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 finalized recruitment.

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 A_1c 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 A_1c 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 A_1c concentrations, blood pressure, serum lipoprotein levels and quality of life. Fasting plasma glucose levels, hemoglobin A_1c 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 A_1c 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 test, χ² 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.

Our study has some limitations. For ethical reasons, patients in the control group had protocol-driven laboratory tests, and they and their physicians received information about diabetes and its management as well as the results of these tests. Thus, control group patients may have received more aggressive treatment and attention than they normally would have. Similarly, patients receiving the intensive multitherapy may have been susceptible to the Hawthorne effect (people who know that performance is being measured perform with more care than they would normally). This may also have played a role in the improvements observed in the intervention group.²³

Attainment of the CDA clinical practice goals was only partly achieved in the intervention group, and this effect did not continue after the end of intensive care. Our results are in accordance with those of the Steno-2 study,²⁴ which showed limited achievement of the goals of the Danish Medical Association. In day-to-day clinical practice, achieving the recommended goals may be even more difficult. Several reasons may explain these relatively disappointing results. First, in this study, the next target to reach was discussed at each visit, along with acceptance of a new medication and dosage by patients. This approach may explain why some medications were not prescribed and dosages not increased. Second, as well as patients' resistance to intensifying treatment, it is well-known that many physicians have concerns about treatment that is too aggressive. The fear of hypoglycemia for this patient population, the belief that even low or average levels of metabolic control can exert a positive effect and the idea that patients are unable to achieve recommended goals^25,26 are strong components of practitioner behaviour. Although it is paradoxical in this experimental setting, we think that this behaviour, as well as the desire to retain patients in the trial, was present in the participating practitioners. However, the therapy given to the patients in our intensive multitherapy group was aggressive when compared with that described in a recent Canadian survey:²⁷ among those with high blood pressure or dyslipidemia, 76% (v. 20% in the survey) were taking statins (plus 10% who were taking fibrates) and 89% (v. 41%) were prescribed angiotensin-converting enzyme inhibitors. It is important to point out that the intervention group and control group patients were taking the same number of pills; patients in the intervention group may have experienced better outcomes because dosages were more appropriate in this group.

Hypoglycemia and weight gain are major concerns in intensive treatment. In this study, the number of hypoglycemic episodes in the intervention group was comparable to those seen in studies in which comparable fasting plasma glucose levels and hemoglobin A_1c concentrations were achieved.^1,11 However, as in the Steno-2 study,¹¹ we did not find a difference in the number of episodes between the 2 groups. More hypoglycemic episodes would have been recorded if lower hemoglobin A_1c concentrations had been reached.²⁵ Body weight was stable over the 12-month intervention period, as was also observed in 2 earlier studies,^1,11 even though many patients started or increased insulin therapy, which is usually associated with weight increase.²⁸

At 6 months post-intervention, body weight, hemoglobin A_1c concentrations and systolic blood pressure had increased significantly. This deterioration contrasts with the sustained quality-of-life scores achieved during the demanding multitherapy program. Thus it can be concluded that multitherapy is not detrimental to quality of life. The success of permanent lifestyle changes is dependent on patients' degree of motivation, psychosocial condition, risk profile and compliance: patient nonadherence to the lifestyle regimen is the most common barrier to care.^29,30 Further studies are required to determine the best process for inducing long-lasting change in behaviour in type 2 diabetic patients. The Diabetes Control and Complications Trial, which studied intensive management of type 1 diabetes, also reported post-intervention worsening, but this occurred 4 years after the intervention.³¹ The rapid deterioration seen in our study seems to be related to a decrease in physical activity (–50%) and probably in diet compliance, as suggested by the statistically significant increase in weight at 18 months and the negative correlations of exercise with weight and with systolic blood pressure. These results underline the importance of close follow-up organized around a multidisciplinary team that provides comprehensive and shared care.^30,32,33 We may conclude that patients adhered to the program as long as they were being “coached.”

Our intention was not to evaluate the contribution of each component of the intensive multitherapy management separately. Many other trials have focused on one or 2 interventions.^34,35,36,37 We targeted lifestyle intervention through education and intense team-based follow-up, as is recommended in national association guidelines.^15,16 In the absence of precise recommendations, we arbitrarily chose monthly follow-up, but the intensity and frequency of the monitoring should be evaluated in future studies.

Although intensive multitherapy is feasible and effective if maintained for 12 months, the benefits vanish rapidly when the patients resume usual care. The CDA treatment goals are very difficult to reach for patients with poorly controlled type 2 diabetes.