2008 Clinical Practice Guidelines - Canadian Diabetes Association

2008 CLINICAL PRACTICE GUIDELINES
S124
out diabetes. Generally, heart failure in people with diabetes
should be treated similarly to those without diabetes, although
comorbidities such as renal dysfunction may be more prevalent
in people with diabetes and may influence heart failure
drug doses and monitoring of therapy. Treatment choices for
diabetes (i.e. dietary and/or pharmacologic therapy) each
have advantages and disadvantages in heart failure patients.
Metformin
Metformin is an effective oral antihyperglycemic agent but,
based on isolated case reports and a biochemical rationale for
a risk of lactic acidosis (16-18), it is approved for use under
a warning in the setting of several conditions, including heart
failure.Two large meta-analyses and a smaller case series have
evaluated the occurrence and outcomes of lactic acidosis
with the use of metformin or other antihyperglycemic agents
in over 40 000 subjects, including those with heart failure.
Only subjects with a serum creatinine of up to 150 µmol/L
were included in the meta-analyses, and up to 200 µmol/L in
the case series. Lactic acidosis was not increased, and cardiovascular
outcomes in heart failure patients taking metformin
were better than in those taking other antihyperglycemic
agents.The current evidence suggests that patients with heart
failure fare at least as well, if not better, with metformin than
with other antihyperglycemic agents if they have only mild to
moderate renal dysfunction (estimated glomerular filtration
rate [eGFR] >30 mL/min). As such, metformin should still
be considered as first-line therapy in heart failure patients
with mild to moderate renal dysfunction (16-18).
Thiazolidinediones
Thiazolidinediones (TZDs) are known to cause fluid retention,
although this is generally mild. Recent studies suggest that this
is not a direct toxic effect on the myocardium.The Prospective
Pioglitazone Clinical Trial In Macrovascular Events (PROAC-
TIVE) study of pioglitazone in individuals at risk of cardiac
ischemic events showed that TZDs were associated with fewer
cardiac ischemic events, but at the cost of an increase in heart
failure hospitalizations (2% absolute excess over 2.8 years, or
5000 subjects, a significant reduction
of new glucose intolerance and cardiovascular events
(0.8% absolute reduction) were seen with rosiglitazone, but a
small excess of new-onset heart failure was also observed
(0.4% absolute excess) (20). A recently completed randomized
trial comparing the efficacy of rosiglitazone, metformin or
glyburide monotherapy in people with type 2 diabetes reported
a greater treatment failure rate of monotherapy with glyburide
or metformin compared to rosiglitazone, but an
increase in reported heart failure with rosiglitazone. When
only adjudicated events were considered, there was no signifi-
cant difference in cardiovascular-related or heart failure-related
mortality in any arm (21). Recent reports suggest that the
fluid retention can be safely managed with careful observation,
taking care not to increase diuretic therapy in the absence of
either symptoms or signs of central volume overload rather
than just peripheral edema (17,18). In an addition to product
monographs in November 2007, Health Canada advised that,
“Treatment with all rosiglitazone products is now contraindicated
in patients with any stage of heart failure, (i.e. NYHA
Class I, II, III or IV).” (22) A recent meta-analysis (23) has not
confirmed any difference in the risk of congestive heart failure
between rosiglitazone and pioglitazone. Glitazones may be
used cautiously in patients with stable mild heart failure if close
specialist monitoring is available, but should not be used in
patients with unstable or severe heart failure.
A detailed discussion of the rationale and evidence for the
treatment approach to heart failure patients is available in the
Canadian Cardiovascular Society consensus recommendations
(http://www.hfcc.ca) (1,24).
RECOMMENDATIONS
1. Individuals with diabetes and heart failure should receive the
same heart failure therapies as those identified in the evidence-based
Canadian Cardiovascular Society heart failure
recommendations (http://www.hfcc.ca) [Grade D, Consensus].
2. Unless contraindicated, metformin may be used in people
with type 2 diabetes and heart failure [Grade C, Level
3 (16,17)]. Metformin should be temporarily withheld if
renal function acutely worsens, and should be discontinued
if renal function significantly and chronically worsens
[Grade D, Consensus].
3. Physicians should be aware that people taking TZDs are
at increased risk of heart failure and may present with
symptoms such as increased dyspnea and peripheral
edema [Grade B, Level 2 (19,20)].
4. In people with diabetes and heart failure and an eGFR