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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.
Diabetic Nephropathy
Vijay Viswanathan |
Click here to download PowerPoint slides of this commentary. |
Background
Diabetic nephropathy remains the major complication of diabetes mellitus and the leading cause of end-stage renal disease (ESRD) worldwide. A progressive decline in renal function can lead to overt diabetic nephropathy and ESRD. The likelihood of cardiovascular disease is also increased. Early diagnosis, good control of blood pressure (Casas et al, 2005), and good glycaemic control (Hovind et al, 2001) are crucial to achieve better therapeutic outcomes and to prevent this diabetic complication.
Several coordinated therapeutic regimens have emerged which may prevent the development of diabetic nephropathy and slow the progression of kidney disorder. In the MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes in the Heart Outcomes Prevention Evaluation) substudy, it was shown that an angiotensin-converting enzyme (ACE) inhibitor (ramipril, 10 mg/day) decreased the risk of overt nephropathy by 24% and the risk of cardiovascular death by 37% in patients with diabetes who were 55 years of age or older and had experienced a cardiovascular event or had one additional risk factor for cardiovascular disease (Cooper, 1998; MICRO-HOPE, 2000). A meta-analysis of 12 trials evaluating 698 patients with Type 1 diabetes who were non-hypertensive but microalbuminuric showed that treatment with an ACE inhibitor decreased the risk of progression of microalbuminuria by 60% and increased the chances of regression to normoalbuminuria (ACE Group, 2001). Thus, an ACE inhibitor has been shown to provide both renoprotection and cardioprotection in patients with diabetes.
Angiotensin receptor blockers (ARBs) are also effective in reducing the development of macroalbuminuria in patients with Type 2 diabetes who are microalbuminuric. Irbesartan (300 mg/day) reduced the risk of progression to overt diabetic nephropathy by 70% in a 2-year follow-up study of 590 patients with Type 2 diabetes who were hypertensive and microalbuminuric. Additionally, a 38% reduction in urinary albumin excretion was observed, with 34% of patients reversing to normoalbuminuria (Parving et al, 2001). Although there is no long-term study comparing the effects of ACE inhibitors or ARBs on the progression from microalbuminuria to overt diabetic nephropathy, both agents led to a similar reduction in albuminuria in a 12-week study (Hollenberg et al, 1998) and a 1-year study (Lacourcière et al, 2000).
Methods and Key Results
Several studies suggest that dual renin-angiotension-aldosterone system (RAAS) blockade therapy—ACE inhibitors and ARBs—provides a synergistic effect in diabetic nephropathy. In a meta-analysis of 10 trials, Jennings and colleagues examined the benefit of combination therapy in diabetic nephropathy. A search of MEDLINE, EMBASE, and other sources was conducted to identify the trials using the combination of an ACE inhibitor and ARB for treatment of diabetic nephropathy. In addition, a manual search of the literature using the references of original manuscripts and review articles was done. All the randomized, controlled, parallel, or crossover trials reporting 24-hour urinary protein excretion were included for meta-analysis. The primary outcome studied was the change in 24-hour urinary protein excretion.
To establish the effect of clinical heterogeneity of the included studies on the results of the meta-analysis, subgroup analysis was performed. Based on the effect of dose of medication used, all studies included for subgroup analysis were divided into 2 groups. An ACE inhibitor (maximal dose) and ARB was one group (156 patients), and an ACE inhibitor (submaximal dose) with ARB was another group (159 patients). It was observed that there was more benefit in the first group compared with the second group in terms of reducing proteinuria. Combination therapy had small effects on glomerular filtration rate, serum creatinine, potassium, and blood pressure.
Clinical Implications
It is known that single-drug therapy leads to incomplete blockade of the RAAS, which is defined as ‘ACE escape’ (Hollenberg et al, 1998; Parving et al, 2001). It is also interesting to know that an ACE inhibitor leads to a prolonged half-life of bradykinin, a potent vasodilator having cardiovascular benefit and a possible renoprotective effect (Imig, 2004). ARBs do not increase the half-life of bradykinin. ARBs, on the other hand, reduce the damaging effects resulting from production of angiotensin II by non-ACE pathways, which is not completely blocked by an ACE inhibitor. Thus, it seemed plausible that combining these 2 agents could more effectively oppose the RAAS than either agent alone. Moreover, combined therapy with an ACE inhibitor and ARB shows superior suppression of left ventricular remodeling and RAAS neurohormones compared with single-drug therapy (Mckelvie et al, 1999). Levels of brain natriuretic are also reduced significantly (Parving et al, 2001).
In the meta-analysis by Jennings and colleagues, it was shown that those with a greater degree of proteinuria derived the greatest benefit from combination therapy. The optimal anti-proteinuric dose of an ACE inhibitor and ARB has never been established, but recent studies show that higher doses of an ACE inhibitor or ARB are superior to lower doses for reducing proteinuria. Since all the trials included in this meta-analysis were of short duration (12 weeks maximum), the effect of longer duration of dual RAAS blockade was not interpreted. A decrease in glomerular filtration rate was also considered as a transient reduction, although a decrease of nearly 4 ml/minute in glomerular filtration rate after 2 to 3 months of dual therapy should be considered in assessing the risk/benefits of this treatment.
In conclusion, the results of this meta-analysis suggest that short-term (8 to 12 weeks) combination therapy with an ACE inhibitor and ARB is superior to an ACE inhibitor alone in reducing 24-hour urinary protein excretion in patients with diabetic nephropathy. Further studies evaluating accepted clinical end points (doubling of serum creatinine and onset of ESRD) need to be done to establish the long-term benefit of combination treatment of an ACE inhibitor and ARB.
This Website Feature is funded by an unrestricted educational grant from Pfizer Inc.
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