Abstract
Aims/Introduction
We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD).
Materials and Methods
The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population.
Results
The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups.
Conclusions
The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease.
Keywords: Diabetic kidney disease, Diabetic nephropathy, Diabetic Nephropathy Remission and Regression Team Trial in Japan
The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.
Introduction
Diabetic kidney disease (DKD) is the leading cause of end‐stage renal failure in developed and developing countries 1 , 2 . DKD is also an important risk for cardiovascular disease 3 , 4 . Although the prognosis of DKD has been improving, effective intervention against the progression to end‐stage renal disease (ESRD) is still required 5 , 6 , 7 . The Steno 2 study showed that multifactorial intervention can prevent the progression of DKD in patients with type 2 diabetes associated with microalbuminuria 8 , 9 , 10 . Recently, the Japan Diabetes Optimal Integrated Treatment study for three major risk factors of cardiovascular diseases (J‐DOIT3) showed that multifactorial intervention prevents the onset and advancement of early‐stage DKD in patients with Japanese type 2 diabetes as a secondary outcome 11 . The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study showed a significant effect of prior intensive treatment (IT) on estimated glomerular filtration rate (eGFR) down to a level of 45 mL/min/1.73 m2 in patients with type 1 diabetes 12 . However, it has remained unclear that intensified multifactorial treatment can prevent the progression of advanced‐stage DKD to ESRD. To clarify the efficacy of intensified multifactorial intervention on the progression of DKD in an advanced stage, we carried out a clinical study – the Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) 13 . DNETT‐Japan is a multicenter, randomized, open‐label, parallel‐group trial to clarify whether intensive multifactorial intervention, including behavioral modifications and pharmacological intervention, can prevent the progression to ESRD in patients with type 2 diabetes with overt proteinuria. As described in the previous study, DNETT‐Japan includes two protocols 13 . In the present study, we analyzed the results of protocol B, in which the patients with advanced‐stage DKD are included.
Methods
Trial design
The trial design was described previously 13 . Briefly, this study was a multicenter randomized, open, parallel trial carried out in Japan (Clinical Trials gov number, NCT00253786). The trial was approved by the institutional review board at each trial site, and carried out in accordance with the principles of the Declaration of Helsinki. All participants were informed fully by the investigators and gave written informed consent before trial entry. Members of the steering committee designed the trial, supervised its conduct and were responsible for reporting the results.
Patients
In a 2‐month screening period, patients with type 2 diabetes who met the inclusion and exclusion criteria were enrolled in the trial (Table S1) 13 . Briefly, Japanese adults aged 20–75 years with type 2 diabetes, two consecutive urinary albumin‐to‐creatinine ratio (UACR) of ≥300 mg/g creatinine (first morning urine) and serum creatinine level of 1.2–2.5 mg/dL (men) or 1.0–2.5 mg/dL (women) were eligible for participation 13 . Exclusion criteria are described in Table S1.
Procedures
After the 2‐month screening period, patients were randomly assigned by the block method in a 1:1 ratio to the two treatment groups: the multifactorial IT group and conventional treatment (CT) group (Table S2) 13 . The active treatment period was 5 years.
Patients of the IT group were treated and cared by a project team of a doctor, nurse, dietician and pharmacologist at each site, and managed to achieve the following predefined treatment goals 13 (Table S2): (i) hemoglobin A1c (HbA1c) <6.2%; (ii) systolic blood pressure <125 mmHg and diastolic blood pressure <75 mmHg by inhibitors of renin–angiotensin system: angiotensin‐converting enzyme inhibitors (ACE‐Is) or angiotensin receptor blockers (ARBs); (iii) total cholesterol <180 mg/dL, low‐density lipoprotein (LDL) cholesterol <100 mg/dL and high‐density lipoprotein cholesterol >40 mg/dL; and (iv) total intake of protein <0.8 g/kg/day, sodium intake <5 g/day and total daily energy intake <30 kcal/kg/day. Blood pressure was measured in the sitting position, and if the target blood pressure was not reached, both ACE‐I and ARB were used concomitantly (long‐acting calcium channel blockers were also added, if required). 3‐Hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase inhibitors were added if the LDL cholesterol level was ≥100 mg/dL. Patients in the IT group who smoked were invited to smoking cessation courses. All patients in the IT group received a multivitamin supplement (Multivitamin; Takeda Pharmaceutical Company Limited, Tokyo, Japan) daily to avoid vitamin deficiency caused by protein restriction (Table S2).
All patients visited the outpatient of each site every 3 months. Blood pressure was measured, and blood and urine samples were collected at each visit. eGFR was calculated using the modified Modification of Diet in Renal Disease formula for Japanese participants 14 . Laboratory tests of HbA1c, serum creatinine level, LDL cholesterol level, urinary protein concentration, urinary albumin concentration and urinary creatinine concentration were carried out centrally at SRL (Hachioji, Japan). Other laboratory tests were carried out at each clinical site.
Trial outcomes
The outcomes were described previously and are shown in Table S3. 13 Briefly, the primary outcome is a composite of end‐stage kidney failure (chronic dialysis or renal transplantation), doubling of serum creatinine or death. The secondary outcomes are eGFR, cardiovascular event, progression of retinopathy, UACR and urinary protein‐to‐creatinine ratio.
Trial safety monitoring
In the middle of the intervention period, we obtained the information regarding intervention‐related serious adverse events from two major clinical trials; The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial 15 and The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) 16 . In the ACCORD trial, the intensive‐therapy regimen (targeting a HbA1c level of <6.0%) was discontinued in February 2008 because of the increased incidence of death in the intensified therapy group than in the standard therapy group (targeting a HbA1c level from 7.0 to 7.9%). In the present trial, the adverse events related to hypoglycemia were assessed by the independent study monitoring committee in 2008; however, there was no evidence suggesting a hypoglycemia‐related increase in adverse events in the IT group, and the continuation of the trial was approved by the independent study monitoring committee. In the ONTARGET, it was reported that the adverse events including renal dysfunction were increased by combination therapy with ACE‐Is and ARBs, which raised concerns about the safety of combination therapy in the present trial. The continuation of this trial was approved by the independent study monitoring committee in 2008, because an increase of adverse effects related to the combination therapy was not found in the IT group.
Statistical analysis
The procedure of statistical analysis was described previously 13 . Briefly, we used the full analysis set (FAS) for the primary efficacy analysis set, and per‐protocol set for the secondary efficacy analysis set, as described previously 13 . We used the Kaplan–Meier method to analyze the primary end‐point and cardiovascular event. The Cox proportional hazards model was used to estimate the hazard ratios with 95% confidence intervals in the event rates. The covariates were sex, age, ACE‐I treatment, baseline UACR and baseline serum creatinine level.
The Kaplan–Meier method was used to compute the cumulative event rate for each defined event for each treatment group. The overall mean values of risk factors and surrogate kidney outcomes (eGFR, UACR and urinary protein‐to‐creatinine ratio) during follow up were compared between treatment groups by using the linear mixed effects model including treatment groups, visit times and their interaction terms. For the adjusted analysis of surrogate kidney outcomes, baseline values of each outcome were also added to the relevant liner mixed model.
The frequency of the progression of diabetic retinopathy and all adverse events during the follow‐up period were compared by using the χ2‐test. The associations of the risk factors at baseline or during follow up with the development of the primary outcome among the patients were estimated by using the Cox proportional hazards model with time‐dependent covariates.
The mean, median and standard deviation for the clinical test values were calculated at each measurement point 13 . A two‐sided value of P < 0.05 was considered to be statistically significant. The SAS statistical software program, version 9.3 (SAS Institute Inc., Cary, NC, USA) was used for the statistical analysis.
The sample size was determined based on the following considerations: (i) incidence of the primary composite outcome of 40% in the CT group and 25% in the IT group; (ii) two‐sided type I error rate (α) of 0.05; (iii) power of 80%; and (iv) loss‐to‐follow‐up of 20% in the study period. We calculated a sample size of 200 subjects for each study group, which would allow an 80% power to detect differences between groups with a significance level of <0.05.
Results
From September 2005 through May 2009, a total of 438 patients were screened, of whom 274 were excluded because they did not meet inclusion and exclusion criteria; 164 underwent randomization at 65 sites in Japan and were randomly assigned to IT (n = 80) or CT (n = 84; Figure 1). The mean follow‐up period was 168.4 weeks (standard deviation 88.4 weeks), the median follow‐up period was 162.0 weeks (interquartile range 82.1–260.4 weeks). The baseline characteristics were similar in the two groups (Table 1).
Figure 1.
Trial profile.
Table 1.
Baseline characteristics of randomized patients enrolled in the study
| Intensive (n = 73) | Conventional (n = 80) | P‐value | |
|---|---|---|---|
| Age (years) | 56.8 (10.5) | 57.6 (8.8) | 0.62 |
| Male sex (%) | 58.9 | 55.0 | 0.63 |
| Duration of diabetes † (years) | 15.9 (9.6) | 15.1 (8.0) | 0.62 |
| Systolic blood pressure (mmHg) | 138.5 (19.7) | 139.5 (17.6) | 0.74 |
| Diastolic blood pressure (mmHg) | 76.9 (12.6) | 76.6 (10.2) | 0.88 |
| Body mass index (kg/m2) | 25.5 (4.8) | 26.5 (5.4) | 0.25 |
| Waist circumstance (cm) | 89.6 (11.7) | 91.0 (12.7) | 0.49 |
| Urinary chemistry | |||
| Urinary protein‐to‐creatinine ratio (g/gCr) | 2.0 (1.1–3.8) | 2.3 (1.1–4.2) | 0.58 |
| Urinary albumin‐to‐creatinine ratio (mg/gCr) | 1,450 (814–2,560) | 1,725 (790–2,945) | 0.51 |
| Serum chemistry | |||
| Urea nitrogen (mg/dL) | 28.4 (9.3) | 28.4 (9.8) | 0.99 |
| Creatinine (mg/dL) | 1.6 (0.4) | 1.6 (0.4) | 0.92 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 40.1 (11.4) | 39.5 (12.2) | 0.76 |
| Potassium (mEq/L) | 4.6 (0.5) | 4.6 (0.6) | 0.54 |
| Fasting blood glucose (mg/dL) | 133.5 (43.7) | 131.7 (47.3) | 0.83 |
| Hemoglobin A1c (%) | 7.1 (1.4) | 7.1 (1.1) | 0.92 |
| Total cholesterol (mg/dL) | 205.4 (46.9) | 207.6 (49) | 0.78 |
| HDL cholesterol | 54.3 (17) | 56 (22.2) | 0.61 |
| LDL cholesterol | 118 (36.3) | 118.9 (36.3) | 0.88 |
| Uric acid (mg/dL) | 6.9 (1.6) | 7 (1.2) | 0.77 |
| Total protein (mg/dL) | 6.7 (0.6) | 6.6 (0.9) | 0.16 |
| Albumin (mg/dL) | 3.6 (0.6) | 0.33 | |
| Total bilirubin (mg/dL) | 0.5 (0.2) | 0.5 (0.1) | 0.75 |
| Aspartate aminotransferase (IU/L) | 20.7 (6.6) | 21.5 (8.2) | 0.51 |
| Alanine aminotransferase (IU/L) | 17.7 (7.9) | 20.3 (11) | 0.10 |
| Gamma glutamyl transpeptidase (IU/L) | 28.8 (27.2) | 36.2 (35.9) | 0.18 |
| Lactate dehydrogenase (IU/L) | 217.1 (48.7) | 228.8 (63.5) | 0.23 |
| Hemoglobin (g/dL) | 11.6 (1.6) | 11.9 (2) | 0.46 |
| Other factors | |||
| Smoking status (%) | |||
| Never smoker | 50.7 | 50.0 | 0.99 |
| Ex‐smoker | 28.8 | 30.0 | |
| Current smoker | 20.6 | 20.0 | |
| Alcohol intakes (%) | 28.8 | 27.9 | 0.90 |
| Diabetic retinopathy status (%) | |||
| No | 7.5 | 13.2 | 0.32 |
| Simple | 23.9 | 32.9 | |
| Pre‐proliferative | 20.9 | 18.4 | |
| Proliferative | 47.8 | 35.5 | |
| Electrocardiogram abnormalities (%) | 15.3 | 11.3 | 0.46 |
| Diet therapy (%) | 97.3 | 97.5 | 0.93 |
| Therapeutic exercise (%) | 42.5 | 42.5 | 1.00 |
Values are shown as mean (standard deviation), median (interquartile range) or frequency.
Numbers of participants with available data of duration of diabetes were 70 participants for the intensive group and 71 participants for the conventional group.
Concomitant drug treatment during the follow‐up period
Blood pressure‐lowering agents were used for all patients in the IT group and 97.4% of the patients in the CT group (P = 0.17; Table S4). ARB was used for 98.6% of the patients in the IT group and 94.8% of the patients in the CT group (P = 0.20). The combination therapy of ACE‐I and ARB was used for more patients in the IT group (53.4%) compared with the CT group (31.3%; P = 0.006).
The use of oral glucose‐lowering agents was similar in the two groups, except for metformin. Metformin was used by more patients in the IT group (23.9%) compared with the CT group (7.8%; P = 0.01). The use of insulin was similar in the two groups. Glucagon‐like peptide‐1 receptor agonist was used for five patients in the CT groups.
Blood glucose
Key baseline characteristics were not different in the two groups (Table 1). At baseline, the mean HbA1c was 7.1% in both treatment groups (Table 1). The overall mean HbA1c was 6.8 % (95% confidence interval [CI] 6.63–7.09) in the IT group and 6.94% in the CT group (95% CI 6.72–7.16). There was no significant difference of HbA1c between the two groups throughout the observation period (Figure S1a).
Blood pressure
The mean systolic and diastolic blood pressure was 138.5/76.9 mmHg in the IT group and 139.5/76.6 mmHg in the CT group at baseline. There was no significant difference in baseline blood pressure between the two groups. The overall mean systolic blood pressure was 132.2 mmHg (95% CI 129.5–134.9) in the IT group and 132.4 mmHg in the CT group (95% CI 129.9–135.0). The overall mean diastolic blood pressure was 72.2 mmHg (95% CI 70.2–14.2) in the IT group and 72.0 mmHg in the CT group (95% CI 72.2–73.9). There was no significant difference in blood pressure between the two groups through the observation period (Figure S1b).
Serum LDL cholesterol concentration
At baseline, the mean LDL cholesterol level was 118.0 mg/dL in the IT group and 118.9 mg/dL in the CT group. The serum LDL cholesterol level was not different at baseline between the two groups. The overall mean serum concentration of LDL cholesterol was 98.6 mg/dL (95% CI 92.2–105.1) in the IT group and 104.0 mg/dL in the CT group (95% CI 97.8–110.1). There was no significant difference of serum LDL cholesterol level between the two groups through the observation period, although the mean values of serum LDL cholesterol level were lower in the IT group (Figure S1c).
Waist circumference
The average waist circumference was 89.6 cm in the IT group and 91.0 cm in the CT group at baseline. There was no significant difference of waist circumference at baseline between the two groups. The overall mean waist circumference was 91.4 cm (95% CI 88.4–94.6) in the IT group and 92.3 cm (95% CI 89.5–95.1) in the CT group. There was no significant difference of waist circumference between two groups through the observation period (Figure S1d).
Smoking status
Smoking status was not different between the two groups. The frequency of being a current smoker during the follow‐up period was 20.6% in the IT group and 20.0% in CT group.
Primary outcome
IT tended to reduce the risk of primary end‐points, consisting of end‐stage kidney failure, doubling of serum creatinine level or death, as compared with CT, but the difference between the treatment groups did not reach the statistically significant level (hazard ratio [HR] 0.69, 95% CI 0.43–1.11, P = 0.13; Figure 2). For each component of the composite primary outcome, there was no significant difference between the IT group and the CT group in both the full analysis set and per‐protocol set (Figure 3).
Figure 2.
Event‐free survival of primary outcomes (dialysis, doubling of serum creatinine or death) in the randomized patients (full analysis set). The effects of treatment (hazard ratios with 95% confidence intervals, and P‐values) were estimated by using a Cox proportional hazards model. CI, confidence interval; HR, hazard ratio.
Figure 3.
Effects of trial treatment on each outcome in the randomized patients. The effects of treatment (hazard ratios with 95% confidence intervals and P ‐values) were estimated by using a Cox proportional hazards model. CI, confidence interval; HR, hazard ratio.
Secondary outcomes
Cardiovascular events were not changed between IT and CT (HR 0.56, 95% CI 0.19–1.64 P = 0.29). Progression of diabetic retinopathy was reached in four patients in the IT group (5.5%) and seven patients in the CT group (8.8%; P = 0.43). Overall geometric mean UACR was 986.7 mg/gCr in the IT group and 1,258.7 g/gCr in the CT group (Figure S2a). Overall geometric mean urinary protein excretion was 1.47 g/gCr in the IT group and 1.84 g/gCr in the CT group (Figure S2B). There was no significant difference of urinary albumin excretion and urinary protein excretion between the two groups. The overall mean eGFR was 31.1 mL/min/1.73 m2 in the IT group and 29.2 mL/min/1.73 m2 in the CT group, without significant difference (Figure S2c).
Relative risk of outcomes
The relationship between the risk factors at baseline or during the follow‐up period and the development of primary composite outcome was analyzed using the Cox proportional hazards model (Table 2). Serum LDL cholesterol and use of statin were significantly related to the improvement of primary composite outcome. Combination therapy of ACE‐I and ARB did not significantly contribute to the outcome. In the baseline risk factors, UACR (HR 3.00, 95% CI 1.91–4.72, P < 0.0001)) and eGFR (HR 1.49, 95% CI 1.13–1.96, P = 0.0004) were significantly related to the primary composite outcome (Table 2).
Table 2.
Relationship between the risk factors at baseline or during follow up and the development of the primary end‐point among the patients (full analysis set)
| Variables | Unit | HR (95% CI) | P |
|---|---|---|---|
| Risk factors during follow up | |||
| Systolic blood pressure (mmHg) | per 10 mmHg increment | 1.07 (0.93–1.23) | 0.35 |
| Serum LDL cholesterol (mg/dL) | per 10 mg/dL increment | 1.14 (1.05–1.23) | 0.001 |
| Serum HDL cholesterol (mg/dL) | per 10 mg/dL decrement | 0.93 (0.81–1.08) | 0.37 |
| HbA1c (%) | per 1% increment | 0.96 (0.78–1.2) | 0.74 |
| Combination of ACE‐I + ARB | vs no combination of ACE‐I + ARB | 0.79 (0.46–1.36) | 0.4 |
| Statin use | vs no statin use | 0.53 (0.28–0.998) | 0.049 |
| Risk factors at baseline | |||
| Age (years) | per 5 years older | 0.99 (0.85–1.16) | 0.93 |
| Men | vs women | 1.92 (0.99–3.7) | 0.05 |
| eGFR (mL/min/1.73 m2) | per 10 mL/min/1.73 m2 decrement | 1.49 (1.13–1.96) | 0.0004 |
| Log transformed UACR (log[mg/gCr]) | per 1 log(mg/gCr) increment | 3.00 (1.91–4.72) | <0.0001 |
| Hemoglobin (g/dL) | per 1 g/dL increment | 1.02 (0.86–1.21) | 0.84 |
| Electrogram abnormalities | vs no | 0.92 (0.41–2.07) | 0.85 |
| Diet therapy | vs no | 1.05 (0.12–9.02) | 0.97 |
| Therapeutic exercise | vs no | 1.29 (0.74–2.22) | 0.37 |
| Current smoker | vs no | 0.89 (0.43–1.83) | 0.75 |
| Alcohol intakes | vs no | 0.78 (0.4–1.52) | 0.47 |
The model included the risk factors during follow up (systolic blood pressure, serum high‐density lipoprotein [HDL] cholesterol, serum low‐density lipoprotein [LDL] cholesterol, hemoglobin A1c [HbA1c], statin use and combined use of angiotensin‐converting enzyme inhibitor [ACE‐I] and angiotensin‐receptor blocker [ARB]) and the other risk factors at baseline. eGFR, estimated glomerular filtration rate; UACR, urinary albumin‐to‐creatinine ratio.
Adverse events
A total of 154 adverse events, including 39 severe adverse events, occurred in this trial (Table S5). The incidence of adverse events was not significantly different between the two groups (32 in the IT group and 35 in the CT group, P = 0.95). There was also no significant difference in severe adverse events, life‐threatening adverse events, adverse events requiring hospital admission and adverse events with physical disability between the two groups (16 in the IT group and 23 in the CT group, P = 0.31). As for the event of death, one deceased patient in the IT group was not reported as an adverse event, because detailed information of death was not obtained.
Discussion
In the current study, IT tended to reduce the risk of the primary end‐points compared with CT, but the difference between the treatment groups did not reach the statistically significant level.
It is clear that blood glucose lowering prevents new onset or progression of early‐stage DKD 17 , 18 , 19 , 20 , 21 , 22 . Recent meta‐analysis has suggested that intensive glucose control decreases the risk for surrogate renal outcomes; microalbuminuria and macroalbuminuria. However, it has remained unclear whether intensive glycemic control decreases the risk for renal outcomes, including doubling of the serum creatinine concentration, ESRD or death 23 . In DNETT‐Japan, Cox regression analyses did not show the superiority of strict blood glucose control. It might be possible that this trial could not show the efficacy of blood glucose control, because the HbA1c level was controlled <7.0% in both groups and there was little difference.
Antihypertensive treatment is another substantial strategy for the therapy of DKD 24 , 25 . Several guidelines recommend maintaining blood pressure <130/80 mmHg in patients with DKD 26 , 27 . In the present trial, the average level of systolic/diastolic blood pressure during the trial period was 132/72 mmHg in both groups, and there was no difference between the two groups. Although blood pressure was considerably well managed, it seems to be difficult to achieve the treatment goal in the IT group. In particular, in the first year, the average level of blood pressure was elevated in the IT group, because some patients resistant to antihypertensive drugs were included.
There have been several randomized controlled trials that showed the strong effect of ARBs and ACE‐Is on DKD 28 , 29 , 30 . In the current trial, 100% of the patients in the IT group and 97.4% in the CT group were taking renin–angiotensin system inhibitors. Dual blockade of the renin–angiotensin system did not significantly contribute to the outcome, whereas the incidence of adverse events was not increased by the dual blockade. A previous meta‐analysis showed that reduction of proteinuria by ACE‐Is and ARB was similar, but their combination was more effective than either drug alone 31 . However, in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), no renal benefit was shown by combination treatment, and the risk of hyperkalemia and acute kidney injury was increased 16 . In addition, in The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON‐D) study, combination treatment of ACE‐I and ARB was associated with an increased risk of adverse events in patients with DKD 32 . Combination therapy with ACEIs and ARB seems not to be beneficial for patients with advanced‐stage DKD compared with monotherapy in the current trial.
Interestingly, a decrease in serum LDL cholesterol level and use of statin are significantly related to the decrease in primary composite outcome. Statin treatment reduces the risk for cardiovascular diseases in patients with chronic kidney disease, including DKD 33 . In contrast, it is still controversial whether lipid‐lowering therapy using statins is beneficial for the development of DKD or not. Several studies and systematic reviews showed that statin reduces proteinuria in patients with DKD, although it is uncertain whether statin prevents ESRD 34 , 35 , 36 . Statin treatment is recommended for patients with DKD in the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline 37 . It has been suggested that pleiotropic effects of statin might be beneficial for DKD in animal experiments 38 . It has remained unclear whether LDL cholesterol lowering per se was effective for the prevention of the primary end‐point, because we cannot statistically analyze the effects of LDL cholesterol lowering independent from the effect of statin in the present study. The results from the current trial suggest that LDL cholesterol lowering by statin was effective on the primary composite outcome in patients with advanced‐stage DKD. Recent clinical trials showed the protective effect of sodium–glucose cotransporter 2 inhibitors and glucagon‐like peptide‐1 receptor agonists on DKD 39 , 40 . Sodium–glucose cotransporter 2 inhibitor and glucagon‐like peptide‐1 receptor agonist are new options to improve the prognosis of DKD.
The limitations of this trial are as follows. The number of patients enrolled in the analysis was small and the statistical power was not sufficient. The rate of continuation of this trial was lower in the IT group. In addition, the majority of the patients in the IT group were not able to achieve the predefined treatment goals, and therefore, there was little difference between two groups. One of the explanations might be that the patients in both groups were treated by the same doctors, who are diabetologists or nephrologists at each site. The factor that contributed to the tendency of decrease in renal events by IT was unclear. The lower level of serum LDL cholesterol might have contributed.
In conclusion, there was an overall trend toward a lower risk of the development of kidney events in the IT group than in the CT group in the present trial, but the benefit of IT could not be confirmed statistically. Lipid control by statin was associated with a lower risk of kidney events in addition to strict control of blood glucose and blood pressure. Further follow‐up study is required to clarify the efficacy of multifactorial intensified intervention on delaying progression of DKD to ESRD.
Disclosure
KS received speaker fees from MSD, Eli Lilly Japan, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Mitsubishi Tanabe and Kyowa Hakko Kirin; research support from Takeda, MSD, Kyowa Hakko Kirin and Mitsubishi Tanabe; and a consulting fee from Daiichi Sankyo. MH has received speaker fees from Astellas, Taisho‐Toyama, Tanabe‐Mitsubishi, Boehringer Ingelheim, Taisho, Kowa, Ono, MSD, Novartis and Novo‐Nordisk; and research support from Novo‐Nordisk, Ono, Shionogi and Johnson & Johnson. DK received speaker fees from MSD, Astellas Pharma Inc., Ono, Taisho, Mitsubishi Tanabe, Eli Lilly Japan, Boehringer‐Ingelheim Japan and Novo Nordisk Pharma; and research support from Ono., Taisho, Mitsubishi Tanabe and Boehringer‐Ingelheim Japan. HA received a research grant from Ono and Boehringer Ingelheim GmbH. MN received speaker fees from Mitsubishi Tanabe, Takeda, Kyowa Kirin, Taisho, Novo Nordisk Pharma and Daiichi Sankyo. HM is a consultant for AbbVie, Teijin and Boehringer‐Ingelheim Japan. TN, YS, SM, DS, TY, TU, DO and SM declare no conflict of interest.
Supporting information
Figure S1 | Mean hemoglobin A1c, blood pressure, serum low‐density lipoprotein cholesterol and waist circumference during the follow‐up period among the randomized patients.
Figure S2 | Mean urinary protein‐to‐creatinine ratio, urinary albumin‐to‐creatinine ratio and estimated glomerular filtration rate during the follow‐up period.
Table S1 | Eligibility criteria.
Table S2 | Treatment goals and interventions for conventional and intensive treatment groups.
Table S3 | Primary and secondary end‐points.
Table S4 | Concomitant treatments during the follow‐up period.
Table S5 | Number and frequency of adverse event for each treatment group.
Appendix S1 | List of clinical sites and participating investigators. List of committee members.
Acknowledgments
DNETT‐Japan was supported in part by a Grant‐in‐Aid for Scientific Research (200624010B to H Makino) from the Ministry of Health, Labor and Welfare of Japan from 2006 to 2009. This trial was also supported by Okayama Medical Foundation, Asahi Kasei Pharma, Astellas, AstraZeneca, Otsuka, Kowa Pharmaceutical, Daiichi Sankyo, Sanwa Kagaku, Sanofi Aventis, Sumitomo Dainippon Pharma, Takeda, Mitsubishi Tanabe Pharma, Chugai, Terumo, Eli Lilly, Novartis Pharma, MSD, Bayer, Boehringer Ingelheim, Eizai and Teijin Pharma. We thank Professor Michihiro Yoshida, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan, for reviewing the paper.
J Diabetes Investig 2021; 12: 207–216
References
- 1. Collins AJ, Foley RN, Chavers B, et al US renal data system 2013 annual data report. Am J Kidney Dis 2014; 63: A7. [DOI] [PubMed] [Google Scholar]
- 2. de Boer IH, Rue TC, Hall YN, et al Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 2011; 305: 2532–2539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Gerstein H, Mann J, Yi Q, et al Albuminuria and risk of CV events, death, and heart failure in diabetic and non‐diabetic individuals. JAMA 2001; 286: 421–446. [DOI] [PubMed] [Google Scholar]
- 4. Go AS, Chertow GM, Fan D, et al Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1295. [DOI] [PubMed] [Google Scholar]
- 5. Andresdottir G, Jensen ML, Carstensen B, et al Improved survival and renal prognosis of patients with type 2 diabetes and nephropathy with improved control of risk factors. Diabetes Care 2014; 37: 1660–1667. [DOI] [PubMed] [Google Scholar]
- 6. Parving H‐H, Rossing P. Diabetic nephropathy in 2014: improved cardiorenal prognosis in diabetic nephropathy. Nat Rev Nephrol 2015; 11: 68–70. [DOI] [PubMed] [Google Scholar]
- 7. Molitch ME, Adler AI, Flyvbjerg A, et al Diabetic kidney disease: a clinical update from kidney disease: improving global outcomes. Kidney Int 2015; 87: 20–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Gæde P, Vedel P, Parving H‐H, et al Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999; 353: 617–622. [DOI] [PubMed] [Google Scholar]
- 9. Gaede P, Vedel P, Larsen N, et al Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383–393. [DOI] [PubMed] [Google Scholar]
- 10. Oellgaard J, Gæde P, Rossing P, et al Intensified multifactorial intervention in type 2 diabetics with microalbuminuria leads to long‐term renal benefits. Kidney Int 2017; 91: 982–988. [DOI] [PubMed] [Google Scholar]
- 11. Ueki K, Sasako T, Okazaki Y, et al Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J‐DOIT3): an open‐label, randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5: 951–964. [DOI] [PubMed] [Google Scholar]
- 12. de Boer IH, DCCT/EDIC Research Group . Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 2014; 37: 24–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Shikata K, Haneda M, Koya D, et al Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan): rationale and study design. Diabetes Res Clin Pract 2010; 87: 228–232. [DOI] [PubMed] [Google Scholar]
- 14. Matsuo S, Imai E, Horio M, et al Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982–992. [DOI] [PubMed] [Google Scholar]
- 15. Bonds DE, Miller ME, Bergenstal RM, et al The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340: b4909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. ONTARGET Investigators , Yusuf S, Teo KK, et al Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–1559. [DOI] [PubMed] [Google Scholar]
- 17. UK Prospective Diabetes Study (UKPDS) Group . Intensive blood‐glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853. [PubMed] [Google Scholar]
- 18. Holman RR, Paul SK, Bethel MA, et al 10‐year follow‐up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–1589. [DOI] [PubMed] [Google Scholar]
- 19. Ohkubo Y, Kishikawa H, Araki E, et al Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non‐insulin‐dependent diabetes mellitus: a randomized prospective 6‐year study. Diabetes Res Clin Pract 1995; 28: 103–117. [DOI] [PubMed] [Google Scholar]
- 20. ADVANCE Collaborative Group , Patel A, Mac Mahon S, et al Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560–2672. [DOI] [PubMed] [Google Scholar]
- 21. Wong MG, Perkovic V, Chalmers J, et al Long‐term benefits of intensive glucose control for preventing end‐stage kidney disease: ADVANCE‐ON. Diabetes Care 2016; 39: 694–700. [DOI] [PubMed] [Google Scholar]
- 22. Ruospo M, Saglimbene VM, Palmer SC. Glucose targets for preventing diabetic kidney disease and its progression. Cochrane Database Syst Rev 2017; 6: CD010137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Coca SG, Ismail‐Beigi F, Haq N, et al Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta‐analysis intensive glucose control in type 2 diabetes. Arch Intern Med 2012; 172: 761–769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. de Galan BE, Perkovic V, Ninomiya T, et al Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol 2009; 20: 883–892. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Hsieh MC, Hsieh YT, Cho TJ, et al Remission of diabetic nephropathy in type 2 diabetic Asian population: role of tight glucose and blood pressure control. Eur J Clin Invest 2011; 41: 870–878. [DOI] [PubMed] [Google Scholar]
- 26. ADA Position Statements . Microvascular complications and foot care. Diabetes Care 2017; 40(Supplement 1): S88–S98. [DOI] [PubMed] [Google Scholar]
- 27. Stanton C. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis 2014; 63(suppl 2): S3–S21. [DOI] [PubMed] [Google Scholar]
- 28. Brenner BM, Cooper ME, de Zeeuw D, et al Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869. [DOI] [PubMed] [Google Scholar]
- 29. Lewis EJ, Hunsicker LG, Clarke WR, et al Renoprotective effect of the angiotensin‐receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–860. [DOI] [PubMed] [Google Scholar]
- 30. Parving H‐H, Lehnert H, Brochner‐Mortensen J, et al The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–878. [DOI] [PubMed] [Google Scholar]
- 31. Kunz R, Friedrich C, Wolbers M, et al Meta‐analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008; 148: 30–48. [DOI] [PubMed] [Google Scholar]
- 32. Fried LF, Emanuele N, Zhang JH, et al Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369: 1892–1903. [DOI] [PubMed] [Google Scholar]
- 33. Palmer SC, Navaneethan SD, Craig JC, et al HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2014; 5: CD007784. [DOI] [PubMed] [Google Scholar]
- 34. de Zeeuw D, Anzalone DA, Cain VA, et al Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial. Lancet Diabetes Endocrinol 2015; 3: 181–190. [DOI] [PubMed] [Google Scholar]
- 35. Su X, Zhang L, Lv J, et al Effect of statins on kidney disease outcomes: a systematic review and meta‐analysis. Am J Kidney Dis 2016; 67: 881–92. [DOI] [PubMed] [Google Scholar]
- 36. Sandhu S, Wiebe N, Fried LF, et al Statins for improving renal outcomes: a meta‐analysis. J Am Soc Nephrol 2006; 17: 2006–2016. [DOI] [PubMed] [Google Scholar]
- 37. Wanner C, Tonelli M. Kidney disease: improving global outcomes lipid guideline development work group M. KDIGO clinical Practice guideline for lipid management in CKD: summary of recommendation statements and clinical approach to the patient. Kidney Int 2014; 85: 1303–1319. [DOI] [PubMed] [Google Scholar]
- 38. Usui H, Shikata K, Matsuda M, et al HMG‐CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol Dial Transplant 2003; 18: 265–272. [DOI] [PubMed] [Google Scholar]
- 39. Perkovic V, Jardine MJ, Neal B, et al Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 13: 2295–2306. [DOI] [PubMed] [Google Scholar]
- 40. Marso SP, Daniels GH, Brown‐Frandsen K, et al Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 28: 311–322. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1 | Mean hemoglobin A1c, blood pressure, serum low‐density lipoprotein cholesterol and waist circumference during the follow‐up period among the randomized patients.
Figure S2 | Mean urinary protein‐to‐creatinine ratio, urinary albumin‐to‐creatinine ratio and estimated glomerular filtration rate during the follow‐up period.
Table S1 | Eligibility criteria.
Table S2 | Treatment goals and interventions for conventional and intensive treatment groups.
Table S3 | Primary and secondary end‐points.
Table S4 | Concomitant treatments during the follow‐up period.
Table S5 | Number and frequency of adverse event for each treatment group.
Appendix S1 | List of clinical sites and participating investigators. List of committee members.