Multifactorial intervention has a significant effect on diabetic kidney disease in patients with type 2 diabetes

To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care. To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care. Type 2 diabetes is associated with vascular complications that decrease life expectancy and impair quality of life.1Seshasai S.R. Kaptoge S. Thompson A. et al.Diabetes mellitus, fasting glucose, and risk of cause-specific death.N Engl J Med. 2011; 364: 829-841Crossref PubMed Scopus (1783) Google Scholar Reduction of glucose levels decreases the risk of microvascular complications, such as diabetic kidney disease (DKD) and diabetic eye disease.2The Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (22363) Google Scholar, 3UK Prospective Diabetes Study (UKPDS) GroupIntensive 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: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18693) Google Scholar, 4Ohkubo 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: 103-117Abstract Full Text PDF PubMed Scopus (2808) Google Scholar, 5Patel A. MacMahon S. Chalmers J. et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (43) Google Scholar While the incidence of end-stage DKD and related mortality are on the decline, presumably due to advances in the treatment of hyperglycemia,6Gregg E.W. Li Y. Wang J. et al.Changes in diabetes-related complications in the United States, 1990-2010.N Engl J Med. 2014; 370: 1514-1523Crossref PubMed Scopus (1084) Google Scholar,7Nakamura J. Kamiya H. Haneda M. et al.Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001-2010: report of Committee on Causes of Death in Diabetes Mellitus.Diabetol Int. 2017; 8: 117-136Crossref PubMed Scopus (6) Google Scholar a large number of patients with diabetes still undergo hemodialysis or kidney transplantation annually in Japan and other countries.6Gregg E.W. Li Y. Wang J. et al.Changes in diabetes-related complications in the United States, 1990-2010.N Engl J Med. 2014; 370: 1514-1523Crossref PubMed Scopus (1084) Google Scholar,8Oshima M. Toyama T. Haneda M. et al.Estimated glomerular filtration rate decline and risk of end-stage renal disease in type 2 diabetes.PLoS One. 2018; 13e0201535Crossref PubMed Scopus (19) Google Scholar On the other hand, blood pressure (BP) control is also shown to be important for the prevention of DKD,9UK Prospective Diabetes Study GroupEfficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39.BMJ. 1998; 317: 713-720Crossref PubMed Google Scholar,10Patel A. MacMahon S. Chalmers J. et al.Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.Lancet. 2007; 370: 829-840Abstract Full Text Full Text PDF PubMed Scopus (1760) Google Scholar and statin-based management of low-density lipoprotein cholesterol (LDL-C) is also shown to reduce the risk of albuminuria.11Shen X. Zhang Z. Zhang X. et al.Efficacy of statins in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials.Lipids Health Dis. 2016; 15: 179Crossref PubMed Scopus (33) Google Scholar Indeed, in the Steno-2 Study, multifactorial intervention for glycemia, BP, and LDL-C led to reductions in the number of patients with diabetes and microalbuminuria progressing to nephropathy.12Gaede P. Vedel P. Larsen N. et al.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3755) Google Scholar However, the study size was small and the individual parameters were insufficiently controlled compared with those recommended by current guidelines.13Tajima N. Noda M. Origasa H. et al.Evidence-based practice guideline for the treatment for diabetes in Japan 2013.Diabetol Int. 2015; 6: 151-187Crossref Scopus (63) Google Scholar,14American Diabetes Association10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2019.Diabetes Care. 2019; 42: S103-S123Crossref PubMed Google Scholar Furthermore, it remained unclear how efficacious multifactorial intervention may be in preventing the progression of DKD among those without preexisting DKD. Therefore, a randomized controlled trial, the Japan Diabetes Optimal Integrated Treatment Study for 3 major risk factors of cardiovascular diseases (J-DOIT3)15Ueki K. Sasako T. Kato M. et al.Design of and rationale for the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3): a multicenter, open-label, randomized, parallel-group trial.BMJ Open Diabetes Res Care. 2016; 4e000123Crossref PubMed Scopus (11) Google Scholar,16Yazaki Y. Kadowaki T. Combating diabetes and obesity in Japan.Nat Med. 2006; 12: 73-74Crossref PubMed Scopus (47) Google Scholar was conducted to compare the effectiveness and safety of aggressive multifactorial intervention for glucose, BP, and LDL-C aimed at achieving current targets recommended by the Japanese guidelines13Tajima N. Noda M. Origasa H. et al.Evidence-based practice guideline for the treatment for diabetes in Japan 2013.Diabetol Int. 2015; 6: 151-187Crossref Scopus (63) Google Scholar for prevention of vascular complications and mortality in patients with type 2 diabetes. We have recently reported that intensive therapy reduced the renal outcome of all secondary outcome measures by 32%.17Ueki 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: 951-964Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar This report presents a detailed analysis of the effects of intensive therapy on the suppression of renal outcome in the study. From June 16, 2006, through March 31, 2009, a total of 2542 patients (11% with a history of cardiovascular disease) were randomly assigned to intensive therapy or conventional therapy (Figure 1). After a blinded review of all patients, 2 ineligible patients were removed from all analyses (Figure 1).17Ueki 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: 951-964Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar The 1269 patients receiving intensive therapy and 1271 patients receiving conventional therapy had similar characteristics at baseline, except for smoking status, which was shown to be severer in the intensive therapy group than in the conventional therapy group (Table 1).17Ueki 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: 951-964Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar We found that 20.4% and 3.0% of the patients in the intensive therapy group had microalbuminuria and macroalbuminuria, respectively, as did 19.0% and 3.7% of those in the conventional therapy group, respectively. The mean estimated glomerular filtration rate (eGFR) was 82.3 ml/min per 1.73 m2 and 82.2 ml/min per 1.73 m2 in in the intensive therapy and conventional therapy groups (Table 1). The patients shown to have eGFR <60 ml/min per 1.73 m2 accounted for 8.1% and 8.7% of those in the intensive therapy and conventional therapy groups (Table 1). The median duration of follow-up was 8.5 (interquartile range: 7.3 to 9.0) years.Table 1Baseline characteristicsCharacteristicConventional (n = 1271)Intensive (n = 1269)Age,aDynamic allocation was performed by randomization adjusted for age, male-to-female ratio, history of CVD, and HbA1c. yr59.1 ± 6.358.9 ± 6.4FemaleaDynamic allocation was performed by randomization adjusted for age, male-to-female ratio, history of CVD, and HbA1c.480 (37.8)485 (38.2)Duration of diabetes, yr8.47 ± 6.998.58± 7.00Smoking status Current267 (21.0)328 (25.8) Former416 (32.7)370 (29.2) Never588 (46.3)571 (45.0)History of CVDaDynamic allocation was performed by randomization adjusted for age, male-to-female ratio, history of CVD, and HbA1c.142 (11.2)146 (11.5)Body weight, kg65.9 ± 12.065.4 ± 11.9BMI, kg/m224.9 ± 3.824.8 ± 3.6Fasting plasma glucose, mg/dl158.7 ± 39.4159.6 ± 41.5HbA1c,aDynamic allocation was performed by randomization adjusted for age, male-to-female ratio, history of CVD, and HbA1c. %7.98 ± 1.058.01 ± 1.05HbA1c,aDynamic allocation was performed by randomization adjusted for age, male-to-female ratio, history of CVD, and HbA1c. mmol/mol63.7 ± 11.564.0 ± 11.5Systolic blood pressure, mm Hg134.1 ± 16.3133.5 ± 16.9Diastolic blood pressure, mm Hg80.0 ± 11.179.3 ± 10.8LDL cholesterol, mg/dl125.6 ± 31.7125.5 ± 30.6HDL cholesterol, mg/dl54.5 ± 14.054.4 ± 14.9Triglycerides, mg/dl123 (88, 177)121 (85, 180)Urine albumin-creatinine ratio, mg/g Cr10.8 (5.8, 26.3)11.1 (5.9, 27.6)Urine albumin-creatinine ratio ≥30 mg/g Cr289 (22.7)297 (23.4)Urine albumin-creatinine ratio ≥300 mg/g Cr47 (3.7)38 (3.0)eGFR, ml/min per 1.73 m282.2 ± 18.182.3 ± 17.8eGFR <60 ml/min per 1.73 m2110 (8.7)103 (8.1)BMI, body mass index; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.Data are median (interquartile range), n (%), or mean ± SD. To convert values for glucose to millimoles per liter, multiply by 0.05551. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129.a Dynamic allocation was performed by randomization adjusted for age, male-to-female ratio, history of CVD, and HbA1c. Open table in a new tab BMI, body mass index; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Data are median (interquartile range), n (%), or mean ± SD. To convert values for glucose to millimoles per liter, multiply by 0.05551. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129. Treatment regimens were described in the methods section and summarized in Table 2. Glycated hemoglobin (HbA1c), BP, and LDL-C levels were improved and reached plateaus at 1 to ∼3 years after the study entry. During the intervention period, the mean HbA1c level was 6.8% in the intensive therapy group (proportion of those achieving HbA1c <6.2% and <6.9% at 3 years, 11.2% and 61.3%, respectively) and 7.2% in the conventional therapy group (proportion of those achieving HbA1c <6.2% and <6.9% at 3 years, 3.6% and 27.4%, respectively), mean BP was 123/71 mm Hg in the intensive therapy group (proportion of those achieving systolic blood pressure [SBP] <120 mm Hg and <130 mm Hg at 3 years, 42.2% and 76.6%, respectively; proportion of those achieving diastolic blood pressure [DBP] <75 mm Hg and <80 mm Hg at 3 years, 63.4% and 82.5%, respectively) and 129/74 mm Hg in the conventional therapy group (proportion of those achieving SBP <120 mm Hg and <130 mm Hg at 3 years, 22.2% and 56.1%, respectively; proportion of those achieving DBP <75 mm Hg and <80 mm Hg at 3 years, 44.9% and 66.8%, respectively), and the mean LDL-C level was 86 mg/dl in the intensive therapy group (proportion of those achieving <80 mg/dl and <120 mg/dl at 3 years, 38.9% and 90.3%, respectively) and 104 mg/dl in the conventional therapy group (proportion of those achieving <80 mg/dl and <120 mg/dl at 3 years, 8.9% and 64.0%, respectively). The differences between the 2 groups in HbA1c, SBP, DBP, or LDL-C were statistically significant, (all P < 0.0001) (Table 3).17Ueki 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: 951-964Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar The high-density lipoprotein cholesterol (HDL-C) levels were elevated and sustained in both groups during the intervention period but were consistently significantly greater in the intensive therapy group than in the conventional therapy group (P < 0.0001) (Table 3).Table 2Multifactorial stepwise treatment in the intensive therapy groupStepMedicationsaIt is to be left up to the physician in charge how to optimize the medications by taking adverse events (including hypoglycemia and fluid retention) and results of self-monitoring into account.Blood glucosebCategory A: pioglitazone, biguanides, glucagon-like peptide-1 receptor agonists; category B: sulfonylurea and glinides; category C: insulin; category D: α-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors.0Diet or exercise (or both) therapy (+ category D)1Category A, if BMI ≥25 (+ category D)Category A or B, if BMI 22 to <25 (+ category D)Category B or A, if BMI <22 (+ category D)2Category A + category B (+ category D)3Category C (+ categories A, B, and D)Blood pressure1ARB or ACEI, escalated to its maximal dose2Maximal dose of ARB or ACEI + a long-acting CCB3Maximal dose of ARB or ACEI + a long-acting CCB + others (a diuretic, β-blocker, and/or α-blocker)LipidcThe omega-3 fatty acids are to be given if the goal for triglycerides has not been achieved. Standard doses of atorvastatin, pitavastatin, and rosuvastatin are 10, 2, and 5 mg, respectively, whereas maximum doses are 20, 4, and 10 mg.1A standard dose of atorvastatin, pitavastatin, or rosuvastatin2Maximal dose of atorvastatin, pitavastatin, or rosuvastatin3Maximal dose of atorvastatin, pitavastatin, or rosuvastatin + others (an anion-exchange resin and/or ezetimibe)ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II–receptor blocker; BMI, body mass index; CCB, Ca channel blocker.a It is to be left up to the physician in charge how to optimize the medications by taking adverse events (including hypoglycemia and fluid retention) and results of self-monitoring into account.b Category A: pioglitazone, biguanides, glucagon-like peptide-1 receptor agonists; category B: sulfonylurea and glinides; category C: insulin; category D: α-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors.c The omega-3 fatty acids are to be given if the goal for triglycerides has not been achieved. Standard doses of atorvastatin, pitavastatin, and rosuvastatin are 10, 2, and 5 mg, respectively, whereas maximum doses are 20, 4, and 10 mg. Open table in a new tab Table 3Control of risk factors during interventionRisk factorConventional (n = 1271)Intensive (n = 1269)P valueaTime-varying measurements were analyzed with generalized estimating equation models using robust variance adjustment.HbA1c, %7.20 (7.17 to 7.24)6.79 (6.76 to 6.83)<0.0001Systolic blood pressure, mm Hg128.7 (128.2 to 129.3)123.4 (122.9 to 124.0)<0.0001Diastolic blood pressure, mm Hg74.4 (74.0 to 74.8)71.5 (71.1 to 71.9)<0.0001LDL cholesterol, mg/dl103.7 (102.6 to 104.8)85.5 (84.3 to 86.7)<0.0001HDL cholesterol, mg/dl56.6 (56.1 to 57.1)59.1 (58.6 to 59.6)<0.0001BMI, kg/m224.7 (24.7 to 24.8)24.8 (24.7 to 24.8)0.321BMI, body mass index; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.Data are mean (95% confidence interval). To convert values for glucose to millimoles per liter, multiply by 0.05551. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129.a Time-varying measurements were analyzed with generalized estimating equation models using robust variance adjustment. Open table in a new tab ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II–receptor blocker; BMI, body mass index; CCB, Ca channel blocker. BMI, body mass index; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Data are mean (95% confidence interval). To convert values for glucose to millimoles per liter, multiply by 0.05551. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129. With regard to the antidiabetic drugs, sulfonylurea, metformin, α-glucosidase inhibitor, pioglitazone, and insulin were more frequently used in the intensive therapy group than in the conventional therapy group (Supplementary Table S1),17Ueki 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: 951-964Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar whereas insulin was much less frequently used in both groups than in previous studies5Patel A. MacMahon S. Chalmers J. et al.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (43) Google Scholar,18Gerstein H.C. Miller M.E. Byington R.P. et al.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6313) Google Scholar,19Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (3772) Google Scholar and sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor (GLP-1R) agonists were seldom used in both groups. Again, angiotensin II-receptor blockers were more frequently prescribed in the intensive therapy group than in the conventional therapy group (Supplementary Table S1) and high-intensity statins and ezetimibe were more frequently prescribed in the intensive therapy group than in the conventional therapy group (Supplementary Table S1).17Ueki 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: 951-964Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Although, the use of antiplatelets did not significantly differ between the 2 groups during the intervention period (Supplementary Table S1).17Ueki 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: 951-964Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar A total of 438 renal events occurred as time-to-first events of onset or progression of DKD during the intervention period (181 in the intensive therapy group and 257 in the conventional therapy group; 19.9 per 1000 person-years vs. 29.2 per 1000 person-years) and intensive therapy, compared with conventional therapy, was associated with a significant 32% relative risk reduction in renal events (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.56 to 0.82; P < 0.0001) (Figure 2a). The number needed to treat is 16.8 (95% CI: 7.90 to 25.72) at 8 years. Progression to microalbuminuria occurred in 139 patients in the intensive therapy group and 197 in the conventional therapy group (15.2 per 1000 person-years vs. 22.3 per 1000 person-years), accounting for a significant 30.9% relative risk reduction in the intensive therapy group (HR: 0.69; 95% CI: 0.56 to 0.86; P < 0.0001) (number needed to treat at 8 years: 20.2; 95% CI: 8.43 to 31.87), whereas there was no difference in progression to macroalbuminuria (31 vs. 38; 3.4 per 1000 person-years vs. 4.3 per 1000 person-years) between groups (HR: 0.78; 95% CI: 0.49 to 1.25; P = 0.30). Doubling of serum creatinine occurred in 11 patients in the intensive therapy group and 22 in the conventional therapy group (1.2 per 1000 person-years vs. 2.5 per 1000 person-years), accounting for a 50.6% relative risk reduction in the intensive therapy group (HR: 0.49; 95% CI: 0.24 to 1.02; P = 0.05) (number needed to treat at 8 years: 80.3; 95% CI: 9.68 to 151.03) (Figure 2b). Renal replacement therapy did not occur in either group as time-to-first events, but 5 hemodialysis events occurred in the conventional therapy group alone during the intervention period. There was no death from renal disease in either group. Remission, defined as changes from macroalbuminuria to microalbuminuria or normoalbuminuria or from microalbuminuria to normoalbuminuria, is known to be achieved by multifactorial approaches.20Gaede P. Tarnow L. Vedel P. et al.Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria.Nephrol Dial Transplant. 2004; 19: 2784-2788Crossref PubMed Scopus (185) Google Scholar, 21Araki S. Haneda M. Sugimoto T. et al.Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes.Diabetes. 2005; 54: 2983-2987Crossref PubMed Scopus (165) Google Scholar, 22Yokoyama H. Araki S. Honjo J. et al.Association between remission of macroalbuminuria and preservation of renal function in patients with type 2 diabetes with overt proteinuria.Diabetes Care. 2013; 36: 3227-3233Crossref PubMed Scopus (35) Google Scholar In this trial, remission occurred in 89 of the 297 patients with nephropathy (30.0%) in the intensive therapy group and 47 of the 289 patients with nephropathy (16.3%) in the conventional therapy group at the end of the intervention, thus accounting for a significant difference (P < 0.001). The Cox regression analysis using the baseline data revealed that older age, higher HbA1c, smoking status, higher serum triglycerides, and lower eGFR were associated with a significant increase in the relative risk of the renal outcome (Table 4). To determine the effect of each component of the treatment on the renal outcome, additional Cox regression analysis was performed using the data at 1 year after initiation of the intervention, which demonstrated that HbA1c alone was significantly associated with the risk of the renal outcome (Table 5) after adjustment for risk factors at baseline (a 1% elevation in HbA1c leads to a 21% increase in the renal outcome).Table 4Cox regression for the renal outcome (factors at baseline)Explanatory variablesRegression coefficient (95% CI)P valueTreatment groupConventional/intensive0.66 (0.54 to 0.80)<0.001Age, yr<60/≥601.23 (1.00 to 1.51)0.046SexMale/female1.12 (0.86 to 1.40)0.394History of CVDsNo/yes0.99 (0.74 to 1.34)0.964HbA1c, %<8.9/≥8.91.32 (1.01 to 1.72)0.042BMI, kg/m2<25/≥ 251.08 (0.885 to 1.327)0.439Smoking statusNever/current or former1.45 (1.13 to 1.85)0.004Duration of diabetes, yr<10/≥101.06 (0.86 to 1.31)0.594Fasting plasma glucose, mg/dl<180/≥1800.96 (0.75 to 1.24)0.752Systolic blood pressure, mm Hg<130/≥1301.13 (0.90 to 1.43)0.284Diastolic blood pressure, mm Hg<80/≥800.98 (0.783 to 1.22)0.831LDL cholesterol, mg/dl<120/≥1201.11 (0.91 to 1.35)0.318HDL cholesterol, mg/dl<40/≥400.87 (0.65 to 1.17)0.372Triglycerides, mg/dl<150/≥1501.28 (1.04 to 1.56)0.019Urine albumin-creatinine ratio, mg/g Cr<30 /≥300.85 (0.67 to 1.08)0.172eGFR, ml/min per 1.73 m2<60/≥600.65 (0.48 to 0.89)0.006BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.Cox regression for the renal outcome that included allocation factors and prespecified factors at baseline. The referred category is indicated on the left. Open table in a new tab Table 5Cox regression for the renal outcome (factors at 1 year)Explanatory variablesRegression coefficient (95% CI)P valueTreatment groupConventional/intensive0.72 (0.56 to 0.93)0.011Risk groupLow/middle1.84 (1.37 to 2.46)<0.001Low/high1.26 (0.97 to 1.63)0.087Smoking statusNever/current or former1.12 (0.85 to 1.48)0.410BMI, kg/m21.03 (1.00 to 1.06)0.051HbA1c, %1.21 (1.07 to 1.36)0.002Systolic blood pressure, mm Hg1.01 (1.00 to 1.02)0.172Diastolic blood pressure, mm Hg0.99 (0.98 to 1.01)0.381HDL cholesterol, mg/dl1.00 (0.99 to 1.01)0.384LDL cholesterol, mg/dl1.00 (1.00 to 1.01)0.587Triglycerides, mg/dl1.00 (1.00 to 1.00)0.776BMI, body mass index; CI, confidence interval; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.Cox regression for the renal outcome that included prespecified factors at 1 year of intervention. The referred category is indicated on the left. The risk groups were determined by the blind review using the stratification factors (age, sex, history of cardiovascular disease, and HbA1c) as follows:Low-risk group, 8 strata: (i) <60 years, female, yes, <8.9%; (ii) <60 years, female, yes, ≥8.9%; (iii) <60 years, female, no, <8.9%; (iv) <60 years, female, no, ≥8.9%; (v) <60 years, male, no, <8.9%; (vi) <60 years, male, no, ≥8.9%; (vii) ≥60 years, femal