Un estudio publicado en NEJM evidencia que retrasan el avance del daño ocular diabético en más del 65% de los pacientes.
Los fármacos Enalapril y Losartan, usualmente empleados para tratar la hipertensión arterial, previenen el desarrollo de retinopatía en la población diabética, de acuerdo con los resultados de un estudio llevado a cabo por investigadores de la Universidad de Minnesota (Estados Unidos) y publicado en el último número de la revista The New England Journal of Medicine (2009;361:40-51). Concretamente, los resultados muestran como ambos fármacos retrasaron el avance del daño ocular diabético en más del 65% de los pacientes. La investigación fue diseñada originalmente para evaluar si el tratamiento temprano con alguno de estos fármacos, por lo general utilizados para regular la función renal y la hipertensión, podría desacelerar el deterioro de los riñones de los pacientes con diabetes tipo 1. Así, y poco después de iniciado el estudio, el equipo dirigido por el Dr. Michael Mauer decidió incluir evaluaciones de la retinopatía diabética. Después de seguir a 285 pacientes durante cinco años, los investigadores descubrieron que los ojos de los diabéticos se beneficiaban del uso de estos fármacos. La retinopatía progresó de manera significativa en el 38% de los voluntarios que recibieron placebo, comparado con únicamente el 25% de los pacientes tratados con el inhibidor de la enzima de conversión de la angiotensina (IECA) enalapril y el 21% de aquellos que tomaron el antagonista de los receptores de angiotensina II (ARAII) losartan. En definitiva, como concluye el Dr. Mauer, “existe un beneficio con la administración de estos fármacos, y el beneficio parece ser más fácil de detectar en las personas con pocos o nulos cambios oculares que en aquellas con cambios graves en la vista”.
Fuente: NEJM 2009;361:40-51
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From Medscape Medical News CME
Enalapril, Losartan May Have Retinal, but Not Renal, Benefits in Type 1 Diabetes
News Author: Laurie Barclay, MDCME Author: Hien T. Nghiem, MD
July 1, 2009 — Early blockade of the renin-angiotensin system does not slow the progression of nephropathy but may slow the progression of retinopathy in patients with type 1 diabetes, according to the results of a multicenter, randomized controlled trial by Michael Mauer, MD, and colleagues reported in the July 2 issue of the New England Journal of Medicine.
"The study of Mauer et al. is critically important because it evaluates the benefit of renin angiotensin system blockade on the earliest stages of type 1 diabetes before clinical markers of renal damage become apparent," Carlos M. Ferrario, MD, FAHA, FASA, FACC, a professor at the Hypertension and Vascular Research Center of the Wake Forest University School of Medicine in Winston Salem, North Carolina, told Medscape Diabetes & Endocrinology when asked for independent comment.
"The study's outcome challenges the idea, extrapolated from studies of more advanced degrees of diabetes nephropathy, that the use of losartan or enalapril will prevent progression of renal function decline in diabetic patients that are both normotensive and normoalbuminuric," said Dr. Ferrario, who is also editor in chief of Therapeutic Advances in Cardiovascular Disease.
"On the other hand, the separate finding that these treatments prevent progression of retinopathy underscores that the processes accounting for vascular injury are independent of the mechanisms that affect renal structure and function," said Dr. Ferrario.
Study Findings
In this trial, 285 normotensive patients with type 1 diabetes and normoalbuminuria were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and were followed up for 5 years. The main outcome measure was a change in the fraction of glomerular volume occupied by mesangium in renal biopsy specimens, and the retinopathy outcome was a progression of 2 steps or more on a retinopathy severity scale. Linear regression and logistic regression models were used for intent-to-treat analysis.
Complete renal biopsy data were available in 90% of patients and retinopathy data in 82%. During the 5-year follow-up, change in mesangial fractional volume per glomerulus was not significantly different between the placebo group (0.016 units) and the enalapril group (0.005 units; P = .38) or the losartan group (0.026 units; P = .26). Other structural variables determined from kidney biopsy also did not differ significantly among groups. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group, 17% with losartan (P = .01 by the log-rank test), and 4% with enalapril (P = .96 by the log-rank test).
"While these unexpected findings will require additional confirmation and further research as to how and when activation of the renin angiotensin system contributes to the development of renal damage in the presence of altered glucose utilization, the current data should force a reconsideration of clinical indications using these agents in patients with diabetes and no clinical markers of suspected loss of renal function," Dr. Ferrario said. "[These data] support the concept that the presence of albumin in urine is an indicator of generalized increased vascular permeability rather than simply increased glomerular permeability. This is a concept which is [generally] forgotten."
Independently of changes in blood pressure, the odds of progression of retinopathy by at least 2 steps was 65% lower with enalapril vs placebo (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.14 - 0.85) and 70% lower with losartan vs placebo (OR, 0.30; 95% CI, 0.12 - 0.73).
"Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy," the study authors write.
Adverse events included 3 serious, biopsy-related adverse events that resolved completely and chronic cough, which occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo.
Limitations of this study include inability to rule out blood pressure effects on diabetic retinopathy outcomes.
More Research Needed
In an accompanying editorial, Bruce A. Perkins, MD, MPH, from the University of Toronto in Ontario, Canada, and colleagues call the retinopathy results "very encouraging" but note additional questions. They recommend additional research before enalapril or losartan could be used for retinopathy prevention in clinical practice.
"The duration of therapy remains to be determined," the editorialists write. "From a risk-benefit perspective, the subgroup of patients less likely to benefit from inhibition of the renin-angiotensin system must be identified, including, for example, those with the best glycemic control or those with more advanced stages of retinopathy. Determining these thresholds and the logistical framework for standardized, accurate, and timely reporting of retinal findings between eye specialists and diabetes care providers requires active research — these are not trivial tasks."
The editorialists note that most subjects had no, minimal, or early nonproliferative diabetic retinopathy, raising questions about the benefits of treatment in patients with more advanced stages. It is still unknown whether the protective effect persists beyond 5 years or in the absence of inhibition of the renin-angiotensin system. Finally, diabetic macular edema was not addressed in this study.
"Losartan, other angiotensin II antagonists, [and] ACE [angiotensin-converting enzyme] inhibitors have been shown to reverse vascular hypertrophy even in its early stages," Dr. Ferrario told Medscape Diabetes & Endocrinology. "Therefore, this study provides additional evidence for this concept which, again, should be considered in the evaluation of when renin-angiotensin system blockers will provide greater benefit. Lastly, this study should stimulate more research into the question of what are the earliest changes through which diabetes affects renal structure and function, as at the incipient stages of diabetes, factors other than the renin-angiotensin system may be involved."
"The study of Mauer et al. is critically important because it evaluates the benefit of renin angiotensin system blockade on the earliest stages of type 1 diabetes before clinical markers of renal damage become apparent," Carlos M. Ferrario, MD, FAHA, FASA, FACC, a professor at the Hypertension and Vascular Research Center of the Wake Forest University School of Medicine in Winston Salem, North Carolina, told Medscape Diabetes & Endocrinology when asked for independent comment.
"The study's outcome challenges the idea, extrapolated from studies of more advanced degrees of diabetes nephropathy, that the use of losartan or enalapril will prevent progression of renal function decline in diabetic patients that are both normotensive and normoalbuminuric," said Dr. Ferrario, who is also editor in chief of Therapeutic Advances in Cardiovascular Disease.
"On the other hand, the separate finding that these treatments prevent progression of retinopathy underscores that the processes accounting for vascular injury are independent of the mechanisms that affect renal structure and function," said Dr. Ferrario.
Study Findings
In this trial, 285 normotensive patients with type 1 diabetes and normoalbuminuria were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and were followed up for 5 years. The main outcome measure was a change in the fraction of glomerular volume occupied by mesangium in renal biopsy specimens, and the retinopathy outcome was a progression of 2 steps or more on a retinopathy severity scale. Linear regression and logistic regression models were used for intent-to-treat analysis.
Complete renal biopsy data were available in 90% of patients and retinopathy data in 82%. During the 5-year follow-up, change in mesangial fractional volume per glomerulus was not significantly different between the placebo group (0.016 units) and the enalapril group (0.005 units; P = .38) or the losartan group (0.026 units; P = .26). Other structural variables determined from kidney biopsy also did not differ significantly among groups. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group, 17% with losartan (P = .01 by the log-rank test), and 4% with enalapril (P = .96 by the log-rank test).
"While these unexpected findings will require additional confirmation and further research as to how and when activation of the renin angiotensin system contributes to the development of renal damage in the presence of altered glucose utilization, the current data should force a reconsideration of clinical indications using these agents in patients with diabetes and no clinical markers of suspected loss of renal function," Dr. Ferrario said. "[These data] support the concept that the presence of albumin in urine is an indicator of generalized increased vascular permeability rather than simply increased glomerular permeability. This is a concept which is [generally] forgotten."
Independently of changes in blood pressure, the odds of progression of retinopathy by at least 2 steps was 65% lower with enalapril vs placebo (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.14 - 0.85) and 70% lower with losartan vs placebo (OR, 0.30; 95% CI, 0.12 - 0.73).
"Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy," the study authors write.
Adverse events included 3 serious, biopsy-related adverse events that resolved completely and chronic cough, which occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo.
Limitations of this study include inability to rule out blood pressure effects on diabetic retinopathy outcomes.
More Research Needed
In an accompanying editorial, Bruce A. Perkins, MD, MPH, from the University of Toronto in Ontario, Canada, and colleagues call the retinopathy results "very encouraging" but note additional questions. They recommend additional research before enalapril or losartan could be used for retinopathy prevention in clinical practice.
"The duration of therapy remains to be determined," the editorialists write. "From a risk-benefit perspective, the subgroup of patients less likely to benefit from inhibition of the renin-angiotensin system must be identified, including, for example, those with the best glycemic control or those with more advanced stages of retinopathy. Determining these thresholds and the logistical framework for standardized, accurate, and timely reporting of retinal findings between eye specialists and diabetes care providers requires active research — these are not trivial tasks."
The editorialists note that most subjects had no, minimal, or early nonproliferative diabetic retinopathy, raising questions about the benefits of treatment in patients with more advanced stages. It is still unknown whether the protective effect persists beyond 5 years or in the absence of inhibition of the renin-angiotensin system. Finally, diabetic macular edema was not addressed in this study.
"Losartan, other angiotensin II antagonists, [and] ACE [angiotensin-converting enzyme] inhibitors have been shown to reverse vascular hypertrophy even in its early stages," Dr. Ferrario told Medscape Diabetes & Endocrinology. "Therefore, this study provides additional evidence for this concept which, again, should be considered in the evaluation of when renin-angiotensin system blockers will provide greater benefit. Lastly, this study should stimulate more research into the question of what are the earliest changes through which diabetes affects renal structure and function, as at the incipient stages of diabetes, factors other than the renin-angiotensin system may be involved."
Clinical Implications
The most effective antihypertensive medications for patients who have proteinuria, diabetes mellitus, and reduced GFR are the blockers of the renin-angiotensin system.
Early blockade of the renin-angiotensin system in patients with type 1 diabetes and normoalbuminuria did not slow the progression of nephropathy but slowed the progression of retinopathy.
The most effective antihypertensive medications for patients who have proteinuria, diabetes mellitus, and reduced GFR are the blockers of the renin-angiotensin system.
Early blockade of the renin-angiotensin system in patients with type 1 diabetes and normoalbuminuria did not slow the progression of nephropathy but slowed the progression of retinopathy.
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