with type 2 diabetes and macroalbuminuria. In this case, the difference in cost between the two drugs becomes much more important. Second, clinicians are clamoring for such a trial because type 2 diabetes is so prevalent.5 Finally, there is the example of the Evaluation of Losartan in the Elderly (ELITE) trial: an initial analysis suggested that angiotensin-receptor blockade unexpectedly benefited older patients with heart failure, although this finding was not confirmed on formal testing.
Which drug should be used for treating people with type 2 diabetes? In the absence of ACE-inhibitor–associated cough or angioedema, clinical trials indicate that either an ACE inhibitor or an angiotensin-receptor blocker is effective in hypertensive patients who have type 2 diabetes with or without microalbuminuria (see Figure). For patients with macroalbuminuria, the results reported by Barnett et al., based largely on patients with microalbuminuria, are not conclusive, and there is more evidence supporting the use of angiotensin-receptor blocker therapy. However, the care of patients with type 2 diabetes involves much more than giving an ACE inhibitor or an angiotensin-receptor blocker. Monitoring of the blood pressure, albuminuria, and blood glucose levels is required; excess weight should be lost; and regular exercise is needed. Important goals are to lower the blood pressure to less than 130/80 mm Hg and to eliminate albuminuria. Controlling hypertension invariably requires dietary salt restriction and the use of diuretics, but controlling hypertension while blocking the renin–angiotensin system can have an important effect on nephropathy and possibly other complications of type 2 diabetes.
Figure. ACE Inhibition versus Angiotensin-Receptor Blockade in Progressive Nephropathy Associated with Type 2 Diabetes.
Clinical trials indicate that drugs that interrupt the renin–angiotensin system can suppress progressive kidney damage in type 2 diabetes. Angiotensin-converting–enzyme (ACE) inhibitors and angiotensin II–receptor blockers have similar benefits, but they have not been adequately compared in patients in whom macroalbuminuria has been detected. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
Source Information
From the Renal Division, University of Texas Medical Branch, Galveston.
References
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-869.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-860.
de Zeeuw D, Remuzzi G, Parving H-H, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004;110:921-927.
de Zeeuw D, Remuzzi G, Parving H-H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309-2320.
Lewis EJ, Lewis JB. ACE inhibitors versus angiotensin receptor blockers in diabetic nephropathy: is there a winner? J Am Soc Nephrol 2004;15:1358-1360.(William E. Mitch, M.D.)