Landmark Trials

1. ACCORD
The ACCORD Study Group. “Effects of intensive
glucose lowering in Type 2 Diabetes” New England
Journal of Medicine. 2008. 358(24):2545-59.
SUMMARIZED BY MARIA MORKOS

2. Action to Control Cardiovascular Risk in Diabetes (ACCORD)
Summarized by: Maria Morkos, MD; Laxmi Suthar, MD

3. BACKGROUND
 Research has shown that in T2DM
patients, a relationship exists
between A1c levels and CV events
 No previous study has investigated
if intensive therapy to target normal
A1c levels would decrease CV events
in T2DM patients who had CV
disease/risk factors

4. CLINICAL QUESTION
Would a therapeutic strategy targeting normal A1c
levels
(below 6% vs targeting A1c levels of 7.0-7.9%)
reduce the rate of cardiovascular events in T2DM
persons with established cardiovascular disease
and/or additional cardiovascular risk factors?

5. DESIGN
 Analysis: chi square tests and two-sample t-tests
 77 clinical centers across the US and Canada
 N = 10,251
 Group 1: received intensive therapy targeting an A1c of less than 6.0%
 Group 2: received standard therapy targeting an A1c of 7.0 to 7.9%
 Follow-up was 3.5 years (intensive therapy was discontinued after higher mortality was found
in the intensive therapy group)
 Primary outcomes:
 first occurrence of nonfatal MI or stroke
 or death from CV causes (MI, HF, stroke, CV cause of death after non-cardiovascular surgery)
 Secondary outcome: death from any cause

6. POPULATION
Inclusion Criteria
 T2DM and A1c of 7.5% or higher
 ages 40-79 yo
 CV disease or between 55-79 yo and had
anatomical evidence of significant
atherosclerosis, albuminuria, LVH, or at
least 2 additional risk factors for CV
disease (dyslipidemia, HTN, currently
smoking, obesity)
Exclusion Criteria
 Frequent or recent serious hypoglycemic
events
 Unwillingness to do home glucose
monitoring or inject insulin
 BMI > 45
 Serum Cr of > 1.5
 Or other serious illness

7. INTERVENTIONS
 Group 1
 received intensive therapy targeting A1c of less than 6.0%
 attended monthly visits for the first 4 months then q2 months after that, with at least one interim
phone call
 Group 2 (Placebo Control)
 received standard therapy targeting A1c of 7.0 to 7.9%
 glycemic management visits q4 months
 All patients received study formulary meds as well as glucose monitoring supplies
 Any marketed anti-hyperglycemic therapy that was not provided by formulary could also be prescribed
but was not provided by study investigators
 Also received instructional materials and behavioral counseling regarding diabetes
 Therapeutic regimens were individualized at investigators’ and patients’ discretion based on
study-group assignment and response to therapy

8. INTERVENTIONS (CONT’D)
 Glucose lower drugs included: metformin, secretagogues, thiazolidinediones, an alpha
glucosidase inhibitor, incretin, insulin
 In addition…
 4733 patients were randomly assigned to lower their BP by receiving either intensive
therapy (SBP target <120) or standard therapy (SBP target <140)
 5518 patients were randomly assigned, while on simvastatin, to either fenofibrate or
placebo
 At time of study publication, BP and lipid trials were still continuing

9. RESULTS
 At 1 year and after, throughout the follow-up period,
 median A1c for intensive therapy group was 6.4%
 median A1c for standard therapy group was 7.5%
 The intensive therapy group had significantly higher rates of:
 hypoglycemia (requiring assistance)
 weight gain (>10 kg)
 and fluid retention
 The intensive therapy group had a lower rate of nonfatal MI BUT higher rate of
death from CV causes; no significant difference in rates of nonfatal stroke
 Rate of death from any cause was HIGHER in the intensive therapy group

10. CRITICISMS/LIMITATIONS
 Did not study the components of the intervention strategies used
 Did not address an optimal rate to lower glucose levels
 Glucose lowering strategies were adjusted for each patient in an open fashion
based on their glycemic response to a drug/drug combination and the
development of clinical sx such as hypoglycemia
 No clear explanation for higher mortality found in intensive therapy group
 ?Application to T2DM patients with A1c lower than 7.5% or T2DM patients w/o
CV history or risk factors
 Benefits from intensive glucose lowering therapy may need more than 3.5
years to emerge

11. BOTTOM LINE
Therapeutic targeting of A1c
levels below 6.0% INCREASED the
rate of death from any cause after
a mean of 3.5 years,
as compared with a strategy
targeting levels of 7.0-7.9%
In patients with a median A1c 8.1%
and previous CV events/multiple CV
risk factors

12. DISCUSSION QUESTIONS
 What are two important inclusion criteria for the diabetic population this trial
targeted?
 What were the target A1c levels of the two different therapy groups?
 What was the outcome discovered after ~3 years of the trial?

13. DISCUSSION ANSWERS
 What are two important facts about the patient population this trial targeted?
 ANSWER: Had A1c greater than 7.5% and had to have either a CV event in past or several
CV risk factors
 What were the target A1c levels of the two different therapy groups?
 ANSWER: intensive therapy group target was A1c < 6.0%; standard therapy group target
was A1c 7.0-7.9%
 What was the outcome discovered after ~3 years of the trial?
 ANSWER: intensive therapy to target lower A1c levels (<6.0%) increased mortality and
did not significantly reduce major cardiovascular events

14. BOARD-LIKE QUESTION
43 yo M is evaluated during a follow-up visit
for management of T1DM. Pt has had
multiple complications including ESRD,
gastroparesis, frequent hypoglycemia with
hypoglycemic unawareness, painful
neuropathy, and proliferative retinopathy.
He uses an insulin pump and checks
fingerstick glucoses several times during the
day, which range from 65 to 250. Most
recent A1c is 7.5%
(Adapted from MKSAP 17)
QUESTION
Which of the following is the most
appropriate next step in the management of
this patient?
A. Alter insulin pump settings to attain an
A1c of less than 7.0%
B. Alter insulin pump settings to decrease
the insulin doses
C. Discontinue the insulin pump, start
subQ insulin injections
D. Start gabapentin for treatment of painful
peripheral neuropathy

15. BOARD-LIKE QUESTION
Educational Objective:
Liberalize glycemic targets in a patient with
multiple diabetic complications and
advanced microvascular disease
Key Point:
- Frequent hypoglycemia/hypoglycemic
unawareness increases the risk of
morbidity and mortality
- A less stringent A1c goal (such as 8%, per
the ADA) is appropriate for persons with
DM with a decreased life expectancy,
history of severe hypoglycemia, multiple
comorbidities, or advanced
micro/macrovascular disease
QUESTION
Which of the following is the most appropriate
next step in the management of this patient?
A. Alter insulin pump settings to attain an A1c
of less than 7.0%
B. Alter insulin pump settings to decrease the
insulin doses
C. Discontinue the insulin pump, start subQ
insulin injections
D. Start gabapentin for treatment of painful
peripheral neuropathy

16. REFERENCES
 Effects of intensive glucose lowering in Type 2 Diabetes (2008). New England Journal of Medicine,
358:2545.-2559. doi 10.1056/NEJMoa0802743