Improving antihypertensive therapy in patients with diabetic nephropathy.

Abstract: Nearly all patients with diabetic nephropathy have comorbid hypertension, which greatly elevates the risk for cardiovascular events. As patients are surviving longer, their risk of progressing to end-stage renal disease is increasing, particularly in patients with type 2 diabetes. Prevention of cardiovascular and renal events in this population requires diligent efforts to control blood pressure, serum glucose, and serum lipids. Improving antihypertensive therapy in patients with diabetic nephropathy relies on the following unified strategies: reducing blood pressure to <130/80 mm Hg, prescribing an agent that blocks the renin-angiotensin system, and designing an antihypertensive regimen that both reduces albuminuria and provides cardiovascular protection. A majority of patients will require three or more antihypertensive agents to achieve these objectives. Appropriate antihypertensive therapy in patients with diabetic nephropathy delays progression of renal disease and leads to substantial cost savings.

Key Words: antihypertensive therapy, diabetic nephropathy, reninangiotensin system blockade

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The prevalence of diabetes is escalating rapidly world-wide, resulting in increased demand for medical care and higher health care costs. (1) In the United States, the total annual cost of diabetes was estimated to be $132 billion in 2002, which includes $24.6 billion for chronic complications attributable to diabetes. (2) The majority of patients with type 2 diabetes have hypertension, and a substantial portion of patients with both type 1 and type 2 diabetes will develop diabetic nephropathy.

End-stage renal disease (ESRD) requires a high expenditure of health care dollars, with health care costs on average exceeding $50,000 per patient per year. In 2000, an estimated $20 billion was spent for the nearly 400,000 patients with ESRD in the United States. (3) The National Kidney Foundation (NKF) notes that total Medicare and non-Medicare costs for ESRD treatment in 1998 were $12.0 billion and $4.7 billion, respectively. Mortality, morbidity, hospitalizations, quality of life, and costs for caring for patients with earlier stages of chronic kidney disease have not been systematically studied. (4) Advances in cardiovascular medicine are increasing survival rates in these patients, which leads to an increasing number of patients with ESRD. Increased survival rates, however, are mitigated by this dire prediction: Among patients on dialysis, the 5-year survival rate is typically only about 32%.

Diabetes is now the most common cause of ESRD in the United States. (5) Diabetic nephropathy is the leading contributor to the total cost of diabetic care in the United States. (6) The patient with diabetic nephropathy who develops ESRD also has an extraordinarily high risk of cardiovascular events. The US Renal Data System predicts that in the year 2030, nearly 300,000 patients with diabetes will begin therapy for ESRD, bringing the total prevalence of the diabetic population undergoing renal replacement therapy to 1.3 million persons. (7) Moreover, the personal, social, and financial costs of diabetic nephropathy and ESRD are so high that even costly interventions, if effective, have a favorable cost/benefit ratio. (8, 9)

Good medical management can reduce the incidence of cardiovascular disease and diabetic nephropathy among patients with diabetes. Similarly, among patients who develop diabetic nephropathy, good medical management can slow the progression of both cardiovascular and renal disease. Without improvements in prevention and because of changes in demographics and increases in the number of cases of diabetes, rates of new cases of treated chronic kidney failure are expected to continue to rise between 5% and 8% per year. The Healthy People 2010 report includes a new national target of 217 new cases of ESRD per million population, noting that the current average annual increase in new cases of treated chronic kidney failure rate is 6%. Therefore, the expected rate in 2010 would be 612 new cases per million population. (10) Control of hypertension in patients with diabetic nephropathy has been shown to improve mortality and slow progression of renal disease. (11) However, data from the most recent National Health and Nutrition Examination Survey (NHANES) for 1999 to 2000 found that nearly two thirds of diabetic patients had not achieved the currently recommended blood pressure goal (<130/80 mm Hg), and only 7% had achieved the combined targets for blood pressure, total cholesterol (<200 mg/dL), and glycosylated hemoglobin (HbA[.sub.1c] <7%). (12) Among these three important risk factors, intensive blood pressure control has been reported to be the most cost-effective intervention to prevent diabetic complications. (13) In patients with diabetic nephropathy, the key interventions for curbing progression of renal disease are lowering blood pressure to levels <130/80 mm Hg, reducing albuminuria, and prescribing an agent that blocks the renin-angiotensin system (RAS). This article focuses on improving antihypertensive therapy in patients with diabetic nephropathy.

Diabetic Nephropathy: Clinical Profile

About 20 to 30% of patients with diabetes develop diabetic nephropathy; progression to ESRD is more common in patients with type 1 diabetes than in patients with type 2 diabetes. (5) Native Americans, Hispanics, and African Americans with diabetes are at a greater risk of developing nephropathy, compared with non-Hispanic white Americans. (7) A large majority of patients with diabetic kidney disease are also hypertensive; however, the prevalence of hypertension (when defined as blood pressure >140/90 mm Hg) is consistently higher among patients with type 2 diabetic nephropathy (78-96%) than in patients with type 1 diabetic nephropathy (65-88%). (4) This is primarily because the development of hypertension is generally secondary to the onset of nephropathy in patients with type 1 diabetes, while in patients with type 2 diabetes, hypertension may predate the development of diabetes and is common even in the absence of nephropathy. Regardless of the cause of chronic kidney disease, hypertension accelerates its progress. Prospective epidemiologic studies in both men and women have shown that higher blood pressure values--particularly elevated systolic blood pressure values--are strongly associated with increased risk of ESRD. (14-16) The UK Prospective Diabetes Study (UKPDS), which compared the results of tight control of blood pressure (mean achieved pressure, 144/82 mm Hg) with less tight control (mean achieved pressure, 154/87 mm Hg), indicated that tight blood pressure control--a reduction in systolic pressure of [greater than or equal to]10 mm Hg--reduced the risk of any diabetes-related endpoint by 24%. This reduction was twice the risk reduction achieved by intensive blood glucose control. (17)

The onset of diabetic kidney disease is heralded by the presence of small amounts of urinary albumin, referred to as microalbuminuria or incipient nephropathy, and defined as urinary albumin excretion [greater than or equal to]30 mg/d or [greater than or equal to]20 [micro]g/min. (5) Without intervention, increasing amounts of albumin and protein appear in the urine. About 80% of patients with type 1 diabetes and up to 40% of patients with type 2 diabetes will progress to overt nephropathy (urinary albumin excretion [greater than or equal to]300 mg/d or [greater than or equal to]200 [micro]g/min). (5) As diabetic nephropathy progresses, the glomerular filtration rate (GFR) declines at a variable rate, ranging from 2 to 20 mL/min per year.

Among diabetic patients with overt nephropathy, within 20 years, approximately 75% and 20% of those with type 1 and type 2 diabetes, respectively, will develop ESRD. (5) This discrepancy is due in part to the greater risk of dying from coronary artery disease than of developing ESRD in patients with type 2 diabetes. Recent studies indicate that the onset and progression of diabetic nephropathy can be delayed with appropriate interventions; however, these interventions must be instituted early in the course of the disease to be beneficial.

Diabetic Nephropathy: Economic Impact

Overwhelming evidence has established a connection between diabetes and both microvascular and macrovascular complications. (17) Major cardiovascular events produce a greater financial burden than early-stage microvascular complications, such as microalbuminuria. (18) However, complications that are initially low in expenditure will progress to more costly advanced stages if left untreated. As diabetic nephropathy progresses from microalbuminuria to overt nephropathy and ESRD, the average weekly costs for managing diabetic nephropathy increase from $24 to $605. (19)

Diabetic nephropathy is a strong predictor of cardiovascular morbidity and mortality. (20) Appropriate management of diabetic nephropathy may be able to control costs associated with both renal and cardiovascular complications.

Improving Antihypertensive Therapy: Clinical Strategies

Therapeutic Lifestyle Management

Minimizing the risk of cardiovascular and renal events in patients with diabetic nephropathy requires aggressive management of a number of concomitant risk factors. Physicians and patients should work together to achieve control of blood pressure, and glucose and lipid levels; therapy should be optimized according to current guidelines. (2, 4, 21, 22) Smoking cessation, exercise, sodium restriction, and weight management are other important lifestyle modifications. The recently published NKF clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease make specific diet and lifestyle recommendations for all patients with diabetic kidney disease. (4) These include dietary sodium intake of less than 2.4 g/d, body mass index less than 25 kg/[m.sup.2], regular physical activity, limited alcohol intake, and smoking avoidance. Studies suggest that lifestyle interventions may carry a high economic cost, especially because of indirect costs (time off from work, transportation costs, and specialized diets overseen by professional nutritionists). Thus, if one includes all indirect costs, the cost-effectiveness ratio for lifestyle modifications is likely to exceed the currently accepted upper limit of $50,000 per year of life saved. (23)

Blood Pressure Control

It is well established that intensive lowering of blood pressure preserves renal function in patients with diabetic nephropathy. Clinical trial data show that decreasing levels of achieved systolic blood pressure are linearly associated with a less rapid decline in GFR in this population (Fig. 1). (4) Because of numerous studies showing the benefits of intensive blood pressure control in high-risk patients, four important national publications recommend lower blood pressure goals (<130/80 mm Hg) for all patients with diabetes and all patients with chronic kidney disease: the NKF clinical practice guidelines (Fig. 2), (4) a position statement from the American Diabetes Association, (2) the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), (21) and the consensus paper of the Hypertension in African Americans Working Group. (24)

For patients with diabetic nephropathy, achieving this blood pressure target is essential to slowing the progression of renal disease. Because lower blood pressures are associated with greater decreases in proteinuria in patients with renal disease, some renal experts recommend even lower blood pressure targets (eg, <125/75 mm Hg) for patients with very high levels of proteinuria (>1 g/d). (25) The NKF guidelines state that a lower systolic blood pressure goal may be beneficial in patients with diabetic nephropathy who have a total protein-to-creatinine ratio >500 to 1,000 mg/g; however, this guideline also cautions against lowering systolic blood pressure to levels <110 mm Hg. (4)

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

The important task of lowering blood pressure sufficiently in patients with diabetic nephropathy remains unrealized. Data for the diabetic cohort from NHANES for 1999 to 2000 found that 50% had been diagnosed with hypertension by their physician, and 85% of this group were taking antihypertensive medications. (12) Yet only 35% of the cohort had achieved blood pressure values <130/80 mm Hg, and 28% of patients had microalbuminuria.

RAS Blockade

While achieving a blood pressure target of <130/80 mm Hg is critical to slowing the progression of diabetic nephropathy, the level of albuminuria is actually the strongest predictor of the development of ESRD in these patients. (26) All classes of antihypertensive agents will generally reduce blood pressure in patients with diabetic nephropathy to a similar extent; however, they are not equivalent in the degree to which they reduce albuminuria and protect kidney function.

Abundant data from randomized clinical trials have shown that there are significant renal benefits with agents that block the RAS in all patients with diabetic nephropathy, regardless of baseline blood pressure (Table). (27-36) Moreover, data from these clinical trials show that RAS-blocking agents improve renal outcomes, despite achievement of equivalent blood pressure in placebo or comparator groups, indicating that these agents render this benefit by mechanisms in addition to their blood pressure-lowering effects. Current hypertension, (21) diabetes, (5) and renal (4) clinical guidelines recommend angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) as the preferred agents for patients with diabetic kidney disease because of the compelling data indicating that they slow the progression of renal disease and reduce proteinuria to a greater degree than other agents. Consequently, the RAS blockers are recommended in this population even in the absence of hypertension. Moreover, protection against cardiovascular events is an additional rationale for using an ACE inhibitor in patients with diabetes and renal disease or other cardiovascular risk factors. (31,37-39)

Blocking the RAS is critical to prevent both renal and cardiovascular events in patients with diabetic nephropathy. This is because chronic RAS activation, at both a systemic and tissue level, makes a significant contribution to the pathophysiology of hypertension, heart failure, and renal disease through the direct effects of its biologically active mediator, angiotensin II, in cardiac and renal vascular endothelium. Angiotensin II causes tissue injury at the heart and kidney by the promotion of growth factors, inflammatory cytokines, and interstitial fibrosis. (40)

In brief, diabetic nephropathy occurs because hyperglycemia and hypertension play interrelated roles in causing renal injury, which in turn signals activation of the RAS, creating high systemic and renal levels of angiotensin II in an escalating cycle of renal damage. Individually, either hyperglycemia or hypertension can provoke glomerular hyperfiltration, which leads to renal vascular injury, glomerular hypertension, and increased glomerular permeability. Chronic signaling of the RAS either initiates or intensifies both systemic and renal hypertension. Eventually, diabetic nephropathy is characterized by functional and structural changes in the kidney, including decreasing GFR, renal fibrosis, and eventual ESRD. (41)

Data from large randomized clinical trials completed to date show that ACE inhibitors delay renal decline in patients with type 1 diabetic nephropathy, (28) whereas ARBs have proven particularly beneficial in slowing the progress of renal disease in patients with type 2 diabetic nephropathy (Table). (32,33) The two classes were directly compared in a study in 250 patients with type 2 diabetic nephropathy and hypertension in which both enalapril and telmisartan slowed the progression of renal disease to a similar degree, as measured by loss of GFR from baseline to 5 years. (36) The NKF guidelines point out that, based on their similar antihypertensive and antiproteinuric RAS-blocking effects, both classes can be considered equally beneficial in patients with type 1 or type 2 diabetic nephropathy. (4) Furthermore, the NKF guidelines recommend that moderate-to-high doses of RAS-blocking agents should be used, rather than low doses, to maximize potential benefits, and that combined therapy with an ACE inhibitor and an ARB may provide additional benefits to the kidney. (4)

Combination Antihypertensive Therapy

Combination antihypertensive therapy is an essential strategy in the treatment of patients with diabetic nephropathy who should maintain a blood pressure level of < 130/80 mm Hg. Data from numerous randomized clinical trials have shown that the typical antihypertensive regimen includes two or more different medications to achieve this level of blood pressure reduction. (42)

The NKF guidelines make specific recommendations for combination antihypertensive therapy in patients with diabetic nephropathy (Fig. 2) and note that a diuretic should be included in the regimen of most patients, particularly since diuretic therapy may reduce the risk of hyperkalemia. (4) On the other hand, some diuretics may cause hypokalemia. The recommendation for use of a diuretic in patients with diabetic nephropathy is driven by data from clinical trials of RAS-blocking agents in this population, in which 60 to 90% of patients used either a thiazide-type or a loop diuretic in addition to their assigned RAS-blocking agent. (28,30,32,33) The type of diuretic selected should be governed by the patient's renal function. Patients with serum creatinine levels >1.7 mg/dL would likely derive greater benefit from a loop diuretic.

In general, a RAS-blocking agent can be combined with a diuretic, a calcium channel blocker (CCB), and/or a [beta]-blocker to achieve optimal blood pressure control as quickly as possible in patients with diabetic nephropathy. There is clinical evidence that combination therapy results in earlier achievement of blood pressure goals and better long-term control rates in patients with type 2 diabetes. (11) The pros and cons of different drug classes to use with a RAS blocker depends on the comorbid conditions of the patient. The JNC 7 lists compelling indications for specific antihypertensive classes (Fig. 3). (21)

There are two major compelling reasons for adding agents to the antihypertensive regimen of a patient with diabetic nephropathy: inadequate blood pressure control and significant proteinuria despite treatment with a RAS-blocking agent. If a patient with diabetic nephropathy requires further reductions in proteinuria (eg, persistent total protein-to-creatinine ratio >500-1000 mg/d), the NKF practice guidelines recommend the addition of either a RAS-blocking agent from the alternative class or a nondihydropyridine CCB (eg, verapamil), as both combinations appear to provide additive reductions in proteinuria. (4, 43) The utility of adding a dihydropyridine CCB (eg, amlodipine) to the regimen of a patient with diabetic nephropathy has previously been questioned; however, the NKF guidelines state that dihydropyridine CCBs can be used safely in combination with an ACE inhibitor or an ARB. (4) In fact, this combination may be of particular benefit in patients who require further reductions in blood pressure.

Data from small studies suggest that this combination may also enhance clinical benefits. (25, 44, 45) In a 6-month study (44) of hypertensive patients with type 2 diabetes and microalbuminuria, the combination of benazepril and amlodipine produced greater reductions in urinary albumin excretion than with benazepril monotherapy. The additional renal benefit with this combination is likely due to enhanced blood pressure reduction, since combination therapy was more effective than monotherapy in lowering both systolic and diastolic blood pressures. Data from a retrospective study of patients with advanced diabetic nephropathy support this finding. (46) The study involved 171 patients attending a nephrology clinic; at entry, patients receiving a CCB tended to have lower blood pressure and had a significant 8-mm Hg decrease in mean arterial pressure during 4 years of follow-up. Patients receiving an ACE inhibitor tended to have lower levels of serum creatinine both at entry and during follow-up. While CCB monotherapy was associated with poorer renal outcomes than with ACE inhibitor monotherapy, the combination had no adverse renal association. In contrast, lower mean arterial pressure was negatively associated with the development of ESRD in patients who were receiving the combination of both an ACE inhibitor and a CCB. (46)

Economic Impact

Lowering blood pressure to levels <130/80 mm Hg with a regimen including a RAS-blocking agent not only has been shown to postpone ESRD and improve survival in patients with either type 1 or type 2 diabetic nephropathy, but has also been shown to be economically advantageous. An economic model (3) based on outcome data from a US randomized controlled trial involving 409 patients with type 1 diabetic nephropathy, matched with US cost estimates for treating ESRD, estimated that, compared with placebo, treatment with the ACE inhibitor captopril would yield an absolute direct lifetime cost savings of $32,550 and $9,900 per patient with type 1 and type 2 diabetic nephropathy, respectively. Cumulatively, these savings would be expected to total approximately $475 million for the year 2004. (3) Using these same outcome data, the UK Diabetic Nephropathy Collaborative Study Group estimated a total per-patient direct cost savings of [pounds sterling]953 (approximately US $1,800) over 4 years for patients with type 1 diabetic nephropathy; the annual population cost savings would be expected to be [pounds sterling]400,000 (approximately US $750,000). (47) In a Canadian cost-utility analysis, a decision tree was utilized to determine if the government health system, which pays for the total costs of ESRD, would benefit economically by paying for the costs of ACE inhibitor therapy in patients with type 1 diabetic nephropathy. (48) This study, which estimated a high rate of noncompliance with ACE inhibitor therapy in patients who incurred the cost of therapy out-of-pocket, estimated improved compliance with coverage for the therapy that translated into an annual per-patient savings of $894 Canadian dollars (US $722). All three of these analyses were based on cost estimates for treating type 1 diabetic nephropathy, which progresses more rapidly and thus incurs greater annual medical expenses than type 2 diabetic nephropathy. Although annual per-patient savings are less in patients with type 2 diabetic nephropathy, the population is so much larger that the total economic impact could be expected to be substantial.

Conclusion

The overriding considerations for improving clinical outcomes in patients with diabetic nephropathy include controlling the triad of hyperglycemia, hypertension, and dyslipidemia. The vast majority of patients with diabetic nephropathy have hypertension. Intensive blood pressure control is a critical and cost-saving strategy for improving both cardiovascular and renal outcomes in this population.

The three cornerstones of treatment of hypertension in patients with diabetic nephropathy are: 1) reduce and maintain blood pressure levels to <130/80 mm Hg; 2) prescribe a RAS-blocking agent; and 3) reduce albuminuria and proteinuria. Nearly all of these very high-risk patients will require combination antihypertensive therapy to achieve these objectives. Unless contraindicated, the regimen should include an ACE inhibitor or an ARB. A diuretic, CCB, or both, plus additional agents as necessary, should be combined to achieve blood pressure control, reduce albuminuria, and provide optimal cardiovascular protection. The combination regimen should be designed with consideration of the patient's entire cardiovascular risk profile.

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38. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICROHOPE substudy. Lancet 2000;355:253-259.

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40. Dzau VJ. Theodore Cooper lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001;37:1047-1052.

41. Norris K, Vaughn C. The role of renin-angiotensin-aldosterone system inhibition in chronic kidney disease. Expert Rev Cardiovasc Ther 2003;1:51-63.

42. Bakris GL. A practical approach to achieving recommended blood pressure goals in diabetic patients. Arch Intern Med 2001;161:2661-2667.

43. Bakris GL, White D. Effects of an ACE inhibitor combined with a calcium channel blocker on progression of diabetic nephropathy. J Hum Hypertens 1997;11:35-38.

44. Fogari R, Zoppi A, Mugellini AM, et al. Effect of benazepril plus amlodipine vs benazepril alone on urinary albumin excretion in hypertensive patients with type II diabetes and microalbuminuria. Clin Drug Invest. 1997;13 (Suppl 1): 50-55.

45. Bakris GL, Smith AC, Richardson DJ, et al. Impact of an ACE inhibitor and calcium antagonist on microalbuminuria and lipid subfractions in type 2 diabetes: a randomised, multi-centre pilot study. J Hum Hyperiens 2002;16:185-191.

46. Crook ED, Preddie DC. Relative effects of angiotensin converting enzyme inhibitors and calcium antagonists in advanced diabetic nephropathy. Ethn Dis 2004;14:87-93.

47. Hendry BM, Viberti GC, Hummel S, et al. Modelling and costing the consequences of using an ACE inhibitor to slow the progression of renal failure in type 1 diabetic patients. QJM 1997;90:277-282.

48. Clark WF, Churchill DN, Forwell L, et al. To pay or not to pay? A decision and cost-utility analysis of angiotensin-converting-enzyme inhibitor therapy for diabetic nephropathy. CMAJ 2000;162:195-198.</p> <pre> Do not spoil what you have by desiring what you have not; remember that what you now have was once among the things you only hoped for. --Epicurus </pre> <p>Christian W. Mende, MD, FACP, FACN, FASN 

From the University of California, San Diego. San Diego, CA.

Reprint requests to Christian W. Mende, MD, 9850 Genesee Avenue, Suite 810. La Jolla, CA 92037. Email: [e-mail]

Accepted October 10, 2005.

Dr. Mende is on the Speaker's Bureau for Novartis, Merck, and Bristol Myer Squibb.

RELATED ARTICLE: Key Points

* Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD).

* End-stage renal disease is very expensive to manage and any interventions that may prevent or delay the onset of ESRD in patients with diabetes would lead to major cost savings.

* Reducing the risk of renal and cardiovascular events in patients with diabetic nephropathy relies on controlling blood pressure, hyperglycemia, and dyslipidemia.

* The vast majority of patients with diabetic nephropathy have hypertension.

* All patients with diabetic nephropathy should have blood pressure controlled to levels < 130/80 mm Hg, per clinical guideline recommendations.

* Regardless of blood pressure levels, agents that block the renin-angiotensin system should be the cornerstone of antihypertensive therapy in patients with diabetes.

* Most patients with diabetic nephropathy will require combination antihypertensive therapy. The antihypertensive regimen should be designed to bring the patient to blood pressure goal, reduce albuminuria, and provide cardiovascular protection.

* Treating diabetic nephropathy appropriately slows progression of renal disease and may prevent progression to renal failure, thereby prolonging life while lowering direct medical costs.

Table. Randomized controlled trials with renal outcomes in diabetic
patients (a)

Study, year of publication     Population            Comparators

Collaborative Study Group,     Type 1/DN             Captopril vs
  1993 (28)                      (n = 409; ~25%        placebo
                                 normotensive)
Ravid et al. 1993 (27)         Normotensive type 2/  Enalapril vs
                                 MA (n = 94)           placebo
European Microalbuminuria      Normotensive type 2/  Captopril vs
  Captopril Study, 1994 (29)     MA (n = 92)           placebo
ABCD, 2000; 2002 (30,31)       Type 2 (n = 470)      More intensive vs
                                                       less intensive BP
                                                       control;
                                                       enalapril vs
                                                       nisoldipine
IDNT, 2001 (33)                Type 2/DN (n = 1715)  Irbesartan vs
                                                       amlodipine vs
                                                       placebo
RENAAL, 2001 (32)              Type 2/DN (n = 1513)  Losartan vs placebo
IRMA, 2001 (34)                Type 2/MA (n = 590)   Irbesartan vs
                                                       placebo
MARVAL, 2002 (35)              Type 2/MA (n = 332;   Valsartan vs
                                 ~35% normotensive)    amlodipine
DETAIL, 2004 (36)              Type 2/DN (n = 250)   Telmisartan vs
                                                       enalapril

                                                              No. of
Study, year of publication     Renal outcome (b)              agents (c)

Collaborative Study Group,     Captopril reduced renal        NA
  1993 (28)                      endpoints by 50%, despite
                                 comparable BP reduction
Ravid et al. 1993 (27)         Enalapril slowed progression   NA
                                 to overt DN
European Microalbuminuria      Captopril slowed progression   NA
  Captopril Study, 1994 (29)     to overt DN
ABCD, 2000; 2002 (30,31)       Both treatments slowed         2.4
                                 progression to incipient
                                 and overt DN
IDNT, 2001 (33)                Irbesartan superior to         2.6
                                 placebo and amlodipine,
                                 despite comparable BP
                                 reduction
RENAAL, 2001 (32)              Losartan superior to placebo,  2.7
                                 despite comparable BP
                                 reduction
IRMA, 2001 (34)                Irbesartan reduced onset of    NA
                                 overt nephropathy, despite
                                 comparable BP reduction
MARVAL. 2002 (35)              Valsartan superior at          NA
                                 reducing albuminuria,
                                 despite comparable BP
                                 reduction
DETAIL, 2004 (36)              Both treatments slowed         NA
                                 decline in renal function
                                 to similar degree despite
                                 comparable BP reduction

(a) Patients were hypertensive, unless otherwise specified. Where
indicated, equivalency in achieved blood pressure was accomplished by
adding investigated therapies to conventional therapy.
(b) Renal outcome refers to the statistically significant difference in
disease progression based on increased serum creatinine, decline in
glomerular filtration rate or creatinine clearance, or progression to
ESRD, unless otherwise specified.
(c) Mean number of agents used to achieve predetermined BP targets.
DN, diabetic nephropathy; NA, not available; MA, microalbuminuria; ABCD,
Appropriate Blood Pressure Control in Diabetes; BP, blood pressure;
IDNT, Irbesartan Diabetic Nephropathy Trial; RENAAL, Reduction of
Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IRMA,
Irbesartan in Patients with type 2 Diabetes and Microalbuminuria;
MARVAL, Microalbuminuria Reduction with Valsartan; DETAIL, Diabetics
Exposed to Telmisartan and Enalapril; ESRD, end-stage renal disease.

                  Diuretic  [beta]B  ACEI     ARB      CCB      AA

Heart failure     [check]   [check]  [check]  [check]           [check]
Post-MI                     [check]  [check]                    [check]
High CAD risk     [check]   [check]  [check]           [check]
Diabetes          [check]   [check]  [check]  [check]  [check]
Chronic kidney                       [check]  [check]
disease
Recurrent stroke  [check]            [check]
prevention

Fig. 3 The seventh report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure guidelines
describe compelling indications that require certain antihypertensive
drug classes, based on favorable outcome data from clinical trials.
[beta]B, [beta]-blocker; ACEI, angiotensin-converting enzyme inhibitor;
ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; AA,
aldosterone antagonist; MI, myocardial infarction; CAD, coronary artery
disease.