| Methods |
The primary endpoint of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. 80 participants were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. |
| Participants |
Participants with persistent type 2 diabetes and microalbuminuria were selected, since microalbuminuria is a well‐established independent risk factor for cardiovascular disease (the primary endpoint) as well as for nephropathy, retinopathy, and neuropathy (secondary endpoints) |
| Interventions |
The aim of dietary intervention was a total daily intake of fat that was less than 30% of the daily energy intake and an intake of saturated fatty acids that was less than 10% of the daily energy intake. Light‐to‐moderate exercise for at least 30 minutes 3 to 5 times weekly was recommended. If participants were unable to maintain glycated hemoglobin values below 6.5% by means of diet and increased physical activity alone after 3 months, an oral hypoglycemic agent was started. As the initial step, overweight participants (defined as those with a body mass index (the weight in kg divided by the square of the height in m above 25) received metformin (maximum, 1 g twice daily); lean participants, or overweight participants who had contraindications to metformin therapy, received gliclazide (maximum, 160 mg twice daily). As the second step, metformin was added to the regimen of lean participants and gliclazide to that of overweight participants if hyperglycemia was not controlled. If the glycated hemoglobin value exceeded 7.0 percent despite maximal doses of oral agents, the addition of neutral protamine Hagedorn (NPH) insulin at bedtime was recommended. When insulin was started, lean participants stopped metformin treatment and overweight participants stopped gliclazide therapy unless it was the only oral hypoglycemic agent given. The insulin dose was adjusted on the basis of the morning fasting blood glucose concentration. If the daily dose of insulin exceeded 80 IU at bedtime or there was no decrease in the glycated hemoglobin value, participants were switched to regimens in which regular and NPH insulin was given 2 to 4 times a day. |
| Outcomes |
Peripheral neuropathy was measured with a biothesiometer |
| Notes |
|
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
160 participants stratified according to urinary albumin excretion and then randomly assigned to treatment groups |
| Allocation concealment (selection bias) |
Low risk |
Randomization was performed with the use of sealed envelopes |
| Blinding (performance bias and detection bias)
All outcomes |
Low risk |
The study was a randomized, open, parallel trial therefore participants and physicians were not blinded to treatment. However, the outcome assessors were blinded and there was an independent committee for adjudication |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
15 versus 12 participants died in the conventional versus intensive groups. 2 versus 1 withdrew. |
| Selective reporting (reporting bias) |
Low risk |
Report on clinical neuropathy as defined as symptoms + abnormal nerve conduction studies in one nerve |
| Other bias |
Low risk |
None |
