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How Should Diabetes Be Treated to Minimize the Risk of Cardiovascular Complications?
outcome of death, MI, or stroke, there were fewer events with Discussion
pioglitazone then with placebo or an active comparator (HR 0.82, 95% CI It should be clear from the above review of recent data that we still lack
0.72–0.94; p=0.005), and each component CVD event was similarly consistent evidence that lowering blood glucose (HbA
1c
) reduces the
reduced. By contrast, serious heart failure was increased by risk of CVD. What are the possible reasons that randomized clinical trials
pioglitazone (HR 1.41, 95% CI 1.14–1.76; p=0.002). have thus far failed to demonstrate this benefit conclusively?
Rosiglitazone The direct association of HbA
1c
with CVD outcomes in observational
Four major meta-analyses of rosiglitazone trials have been published, studies may be just that: hyperglycemia may be only a marker for the
with non-uniform results. real causative factor(s) that are not proportionately reduced when
blood glucose is actively lowered.
The original meta-analysis, which set off a controversy over the role of The effect of hyperglycemia reduction on CVD risk may be small
this thiazolidinedione (TZD), involved 42 trials with follow-up times of compared with the effect on microvascular complications and
six months to three years. Patients with type 2 diabetes or in a pre- therefore beneath the power of feasible studies to detect.
diabetic state (n=27,843) were randomly assigned to rosiglitazone or Blood glucose may need to be kept down (HbA
1c
<7.0%) from early
either placebo or comparator drugs.
37
Mean baseline HbA
1c
was 8.2%. on in type 2 diabetes and for many years to reap a CVD benefit. The
Rosiglitazone was associated with an increased incidence of MI (86 UKPDS results point to such a conclusion. If this is so, intensive
versus 72 events, OR 1.43, 95% CI 1.03–1.98; p=0.03) and CVD death (OR treatment begun in elderly patients at greater CVD risk but with
1.64, 95% CI 0.98–2.74; p=0.06).
37
Important limitations pointed out in an shorter life expectancies may be both ineffectual and, as per the
editorial
38
were: ACCORD results, dangerous.
The actual event rates in the control groups of recent major
no access to individual patient data; randomized clinical trials have turned out to be lower than projected,
use of non-adjudicated CVD events; probably because of better management of other even more
a small number of events; powerful risk factors, limiting study power.
the inclusion of trials with zero events in one of the two arms; and
a heterogeneous population. In this context it may be asked whether any additional CVD benefit will be
attainable by lowering blood glucose, given the effectiveness of reducing
A second meta-analysis included only four major trials comprising low-density lipoprotein (LDL) cholesterol and systolic blood pressure and
14,291 diabetic and pre-diabetic patients followed for at least one the possible benefit of increasing HDL cholesterol and reducing
year.
39
CVD events were mostly adjudicated, but time-to-event data triglycerides.
42
Patients with diabetes respond as well as those without to
were not available. Results for MI were similar to those recorded statin therapy in randomized clinical trials.
42,43
In a meta-analysis of statin
above: rosiglitazone increased MI incidence (94 versus 83 events, therapy involving 90,000 patients, 21% of whom had diabetes, each mmol/l
relative risk [RR] 1.42, 95% CI 1.06–1.91; p=0.02) but there was no reduction (39mg/dl) in LDL cholesterol was associated with a 23%
significant increase in CVD death (RR 0.90; p=0.53). There was a clear reduction in coronary death or MI and a similar reduction in need for
increase in the risk of congestive heart failure (RR 2.09, 95% CI coronary revascularization. Statin therapy was also associated with a 17%
1.52–2.88; p<0.001).
39
reduction in fatal or non-fatal stroke.
43
Moreover, a greater reduction in
events can be achieved using a maximum statin dose that lowers LDL
Another meta-analysis concerned with the ‘cardiac safety profile’ of cholesterol to 77mg/dl.
44
Reducing systolic blood pressure—and with it
rosiglitazone included 164 trials with a duration of more than four diastolic blood pressure—also decreases the risk of CVD events, especially
weeks. It included 45,875 patients with diabetes, impaired glucose strokes, in patients with and without diabetes.
41
In a large meta-analysis
metabolism, and diseases characterized by insulin resistance, e.g. involving 159,000 patients (21% with diabetes), more compared with less
polycystic ovary syndrome.
40
ORs for all-cause mortality (0.93, 95% CI intensive blood-pressure-lowering significantly reduced stroke by 36%,
0.76–1.14), for CVD mortality (0.94, 95% CI 0.68–1.29), and for non-fatal major CVD events by 25%, and total mortality by 27%, but not coronary
MI (1.14, 95% CI 0.90–1.45) showed no evidence of risk for rosiglitazone. heart disease, in patients with diabetes.
45
Similar benefits have been
The OR for congestive heart failure (1.64, 95% CI 1.21–2.36), on the other individually noted in the UKPDS,
46
Antihypertensive and Lipid-Lowering
hand, confirmed this adverse effect of TZDs.
40
Treatment to Prevent Heart Attack Trial (ALLHAT),
47
and ADVANCE trials.
48
A final meta-analysis focused on the effects of TZD treatment in type 2 The ACCORD study is simultaneously testing an intensive systolic blood
diabetes and pre-diabetes on the outcomes of CVD death and pressure target of <120mmHg versus <140mmHg in 4,733 hypertensive
congestive heart failure. A total of 20,191 patients were included: 72% subjects and the addition of fenofibrate versus placebo added to statin
enrolled in five rosiglitazone trials and 28% in two pioglitazone trials.
41
therapy in 5,518 patients with dyslipidemia.
19
This double factorial design
The risk of congestive heart failure was increased by TZDs (RR 1.72, 95% may enable separate determination of the influence of intensive glycemic
CI 1.21–2.42; p=0.02), but the risk of CVD death was not increased (RR control when added to optimal blood pressure control and the guideline
0.93, 95% CI 0.67–1.29; p=0.68).
41
There were no statistically significant level of LDL cholesterol control, with and without a supplemental increase
differences in congestive heart failure event rates between rosiglitazone in HDL cholesterol and decrease in triglycerides. These data should be
and pioglitazone, although the RR was higher with rosiglitazone (2.18 publicly available within a few months. If a beneficial effect of intensive
versus 1.32). glycemic treatment is ultimately observed only in the conventional but
US ENDOCRINOLOGY 93
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