Renin-AngiotensinA l d o s t e ro n e S y s t e m Inhibition Overview of the Therapeutic Use of AngiotensinConverting Enzyme Inhibitors, Angiotensin Receptor Blockers, Mineralocorticoid Receptor Antagonists, and Direct Renin Inhibitors Kelly Mercier,
DO
a
, Holly Smith,
DO
b
, Jason Biederman,
DO
b,c,
*
KEYWORDS Renin Angiotensin Aldosterone Review Combination Diabetes Kidney disease Albuminuria KEY POINTS Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at this time. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors (DRIs) has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. An ACE inhibitor or ARB in proteinuric, hypertensive, nondiabetic kidney disease is renoprotective, as long as blood pressure is maintained below 140/90 mm Hg. At present, the combination therapy with ACE inhibitors and ARBs or with DRI, aliskiren, and ACE-inhibitor or ARB therapy cannot be advocated for routine use.
Disclosures: None. a Botsford Hospital, 28050 Grand River Avenue, Farmington Hills, MI 48336, USA; b Garden City Hospital, 6245 N. Inkster Road, Garden City, MI 48135, USA; c Hypertension Nephrology Associates, PC, 18302 Middlebelt Road, Livonia, MI 48152, USA * Corresponding author. Hypertension Nephrology Associates, PC, 18302 Middlebelt Road, Livonia, Michigan 48152. E-mail address: [email protected] Prim Care Clin Office Pract - (2014) -–http://dx.doi.org/10.1016/j.pop.2014.08.002 primarycare.theclinics.com 0095-4543/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Mercier et al
CAVEATS
There are 3 points to bear in mind in examining recent literature on inhibition of the renin-angiotensin-aldosterone system (RAAS). First, although the rationale for RAAS inhibition in the therapy for diabetic kidney disease is well established in experimental models of diabetic nephropathy,1,2 clinically it remains difficult to demonstrate that the effectiveness of these agents is related to a mechanistic effect and is not due to superior blood pressure control. One example is Svensson and colleagues’3 reanalysis of the HOPE study, demonstrating reduced 24-hour ambulatory blood pressure profiles by ramipril despite the office blood pressures being similar. Hence, the original conclusion that angiotensin-converting enzyme (ACE) inhibition reduced cardiovascular mortality was likely due to better blood pressure control and not to a class effect of ACE inhibitors. Second, nephrology literature commonly relies on the surrogate marker, proteinuria, to predict future outcomes, such as doubling of serum creatinine or development of end-stage renal disease (ESRD). This approach is necessary because of the tremendous time and expense needed to study true renal outcomes, especially as established treatments delay the progression of disease. However, surrogate markers do not always correlate with outcomes. Third, the term diabetic nephropathy currently is reserved for those with renal biopsies showing classic diabetic glomerulosclerosis. Hence, this article uses the more general term diabetic kidney disease, as most clinical trials lack biopsy data. THERAPEUTIC CONSIDERATIONS WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITOR OR ANGIOTENSIN RECEPTOR BLOCKER COMBINATION MEDICATIONS
ACE inhibitor/thiazide and ARB/thiazide combination medications have been widely used for the treatment of stage 2 hypertension since the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.4 The attractiveness of these combinations was based on recognition that: stage 2 hypertension (blood pressure >160/100 mm Hg) was difficult to treat to goal with monotherapy5,6; the side-effect profile is better with 2 antihypertensive medications at lower doses than with the maximal dose of a single medication7,8; these combinations are synergistic in their blood pressure–lowering ability4,7; and patient adherence is improved by reducing pill burden and the lower cost of thiazide diuretics.9 These recommendations came on the heels of the ALLHAT study demonstrating the utility of thiazide diuretics in comparison with other classes of antihypertensive therapy.10 Although these combinations are useful, other factors should be considered before choosing an ACE inhibitor/thiazide or ARB/thiazide combination. First, the ACCOMPLISH trial demonstrated improved cardiovascular outcomes with benazepril and amlodipine as opposed to benazepril and hydrochlorothiazide.11 Over the 2.9-year study, faster progression of chronic kidney disease, hypokalemia, and hypotensive episodes was more likely in the benazepril and hydrochlorothiazide arm. Second, hydrochlorothiazide will increase the incidence of impaired glucose tolerance and new-onset diabetes, important considerations in those with or at risk of diabetes mellitus. Lastly, thiazide diuretics also raise total cholesterol and lowdensity lipoprotein levels, which may be important, especially in younger patients.12 Despite these potential deleterious effects of thiazides, it must be acknowledged that diuretic use is important, if not imperative, in certain patient populations, such as blacks, and persons with salt-sensitive hypertension, congestive heart failure, or resistant hypertension. Although ACE inhibitor/amlodipine and ARB/amlodipine fixed-dose combinations are more widely used because of their availability, an ACE
RAAS inhibition
inhibitor and nondihydropyridine calcium-channel blocker (NDCCB) combination may be preferable, because of the negative chronotropic effects of NDCCBs and their equivalence to b-blockers in primary prevention of cardiovascular events in those without heart failure.13 In addition, an ACE inhibitor/verapamil combination can reduce proteinuria even further in patients with type 2 diabetes.14 DO ANGIOTENSIN RECEPTOR BLOCKERS INCREASE THE RISK OF CANCER?
In 2010, a meta-analysis of 9 trials suggested an association between ARB therapy and cancer risk, primarily lung cancer, over an average follow-up of 4 years.15 One important pitfall of this study was the lack of access to individual patient data, preventing time-to-event analysis. Subsequently using the Danish national registries with individual patient data, Pasternak and colleagues16 compared 107,466 new ARB users and 209,692 new ACE-inhibitor users. No increased rate of cancer was found in ARB users, nor was there any increased cancer risk with ongoing ARB exposure among 15 different cancer subgroups, with the exception of male genital cancers. Of importance, no increased risk of lung cancer was observed. The US Food and Drug Administration completed its own analysis in September 2011. Thirty-one trials including 84,461 patients randomized to ARB and 71,355 patients randomized to non-ARB comparators disclosed no increased risk of cancer or cancer-related death over an average follow-up of 39 months.17 INHIBITION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN HYPERTENSIVE DIABETICS WITH MACROALBUMINURIA
The Collaborative Study Group showed attenuation of proteinuria (>500 mg/24 h) and preservation of glomerular filtration rate (GFR) using the ACE inhibitor, captopril, to treat type 1 diabetic kidney disease in 1993.18 Several years later, the RENAAL and IDNT studies demonstrated the effectiveness of the ARBs losartan and irbesartan in reducing macroalbuminuria and delaying progression of type 2 diabetic nephropathy.19,20 Pohl and colleagues21 later conducted a post hoc analysis of the IDNT, showing a direct correlation between the degree of blood pressure lowering and renal outcomes as long as the systolic blood pressure was maintained higher than 120 mm Hg. Below this threshold, renoprotection was no longer conferred and all-cause mortality rose. Regarding diastolic blood pressure, the HOT trial established a 51% reduction in cardiovascular events when diastolic blood pressure was less than 80 mm Hg in diabetics (Table 1).22 INHIBITION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN HYPERTENSIVE DIABETES WITH MICROALBUMINURIA
Parving and colleagues23 demonstrated that irbesartan could prevent progression of microalbuminuria to macroalbuminuria in hypertensive type 2 diabetics. Similarly, the MARVAL study compared valsartan with amlodipine in reduction of urinary albumin excretion in type 2 diabetics with urine albumin excretion rates (UAER) of 20 to 200 mg/min and blood pressure less than 180/105 mm Hg. After 24 weeks of treatment, the patients in the valsartan group had significantly less UAER compared with the amlodipine group despite identical reduction in blood pressure.24 Additional studies have established the role of ACE inhibitors or ARBs in decreasing microvascular and macrovascular events in the treatment of hypertensive diabetic patients.25,26
3
4
Mercier et al
Table 1 Summary of major trials in diabetic kidney disease Degree of Proteinuria Trial (year)Ref.
Diabetes Type RAAS Agent Key Finding
Normoalbuminuria (
DO
a
, Holly Smith,
DO
b
, Jason Biederman,
DO
b,c,
*
KEYWORDS Renin Angiotensin Aldosterone Review Combination Diabetes Kidney disease Albuminuria KEY POINTS Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at this time. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors (DRIs) has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. An ACE inhibitor or ARB in proteinuric, hypertensive, nondiabetic kidney disease is renoprotective, as long as blood pressure is maintained below 140/90 mm Hg. At present, the combination therapy with ACE inhibitors and ARBs or with DRI, aliskiren, and ACE-inhibitor or ARB therapy cannot be advocated for routine use.
Disclosures: None. a Botsford Hospital, 28050 Grand River Avenue, Farmington Hills, MI 48336, USA; b Garden City Hospital, 6245 N. Inkster Road, Garden City, MI 48135, USA; c Hypertension Nephrology Associates, PC, 18302 Middlebelt Road, Livonia, MI 48152, USA * Corresponding author. Hypertension Nephrology Associates, PC, 18302 Middlebelt Road, Livonia, Michigan 48152. E-mail address: [email protected] Prim Care Clin Office Pract - (2014) -–http://dx.doi.org/10.1016/j.pop.2014.08.002 primarycare.theclinics.com 0095-4543/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Mercier et al
CAVEATS
There are 3 points to bear in mind in examining recent literature on inhibition of the renin-angiotensin-aldosterone system (RAAS). First, although the rationale for RAAS inhibition in the therapy for diabetic kidney disease is well established in experimental models of diabetic nephropathy,1,2 clinically it remains difficult to demonstrate that the effectiveness of these agents is related to a mechanistic effect and is not due to superior blood pressure control. One example is Svensson and colleagues’3 reanalysis of the HOPE study, demonstrating reduced 24-hour ambulatory blood pressure profiles by ramipril despite the office blood pressures being similar. Hence, the original conclusion that angiotensin-converting enzyme (ACE) inhibition reduced cardiovascular mortality was likely due to better blood pressure control and not to a class effect of ACE inhibitors. Second, nephrology literature commonly relies on the surrogate marker, proteinuria, to predict future outcomes, such as doubling of serum creatinine or development of end-stage renal disease (ESRD). This approach is necessary because of the tremendous time and expense needed to study true renal outcomes, especially as established treatments delay the progression of disease. However, surrogate markers do not always correlate with outcomes. Third, the term diabetic nephropathy currently is reserved for those with renal biopsies showing classic diabetic glomerulosclerosis. Hence, this article uses the more general term diabetic kidney disease, as most clinical trials lack biopsy data. THERAPEUTIC CONSIDERATIONS WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITOR OR ANGIOTENSIN RECEPTOR BLOCKER COMBINATION MEDICATIONS
ACE inhibitor/thiazide and ARB/thiazide combination medications have been widely used for the treatment of stage 2 hypertension since the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.4 The attractiveness of these combinations was based on recognition that: stage 2 hypertension (blood pressure >160/100 mm Hg) was difficult to treat to goal with monotherapy5,6; the side-effect profile is better with 2 antihypertensive medications at lower doses than with the maximal dose of a single medication7,8; these combinations are synergistic in their blood pressure–lowering ability4,7; and patient adherence is improved by reducing pill burden and the lower cost of thiazide diuretics.9 These recommendations came on the heels of the ALLHAT study demonstrating the utility of thiazide diuretics in comparison with other classes of antihypertensive therapy.10 Although these combinations are useful, other factors should be considered before choosing an ACE inhibitor/thiazide or ARB/thiazide combination. First, the ACCOMPLISH trial demonstrated improved cardiovascular outcomes with benazepril and amlodipine as opposed to benazepril and hydrochlorothiazide.11 Over the 2.9-year study, faster progression of chronic kidney disease, hypokalemia, and hypotensive episodes was more likely in the benazepril and hydrochlorothiazide arm. Second, hydrochlorothiazide will increase the incidence of impaired glucose tolerance and new-onset diabetes, important considerations in those with or at risk of diabetes mellitus. Lastly, thiazide diuretics also raise total cholesterol and lowdensity lipoprotein levels, which may be important, especially in younger patients.12 Despite these potential deleterious effects of thiazides, it must be acknowledged that diuretic use is important, if not imperative, in certain patient populations, such as blacks, and persons with salt-sensitive hypertension, congestive heart failure, or resistant hypertension. Although ACE inhibitor/amlodipine and ARB/amlodipine fixed-dose combinations are more widely used because of their availability, an ACE
RAAS inhibition
inhibitor and nondihydropyridine calcium-channel blocker (NDCCB) combination may be preferable, because of the negative chronotropic effects of NDCCBs and their equivalence to b-blockers in primary prevention of cardiovascular events in those without heart failure.13 In addition, an ACE inhibitor/verapamil combination can reduce proteinuria even further in patients with type 2 diabetes.14 DO ANGIOTENSIN RECEPTOR BLOCKERS INCREASE THE RISK OF CANCER?
In 2010, a meta-analysis of 9 trials suggested an association between ARB therapy and cancer risk, primarily lung cancer, over an average follow-up of 4 years.15 One important pitfall of this study was the lack of access to individual patient data, preventing time-to-event analysis. Subsequently using the Danish national registries with individual patient data, Pasternak and colleagues16 compared 107,466 new ARB users and 209,692 new ACE-inhibitor users. No increased rate of cancer was found in ARB users, nor was there any increased cancer risk with ongoing ARB exposure among 15 different cancer subgroups, with the exception of male genital cancers. Of importance, no increased risk of lung cancer was observed. The US Food and Drug Administration completed its own analysis in September 2011. Thirty-one trials including 84,461 patients randomized to ARB and 71,355 patients randomized to non-ARB comparators disclosed no increased risk of cancer or cancer-related death over an average follow-up of 39 months.17 INHIBITION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN HYPERTENSIVE DIABETICS WITH MACROALBUMINURIA
The Collaborative Study Group showed attenuation of proteinuria (>500 mg/24 h) and preservation of glomerular filtration rate (GFR) using the ACE inhibitor, captopril, to treat type 1 diabetic kidney disease in 1993.18 Several years later, the RENAAL and IDNT studies demonstrated the effectiveness of the ARBs losartan and irbesartan in reducing macroalbuminuria and delaying progression of type 2 diabetic nephropathy.19,20 Pohl and colleagues21 later conducted a post hoc analysis of the IDNT, showing a direct correlation between the degree of blood pressure lowering and renal outcomes as long as the systolic blood pressure was maintained higher than 120 mm Hg. Below this threshold, renoprotection was no longer conferred and all-cause mortality rose. Regarding diastolic blood pressure, the HOT trial established a 51% reduction in cardiovascular events when diastolic blood pressure was less than 80 mm Hg in diabetics (Table 1).22 INHIBITION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN HYPERTENSIVE DIABETES WITH MICROALBUMINURIA
Parving and colleagues23 demonstrated that irbesartan could prevent progression of microalbuminuria to macroalbuminuria in hypertensive type 2 diabetics. Similarly, the MARVAL study compared valsartan with amlodipine in reduction of urinary albumin excretion in type 2 diabetics with urine albumin excretion rates (UAER) of 20 to 200 mg/min and blood pressure less than 180/105 mm Hg. After 24 weeks of treatment, the patients in the valsartan group had significantly less UAER compared with the amlodipine group despite identical reduction in blood pressure.24 Additional studies have established the role of ACE inhibitors or ARBs in decreasing microvascular and macrovascular events in the treatment of hypertensive diabetic patients.25,26
3
4
Mercier et al
Table 1 Summary of major trials in diabetic kidney disease Degree of Proteinuria Trial (year)Ref.
Diabetes Type RAAS Agent Key Finding
Normoalbuminuria (
