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Cardiovascular Risk in Type 2 Diabetes—Reflecting on the ADVANCE Study
an 18% (95% CI 2–32; p=0.027) reduction in cardiovascular mortality, as of follow-up (p<0.001).
2
No increase in death was observed with
well as reductions in coronary events (14%; p=0.02) and renal events intensive glucose control compared with standard glucose control.
2
(21%; p=0.0001). No statistically significant reductions were observed in
cerebrovascular events or microvascular eye disease. There was no Treatment of Blood Pressure in Type 2 Diabetes
evidence of heterogeneity in treatment effect in subgroups of BP is a particularly important determinant of the risk for macrovascular
participants defined by major baseline characteristics. In particular, the and microvascular complications in patients with type 2 diabetes.
6,7
In
effects of the treatment were similar across a range of initial BP levels observational analyzes, systolic BP levels have been shown to be
and regardless of use of concomitant therapies (including ACE linearly associated with the risks of myocardial infarction and
inhibitors, statins, and aspirin).
1
microvascular events.
8
Although the strength of the association appears
to attenuate somewhat with age, BP remains a leading determinant of
In the glucose-lowering arm, the mean entry HbA
1c
of participants was risk in both older and younger individuals.
9
The effectiveness of BP
7.5%, with 91% already receiving oral hypoglycemic agents.
2
By the end of lowering in patients with type 2 diabetes has been consistently
follow-up of those in the intensive control group and standard care group, observed in trials of individuals with hypertension.
10–15
Current treatment
respectively, 92 and 59% were receiving sulfonylurea, 74 and 67% guidelines recommend aiming for a target BP level of 130/80mmHg or
metformin, 40 and 24% insulin, and 17 and 11% thiazolidinediones. lower, with initial therapy including an ACE inhibitor or an angiotensin
Intensive glucose control resulted in a mean HbA
1c
of 6.5%, compared receptor blocker.
16
However, observational data demonstrating a
with 7.3% in the standard arm, to produce an average difference during continuous association between BP and cardiovascular risk have been
follow-up of 0.7% between the groups (see Figure 3).
2
In addition, the largely ignored despite suggesting potential benefits of BP lowering for
target HbA
1c
of 6.5% or less was achieved by 65% of those assigned a broader range of people with diabetes. In addition, the relative benefits
intensive glucose control, compared with 29% of those assigned of specific therapeutic regimens continue to be debated. The recently
standard care. Intensive glucose control reduced the incidence of published results of the ADVANCE trial are therefore highly relevant to
combined major macrovascular and microvascular events by 10% (95% CI these important clinical questions.
2–18; p=0.01). This was primarily due to a significant 21% reduction in the
incidence of new or worsening nephropathy. There were no significant The BP-lowering arm of the trial indicated that, regardless of initial BP
effects of intensive glucose control on major macrovascular events level, the presence or absence of hypertension and any other treatment
(relative risk reduction [RRR)] 6%, 95% CI -6 to 16; p=0.32) (see Figure 2), being taken, routine administration of the fixed combination of
cardiovascular mortality (RRR 12%, 95% CI -4 to 26; p=0.12), or perindopril and indapamide to individuals with type 2 diabetes was well
all-cause mortality (RRR 7%, 95% CI -6 to 17; p=0.28).
2
The treatment tolerated and reduced the risk for death and major vascular events.
1
In
effects were consistent across a range of participant subgroups defined addition, the results suggested that treatment with a single tablet of
by major baseline characteristics, including duration of diabetes and prior perindopril–indapamide once daily would prevent one major vascular
history of macrovascular or microvascular disease (p>0.1 for event among every 66 patients, one death among every 79 patients, one
heterogeneity for all comparisons).
2
coronary event among every 75 patients, and one renal event among
every 20 patients treated for five years.
1
From a global perspective, if
Safety and Tolerability of the only half of all patients with type 2 diabetes were to be treated with the
ADVANCE Trial Interventions fixed combination of perindopril and indapamide over five years, over
The fixed combination of perindopril and indapamide was well tolerated. 1.5 million deaths would be prevented. The trial thus highlighted the
At the end of follow-up, 73 and 74% of patients in the active treatment potential benefits of an alternative effective strategy for delivering a BP-
and placebo groups, respectively, remained adherent to their lowering treatment to patients with a broader range of BPs, including
randomized treatment.
1
Serious suspected adverse drug reactions those with ‘normal’ BP, and a strategy that would also be applicable to
leading to discontinuation were reported in 47 (0.8%) of patients on the vast majority of patients who fail to reach recommended BP targets.
active treatment and 31 (0.6%) of patients on placebo. These included 14
cases of hyperkalemia (six active, eight placebo), two cases of Treatment of Glucose Levels in Type 2 Diabetes
hypokalemia (two active), and five cases of hyponatremia (four active, Epidemiological studies have also demonstrated a strong relationship
one placebo). There were also five non-fatal cases of angioedema (three between the level of glycemic control (HbA
1c
) and risks of macrovascular
active, two placebo).
1
and microvascular complications in people with type 2 diabetes. In the
United Kingdom Prospective Diabetes Study (UKPDS) of newly diagnosed
As expected, in the glucose control arm severe hypoglycemia was more individuals with type 2 diabetes, for example, each 1% higher level of
frequent with intensive glucose control (0.7 cases per 100 patient-years) mean HbA
1c
level was associated with an approximate 14% greater risk
than with standard care (0.4 cases per 100 patient-years).
2
However, the for all-cause death, 14% greater risk for myocardial infarction, and 37%
overall incidence of severe hypoglycemia in ADVANCE was much less greater risk for microvascular disease.
17
Tight glucose control in the
than that reported by other studies of more intensive glucose UKPDS was also shown to produce significant reductions in the risk for
lowering.
3–5
In addition, there was no increase in mean bodyweight microvascular events but only a non-significant trend towards a reduction
among patients randomized to intensive glucose control, but a small in myocardial infarction.
3,18
In combination, the observational data and
reduction in mean bodyweight among those allocated to standard the randomized evidence provided by the UKPDS provided support for the
glucose control, so the mean bodyweight of the participants in the notion that strategies that lowered glucose levels to below those
intensive arm was 0.7kg higher than in the standard care arm at the end achieved in the UKPDS should further reduce the risks of macrovascular
US ENDOCRINOLOGY 97
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