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Hyperglycemia management in
patients with CVD
Hashemipour .S MD
Endocrinologist
Qazvin University of medical science
Outline
• Acute setting:
• New hyperglycemia vs known diabetics
• Complications
• Management
• Chronic setting:
•
•
•
•
Sulfonylureas
Metformin
Thiazolidendiones
DPP-IV inhibitors
Acute hyperglycemia in patients
with
acute myocardial infarction
Definition
• Threshold glucose concentration used to
define acute hyperglycemia has ranged from
108 mg/dl to 200 mg/dl
• In most of the recent studies, blood glucose
of 180-200 mg/dl on admission is used to
define acute hyperglycemia
Circulation J,2012; 76:563–571
Relationship between admission
glucose and mortality after AMI
Hyperglycemia and mortality
Am Heart J 2005; 150:814 – 820
Diabetic patients vs non-diabetics
In metaanalysis by Capes et al. :
• In patients without history of diabetes, blood
glucose on admission ≥108–144 mg/dl :3.9 times
mortality
• In patients with diabetes, blood glucose ≥180200mg/dl: 1.7 times mortality .
• This meta-analysis, however, included mostly
older studies from the pre-reperfusion era or in the
thrombolysis era
Lancet 2000; 355:773 – 778.
Findings From the Japanese
Acute Coronary
Syndrome Study (JACSS)
Am J Cardiol 2009; 104:769 – 774.
Why mortality in hyperglycemic
non-diabetic patients is higher than
diabetic ones?
Mortality id diabetic vs nondiabetic patients
• Acute fluctuation of the blood glucose
is important for some mechanisms
augmenting myocardial damage
• Another possible explanation is a
paradoxical resistance of diabetic
hearts to ischemic challenge.
Circulation J,2012; 76:563–571
Does Acute Hyperglycemia in NonDiabetic Patients Represent Previously
Undiagnosed Diabetes?
Undiagnosed DM in hyperglycemic
patients whithout history of DM
Eur Heart J 2006; 27:2413 – 2419
Is Acute Hyperglycemia a Cause or
a Consequence of Severe Myocardial
Damage?
LVEF and hyperglycemia
Am Heart J 2003; 146:674 – 678
Mechanisms by Which Acute Hyperglycemia
Exacerbates Myocardial Damage
Inflammation
3 consecutive pulses of intravenous glucose
separated by a 2-h interval show increasing levels of
cytokines in normal and IGT subjects but
returned to normal as glucose returned to normal
levels.
Interestingly, when the first elevation in the blood
glucose level was maintained by subsequent
continuous intravenous glucose infusion, plasma
cytokine concentrations gradually returned to normal
Levels despite hyperglycemia
Circulation 2002; 106:2067 – 2072
Apoptosis
Apoptosis is enhanced in human umbilical
vein endothelial cells exposed to intermittent,
rather than constant, high glucose
concentrations
Am J Physiol Endocrinol Metab2001; 281:E924 – E930
Other mechanisms
•
•
•
•
•
Oxidative stress
Endothelial dysfunction
Hypercoagolability
Platelet hyperactivity
Impaired recondition
Management of acute
hyperglycemia
IV insulin therapy
2 major questions.
• Is insulin infusion or GIK infusion
preferable for the management of acute
hyperglycemia in patients with AMI?
• What is the optimal goal of the blood
glucose level for patients with AMI?
DIGAMI 1
• An RCT on patients admission glucose
≥198mg/dl to ≥24-h
• insulin-glucose infusion followed by
subcutaneous insulin or routine antidiabetic
therapy
• Blood glucose in insulin-glucose in fusion:
172.8±59.4 mg/dl, in controls :210.6±74.8
mg/dl
J Am Coll Cardiol1995; 26:57 – 65
• Mortality during the 3.4 years was 33% in
the insulin-glucose group and 44% in the
control group (P<0.011).
• The mortality reduction by insulin-glucose
infusion was most obvious in baseline
glucose level >297mg/dl
J Am Coll Cardiol1995; 26:57 – 65
CREATE-ECLA study
• An RCT on 20,201 patients to fixed dose of
GIK for 24 h or usual care
• Most patients did not have hyperglycemia
• The mean of baseline BG was 162mg/dl
• Mean BG at 24h in GIK: 154.8mg/dl and in
control:135mg/dl
JAMA 2005; 293:437 – 446
CREATE-ECLA study
• Results : high-dose GIK infusion had a
neutral effect on mortality, or complications
in patients with acute ST-elevation MI
JAMA 2005; 293:437 – 446
Conclusion
These 2 studies, as well as the other previous
studies, suggest that blood glucose control
using insulin, but not metabolic modulation
by GIK, is important to improve the outcomes
of patients with AMI and acute hyperglycemia
Glucose target
Glucose target
• Prior ACC/AHA Guidelines ,(until revised
in 2009), recommended insulin infusion to
normalize blood glucose level in patients
with ST-elevation MI as Class I in patients
with complicated course complicated
course, and Class II in patients without a
complicated course.
• Metaanalysis of the 7 largest randomized
trials, in 6 of which the target glucose level
was 80–110 mg/L, showed that intensive
insulin therapy provided no survival benefit,
but rather was associated with a higher
incidence of hypoglycemia and increased
morbidity.
Chest 2010; 137:544 – 551
Glucose targets
The current AHA/ACC guideline
recommends the use of an insulin-based
regimen to achieve and maintain a blood
glucose level <180 mg/dl, avoiding
hypoglycemia in patients with STEMI with
either a complicated or uncomplicated course.
J Am Coll Cardiol2009; 54:2205 – 2241
IV insulin infusion
• Infusion Initiation:
Start infusion at rate of 1–5 units per hour,
depending on degree of hyperglycemia and
insulin resistance
Transferring a patient from SQ to IV insulin:
divide 50% of the total daily insulin dose by
24 hrs for an hourly rate (depending on patient
status/condition).
IV insulin infusion
• When patient is NPO :D5W solution at
75–125 cc/hr (unless patient is still very
hyperglycemic i.e., >200 mg/dL)
• Check BG Q1 hr for first 4–6 hrs until
stable, then Q2 hrs. For prolonged
infusions, if very stable, can decrease BG
checks to Q4 hrs.
Starting IV infusion
Joslin Diabetes Center publication 2009
IV insulin infusion
Joslin Diabetes Center publication 2009
Key massages
• Complications of AMI are higher in patients wit
new hyperglycemia vs known diabetics
• BS fluctuations has detrimental effect on myocard
• Beneficial effects of IV insulin is related to
glucose control, not insulin per se
• Glucose target<180mg/dl is appropriate for AMI
setting
Non-acute setting
HbA1C target in patients with
CVD
Myocardial Infarction and Microvascular Disease
UKPDS 10 years follow up
Incidence per
1000 patient-years
80
60
Microvascular
disease
40
Myocardial
infarction
20
0
0 5 6 7 8 9 10 11
Updated mean HbA1c (%)
UKPDS 35. BMJ 2000; 321: 405-12
HBA1C and CVD
In ACCORD study, patients showed increased
mortality when randomized to intensified
treatment regimens that targeted normal A1C
levels (<6.0%) with one or more of
the following drugs taken alone or in
combination: metformin, SFUs, TZDs, and
insulin
HbA1C target in patients with
CVD
Higher HbA1c goals (7.5–8.0%) or even
slightly higher are appropriate for patients
with a history of severe hypoglycemia,
limited life expectancy, advanced
complications , established vascular disease
Diabetes Care June 2012 , 6 1364-1379
Sulfonylureas
• These agents induce closure of the adjacent
potassium ATP-dependen receptors.While
SUR1 is expressed in beta cells, SUR2A are
expressed in cardiomyocytes.
• The K- ATP channel in cardiomyocytes has
an important function in its adaptation to
cardiac ischemia.
• Detrimental effect of Glibenclamide has
been shown on cardiomyocyte adaptation
to ischemia in animal models
DIABETES CARE, 2009,s337-341
Sulfonylureas
• In the UKPDS, combination therapyof
metformin and sulfonylureas was associated with an increased risk of fatal MI
(HR 1.79)
• In a recent cohort study, sulfonylurea
therapy was associated with 2.1 and 1.3
increased cardiovascular mortality with a
for older sulfonylurea agents and
glibenclamide respectively
Sulfonylureas
• The second mechanism for the higher risk
of adverse cardiovascular effects associated
with sulfonylurea involves
hypoglycaemia—a common, well known
adverse effect of sulfonylurea treatment.
• Episodes of hypoglycaemia can prolong the
QT interval and are associated with cardiac
ischaemia
Sulfonylureas
• The third cause could be attributed to the
weight gain and worsening obesity ,
together with the adverse consequences of
this undesirable side effect
All-cause mortality and
sulfonylureas
Lancet Diabetes Endocrinol 2014
Cardiovascular mortality and
sulfonylureas
Lancet Diabetes Endocrinol 2014
• Several limitations should be considered
when interpreting our findings:
First and foremost, selection bias could
have affected the reported associations
because data for these network meta-analyses
were taken mainly from cohort studies.
Glibenclamide & Glipizide : Interact with the cardiac and
vascular SUR2A/B
Glimepiride & Gliclazide : show very little interaction with
SUR2A/B
Metformin
UKPDS
Metformin Substudy Design
Aim: to determine effect of metformin on outcome in
overweight patients with type 2 diabetes
Main Randomization
4209
Overweight
1704
Conventional Policy
411
Nonoverweight
2505
Intensive Policy
1293
Insulin or Sulfonylurea
951
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
Metformin
342
Metformin: post trial study
• In the UKPDS, Metformin monotherapy in
conjunction with diet decreased MI rates by
39% , compared with conventional therapy
alone in overweight patients
• Increased insulin sensitivity and enhanced
fibrinolytic activity are possible
explanations for this beneficial effect
Thiazolidinediones
Mechanism of action
Thiazolidinediones
• In PROactive study pioglitazone was
examined for secondary prevention in
patients with established macrovascular
disease.
• Post hoc analysis of the subgroup with
previous MI demonstrated significant risk
reduction of recurrent MI, or acute coronary
syndrome
Thiazolidinediones
• Pioglitazone therapy is associated with
reduced carotid IMT and reduced stent
restenosis
• However, cardiovascular outcome results
can not be extrapolated from these data
Thiazolidinediones
• The meta-analysis by Nissen demonstrated
an increased incidence of MI in patients
treated with rosiglitazone Although not
statistically non-significant, a trend of
increased cardiovascular death (P 0.06) is a
cause for concern.
• In a subsequent meta-analysisby Singh et al.
the data on increased MI was confirmed
Weight gain, Edema & CHF with
thiazolidinediones
Weight gain
Median weight gains with pioglitazone of 0.9,
1.0, and 2.6 kg at the 15, 30, and 45mg daily
doses, respectively
When pioglitazone added to insulin: Median
weight gains of 2.3 and3.6 kg (or as high as
5.4 kg in some studies) occurred at 15
and 30 mg daily
Edema
• Mono-therapy: the incidence of pedal
edema ranges from 3% to 5% for each of
the TZDs.
• The incidence is greater when the drugs are
used in combination with other glucose
lowering agents (6-7.5% with other OHA
and 15% with insulin)
• Higher incidence (up to 18%) when older
age or comorbidities (HTN,IHD,CRF)exist
DIABETES CARE,2004,27,256-263
Causes of edema
• Increased plasma volume : may result from a
reduction in renal excretion of sodium
• TZDs may interact synergistically with insulin to
cause arterial vasodilatation, leading to sodium
reabsorption.
• Increased sympathetic nervous system activity
endothelial permeability
DIABETES CARE,2004,27,256-263
CHF
• In clinical trials using TZDs, the incidence
of CHF was 1% for rosiglitazone
monotherapy or in combination with
sulfonylurea or metformin, and was similar
to thatobserved during treatment with a
placebo
DIABETES CARE,2004,27,256-263
CHF in combination with insulin
• Combination therapy of rosiglitasone 4mg
or 8mg with insulin : CHF increased to 2%
and 3% , respectively ( compared with 1%
in the group treated with insulin alone)
TZD in patients with CHF
in another observational analysis of patients with
class I to III CHF, and an ejection fraction of <45%
who were treated with thiazolidinedione over a 2year period.
Fluid retention: 17%
Worsening CHF: 5.4% (worsening jugular venous
distension)
J Am Coll Cardiol41:1394–1398, 2003
PATHOGENESIS OF CHF
WITH TZD USE
• Increase in plasma volume is the main
pathophysiology, either alone or
superimposed on preexisting heart disease
• Pioglitazone to a maximum dose of 60 mg
q.d. for up to 48 weeks had no adverse
effect on cardiac structure and function as
evaluated by echocardiography.
Diabetes 2000-(Suppl.1):A124
• Indeed ,improvement of left ventricular
remodeling and partially normalized
systolic function in mice after extensive
anterior myocardial function after receiving
pioglitazon is reported
Circulation106:3126–3132, 2002
Recommendation
Instruct the patient to report any new sign or
symptom during the course of treatment:
• Weight gain 3 kg
• Pedal edema (particularly if the onset is
acute and the amount progresses rapidly)
• Shortness of breath or fatigue without other
apparent cause
Use of TZDs in Patients With
Heart Disease
In patients who are not functional class III &
IV CHF but are known to have a depressed
ejection fraction (e.g <40%), TZDs may be
used at the lower dosage range of each drug
and increased gradually during months with
monitoring edema and other symptoms of
CHF
DPP-IV inhibitors
Diabetes is a Multi-System Disorder:
“The Incretin Effect”
Liver
Pancreas
Suppressed postprandial glucagon
Decreased Glucose
Output
Enhanced
Insulin
secretion
GLP-1
release
Food
GLP-1 and other gut
hormones released in
response to food:
“entero-insular axis”
This ability is reduced or
lost in type 2 diabetes
Slowed gastric
emptying
Increased
Satiety
Actions of GLP-1
The Problem
• Unfortunately, GLP-1 is rapidly broken down
by the DPP-IV enzyme (very short half-life in
plasma - requires continuous IV infusion).
Who is ideal candidate for using
DPP-4 Inhibitors?
• Excellent in patients with mild
hyperglycemia(especially postprandial
hypoglycemia) requiring insulin secretagogue
• Can be used in renal insufficiency without risk
of hypoglycemia or lactic acidosis
• Patients with heart failure ( no risk of edema or
lactic acidosis)
• Regarding relative short history of GLP1
and DDP4 inhibitors compared with other
OAD, safety issues do not completely
understood.
GLP-1 and heart
Data from animal models and pilot clinical
studies have indicated that native GLP-1 may
have cardioprotective effects in the setting of
ischaemia, or following ischaemic injury
Cardiovascular Diabetology2013,12:130
DPP-4 inhibitors and HEART
• DPP-4 inhibitors do not have major effects
on weight
• Limited evidence suggests that sitagliptin
may reduce systolic blood pressure
• Can reduce postprandial hyperlipidemia
• These drugs are not associated with QT
interval prolongation
DPP-4 inhibitors and HEART
• Data about long term effects of DPP-IV
inhibitors and cardiac outcome are very
limited
Key massages
• Hb A1C target is higher in patients with CVD.
• Sulfonylureas (especially older generations ) may
has detrimental effect on CVD events
• Metformin has beneficial long term effect on MI
rate and all cause mortality
• Data shows beneficial effects of pioglitazone on
surrogate cardiac outcomes
• Data about DPP-4 inhibitors is very limited