The aim of this study was to examine whether motivating patientsto gain expertise and closely follow their risk parameters willattenuate the course of microvascular and cardiovascular sequelaeof diabetes. A randomized, prospective study was conducted of165 patients who had type 2 diabetes, hypertension, and hyperlipidemiaand were referred for consultation to a diabetes clinic in anacademic hospital. Patients were randomly allocated to standardconsultation (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 annualconsultations. The PP patients initiated on average one additionalconsultation per year. There were 80 cardiovascular events (eightdeaths) in the SC group versus 47 events (five deaths) in thePP group (P = 0.001). The relative risk (RR) over 8 yr for acardiovascular 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% confidenceinterval, 0.85 to 0.32). In the SC group, 14 patients developedovert nephropathy (four ESRD) versus seven (one ESRD) in thePP group (P = 0.05). Throughout the study period, BP, LDL cholesterol,and hemoglobin A1c were significantly lower in the PP than inthe SC patients. Well informed and motivated patients were moresuccessful in obtaining and maintaining good control of theirrisk factors, resulting in reduced cardiovascular risk and slowerprogression of microvascular disease.
Educational and behavioral interventions hitherto publishedin patients with diabetes had only modest effects on alleviationof disease progression (1). The poor outcomes may be partiallydue to deficiencies in diabetes knowledge, compliance, and motivation(2,3). Intensive therapeutic programs are effective in reducingdiabetic complications and cardiovascular morbidity and mortality(4–9). These programs, however, all have been randomized,prospective trials conducted by experts in academic medicalcenters. The extrapolation of the achievements of these programsto primary care is difficult because of both financial and organizationalshortcomings. We showed previously that sharing the therapeuticresponsibility with the patients themselves had a major impacton retarding the progress of microvascular complications (10).Reported herein is the second, 4-yr, phase of the study highlightingthe influence of the intervention on cardiovascular outcomes.
A total of 167 patients who had type 2 diabetes, hypertension,and dyslipidemia and referred for consultation to the diabetesclinic of Meir Hospital during the years 1995 to 1996 were randomizedto a standard consultation (SC) or to a patient-participationprogram (PP). The inclusion criteria were age 40 to 70 yr; type2 diabetes of <10 yr duration; BMI 35 kg/m2; BP values 140/90mmHg; LDL 120 mg/dl; serum creatinine 2 mg/dl (176 µmol/L);albumin/creatinine ratio <200 mg/g; and no history of myocardialinfarction, angina pectoris, vascular surgery, stroke, or anysystemic or malignant disease.
A total of 154 patients signed informed consent forms, 13 patientswere excluded, and 141 were randomized by the help of computer-generatedrandom numbers to either SC (n = 70) or PP (n = 71) programs.The flow of the patients throughout the study is outlined inFigure 1.
Patients of both groups were initially interviewed and examinedtwice over 2 wk and annually thereafter. Consultation letterswere written to the family physicians. No prescriptions wereever issued by members of the consultation team. The patientsof the SC group attended standard consultation visits, whereasthe patients of the PP program were given two 2-h teaching sessionsabout ways to achieve tight control of the modifiable risk factorsincluding also an individualized plan of lifestyle modificationand a fitness program, instructed to measure BP weekly, keeprecords of the results of the laboratory investigations, andurge their physicians to change or intensify treatment if thetarget values of BP (130/80 mmHg), LDL cholesterol (100 mg/dl),and hemoglobin A1c (HbA1c) (7%) were not reached. These patientswere encouraged to call the consultants when they believed thatthey needed advice.
Sixty-five patients in the SC group and 64 in the PP group completedthe first 4-yr phase. The follow-up was continued for an additional4 yr, bringing the mean follow-up period to 7.7 ± 0.2yr. Data on clinical outcome events were obtained from the lettersof the primary care physicians, hospital discharge summaries,or other consultants’ reports. The protocol was approvedby the institutional ethical committee. The hospital laboratoryserves the whole area; all laboratory examinations thereforewere done centrally. The assays were unchanged during the studyperiod. The analytical methods were previously described (10).Renal outcome was assessed by estimated GFR (e-GFR) (11).
Statistical Analyses
The power calculations and the ascertainment of adequate randomizationwere previously described (10). The primary end points for thefirst 4-yr analysis were the change in renal function as expressedby e-GFR and the change in albumin/creatinine ratio. For the8-yr analysis, the primary end points were total mortality andthe combined cardiovascular event index (cardiovascular mortality,nonfatal myocardial infarction [MI], nonfatal stroke, coronarybypass surgery, coronary angioplasty, amputation, or vascularsurgery for peripheral atherosclerotic artery disease). Secondaryend points were e-GFR and albumin/creatinine ratio. The annualmeans of the various measurements were compared by ANOVA andby paired or unpaired t test. The renal outcome parameters wereassessed by linear regression analysis. The analysis was doneon an intention-to-treat basis. The last available data of participantswho died or left the study were carried forward to be includedin the final analysis. The detailed statistical methods werepreviously described (10). This study was carried out by theauthors without external financial support.
The baseline characteristics of the patients of the PP and SCgroups were previously described (10) and are shown in the firstcolumn of Table 1. There was no difference in any of the baselinecharacteristics between the two groups. Over 8 yr, the patientsof the PP group initiated 826 additional visits to the consultationclinic, an average of 1.2 ± 0.8 visits/patient per yr.The main reason given by the patients was a failure to meetone or more of the target values of the risk factors.
Table 1. Initial, 4-yr, and 8-yr values of the main risk parameters and renal outcome measuresa
The patients in the PP group were more likely to receive angiotensin-convertingenzyme inhibitors or angiotensin II antagonists than those ofthe SC group. Also, all PP patients were prescribed lipid-loweringmedication versus one half of the SC patients. Glucose-loweringregimens were not different in the two groups. The prescribeddaily doses of most of antihypertensive agents and those ofstatins were higher in the PP than in the SC patients. The dataon drug treatment are summarized in Table 2.
Table 2. Drug treatment of the patients in the PP and SC groups, initially, after 4 yr, and at the end of the studya
Modifiable Risk Parameters
There was a decrease in all risk parameters in both groups;the values were significantly lower in the patients of the PPgroup. The differences in BP and LDL cholesterol values werehighly significant, whereas those of BMI and HbA1c were modest(Table 1).
Nephropathy and Retinopathy
The average annual decline in estimated e-GFR in the SC andthe PP groups was 4.6 ± 2.1 and 3.0 ± 1.8 ml/minper 1.73 m2, respectively (P = 0.01). Overt nephropathy (albumin/creatinineratio >300 mg/g) developed in 14 (22%) patients in the SCgroup versus 7 (12.5%) in the PP group (P = 0.01). The numbersof patients who developed ESRD were four and one in the SC andPP groups, respectively. Retinopathy was found in 35 versus21 patients in the SC and PP groups, respectively (P = 0.03).The relative risk reduction of microvascular complications inthe intervention (PP) versus the control (SC) group was 0.57(95% confidence interval, 0.91 to 0.28). These data are listedin Table 1 and shown in Figure 2. No standard method to assessneuropathy was used.
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.
Cardiovascular Disease
In the SC group 12 patients died, eight of cardiovascular causes(five MI, three strokes). Among the PP patients, there werenine deaths, five of which were cardiovascular (three MI, twostrokes).
The number of nonfatal cardiovascular events was 72 in 45 patientsof the SC group versus 47 in 31 patients of the PP group. Togetherwith the cardiovascular fatal events, the total number of cardiovascularevents was 80 versus 52 (P = 0.001). There were significantlyfewer 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 interventionsin the PP than in the SC patients (fatal + nonfatal MI + coronaryartery bypass graft + PCI, 56 versus 41; P = 0.046). Also, theparticipants of the PP program had fewer amputations and bypasssurgeries than their SC counterparts (3 versus 7).
A Kaplan-Meier estimation of event-free survival in the SC andPP groups is shown in Figure 3. The relative risk reductionof the main cardiovascular parameters is outlined in Table 3.
Figure 3. Kaplan-Meier estimation of combined cardiovascular event-free survival in SC and PP groups (P = 0.004 by the log-rank test). Cum survival, cumulative survival; GRP, group.
The patients with diabetes were provided with in-depth informationabout their disease, motivated to actively pursue their therapeuticgoals, and given tools to monitor their modifiable risk factors.This was achieved via individual teaching sessions and enablingcontact between patients and consultants. During 8 yr of follow-up,the cardiovascular morbidity was significantly reduced in thePP versus the SC patients. The progress of microvascular diseaseexpressed by the annual decline in e-GFR, the rise in albuminuria,and the number of patients with retinopathy was significantlyretarded already after 4 yr; at 8 yr, this difference grew infavor of the PP group.
The more favorable clinical outcome of the PP patients is borneout by the significantly lower values of the major risk parameters.Thus, the PP patients had lower BMI, lower systolic (7 mm) anddiastolic (5 mm) BP, lower LDL (116 versus 128 mg/dl), and lowerHbA1c values (8.3 versus 9.2%). These differences may be partiallyaccounted for by some differences in therapeutic policies. AllPP patients received renin-angiotensin system blockers throughoutthe study period as compared with 54 and 74% of the patientsin the SC group during 4 and 8 yr, respectively. All PP patientswere on lipid-lowering medications as compared with only 34to 59% of the SC patients at 4 and 8 yr. Furthermore, the averagedaily dose of angiotensin-converting enzyme inhibitors and statinswas higher in the PP than in the SC patients. Also, more PPpatients were on three antihypertensive drugs than their SCcounterparts. The differences in glucose-lowering therapy betweenthe groups were less conspicuous. The better compliance, perseverance,and strictness in recording personal data of the PP patientsare, most probably, the main reasons for the lower values ofthe main risk factors in this group. The results of this studycompare favorably with early as well as recently published intensivecare interventions in high-risk patients with diabetes (4–9).
Most randomized, controlled studies that have compared intensiveand less intensive regimens (4,7,12–15) concentrated ona single intervention, lowering BP, lipids, or glucose. Thefavorable outcome of the intensive versus less intensive patientgroups in such studies compares well with the results of similarstudies that used multiple interventions (6,8–10). Thissimilarity is probably due to better compliance of patientswho participate in clinical trials also with other prescribedmedications on top of the trial drug. Every intensive interventionhas a dual effect: A direct effect of the trial interventionitself and an indirect, perhaps not less powerful, effect ofimproved general motivation and compliance. The present studyisolates and highlights the indirect effect because there wasno direct pharmaceutical intervention in either of the groups.
The power of the patients to attenuate the clinical course oftheir disease stands out in view of failures of educationalprograms previously published (1,16–18). The differencelies perhaps in the availability of the contact with the consultantsthroughout the study period and the reinforcement of educationand motivation of the patients during the repeated annual consultationsessions.
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Abstract
Introduction
35 kg/m2; BP values 
140/90 mmHg; LDL 
