Controlling Blood Glucose Levels in Patients with Type 2 Diabetes Mellitus An Evidence-Based Policy Statement by the American Academy of Family Physicians and American Diabetes Association
Steven H. Woolf, MD, MPH Mayer B. Davidson, MD Sheldon Greenfield, MD Hanan S. Bell, PhD Theodore G. Ganiats, MD Michael D. Hagen, MD Valerie Anne Palda, MD, MSc Robert A. Rizza, MD Stephen J. Spann, MD Fairfax, Virginia; Los Angeles, California; Boston, Massachusetts; Seattle, Washington;San Diego, California; Lexington, Kentucky; Toronto, Canada; Rochester, Minnesota; and Houston, Texas Submitted, revised, March 6, 2000. From the Department of Family Medicine, Medical College of Virginia-Virginia Commonwealth University, Richmond (S.H.W.); the Clinical Trials Unit, Charles R. Drew University of Medicine and Science, and the Department of Medicine, University of California-Los Angeles School of Medicine (M.B.D.); the Department of Medicine, Tufts University School of Medicine, Medford (S.G.); the American Academy of Family Physicians, Leawood (H.S.B.); the Department of Family and Preventive Medicine, University of California-San Diego School of Medicine (T.G.G.); the Department of Family Practice, University of Kentucky College of Medicine, Lexington (M.D.H.); the Department of Medicine, University of Toronto (V.A.P.); the Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic and Foundation, Rochester (R.A.R.); and the Department of Family and Community Medicine Baylor College of Medicine, Houston (S.J.S.). Reprint requests should be addressed to Steven H. Woolf, Department of Family Practice, Virginia Commonwealth University, Medical College of Virginia Campus, 3712 Charles Stewart Drive, Fairfax, VA 23298-0251. E-mail: SHWoolf@aol.com.
References
Methods
Systematic Review
The review methods are provided in detail in the full report. The literature search retrieved published evidence on the effects of glycemic control on microvascular and macrovascular complications in type 1 and type 2 diabetes and on adverse effects. RCT evidence for type 1 diabetes was considered relevant in evaluating the effects of glycemic control in type 2 disease. A total of 798 citations met initial inclusion criteria. All articles underwent structured abstraction. We closed the search with the publication of the UKPDS results in September 1998.
In reviewing the evidence, the panel gave greater weight to RCTs than to observational studies and emphasized data on health outcomes perceptible to patients (eg, visual acuity) over those for intermediate or surrogate end points (eg, retinopathy) that precede or are associated with such outcomes. Most trials did not designate health outcomes as primary end points and therefore lacked the statistical power and duration to prove an effect. Panel recommendations were evidence-based and did not reflect expert opinion. Fourteen outside diabetologists and family physicians externally reviewed the full report, and revisions consistent with the evidence were adopted. The American Academy of Family Physicians and the American Diabetes Association endorsed the full report in March 1999 and this policy statement in October 1999.
We focused the review on the benefits of glycemic control in general and not on specific agents (eg, sulfonylureas, metformin). Interventions not associated with glycemic control (eg, laser phototherapy, angiotensin-converting enzyme inhibitors), which also mitigate the effects of microvascular disease, were not examined in our review.
Results
Microvascular Outcomes
Evidence from Observational Studies. Many cross-sectional studies indicate that people with type 2 diabetes who have higher plasma glucose or glycated hemoglobin (e.g., hemoglobin A1c) levels are more likely to have evidence of retinopathy, neuropathy, or albuminuria.11 Numerous prospective longitudinal studies also show that an elevated fasting plasma glucose (FPG) concentration or glycated hemoglobin level at baseline or over time increases the chances that type 2 patients will develop new or worsened retinopathy, abnormal electrophysiologic findings, or renal dysfunction.12-15 However, observational data, unlike evidence from RCTs, does not prove that lowering blood glucose levels reduces the incidence of these complications.
Evidence from RCTs. Ten RCTs do provide this evidence.9,10,16-24 Three trials involved patients with type 2 diabetes: the very large UKPDS10 (approximately 4200 patients) and 2 small Japanese studies.16,19 The largest of the 7 trials of patients with type 1 diabetes was the DCCT (1441 patients).9 In most trials, patients were randomly allocated to an intensive treatment group that received multiple or continuous insulin administrations or to a control group that received conventional insulin therapy. Most studies confirmed (through mean glycated hemoglobin levels) better glycemic control with intensive treatment. For example, mean hemoglobin A1c levels in the intensive/conservative treatment groups of the DCCT and UKPDS were 7.2%/9.1% and 7.0%/7.9%, respectively.9,10 An old RCT (University Group Diabetes Program) that did not produce significant differences in glucose control in some treatment arms and lacked statistical power was excluded from our review.25 Average lengths of follow-up in the RCTs ranged from 2 to 12.5 years (6.5 and 10 years, respectively, in the DCCT and UKPDS).
Retinopathy in Patients with Type 2 Diabetes. RCTs provide good evidence that glycemic control reduces the incidence of retinopathy. In a Japanese trial, among patients with no retinopathy at baseline, the 6-year incidence of new disease (progression Ž2 steps on the Early Treatment Diabetic Retinopathy Study [ETDRS] scale26) in the intensive and conservative treatment groups was 6% and 36%, respectively, a relative reduction of 83%. In patients with retinopathy at baseline (secondary prevention group), the incidence rates for intensive and conservative treatment groups were 17% and 44%, respectively.16
The authors of the UKPDS results, who reported a 25% relative reduction in the incidence of microvascular complications (11.4 vs 8.6 events/1000 patient-years) attributed much of the benefit to reduced retinopathy.10 The need for laser therapy was lowered from 11.0 to 7.9 events/1000-patient years, a 29% relative reduction. Within 6 years, the incidence of a 2-step progression on the ETDRS scale was lowered from 28% to 23%. The relative reduction in cataract extraction was 24%. The incidence of decreased visual acuity, blindness, and vitreous hemorrhage was not lowered significantly. The extent to which the latter resulted from treatment for early complications is not known.
Retinopathy in Patients with Type 1 Diabetes. Among patients with no baseline retinopathy in the DCCT (primary prevention group), the 6.5-year incidence of a sustained 3-step change on the ETDRS scale was reduced by 76% (from 4.7 to 1.2/100 patient-years).9 In the secondary prevention group, the rate of progression was lowered by 54% (from 7.8 to 3.7/100 patient-years). In this group intensive treatment was also associated with a lower incidence of severe retinopathy, need for laser treatment, and sustained progression worsening for at least 6 months (adjusted relative risk reduction=47%, 56%, and 65%, respectively).9,27 A Swedish trial reported improved ETDRS scales and a lower prevalence of visual impairment (14% vs 35%) at 7.8 years median follow-up.17
