2008 Clinical Practice Guidelines - Canadian Diabetes Association

2008 CLINICAL PRACTICE GUIDELINES
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at least 2 years showed decreased overall mortality (OR 0.86,
95% CI, 0.79–0.93), CV mortality (OR 0.81, 95% CI,
0.73–0.90), MI (OR 0.82, 95% CI, 0.75–0.89) and stroke
(OR 0.77, 95% CI, 0.66–0.88).
Whether the benefits of ACE inhibition result from a
reduction of BP remains controversial. The benefits of ACE
inhibition in both the HOPE and EUROPA trials were
observed in individuals with or without a history of hypertension,
and in those with higher and lower BP readings (4,5).
Furthermore, recent analyses of BP trials have indicated a
benefit of ACE inhibition beyond that of BP lowering (10).
Also, trials of other agents such as calcium channel blockers,
which lower BP in normotensive individuals with CAD, have
failed to reduce coronary events other than those related to a
reduction of angina (11).
The HOPE and EUROPA studies confirmed the benefit of
ACE inhibition in people with diabetes and established vascular
disease (4,5). The HOPE study is the only study that has
included individuals with diabetes and no evident vascular disease.
In this relatively small subgroup, the point estimate of
benefit was of similar magnitude to the overall group, yet did
not achieve significant benefit. Hence, the level of evidence
and the recommendation are less robust for this population
than for people with both diabetes and CVD.
ARBs have been shown to be noninferior to ACE inhibition
for the prevention of events in patients with heart failure
and in those with reduced LV ejection fraction after MI.
The Ongoing Telmisartan Alone and in Combination with
Ramipril Global Endpoint Trial (ONTARGET) study (12)
compared the vascular protective properties of the ACE
inhibitor ramipril with the ARB telmisartan and the combination
of the ACE and the ARB in patients at high risk for vascular
events. Of the 25 620 patients entered in the study,
9632 had diabetes. Of these patients, 7406 had diabetes and
vascular disease, and 2226 had “high-risk diabetes.” The
ONTARGET patients with “high-risk diabetes” (defined as
diabetes with non-macrovascular end-organ damage [i.e.
with diabetic nephropathy or retinopathy]) were different
from the HOPE patients (diabetes with ≥1 CV risk factors).
In the overall study, telmisartan 80 mg daily was noninferior
to ramipril 10 mg daily for the primary endpoint of death,
MI, stroke and admission to hospital with heart failure, when
administered for a median period of 56 months (RR 1.01,
95% CI, 0.94–1.09). The telmisartan-treated patients had
less cough and angioedema, but more hypotensive episodes.
The combination of ramipril and telmisartan was not superior
to ramipril alone, and hypotensive adverse effects, including
syncope were more frequent in the dual-treatment arm.
For patients with diabetes, the primary end-point relative
risk point estimate was close to 1 and similar to the group
without diabetes, both for those receiving telmisartan compared
to ramipril, as well as for those receiving the combination
of telmisartan and ramipril compared to ramipril alone.
For patients with diabetes and nonvascular end-organ dam-
age, the point estimate was also close to 1, however due to
the small sample size the confidence intervals were wide. In
summary, for patients with diabetes with vascular disease,
the ARB telmisartan was not inferior to ramipril to prevent
vascular events, however no confidence intervals or noninferiority
margins for this population have yet been published.
For patients with diabetes and nonvascular end-organ
damage the sample size is too small to make any conclusive
recommendation.
ANTIPLATELET THERAPY
In addition to traditional risk factors for CVD such as smoking,
hypertension, hyperglycemia and dyslipidemia, atherosclerosis
in people with diabetes can be accelerated by a
procoagulant state. Individuals with diabetes have a variety of
alterations in platelet function that can predispose them to
increased platelet activation and thrombosis, including
increased turnover (13), enhanced aggregation (14) and
increased thromboxane synthesis (15). The efficacy of
antiplatelet agents in people with diabetes also appears to be
reduced, particularly in those with poor metabolic control
(16,17).
Acetylsalicylic acid (ASA) is the antiplatelet agent most
commonly studied in the prevention of CV events in people
with diabetes. A number of primary, mixed primary/secondary,
and secondary CV event prevention trials have studied
the effect of ASA in diabetes with varied results. The US
Physicians Health Study (18) was a primary prevention trial
with a subgroup of 533 male physicians with diabetes treated
with 325 mg ASA every 2 days. ASA use reduced the risk of
MI by 60%, although the results were not significant due to
the small number of events (11/275 in the ASA group vs.
26/258 in the placebo group, p=0.22). The Primary
Prevention Project (PPP) trial (19) studied the effect of lowdose
ASA (100 mg/day) in over 1000 people with diabetes
and found a marginal decrease in major CV events (RR 0.90,
95% CI, 0.50–1.62) with a nonsignificant 23% increase in
CV deaths. This result is in contrast to the significant 41%
reduction in major CV events seen in individuals without diabetes.The
Hypertension Optimal Treatment (HOT) (20) trial
studied the effect of 75 mg ASA daily in a subset of 1501 highrisk
subjects with diabetes and hypertension. Fewer than 10%
of subjects had clinical evidence of previous MI, stroke or
other CAD. In the whole HOT population, ASA reduced the
risk of pooled CV events by 15% and the risk of MI by 36%.
Specific data on the diabetes subgroup were not included, but
the subjects with diabetes and CVD were reported to have
had similar outcomes to the overall HOT population.
The Antithrombotic Trialists (21) reported a meta-analysis
of 195 randomized trials of antiplatelet therapy published up
to 1997, including 9 trials with almost 5000 people with diabetes.
Compared to a 22% reduction in the risk of major CV
events among all 140 000 high-risk subjects on antiplatelet
therapy, subjects with diabetes showed no significant benefit