Download Heart failure in diabetes mellitus

1
Heart failure and
diabetes mellitus
H.R Javadi.
1393
2
•
•
•
•
•
•
•
•
•
DEFINITION
EPIDEMIOLOGY
CHARACTERISTICS
Pathology
ETIOLOGY
PROGNOSIS
THERAPY
DIABETES DRUGS IN HF
SUMMARY
3
INTRODUCTION AND DEFINITION
• Diabetes mellitus (DM) increases the risk of
heart failure (HF) independent of coronary
heart disease and hypertension and may
cause a cardiomyopathy.
• The term “diabetic cardiomyopathy” was
initially introduced based upon postmortem
findings in four diabetic adults who had HF in
the absence of coronary heart disease.
4
• Diabetic cardiomyopathy has been defined as
ventricular dysfunction that occurs in diabetic
patients independent of a recognized cause
(eg, coronary heart disease, hypertension).
• However, the frequency with which this occurs
is not well defined and there is some evidence
that diabetic cardiomyopathy is uncommon in
patients with type 1 diabetes in the era of
intensive insulin therapy.
5
EPIDEMIOLOGY
• There is a well established association between
diabetes mellitus (DM) and heart failure (HF).
• Associations have also been reported between
absolute blood glucose levels, glycemic control,
and HF.
6
Prevalence of HF in patients with
diabetes
• In the general population the prevalence of patients
with both HF and diabetes is estimated at 0.5% in
men and 0.4% in women.
• In patients with diabetes the prevalence of HF is
between 9–22%, which is much higher compared to
the general population.
• The prevalence is highest in women aged 70 years
and older.
• The prevalence of asymptomatic diastolic
dysfunction in patients with diabetes is probably
higher, and estimated to be between 52–60%.
7
Diabetes and HF
• The Framingham Study firmly established the
epidemiologic link between diabetes and HF.
• The risk of HF was increased
2.4-fold in men and
5-fold in women.
• When patients with prior coronary or
rheumatic heart disease were excluded, the
relative risk of HF remained elevated at 3.8 in
diabetic men and 5.5 in diabetic women.
8
• Similar findings in other studies:
• In a report of 9591 subjects with type 2
diabetes and matched controls, HF was more
frequent at baseline in diabetics (11.8 versus
4.5 percent).
• Among those free of HF at baseline, HF
developed more often in diabetics during a
30-month follow-up (7.7 versus 3.4 percent).
9
• elderly adults:
• The frequency of HF in diabetic patients is
even higher among elderly adults.
• This was demonstrated in a national sample of
Medicare claims from 1994 to 1999 for over
150,000 beneficiaries with diabetes who were
≥65 years of age.
• The prevalence of HF was 22.3% in 1994, with
a subsequent incidence of newly diagnosed
HF of 12.6% per year.
10
Factors associated with HF in adult
diabetic patients:
●Age
●Duration of diabetes
●Insulin use
●Ischemic heart disease
●Peripheral artery disease
●Elevated serum creatinine
●Poor glycemic control
●Microalbuminuria
11
• after revascularization:
• The incidence of HF after revascularization with
angioplasty or bypass surgery is also greater in
diabetic patients;
• In one study of patients followed for 13 years
after revascularization, the cumulative incidence
of hospitalizations for HF was higher in diabetics
(25 versus 11% for nondiabetics), with a rapidly
increasing incidence after five years.
12
• Reciprocal causal relation:
• In addition to the increased risk of HF in
patients with diabetes, there is also a high
rate of diabetes among patients with HF.
• In the OPTIMIZE-HF registry of 48,612 patients
hospitalized with HF, 42% had diabetes.
13
Glycemic control and blood glucose
levels
• In patients with diabetes, the risk of
development of HF is associated with
hyperglycemia, as illustrated by the following
studies:
14
• Glycemic control:
• A report from Kaiser Permanente of 48,858
adults with DM (predominantly type 2) and no
HF who were followed for a mean of 2.2 years.
• The risk of HF was associated with the HbA1c
and varied from 4.5 to 9.2 per 1000 patientyears. After adjustment for covariates, each
1% increase in HbA1c was associated with an
8% increased relative risk of HF.
An HbA1c ≥10 increased the risk of HF by 1.56fold compared to an HbA1c <7.
15
• blood glucose:
• A relationship was found between blood glucose
levels and hospitalization for HF in patients with
or without type 2 DM in a cohort of 31,546
adults (mean age 67 years) at high cardiovascular
risk from two clinical trials.
• At a mean follow-up of 2.4 years, each
18 mg/dL increase in baseline FBS was
associated with a modest but statistically
significant increase in the risk of HF
hospitalization (adjusted hazard ratio 1.05, CI 1.02-1.08).
16
• DM TYPE 1
• A similar relationship was found in a cohort of
20,985 adults with type 1 DM (mean age 39
years) followed for a median of 9 years.
• The incidence of HF ranged from
1.42 per 1000 patient-years for HbA1c <6.5%
to 5.20 per 1000 for ≥10.5%.
• After adjustment for covariates, each
1% increase in HbA1c was associated with a
30% increased relative risk of HF during follow-up.
17
• However, the available data have not shown a
causal relationship, ie, improved glucose control
has not been shown to reduce incident HF in
patients with type 2 DM.
• A meta-analysis including 27,049 patients with
type 2 DM found that more intensive glucose
control, compared to less intensive control, did
not decrease incident HF or mortality, although
major cardiovascular events (primarily MI) were
decreased.
18
• In patients with type 1 DM, data are lacking
on the effect of intensive glucose control on
risk of incident HF.
19
CHARACTERISTICS
• Functional abnormalities:
• LV dysfunction due to diabetic
cardiomyopathy is manifested by
systolic and/or diastolic dysfunction.
20
• spectrum of functional changes:
• In a report from the Strong Heart Study, diabetic
patients had
higher LV mass,
wall thickness,
and arterial stiffness
and reduced systolic function compared to
individuals without diabetes.
(independent of body mass index and blood pressure).
21
• Noninvasive evaluation of cardiac
performance in diabetic patients without
overt HF has demonstrated a
prolonged preejection period and
a shortened ejection time,
correlate with reduced resting LVEF and
diminished systolic function.
also a lower LVEF in response to exercise,
suggesting a reduction in cardiac reserve.
22
• Diastolic dysfunction is common in diabetic
patients, which may be due in part to
increased LV mass.
For example, an E/e’ ratio >15 (a marker of elevated
LV diastolic pressure) was observed in 23% of 1760
diabetic patients studied in Olmsted County.
•Greater diastolic dysfunction is observed in
those with worse glycemic control and in those
who are also hypertensive.
23
• An observational study of 1085 individuals
with glucose metabolism ranging from normal
to insulin treated type 2 diabetest reported
Further evidence for diastolic dysfunction as a
mediator of the relationship between
glycemic control and functional status.
• On multivariate analysis, HbA1c level
correlated with E/e’ ratio as well as reduced
six-minute walk distance.
24
• Other drangments:
• altered insulin signalling and mitochondrial
dysfunction, increased (deposition of)
advanced glycation end products (AGEs),
oxidative stress, and lipid accumulation.
25
Pathology
• Pathologic changes in the myocardium in
diabetic patients include:
fibrosis,
infiltration of the interstitium with periodic acidSchiff (PAS)-positive material,
and alterations in the myocardial capillary
basement membrane, including the formation of
microaneurysms.
• (they may occur in the absence of functional abnormalities).
26
• Myocardial fibrosis, advanced glycation end
product deposition (AGEs), and cardiomyocyte
resting tension were compared in diabetic and
nondiabetic HF patients without coronary
disease with normal LVEF (28 patients, 16
diabetic) or reduced LVEF (36 patients, 10
diabetic), Diabetic HF patients had higher
diastolic LV stiffness irrespective of LVEF.
27
• Significantly increased myocardial collagen
volume fraction and increased myocardial
advanced glycation end product deposition
was observed only among diabetic patients
with reduced LVEF;
• on the other hand, increased cardiomyocyte
resting tension was observed only in diabetic
patients with normal LVEF.
28
ETIOLOGY
• 1- Autonomic neuropathy may play a role in
the development of LV dysfunction.
• Sympathetic stimulation improves LV
contraction and increases LV relaxation rates.
• Autopsy studies have found that myocardial
catecholamine stores are depleted in diabetic
patients which could impair both systolic and
diastolic function. These changes may be
associated with functional impairment in
cardiac sympathetic nerve fibers.
29
• 2- Abnormal epicardial vessel tone and
microvascular dysfunction impaire the capacity
of the vascular bed to meet metabolic demands.
• 3- Impaired endothelium-dependent relaxation,
a defect that may be related to inactivation of
nitric oxide by advanced glycation end products
and increased generation of free radicals.
The abnormal vasodilator response in diabetes
extends to the coronary microcirculation.
30
• Microcirculatory dysfunction in diabetics may
be due in part to downregulation of the
expression of vascular endothelial growth
factor (VEGF).
• In an animal model, local replenishment of
VEGF via DNA gene therapy was associated
with increased capillary density and a
significant improvement in cardiac function.
31
• 4- Advanced glycation end product deposition
may increase LV diastolic stiffness directly by
cross-linking collagen, or indirectly by
enhancing collagen formation or reducing
nitric oxide bioavailability.
32
• 5- Decreased insulin availability or responsiveness
can impair energy-independent transport of
glucose across the cell membrane. Since ischemic
myocardium depends upon anaerobic metabolism
of glucose, increased glucose uptake and
metabolism are necessary for maintenance of
myocardial function.
• Diminished insulin activity limits glucose
availability, resulting in a shift toward fatty acid
metabolism.
• These changes increase myocardial oxygen
utilization and can reduce the compensatory
capacity of noninfarcted myocardium .
33
• 6- Other factors include
myocardial accumulation of lipid and other
toxic products of fatty acid metabolism,
impaired calcium handling,
upregulation of the renin-angiotensin system,
increased reactive oxygen species,
and mitochondrial defects.
34
• A reciprocal causal relation has been
postulated in which HF promotes insulin
resistance.
• Neurohumoral activation in HF causes
increased free fatty acid metabolism, which
may cause systemic and myocardial insulin
resistance.
• These metabolic alterations may impair
myocardial energetics so that a vicious cycle is
produced of HF leading to altered metabolism
leading to HF.
35
Potential mechanisms linking diabetes mellitus
to heart failure.
36
PROGNOSIS
• Among patients with heart failure (HF), those with
diabetes have higher mortality rates.
• In Studies of Left Ventricular Dysfunction (SOLVD),
which enrolled 6791 patients, including 1310 with
diabetes.
• Compared to nondiabetics, diabetic patients were
significantly;
more likely to be admitted for HF (risk ratio 1.6)
higher rates at one year of all-cause mortality (32
versus 22%),
cardiovascular mortality (28 versus 19%), and
mortality related to pump failure (11 versus 6%).
37
• In the presence of CAD, diabetes was
independent of other risk factors for predicting
worsening of HF and it was third in order of
importance, after age and LVEF.
• Previous surgical revascularization may identify
diabetic patients with HF who have improved
survival (91 versus 86% without
revascularization).
38
• Among patients with diabetes, those who
develop HF have markedly poorer survival
than in those who do not.
• In the national sample of Medicare claims, the
mortality rates were 32.7 and 3.7% per year,
respectively (hazard ratio [HR] 10.6).
• This risk was only slightly attenuated by
adjustment for age, sex, and race (HR 9.5).
• The five-year survival rate for diabetics with
HF was 12.5%.
39
• The prognostic significance of pre-clinical
diastolic dysfunction was demonstrated in a
study of 1760 patients with diabetes in
Olmsted County.
• The presence of an E/e’ ratio >15 was an
independent predictor of HF (HR 1.6, 95% CI
1.2 to 2.2) and increased mortality (HR 2.0,
95% CI 1.3 5o 3.1) at five years.
40
THERAPY
• General considerations — Diabetic patients with HF are
treated in the same fashion as nondiabetics.
• In a meta-analysis of beta blocker trials in HF that included
1883 diabetics and 7042 nondiabetics, the survival benefit
with beta blocker therapy was significant for both those
with diabetes and for those without. The difference in risk
reduction between diabetics and nondiabetics was not
significant.
• Both the SOLVD and SAVE trials showed that diabetics
benefit from ACE inhibitors to the same degree as
nondiabetics.
• In a meta-analysis of ACE inhibitor trials in HF that included
2398 diabetics and 10,188 nondiabetics, the survival
benefit with ACE inhibitor therapy was the same for those
with diabetes as for those without.
41
• Role of glycemic control — As noted above, tighter
glycemic control is associated with lower risk of HF.
However, a causal relationship between glycemic
control and HF has not been established.
• The impact of diabetes therapies on cardiac function
has not been defined. Although thiazolidinedione (TZD)
use is associated with increased HF risk, some studies
suggest a beneficial impact on myocardial
metabolism and/or function. In the PIRAMID trial, 78
men with type 2 diabetes were randomly assigned to
TZD (pioglitazone) or metformin for 24 weeks. TZD
treatment improved some measures of left ventricular
diastolic function but did not change myocardial highenergy phosphate metabolism. The clinical significance
of this observation is unclear.
42
• Heart transplantation — Diabetes mellitus, is a
relative contraindication to heart transplantation.
However, the outcome in properly selected patients
is comparable to that in nondiabetics. This was
illustrated in an analysis of 345 consecutive heart
transplant recipients, 101 with diabetes.
• Diabetics, compared to nondiabetics, had a
nonsignificant trend toward decreased survival at 1
year (85 versus 91%) but comparable survival at 5
years (82%).
• Rates of infection severe enough to require
hospitalization were higher among diabetics at 90
days (14 versus 3%) and four years (29 versus 15%).
• There were no differences in the incidence of
rejection, transplant coronary disease, or renal
dysfunction.
43
• Possible prevention with angiotensin inhibition —
ACE inhibitors and angiotensin II receptor blockers
(ARBs) reduce disease progression and mortality in
patients with overt HF.
• The possible preventive effect of losartan in diabetic
patients with type 2 diabetes was evaluated in
subset analysis of two large randomized trials:
RENAAL for renal protection and LIFE for hypertension
with LVH. losartan significantly reduced the incidence
of first hospitalization for HF: 39 versus 54% in RENAAL
(adjusted HR 0.69); and 11 versus 19% in LIFE (adjusted HR
0.50).
• These findings are consistent with the use of ACE
inhibitors or ARBs for the treatment of hypertension
and renal disease in patients with diabetes.
44
DIABETES DRUGS TO USE WITH
CAUTION IN HF
• The thiazolidinediones and metformin, have
toxicities that have made them relatively or
absolutely contraindicated in HF patients :
• Thiazolidinediones can cause fluid retention. As a
result, they are not recommended in patients with
symptomatic HF and are contraindicated in NYHA
class III or IV HF.
• Metformin is contraindicated in HF requiring
pharmacologic therapy because of the risk of lactic
acidosis. However, the risk for lactic acidosis in the
setting of metformin is extremely low.
45
Thiazolidinediones
• Thiazolidinediones (TZDs) act by increasing
insulin sensitivity.
• There is strong evidence that TZDs contribute
to fluid retention and increase the risk of HF.
46
• In meta-analyses of randomized trials of
thiazolidinediones for the treatment or
prevention of type 2 diabetes, the estimated
relative risk of HF in patients randomly
assigned to TZDs compared with placebo
ranged from 1.7 to 2.1 (95% CIs 1.2-2.4 and
1.1-4.1, respectively).
• The incidence of HF was not limited to the
elderly and occurred at high and low doses
after a median treatment duration of 24
weeks.
47
• Similar findings were noted in a later
randomized trial (RECORD) that evaluated the
addition of rosiglitazone to metformin or
sulfonylurea therapy compared to
combination metformin and sulfonylurea
therapy; there was a 2.1-fold (95% CI 1.353.27) increased risk of HF resulting in
hospitalization or death with the addition of
rosiglitazone.
• There was no difference in the primary end
point of cardiovascular hospitalization or
cardiovascular death.
48
• One mechanism by which TZDs increase HF risk is
renal sodium retention. Peripheral edema occurs in
4 to 6% of patients treated with TZDs (compared to
1 to 2% with placebo) and in a higher percentage
of patients with a history of HF.
• In both randomized and observational studies, TZD
use has been associated with worsening HF and
pulmonary edema.
• Weight gain and fluid retention are more common
with concomitant insulin therapy.
• Fluid retention induced by TZDs appears to be
relatively resistant to loop diuretics but responds
promptly to withdrawal of therapy.
49
• To the degree that increased activity of the
collecting tubule sodium channel is involved,
blockade of this channel may be effective.
• Administration of a mineralocorticoid receptor
antagonist, such as spironolactone or eplerenone,
is part of the standard medical regimen of many
patients with HF and in a study of diabetic
patients without HF who were treated
with rosiglitazone, spironolactone produced more
fluid removal than a loop diuretic.
• Amiloride, may also be effective. Hyperkalemia is
a potential problem with any of these drugs.
50
Major society and FDA guidelines
• In May 2011, FDA announced restrictions on access
to rosiglitazone that were placed based on data
suggesting increased risk of MI in patients treated
with the drug. Under this program, access to
rosiglitazone is now limited to patients already
successfully treated with it or patients whose
blood sugar cannot be controlled with other
diabetes drugs and who decide not to
take pioglitazone after consulting with the
healthcare provider. Use of rosiglitazone had
already declined sharply prior to this
announcement and is now severely restricted.
51
• In December 2003, a consensus statement on
this issue was published by the American
Heart Association and the American Diabetes
Association. Given the restrictions
on rosiglitazone use, this statement now
applies chiefly to pioglitazone. The following
approach was recommended:
52
• In patients without established heart
disease, rosiglitazone and pioglitazone should be
prescribed according to the package insert
guidelines. Weight gain and edema will occur
more often with concomitant insulin therapy.
• In patients with one or more risk factors for HF
with TZD therapy, in patients with a decreased
LVEF but no signs or symptoms of HF, and in
patients with NYHA class I or II HF, the initial dose
of the TZD should be low (eg, 2 to 4
mg rosiglitazone daily or 15 mg pioglitazone daily).
• Patients should be observed for weight gain or
edema.
• Dose escalation should be performed gradually
while reassessing the patient for signs of HF.
53
• In patients with NYHA class III or IV HF, TZDs
should not be used.
• If weight gain and edema develop in a patient
taking a TZD, a careful assessment for
evidence of HF should be made. This may
include review of symptoms of HF, physical
examination, ECG, echocardiogram, and
serum BNP concentration.
54
• If there is no evidence of HF, other possible
causes of edema should be investigated,
including other drugs, venous insufficiency, and
renal dysfunction.
• Diuretics may be prescribed, although the
efficacy of such therapy in TZD-induced edema is
variable. Dosage change or discontinuation of the
TZD are options.
• If there is evidence of HF, the use of the TZD
should be reconsidered. Dosage change and
temporary or permanent discontinuation are
options; the drug should be discontinued in
patients who also have known left ventricular
dysfunction.
• Therapy for HF should be initiated as necessary.
55
• The FDA has issued a boxed warning for TZDs. The
FDA recommends that patients who are initiating
or currently taking rosiglitazone or pioglitazone be
observed for signs and symptoms of HF, and the
TZD should be stopped "if any deterioration in
cardiac status occurs."
• The FDA also concluded that drugs in this class are
not recommended in patients with symptomatic
HF and are contraindicated in patients with NYHA
class III or IV HF.
• Health Canada usage restrictions for TZDs include
contraindicating these agents with any stage (class
I to IV) of HF.
56
• The European Society of Cardiology (ESC) HF
guidelines note that TZDs are contraindicated in
patients with NYHA class III to IV HF, but that
they may be considered in patients with NYHA
functional class I to II HF with careful monitoring
for fluid retention.
• The 2005 ACC/AHA HF guidelines with 2009
update note that TZDs are contraindicated in
patients with class III to IV HF, that risk of fluid
retention is low in patients with class I to II HF,
and that TZDs should be used with caution in
patients with reduced cardiac reserve.
57
TZD summary
• In summary, strong evidence indicates that TZDs
cause fluid retention that can precipitate HF.
• Thus, TZDs are not generally recommended in
patients with symptomatic HF and are
contraindicated in patients with NYHA class III to
IV HF.
• TZDs may be considered as part of diabetes
management in selected patients with class I to II
HF with careful monitoring for fluid retention.
• Current evidence does not support the
preferential use of TZDs for the purpose of
improving cardiovascular risk.
58
Metformin
• Patients with HF who take metformin are at
increased risk of potentially lethal lactic
acidosis, especially in the presence
hemodynamic instability or of other concurrent
medical conditions such as renal insufficiency,
liver disease, or severe infection with
decreased tissue perfusion. (in particular those with
unstable or acute HF at risk of hypoperfusion and hypoxemia).
59
• However, metformin is an effective and useful
agent in the management of diabetes mellitus,
and the general safety of and possible survival
benefit in this setting has been suggested.
• The risk of lactic acidosis is probably small in
patients with stable, well-compensated HF who
have a serum creatinine concentration below
1.5 mg/dL.
• In the ESC HF guidelines, metformin is suggested
as a first-line agent in overweight patients with
type 2 diabetes without significant renal
dysfunction (GFR>30 mL/min).
60
SUMMARY AND RECOMMENDATIONS
• Independent of coronary heart disease and hypertension,
diabetes is a cause of systolic and/or diastolic ventricular
dysfunction, which has been termed “diabetic
cardiomyopathy.”
• Despite the relationship of glycemia to the risk of developing
HF, there is no evidence that tight glycemic control affects the
natural history of HF.
• Diabetes is associated with a variety of derangements that may
reduce left ventricular compliance and contribute to the risk of
diastolic dysfunction and HF.
• Thiazolidinediones (TZDs) cause fluid retention that can
precipitate HF. Thus, TZDs are not generally recommended in
patients with symptomatic HF and are contraindicated in
patients with NYHA class III to IV HF. TZDs may be considered
as part of diabetes management in selected patients with class
I to II HF with careful monitoring for fluid retention.
61
• The CHF incidence rate in type 2 diabetes may
be much greater than previously believed. Our
multivariate results emphasize the importance
of controlling modifiable risk factors for CHF,
namely hyperglycemia, elevated blood
pressure, and obesity.
• Younger patients may benefit most from risk
factor modification.
62
• All topics are updated as new evidence
becomes available and our peer review
process is complete.
• Literature review current through: Jan 2015.
63