Intensive Diabetes Therapy and Glomerular Filtration Rate in Type 1 Diabetes

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de Boer, IH et al. "Intensive Diabetes Therapy and Glomerular Filtration Rate in Type 1 Diabetes". The New England Journal of Medicine. 2011. 365(25):2366-2376.
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Clinical Question

In patients with type I diabetes mellitus, what is the benefit of intensive therapy in preserving the glomerular filtration rate?

Bottom Line

Intensive glucose control in patients with type I diabetes mellitus (T1DM) is associated with preservation of GFR.

Major Points

The long-term risk of an impaired GFR was significantly lower by 50% among persons treated for an average of 6.5 years with DCCT intensive-therapy than among those treated with conventional-therapy. This effect was not evidence until more than 10 years after randomization, beyond the period of the DCCT treatment intervention. The data suggests that giving approximately 29 persons with T1DM for 6.5 years prevents one case of an impaired GFR over a total follow-up period of 20 years.

Hyperglycemia contributes to an impaired GFR in patients with T1DM.

Design

  • Multicenter, prospective, randomized, observational study
  • In DCCT (1983-1989), 1,441 patients with T1DM randomly assigned to 6.5 years of:
    • Intensive therapy targeted at near-normal glucose concentrations versus
    • Conventional therapy targeted at preventing hyperglycemic symptoms
  • Subsequently, all DCCT participants were invited to join EDIC, which was an observational extension of DCCT, and 1375 (96% of surviving cohort) were followed
  • Mean follow-up: 22 years in combined studies

Enrollment criteria

Inclusion criteria

Exclusion criteria

Interventions

  • Serum creatinine levels measured annually throughout course of both studies
  • Impairment of GFR defined as estimated GFR ≤60 ml/min/1.73 m2 at two consecutive study visits, usually 1 year apart
  • ESRD defined as: need for kidney transplantation or initiation of maintenance dialysis

Outcomes

Baseline Characteristics

All comparisons are DCCT intensive-therapy vs DCCT conventional-therapy.

DCCT

  • Mean age: 27 years
  • Mean duration of diabetes: 6 years
  • None were taking antihypertensive medications
  • Albumin excretion rates (30 to 200 mg/24 hours): 157 participants (11%)
  • Mean HbA1c: 7.3% vs 9.1%

EDIC Year 16 (2008-2010) n=1222 (85% of all who underwent randomization)

  • Mean age: 50 years
  • Mean duration of diabetes: 28 years
  • Taking antihypertensive medications: 56.2% vs 59.3%
    • Taking inhibitors of RAAS: 53.1% vs 57.0%
  • Albumin excretion rates ≥30 mg/24 hours: 19.4% vs 22.6%
  • Time-averaged mean HbA1c: similar

Primary Outcomes

All comparisons are DCCT intensive-therapy vs DCCT conventional-therapy.

  • Impairment of GFR (≤60 ml/min/1.73 m2 at two consecutive study visits): 24 patients vs 46 patients (RR 50%, 95% CI 18-69; p=0.006)
    • Cumulative incidence of impaired GFR 20 years after randomization: 2.0% vs 5.5% (ARR 3.5%)
    • End-stage renal disease: 8 patients vs 16 patients

Secondary Outcomes

  • During DCCT study, intensive-therapy was associated with reduction in mean estimated GFR of 1.7 ml/min/1.73 m2 compared to conventional therapy (95% CI, 0.6-2.2, p<0.001).
  • During EDIC study, intensive-therapy was associated with:
    • higher estimated GFR (difference, 2.5 ml/min/1.73 m2 95% CI 1.4 to 3.6, p<0.001)
    • slower decline in GFR (difference in slow, 0.23 ml/min/1.73 m2 per year, 95% CI 0.05-0.41, p=0.01)
  • Over the course of the combined studies, average decrease in estimated GFR was 1.27 ml/min/1.73 m2 per year (95% CI, 1.20 to 1.35) with intensive therapy, as compared with 1.56 ml/min/1.73 m2 per year (95% CI, 1.48 to 1.63) with conventional-therapy (p<0.001).

Subgroup analysis

  • BMI, BP, HbA1c measured quarterly during DCCT and yearly during EDIC
  • Albumin excretion rate measured yearly during DCCT and every 2 years during EDIC
  • ACEi strongly discouraged during DCCT; use of inhibitors of RAAS assessed yearly during EDIC


  • Higher HbA1c, higher albumin excretion rate, higher BP, and use of antihypertensive medications and RAAS inhibitors each strongly associated with increased risk of impaired GFR when evaluated as time-dependent covariates in separate models
  • Beneficial effect of intensive-therapy on risk of impaired GFR was fully attenuated after adjustment for between-group differences in mean HbA1c or albumin excretion rate.
  • Effect of intensive-therapy remained significant after separate adjustment for between-group differences in BP, BMI, use of antihypertensive agents, or use of RAAS inhibitors.


Adverse events

Criticisms

Internal

External

Funding

External links