The Diabetes Control and Complications Trial (DCCT) has demonstrated that intensive diabetes treatment delays the onset and slows the progression of retinopathy, nephropathy, and neuropathy in patients with IDDM. A detailed description of the effects of this treatment on diabetic nephropathy is presented here. In the primary prevention cohort, intensive treatment reduced the mean adjusted risk of the cumulative incidence of microalbuminuria (≥28 μg/min) by 34 % (95 % CI 2, 56 %; P = 0.04). Furthermore, intensive treatment decreased the albumin excretion rate (AER) by 15 % after the first year of therapy (6.5 vs. 7.7 μg/min, P < 0.001). Thereafter the rates of change for AER within each treatment group were no different from zero, retaining a constant difference in AER between groups in the trial. In the secondary intervention cohort with baseline AER <28 μg/min, intensive therapy reduced the mean adjusted risk of microalbuminuria (≥28 μg/min) by 43 % (95 % CI 21, 58 %; P < 0.0001); the risk of a more advanced level of microalbuminuria (≥70 μg/min) by 56 % (95 % CI 26, 74 %; P = 0.002); and the risk of clinical albuminuria (≥208 μg/min) by 56 % (95 % CI 18, 76 %; P < 0.01). In the secondary intervention cohort, values for AER at year 1 were identical at 9 μg/min, but the 6.5 % change per year in the conventional group greatly exceeded the rate of change of −0.3 % in the intensive group (P < 0.001). Among the 73 secondary cohort subjects with AER levels ≥28 μg/min but ≤139 μg/min at baseline, the reduction of progression to clinical albuminuria with intensive therapy was not statistically significant. The longitudinal treatment effect of conventional versus intensive therapy (11.0 % vs. 2.5 % per year, respectively, P = 0.087) was similar in magnitude to that among patients with AER <28 μg/min at baseline. For the primary, secondary, and combined cohorts, there were no significant differences in the rates of change in creatinine clearance (CCr) between treatment groups during the study. Only seven subjects in the entire study (2 intensive, 5 conventional) developed urinary AER ≥208 μg/min coupled with a CCr < 70 ml/min/1.73 m². Neither the rate of change of blood pressure nor the appearance of hypertension (BP > 140/90 mmHg) differed significantly between treatment groups in the primary, secondary, or combined cohorts.

The DCCT trial had previously demonstrated a beneficial effect of intensive glycemia control on diabetic complications including retinopathy and neuropathy [12]. In this study, it focused on renal outcomes, both prevention and development/progression of albuminuria.

It showed that intensive and sustained glycemia control, with an HbA1c around 7 % compared to 9 % in standard therapy group, reduced the incidence of microalbuminuria and its progression by 34 and 43 %, respectively.

Limitations of the DCCT study:

The DCCT study has been the key study underlying the importance of tight glycemia control in minimizing the complications of T1DM. It was supported by the long-term DCCT EDIC follow-up (22 years) observations of persistent benefit [15]. It was also supported by the STENO multi-intervention study that showed a protective effect on T2DM vascular and renal complications with intensive multi-targeted therapy [15]. The primary endpoint of the STENO study was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation.

However, other studies in T2DM such as ACCORD, ADVANCE, and VADT failed to show an impact of strict glycemia control on cardiovascular outcomes (reviewed in [16]). It has been argued that the potential beneficial effect of strict glycemia control may largely depend on patients’ characteristics, including age, diabetes duration, previous glucose control, presence of cardiovascular disease, and risk of hypoglycemia. Other confounders include the extent and frequency of hypoglycemic events and the impact of glucose-lowering medication itself on the cardiovascular system [16].

Lewis EJ, Hunsicker LG, Bain RP, Rohde RD.

Background: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy.

Methods: A total of 1,513 patients were enrolled in this randomized, double-blind study comparing losartan (50–100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the baseline serum creatinine concentration, end-stage renal disease, or death. Secondary endpoints included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.

Results: A total of 327 patients in the losartan group reached the primary endpoint, as compared with 359 in the placebo group (risk reduction, 16 %; P = 0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 %; P = 0.006) and end-stage renal disease (risk reduction, 28 %; P = 0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 %; P = 0.005). The level of proteinuria declined by 35 % with losartan (P < 0.001 for the comparison with placebo).

Conclusions: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.

The RENAAL study is the pivotal study on angiotensin receptor blockade (ARB) efficacy in slowing the progression of T2DM-associated nephropathy. It showed a significant (16 %) reduction in the rate of reaching the composite endpoints of doubling of serum creatinine, ESRD or death. It also showed a significant reduction in proteinuria. Of interest, there was no significant difference between the groups in secondary CVD outcomes, as anticipated by the premature termination of the study based on the reported data from HOPE [22].

Limitations of the RENAAL study:

RENAAL is a major study that claimed that ARB slows the progression of DN. Its conclusion is confounded by the premature termination of the study thus raising concerns over its power and the use of serum creatinine as a primary endpoint without measuring changes in GFR.

Background: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure.

Methods: We randomly assigned 1,715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mmHg or less in all groups. We compared the groups with regard to the time to the primary composite endpoint of a doubling of the baseline serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite endpoint.

Results: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite endpoint that was 20 % lower than that in the placebo group (P = 0.02) and 23 % lower than that in the amlodipine group (P = 0.006). The risk of a doubling of the serum creatinine concentration was 33 % lower in the irbesartan group than in the placebo group (P = 0.003) and 37 % lower in the irbesartan group than in the amlodipine group (P < 0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 % lower than that in both other groups (P = 0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 % more slowly in the irbesartan group than in the placebo group (P = 0.008) and 21 % more slowly than in the amlodipine group (P = 0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite endpoint.

Conclusions: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

The IDNT study results are similar to those of RENAAL in that an ARB slowed the rate of changes in serum creatinine over a reasonably long observation period.

It has the same limitations as RENAAL:

IDNT along with RENAAL are often cited as the ultimate proof that ARBs are protective against the decline in kidney function in DN. While this may be the case, these studies have their limitations highlighted above that confound irrefutable evidence.

Background: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain.

Methods: We provided losartan (at a dose of 100 mg/day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0–89.9 ml/min/1.73 m² of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10–40 mg/day) or placebo. The primary endpoint was the first occurrence of a change in the estimated GFR (a decline of ≥30 ml/min/1.73 m² if the initial estimated GFR was ≥60 ml/min/1.73 m² or a decline of ≥50 % if the initial estimated GFR was <60 ml/min/1.73 m²), end-stage renal disease (ESRD), or death. The secondary renal endpoint was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury.

Results: The study was stopped early owing to safety concerns. Among 1,448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95 % confidence interval [CI], 0.70–1.12; P = 0.30). A trend toward a benefit from combination therapy with respect to the secondary endpoint (hazard ratio, 0.78; 95 % CI, 0.58–1.05; P = 0.10) decreased with time (P = 0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95 % CI, 0.73–1.49; P = 0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years vs. 2.6 events per 100 person-years with monotherapy; P < 0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P < 0.001).

Conclusions: Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

The VA NEPHRON-D study confirmed the observations made in previous studies on the negative impact of dual RAS blockade; ONTARGET in high cardiovascular risk patients including people with high risk diabetes mellitus [34] as well as the ALTITUDE study that investigated the combination of a renin antagonist with ACE inhibition in patients with diabetic nephropathy [35]. These studies had to be discontinued due to a high rate of side effects and morbidity. VA NEPHRON-D was also stopped prematurely due to the increased rate of side effects, hyperkalemia, and AKI. During the observation time, the study failed to show benefit on the primary endpoint of decline in eGFR or in other endpoints of cardiovascular complications or mortality. Of note the highest rate of albuminuria decline took place in the combination group.

Limitations of the VA NEPHRON-D trial:

The VA NEPHRON-D study was the third major RCT that showed the risks associated with dual blockade of the RAS. Like previous studies such focus has been on older patients with DM (mean age 64 years) compared to 66 years in ONTARGET and 60 years in ALTITUDE. Whether dual RAS blockade is equally harmful in younger patients with lower cardiovascular risk is unknown.

Background: Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy.

Methods: We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.

Results: The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20 % (95 % confidence interval, 9–30; P < 0.001), with a reduction of 50 % or more in 24.7 % of the patients who received aliskiren as compared with 12.5 % of those who received placebo (P < 0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mmHg lower [P = 0.07] and diastolic, 1 mmHg lower [P = 0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups.

Conclusions: Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).

The AVOID study opened the way to dual blockade of RAS combining an ARB with a renin inhibitor (Aliskiren). It showed a significant reduction in albuminuria over and above that achieved with an ARB (Losartan) alone. This effect was obtained independently of changes in eGFR or blood pressure control.

The AVOID trial limitations are:

It is imperative that studies relying on changes in albuminuria as the primary endpoint are conducted long enough to ascertain the impact of the intervention on renal function (measured GFR) as well as blood pressure control and side effects. The assumption that a reduction of albuminuria by a given intervention will inevitably lead to a slowing of CKD progression is no longer tenable in view of the results of ALTITUDE [38] but also ONTARGET [37] and ACCOMPLISH [36].

Background: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.

Methods: In a double-blind fashion, we randomly assigned 8,561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary endpoint was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.

Results: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary endpoint had occurred in 783 patients (18.3 %) assigned to aliskiren as compared with 732 (17.1 %) assigned to placebo (hazard ratio, 1.08; 95 % confidence interval [CI], 0.98–1.20; P = 0.12). Effects on secondary renal endpoints were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mmHg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95 % CI, 11–17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol/l) was significantly higher in the aliskiren group than in the placebo group (11.2 % vs. 7.2 %), as was the proportion with reported hypotension (12.1 % vs. 8.3 %) (P < 0.001 for both comparisons).

Conclusions: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).