DCCT

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DCCT Research Group. "The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus". The New England Journal of Medicine. 1993. 329(14):977-986.
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Clinical Question

In patients with T1DM, how does strict glycemic control with intensive therapy compare with conventional therapy in preventing microvascular complications?

Bottom Line

Among patients with T1DM, strict glycemic control prevents up to 70% of microvascular complications, particularly retinopathy.

Major Points

The Diabetes Control and Complications Trial (DCCT) demonstrated that strict glycemic control targeting lower HbA1c goals among patients with T1DM can both delay the onset of retinopathy, nephropathy, and neuropathy and slow the progression of existing microvascular complications. This came at the expense of a threefold higher risk of hypoglycemia, underlying the fact that HbA1c goals should be tailored to the individual.

DCCT was unable to demonstrate a reduction in CV events, likely because the study population was relatively young at the time. However, EDIC and other follow-up studies did demonstrate such benefits.

Despite the fact that DCCT studied only patients with T1DM, many physicians began recommending strict glycemic control to patients with T2DM as well.

Design

  • Multicenter, parallel-group, randomized controlled trial
  • N=1,441
    • Primary prevention (n=726) with no retinopathy at baseline
    • Secondary intervention (n=715) with mild retinopathy at baseline
  • Setting: 29 international centers
  • Enrollment: 1983 to 1989
  • Mean follow-up: 6.5 years (9,300 patient-years)

Population

Inclusion Criteria

  • T1DM, as evidenced by deficient C-peptide secretion
  • Age: 13-39 years
  • To be eligible for primary prevention cohort:
    • T1DM for 1-5 years
    • No retinopathy as detected by seven-field stereoscopic fundus photography
    • Urinary albumin excretion ≥40 mg/day
  • To be eligible for secondary prevention cohort:
    • T1DM for 1-15 years
    • Very-mild-to-moderate nonproliferative retinopathy
    • Urinary albumin excretion ≤200 mg/day

Exclusion Criteria

  • T1DM diagnosed <1 year or >15 years prior to enrollment
  • T2DM
  • History of cardiovascular disease
  • Hypertension (BP ≥140/90 mmHg)
  • Hyperlipidemia
  • Serum creatinine ≥1.2 mg/dL or creatinine clearance ≤100 ml/min/1.73 m2 BSA
  • Severe diabetic complications (e.g., greater degrees of retinopathy)
  • Severe medical comorbidities

Baseline Characteristics

  • Mean age: 27 years
  • Male: 53%
  • White: 97%
  • Duration of T1DM: 2.6 years in primary-prevention vs 8.8 years in secondary-intervention
  • HbA1c: 8.9%
  • Mean blood glucose: 232 mg/dL
  • SBP 114 mm Hg, DBP 73 mm Hg
  • IBW: 104%
  • Current smokers: 19%
  • Serum LDL: 110

Interventions

  • Randomized to intensive vs. conventional therapy
  • Stratified according to primary-prevention and secondary-intervention cohorts at each center
  • Retinopathy assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) protocol
    • Scale of 25 steps which represent overall extent of retinopathy
    • Development or progression of retinopathy defined as sustained (≥6 month) change of ≥3 steps from baseline

Intensive therapy: injections of insulin ≥3 times daily or via external pump; dosages adjusted according to self-monitoring of blood glucose QID

  • Preprandial glucose between 70-120 mg/dL
  • Postprandial glucose <180 mg/dL
  • Weekly 3am glucose >65 mg/dL
  • Monthly HbA1c <6.05%
  • Appointments every 1 month and frequent telephone calls

Conventional therapy: injections of insulin one or two times daily; self-monitoring of urine or blood glucose daily, ± daily adjustments

  • Absence of symptoms attributable to glycosuria or hyperglycemia
  • Absence of ketonuria
  • Maintenance of normal group, development, IBW
  • Freedom from severe or frequent hypoglycemia
  • Appointments every 3 months

Outcomes

Comparisons are intensive vs. conventional therapy.

Primary Outcomes

Development of retinopathy (primary-prevention cohort)
6.0% vs 24.1% (RR 0.26; 95% CI 0.15-0.38; P<0.001)
Progress of retinopathy (secondary-intervention cohort)
21.2% vs 40.6% (RR 0.46; 95% CI 0.34-0.61; P<0.001)
Development of proliferative or severe non-proliferative retinopathy
(RR 0.53; 95% CI 0.33-0.86; P=0.011)
Microalbuminuria (urinary albumin excretion of ≥40 mg/24 hours)
34% reduction (P=0.04) in primary-prevention cohort
43% reduction (P=0.001) in secondary-intervention cohort
Albuminuria (urinary albumin excretion of ≥300 mg/24 hours)
56% reduction (P=0.01) in secondary-intervention cohort
Peripheral sensorimotor neuropathy
3% vs 10% (RR 0.30; P=0.006) in primary-prevention cohort at 5 years
7% vs 16% (RR 0.44; P<0.001) in secondary-intervention cohort at 5 years
Glycemic control
Mean glucose: 155 vs 231 mg/dL (P<0.001)
Mean HbA1c: 7.2% vs 9.1% (P<0.001); HbA1c reached nadir at 6 months in patients receiving intensive therapy

Subgroup Analysis

  • Intensive therapy consistently reduced risk of retinopathy and nephropathy in all subgroups in both cohorts among all clinics.
  • Baseline covariates, including age, sex, duration of T1DM, % IBW, level of retinopathy, mean BP, presence of clinical neuropathy, baseline HbA1c, history of smoking, and albuminuria

Adverse Events

Incidence of hypoglycemia
62 vs 19 episodes per 100 patient-years (P<0.001)
16 vs 5 episodes of coma or seizure per 100 patient-years
54 hospitalizations in 40 patients vs 36 hospitalizations in 27 patients to treat severe hypoglycemia

Funding

Supported by the Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases and by the National Heart, Lung, and Blood Institute, the National Eye Institute, the National Center for Research Resources, and various corporate sponsors.