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How Should Diabetes Be Treated to Minimize the Risk of Cardiovascular Complications?
of conventional treatment. Over 6.5 years of DCCT follow-up, median a 22% increase in total mortality (p=0.04) and a 35% increase in CVD
HbA
1c
levels were 7.0% in the intensive group and 8.9% in the standard mortality (p=0.02) after 3.5 years.
20
This prompted a transfer of this
group. The intensive group had striking reductions in the development patient group to standard therapy for the remainder of the trial. The
or progression of retinopathy, nephropathy and neuropathy.
13
During increased mortality with intensive treatment was not associated with
further observational follow-up of 11 years in EDIC, mean HbA
1c
severe hypoglycemic episodes or lower HbA
1c
, but with a failure to
converged in the original two treatment groups at about 8.0%. The risk reduce HbA
1c
promptly. Up to this point, the median HbA
1c
was 6.4% in
reductions in retinopathy, nephropathy, and neuropathy in the original the intensive and 7.5% in the standard group. The intensive treatment
intensive group, however, have persisted—a phenomenon referred to as group had a 24% reduction in non-fatal MI (p=0.004).
20
Moreover, in
‘metabolic memory.’
14
Moreover, at a mean diabetes duration of 24 subgroup analyses, patients with no previous CVD events and patients
years, a critical composite of CVD death, non-fatal MI, and non-fatal with HbA
1c
≤8.0% at baseline had reductions in the primary outcome
stroke was reduced by 57% (p=0.02).
15
Most of this intensive treatment compared with those with the opposite characteristics. Intensive
effect was accounted for by the lowering of HbA
1c
during the DCCT therapy was again associated with three times the number of severe
period—another example of metabolic memory.
15
hypoglycemic episodes as standard therapy.
20
The UKPDS The ADVANCE Trial
The United Kingdom Prospective Diabetes Study (UKPDS) randomized The Action in Diabetes and Vascular Disease: Preterax and Diamicron
4,209 volunteers with type 2 diabetes (median age 54 years), three Modified-Release Controlled Evaluation (ADVANCE) trial was factorially
months from diagnosis, to intensive treatment with insulin, a designed. It randomized 11,140 patients with type 2 diabetes (mean age
sulfonylurea, or conventional treatment with a ‘dietary policy.’
16
Mean 66 years, 42% female) to open-label intensive treatment (HbA
1c
target
HbA
1c
over an 11-year follow-up was 7.0% with intensive and 7.9% with ≤6.5%) or standard treatment (HbA
1c
target as per ‘local guidelines’).
21
conventional treatment. Microvascular complications were significantly Modified-release gliclazide (a sulfonylurea) was added to the usual
reduced by 25% (p<0.01) and MI was reduced by 16% (p=0.052).
16
After regimen of the intensive group. Both groups received further
the randomized trial, the UKPDS cohorts were followed observationally hypoglycemic agents, including insulin, if needed to reach their glycemic
for an additional 10 years, with no significant difference in HbA
1c
targets. During the five-year follow-up period, mean HbA
1c
was 0.7%
between the original treatment groups. The reduction in microvascular lower in the intensive group. For the primary macrovascular outcome, a
outcomes was maintained, referred to as a ‘legacy effect.’
17
Importantly, composite of CVD death, non-fatal MI, or stroke was evaluated.
however, the reduction in risk of MI remained 15% and became Intensive treatment led to a non-significant reduction of 6% (p=0.32).
21
statistically significant (p=0.01). Thus, there is substantial evidence that Severe hypoglycemia was more common in the intensive group (2.7
the incidence of MI can be decreased by lowering HbA
1c
to 7.0% or less versus 1.5%; p<0.001).
for seven to 10 years, although it takes another 10–11 years to detect a
statistically significant benefit. This last point is important when Meta-analysis of Trials
choosing glycemic targets for elderly patients or those with otherwise A recent meta-analysis
22
included data from the UKPDS, VADT,
limited life expectancies. ACCORD, ADVANCE, and PROspective pioglitAzone Clinical Trial In
macroVascular Events (PROACTIVE). A total of 33,040 patients with
The VADT type 2 diabetes were included (mean age 62 years, 62% male, mean
The Veterans Affairs Diabetes Trial (VADT) randomly assigned 1,791 diabetes duration ranging from less than one to 12 years and mean
patients with type 2 diabetes (97% male, mean age 60 years) to intensive baseline HbA
1c
7.1–9.4%). Mean HbA
1c
during follow-up was 6.6% on
versus standard glycemic control for a median follow-up of five to intensive treatment and 7.5% on standard treatment. Intensive
six years, during which median HbA
1c
levels were 6.9 and 8.5%, compared with standard treatment was associated with reductions in
respectively.
18
There was a non-significant 12% reduction in the primary non-fatal MI (odds ratio [OR] 0.83, 95% confidence interval [CI]
composite CVD outcome (p=0.14), no significant difference in MI, a 32% 0.75–0.93) and non-fatal MI or all cardiac mortality (OR 0.85, 95% CI
increase in CVD mortality (p=0.24), a 7% increase in total mortality 0.77–0.93), but not in stroke or total mortality. This meta-analysis,
(p=0.64) with intensive treatment, and severe episodes of hypoglycemia however, is limited by lack of access to individual patient data, wide
were three times as frequent.
18
Of note, the difference in CVD event diversity of the trial cohorts in duration of diabetes and intensive
rates between the treatment groups was inversely proportional to the treatment regimens, and great variation in baseline HbA
1c
. Also, the
duration of diabetes at baseline. inclusion of PROACTIVE is debatable, since all participants in that study
were to be treated to a HbA
1c
target <6.5% and were not separated
The ACCORD Trial into intensive and standard treatment groups.
The Action to Control Cardiovascular Risk in Diabetes  (ACCORD) trial
was a double 2x2 factorially designed trial. It randomized 10,251 Trials Investigating the Effects of Specific
patients with type 2 diabetes (62% male, mean age 62 years) to intensive Blood-glucose-lowering Strategies on
(target HbA
1c
<6%) versus standard (target HbA
1c
range 7.0–7.9%) Cardiovascular Disease Events
treatment for a planned follow-up of 5.5 years.
19
All US Food and Drug Metformin
Administration (FDA)-approved drugs were used in both treatment A subset of 753 obese UKPDS participants were randomly assigned to
groups. The primary outcome was a composite of CVD death and non- intensive therapy with metformin or standard therapy with diet policy.
23
fatal MI and stroke. The intensive glycemic treatment group experienced Mean HbA
1c
during follow-up was 7.4 and 8.0%, respectively. Metformin
US ENDOCRINOLOGY 91
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