Educational and behavioral interventions hitherto published

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1 Treatment of High-Risk Patients with Diabetes: Motivation and Teaching Intervention: A Randomized, Prospective 8-Year Follow-Up Study Rita Rachmani, Inna Slavacheski, Maya Berla, Ronni Frommer-Shapira, and Mordchai Ravid Department of Medicine, Sackler School of Medicine, Tel-Aviv University, and Meir Hospital, Kfar-Sava, Israel The aim of this study was to examine whether motivating patients to gain expertise and closely follow their risk parameters will attenuate the course of microvascular and cardiovascular sequelae of diabetes. A randomized, prospective study was conducted of 165 patients who had type 2 diabetes, hypertension, and hyperlipidemia and were referred for consultation to a diabetes clinic in an academic hospital. Patients were randomly allocated to standard consultation (SC) or to a patient participation (PP) program. Both groups were followed by their primary care physicians. The mean follow-up was 7.7 yr. The SC group attended eight annual consultations. The PP patients initiated on average one additional consultation per year. There were 80 cardiovascular events (eight deaths) in the SC group versus 47 events (five deaths) in the PP group (P 0.001). The relative risk (RR) over 8 yr for a cardiovascular event in the intervention (PP) versus the control (SC) group was 0.65 (95% confidence interval, 0.89 to 0.41). There were 17 and eight cases of stroke in the SC and PP groups, respectively (P 0.05). RR for stroke was 0.47 (95% confidence interval, 0.85 to 0.32). In the SC group, 14 patients developed overt nephropathy (four ESRD) versus seven (one ESRD) in the PP group (P 0.05). Throughout the study period, BP, LDL cholesterol, and hemoglobin A 1c were significantly lower in the PP than in the SC patients. Well informed and motivated patients were more successful in obtaining and maintaining good control of their risk factors, resulting in reduced cardiovascular risk and slower progression of microvascular disease. J Am Soc Nephrol 16: S22 S26, doi: /ASN Educational and behavioral interventions hitherto published in patients with diabetes had only modest effects on alleviation of disease progression (1). The poor outcomes may be partially due to deficiencies in diabetes knowledge, compliance, and motivation (2,3). Intensive therapeutic programs are effective in reducing diabetic complications and cardiovascular morbidity and mortality (4 9). These programs, however, all have been randomized, prospective trials conducted by experts in academic medical centers. The extrapolation of the achievements of these programs to primary care is difficult because of both financial and organizational shortcomings. We showed previously that sharing the therapeutic responsibility with the patients themselves had a major impact on retarding the progress of microvascular complications (10). Reported herein is the second, 4-yr, phase of the study highlighting the influence of the intervention on cardiovascular outcomes. Materials and Methods A total of 167 patients who had type 2 diabetes, hypertension, and dyslipidemia and referred for consultation to the diabetes clinic of Meir Hospital during the years 1995 to 1996 were randomized to a standard consultation (SC) or to a patient-participation program (PP). The inclusion criteria were age 40 to 70 yr; type 2 diabetes of 10 yr duration; BMI 35 kg/m 2 ; BP values 140/90 mmhg; LDL 120 mg/dl; serum Address correspondence to: Prof. M. Ravid, Maaynei-Hayeshua Medical Centre, Bnei Brack, Israel. Fax: ; ravidm@netvision.net.il creatinine 2 mg/dl (176 mol/l); albumin/creatinine ratio 200 mg/g; and no history of myocardial infarction, angina pectoris, vascular surgery, stroke, or any systemic or malignant disease. A total of 154 patients signed informed consent forms, 13 patients were excluded, and 141 were randomized by the help of computergenerated random numbers to either SC (n 70) or PP (n 71) programs. The flow of the patients throughout the study is outlined in Figure 1. Patients of both groups were initially interviewed and examined twice over 2 wk and annually thereafter. Consultation letters were written to the family physicians. No prescriptions were ever issued by members of the consultation team. The patients of the SC group attended standard consultation visits, whereas the patients of the PP program were given two 2-h teaching sessions about ways to achieve tight control of the modifiable risk factors including also an individualized plan of lifestyle modification and a fitness program, instructed to measure BP weekly, keep records of the results of the laboratory investigations, and urge their physicians to change or intensify treatment if the target values of BP (130/80 mmhg), LDL cholesterol (100 mg/dl), and hemoglobin A 1c (HbA 1c ) (7%) were not reached. These patients were encouraged to call the consultants when they believed that they needed advice. Sixty-five patients in the SC group and 64 in the PP group completed the first 4-yr phase. The follow-up was continued for an additional 4 yr, bringing the mean follow-up period to yr. Data on clinical outcome events were obtained from the letters of the primary care physicians, hospital discharge summaries, or other consultants reports. The protocol was approved by the institutional ethical committee. The hospital laboratory serves the whole area; all laboratory examinations therefore were done centrally. The assays were unchanged during the Copyright 2005 by the American Society of Nephrology ISSN: /

2 J Am Soc Nephrol 16: S22 S26, 2005 Teaching Diabetic Patients to Monitor Their Risk Factors S23 Statistical Analyses The power calculations and the ascertainment of adequate randomization were previously described (10). The primary end points for the first 4-yr analysis were the change in renal function as expressed by e-gfr and the change in albumin/creatinine ratio. For the 8-yr analysis, the primary end points were total mortality and the combined cardiovascular event index (cardiovascular mortality, nonfatal myocardial infarction [MI], nonfatal stroke, coronary bypass surgery, coronary angioplasty, amputation, or vascular surgery for peripheral atherosclerotic artery disease). Secondary end points were e-gfr and albumin/ creatinine ratio. The annual means of the various measurements were compared by ANOVA and by paired or unpaired t test. The renal outcome parameters were assessed by linear regression analysis. The analysis was done on an intention-to-treat basis. The last available data of participants who died or left the study were carried forward to be included in the final analysis. The detailed statistical methods were previously described (10). This study was carried out by the authors without external financial support. Figure 1. Flow of participants through the trial. study period. The analytical methods were previously described (10). Renal outcome was assessed by estimated GFR (e-gfr) (11). Results The baseline characteristics of the patients of the PP and SC groups were previously described (10) and are shown in the first column of Table 1. There was no difference in any of the baseline characteristics between the two groups. Over 8 yr, the patients of the PP group initiated 826 additional visits to the consultation clinic, an average of visits/patient per yr. The main reason given by the patients was a failure to meet one or more of the target values of the risk factors. The patients in the PP group were more likely to receive angiotensin-converting enzyme inhibitors or angiotensin II antagonists than those of the SC group. Also, all PP patients were prescribed lipid-lowering medication versus one half of the SC patients. Glucose-lowering regimens were not different in the two groups. The prescribed daily doses of most of antihypertensive agents and those of statins were higher in the PP than in Table 1. Initial, 4-yr, and 8-yr values of the main risk parameters and renal outcome measures a Variable Initial (n 141) 4yr (n 129) 8yr (n 111) SBP (mmhg) SC b b PP DBP (mmhg) SC b b PP LDL cholesterol (mg/dl) SC b b PP HbA 1c (%) SC b b PP e-gfr (ml/min per 1.73 m 2 ) SC group b b PP group Alb/Cr ratio (mg/g) SC group 39 (17 186) 58 (25 673) b 185 ( ) b PP group 41 (15 194) 39 (15 374) 84 ( ) a Data are mean SD. SBP, systolic BP; SC, standard consultation; PP, patient participation; DBP, diastolic BP; HbA 1c, hemoglobin A 1c ; e-gfr, estimated GFR; Alb/Cr, albumin/creatinine. b P 0.05 for PP group versus SC group.

3 S24 Journal of the American Society of Nephrology J Am Soc Nephrol 16: S22 S26, 2005 the SC patients. The data on drug treatment are summarized in Table 2. Modifiable Risk Parameters There was a decrease in all risk parameters in both groups; the values were significantly lower in the patients of the PP group. The differences in BP and LDL cholesterol values were highly significant, whereas those of BMI and HbA 1c were modest (Table 1). Nephropathy and Retinopathy The average annual decline in estimated e-gfr in the SC and the PP groups was and ml/min per 1.73 m 2, respectively (P 0.01). Overt nephropathy (albumin/creatinine ratio 300 mg/g) developed in 14 (22%) patients in the SC group versus 7 (12.5%) in the PP group (P 0.01). The numbers of patients who developed ESRD were four and one in the SC and PP groups, respectively. Retinopathy was found in 35 versus 21 patients in the SC and PP groups, respectively (P 0.03). The relative risk reduction of microvascular complications in the intervention (PP) versus the control (SC) group was 0.57 (95% confidence interval, 0.91 to 0.28). These data are listed in Table 1 and shown in Figure 2. No standard method to assess neuropathy was used. Cardiovascular Disease In the SC group 12 patients died, eight of cardiovascular causes (five MI, three strokes). Among the PP patients, there were nine deaths, five of which were cardiovascular (three MI, two strokes). The number of nonfatal cardiovascular events was 72 in 45 patients of the SC group versus 47 in 31 patients of the PP group. Together with the cardiovascular fatal events, the total number of cardiovascular events was 80 versus 52 (P 0.001). There were significantly fewer events of stroke in the PP than in the SC group (fatal nonfatal stroke, 8 in the PP versus 17 in the SC group; P 0.01). There were also fewer coronary artery events and interventions in the PP than in the SC patients (fatal nonfatal MI coronary artery bypass graft PCI, 56 versus 41; P 0.046). Also, the participants of the PP program had fewer amputations and bypass surgeries than their SC counterparts (3 versus 7). A Kaplan-Meier estimation of event-free survival in the SC and PP groups is shown in Figure 3. The relative risk reduction of the main cardiovascular parameters is outlined in Table 3. Discussion The patients with diabetes were provided with in-depth information about their disease, motivated to actively pursue Table 2. Drug treatment of the patients in the PP and SC groups, initially, after 4 yr, and at the end of the study a Initial 4 Yr 8 Yr (n 70) (n 71) (n 65) (n 64) (n 54) (n 56) Antihypertensive ACE-I or ARB 13 (19) 15 (21) 34 (54) 64 (100) b 40 (74) 56 (100) b HCTZ 4 (6) 4 (6) 24 (37) 62 (97) b 39 (72) 50 (89) b CCB 24 (34) 26 (37) 36 (55) b 15 (23) 31 (57) b 16 (29) -blockers 16 (23) 18 (25) 24 (37) 23 (36) 28 (52) 22 (39) -blockers 6 (9) 5 (7) 15 (23) 16 (25) 19 (33) 14 (25) Patients on drug 2 drugs drugs Lipid lowering statins 6 (9) 5 (7) 22 (34) 52 (81) b 32 (59) 54 (96) b fibrates 3 (4) 4 (6) 4 (6) 13 (20) b 4 (7) 0 statins and fibrates 2 (3) 10 (16) 4 (7) 2 (4) Glucose lowering diet alone 16 (23) 18 (25) 4 (6) 0 0 sulfonylurea 29 (41) 27 (38) 14 (28) 9 (14) b 10 (19) b 2 (4) metformin 7 (10) 9 (13) 6 (9) 12 (19) b 6 (11) 4 (7) sulfonylurea metformin 10 (14) 7 (10) 18 (28) 25 (38) 10 (19) 19 (34) glitazones 4 (7) 6 (11) insulin 8 (11) 10 (14) 23 (35) 18 (28) 24 (44) 25 (44) aspirin 21 (30) 23 (32) 37 (57) 60 (94) b 42 (78) 56 (100) b a Data are n (%). ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; HCTZ, hydrochlorothiazide; CCB, calcium channel blockers. b P 0.05 for the difference between PP and SC groups.

4 J Am Soc Nephrol 16: S22 S26, 2005 Teaching Diabetic Patients to Monitor Their Risk Factors S25 Figure 3. Kaplan-Meier estimation of combined cardiovascular event-free survival in SC and PP groups (P by the log-rank test). Cum survival, cumulative survival; GRP, group. Table 3. Relative risk reduction (95% CI) of the main cardiovascular parameters in the intervention (PP) versus the control (SC) groups a Parameter RR (95% CI) MI 0.79 ( ) Stroke 0.47 ( ) CABG PCI 0.70 ( ) Nonfatal CV events 0.65 ( ) CV mortality 0.62 ( ) Non-CV mortality 1.0 Figure 2. Mean values of estimated GFR (e-gfr; see Results) and albumin/creatinine ratio (ACR). Standard care (SC) and patient participation (PP) groups during 8 yr. a CI, confidence interval; MI, myocardial infarction; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; CV, cardiovascular. their therapeutic goals, and given tools to monitor their modifiable risk factors. This was achieved via individual teaching sessions and enabling contact between patients and consultants. During 8 yr of follow-up, the cardiovascular morbidity was significantly reduced in the PP versus the SC patients. The progress of microvascular disease expressed by the annual decline in e-gfr, the rise in albuminuria, and the number of patients with retinopathy was significantly retarded already after 4 yr; at 8 yr, this difference grew in favor of the PP group. The more favorable clinical outcome of the PP patients is borne out by the significantly lower values of the major risk parameters. Thus, the PP patients had lower BMI, lower systolic (7 mm) and diastolic (5 mm) BP, lower LDL (116 versus 128 mg/dl), and lower HbA 1c values (8.3 versus 9.2%). These differences may be partially accounted for by some differences in therapeutic policies. All PP patients received renin-angiotensin system blockers throughout the study period as compared with 54 and 74% of the patients in the SC group during 4 and 8 yr, respectively. All PP patients were on lipid-lowering medications as compared with only 34 to 59% of the SC patients at 4 and 8 yr. Furthermore, the average daily dose of angiotensinconverting enzyme inhibitors and statins was higher in the PP than in the SC patients. Also, more PP patients were on three antihypertensive drugs than their SC counterparts. The differences in glucose-lowering therapy between the groups were less conspicuous. The better compliance, perseverance, and strictness in recording personal data of the PP patients are, most probably, the main reasons for the lower values of the main risk factors in this group. The results of this study compare favorably with early as well as recently published intensive care interventions in high-risk patients with diabetes (4 9). Most randomized, controlled studies that have compared intensive and less intensive regimens (4,7,12 15) concentrated on a single intervention, lowering BP, lipids, or glucose. The favorable outcome of the intensive versus less intensive patient groups in such studies compares well with the results of similar

5 S26 Journal of the American Society of Nephrology J Am Soc Nephrol 16: S22 S26, 2005 studies that used multiple interventions (6,8 10). This similarity is probably due to better compliance of patients who participate in clinical trials also with other prescribed medications on top of the trial drug. Every intensive intervention has a dual effect: A direct effect of the trial intervention itself and an indirect, perhaps not less powerful, effect of improved general motivation and compliance. The present study isolates and highlights the indirect effect because there was no direct pharmaceutical intervention in either of the groups. The power of the patients to attenuate the clinical course of their disease stands out in view of failures of educational programs previously published (1,16 18). The difference lies perhaps in the availability of the contact with the consultants throughout the study period and the reinforcement of education and motivation of the patients during the repeated annual consultation sessions. References 1. Gary TL, Gentringer JM, Guallar E, Peyrot M, Brandcati FL: Meta-analysis of randomized educational and behavioral interventions in type 2 diabetes. Diabetes Educ 29: , Murata GH, Shah JH, Adam KD, Wendel CS, Bokhari SU, Sulvan PA, Hoffman RM, Dudkworth WC: Factors affecting diabetes knowledge in type 2 diabetic veterans. Diabetologia 46: , Alazvi MH, Neal RD: The association between satisfaction with services provided in primary care and outcomes in type 2 diabetes mellitus. Diabet Med 20: , UK Prospective Diabetes Study Group: Intensive blood glucose control with sulphonylurea or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. UKPDS 33. Lancet 352: , UKPDS Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 38. BMJ 317: , Sawicki PT, Mullhanser I, Didjurgeit M, Reimann M, Bender R, Berger M: Mortality and morbidity in treated hypertensive type 2 diabetic patients with micro or macroproteinuria. Diabet Med 12: , Hansson L, Zanchetti A, Julius S: Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 351: , Gaede P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The Steno Type 2 Randomized Study. Lancet 353: , Gaede P, Vedel P, Larsen N, Jensen GVH, Parving HH, Pedersen O: Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348: , Rachmani R, Levi Z, Slavachevski I, Avin M, Ravid M: Teaching patients to monitor their risk factors retards the progression of vascular complications in high-risk patients with type 2 diabetes mellitus A randomized prospective study. Diabet Med 19: , Levy AS, Bosch JP, Breyer Lewis J, Green T, Togers N, Toth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130: , Pyorala K, Pedersen TR, Kjekshus J, Fargeman O, Olsson AC, Thorgeirsson G: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 20: , Ravid M, Lang R, Rachmani R, Lishner M: Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus: A 7-year follow-up study. Arch Intern Med 156: , The Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342: , The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 339: , Kanters SDJM, Algra A, de Bruint TWA, Erkelens DM, Banga JD: Intensive lipid lowering strategy in patients with diabetes mellitus. Diabet Med 16: , Holt W, Johnson A, de Belder M: Patient empowerment in secondary prevention of coronary heart disease. Lancet 356: 314, White WB, Asmar R, Imai Y: Task force VI: Self-monitoring of the blood pressure. Blood Press Monit 4: , 1999

Prevention And Treatment of Diabetic Nephropathy. MOH Clinical Practice Guidelines 3/2006 Dr Stephen Chew Tec Huan

Prevention And Treatment of Diabetic Nephropathy MOH Clinical Practice Guidelines 3/2006 Dr Stephen Chew Tec Huan Prevention Tight glucose control reduces the development of diabetic nephropathy Progression