Postgraduate Medicine: Volume 122: No.2

Reducing Proteinuria in Patients with Diabetic Nephropathy with Telmisartan Versus Losartan

Peter P. Toth, MD, PhD

Abstract: Original article Bakris G, Burgess E, Weir M, Davidai G, Koval S; AMADEO Study Investiagtors. Telmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathy. Kidney Int. 2008;74(3):364–369. PRACTICE PEARL A telmisartan-based regimen showed a greater antiproteinuric effect than a losartan-based regimen at similarly achieved BP levels.

Chronic kidney disease (CKD) can be a complication of diabetes, leading to end-stage renal disease (ESRD). Proteinuria, a marker of renal injury and a risk factor for CKD progression, is reduced with blood pressure (BP) control via a renin-angiotensin system (RAS) blocker.¹ The Efficacy of Telmisartan Compared with Losartan in Reducing Proteinuria in Hypertensive Type 2 Diabetic Patients with Overt Nephropathy (AMADEO) study² was the first trial to compare 2 angiotensin receptor blockers (ARBs) for ability to reduce proteinuria.

The primary objective of AMADEO, a multicenter, prospective, randomized, double-blind, double-dummy study, was to compare the efficacy of telmisartan 40 to 80 mg with losartan 50 to 100 mg for reducing urinary protein-to-creatinine (UPC) ratio from baseline after 52 weeks of therapy in hypertensive patients with type 2 diabetes and overt nephropathy.

After a 4-week placebo washout period that included discontinuation of any ARB, angiotensin-converting enzyme (ACE) inhibitor, or direct vasodilator, patients were randomly assigned to receive either telmisartan or losartan. For the first 2 weeks, patients were administered 40-mg and 50-mg doses, respectively; for the remaining 50 weeks, patients were force-titrated to 80 mg and 100 mg, respectively. Additional medications could be given to achieve BP < 130/80 mm Hg.

The AMADEO study enrolled 860 participants with diabetes from 10 countries. Inclusion criteria were: age 21 to 80 years, hemoglobin A_1c ≤ 10%, serum creatinine ≤ 3 mg/dL (women) or ≤ 3.2 mg/dL (men), and first morning spot UPC ratio ≥ 700 mg/g creatinine. Enrolled patients had BP > 130/80 mm Hg or were taking antihypertensive medication. Patients were withdrawn if systolic BP was > 160 mm Hg or diastolic BP was > 110 mm Hg.

Telmisartan, an ARB, is currently approved by the US Food and Drug Administration for reducing risk of myocardial infarction, stroke, or death from cardiovascular causes in patients aged ≥ 55 years at high risk for major cardiovascular events who are unable to take ACE inhibitors. However, unlike losartan-based regimens, telmisartan-based regimens are not indicated for proteinuria reduction in patients with hypertension and diabetes. The AMADEO trial demonstrated that treatment with telmisartan reduced UPC 30% more than treatment with losartan.

Telmisartan was superior to losartan in reducing proteinuria while achieving a similar reduction in diastolic BP. Telmisartan reduced the adjusted mean UPC ratio by 29.8% (P < 0.0001) from baseline, whereas losartan did so by 21.4% (P < 0.0001); 15.5% of the telmisartan group and 22.4% of the losartan group reported severe adverse events. The reduction in UPC was significantly greater for telmisartan than losartan (P = 0.03).

The AMADEO study showed that there are differences among the ARBs regarding their ability to reduce proteinuria in patients with hypertension and diabetic nephropathy. A telmisartan-based regimen in this population showed a greater antiproteinuric effect than a losartan-based regimen at similarly achieved BP levels.

It has been commonly postulated that the effect of ARBs on hypertension and proteinuria is a class effect; that is, all ARBs would be equally effective at reducing proteinuria and concurrently reducing risk for developing CKD. However, the results of the AMADEO trial in patients with hypertension and diabetic nephropathy demonstrated that a telmisartan-based regimen may be preferred to a losartan-based regimen for reducing proteinuria, given similar levels of BP reduction. No differences were detected between groups in sodium excretion during the course of the trial. One possible explanation for the between-group differences observed in proteinuria could be that BP was lower in one group; however, there was no statistically significant difference in diastolic BP, and a trend toward lower systolic BP in the telmisartan group failed to reach statistical significance. The need for additional antihypertensive agents was similar in both groups. Another possible explanation for the results may be differences between ARBs in angiotensin 2 type 1-receptor binding affinity; however, receptor binding was not measured in this trial.

Diabetic nephropathy occurs in 20% to 40% of patients with diabetes^3-5 and accounts for 44% of new cases of kidney disease annually.⁶ Microalbuminuria, defined as a urinary albumin excretion rate in the range of 30 to 299 mg/24 h, is considered a marker for development of nephropathy in type 2 diabetes and is the leading cause of ESRD. Patients with microalbuminuria who progress to macroalbuminuria (urinary albumin excretion rate ≥ 300 mg/24 h) are likely to progress to ESRD, requiring either dialysis or renal transplantation.^7,8 However, studies have shown that early detection and aggressive treatment can slow the progression of renal disease.⁹

The mechanism by which microalbuminaria affects the kidney is an important factor in the overall pathogenesis of diabetic nephropathy. Microalbuminaria arises from the increased passage of albumin through the glomerular filtration barrier. Ultrastructural changes rather than alterations in glomerular pressure or filtration rate alone allow for this increase to take place. Glomerular permeability is one of the first signs of early diabetic nephropathy but does not correlate well with long-standing disease. Because the epidemiology of microalbuminuria shares a close association with systemic endothelial dysfunction and vascular disease, glomerular endothelial dysfunction also plays a significant role in microalbuminuria.¹⁰

Screening for microalbuminuria is usually performed by measurement of the albumin-to-creatinine ratio, using either random, untimed “spot” collection or timed collection (eg, overnight or 24 h).⁹ The latter tends to be more burdensome for the patient and does not add significant increased accuracy or decreased cost.^11-13 The use of urine tests for albumin only, whether by immunoassay or an in-office dipstick test, is somewhat less expensive but susceptible to false-negative and false-positive results due to variations in hydration levels and other factors. There have not been any large-scale, prospective, randomized trials of microalbuminuria screening to determine the overall success of these techniques. There continues to be uncertainty about what method of screening is most effective and practical in primary care settings, though most primary care physicians favor the random spot collection.¹³ A large randomized controlled trial showing long-term renal and vascular disease outcomes would be needed to provide validity and direction for future microalbuminuria screening strategies.

Once albuminuria is established, the current American Diabetes Association guidelines state that patients should be treated with either ACE inhibitors or ARBs, citing a significant body of evidence for use of these agents.³ Although ARBs do not prevent microalbuminuria in normotensive patients with type 2 diabetes,¹⁴ they have been shown to reduce the rate of progression from microalbuminuria to macroalbuminuria, increase time to doubling of serum creatinine, and decrease the incidence of ESRD in patients with type 2 diabetes mellitus. Trials such as Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA),^15,16 the Irbesartan Diabetic Nephropathy Trial (IDNT),¹⁷ Microalbuminuria Reduction with Valsartan (MARVAL),¹⁸ Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL),^19,20 and AMADEO have highlighted the significant renoprotective effects of ARBs. Inhibition of the RAS axis has been shown to reduce loss of kidney function in patients with diabetic nephropathy above and beyond any such effect attributable to a reduction in systemic BP alone.

Although combinations of drugs that block the RAS have been shown to provide additional lowering of albuminuria,^21,22 data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) do not support the use of the combination of an ARB plus an ACE inhibitor.²³ No correlation of risk reduction was demonstrated in ONTARGET despite lower BP in the combination group. Combination therapy was also associated with a higher incidence of adverse events.22 The long-term efficacy of ACE inhibitor/ARB combinations on renal outcomes have not yet been evaluated in clinical trials.

Renin-angiotensin system blockade is a cornerstone of antihypertensive therapy in high-risk patients. Blockade of the RAS through the use of ARBs is recommended as first-line therapy and provides renal protection by reducing microalbuminuria as well as rates of progression to macroalbuminuria and ESRD.

This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). Writing and editorial assistance was provided by Julia Wenniger, PhD, of Publication CONNEXION (Newtown, PA), which was contracted by BIPI for these services. The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), was fully responsible for all content and editorial decisions, was involved at all stages of manuscript development and preparation, and received no compensation.



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