Patients with type 2 diabetes mellitus (1985 World Health Organization criteria) and receiving any therapy regimen, between 30 and 70 years of age and with hemoglobin A1c
concentrations of 8% or greater were eligible to participate in the study. We excluded patients with hypoglycemia unawareness, severe or uncontrolled cardiovascular disease (defined as a cardiovascular event within the last year), dyspnea higher than class II,17
proteinuria greater than 300 mg/day, proliferative retinopathy (defined as growth of new blood vessels on the retina and posterior surface of the vitreous), chronic foot ulcers or wounds, or psychiatric disease or cognitive impairment interfering with treatment compliance. We also excluded patients who were unable to perform the exercise program or detect sensation with the use of a 10-g monofilament.
Recruitment lasted 13 months. All patients who participated in educational sessions at the Diabetes Daycare Centre at our hospital were contacted by mail. Patients first received a letter explaining they would be contacted by the study coordinator to participate in a study. Other patients contacted us directly, after endocrinologists and primary care physicians in the Sherbrooke area were canvassed and newspapers advertisements were published. Prospective participants were first screened for exclusion criteria by telephone, and the design and aims of the study were explained. Thereafter, the screening visit, which included an exercise tolerance test,17
The study was designed as a 12-month controlled trial with a 6-month post-intervention assessment. Using a blocked randomization (n = 4) stratified by hemoglobin A1c value (< 10% and ≥ 10%), patients were assigned by an independent person using a computer program to receive intensive multitherapy or usual care. At the end of the 12-month intervention period, patients who had received intensive multitherapy resumed usual care. A final assessment was performed at 18 months.
Patients in the intensive multitherapy group each had monthly visits to the Clinical Research Centre of the Centre Hospitalier Universitaire de Sherbrooke, where they received individualized education regarding diet, physical exercise and information on managing diabetes, hypertension and hyperlipidemia. Between each visit, patients monitored their blood glucose levels at least twice daily and received at least 2 phone calls for information on test results, therapy adjustments and motivation.
The dietary intervention was based on the Canadian Nutrition Recommendations:15
carbohydrates contributed 50%–55% to the total daily energy intake, total fats less than 30%, and saturated fatty acids less than 10%. Dietary compliance was assessed at baseline and at 6 and 12 months using a food record of 3 nonconsecutive days (one weekend day and 2 weekdays). The Candat software18
was used to calculate intake of energy and nutrients.
The individualized home-based physical exercise program included use of an exercise bicycle (Weider Electronic Ergocycle, St. Jerome, Qué.) and elastic exercise bands (Hygienic Corporation, Akron, Ohio). Each session was monitored with a heart rate monitor (Polar Electro, Woodbury, NY) and included 4 phases: warm-up, cardiovascular, resistance and cool-down stretching. The frequency (3–5 times/week), duration (45–55 minutes) and intensity (50%–80% of the maximum heart rate) of the sessions were adapted to the patient's baseline exercise tolerance test19
and progressively increased. Exercise tolerance tests were repeated at 12 months. Physical exercise was assessed using a standardized questionnaire20
at baseline and at 6 and 12 months. The weekly exercise volume was calculated as metabolic equivalent task (MET) according to the type of activity х frequency х duration.21
Pharmacologic therapy was introduced or increased at 3 months in patients who had not reached the treatment goals with lifestyle interventions and their current medications. Glyburide was started or increased to a maximum of 20 mg daily, metformin to a maximum of 2550 mg daily and α-glucosidase inhibitors to a maximum of 300 mg daily. If hemoglobin A1c
concentrations remained at 7% or greater after the maximum oral antihypoglycemic treatment was reached, bedtime intermediate-acting insulin was added. Then, as with those patients already taking insulin, the type of insulin (intermediate, premixed preparations, regular or lispro), number of injections (1–4) and dosages were adjusted. For hypertension, fosinopril (an angiotensin-converting enzyme inhibitor) was used as first-line therapy, and amlodipine (a calcium-channel antagonist), hydrochlorothiazide (a diuretic), atenolol (a β-blocker), irbesartan (an angiotensin-II receptor antagonist) and doxazosin (an α-blocker) were added and increased as recommended.15
Fibrates (bezafibrate) or statins (pravastatin) or a combination of both was used as indicated.15
ASA (80 mg daily) was given as a secondary prevention strategy. The optimal dosages and number of pills were increased according to therapeutic goals, secondary effects and patient agreement. Information about medications and compliance was obtained from detailed patient interviews at baseline and at 6, 12 and 18 months. To simplify comparisons and calculations, given that other types of antihyperglycemic, antihypertensive and lipid-lowering drugs could be given to the patients in the control group, each drug dosage was calculated as a percentage of the maximum dosage according to the 1998 Compendium of Pharmaceuticals and Specialties
Patients in the control group remained under the care of their family physician or endocrinologist or both. For ethical reasons, they were given general health and diabetes-related advice at each laboratory visit. Patients in the control group visited the the Clinical Research Centre of the Centre Hospitalier Universitaire de Sherbrooke at baseline and at 6, 12 and 18 months. Laboratory test results were given to the patients by telephone. Clinical (weight, body mass index, blood pressure) and biochemical data, as well as recommended guidelines for therapy, were mailed to their physicians.
The outcome variables were fasting plasma glucose levels, hemoglobin A1c concentrations, blood pressure, serum lipoprotein levels and quality of life. Fasting plasma glucose levels, hemoglobin A1c concentrations, blood pressure and serum lipoprotein levels were measured after a 12-hour, overnight fast at baseline and at 6, 12 and 18 months. Weight and height were measured, and body mass index (kg/m2) was calculated. Fasting plasma glucose levels were measured using a glucose oxidaze method. Cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were measured using a colorimetric process (Johnson & Johnson Ortho-Clinical Diagnostics, Rochester, NY). Low-density lip0protein cholesterol levels were calculated with the Friedewald formula. Hemoglobin A1c concentrations were measured by high-performance liquid chromatography (Bio-Rad VARIANT, Hercules, Calif.). The nondiabetic reference range in our laboratory is 4.0%–6.0%. Systolic and diastolic blood pressure were calculated as the average of 3 readings taken at 2-minute intervals using the arm with the highest blood pressure, with the patient in a sitting position after 5 minutes of rest. A mercury-column sphygmomanometer was used, with cuff-size adjustment based on arm circumference.
The frequency and severity of hypoglycemic episodes or any other adverse events were recorded at each visit. Hypoglycemia was defined as any glucose measurement of 3.5 mmol/L or less, and an episode was recorded as “severe” if the assistance of another person was required.
To address quality of life, a specific questionnaire was developed and validated. Satisfaction, impact and diabetes-related worry were scored according to a 5-point Likert scale ranging from 1 (very satisfied, no impact, no worry) to 5 (very dissatisfied, very impacted, very worried). To make the results easier to understand, scores were converted to a 100-point scale, 100 reflecting highest quality of life. A detailed description of the instrument and the validation process will be presented in a separate paper. The questionnaire was self-administered at baseline and at 6 and 12 months.
Statistical analyses were carried out according to the intention-to-treat principle. Baseline characteristics of the 2 groups were compared using an unpaired Student's t
or Fisher's exact test. Outcome variables measured at baseline and at 6 and 12 months were compared using repeated-measurements analysis of covariance with the baseline values used as covariates.22
The change in outcome variables between 12 and 18 months and between baseline and 18 months was tested with paired Student's t
test or Wilcoxon test. An unpaired Student's t
test or the Mann–Whitney test was used to test group differences at 18 months. Changes in proportion in the same group were assessed with the McNemar test. All p
values were computed for 2-tailed tests at an α level of 0.05.
The study was approved by the ethics committee of the Centre Hospitalier Universitaire de Sherbrooke, and participants signed a written informed consent in accordance with the Helsinki declaration.