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Keywords:

  • diabetes mellitus;
  • elderly;
  • geriatric assessment;
  • intervention;
  • vascular complications

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix

Aim:  To evaluate long-term, multiple risk factor intervention on physical, psychological and mental prognosis, and development of complications and cardiovascular disease in elderly type 2 diabetes patients.

Methods:  Our randomized, controlled, multicenter, prospective intervention trial included 1173 elderly type 2 diabetes patients who were enrolled from 39 Japanese institutions and randomized to an intensive or conservative treatment group. Glycemic control, dyslipidemia, hypertension, obesity, diabetic complications and atherosclerotic disease were measured annually. Instrumental activity of daily living, cognitive impairment, depressive symptoms and diabetes burden were assessed at baseline and 3 years.

Results:  There was no significant difference in clinical or cognitive parameters at baseline between the two groups. The prevalence of low activities of daily living, depressive symptoms and cognitive impairment was 13%, 28% and 4%, respectively, and was similar in the two groups. A small, but significant difference in HbA1c between the two groups was observed at 1 year after the start of intervention (7.9% vs 8.1%, P < 0.05), although this significant difference was not observed after the second year. With the exception of coronary revascularization, there was no significant difference in fatal or non-fatal events between the two groups. Composite events were also similar in the two groups.

Conclusions:  This study showed no significant differences in fatal or non-fatal events between intensive and conventional treatment. The present study might clarify whether treatment of risk factors influences function and quality of life in elderly diabetic patients. Geriatr Gerontol Int 2012; 12 (Suppl. 1): 7–17.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix

The prevalence of diabetes increases with age, with approximately 15% of elderly people in Japan having the disorder.1 These patients often suffer from diabetic microvascular and macrovascular complications.2 Treatment goals in this elderly diabetic population are to maintain functional abilities and quality of life, and to prevent diabetic complications. Physical functional activities3,4 and cognitive function5,6 are more impaired in elderly diabetic patients, with depression and low well-being being major concerns.7,8 It is therefore important to evaluate the effects of clinical interventions on physical, psychological and mental functions, as well as on disease-related variables, such as diabetic complications, atherosclerotic disease and mortality.

The impact of intensive blood glucose, blood pressure or multiple risk factor intervention on diabetic complications in type 2 diabetes has been evaluated in the United Kingdom Prospective Diabetes Study (UKPDS),9,10 Kumamoto Study11 and Steno-2 Study.12 As only a few elderly people were included in these studies, little is known on the effects of multiple risk factor intervention on diabetic complications and functional prognosis.

We therefore carried out a randomized clinical trial to evaluate the efficacy of multiple risk factor intervention on functional prognosis, and development and/or progression of diabetic complications and cardiovascular disease in elderly people with type 2 diabetes. The present study presents baseline demographic and biomedical characteristics, and describes the major outcome variables measured at baseline.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix

Participants

The participants recruited for the Japan Elderly Diabetes Intervention Trial (J-EDIT) were diabetic outpatients at 39 representative hospitals in Japan between March 2001 and February 2002. Written informed consent was obtained from all participants before screening, consistent with the Helsinki Declaration and the guidelines of each center's institutional ethical committee.

Initial screening tests included glycated hemoglobin A1c (HbA1c), body mass index (BMI), blood pressure, serum total cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL-C). Inclusion criteria included age 65–85 years, HbA1c ≥ 7.9% or HbA1c ≥ 7.4% with at least one of following criteria: BMI ≥ 25 kg/m2, blood pressure ≥ 130/85 mmHg, serum total cholesterol ≥ 200 mg/dL (or low-density lipoprotein cholesterol [LDL-C] ≥ 120 mg/dL in participants without coronary heart disease [CHD]) or ≥180 mg/dL (or LDL-C ≥100 mg/dL in participants with CHD), triglycerides ≥ 150 mg/dL and HDL-C < 40 mg/dL. Exclusion criteria included a recent (<6 months) myocardial infarction (MI) or stroke, acute or serious illness, aphasia and severe dementia.

Randomization and intervention

A total of 1173 diabetic outpatients were enrolled and randomly allocated to either the intensive or conventional treatment group. The randomized factors were age, sex, diabetes treatment, HbA1c, total cholesterol, triglycerides, HDL-C, blood pressure, diabetic microangiopathy, atherosclerotic disease, hypertension, hyperlipidemia and institutions.

The treatment goal in the intensive treatment group was HbA1c < 6.9%, BMI < 25 kg/m2, systolic blood pressure (SBP) < 130 mmHg, diastolic blood pressure (DBP) < 85 mmHg, HDL-C > 40 mg/dL, serum triglycerides < 150 mg/dL and serum total cholesterol < 180 mg/dL (or LDL-C < 100 mg/dL if patients had CHD) or <200 mg/dL (or LDL-C < 120 mg/dL if patients did not have CHD; Table 1). If HbA1c levels did not reduce to <6.9%, oral hypoglycemic drugs (sulphonylurea, biguanides, α-glucosidase inhibitors and pioglitazone) or insulin therapy was introduced by the physician. If total cholesterol or LDL-C levels did not reach the treatment goal, the physicians were advised to use atorvastatin. Patients with a history of cerebral infarction also had antiplatelet therapy where possible.

Table 1.  Treatment goals of multiple risk factor intervention studies in patients with type 2 diabetes
 J-EDITUKPDSSteno-2 Study
  1. CHD, coronary heart disease; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol, J-EDIT, Japan Elderly Diabetes Intervention Trial; UKPDS, United Kingdom Prospective Diabetes Study.

Mean age (years)725255
Range(65–84)(25–65)(40–65)
Treatment goals
 Glucose control   
 FPG (mmol/L) <6.0 
 HbA1c (%)<6.9 <6.5
Blood pressure control (mmHg)<130/85<150/85<140/85 (1993–1999)
<130/80 (2000–2001)
Cholesterol (mg/dL)<200none<190 (1993–1999)
(<180) if one has CHD<175 (2000–2001)
Triglycerides (mg/dL)<150none<150
HDL-C (mg/dL)>40none>40
Other interventionsBMI <25 Smoking cession
Aspirin use

The conventional treatment group continued their baseline treatment for diabetes, hypertension or dyslipidemia without a specific treatment goal.

Each participant had a standardized medical history and physical examination at baseline, and then annually. Baseline information included age, sex, medical history, family members with whom they lived, education, employment, height, bodyweight, waist-to-hip ratio, maximum body weight, diabetes duration, family history of diabetes and diabetes treatment. Standardized questionnaires were used to obtain self-reported data on smoking, alcohol, hypoglycemia frequency, nutritional status, dietary habits and adherence, self-efficacy, activities of daily living (ADL), physical activities, comprehensive cognitive function, and psychological status including diabetes burden and depressive symptoms.

Basic ADL was assessed by the Barthel index,13 whereas functional disabilities were examined by the Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence.14 This index includes 13 items and three subscales: instrumental ADL, intellectual activity and social role. The index is well validated and is widely used to measure functional abilities in community-dwelling or institutionalized elderly subjects.15

Physical activities were assessed using the Baecke questionnaire.16 The Folstein Mini-Mental State Examination (MMSE) was carried out to assess comprehensive cognitive function including orientation, memory recall and calculations.17

Depressive symptoms were evaluated using a short form of the Geriatric Depression Scale (15 items, GDS-15),18 whereas diabetes-specific burden and concerns were examined using the elderly diabetes burden scale (EDBS).19 EDBS is a short revised version of the elderly diabetes impact scale reported previously,4 and consists of six subscales: symptom burden (4 items), social burden (5 items), diet restrictions (4 items), concern (4 items), treatment satisfaction (3 items) and burden by tablets or insulin (3 items). Each of the 23 EDBS items was rated on a four-point multiple-choice scale. The elderly diabetes burden score was calculated by reversing the scores of the treatment satisfaction subscale and summing the scores of the six subscales. EDBS has good test–retest reliability, construct validity, convergent validity and satisfactory internal consistency.

The frequency of mild or severe hypoglycemia was assessed using questionnaires (number of hypoglycemic episodes and number of comas or emergency hospital visits or admissions as a result of hypoglycemia in a year, month or week). Mild hypoglycemia episodes included the appearance of or recovery from hypoglycemic symptoms. Severe hypoglycemia episodes were defined as coma, convulsion or incapacity of the patient sufficient to require the assistance of another person.

Nutritional intake was assessed for 1 week using the Yoshimura food frequency questionnaire20 that estimated food and total energy intake, carbohydrate-, protein- and fat-to-energy ratios, and intake of cholesterol, salt, iron, calcium, vitamins and dietary fiber from portion sizes (relative to the standard amount) and frequency (intake number for 1 week) of 29 food groups.

Measurements

Venous blood was drawn for determination of blood glucose, HbA1c and serum concentrations of total cholesterol, HDL-C and triglycerides at baseline, and then at least twice a year. Plasma glucose was measured by the glucokinase method, and HbA1c by ion-exchange high-performance liquid chromatography. The Japan Diabetes Society (JDS) has standardized several HbA1c assays with the international standard value adjusted by the equation of HbA1c (JDS) (%) plus 0.4%. Serum insulin was measured by an enzyme immunoassay, and total cholesterol, triglycerides, HDL-C, white blood cells, red blood cells, hematocrit (Ht), blood urea nitrogen (BUN), serum creatinine, uric acid, total protein and albumin by established methods.

Blood pressure was measured with a mercury sphygmomanometer using a cuff of appropriate size. Diastolic blood pressure was determined as Korotkoff phase V. Body mass index was calculated as weight in kilograms / (height in meters)2.

Microangiopathy (retinopathy, nephropathy and neuropathy), macroangiopathy (ischemic heart disease [IHD]), stroke and peripheral vascular disease [PVD]) were assessed at baseline, and then annually. Funduscopic examinations were carried out on dilated pupils by experienced ophthalmologists using direct ophthalmoscopy. Retinopathy status was assessed by the Japanese Diabetes Complication Study method and classified into five stages: stage 0: no retinopathy; stage 1: dot hemorrhages, hemorrhages or hard exudates; stage 2: soft exudates; stage 3: IRMA or venous deformities; stage 4: neovascularization, preretinal proliferative tissues, vitreous hemorrhages or retinal detachment. Diabetic maculopathy was assessed according to findings of hemorrhages, local edema, hard exudates and diffuse edema at macular areas. Uncorrected and corrected visual acuities, the occurrence of cataract, corneal opacity, glaucoma, age-related macular degeneration, laser photocoagulation, cataract operations and vitrectomy were assessed. Urinary albumin was measured by immunological assay. Mean urinary albumin-to-creatinine ratio (ACR; µg/mg creatinine) in two or three successive urinalyses was used to classify diabetic nephropathy as no nephropathy (ACR < 30), microalbuminuria (30 ≤ ACR < 300) or persistent proteinuria (ACR ≥ 300 or urinary protein ≥30 mg/dL). Diabetic neuropathy was defined as loss of Achilles tendon reflexes and diminished vibration sensation, and/or neuropathic symptoms including paresthesia.

Follow up

The annual examinations included bodyweight, BMI, waist-to-hip ratio, treatment of diabetes, fasting plasma glucose, serum insulin, total cholesterol, triglycerides, HDL-C, lipoprotein(a), white blood cells, red blood cells, Ht, platelet, BUN, serum creatinine, uric acid, total protein, albumin, blood pressure, visual acuity, microalbuminuria, deep tendon reflexes, neuropathic symptoms, resting electrocardiogram (ECG), chest X-ray, and the occurrence of retinopathy, nephropathy, neuropathy, IHD, stroke and PVD. HbA1c and ACR were measured biannually. Basic ADL, functional abilities, cognitive function, depressive symptoms and nutrition were assessed every other year. Use of medications, including insulin and hypoglycemic, antihypertensive, antihyperlipidemic, antiplatelet and anticoagulant drugs, was checked annually.

Data management and analyses

The main database was stored at the data management and statistical analysis center. A data sheet of each patient was mailed from the study institutions to the data management and statistical analysis center each year. The data was validated by range, combinatorial and historical checks of compatibility with previous data. A visual check of the list of abnormalities and information in the data sheets was carried out by trained staff. The study institutions were notified of unexplained abnormalities in the data that were completed or corrected before entry into the main database.

Data are presented as means ± SD or as proportions, unless otherwise specified. Data for analysis was extracted from the main database, and statistical analysis was carried out using the sas computer programs. For univariate analysis, we used unpaired t-test and χ2-test to compare baseline clinical characteristics in the two treatment groups. P < 0.05 was considered statistically significant.

Data security was maintained by exclusion of patient identities, password access and secure output within the data management and statistical analysis center.

End-points

Fatal and non-fatal events during follow up were certified by at least two members of the expert committee, masked to the participants' diagnosis and risk factor status. Death as a result of diabetes was defined as sudden death or death from atherosclerotic CHD (MI or heart failure as a result of ischemia) or stroke, death as a result of renal failure, hyperglycemia or hypoglycemia. The history of macroangiopathy was obtained from medical records. Ischemic heart disease was classified as present when the patient had (i) a history of MI characterized by a typical clinical picture (chest pain, chest oppression and dyspnea), typical ECG alterations with occurrence of pathological Q waves and/or localized ST variations) and typical enzymatic changes (creatine phosphokinase); and (ii) a history of angina pectoris, positive treadmill ECG test or positive postload cardiac scintigram, confirmed by coronary angiography. Stroke was defined as clinical signs of a focal neurological deficit with rapid onset persisting ≥24 h, confirmed by either brain computed tomography or magnetic resonance imaging. No cases of asymptomatic lesions detected by brain imaging (i.e. silent infarction) were included. PVD was defined as the absence of dorsal pedal artery or posterior tibial artery pulsation and ankle–brachial index <0.8 or the presence of foot gangrene or ulcers.

All events related to diabetes were defined as any complications of cardiovascular events, fatal or non-fatal stroke, sudden death, renal death, diabetic foot complications and heart failure. All events included death unrelated to diabetes, as well as all events related to diabetes.

End-point validation

Possible clinical end-points were noted in the annual data sheets, with the diagnostic criteria for each end-point being predetermined. When an end-point was notified on a data sheet, the administrator requested full information from the data management and statistical analysis center, followed by a review by two clinical assessors of the event assignment committee. Two separate assessments for each end-point were entered on a special data sheet. If there was disagreement on the assessment, a final decision was made after discussions of the committee. The definition of the end-points is shown in the Appendix.

Statistical analysis and criteria for stopping the study

Differences in end-points (deaths or complications) between the two groups were analyzed using the log–rank test. Uni- and multivariate survival analyses were carried out using Cox proportional hazard regression models. All major analyses were according to assigned allocations (intention to treat), without exclusion of protocol deviants.

The Data and Safety Monitoring Committee examine the end-points annually and will stop the study when the difference in diabetes-related deaths or complications (disease) between the two groups becomes significant (P < 0.001, log–rank test).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix

A total of 1173 outpatients with diabetes, aged over 65 years, were registered between March 2001 and February 2002. After randomization, 585 and 588 patients were allocated to intensive or conventional treatment, respectively. There were no significant differences between the two groups for age, sex, diabetes treatment, BMI, HbA1c, SBP and DBP, total cholesterol, triglycerides, HDL-C levels (Table 2), and number of risk factors (data not shown).

Table 2.  Clinical characteristics of the participants at baseline
 Conventional treatment (n = 588)Intensive treatment (n = 585)
  1. ARB, angiotensin II receptor blockers; ACE, angiotensin-converting enzyme; ATR, Achilles tendon reflex; BP, blood pressure; EPA, eicosapentenoic acid; HbA1c, glycated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; MMSE, Mini-Mental State Examination; OHA, oral hypoglycaemic agents; TMIG, Tokyo Metropolitan Institute of Gerontology. *P < 0.05.

General characteristics  
 Age (years)71.7 ± 4.771.9 ± 4.6
 Male (%)46.346.3
 Duration of diabetes (years)18.0 ± 9.916.7 ± 8.5
 Body mass index (kg/m2)24.3 ± 7.324.0 ± 3.9
 Waist (cm)83.6 ± 9.984.3 ± 10.4
 Waist-to-hip ratio0.89 ± 0.070.90 ± 0.07
 Smoking (%) (non-/ex-smoker/current smoker)16:31:5315:29:56
 Smoking (package × years)848 ± 762789 ± 601
 Family history of diabetes (%)45.839.7
 Systolic BP (mmHg)137 ± 17137 ± 16
 Diastolic BP (mmHg)75 ± 1076 ± 10
Clinical status  
 Ischemic heart disease (%)16.314.9
 Cerebrovascular disease (%)12.413.3
Retinopathy (%)  
 Stage 053.651.7
 Stage 130.531.4
 Stage 27.89.1
 Stage 33.33.4
 Stage 44.74.7
Nephropathy (%) (no/microalbuminuria/persistent proteinuria)51:30:1953:30:17
Loss or weakness of ATR (%)56.857.1
Paresthesia (%)18.522.3
Laboratory data  
 HbA1c (%)8.5 ± 0.98.4 ± 0.8*
 Fasting plasma glucose (mg/dL)170 ± 53168 ± 49
 Fasting insulin (mIU/mL)10.9 ± 12.010.3 ± 9.6
 Total cholesterol (mg/dL)202 ± 34203 ± 34
 Triglycerides (mg/dL)131 ± 70137 ± 110
 HDL-C (mg/dL)56 ± 1857 ± 19
 Uric acid (mg/dL)5.1 ± 2.05.1 ± 1.4
 Blood urea nitrogen (mg/dL)16.9 ± 5.917.2 ± 6.1
 Creatinine (mg/dL)0.93 ± 1.20.83 ± 0.36
Treatment
Treatment of diabetes (diet/OHA/insulin)9.0:60.7:30.38.7:61.0:30.3
 Sulfonylurea drugs54.656.0
 α-Glucosidase inhibitors (%)30.528.0
 Biguanides (%)16.415.5
 Pioglitazone (%)4.55.2
 Glinides (%)2.32.1
Antihypertensive drugs (%)56.457.4
 ACE inhibitors (%)22.923.3
 ARB (%)10.19.3
 Calcium blockers (%)42.941.0
 β-Blockers (%)6.25.7
 α-Blockers (%)6.1*3.4
 Diuretics (%)5.17.5
Antihyperlipidemic drugs (%)40.236.8
 Statins (%)30.326.5
 Fibrates (%)3.43.9
 EPA (%)0.7*2.7
 Nicotinates (%)1.31.4
 Probucol2.21.6
Antiplatelet drugs (%)25.927.4
 Aspirin (%)1315
Geriatric Assessment  
 Barthel index (full score: 20)19.8 ± 0.919.8 ± 0.8
 Prevalence of any disabilities (%)1114
 Functional abilities (TMIG index of competence) (full score: 13)11.6 ± 2.211.6 ± 2.2
 Geriatric depression scale (full score: 15)4.3 ± 3.34.0 ± 3.2
 Depressive symptoms (%) (Geriatric depression scale ≥5)4136
 MMSE (full score: 30)28.0 ± 2.427.8 ± 3.0
 Cognitive impairment (%) (MMSE ≤23)76
 Visual impairment (%) (≤0.1)912

At baseline, the proportion of patients with a low ADL (TMIG Index of Competence ≤ 9), depressive symptoms (GDS-15 ≥ 5), or cognitive impairment (MMSE ≤ 23) were 13%, 28% and 4%, respectively. The prevalence of low ADL, depressive state and cognitive impairment was similar in the two groups (Table 2).

The dropout rate after 6 years was 8.9% (104 cases). HbA1c, total cholesterol, triglycerides, blood pressures and BMI at baseline and during follow up are shown in Table 3 and Figures 1–4. A small, but significant difference in HbA1c between the two groups was observed at 1 year after the start of intervention (7.9% vs 8.1%, P < 0.05), although this significant difference was not observed after the second year. Although SBP and DBP, total cholesterol and triglycerides levels tended to decrease by the sixth year compared with the baseline data in both groups, no significant differences in these variables were observed between the two groups during follow up (Figs 1–4). BMI and HDL-C levels did not change over the follow-up period in either group.

Table 3.  Changes in bodyweights, glycated hemoglobin A1c, serum lipids, and blood pressure at baseline and during the follow-up period
 Conventional treatmentIntensive treatment
  1. BMI, body mass index; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides.

Follow up (years)01234560123456
BMI (kg/m2)23.623.623.623.423.523.523.423.923.823.823.823.823.723.5
HbA1c (%)8.58.18.07.97.97.97.88.47.97.87.87.87.87.7
TC (mg/dL)202200199195193190190202196198194190188188
TG (mg/dL)112111109108103101101114110110108110104104
HDL-C (mg/dL)5656555655555457545455555555
SBP (mmHg)137137135135135135134138136136133134136134
DBP (mg/dL)7574737272727174737472717171
image

Figure 1. Clinical course of (a) glycated hemoglobin A1c (HbA1c) and (b) body mass index (BMI) in the conventional and intensive treatment groups.

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image

Figure 2. Clinical course of (a) total cholesterol and (b) triglycerides in the conventional and intensive treatment groups.

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image

Figure 3. Clinical course of (a) high-density lipoprotein cholesterol (HDL-C) and (b) non-HDL-C in the conventional and intensive treatment groups.

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image

Figure 4. Clinical course of (a) systolic and (b) diastolic blood pressures (BP) in the conventional and intensive treatment groups.

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Table 4 shows the fatal and non-fatal events during follow up in the two groups. With the exception of coronary revascularization, there were no significant differences in fatal or non-fatal events between the groups (P < 0.05, log-rank test). Composite events (death as a result of diabetes, death unrelated to diabetes, coronary vascular events, stroke, total diabetes-related events and all events) were also similar in the two groups (Table 5).

Table 4.  Comparison of fatal events and non-fatal events during the 6-year follow-up period in the conventional and intensive treatment groups
  NumberP-value
Fatal eventMyocardial infarction120.083
Sudden death130.993
Stroke60.656
Death due to renal failure30.084
Death due to hyper/hypoglycemia10.322
Malignancy370.506
Pneumonia100.525
Others130.570
Subtotal950.291
Nonfatal eventMyocardial infarction170.998
Angina pectoris210.517
Coronary revascularization180.0282
Hospitalization due to heart failure150.190
Stroke630.281
Diabetic ulcer or gangrene120.564
Subtotal146 
Total 241 
Table 5.  Comparisons of composite events (death due to diabetes, death unrelated to diabetes, coronary vascular events, stroke, total diabetes-related events and all events) in the conventional and intensive treatment groups
 No. eventsP-value (log–rank test)
Conventional vs intensive
  1. Death due to diabetes was defined as sudden death or death from atherosclerotic coronary heart disease (myocardial infarction or heart failure due to ischemia) or stroke, death due to renal failure, hyperglycemia or hypoglycemia. All events related to diabetes were defined as any complications of cardiovascular events, fatal or non-fatal stroke, sudden death, renal death, diabetic foot complications and heart failure. All events included death unrelated to diabetes, as well as all events related to diabetes.

Death due to diabetes350.8495
Death not related to diabetes590.2991
Coronary vascular events550.9868
Stroke670.2915
All events related to diabetes1550.5573
All events2060.2239

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix

The J-EDIT study has the potential to determine whether multiple risk factor intervention prevents aggravation of complications and quality of life, and reduces mortality in elderly diabetic patients. The study has three characteristics. First, it is a large-scale study of multiple risk factor intervention in elderly diabetic patients. No or very few elderly patients were included in the UKPDS9,10 or Steno-2 Study.12 Second, the multiple interventions involved control of blood pressure, serum lipids, bodyweight and blood glucose. The treatment goals in the intensive treatment group were similar to those in the Steno-2 Study12 and considerably stricter than those in the UKPDS9,10 (Table 1). Third, outcome in the study included ADL, cognitive function, depressive mood, well-being and the diabetic-specific psychological state, important components for geriatric assessment of elderly people.

The treatment groups in the study had similar general characteristics, diabetic complications, atherosclerotic disease, blood pressure, metabolic risk factors and prevalence of drug therapy for diabetes, hypertension, and hyperlipidemia, with the prevalence of micro- and macrovascular complications being 50% and 15%, respectively. As patients with poor diabetes control were selected, the prevalence of drug-treated hypertension and hyperlipidemia was high (47% and 65%, respectively). Mean HbA1c level at baseline was 8.5%, lower than that of the UKPDS, but still worthy of improvement. The prevalence of patients with SBP ≥ 130 mmHg (70%), DBP ≥85 mmHg (14%), serum total cholesterol ≥ 200 mg/dL (52%), triglycerides ≥ 150 mg/dL (30%), HDL-C ≤ 40 mg/dL (15%) or BMI ≥ 25 (34%) was also high, showing a need for intervention. The high prevalence and presumably high rate of deterioration of complications and potential risk factors show that the present study had a good chance of determining whether multiple risk factor intervention prevented the development and progression of complications. Therefore, we included both primary and secondary prevention trials.

The oral hypoglycemic drugs differed from those used in previous studies. Oral hypoglycemic drugs might be more beneficial than sulfonylurea drugs for preventing cardiovascular disease in patients with type 2 diabetes. α-Glucosidase inhibitors also prevent cardiovascular disease and progression of carotid atherosclerosis,21–23 whereas metformin use is associated with lower cardiovascular morbidity and mortality, and attenuated progression of carotid atherosclerosis compared with sulfonylurea therapy.24,25 Thiazolidinediones attenuate carotid atherosclerosis and restenosis after coronary stent implantation in patients with type 2 diabetes.26,27

We did not observe any significant differences in fatal or non-fatal cardiovascular events and composite events, including diabetes-related mortality, between the two treatment groups over the follow-up period. Although we observed significant improvements in HbA1c and LDL-C during the first 2 years in the intensive treatment group, there were no differences in HbA1c, lipid or blood pressure after that time. The similar values in atherosclerotic risk factors in both groups during follow up might account for the same prevalence of events, including cardiovascular and stroke, in the two groups. The results show it is difficult to markedly reduce HbA1c, blood pressure and lipid levels in elderly diabetic patients. The high prevalence of depressive and hypoglycemic symptoms at baseline in our cohort was notable. The intention of physicians to avoid hypoglycemic events and psychological barriers to providing elderly patients with extremely strict glucose control might explain the difficulties associated with aggressive intervention. In fact, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, aggressive glucose control was reported to lead to increased mortality in patients with longstanding diabetes.28 Cardiovascular autonomic abnormalities, arrhythmia and hypercoagulability as a result of hypoglycemia might be responsible for increasing mortality during aggressive treatment. In addition, elderly patients do not accept the increase in the number of oral drugs or the initiation of insulin therapy.

In conclusion, preliminary analysis in the present study showed no significant differences in fatal or non-fatal events between the intensive and conventional treatment groups. However, as the levels of blood lipids, SBP and HbA1c tended to decrease during the follow-up period, further detailed analysis of the data might clarify to what extent treatment of risk factors influences functions and quality of life in elderly diabetic patients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix

We thank all patients, physicians, and staff who took part in the J-EDIT study.

The registration number for this clinical trial was UMIN000000890. This study was financially supported by Research Grants for Longevity Sciences from the Ministry of Health and Labour, and Welfare (H12-Choju-016, H15-Chojyu-016, H17-Choju-Ordinal-013) and the Japan Foundation for Aging and Health.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix

There is no conflict of interest. The Japanese Elderly Diabetes Intervention Trial (J-EDIT) Study Group has not cleared any potential conflicts.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of interest
  9. References
  10. Appendix
  • 1
    Atherosclerotic coronary heart disease (CHD) death – either or both of the following categories:
    • A. 
      Death with consistent underlying or immediate cause plus either of the following:
      • 1
        Preterminal hospitalization with definite or suspected myocardial infarction (MI).
      • 2
        Previous definite angina or definite or suspected MI when no cause other than atherosclerotic CHD could be ascribed as the cause of death.
    • B. 
      Sudden and unexpected death (requires all three characteristics).
      • 1
        Deaths occurring within 1 h with or without the onset of severe symptoms.
      • 2
        No known non-atherosclerotic acute or chronic process or event that could have been lethal.
      • 3
        An unexpected death of a person who was not confined to their home, hospital or other institution as a result of illness within 24 h before death.
  • 2
    Criteria for non-fatal MI – any one or more of the following categories using the stated definition:
    • A. 
      Diagnostic electrocardiogram (ECG) at the time of the event.
    • B. 
      Ischemic cardiac pain and diagnostic enzyme profile.
    • C. 
      Ischemic cardiac pain and equivocal enzymes and equivocal ECG.
    • D. 
      A routine ECG diagnostic for MI while the previous ECG was not.
  • 3
    Angina pectoris
    The participants must report pain or discomfort with all of the following characteristics:
    • 1
      The site must include the sternum at any level.
    • 2
      It must occur during a form of exertion or stress and must usually last at least 30 s.
    • 3
      It must on most occasions disappear within 10 min or less from the time of resting or decrease the intensity of exertion.
    • 4
      It must usually be relieved in 2–5 min by nitroglycerine (does not apply if participant has never taken nitroglycerine).
      In the case of angina pectoris at baseline, chest pain or discomfort should disappear or be controlled at entry. Reappearance or exacerbation of chest pain or discomfort and fulfilling points (1)–(4) were considered as an event. Subjects with uncontrolled angina pectoris at entry were not enrolled in the study.
  • 4
    Cerebrovascular disease
    A diagnosis required all of the following:
    • 1
      History of recent onset of unequivocal and objective findings of a localizing neurological deficit documented by a physician.
    • 2
      Findings persist longer than 24 h.
    • 3
      The neurological findings were not referable to an extracranial lesion.
    • 4
      Findings of computed tomographic (CT) or magnetic resonance image (MRI) taken within 3 weeks after onset, or autopsy records classifying the cerebrovascular disease into cerebral hemorrhage, cerebral infarction, or subarachnoidal hemorrhage. Cerebral infarction was defined as a stroke accompanied by CT and/or MRI scan(s) that showed an infarct in the expected area, and also on the basis of clinical findings of stroke, for which there was evidence of cerebral infarction at autopsy. Cerebral or subarachnoid hemorrhage was classified on the basis of evidence obtained on CT or MRI scans or at autopsy, excluding hemorrhagic conversion of infarction.
      In the case of cerebrovascular disease at baseline, the appearance of new unequivocal and objective findings of a localizing neurological deficit documented by a physician that persisted longer than 24 h was considered as an event and classified on the basis of evidence obtained on CT or MRI scanning or at autopsy. Cerebral infarction without obvious neurological symptoms shown by CT or MRI scans taken incidentally was not considered as an event.
  • 5
    Composite events
    Death as a result of diabetes was defined as sudden death or death from atherosclerotic CHD (MI or heart failure as a result of ischemia) or stroke, death as a result of renal failure, hyperglycemia or hypoglycemia. All events related to diabetes were defined as any complications of cardiovascular events, fatal or non-fatal stroke, sudden death, renal death, diabetic foot complications and heart failure. All events included death unrelated to diabetes, as well as all events related to diabetes.