Landmark Trials, NEJM

1. DCCT
OVMC LANDMARK TRIALS SERIES
The Diabetes Control and Complications Trial (DCCT).
“The effect of intensive treatment of diabetes on the
development and progression of long term
complications in insulin-dependent diabetes mellitus.”
New England Journal of Medicine.1993; 329:977-986

2. The Diabetes Control and Complications Trial (DCCT)
Summarized by: Maria Morkos, MD; Laxmi Suthar, MD

3. BACKGROUND
 Insulin dependent diabetes mellitus
causes much morbidity and
mortality, including many long term
microvascular and neurological
complications
 Up until this study it was unclear if
tight glycemic control could
decrease or prevent such
complications

4. CLINICAL QUESTION
How would intensive diabetes
management compare with
conventional therapy in regards to the
development and progression of early
vascular and neurologic complications
of IDDM?
retinopathy
nephropathyneuropathy

5. DESIGN
 Analysis: intention to treat; chi-square test, Wilcoxon rank-sum test
 Randomized, unblinded, multicenter design (29 centers in United States)
 N= 1441
 Group 1: 726 primary prevention
 Group 2: 715 secondary intervention
 Participants in each group were randomized to either conventional or intensive
treatment
 Median follow-up: 6.5 years
 Outcomes: microvascular complications (neuropathy, nephropathy,
retinopathy)

6. POPULATION
Inclusion Criteria
 13-39 years old
 T1DM defined by C-peptide deficiency
 Primary prevention group
 T1DM 1-5 years
 No retinopathy
 Urinary albumin excretion <40 mg/24
hours
 Secondary intervention group
 T1DM 1-15 years
 Mild-moderate non-proliferative
retinopathy
Exclusion Criteria
 Hypertension
 Hyperlipidemia
 Severe diabetic complications

7. INTERVENTIONS
 Intensive therapy
 >3 insulin injections/day, or use of an insulin pump
 Goal pre-prandial blood glucose 70-120; goal post-prandial <180
 Goal A1c <6.05%
 Conventional therapy
 1-2 daily insulin injections
 Adjustments to insulin only to avoid sx of hypo/hyperglycemia or ketonuria

8. RESULTS
 In primary prevention group, intensive insulin therapy (compared to conventional therapy) reduced
adjusted mean relative risk of developing
 retinopathy by 76%
 microalbuminuria by 34%
 clinical neuropathy by 69%
 In secondary intervention group, intensive insulin therapy (compared to conventional tx) reduced
adjusted mean relative risk of worsened
 retinopathy by 54%
 microalbuminuria by 43%
 clinical neuropathy by 57%

9. RESULTS
 Mean blood glucoses were
 155+/-30 mg/dL in intensive tx group
 231 +/- 55 mg/dL in conventional tx group
 Hypoglycemia 3x higher in intensive group
 Increased weight gain in intensive group
 No differences in macrovascular events
 No difference in mortality

10. CRITICISMS
 Follow-period (6.5 years) was too short to evaluate for macrovascular outcomes
 Did not look at patients with severe microvascular complications
 Limited age range
 Excluded pts with HTN and HLD (?applicability)
 Types of insulin were not standardized
 Unblinded trial

11. BOTTOM LINE
In Type 1 diabetics, intensive
therapy with insulin slows
progression of microvascular
complications (nephropathy,
neuropathy, and retinopathy)

12. DISCUSSION QUESTIONS
 What were the two arms of the study, in general terms?
 What outcomes/endpoints did the study look at?
 What were two negative outcomes in the intensive therapy group?
 What were two outcomes that did not differ between the two groups (intensive
and conventional therapy groups)?

13. DISCUSSION ANSWERS
 What were the two arms of the study, in general terms?
 ANSWER: primary prevention (early T1DM) and secondary intervention (more progressed T1DM)
 What outcomes/endpoints did the study look at?
 ANSWER: microvascular complications (retinopathy/nephropathy/neuropathy)
 What were two negative outcomes in the intensive therapy group?
 ANSWER: higher risk of hypoglycemia and weight gain
 What were two outcomes that did not differ between the two groups (intensive and
conventional therapy groups)?
 ANSWER: macrovascular events and mortality

14. BOARD-LIKE QUESTION
57 yo M with a history of DM and CAD is
evaluated for b/l burning sensation in his
feet for the last 6 months. The sensation
worsens at night. His A1c’s were <7% for the
last two years but previously were 8-9%
(prior to switching to insulin two years ago).
Medications are regular insulin, NPH insulin,
aspirin, metoprolol, atorvastatin, and
lisinopril.
PE findings are compatible with distal
polyneuropathy. Labs including CBC are wnl.
(Adapted from MKSAP)
QUESTION
Which of the following is the most
appropriate management of this patient’s
neuropathy?
A. Amitriptyline
B. Duloxetine
C. Nerve conduction study
D. Vitamin B12 measurement

15. BOARD-LIKE QUESTION
Educational Objective:
Manage diabetic neuropathy
Key Point:
- Damage to small nerve fibers leads to
pain/numbness/burning/tingling;
damage to large nerve fibers leads to
abnormal vibration sensation and
proprioception.
- Amitriptyline in a patient like this one
with CAD increases the risk for
arrhythmias, heart block, and sudden
death.
- NCS not necessary in classic stocking-
glove distribution; B12 measurement
unnecessary since labs are wnl.
QUESTION
Which of the following is the most
appropriate management of this patient’s
neuropathy?
A. Amitriptyline
B. Duloxetine
C. Nerve conduction study
D. Vitamin B12 measurement

16. REFERENCES
 The effect of intensive treatment of diabetes on the development and progression of long term
complications in insulin-dependent diabetes mellitus (1993). New England Journal of Medicine, 329:977-
986. doi 10.1056/NEJM199309303291401