2008 Clinical Practice Guidelines - Canadian Diabetes Association

Add-on therapy consists of combinations of first-line therapies.
The results of a large RCT, the Action in Diabetes and
Vascular Disease: Preterax and Diamicron-MR Controlled
Evaluation (ADVANCE) trial, which assessed the fixed combination
of an ACE inhibitor (perindopril) plus a thiazide-like
diuretic (indapamide) vs. placebo in 11 140 individuals with
type 2 diabetes, were recently published (24). Mean entry BP
was 145±22 / 81±11 mm Hg, and 75% of the patients were
receiving BP-lowering medication prior to the addition of
the combination or placebo. A mean systolic BP reduction of
5.6 mm Hg (95% CI, 5.2–6.0) and a mean diastolic BP
reduction of 2.2 mm Hg (95% CI, 2.0–2.4) were associated
with a reduction in total and CV mortality. No other trials
have specifically compared various second-line medications in
hypertensive patients with diabetes.
The key objective in the management of hypertension is
to obtain systolic and diastolic BP targets, and multiple drugs
will often be needed to meet such targets. Specifically, direct
relationships have been seen between the size of the incremental
BP reduction and the subsequent reduction in hypertension-related
complications (2,13,24). For example, in the
UKPDS, 29% of subjects randomized to tight BP control
required ≥3 antihypertensive drugs by the trial’s end (12). In
ALLHAT (22), the mean number of medications was >2,
and up to one-third of subjects required >3 medications.
Thus, any BP reduction was associated with a lower risk of
complications, but larger BP reductions were associated with
larger reductions in risk and required multiple medications.
Two studies have looked post hoc at the effects of thiazidelike
diuretics (Systolic Hypertension in the Elderly Program
[SHEP]) (25) and long-acting DHP CCBs (Systolic
Hypertension in Europe [Syst-Eur] Trial) (26) in subjects with
isolated systolic hypertension and diabetes. In both cases, there
were statistically significant reductions in CV events.
The recommendation to avoid alpha-blockers as
monotherapy or as add-on therapy ahead of other antihypertensive
classes is based on ALLHAT, in which the alphablocker
arm of the trial was stopped early because of a
significantly higher risk for stroke and combined CV events
compared to subjects randomized to diuretic therapy (27).
OTHER RELEVANT GUIDELINES
Physical Activity and Diabetes, p. S37
Nutrition Therapy, p. S40
Identification of Individuals at High Risk of Coronary
Events, p. S95
Screening for the Presence of Coronary Artery Disease, p. S99
Vascular Protection in People With Diabetes, p. S102
Chronic Kidney Disease in Diabetes, p. S126
RELATED WEBSITES
Canadian Hypertension Education Program. Available at:
http://www.hypertension.ca/chep. Accessed September 1,
2008.
REFERENCES
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COMPLICATIONS AND COMORBIDITIES