Combination therapy—less proteinuria, but…
A number of studies have shown that combination treatment with agents having different targets in the renin-angiotensin-aldosterone system leads to larger reductions in albuminuria than does single-agent therapy.
Mogensen et al34 studied the effect of the ACE inhibitor lisinopril (20 mg per day) plus the ARB candesartan (16 mg per day) in subjects with microalbuminuria, hypertension, and type 2 diabetes. Combined treatment was more effective in reducing proteinuria.
Epstein et al35 studied the effects of the ACE inhibitor enalapril (20 mg/day) combined with either of two doses of the selective aldosterone receptor antagonist eplerenone (50 or 100 mg/day) or placebo. Both eplerenone dosages, when added to the enalapril treatment, significantly reduced albuminuria from baseline as early as week 4 (P < .001), but placebo treatment added to the enalapril did not result in any significant decrease in urinary albumin excretion. Systolic blood pressure decreased significantly in all treatment groups and by about the same amount.
The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) trial36 randomized more than 600 patients with type 2 diabetes and nephropathy to aliskiren (a renin inhibitor) or placebo added to the ARB losartan. Again, combination treatment was more renoprotective, independent of blood pressure lowering.
Worse outcomes with combination therapy?
More recent studies have indicated that although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal and cardiovascular outcomes. The multicenter Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)37 randomized more than 25,000 patients age 55 and older with established atherosclerotic vascular disease or with diabetes and end-organ damage to receive either the ARB telmisartan 80 mg daily, the ACE inhibitor ramipril 10 mg daily, or both. Mean follow-up was 56 months. The combination-treatment group had higher rates of death and renal disease than the single-therapy groups (which did not differ from one another).
Why the combination therapy had poorer outcomes is under debate. Patients may get sudden drops in blood pressure that are not detected with only periodic monitoring. Renal failure was mostly acute rather than chronic, and the estimated GFR declined more in the combined therapy group than in the single-therapy groups.
The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) was designed to test the effect of the direct renin inhibitor aliskiren or placebo, both arms combined with either an ACE inhibitor or an ARB in patients with type 2 diabetes at high risk for cardiovascular and renal events. The trial was terminated early because of more strokes and deaths in the combination therapy arms. The results led the FDA to issue black box warnings against using aliskiren with these other classes of agents, and all studies testing similar combinations have been stopped. (In one study that was stopped and has not yet been published, 100 patients with proteinuria were treated with either aliskiren, the ARB losartan, or both, to evaluate the effects of aldosterone escape. Results showed no differences: about one-third of each group had this phenomenon.)
My personal recommendation is as follows: for younger patients with proteinuria, at lower risk for cardiovascular events and with disease due not to diabetes but to immunoglobulin A nephropathy or another proteinuric kidney disease, treat with both an ACE inhibitor and ARB. But the combination should not be used for patients at high risk of cardiovascular disease, which includes almost all patients with diabetes.
If more aggressive renin-angiotensin system blockade is needed against diabetic nephropathy, adding a diuretic increases the impact of blocking the renin-angiotensin-aldosterone system on both proteinuria and progression of renal disease. The aldosterone blocker spironolactone 25 mg can be added if potassium levels are carefully monitored.
ACE inhibitor plus calcium channel blocker is safer than ACE inhibitor plus diuretic
The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial38 randomized more than 11,000 high-risk patients with hypertension to receive an ACE inhibitor (benazepril) plus either a calcium channel blocker (amlodipine) or thiazide diuretic (hydrochlorothiazide). Blood pressures were identical between the two groups, but the trial was terminated early, at 36 months, because of a higher risk of the combined end point of cardiovascular death, myocardial infarction, stroke, and other major cardiac events in the ACE inhibitor-thiazide group.
Although some experts believe this study is definitive and indicates that high blood pressure should never be treated with an ACE inhibitor-thiazide combination, I believe that caution is needed in interpreting these findings. This regimen should be avoided in older patients with diabetes at high risk for cardiovascular disease, but otherwise, getting blood pressure under control is critical, and this combination can be used if it works and the patient is tolerating it well.
In summary, the choice of blood pressure-lowering medications is based on reducing cardiovascular events and slowing the progression of kidney disease. Either an ACE inhibitor or an ARB is the first choice for patients with diabetes, hypertension, and any degree of proteinuria. Many experts recommend beginning one of these agents even if proteinuria is not present. However, the combination of an ACE inhibitor and ARB should not be used in diabetic patients, especially if they have cardiovascular disease, until further data clarify the results of the ONTARGET and ALTITUDE trials.
STRATEGY 4: METABOLIC MANIPULATION WITH NOVEL AGENTS
Several new agents have recently been studied for the treatment of diabetic nephropathy, including aminoguanidine, which reduces levels of advanced glycation end-products, and sulodexide, which blocks basement membrane permeability. Neither agent has been shown to be safe and effective in diabetic nephropathy. The newest agent is bardoxolone methyl. It induces the Keap1–Nrf2 pathway, which up-regulates cytoprotective factors, suppressing inflammatory and other cytokines that are major mediators of progression of chronic kidney disease.39
Pergola et al,40 in a phase 2, double-blind trial, randomized 227 adults with diabetic kidney disease and a low estimated GFR (20–45 mL/min/1.73 m2) to receive placebo or bardoxolone 25, 75, or 150 mg daily. Drug treatment was associated with improvement in the estimated GFR, a finding that persisted throughout the 52 weeks of treatment. Surprisingly, proteinuria did not decrease with drug treatment.
As of this writing, a large multicenter controlled randomized trial has been halted because of concerns by the data safety monitoring board, which found increased rates of death and fluid retention with the drug. A number of recent trials have shown a beneficial effect of sodium bicarbonate therapy in patients with late-stage chronic kidney disease. They have shown slowing of the progression of GFR decline in a number of renal diseases, including diabetes.