HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Abbott, K. Articles by Bakris, G. L. Search for Related Content PubMed PubMed Citation Articles by Abbott, K. Articles by Bakris, G. L. Social Bookmarking                   What's this?

Blood Pressure Control and Nephroprotection in Diabetes

Walter Reed Army Hospital, Department of Medicine, Division of Nephrology, Bethesda, Maryland (K. Abbott) and Rush Presbyterian/St. Luke's Medical Center, Department of Medicine, Hypertension/Clinical Research Center, Chicago (E. Basta, G. L. Bakris).

Address for reprints: George L. Bakris, MD, Rush Presbyterian/St. Luke's Medical Center, 1700 W. Van Buren Street, Suite 470, Chicago, IL 60612.

	ABSTRACT

TOP ABSTRACT PHARMACOLOGICAL THERAPY TREATMENT OF (MICRO- AND... A SUGGESTED APPROACH TO... SUMMARY REFERENCES

 
Achievement of recommended levels of blood pressure as prescribed by guidelines (i.e., systolic blood pressure of < 130 mmHg in people with nephropathy secondary to type 2 diabetes) generally requires three or more different antihypertensive agents that have complementary modes of action. This systolic goal blood pressure, recommended by generally all international guideline committees, was derived from largely observational studies demonstrating a greater reduction of cardiovascular risk and preservation of kidney function at these levels. Commonly used antihypertensive combinations include angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, which have compelling indications for use in people with kidney disease and/or diabetes, combined with a diuretic, generally a thiazide-type agent. If additional therapy is required, either a beta-blocker or a calcium antagonist may be added to this antihypertensive "cocktail." Beta-blockers are particularly effective in people with a high sympathetic drive (i.e., high pulse rates) to lower blood pressure and reduce cardiovascular risk. Moreover, in recent studies, their benefits on kidney function, both by reducing macroalbuminuria and slowing the decline of kidney function, make them good agents to add in the appropriate clinical setting. With all these potential benefits of achieving blood pressure goals, it is unfortunate that only 11% of people being treated for hypertension with diabetic kidney disease achieve the blood pressure goal of < 130 mmHg, likely contributing to the climbing incidence of people starting dialysis. Physicians need to work harder and educate patients on the importance of achieving these lower blood pressure guidelines.

Key Words: Diabetes • nephropathy • hypertension • ACE inhibitors • angiotensin • receptor

In the setting of chronic renal parenchymal disease, regardless of etiology, hypertension is usually sustained and associated with a greater risk of cardiovascular morbidity and mortality than that conferred by essential hypertension in the absence of kidney disease.⁵ Hypertension in patients with chronic renal parenchymal disease should be thought of as adding "gasoline to a burning fire"; it markedly accelerates the loss of renal function, as well as other processes, such as atherosclerosis.

The results of any clinical trial that tests the efficacy of an antihypertensive drug to slow nephropathy progression must be considered in the context of the type and magnitude of intervention (e.g., BP goal in the trial, ACE inhibitors vs. other agents, and the stage of the disease at the inception of a trial). Renal function declines at different rates based on the etiology of the renal disease (e.g., diabetes vs. membranous nephropathy vs. IgA nephropathy). Moreover, the timing of achieving BP goals is critical in preventing the "avalanche effect" of renal disease progression. Specifically, intervention to a BP goal of < 130 mmHg in the very early stages of renal dysfunction (i.e., glomerular filtration rate [GFR] > 85 mL/min) is very likely to stop or markedly slow disease progression, whereas intervention when GFR is < 50 mL/min will only slow its progression. The difference in timing of intervention is similar to an avalanche coming down a mountain; the farther down the mountain, the less likely it can be stopped.

This concept is exemplified by the results of the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, in which the average levels of GFR were > 80 mL/min at the start of the trial versus other diabetes trials, in which the GFR was generally < 60 mL/min at baseline.⁶ GFR decline was virtually stopped with early BP intervention in the ABCD trial, whereas in other trials of more advanced renal disease, GFR loss occurred at a rate of 2 to 7 mL/min/year.⁷ Furthermore, BP levels attained in the ABCD trial averaged < 130 mmHg in the intense control group. Thus, results of clinical trials in patients with advanced renal disease should not be extrapolated to patients with very early disease since rates of decline in renal function are not uniformly linear. It is clear, however, that the earlier the goal BP is achieved, the more likely kidney function will be preserved and nephropathy progression halted.

Management of BP should focus on agents that not only lower BP but also reduce albuminuria, both micro and macro levels. This is an important association since clinical trials have shown that failure to reduce albuminuria despite BP reduction fails to maximally slow diabetic nephropathy.^7,8 The presence of microalbuminuria (MA) indicates an increased risk for cardiovascular events, the development of nephropathy in all patients, and the presence of nephropathy in those with type 1 diabetes.^9,10 MA is defined as an albumin excretion of between 30 and 299 mg/day, present on two different occasions on first-void morning urines. Albumin excretion > 300 mg/day represents macroalbuminuria. Urinary albumin excretion is best assessed by the albumin-to-creatinine (mg/g) ratio in a spot urine specimen.⁸ These values correlate with those obtained from 24-hour urine collections and are much more practical to collect. A summary of goal BP values from various sets of treatment guidelines is presented in Table I.

	PHARMACOLOGICAL THERAPY

TOP ABSTRACT PHARMACOLOGICAL THERAPY TREATMENT OF (MICRO- AND... A SUGGESTED APPROACH TO... SUMMARY REFERENCES

 
In randomized trials, achieving currently recommended levels of BP required an average of 3.2 different antihypertensive medications, taken daily (Figure 1). These lower BP groups, however, had much lower rates of CV event rates and slower declines in renal function, even though their average was slightly less than 140/90 mmHg. All national and international recommendations, including the sixth report of the Joint National Committee (JNC VI), World Health Organization (WHO), National Kidney Foundation, and the American Diabetes Association, provide a logical and evidence-based approach to the use of antihypertensive agents in patients with diabetes.^11-14 For all people except those with type 2 diabetes who have renal insufficiency and macroalbuminuria, the preferred initial therapy is an angiotensin-converting enzyme (ACE) inhibitor, with the dose titrated upward to the moderate or high dose range, as tolerated. In those with type 2 diabetes who have renal insufficiency, use of angiotensin receptor blockers (ARBs) is preferred, especially if blood pressure is not at recommended goal on a regimen that does not include an agent that blocks the renin-angiotensin system (RAS). As previously noted, additional therapies may be added to either the ACE inhibitor or ARB to achieve goal BP. In many patients with diabetes as well as with normal or slightly reduced kidney function (i.e., GFR > 70 mL/min), low-dose thiazide diuretics (i.e., 12.5-25 mg per day) and/or calcium channel blockers (CCBs) offer an additive effect with RAS blockers to achieve target BP goals.⁷ These agents have additive BP-reducing effects, with common side effects such as edema and hypokalemia abrogated by the concomitant use of an ACE inhibitor or ARB. When used in combination, these agents have also been shown to reduce CV events in clinical trials of participants with hypertension and high cardiovascular event risk.^15-17

View larger version (23K): [in this window] [in a new window]   Figure 1. Average number of different antihypertensive agents needed to achieve lower blood pressure goals in all available trials that randomized for different levels of blood pressure control.

Alternative agents, such as beta-blockers, also have an important role in the control of BP, especially because of their ability to reduce CV events and mortality (Table II). Their benefit on CV risk reduction is clearly present in patients with diabetes, despite their adverse metabolic effects. One beta-blocker that has demonstrated CV risk reduction with neutral metabolic effects is carvedilol.^18,19 There has been no such demonstrated reduction in CV risk for labetalol. An advantage of using beta-blockers is they have additive BP-lowering effects to most agents if the patient has a baseline pulse rate of greater than 80 beats per minute.^20-22

The renoprotective effects and additional benefits of other classes of antihypertensive agents, such as dihydropyridine CCB, are less uniform (Table III). It is clear that this subclass of CCBs is an excellent adjunct to RAS blockers for lowering blood pressure, but they have not been shown in clinical trials to provide any greater benefit apart from this effect. However, the long-acting preparations are safe.^23,24 To date, none of the dihydropyridine CCBs currently available in the United States has been shown to reduce ischemic CV events in randomized secondary prevention trials of survivors of acute myocardial infarction or renal disease progression when used in the absence of an ACE inhibitor or beta-blocker in high-risk patients.^25-28 Furthermore, in retrospective analyses of people with established nephropathy (i.e., serum creatinine > 1.4 mg/dL), this subclass of CCBs has not yet been shown to slow renal disease progression in the absence of an ACE inhibitor.²⁹ However, in some clinical trials, use of the dihydropyridine subclass of CCBs in concert with an ACE inhibitor proved to be safe, was well tolerated, and reduced CV events in patients with diabetes mellitus.

	TREATMENT OF (MICRO- AND MACRO-) ALBUMINURIA

TOP ABSTRACT PHARMACOLOGICAL THERAPY TREATMENT OF (MICRO- AND... A SUGGESTED APPROACH TO... SUMMARY REFERENCES

 
A slowing of kidney disease progression with BP reduction to < 130, in the absence of microalbuminuria reduction, has been reported with dihydropyridine CCBs in people with very early forms of diabetic nephropathy (i.e., GFR values > 80 mL/min in the ABCD trial).⁶ This can easily be explained by the fact that reduction of BP to < 130 mmHg at a very early stage of renal disease can still reduce intraglomerular pressure despite totally impairing renal autoregulation.^27,29,30 Once renal disease is established, however (i.e., GFR < 70 mL/min), use of a dihydropyridine CCB is contraindicated in the absence of an ACE inhibitor or ARB if one is to slow the decline in renal function.^7,17

Until the past decade, reductions in macro-albuminuria (> 300 mg/day) had not been clearly associated with renal benefit. Now, however, there are numerous long-term clinical trials available in patients who have lost more than 35% of their kidney function, with or without diabetes, demonstrating that reductions in macroalbuminuria of approximately 30% or more below their baseline correlate with marked reductions in renal disease progression.^25,31 The proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE) initiative included an analysis of different levels of albuminuria and their impact on renal disease progression.⁸ This, in turn, led to the PARADE recommendation by the National Kidney Foundation that therapies used to treat BP should also target reductions in albuminuria.

Conversely, the data to support an association between reductions in microalbuminuria and preservation of kidney function in people with near-normal levels of renal function (i.e., GFR values of > 80 mL/min) are less consistent. Studies by Ravid et al³² demonstrate that preventing the rise in microalbuminuria correlates with preservation of renal function. In contrast, numerous studies show that reduction of macroalbuminuria along with BP correlates more strongly with preservation of kidney function than does reduction in microalbuminuria.^{15,25,31,33-35} This apparent disparity in renal outcomes may simply be related to the fact that intervention has occurred earlier in the trials with microalbuminuria, thus taking much longer to detect differences in outcomes. However, a recent study from the Netherlands (n = 40,856) that evaluated the magnitude of albuminuria on CV outcomes demonstrated that the presence of albuminuria was an independent predictor of all-cause mortality.^36,37

Data from several trials demonstrate that if an ACE inhibitor is used in concert with a dihydropyridine calcium antagonist, a reduction is seen in albuminuria as well as in CV events.^17,38,39 In addition, other studies demonstrate that addition of a nondihydropyridine calcium antagonist to an ACE inhibitor provides additive reductions on macroalbuminuria in people with type 2 diabetes.⁴⁰ The reduction in albuminuria achieved by this combination occurred at the same level of BP control as seen with either agent individually.

Other classes of antihypertensive agents (i.e., alpha-blockers) are effective in lowering BP and are associated with favorable metabolic profiles in patients with diabetes.⁴¹ However, these agents have not been shown to reduce either albuminuria or CV mortality in people who develop heart failure.⁴² Therefore, alpha-blockers such as dihydropyridine CCBs may be useful as adjunctive therapy to help achieve the BP goal, but they do not appear to have unique CV or renoprotective effects in this patient population.

ARBs are the most recent BP-lowering class to be added to the antihypertensive armamentarium. They are the best tolerated of all antihypertensive drug classes, have an apparent benefit similar to ACE inhibitors, are suitable alternatives to ACE inhibitors for inhibiting the RAS if cough develops, and are preferred first-line agents in those with renal insufficiency and albuminuria that results from type 2 diabetes. Three multicenter randomized, placebo-controlled trials demonstrated that losartan and irbesartan markedly slowed progression of kidney disease in participants with type 2 diabetes. The Irbesartan Diabetic Nephropathy Trial (IDNT) used doses of irbesartan titrated to achieve a target BP of < 135 mmHg (138 mmHg, average achieved), another arm used amlodipine, and a separate arm received placebo and other therapies (non-CCB or ACE-inhibitor/ARB based).³³ As indicated previously, dihydropyridine CCBs should only be used in such patients as adjunctive therapy, including therapy with agents of proven benefit in reducing renal outcomes. This statement was supported by this trial, which showed an outcome with amlodipine to be no different from placebo, with irbesartan generating a 23% risk reduction for renal outcomes compared to amlodipine. The future use of dihydropyridine CCBs as "placebo" or comparator arms in studies of kidney disease with macroalbuminuria should, therefore, be discouraged by institutional review boards. The Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial is the only one to date to demonstrate that reduction of BP with a RAS blocking agent, losartan, markedly reduced the need for dialysis with a 20% risk reduction compared to placebo and conventional, non-ACE inhibitor-based treatment.¹⁵ However, these studies remain the only multicentered, randomized, placebo-controlled trials studying the efficacy of treatment with either ARB or ACE in reducing renal endpoints in patients with type 2 diabetes.

Of ARBs showing a benefit on renal outcomes, only losartan has been studied in people with high CV risk. The Losartan Intervention for Endpoint (LIFE) trial compared losartan with atenolol and showed that losartan significantly reduced cardiovascular endpoints in a cohort of 9193 participants with hypertension and left ventricular hypertrophy followed for at least 4 years.⁴³ In addition, like the Heart Outcomes Prevention Evaluation (HOPE) trial, new cases of diabetes were reduced by 25% in the losartan group.^43,44 Last, the group that garners the greatest risk reduction in any outcome trial, those with type 2 diabetes, also did so in this trial, with a 40% risk reduction for the primary outcome, which included CV events. This was significantly better than the atenolol group.

	A SUGGESTED APPROACH TO ACHIEVE BLOOD PRESSURE GOALS

TOP ABSTRACT PHARMACOLOGICAL THERAPY TREATMENT OF (MICRO- AND... A SUGGESTED APPROACH TO... SUMMARY REFERENCES

 
A paradigm to achieve BP goals in diabetes has been put forth by the National Kidney Foundation.⁷ Based on the most recent data, this paradigm has changed in some ways. These changes and an overview of the paradigm will be discussed in this section. Based on numerous studies that evaluate achievement of BP goals in the setting of an outpatient general medicine clinic, it is apparent that if an individual's systolic BP is greater than 15 mmHg above the desired goal, then two different antihypertensive agents are needed to achieve the goal.⁷ Thus, if the goal systolic BP is 130 mmHg, and the patient has an office reading of greater than 145 mmHg (without treatment), the physician will need to prescribe two different agents to achieve this goal. This has been nicely demonstrated in SHIELD (the Study of Hypertension and the Efficacy of Lotrel in Diabetes), in which combination therapy was given to such individuals with type 2 diabetes and was compared to monotherapy with add-on therapy later in the course.⁴⁵ This demonstrated a twofold greater number achieving the BP goal at 3 months compared to starting with monotherapy and then adding a second agent 2 months later. These data, taken together with the results of clinical trials in cardiovascular and renal disease, have led to the modification of the previously described paradigm to achieve the recommended BP goal for people with renal insufficiency and/or diabetes. It should be noted that the procedure of adding medications in this paradigm applies only to people with renal insufficiency or diabetes without other concomitant conditions such as angina, heart failure, or immediately following myocardial infarction (Figure 2).

View larger version (30K): [in this window] [in a new window]   Figure 2. A suggested paradigm, by which blood pressure goals in people with renal insufficiency and/or diabetes can be achieved by the least intrusive means possible. Note that initiation of this paradigm is suggested for people without other documented preexisting problems such as angina, heart failure, and so on, in whom many of the medications suggested in the schema may already be used. ARB, angiotensin receptor blockers. Everyone with diabetes and/or renal insufficiency should be instructed on lifestyle modifications as per the sixth report of the Joint National Committee (JNC VI). Everyone, however, should be started on therapy if blood pressure is greater than 130/85 mmHg. Note: If blood pressure (BP) < 15/10 mmHg above goal (130/80 mmHg), then the angiotensin-converting enzyme (ACE) inhibitor alone may be used. ACE inhibitor should be the same if two different fixed-dose combinations are used. *Nondihydropyridine calcium channel blockers (CCBs) (verapamil and diltiazem have been shown to reduce cardiovascular (CV) mortality, macroalbuminuria, and diabetic nephropathy progression independent of an ACE inhibitor). Beta-blockers may be substituted for calcium channel blockers if the patient has angina, heart failure, or arrhythmia, necessitating their use. Beta-blockers with proven efficacy to reduce CV events and the lowest side-effect profile are preferred. Note that use of a beta-blocker with a nondihydropyridine CCB should be avoided in the elderly and those with conduction abnormalities. Otherwise, such combinations are safe and particularly effective for lowering blood pressure. Other agents such as minoxidil, hydralazine and clonidine or methyldopa can also be used as adjunctive agents to help achieve goal blood pressure. Clonidine should not be used with beta-blockers for numerous reasons, not the least of which is a high likelihood of severe bradycardia.

ACE inhibitor/diuretic combinations are ideal as initial therapy to achieve the systolic BP goal of 130 mmHg based on the individual record of accomplishment of each drug on reducing CV events as well as renal disease progression. Based on previously discussed data, patients who have type 2 diabetes and renal insufficiency who are not on an ACE inhibitor or have poorly controlled blood pressure should be started on an ARB as initial treatment. Diuretics, especially in African Americans and the elderly, clearly potentiate the BP-lowering effects of ACE inhibitors. CCBs are meaningful second-line agents as well, in that they clearly demonstrate an additive BP-reducing capability when used with either ACE inhibitors or ARBs. Moreover, when ACE inhibitors are used in concert with calcium antagonists, they have resulted in the reduction of CV events. It should also be noted that the combination of a nondihydropyridine and a dihydropyridine calcium antagonist has additive and even synergistic BP-reducing capabilities.⁷ Conversely, combinations of beta-blockers and ACE inhibitors have failed to show any additive benefit on BP reduction, if the baseline pulse rate is less than 75 beats per minute.⁴⁶ Unlike in patients with heart failure, there are no data to support any additive benefit of the combination of a beta-blocker with an ACE inhibitor on CV events or renal disease progression in people with diabetes and/or renal disease. Thus, the role of beta-blockers is primarily one of BP reduction through reduction of heart rate and management of documented ischemic heart disease.

The optimal dose of an ACE inhibitor or ARB to maximally preserve kidney function remains unknown. However, in clinical trials that have shown these agents to be efficacious, generally the highest doses are used (i.e., 100 mg/day losartan, 300 mg/day irbesartan, 160 mg bid valsartan).^15,33,47 Prospective data to reduce an elevated creatinine clearance in early type 1 diabetes evaluated the effects of an ACE inhibitor in a dose-response fashion.⁴⁸ Doses of up to 100 mg/day of lisinopril were achieved. While creatinine clearance was reduced toward normal (e.g., < 120 mL/min), in everyone, it normalized in less than half the cases. Renal size, however, was significantly reduced, and microalbuminuria normalized in all cases at 18 months. The average dose of lisinopril was 82 mg/day used for an average of 18 months. Thus, while no statement can be made yet regarding the maximal dose of ACE inhibition, higher doses may have some additional utility.

The cost of antihypertensive medications and medical care is another major factor limiting success of therapy. It has been argued that the recommendation for more intensive treatment of blood pressure in patients at high risk for CV and renal disease may result in higher costs resulting from more medications and more visits to the health care system. The costs associated with treating people with type 2 diabetes with ACE inhibitors have been examined. Using cost and utilization data from the U.S. Veterans Administration medical system, Golan et al⁴⁹ concluded that all type 2 diabetic patients should be administered an ACE inhibitor, irrespective of whether the amount of macroalbuminuria is quantitated, as this strategy results in the fewest complications and the lowest costs. This was also shown in type 1 diabetes with ACE inhibitor use.^50,51 While such in-depth analyses have not been performed with ARBs, a comparative cost analysis based on blood pressure reduction was performed in South Africa.⁵² These data suggest that the cost variance between ARBs should also be viewed in the context of their antihypertensive effect.

Use of combination antihypertensive medications, such as an ARB or ACE inhibitor combined with either a diuretic or a calcium antagonist, may be useful to reduce pill counts as well as copayments at managed care pharmacies. Such long-acting combinations may also improve patient adherence to medications, in addition to their expected improvement in BP control, resulting in more consistent and cost-effective control of hypertension. Use of an ACE inhibitor with an ARB has been shown to further reduce proteinuria in models of diabetes but not beyond what would be predicted from additional BP reduction.^53,54

	SUMMARY

TOP ABSTRACT PHARMACOLOGICAL THERAPY TREATMENT OF (MICRO- AND... A SUGGESTED APPROACH TO... SUMMARY REFERENCES

 
The best available evidence supports a systolic BP goal of 130 mmHg in patients with diabetes and/or renal insufficiency. These lower BP levels are associated with reduced CV risk in patients with diabetes, whether or not they have preexisting renal disease. Antihypertensive regimens should include an agent that blocks the RAS system—ARB if nephropathy from type 2 diabetes is present or an ACE inhibitor for other types of renal diseases—to provide maximum CV and renal benefits in this cohort. Treatment with combination drugs that include an ARB or ACE inhibitor and another class of antihypertensive agents, such as CCBs or diuretics, can facilitate patient adherence as well as contain costs.

	FOOTNOTES

 
Paper presented at the 31st Annual Scientific Meeting of the American College of Clinical Pharmacology, San Francisco, on September 22, 2002.

DOI: 10.1177/0091270004263046

	REFERENCES

TOP ABSTRACT PHARMACOLOGICAL THERAPY TREATMENT OF (MICRO- AND... A SUGGESTED APPROACH TO... SUMMARY REFERENCES

 

1. Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16(2): 434-444.[Abstract]

2. Perry HM Jr, Miller JP, Fornoff JR, Baty JD, Sambhi MP, Rutan G, et al: Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension 1995;25(4, Pt. 1): 587-594.[Abstract/Free Full Text]

3. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, et al: Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334(1): 13-18.[Abstract/Free Full Text]

4. Cherry D, Woodwell D: National Ambulatory Medical Care Survey: 2000 Summary. Atlanta, GA: Center for Disease Control and Prevention, 2002.

5. Mailloux LU: Hypertension in chronic renal failure and ESRD: prevalence, pathophysiology, and outcomes. Semin Nephrol 2001;21(2): 146-156.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Estacio RO, Jeffers BW, Gifford N, Schrier RW: Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000;23(Suppl. 2): B54-B64.[Web of Science][Medline] [Order article via Infotrieve]

7. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, et al: Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000;36(3): 646-661.[Web of Science][Medline] [Order article via Infotrieve]

8. Keane WF, Eknoyan G: Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis 1999;33(5): 1004-1010.[Web of Science][Medline] [Order article via Infotrieve]

9. Garg JP, Bakris GL: Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. Vasc Med 2002;7(1): 35-43.[Abstract/Free Full Text]

10. Remuzzi G: Renal protection: progression, regression, remission from nephropathy beyond blood pressure control. Int J Clin Pract Suppl 2000;110: 9-15.[Medline] [Order article via Infotrieve]

11. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157(21): 2413-2446.[Abstract/Free Full Text]

12. 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension: Guidelines Subcommittee. J Hypertens 1999;17(2): 151-183.[Web of Science][Medline] [Order article via Infotrieve]

13. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002;39(Suppl. 1): S1-S231.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. American Diabetes Association: Clinical practice recommendations 2002. Diabetes Care 2002;25(Suppl. 1): S1-S147.[CrossRef][Medline] [Order article via Infotrieve]

15. Brenner BM, Cooper ME, De Zeeuw D, Keane WF, Mitch WE, Parving HH, et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12): 861-869.[Abstract/Free Full Text]

16. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, et al: Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21(4): 597-603.[Abstract]

17. Herlitz H, Harris K, Risler T, Boner G, Bernheim J, Chanard J, et al: The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study. Nephrol Dial Transplant 2001;16(11): 2158-2165.[Abstract/Free Full Text]

18. Giugliano D, Acampora R, Marfella R, De Rosa N, Ziccardi P, Ragone R, et al: Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension: a randomized, controlled trial. Ann Intern Med 1997;126(12): 955-959.[Abstract/Free Full Text]

19. Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei CL: Differential effects of beta-blockers in patients with heart failure: a prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 2000;102(5): 546-551.[Abstract/Free Full Text]

20. Ebbehoj E, Poulsen PL, Hansen KW, Knudsen ST, Molgaard H, Mogensen CE: Effects on heart rate variability of metoprolol supplementary to ongoing ACE-inhibitor treatment in type I diabetic patients with abnormal albuminuria. Diabetologia 2002;45(7): 965-975.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

21. Owens PE, Lyons S, O'Brien E: Can heart rate predict blood pressure response to anti-hypertensive drug therapy? J Hum Hypertens 1998;12(4): 229-233.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

22. Soininen K, Gerlin-Piira L, Suihkonen J, Kyllonen T, Parviainen R, Kyllonen E, et al: A study of the effects of lisinopril when used in addition to atenolol. J Hum Hypertens 1992;6(4): 321-324.[Web of Science][Medline] [Order article via Infotrieve]

23. Neal B, MacMahon S, Chapman N: Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet 2000;356(9246): 1955-1964.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

24. Staessen JA, Wang JG, Thijs L: Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001;358(9290): 1305-1315.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

25. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al: Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001;285(21): 2719-2728.[Abstract/Free Full Text]

26. Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, et al: Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996;335(15): 1107-1114.[Abstract/Free Full Text]

27. Griffin KA, Picken MM, Bakris GL, Bidani AK: Class differences in the effects of calcium channel blockers in the rat remnant kidney model. Kidney Int 1999;55(5): 1849-1860.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

28. Kloke HJ, Branten AJ, Huysmans FT, Wetzels JF: Antihypertensive treatment of patients with proteinuric renal diseases: risks or benefits of calcium channel blockers? Kidney Int 1998;53(6): 1559-1573.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

29. Koshy S, Bakris GL: Therapeutic approaches to achieve desired blood pressure goals: focus on calcium channel blockers. Cardiovasc Drugs Ther 2000;14(3): 295-301.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

30. Schrier RW, Estacio RO, Esler A, Mehler P: Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002;61(3): 1086-1097.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

31. Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, et al: Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data. Ann Intern Med 2001;135(2): 73-87.[Abstract/Free Full Text]

32. Ravid M, Lang R, Rachmani R, Lishner M: Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: a 7-year follow-up study. Arch Intern Med 1996;156(3): 286-289.[Abstract/Free Full Text]

33. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, 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(12): 851-860.[Abstract/Free Full Text]

34. Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R: Effect of calcium channel or beta-blockade on the progression of diabetic nephropathy in African Americans. Hypertension 1997;29(3): 744-750.[Abstract/Free Full Text]

35. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S: Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996;50(5): 1641-1650.[Web of Science][Medline] [Order article via Infotrieve]

36. Hillege HL, Fidler V, Diercks GF, Van Gilst WH, de Zeeuw D, van Veldhuisen DJ, et al: Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002;106(14): 1777-1782.[Abstract/Free Full Text]

37. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286(4): 421-426.[Abstract/Free Full Text]

38. Bakris GL, Griffin KA, Picken MM, Bidani AK: Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury. J Hypertens 1997;15(10): 1181-1185.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

39. Bakris GL: A practical approach to achieving recommended blood pressure goals in diabetic patients. Arch Intern Med 2001;161(22): 2661-2667.[Abstract/Free Full Text]

40. Bakris GL, Weir MR, DeQuattro V, McMahon FG: Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998;54(4): 1283-1289.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

41. Rachmani R, Levi Z, Slavachevsky I, Half-Onn E, Ravid M: Effect of an alpha-adrenergic blocker, and ACE inhibitor and hydrochloro-thiazide on blood pressure and on renal function in type 2 diabetic patients with hypertension and albuminuria: a randomized crossover study. Nephron 1998;80(2): 175-182.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

42. ALLHAT Collaborative Research Group: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000;283(15): 1967-1975.[Abstract/Free Full Text]

43. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et al: Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311): 995-1003.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

44. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(3): 145-153.[Abstract/Free Full Text]

45. Bakris G, Weir M, for the SHIELD Trial Investigators: Achieving goal blood pressure in patients with type 2 diabetes: conventional versus fixed-dose combination approaches. J Clin Hypertens (Greenwich) 2003;5(3): 202-209.[Medline] [Order article via Infotrieve]

46. Owens PE, Lyons S, O'Brien E: Can heart rate predict blood pressure response to anti-hypertensive drug therapy? J Hum Hypertens 1998;12(4): 229-233.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

47. Cohn JN, Tognoni G: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345(23): 1667-1675.[Abstract/Free Full Text]

48. Bakris GL, Slataper R, Vicknair N, Sadler R: ACE inhibitor mediated reductions in renal size and microalbuminuria in normotensive, diabetic subjects. J Diabetes Complications 1994;8(1): 2-6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

49. Golan L, Birkmeyer JD, Welch HG: The cost-effectiveness of treating all patients with type 2 diabetes with angiotensin-converting enzyme inhibitors. Ann Intern Med 1999;131(9): 660-667.[Abstract/Free Full Text]

50. Rodby RA, Firth LM, Lewis EJ: An economic analysis of captopril in the treatment of diabetic nephropathy. The Collaborative Study Group. Diabetes Care 1996;19(10): 1051-1061.[Abstract]

51. Hogan TJ, Elliott WJ, Seto AH, Bakris GL: Antihypertensive treatment with and without benazepril in patients with chronic renal insufficiency: a US economic evaluation. Pharmacoeconomics 2002;20(1): 37-47.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

52. Anderson AN, Wessels F, Moodley I, Kropman K: AT1 receptor blockers: cost-effectiveness within the South African context. S Afr Med J 2000;90(5): 494-498.[Web of Science][Medline] [Order article via Infotrieve]

53. Agarwal R: Add-on angiotensin receptor blockade with maximized ACE inhibition. Kidney Int 2001;59(6): 2282-2289.[Web of Science][Medline] [Order article via Infotrieve]

54. Sica DA, Bakris GL: Type 2 diabetes: RENAAL and IDNT—the emergence of new treatment options. J Clin Hypertens (Greenwich) 2002;4(1): 52-57.[Medline] [Order article via Infotrieve]
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Zheng, E. C. Carlson, L. Yang, P. M. Kralik, Y. Huang, and P. N. Epstein Podocyte-Specific Overexpression of the Antioxidant Metallothionein Reduces Diabetic Nephropathy J. Am. Soc. Nephrol., November 1, 2008; 19(11): 2077 - 2085. [Abstract] [Full Text] [PDF]

				L. M. Prisant Diabetes Mellitus: An Imperative for Prevention and Intense Management J. Clin. Pharmacol., April 1, 2004; 44(4): 394 - 396. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Abbott, K. Articles by Bakris, G. L. Search for Related Content PubMed PubMed Citation Articles by Abbott, K. Articles by Bakris, G. L. Social Bookmarking                   What's this?