Goals of Therapy for Patients with Diabetic Nephropathy

Many therapies exist to treat diabetic kidney disease (DKD). Some have been proven to delay the progression of chronic kidney disease (CKD), while others have not been rigorously tested in a controlled way. This article summarizes the major clinical findings that direct DKD treatment and outlines the progress of ongoing trials whose results will direct care.

Glycemic control

Intensive glycemic control reduces albuminuria in type 1 diabetes. The Diabetes Complications and Control Trial (DCCT) randomized 1441 type 1 diabetics (age 13–39) without cardiovascular (CV) disease and with normal kidney function to intensive (A1c < 6.05) versus conventional (A1c ∼9.0) glycemic control. Only 73 individuals had microalbuminuria at the start of the study.

Participants were followed for a mean of 6.5 years. Intensive glycemic control reduced the occurrence of microalbuminuria by 39 percent and overt proteinuria by 54 percent. There were nearly three times as many severe hypoglycemic episodes in the intensive control arm as in the conventional arm. There was no reduction in CV events in the DCCT (probably a result of the cohort’s youth), but these same subjects were followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. EDIC showed a 42 percent reduction in any CV event 10 years after both groups had similar glycemic control (implying that the CV effect of intensive glycemic control persisted after control was loosened).

In type 2 diabetes, however, the results are not as clear. An early study (the University Group Diabetes Program [UGDP]) tested the efficacy of tolbutamide, insulin, phenformin, or placebo, and showed no renal, microvascular, or CV benefit, with increased CV death in the tolbutamide arm. The much larger UK Prospective Diabetes Study (UKPDS) tested sulphonylurea or insulin versus dietary control, and showed no renal benefit, a 25 percent microvascular benefit, and no CV effect, although some subgroups showed a possible effect at 10 years. Three large trials (Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE], and the VA Diabetes Trial [VADT]) (Table 1) have collectively studied nearly 23,000 individuals. CV effects ranged from no benefit to increased risk, and there was variable renal benefit and a significant proportion of hypoglycemia in the intensive groups.

Table 1.
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Evidence supports intensive glucose control as renoprotective therapy in type 1 diabetes. The therapy may also benefit patients with type 2 diabetes who are early in the course of disease, who can achieve glycemic control easily, and who are less prone to hypoglycemia. Current evidence does not support extremely aggressive control of hyperglycemia in all patients with type 2 diabetes.

Single-agent inhibition of the renin-angiotensin system (RAS)

Treatment of type 1 diabetic nephropathy with angiotensin converting enzyme inhibitors (ACE-I) clearly protects against deterioration in renal function. Captopril 25 mg TID was shown to reduce the composite outcome of death, dialysis, or kidney transplantation by 50 percent (relative risk reduction [RRR]; absolute risk reduction [ARR] 9.7 percent, number needed-to-treat [NNT] 10 subjects, for four years). This trial included 409 patients with baseline urinary protein excretion ≥ 500 mg/day and serum creatinine (SCr) ≤ 2.5 mg/dL.

Treatment of patients with type 2 diabetes and early nephropathy (in this case, microalbuminuria) with the angiotensin receptor blocker (ARB) irbesartan has been shown to prevent progression to overt proteinuria. Irbesartan 300 mg daily versus placebo reduced the onset of overt proteinuria by 65.1 percent (RRR), with ARR 9.7 percent (NNT 10 subjects, for 2 years). Irbesartan 150 mg was not statistically significantly different from placebo (in other words, dose mattered).

The treatment of patients with overt proteinuria with irbesartan or losartan has been shown to reduce the composite outcome of doubling of SCr, end stage renal disease, or death, in two large prospective clinical trials (Irbesartan Diabetic Nephropathy Trial [IDNT] and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] study) (Table 2).

Table 2.
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Evidence from multiple clinical trials demonstrates that in patients with type 1 or type 2 diabetes and early or late nephropathy, treatment with drugs that inhibit the RAS clearly improves renal outcomes.

Lipid lowering

Multiple small clinical studies have addressed the question of whether improving lipids can delay the progression of kidney disease. No large prospective trials have been done to test this hypothesis adequately. The best available evidence is a meta-analysis that showed that lipid lowering reduced renal outcomes in patients with kidney disease. The effect of these medications, however, may be independent of their lipid-lowering effects.

Blood pressure (BP) control

Despite current guidelines (which urge a BP goal < 130/80 mm Hg for patients with CKD), there are no well-powered, randomized trials that demonstrate in their primary analyses a benefit to this level of BP control. The lack of such trials is dire in the case of DKD, because the results of the study that form the basis of the guidelines (the Modification of Diet in Renal Disease [MDRD] study) enrolled only 25 subjects with diabetes (essentially, excluding them).

No one doubts that an extremely high blood pressure can cause rapid loss of kidney function in DKD. Early studies showed improvement in loss of GFR with lowering BP. In addition, many observational studies or trials in which achieved BP is reported have demonstrated a continuous benefit of lowering BP (e.g,. the Heart Outcomes Prevention Evaluation [HOPE] trial). IDNT—albeit not designed for this specific outcome—showed a decreasing CV risk with achieved systolic blood pressure (SBP) (from > 180 to 120), but those individuals who achieved SBP < 120 had increased CV risk, on par with those who achieved SBP > 180. In other words, more may be less with respect to BP control in DKD.

Pending the results of ongoing clinical trials, including the BP study of ACCORD, current recommendations are to target BP < 130/80 in patients with DKD. This goal must be individualized, however. Results in nondiabetic adults or children are difficult to generalize to adults with diabetes.

Lifestyle modifications

Smoking cessation, weight control, and increased physical activity should be encouraged. It is known that smoking and obesity increase the rate at which kidney disease progresses. For all the other reasons we tell our patients to stop smoking, perhaps “It may keep you from going on dialysis” will be the motivator to get them to quit.

Combination therapies

Multiple small and potentially underpowered studies using surrogate outcomes (e.g., proteinuria) have inconsistent results, but generally support improvement with ACE-I + ARB, or suprapharmacologic doses of ACE-I or ARB in diabetic nephropathy. Only a few trials have addressed the question of what combinations of inhibitors of the RAS are successful at preventing outcomes. The results of the Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in nondiabetic renal disease (COOPERATE) trial have been called into question and an official retraction has been published; it is therefore excluded from discussion.

The Aliskiren in the eValuation Of proteinuria In Diabetes (AVOID) trial studied the effect on proteinuria of adding aliskiren or placebo to losartan in type 2 diabetic nephropathy: 599 subjects with type 2 diabetes, hypertension, urinary albumin:creatinine ratio 0.3–3.5 g/g (0.2–3.5 g/g if taking agents that blocked the RAS), and estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 were studied. Aliskiren reduced proteinuria at 24 weeks, but the trial was not long enough to assess the effect of aliskirin on the progression of CKD or CV events. Patients treated with combination therapy developed hyperkalemia (K ≥ 6.0 mEq/L) more often (4.7 percent versus 1.7 percent).

The ONgoing Telmisartan Alone and in combination with Ramipril Global EndpoinT (ONTARGET) trial studied 25,260 patients with ramipril, telmisartan, or both, for the effect on the composite primary (CV) outcome, namely death from a CV cause, myocardial infarction, stroke, or hospitalization for heart failure. There was no difference in the primary outcome among the three arms. The renal substudy showed less worsening of proteinuria with combination therapy, but GFR decreased more in the combination arm compared to the single-agent arms (by about 2 mL/min/1.73 m2). Additionally, there was a significant increase in the renal endpoint (dialysis, doubling of SCr, or death) in the combination arm compared to single-agent arms. The biggest contributor to this endpoint was the need for acute dialysis (28 cases in combination, 13 and 20 in the single-agent arms).

It may be that the risk-benefit profile for certain combinations of RAS blockade does not apply to all combinations. Many combinations are limited by hyperkalemia, which is more problematic in the “real world” than in a clinical trial.

Future studies

Several ongoing studies may address current uncertainties in the management of diabetic nephropathy. The Department of Veterans’ Affairs NEPHROpathy iN Diabetes (VA NEPHRON-D) Study is testing whether the combination of the ACE-I lisinopril and ARB losartan is superior to losartan alone to delay the progression of CKD. Approximately 1900 patients will be recruited until 2013.

The ALiskiren Trial In Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) Study is testing whether dual RAS blockade with aliskiren and an ACE-I or ARB reduces CV and renal morbidity and mortality. It aims to recruit 8600 patients followed for four years.

Finally, the BP companion study to ACCORD will help elucidate the target BP for diabetic nephropathy caused by type 2 diabetes.

Conclusions

The cornerstone of the treatment of diabetic nephropathy is delaying the progression of CKD. Control of hyperglycemia and blood pressure, and use of RAS blockade are accepted therapies. Combination therapies and very strict BP control are not, as yet, entirely proven, but ongoing trials will address the limitations of currently completed studies.

Notes

[1] Jamie P. Dwyer, MD, is with the division of nephrology and hypertension and the Nephrology Clinical Trials Center, both at Vanderbilt University Medical Center in Nashville, TN. The material in this article was originally presented as part of renal grand rounds at Drexel University Division of Nephrology in Philadelphia, PA, in 2009.

[2] Disclosures: Jamie P. Dwyer reports research support from Keryx Biopharmaceuticals, Inc.