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ABSTRACT
A lot of trials have been
published recently discussing the benefits of
intensive glucose control versus conventional
glucose control. One of these studies was the
10 - year follow - up of intensive glucose control
in type 2 diabetes, published in the New England
Journal of Medicine in October 2008. Although
this study had interesting findings, the number
of deaths during this study was too high (1851
deaths out of 3277 participants during 10 years).
The contrast between the benefits and number of
deaths force us to ask this question: Do we need
all these deaths?
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INTRODUCTION
I had read with great interest
the results of the 10 Year Follow up of Intensive Glucose
Control in Type 2 diabetes post trial from UKPDS.
Really, I was shocked about the mortality rate mentioned
in the paper and how come the study's supervisors allowed
it to continue all these years.
While I was reading the paper, I asked myself this question:
Do they need all these deaths to reach to their conclusions?
In 1979, Walters et al
(1) followed a group of diabetic patients selected from
NHS central register (849 patients) for 11 years to
identify causes of deaths. He and his colleagues found
that only 306 of the recorded deaths occurred among
recorded diabetics during the period of follow up. The
following Table (Table 1) showed the analysis of their
survey.
Table1 Mortality rate after 11
years
| Total
number of diabetic patients |
849 |
100% |
| Total
number of deaths |
306 |
42.7%This
means that the annual rate for deaths was 9%
per year |
| Number
of IDDM deaths |
65 |
21% |
| Number
of NIDDM deaths |
241 |
79% |
| Number
of deaths related to vascular causes |
168 |
55% |
During 10 years (1998
- 2008) a subgroup from the UKPDS was selected (Number
of participants 3277) and randomly assigned into 3 groups
(2).
The following Table (Table 2) shows some data from this
study.
Table 2
Aggregate outcomes for patients during follow-up
|
|
Intensive
therapyInsulin-Sulphonylurea group N=2729 |
Conventional
therapyDietary restriction only N=1138 |
Metformin
group (overweight patients) N=342 |
Comments |
| Diabetes
related deaths |
618 |
297 |
81 |
Prevalence
of diabetes related deaths in the intensive therapy
group, conventional and metformin group was 22.6%,
26% and 23.6% respectively.Total number of deaths
related to diabetes was 996 which constitutes 53.8%
from total number of deaths. |
| Deaths
from any cause |
1162 |
537 |
152 |
Prevalence
of death from any causes in the intensive therapy
group conventional and metformin group was42.5%,
47.2% and 44.4% respectively.Total number of deaths
was 1851 deaths, so the overall prevalence of deaths
related to any cause was 56.5%. |
| Myocardial
infarction (MI) |
678 |
319 |
81 |
Prevalence
of MI in the intensive therapy group, conventional
and metformin group was 24%, 28% and 23.6% respectively.
|
| Stroke |
260 |
116 |
34 |
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From the methodology of the
study, all patients selected were healthy without any
history or risks of cardiovascular diseases (page 1578).
Selected patients were followed annually in UKPDS clinics
for standardized collection of outcome data; clinical
examinations every 3 years were continued. In the years
6 to 10, questionnaires which were used for patients
not able to attend were used instead of personal interview
due to the lack of funds of the study.
Unfortunately, the study only included the data from
the final year, without mentioning data from previous
years.
In comparison with the
ADVANCE trial(3) which continued for a median of 5
years, the following table (Table 3) showed some results
as regards number of deaths.
Table 3 Comparison of number
of deaths between intensive and conventional therapy
|
|
Intensive therapy N=5571 |
Conventional therapy N=5569 |
Comments |
|
Deaths from CVD |
253 |
289 |
Total number of deaths due to CVDs was 542 (57.5%
from total deaths) |
|
Deaths from any cause |
409 |
533 |
Total number of deaths due to any cause was 942
(8.4%) |
In my opinion, one of the factors
that decreased the number of deaths was the protocol
of follow up. The researchers stated in their follow
up schedule that patients in the intensive group were
seen at week 2 after randomization, then at months 1,
2, 3, 4 and 6 and every 3 months thereafter. Those patients
were also encouraged to attend other unscheduled visits
to improve the monitoring and intensification of glucose
control. This close observation may allow early intervention
to avoid deaths. Even patients in conventional therapy
(standard) were seen at 3, 4 and 6 months after randomization
and every 6 months thereafter.
Again, let us look on another
study testing the outcome of intensive glucose control
which is the ACCORD trial that was extended for 1 year(4).
The following Table (Table 4) showed number of deaths
in the intensive and conventional therapy group.
Table 4 Comparison of the number
of deaths between intensive and conventional therapy
|
|
Intensive therapy N=5128 |
Conventional therapy N=5123 |
Comments |
|
Deaths from CVD |
135 |
94 |
Total number of deaths due to CVD was 229 (49.7%
from total deaths) |
|
Deaths from any cause |
257 |
203 |
Total number of deaths due to any cause was 460
(4.4%) |
After one year the safety monitoring
committee decided to stop the trial. The committee on
January 8, 2008 concluded that the harm associated with
the increased rate of death from any cause in the intensive
therapy group, as compared in that with conventional
therapy (standard) group outweighed any potential benefits.
In my opinion that was the right
decision which respectedhuman life.
IN SUMMARY
The 10 year follow up of
intensive glucose control in type 2 diabetes did not
need 10 years with this high number of deaths to reach
beneficial results.
Number of deaths in comparison
with other studies tested the outcome of intensive therapy
to control blood glucose was so high (Table 5). In my
opinion termination of the study after 5 years from
its beginning might give the same results. This opinion
was supported by the comments of the researchers that
the majority of the participants attended during the
first five years.
Table 5 Comparison of number
of deaths
|
Study |
Total number of participants |
Total number of deaths due to any cause |
(%) |
|
The 10 year follow up of intensive glucose control
in type 2 diabetes trial |
3277 |
1851/
10 years(185 deaths / year) |
56.5% |
|
The ADVANCE trial |
11140 |
942
/ 5 years(188 deaths / year) |
8.4% |
|
The ACCORD trial |
10251 |
460
/ 1 year |
4.4% |
|
Mortality in diabetic subjects: an eleven – year
follow-up of a community – based population |
|
306
/ 11 year28 deaths / year |
42.7%
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REFERENCES
- Walters DP, Gatling W,Houston AC,Mullee MA,Julious
SA and Hill RD. Mortality in diabetic subjects: an
eleven - year follow-up of a community - based population.
Diabet Med.1994; 11(10):968-73.
- Rury R.Holman, Sanjoy K Paul, M.Angelyn Bethel,
David R Matthews and H.Andrew W Neil. 10 - year follow
- up of intensive glucose control in type 2 diabetes.
N Engl J Med 2008;359:1577-89.
- The ADVANCE Collaborative Group. Intensive Blood
Glucose Control and Vascular Outcomes in Patients
with Type 2 Diabetes. N Engl J Med 2008, 358:2560
- 72.
- The action to control cardiovascular risk in diabetes
study group. Effect of intensive Glucose lowering
in type 2 diabetes. N Engl J Med 2008; 358: 2545 -
59.
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