Pharmacologic management of diabetic nephropathy

CLINICAL THERAPEUTICSWOL.

24, NO. 11,2002

Pharmacologic Management of Diabetic Nephropathy Eva M. Vivian, PharmD, BCPS, CDE, and Gail Breen Rubinstein, PharmD, BCPS University of the Sciences in Philadelphia, Philadelphia College of Pharmacy, Department of Pharmacy Practice and Pharmacy Administration, Philadelphia, Pennsylvania

ABSTRACT Background: Diabetes mellitus and hypertension are leading causes of end stage renal disease in the United States. Drug therapy that focuses on tight glycemic control and blood pressure control reduces the progression of nephropathy and cardiovascular complications. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the progression of renal disease in patients with diabetes. The angiotensin II receptor blockers (ARBs) losartan and irbesartan have also been shown to reduce microalbuminuria compared with placebo. The nondihydropyridine calcium channel blockers (CCBs) verapamil and diltiazem have been shown to be as effective as an ACE inhibitor in reducing urinary albumin excretion. Objective: This paper reviews the pathophysiology and diagnosis of diabetic nephropathy and recent clinical trials assessing the most appropriate therapeutic options for delaying the progression of nephropathy in patients with diabetes. Methods: Primary and review articles that addressed the pathophysiology, diagnosis, and therapeutic options for attenuating the progression of diabetic nephropathy were retrieved through a MEDLJNE search (January 1990 to August 2002) and the bibliographies of identified articles were reviewed. English-language sources were searched using the following search terms: diabetes mellitus, nephropathy, proteinuria, ACE inhibitors, and ARBs. Studies published in peer-reviewed journals that were determined to be methodologically sound, with appropriate statistical analysis of the results, were selected for inclusion in this review. Results: Patients with type 1 diabetes mellitus and evidence of nephropathy should be started on an ACE inhibitor unless contraindicated. The ARBs and ACE inhibitors are viable choices for patients with type 2 diabetes mellitus and evidence of proteinuria. Patients who experience adverse events such as dry cough with ACE inhibitors can be switched to ARBs. Clinical literature suggests that if monotherapy with an ACE inhibitor or ARB does not provide an adequate response, a nondihydropyridine CCB should be added to the regimen. Nondihydropyridine CCBs should also be considered when ACE inhibitors and ARBs are contraindicated. Accepted

for publication

August 28, 2002.

Printed in the USA. Reproduction in whole or part is not permitted.

0149.2918/02/$19.00

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Conclusions: ACE inhibitors and ARBs should be considered first-line therapy for patients with type 2 diabetes mellitus and nephropathy. The ACE inhibitors are still the drug of choice for patients with type 1 diabetes mellitus and evidence of incipient or overt nephropathy. If therapeutic goals are not achieved with an ACE inhibitor or ARB, then the addition of a nondihydropyridine CCB should be considered. Key words: angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotension II receptor blockers, diabetic nephropathy, microvascular complications, diabetes mellitus. (C& Thel: 2002; 24:1741-1756) INTRODUCTION Diabetes mellitus and hypertension are leading causes of end stage renal disease (ESRD), accounting for approximately one third and one fifth of all cases, respectively. 1,2 The prevalence of ESRD associated with type 1 diabetes mellitus (40%) is higher than that of type 2 diabetes mellitus (5% to 1O%).3 However, due to the greater prevalence of type 2 diabetes mellitus, a larger percentage of dialysis patients have type 2 versus type 1 diabetes mellitus. Factors important in the pathogenesis of diabetic nephropathy include hyperglycemia, hypertension, lipid abnormalities, ethnicity, genetic predisposition, cigarette smoking, and increasing age.‘T2 The clinical course of diabetic nephropathy includes an initial increase in glomerular filtration rate, thickening of the glomerular basement membrane, expansion of the mesangium, microalbuminuria, proteinuria, and eventually a decline in glomerular filtration.4 As renal function declines, arterial blood pressure

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is increased. Systemic hypertension further contributes to the rate of progression to nephropathy and eventually the syndrome can progress to ESRD.5,6 Diabetes mellitus, hypertension, and nephropathy all increase the morbidity and mortality associated with cardiovascular disease.7 Interventions such as drug therapy to produce tight glycemic control and blood pressure reduction will have a beneficial effect on patients with diabetes by reducing the progression of nephropathy and cardiovascular complications.7,8 Approximately two thirds of all patients with diabetes have hypertension.7 Blood pressure control, regardless of antihypertensive agent chosen, can slow the progression of diabetic nephropathy.7 However, in clinical studies, agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nondihydropyridine calcium channel blockers (CCBs) have slowed the progression of renal disease via mechanisms that cannot be fully accounted for by blood pressure control.3 This paper will discuss the pathophysiology, diagnosis, and therapeutic options for attenuating the progression of nephropathy.

METHODS Primary and review articles that addressed the pathophysiology, diagnosis, and therapeutic options for attenuating the progression of diabetic nephropathy were retrieved through a MEDLINE search (January 1990 to August 2002) and the bibliographies of identified articles were reviewed. English-language sources were searched using the following search terms: diabetes mellitus, nephropathy, proteinuria, ACE inhibitors, and ARBs. Studies

E.M. VIVIAN AND G. BREEN RUBINSTEIN

published in peer-reviewed journals that were determined to be methodologically sound, with appropriate statistical analysis of the results, are presented in this review.

PATHOPHYSIOLOGY OF DIABETIC NEPHROPATHY Several metabolic and hemodynamic processes contribute to the development of diabetic nephropatby. Hyperglycemia may lead to nephropathy by a number of mechanisms, including hypertrophy and thickening of the basement membrane, increased endothelial cell permeability to albumin, and increased matrix protein synthesis. Hyperglycemia may also cause an increase in vasodilatory prostaglandins, which in turn causes an increase in both renal perfusion and intraglomerular pressure. This ultimately results in hyperfiltration. Sustained hyperglycemia is also associated with the formation of advanced glycated end (AGE) products. The accumulation of AGE products in the kidney leads to cytokine production and subsequently mesangial hyperplasia. Excess glucose is converted to sorbitol by aldose reductase in the kidney through the polyol pathway. An increase in intracellular sorbitol results in the depletion of intracellular myoinositol, leading to afferent arteriolar vasodilation, increased renal blood flow, and an increase in glomerular capillary pressure. The polyol pathway also causes an increase in oxidative stress and kidney damage. Hyperglycemia increases the activity of protein kinase C in vascular smooth muscle and endothelial cells, which may also contribute to diabetic nephropathy.8 Systemic hypertension contributes to the development of diabetic nephropathy via

associated glomerular hypertension. Hemodynamic factors alter the function of glometular, mesangial, and epithelial cells, which results in an increase in mesangial matrix formation and basement membrane thickening.4 Vasoregulatory peptides such as endothelial-derived relaxing factor, tissue plasminogen activator, endotbelin- 1, and platelet-derived growth factor beta are also affected by intraglomerular hemodynamic factors.4 An increase in systemic blood pressure ultimately leads to extracellular matrix accumulation, increased glomerular permeability, proteinuria, and glomerulosclerosis.4 There may be a genetic link to the development of diabetic nephropathy.9 One theory is that polymorphism of the gene that codes for ACE production may lead to lower serum ACE levels.1° As a result, affected patients would have an increase in angiotensin II activity and resistance to inhibition of ACE. Although this theory seems plausible, current data on polymorphism are inconclusive. A genetic predisposition is also suggested by a disparity of distribution of diabetic nephropathy among different races. For example, diabetic nephropathy is more prevalent in nonwhite populations, specifically African Americans, Native Americans, Mexican Americans, Asian Americans, and those of Pacific Island descent.” Other factors that are associated with diabetic nephropathy include cigarette smoking and elevated total cholesterol levels.‘*~” There tends to be a more rapid progression to nephropathy in smokers compared with nonsmokers.‘* Patients with diabetes with microalbuminuria have been found to have lipid abnormalities including increased low-density lipoprotein (LDL) cholesterol levels, increased lipoprotein(a) levels, and decreased high-

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density lipoprotein (HDL) cholesterol levels.13 In patients with type 1 diabetes mellitus, total and LDL cholesterol levels have been found to be independent risk factors for the progression of renal disease. In patients with diabetes, microalbuminuria is an early indicator of nephropathy as well as a marker for an increase in cardiovascular morbidity and mortality.3 If left untreated, -80% of patients with type 1 diabetes mellitus experience an increase in albumin excretion of 10% to 20% per year3 Once albuminuria occurs, glomerular filtration falls at a rate of 2 to 20 mL/min per year.3,4 ESRD develops within 10 years in approximately half of the patients with type 1 diabetes mellitus who develop albuminuria.3 For this reason, it is important to intervene once microalbuminuria is detected to prevent the progression of nephropathy and development of ESRD. Many type 2 diabetics have evidence of microalbuminuria at the time of diagnosis because their diabetes went undetected for several years.3 If left untreated, 20% to 40% of type 2 diabetics will progress to albuminuria. However, after 20 years, only 20% will progress to ESRD due to the higher risk of dying from coronary heart disease.

DIAGNOSTIC

PROCEDURES

The diagnosis of diabetic nephropathy can only be confirmed definitively by renal biopsy; however, this procedure is invasive. Therefore, the clinician may choose to rely on other data to help make the diagnosis. A long-standing history of diabetes mellitus and microalbuminuria or proteinuria with an otherwise benign urinalysis are indicative of diabetic nephropathy. The presence of retinopathy also helps with the diagnosis because retinopa-

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thy usually occurs before the development of nephropathy. 1*3,4 Urinalysis for protein should be obtained in patients with diabetes on a yearly basis.3 This test should begin at diagnosis in patients with type 2 diabetes mellitus and 5 years after diagnosis in patients with type 1 diabetes mellitus.s A quantitative test for urine protein should follow a positive result on urinalysis. If results of the urinalysis are negative for protein, a test for microalbuminuria should be done. Microalbuminuria indicates glomerular damage and is predictive of clinical nephropathy. There are 3 methods available for screening of microalbuminuria.3 One method is a measurement of the urine albumin-to-creatinine ratio in a spot urine sample. This method is convenient in the clinical setting because it only requires 1 urine sample. A morning sample is preferred to take into account the diurnal variation of albumin excretion. A second method is a 24-hour urine collection of albumin. This method may be tedious and accuracy relies on proper collection techniques. However, an advantage of this method is that renal function can simultaneously be quantified. A third method, an alternative to the 24-hour collection, is a timed urine collection for albumin. Creatinine can again be collected to measure renal function; however, depending on the duration of the collection, the results may not be as reliable as a 24-hour collection. Microalbuminuria is defined as a urinary albumin excretion (UAE) of 30 to 299 pg/mg of creatinine on a spot urine sample, 30 to 299 mgl24 hours on a 24hour urine collection, or 20 to 199 pg/min on a timed urine collection.3 Transient rises in UAE can be associated with exercise, hyperglycemia, hypertension, urinary tract infection, heart failure, and

E.M. VIVIAN AND G. BREEN RUBINSTEIN

fever; therefore, if any of these conditions is present, it may result in false-positive results on screening tests.3 Variability exists in the excretion of albumin; therefore, microalbumirmria must be confirmed in 2 repeated tests in a 3- to 6-month period. Two of 3 tests with positive results for microalbuminuria confirm the diagnosis. Once a patient is diagnosed with microalbuminuria, the role of microalbuminuria surveillance is unclear3

TREATMENT

OPTIONS

Angiotensin-Converting Enzyme Znhibitors Inhibition of ACE has been shown to decrease systemic blood pressure, albuminuria, and glomerular capillary pressure.14-21 ACE inhibitors exert their effects by inhibiting ACE and blocking the breakdown of vasodilating substances such as bradykinin. ACE inhibitors normalize glomerular capillary pressures and reduce microalbuminuria. With early diagnosis and treatment, ACE inhibitors can delay the progression of nephropathy in patients with microalbuminuria. Numerous trials have shown that the ACE inhibitors are effective in attenuating the progression of nephropathy. l&2’ Dry cough occurs in 0.7% to 48% of patients who are treated with ACE inhibitors. Headache, dizziness, fatigue, and diarrhea occur in 5.2%, 4.3%, 3.0%, and 1.4% of patients, respectively. The incidence of both hypotension and hyperkalemia are >l %.22 Close monitoring of potassium levels is necessary. Rare but serious reactions such as angioedema, acute renal failure, and neutropenia occur in 0.1% to 1% of patients treated with ACE inhibitors. ACE inhibitors may cause rapid declines in re-

nal function in elderly patients with bilateral renal artery stenosis and advanced renal disease, and are contraindicated in pregnancy. There is a potential drug interaction between aspirin and ACE inhibitors. Some studies have reported that the concomitant use of aspirin and ACE inhibitors may decrease the effectiveness of the ACE inhibitor.23 The underlying mechanism is believed to be pharmacologic in nature. Aspirin may inhibit the beneficial effects of ACE inhibitors by inhibiting the formation of prostaglandins, thus interfering with the vasodilating effects of the ACE inhibitor. It is recommended that aspirin be administered at low doses (cl00 mg daily) that do not decrease prostaglandin inhibition.23 Other potential drugs that may interact with ACE inhibitors include potassium-sparing diuretics, lithium, antacids, digoxin, and allopurinol.22 ACE inhibitors lower aldosterone levels, which may contribute to hyperkalemia. Patients with renal insufficiency are at an increased risk of developing hyperkalemia when ACE inhibitors and potassium-sparing diuretics are used concomitantly. Antacids may decrease the bioavailability of ACE inhibitors and should be given 1 to 2 hours before or after the administration of the ACE inhibitor. ACE inhibitors may increase digoxin levels; therefore, periodic monitoring of digoxin levels is warranted. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin may decrease the antihypertensive effect of ACE inhibitors, especially in low-renin or volume-dependent patients. When an ACE inhibitor is added to diuretic therapy, there is an increased risk of postural hypotension secondary to sodium depletion and possible hypovolemia. ACE inhibitors in

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combination with allopurinol have been associated with an increase in hypersensitivity reactions. When administered concomitantly with ACE inhibitors, capsaicin may increase the risk of cough by causing respiratory tract irritation by substance P metabolites.22

Angiotensin Receptor Blockers Like the ACE inhibitors, ARBs reduce systemic blood pressure by decreasing vasoconstriction, releasing aldosterone, and causing vasoconstriction of the efferent arteriole of the glomerulus. However, these drugs inhibit angiotensin II by directly blocking the angiotensin II receptor, thereby decreasing the negative effects of angiotensin II on renal hemodynamics. Unlike the ACE inhibitors, ARBs do not inhibit the breakdown of vasodilating substances such as bradykinin. This is believed to be the reason for a lower incidence of dry cough associated with this class.22 Andersen et a124 conducted a l-year, double-blind, crossover trial in 16 patients with type 1 diabetes mellitus. The investigators compared the ARB losartan with the ACE inhibitor enalapril. The study was divided into five 2-month treatment periods. Patients were randomized to receive losartan 50 mg daily, losartan 100 mg daily, enalapril 10 mg daily, enalapril 20 mg daily, or placebo during each treatment period. Both enalapril and losartan decreased arterial blood pressure. Mean UAE was decreased by 33% (95% CI, 12-51) and 44% (95% CI, 26-57) for the losartan 50- and 100-mg treatment arms, respectively. The enalapril lo- and 20-mg treatment arms had a mean UAE reduction of 45% (95% CI, 23-61) and 59% (95% CI, 39-72), respectively.

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No significant difference was found between losartan 100 mg and enalapril 20 mg.” Brenner et a125 assessed the effects of losartan on renal and cardiovascular outcomes in 15 13 patients with type 2 diabetes mellitus and nephropathy. Patients were randomized to receive losartan 50 to 100 mg daily or placebo for 3.4 years. Patients continued to receive other antihypertensive agents (beta-blockers, diuretics, CCBs, or centrally acting agents) to control blood pressure if necessary. The primary end points were a doubling of the serum creatinine level from baseline, ESRD, or death. Losartan was found to decrease the risk of a doubling of the serum creatinine level compared with placebo (relative risk [RR] = 25%) (P = 0.006). The risk of ESRD also decreased with losartan compared with placebo (RR = 28%) (P = 0.002). Losartan was not found to have any effect on the death rate.25 This landmark study provided evidence that losartan has renal protective properties in patients with type 2 diabetes mellitus and nephropathy. Lewis et a126 investigated the renoprotective effects of irbesartan in 1715 hypertensive patients with type 2 diabetes mellitus and nephropathy. Patients were randomized to 1 of 3 treatment arms: irbesartan (75 mg titrated up to 300 mg/d); amlodipine (2.5 mg titrated up to 10 mg/d); or placebo. The target blood pressure was 135/85 mm Hg. The primary end points were a doubling of the baseline serum creatinine concentration, ESRD, or death. The unadjusted RR of doubling the serum creatinine concentration was 33% lower with irbesartan than with placebo (P = 0.003) and 37% lower than with amlodipine (P c 0.001). The risk of ESRD was 23% lower with irbe-

E.M. VIVIAN AND G. BREEN RUBINSTEIN

sat-tan than with either placebo or amlodipine (P = 0.07). These data indicate that of the 3 treatment choices, irbesartan was associated with better renal outcomes than the other agents. No significant differences in the rate of death were detected between irbesartan and placebo, amlodipine and placebo, or irbesartan and amlodipine.26 This study clearly demonstrated that irbesartan was effective at attenuating the progression of nephropathy. The MicroAlbuminuria Reduction With VALsartan (MARVAL) study27 in patients with type 2 diabetes mellitus compared the effectiveness of valsartan with the CCB amlodipine in the reduction of UAE in 332 patients with type 2 diabetes mellitus and evidence of microalbuminuria. Patients were randomized to receive valsartan 80 mg PO daily or amlodipine 5 mg PO daily for 24 weeks. The dose of each agent was doubled if the goal blood pressure of 135/85 mm Hg was not obtained. Bendrofluazide or doxazosin was added to the regimen if blood pressure goals were not obtained. The primary end point was a percentage change in UAE from baseline to week 24. At the end of the 24-week study period valsartan had a UAE reduction of 56% (95% CI, 49.6-63.0) from baseline that was a 44% reduction in UAE. Treatment with amlodipine resulted in a 92% (95% CI, 81.7-103.7) baseline reduction of UAE, an 8% reduction in UAE. There was a highly significant difference between the treatment arms’ ability to decrease UAE (P < 0.001). Valsartan also resulted in a greater conversion to normoalbuminuria compared with amlodipine (29 vs 14.5%; P = 0.001). No significant differences in blood pressure control between the 2 treatment arms were reported.

Dizziness, headache, fatigue, edema, diarrhea, and rash occur in >l% of patients taking ARBs. 22 Dry cough rarely occurs with this class. During clinical trials, dry cough occurred in 3.4% of patients treated with ARBs, compared with 3.3% in the placebo group. The incidence of hyperkalemia with ARBs is 4.4%. Angioedema, hypotension, and agranulocytosis are rare reactions (cl%) associated with the use of ARBs. As with ACE inhibitors, ARBs should be avoided in elderly patients with bilateral renal artery stenosis and advanced renal disease. ARBs are also contraindicated in pregnancy.22 Interference with the renin-angiotensin system may play a role in attenuating the progression of diabetic nephropathy. ACE inhibitors and ARBs may play a role in attenuating the progression of diabetic nephropathy by reducing systemic blood pressure and slowing UAE.3 Due to recent clinical trials, the American Diabetes Association (ADA) now recommends ARBs as initial agents of choice for hypertensive patients with type 2 diabetes mellitus and microalbuminuria or albuminuria. The ADA endorses ACE inhibitors in normotensive and hypertensive patients with type 1 diabetes mellitus and microalbuminuria or albuminuria. Normotensive patients with type 2 diabetes mellitus may receive an ACE inhibitor or ARB. As with ACE inhibitors, ARBs also inhibit aldosterone; thus, potential drug interactions may occur with potassium-sparing diuretics, potassium supplements, and NSAIDs. Patients with renal insufficiency are at increased risk for this adverse event. Fluconazole, an inhibitor of the cytochrome P450 2C9 enzyme system, inhibits the metabolism of losartan to its active metabolite, thus resulting in a decrease in the pharmacologic effect of losartan.22

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Calcium Channel Blockers There have been conflicting reports about the effectiveness of CCBs in slowing the progression of diabetic nephropathy.28-30 The CCBs dilate the afferent glomerular arteriole, but subclasses of CCBs have various effects on the efferent arteriole.31-34 In clinical trials, the nondihydropyridine CCBs have been shown to be renoprotective. Nondihydropyridine CCBs decreased UAE and improved glomerular barrier size-selectivity in patients with type 2 diabetes mellitus and overt nephropathy. 35 Nondihydropyridine CCBs combined with an ACE inhibitor may produce greater reductions in UAE than either agent alone.31 In a prospective, randomized, crossover trial, Bakri~~~ assessed the effects of diltiazem versus lisinopril on urinary protein excretion in 8 patients with type 2 diabetes mellitus with hypertension and nephrotic-range proteinuria (23.5 mg/24 hours). Diltiazem and lisinopril significantly reduced urinary protein excretion compared with baseline (P c 0.05). Urinary protein excretion was not statistically significant between the agents during either period. The results of this study suggest that diltiazem may be an appropriate alternative agent for patients who cannot tolerate an ACE inhibitor due to adverse effects. Slataper et a134 conducted a prospective, randomized, parallel study in 30 hypertensive patients with type 2 diabetes mellitus to assess the effects of lisinopril (group l), diltiazem (group 2), and a combination of furosemide plus atenolol (group 3) in slowing the progression of diabetic renal disease. After an l&month period, groups 1 and 2 had a mean UAE reduction of 1.4 gld and 1.3 g/d, respec-

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tively. The mean reduction in UAE by group 3 was only 0.2 g/d (P c 0.05). Albuminuria was significantly reduced in groups 1 and 2 compared with group 3 (P c 0.05).34 The results of this study support the use of lisinopril and diltiazem over a loop diuretic plus beta-adrenergic antagonist for attenuating the progression of diabetic renal disease. Smith et a135 compared a nondihydropyridine CCB, diltiazem, with a dihydropyridine CCB, nifedipine, to determine the effect on proteinuria and glomerular membrane permeability. Twenty-one patients with type 2 diabetes mellitus were randomized to receive nifedipine or diltiazem for 21 months. Drug dosing was titrated to achieve a blood pressure goal of <140/90 mm Hg or the maximum dose of diltiazem of 480 mg/d or nifedipine 90 mg/d. Both groups had similar blood pressure control. Diltiazem significantly reduced the mean (SD) amount of proteinuria from baseline (-57% [ 18%]) compared with nifedipine (4% [lo%]) (P c 0.001). Mean (SD) dextran clearance was reduced significantly in the diltiazem group (5.9 [2.3] to 2.6 [1.7] x 10e5) (P < 0.05) compared with the nifedipine group, which had a nonsignificant increase in mean dextran clearance (7.6 [3.1] to 11.2 [4.3] x 10e5). The reduction of large size dextran correlated with the reduction in proteinuria, indicating that reductions in proteinuria may be due to improved glomerular permselectivity. Diltiazem reduced proteinuria and improved glomerular permselectivity, thus slowing nephropathy progression.35 One percent to 10% of patients treated with verapamil and diltiazem may experience dizziness, nausea, hypotension, edema, and fatigue. 22 Gingival hyperplasia occurs in 20% of patients treated with

E.M. VIVIAN

AND G. BREEN RUBINSTEIN

diltiazem and verapamil. Twelve percent to 42% of patients in clinical trials experienced constipation while taking verapamil. Bradycardia, atrioventricular block, and arrhythmias may occur in 1% to 10% of patients with systolic dysfunction or other cardiac disorders. Diltiazem and verapamil should be avoided in patients with atrioventricular node dysfunction (second- or third-degree heart block), and/or left ventricular (systolic) dysfunction when ejection fraction is ~45%.~~ Diltiazem and verapamil may potentiate the pharmacologic effects of amiodarone; therefore, this combination should be avoided in patients with sick sinus syndrome and partial atrioventricular block. Beta-blockers should be used with caution when combined with diltiazem and verapamil because of their additive cardiovascular effects. Diltiazem and verapamil can increase carbamazepine, phenytoin, and cyclosporine levels through inhibition of the cytochrome P450 3A4 enzyme system. If these agents are used concomitantly, patients should be monitored for toxicity. Diltiazem and verapamil may increase digoxin levels by inhibition of renal and extrarenal clearance of digoxin. Cimetidine inhibits the metabolism of diltiazem and verapamil, thus increasing their bioavailability.22 The nondihydropyridine CCBs have been found to be as effective as ACE inhibitors in clinical trials and should be considered an alternative if there is a contraindication to the use of an ACE inhibitor or ARB or if adequate blood pressure control is not obtained with ACE inhibitor or ARB monotherapy33d1 (Figure). The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure6 recommends the use of CCBs in el-

derly patients with isolated systolic hypertension and acknowledges that this class of agents is effective in subpopulations. Clinical data suggest that the dihydropyridine CCBs could worsen the progression of nephropathy. The dihydropyridine CCB nifedipine is believed to have little or no effect on the efferent arteriole and may activate the sympathetic and renin-angiotensin system, resulting in little change in intraglomerular pressure.29g3o A study conducted in African American subjects with chronic renal disease randomized patients to long-term treatment with an ACE inhibitor, dihydropyridine CCB, beta-blocker, or diuretic. The CCB group was discontinued prematurely due to a significant decline in renal function when compared with the other treatment arms.42 The Modification of Diet in Renal Disease Study reported that patients who received dihydropyridine CCBs (nifedipine and amlodipine) had more proteinuria and a faster decline in renal function than those on other antihypertensive agents.43 Because the effect of nifedipine on proteinuria has not been clearly established, and it may have detrimental effects in some patients, the use of nifedipine should be avoided in patients at risk of developing diabetic nephropathy when other options are available.

Combination

Therapy

In 1 study, losartan was added for 1 week to the ACE inhibitor regimen of 7 diabetic patients with abnormal proteinuria. The investigators did not report any reduction in proteinuria with the addition of an ARB. The investigators attributed these results to the ARB’s lack of effect on bradykinin levels, which are responsi-

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Routine Urinalysis

I

1

i

-for protein’

+for protein’

1

1

Test for micmalbuminuria

Quantitative measure

I

I

L Overt nephropathy

Renal artery stenosis, hyperkalemia, pregnant

ARE: type 2 DM with BP >130/80 mm Hg ACEI or ARB: type 1 DM or type 2 DM with BP 430/80

mm Hg

ACEI or ARB adverse effect I no

Yes

Intolerable dry cough or rash with ACEI

Hyperkalemia. acute renal failure, angioedema

repeat urinalysis yearly

Figure.

Screening and treatment of microalbuminuria algorithm. *Must rule out conditions that may invalidate urine albumin excretion. Adapted from American Diabetes Association Clinical Practice Recommendations 2002.3 CCB = calcium channel blocker; ARB = angiotensin II receptor blocker; DM = diabetes mellitus; BP = blood pressure; ACE1 = angiotensin-converting enzyme inhibitor.

ble for glomerular efferent vasodilatation and reduction in glomerular filtration rate. Additional long-term studies are needed to further assess the effectiveness of this combination on diabetic nephropathy.44 The Candesartan and Lisinopril Microalbuminuria Study45 assessed the effects of lisinopril 20 mg and candesartan

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16 mg in reducing UAE in patients with type 2 diabetes mellitus. Patients were randomized to receive candesartan or lisinopril for 12 weeks. Patients were then assigned to 1 of 3 groups: candesartan alone, lisinopril alone, or combination therapy with candesartan and lisinopril for weeks 12 to 24. All 3 treatment groups

E.M. VIVIAN AND G. BRBEN RUBINSTBIN

reduced blood pressure significantly from baseline to 24 weeks (P < 0.001). However, combination therapy resulted in greater reductions in blood pressure and UAE compared with either agent alone. At week 12, urinary albumin:creatinine ratio for the lisinopril group was 46% (95% CI, 35-56) (P c 0.01) and 30% (95% CI, 1542) (P c 0.001) for the candesartan group. At week 24, the combination treatment resulted in a greater reduction in urinary albumin:creatinine ratio (50%) (95% CI, 36-61) (P < 0.001) compared with candesartan (24%) (95% CI, O-43) (P = NS) and lisinopril(39%) (95% CI, 20-54) (P c 0.001). Candesartan was as effective as lisinopril in reducing microalbuminuria in hypertensive patients with type 2 diabetes mellitus. Combinations of ACE inhibitors and CCBs have also been assessed and have shown promising results. A multicenter, open-label, randomized, parallel-group trial compared the effectiveness of the combination of trandolopril and verapamil versus either drug alone in treating blood pressure reduction and slowing progression of nephropathy in 37 patients with type 2 diabetes mellitus.31 The mean (SD) doses for verapamil monotherapy and combination therapy were 157.4 (39.3) mg twice daily and 219 (21.1) mg daily, respectively. The mean (SD) trandolapril monotherapy dose was 5.5 (1.1) mg daily and combination dose was 2.9 (0.8) mg daily. The combination therapy significantly reduced mean (SD) proteinuria from baseline (-62% [lo%]) to a greater extent than either agent alone (trandolapril -33% [8%] or verapamil -27% [8%]) (P < 0.001). Combination therapy produced a lower mean blood pressure compared with either monotherapy. However, the differences in blood

pressure were not statistically significant (P = 0.062). Combination therapy should be considered if monotherapy with an ACE inhibitor fails to reduce UAE or lower blood pressure to a clinically acceptable level.

Protein Intake Some clinicians believe that a proteinrestricted diet may also help delay the decline in renal function. The ADA3 recommends a protein intake of 0.8 g/kg per day in patients with macroalbuminuria (UAE of >300 mg of creatinine on a 24-hour collection). However, if the glomerular filtration rate has fallen or is beginning to fall, a protein intake of 0.6 g/kg per day may be warranted.3 Studies have not clearly demonstrated that a proteinrestricted diet is beneficial.4ti9 Because results are conflicting, further studies are necessary to determine the effect of such a diet on proteinuria.

Glycemic Control Strict glycemic control has been shown to delay the progression of diabetesrelated complications, such as retinopathy, renal disease, or neuropathy. The Diabetes Control and Complications Trial Research Groups0 and UK Prospective Diabetes Study Group51 reported that tight glycemic control can delay the progression of microvascular complications. Every attempt should be made to obtain a glycosylated hemoglobin level of >7% in patients with diabetes mellitus.s2

Cholesterol Control Patients with diabetes mellitus are at high risk for cardiovascular disease.53 Ag-

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gressive treatment of dyslipidemia is necessary to decrease the risk of macrovascular and microvascular complications. Patients with diabetes mellitus tend to have a unique type of dyslipidemia, consisting of an elevated LDL level, reduced HDL levels, elevated triglyceride levels, and increased platelet adhesiveness, all of which can contribute to the development of arteriolar sclerosis. Arteriolar sclerosis can result in an increased susceptibility to pyelonephritis, papillary necrosis, and tubular lesions of the kidney. There is evidence to suggest that there is a relationship between albuminuria and the rate at which LDL is produced. Following glomerular injury and hypoalbuminuria, the liver produces excessive amounts of very LDL. Oxidation of excessive LDL may result in mesangial cell expansion and increased basement membrane permeability and glomerular damage.53*54 Aggressive treatment of dyslipidemia will reduce the risk of cardiovascular disease in patients with diabetes mellitus. Primary therapy should focus on obtaining LDL levels of cl00 mg/dL, triglyceride levels cl50 mg/dL, and HDL levels >45 mg/dL for men and >55 mg/dL for women.55

Blood Pressure Control Both systolic and diastolic hypertension increase the progression of nephropathy. Aggressive treatment of hypertension may slow the progression of nephropathy. The UK Prospective Diabetes Study Group56 reported that tight blood pressure control reduced the risk of death and complications related to diabetes mellitus. The ADA currently recof ommends a goal blood pressure <130/80 mm Hg.57

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CONCLUSIONS Interference with the renin-angiotensin system plays an important role in attenuating the progression of diabetic nephropathy. ACE inhibitors and ARBs attenuate the progression of diabetic nephropathy by reducing systemic blood pressure and slowing UAE. Based on recent clinical trials, the ADA now recommends ARBs as the initial agents of choice for hypertensive patients with type 2 diabetes mellitus and evidence of proteinuria. However, until there is a direct comparison of ARBs with ACE inhibitors, we still support the use of both agents in hypertensive patients with type 2 diabetes. ARBs and ACE inhibitors should be used as the initial agents of choice in normotensive and hypertensive patients with type 2 diabetes mellitus and evidence of microalbuminuria. ACE inhibitors are still the drug of choice for patients with type 1 diabetes mellitus and microalbuminuria or albuminuria. ARBs can be an alternative for patients who would benefit from an ACE inhibitor but are unable to tolerate that class of drugs due to side effects such as an intolerable cough. The nondihydropyridine CCBs should be considered if there is a contraindication to the use of an ACE inhibitor or ARB, or if treatment goals are not obtained with monotherapy. Large multicenter trials have shown the benefits of glycemic control and blood pressure control in attenuating the progression of microvascular complications in patients with diabetes mellitus. Glycemic and blood pressure control combined with a protein-restricted diet may enhance the effects of drug therapy to further reduce proteinuria to an even greater extent than drug therapy alone.

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Address correspondence to: Eva M. Vivian, PharmD, BCPS, CDE, University of the Sciences in Philadelphia, Philadelphia College of Pharmacy, Department of Pharmacy Practice and Pharmacy Administration, 600 South Forty-third Street, Philadelphia, PA 19104-4495. E-mail: [email protected]

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