cvsdm-150402063915-conversion-gate01.pdf

DIABETES AND
CARDIOVASCULAR DISEASE
DR VISHWANATH HESARUR
SENIOR RESIDENT
DEPARTMENT OF CARDIOLOGY
JNMC , BELGAUM

DIABETES MELLITUS
 Diabetes mellitus (DM) refers to a group of common
metabolic disorders that share the phenotype of
hyperglycemia.
 Several distinct types of DM are caused by a complex
interaction of genetics and environmental factors.
 Depending on the etiology of the DM, factors contributing
to hyperglycemia include reduced insulin secretion,
decreased glucose utilization, and increased glucose
production.
 The metabolic dysregulation associated with DM causes
secondary pathophysiologic changes in multiple organ
systems that impose a tremendous burden on the
individual with diabetes and on the health care system.

Classification
 DM is classified on the basis of the pathogenic
process that leads to hyperglycemia .
 The two broad categories of DM are designated type 1
and type 2
Spectrum of glucose homeostasis and DM

EPIDEMIOLOGY
 The worldwide prevalence of DM has risen
dramatically over the past two decades, from an
estimated 30 million cases in 1985 to 285 million in
2010.
 The International Diabetes Federation projects that
438 million individuals will have diabetes by the year
2030
Indian
 40.9 million people in 2001.
 By the year 2025, 80.9 million will have diabetes in
India.
 There is still inadequate population-based data on
the prevalence of CAD in India, particularly
comparing diabetic and nondiabetic subjects.

CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUS
 Symptoms of diabetes plus random blood glucose
concentration 11.1 mmol/L (200 mg/dL)aor
 Fasting plasma glucose 7.0 mmol/L (126 mg/dL)bor
 A1C > 6.5%cor
 Two-hour plasma glucose 11.1 mmol/L (200 mg/dL)
during an oral glucose tolerance testd

CARDIOVASCULAR DISEASE IN DIABETES
 Account for most morbidity and mortality in patients with
diabetes mellitus.
 Diabetic subjects are known to have a two to four times
increased CAD risk, and CAD has been reported to occur
two to three decades earlier in diabetic subjects as
opposed to their nondiabetic counterparts.
 Diabetes causes microvascular diseases, such as
nephropathy, neuropathy, and retinopathy, and
macrovascular disease (e.g., atherosclerosis).
 Atherosclerosis of the coronary, cerebral, and peripheral
arteries accounts for approximately 80 percent of
mortality and for 75 percent of hospitalizations in persons
with diabetes.

 As type 2 diabetes shares several risk factors in
common with coronary artery disease (CAD), such as
age, hypertension, dyslipidemia, obesity, physical
inactivity, and stress, an increase in the prevalence of
diabetes indirectly implicates an escalating risk of
CAD as well.

Indians
 India is predicted to bear the greatest CAD burden,
according to the estimates from the Global Burden of
Disease Study.
 Of the more than 9 million deaths due to CAD in 2005
in developing countries, 2.4 million (25%) occurred in
India.
 The mortality rates in India due to acute myocardial
infarction (MI) were 141 per 100,000 in males and 136
per 100,000 in females
 A matter of serious concern is that 52% of the CAD
deaths in India occurred in people aged below 70 years,
while the same was just 22% in developed countries.

ATHEROSCLEROSIS
 Compared with
nondiabetic individuals,
patients with diabetes
have a twofold to fourfold
increased risk for
development and dying of
CHD
Preis SR, Hwang SJ, Coady S, et al: Trends in
all-cause and cardiovascular disease
mortality among women and men with and
without diabetes mellitus in the Framingham
Heart Study, 1950 to 2005. Circulation
119:1728, 2009.)

 Whereas older studies have suggested a diabetes-
associated CVD risk similar to that observed among
nondiabetic patients with a prior myocardial
infarction (MI)—that is, a “coronary disease
equivalent”—more recent observations from clinical
trials including patients with diabetes suggest a
substantially lower CHD risk, most likely reflecting
the effectiveness of contemporary therapeutic
interventions.

 Diabetes is associated with an increased risk for MI; and
across the spectrum of acute coronary syndrome (ACS)
events, in which diabetes may affect more than one in
three patients, patients with diabetes have worse CVD
outcomes after ACS events
TRITON–TIMI 38 randomized trial.

Cardiovascular medicine at the turn of the
millennium: Triumphs, concerns, and
opportunities. N Engl J Med 337:1360, 1997.

 In addition to CHD, diabetes increases the risks of
stroke and peripheral arterial disease.
 Two fold increased stroke risk compared with
nondiabetic individuals , with hyperglycemia
affecting approximately one in three patients with
acute stroke, associated with a twofold to sixfold
increased risk for adverse clinical outcomes after
stroke.
 Among patients with symptomatic peripheral arterial
disease, diabetes prevalence ranges from 20% to 30%
and accounts for approximately 50% of all lower
extremity amputations.

 Heart Failure
 Diabetes associates independently with a twofold to
fivefold increased risk of heart failure (HF) compared
with those without diabetes, comprising both systolic
and diastolic HF, and diabetes patients have worse
outcomes once HF has developed and an increased
HF risk in the setting of ACS events.
 The increased risk of HF observed in diabetes is
multifactorial, caused by ischemic, metabolic, and
functional myocardial perturbation.s

PATHOPHYSIOLOGY OF DIABETIC VASCULAR
DISEASE
Adipocyte Biology and Inflammation
 We increasingly recognize the role of inflammation in
the pathogenesis of diabetes and the metabolic
syndrome.

 The adipocyte, long regarded as a storage depot for
triglycerides, actually can generate substantial
quantities of proinflammatory mediators, such as tumor
necrosis factor-alpha (TNF-α)
 TNF-α can cause insulin resistance and can thus causally
link adiposity to diabetes.
 TNF-α and allied proinflammatory cytokines derived
from the adipocyte can activate vascular endothelial and
smooth muscle cells to provoke aspects of vascular
dysfunction.
 In this manner, adipocyte products can directly
promote vascular dysfunction and hasten atherogenesis

Diabetic Metabolic and Vascular Dysfunction
 Diabetes causes metabolic abnormalities, including
hyperglycemia, dyslipidemia, and insulin resistance,
that disrupt normal arterial function and render arteries
susceptible to atherosclerosis.
 It specifically alters the function of vascular
endothelium and smooth muscle cells, as well as
platelets, in ways that promote atherogenesis.
 Diabetes impairs the vasodilator function of endothelial
cells and decreases the bioavailability of nitric oxide
(NO).

Orasanu G, Plutzky J: The pathologic continuum of diabetic
vascular disease. J Am Coll Cardiol 53:S35, 2009

 Hyperglycemia decreases NO production from endothelial
nitric oxide synthase (eNOS) and increases its degradation
via generation of reactive oxygen species (ROS).
 Recent evidence suggests that hyperglycaemia-induced
ROS generation is involved in the persistence of vascular
dysfunction despite normalization of glucose levels. This
phenomenon has been called ’metabolic memory’ and
may explain why macro- and microvascular complications
progress, despite intensive glycaemic control, in patients
with DM.
 Hyperglycemia triggers the production of ROS in vascular
cells through enzymatic (protein kinase C and the reduced
form of nicotinamide adenine dinucleotide phosphate
[NADPH] oxidases) and nonenzymatic sources of oxidant
stress (e.g., the formation of advanced glycation end
products, AGEs).

 As oxidative stress increases, the eNOS cofactor
tetrahydrobiopterin becomes oxidized and uncouples
eNOS, which cause the enzyme to produce superoxide
anion instead of NO
 Superoxide anion quenches NO in a diffusion-limited
reaction to produce peroxynitrite.
 Peroxynitrite inhibits prostacyclin synthase and
endothelium-dependent hyperpolarizing factor activity.
 Similar to the effects of hyperglycemia, free fatty acids
activate intracellular enzymatic oxidant sources, including
protein kinase C, NADPH oxidases, and eNOS, yielding
analogous increases in superoxide anion

 The excess adipose tissue that usually accompanies
type 2 diabetes mellitus releases excess fatty acids.
 Free fatty acids attenuate prostacyclin bioavailability
by inhibiting prostacyclin synthase.[34]
 Moreover, free fatty acids interfere with intracellular
signaling pathways to cause not only muscle and
visceral insulin resistance but also vascular insulin
resistance.
 In diabetes, hyperglycemia and increased free fatty
acids increase the concentration in the cell of the
metabolite diacylglycerol.
 Diacylglycerol, in turn, activates a family of enzymes
known as protein kinase C (PKC), that perform key
regulatory functions by phosphorylating proteins
important in metabolic control.

 Activation of PKC can inhibit the expression of
eNOS, augment cytokine-induced tissue factor gene
expression and procoagulant activity in human
endothelial cells, and increase the production of
proinflammatory cytokines, proliferation of vascular
wall cells, and production of extracellular matrix
macromolecules that accumulate during
atherosclerotic lesion formation.

 Diabetes also disturbs vascular function through
nonenzymatic glycation of macromolecules.
 In states of hyperglycemia and increased oxidative
stress, many proteins and even lipids undergo
nonenzymatic glycation
 Glycated proteins can form structures known as AGEs
that cause the macromolecule to take on a brown hue,
similar to burnt sugar.
 AGEs accumulate in the vessel wall and appear to
contribute to the pathobiology of complications of
diabetes, notably the accelerated vascular disease
characteristic of this condition.

 Phospholipids and apolipoproteins can form AGEs
and AGE-modified proteins can accumulate in
diabetic subjects.
 The presence of glycated forms of low-density
lipoproteins (LDLs) can engender an immune
response and contribute to macrovascular disease.
 AGE-modified LDL apoprotein and LDL lipid levels
increase in diabetic subjects compared with
nondiabetics
 Increased AGE production is associated with reduced
nitric oxide bioavailability through impairment of
eNOS transcription and activity, production of
oxygen-derived free radicals, and activation of NF-kB.

 Diabetes impairs vascular smooth muscle function
and augments the production of vasoconstrictor
mediators, angiotensin II and vasoconstrictor
prostanoids, including endothelin-1, which causes
vascular smooth muscle growth and inflammation.
 However, most diabetics have peripheral autonomic
impairment at the time of diagnosis, and vascular
beds regulated by these nerves have decreased
arterial resistance

 Similar to endothelial cells, diabetes activates
atherogenic mechanisms within vascular smooth muscle
cells, including protein kinase C, RAGE, NF-kB and the
production of oxidative stress.[30]
 Diabetes heightens vascular smooth muscle cell
migration in atherosclerotic lesions.
 Advanced atherosclerotic lesions have fewer vascular
smooth muscle cells in diabetic patients than
nondiabetic patients, possibly resulting in decreased
resiliency of the fibrous cap and thereby increasing the
risk of rupture and luminal thrombi

Platelet abnormalities
Colwell JA, Nesto RW: The platelet in diabetes: Focus on prevention of
ischemic events. Diabetes Care 26:2181, 2003.

 Type 2 diabetes and its associated metabolic abnormalities
favor an imbalance in the coagulation and fibrinolytic
systems that support clot formation and stability.
 Type 2 diabetes increases plasminogen activator inhibitor
type 1 (PAI-1) levels, impairing fibrinolytic capacity in
atherosclerotic lesions.
 Moreover, diabetes increases the expression of tissue factor
and levels of plasma coagulation factors, and decreases
levels of endogenous anticoagulant.

 These abnormalities include increased circulating
tissue factor, factor VII, von Willebrand factor, and
plasminogen activator inhibitor 1, with decreased
levels of antithrombin III and protein C.
 In addition, disturbances of platelet activation,
aggregation, morphology, and life span further
contribute to increased thrombotic potential, as well
as to the acceleration of atherosclerosis

ANATOMIC CHARACTERISTICS OF ATHEROSCLEROTIC
DISEASE DEVELOPMENT
 Postmortem studies have documented a more diffuse
distribution of atherosclerotic changes with
increased overall atherosclerotic disease burden in
subjects who had diabetes
 The qualitative morphologic differences between
plaques in diabetic and nondiabetic subjects are
believed to be small, however .

 In atherectomy specimens of coronary arteries’ cell-
rich areas, the extent of the necrotic plaque core,
calcification, and thrombus were increased in
patients who had type 2 diabetes
 These characteristics are likely associated with the
formation of vulnerable plaques and plaque rupture;
diabetes also affects repair mechanisms after plaque
disruption .
 Postmortem studies demonstrated an increased
frequency of healed ruptures in patients who had
type 2 diabetes and died from acute coronary events

 Macroscopic postmortem studies documented the
earlier and more diffuse distribution of
atherosclerotic changes in subjects who had diabetes
 The atherosclerotic changes in diabetic subjects are
not fundamentally different from those in
nondiabetics, but occur at younger age and progress
more rapidly.
 The traditionally angiographic observation of ‘‘small
coronary vessels’’ in diabetics likely reflects the
advanced, diffuse involvement of these patients at the
time of coronary angiography.

CLINICAL MANIFESTATIONS OF ATHEROSCLEROSIS
IN DIABETES
 Coronary Artery Disease
 2- to 4-fold increase in the risk of developing
coronary artery disease.
 type 2 diabetes mellitus was accorded a coronary
artery disease risk-equivalent.
 In patients with known coronary artery disease and
diabetes, the rates of death approach 45% over 7 years
and 75% over 10 years.
 Outcomes are worse in diabetic patients for each
manifestation of coronary artery disease.

 In the Organization to Assess Strategies for Ischemic
Syndromes (OASIS) registry, a 6-nation unstable
angina outcome study, diabetes increased mortality
by 57%.
 The SHOCK (SHould we emergently revascularize
Occluded Coronaries for cardiogenic shocK) trial of
revascularization found a 36% increase in death in
diabetic patients with cardiogenic shock
complicating myocardial infarction.
 After myocardial infarction has occurred, the 1-
month mortality rate is increased in diabetic patients
by 58%.
 Approximately 50% of diabetic patients die 5 years
after a myocardial infarction, double the rate found
in nondiabetic patients.

 Cerebrovascular Disease
 Diabetes increases the risk of stroke.
 For example, the risk of stroke among patients taking
hypoglycemic medications was increased 3-fold
among the nearly 350 000 men in the Multiple Risk
Factor Intervention Trial.
 In the Baltimore-Washington Cooperative Young
Stroke Study, stroke risk increased more than 10-fold
in diabetic patients younger than 44 years of age,
ranging as high as 23-fold in young white men.
 Diabetes also increases stroke related mortality,
doubles the rate of recurrent stroke, and trebles the
frequency of stroke-related dementia.

 Peripheral Arterial Disease
 Diabetes increases the incidence and severity of limb
ischemia approximately 2- to 4-fold.
 Data from the Framingham cohort and Rotterdam
studies show increased rates of absent pedal pulses,
femoral bruits, and diminished ankle-brachial
indices.
 Diabetic peripheral arterial disease often affects
distal limb vessels, such as the tibial and peroneal
arteries, limiting the potential for collateral vessel
development and reducing options for
revascularization.
 As such, patients with diabetes are more likely to
develop symptomatic forms of the disease, such as
intermittent claudication and critical limb ischemia,
and undergo amputation.

 In the Framingham cohort, the presence of diabetes
increased the frequency of intermittent claudication
by more than 3-fold in men and more than 8-fold in
women.
 Diabetes is the most common cause of nontraumatic
amputations in the United States.

LIPID AND LIPOPROTEIN ABNORMALITIES IN NIDDM
VLDL More of large VLDL consequent
of poor clearance- more of
circulatingApoB100
IDL increased
LDL More of unesterified cholesterol,
prolonged half ,life higher
quantities of circulating small
dense LDL
HDL Normal or raised but may be low
in obese patients with
hypercholesterolemia
Triglycerides Increased
Cholesterol May be increased or normal

LIPID AND LIPOPROTEIN ABNORMALITIES IN IDDM
VLDL Increased
LDL Marginally raised
HDL Low or Normal
Triglycerides Increased
Cholesterol Esterified Cholesterol is
diminished

PREVENTION OF CORONARY HEART DISEASE AND ITS
COMPLICATIONS IN THE SETTING OF DIABETES
 Therapeutic lifestyle interventions
 The ADA/AHA overarching therapeutic lifestyle
targets include

 Alcohol : Moderate amounts, not exceeding two
glasses or 20 g/day for men and one glass or 10 g/day
for women.
Beyond lifestyle
 Lipid management
 Blood pressure control
 Aspirin therapy
 Glucose managemaent

LIPID THERAPY
 Insulin resistance and type 2 diabetes – dyslipidemia
 Despite extensive research in modifying triglyceride
and HDL cholesterol levels with a variety of
pharmacologic agents, however, the net influence on
CVD risk of these strategies remains uncertain, and
the modification of LDL cholesterol remains the
cornerstone of therapeutic lipid intervention in
patients with diabetics

Guidelines of the ADA/AHA
 The target lipid values in diabetic individuals (age
>40 years) without cardiovascular disease should be
as follows:
 LDL < 2.6 mmol/L (100 mg/dL)
 HDL >1 mmol/L (40 mg/dL) in men and >1.3 mmol/L (50
mg/dL) in women; and
 Triglycerides < 1.7 mmol/L (150 mg/dL).
 In patients >40 years, addition of a statin, regardless
of the LDL level in patients with CHD & those
without CHD, but who have CHD risk factors.
 If the patient is known to have CHD, the LDL goal of
<1.8 mmol/L (70 mg/dL) as an "option"

ADA GUIDELINES: MAJOR STATIN TRIALS OR SUB-STUDIES IN
DIABETIC PATIENTS
Lancet 2004;364:685
Diabetes Care 2006;29:1220
Lancet 2003;361:2005
*Num. needed to treat (NNT) for moderate-high risk DM to avoid one
death or MI:
3-50
ADA Standards of Care; Diabetes Care, January 2011

Omega-3 Fatty Acids
 Predominantly fish oil preparations – lower
triglycerides by up to 40%
 Absence of interactions with statins
 Add-on therapy to statins
 Minimal effects on HDL and total cholesterol and
modestly raises LDL with no adverse glycemic effects.

The Japan EPA Lipid Intervention Study (JELIS)
 4565 patients
 Randomized trial comparing treatment with 1800 mg
of eicosapentaenoic acid (EPA) plus simvastatin 5mg
daily versus simvastatin 5mg alone.
 In this subset, EPA treatment conferred a 22% risk
reduction (P = 0.048) for major adverse CVD events
compared with simvastatin alone.
 On the basis of the accumulated data, fish oil has
emerged as the primary consideration for add-on
therapy in patients with diabetes who do not achieve
non-HDL targets with maximally tolerated statin
monotherapy.

Fibric Acid Derivatives (Fibrates)
 Agonists of PPAR α that lower triglycerides and
modestly increase HDL cholesterol.
The Fenofibrate Intervention and Event Lowering
in Diabetes (FIELD) trial
 9795 patients with type 2 diabetes
 fenofibrate versus placebo
 failed to demonstrate a statistically significant
reduction in the primary endpoint of coronary death
or nonfatal MI, despite accumulating 544 primary
outcome events for evaluation (5.2% versus 5.9%; HR
= 0.89; 95% CI, 0.75-1.05).

 ACCORD-Lipid trial
 5518 patients with type 2 diabetes at high
cardiovascular risk
 Fenofibrate, compared with placebo each added to
simvastatin background therapy,
 Failed to yield significant improvements on MACE
despite the accumulation of 601 primary endpoint
events of CV death, MI, and stroke

Summary - fibrates remain an option
 Intolerance to statin medications
 Isolated hypertriglyceridemia in diabetic patients at
otherwise low CVD risk, and
 As add-on therapy to maximally tolerated statin
monotherapy when patients do not achieve
therapeutic targets (noting some increased myopathy
risk).

Niacin
 Potent modulator of lipid metabolism
 Greatest effect : Increases HDL-cholesterol while
lowering triglycerides.
 However, the net CVD effects and safety of niacin,
especially in the context of background statin
therapy, remain to be determined.
 A recent meta-analysis estimated a 27% relative risk
reduction associated with niacin in the absence of
statin background therapy.

Summary - niacin remains an option
 Intolerance to statin medications
 Isolated hypertriglyceridemia in diabetic patients
with an otherwise low CVD risk, and
 As add-on therapy to maximally tolerated statin
monotherapy when patients do not achieve
therapeutic targets

RECOMMENDATIONS ON MANAGEMENT OF
DYSLIPIDAEMIA IN DIABETES

HYPERTENSION
 Hypertension affects approximately 70% of diabetic
patients with a steep graded association between blood
pressure and adverse cardiovascular outcomes
 Numerous classes of antihypertensive medications reduce
both macrovascular and microvascular disease
complications, blood pressure management is of principal
importance in this high-risk population.
 Blood pressure goal of <130/80 mm Hg.

 Adler AI, Stratton IM, Neil HA, et al:
Association of systolic blood
pressure with macrovascular and
microvascular complications of type
2 diabetes [UKPDS 36]: Prospective
observational study. BMJ 321:412,
2000.

 Hypertension
Optimal
Treatment (HOT)
trial

 ACCORD trial
 4700 patients were assigned to intensive- (achieved
mean systolic blood pressure 119 mm Hg) or standard
treatment [mean systolic blood pressure (BP) 134
mmHg]
 mean follow-up of 4.7 years

ACCORD BP: Using an average of 3 drugs, the authors achieved a SBP of 119
mmHg vs. 133 mmHg

ACCORD BP: Results
Conclusions: “In patients with type 2 diabetes at high risk for cardiovascular
events, targeting a systolic blood pressure of less than 120 mmHg, as
compared with less than 140 mmHg, did not reduce the rate of fatal and
nonfatal major CVD events.”

Antagonists of the Renin-Angiotensin-Aldosterone
System (RAAS)
 ACE inhibitors and ARBs have become keystones of
therapy for hypertension in diabetes
ACE Inhibitors
 The recommendation for ACE inhibitors as first-line
hypertension therapy in the setting of diabetes is
supported by data from randomized trials of patients
with and without hypertension.

 In the Heart Outcomes Prevention Evaluation
(HOPE) study
 Ramipril versus placebo among patients at increased risk
for CVD,
 Ramipril was superior to placebo in the diabetes subset of
3577 HOPE patients for the primary outcome of
cardiovascular death, MI, and stroke (25% RRR; P = 0.004)
and for overt nephropathy (24% RRR; P = 0.027).
 Similar observations derive from the diabetes subanalysis
of the EUROPA trial,
 Perindopril versus placebo
 19% RRR among the 1502 participants with diabetes was
similar to the 20% risk reduction observed in the overall
trial.

Angiotensin II Receptor Blockers
 The Telmisartan Randomized AssessmeNt Study
in ACE iNtolerant subjects with cardiovascular
Disease (TRANSCEND) trial
 5926 patients with intolerance to ACE inhibitors,
 Randomized to telmisartan 80 mg daily versus
placebo, including 2118 patients with diabetes.
 In the overall trial, telmisartan failed to achieve
statistical superiority over placebo in reducing the
primary composite of CVD death, MI, stroke, or HF
hospitalization (HR = 0.92; 95% CI, 0.81-1.05),
 But it significantly reduced the secondary composite
of CV death, MI, or stroke (HR = 0.87; 95% CI, 0.76-
1.00).

Calcium Channel Blockers
 Dihydropyridine calcium channel blockers, such as
nifedipine, nitrendipine, and amlodipine, are well
tolerated and effective at lowering blood pressure.
 In active controlled comparisons, amlodipine has
been proven superior to hydrochlorothiazide when it
is added to a background of benazepril therapy,
 But in randomized trials directly comparing the
efficacy of calcium channel blockers versus ACE
inhibitors, superior outcomes were observed with
ACE inhibitors

Beta Blockers
 Another key component of effective CVD risk
reduction in diabetes.
 Mask hypoglycemia symptoms and adverse effects on
glucose and lipid metabolism.
 These concerns have been mitigated by the results of
CVD outcomes trials supporting the benefit of beta
blockers for patients with diabetes in the chronic
ambulatory setting and in the post-ACS population.
 Metabolic effects of various beta blockers differ,
which suggests improved metabolic parameters with
non cardioselective beta blockers that also have alpha
receptor–blocking properties; the clinical relevance
of these differential effects remains to be determined.

Combination Therapy for Hypertension
 In the Action in Diabetes and Vascular disease:
preterAx and diamicroN-MR Controlled
Evaluation (ADVANCE) trial
 11,140 patients with type 2 diabetes
 Compared combination therapy with perindopril and
indapamide versus placebo
 9% relative reduction in a composite primary
outcome combining microvascular and
macrovascular disease endpoints, compared with
placebo.

 In the Anglo-Scandinavian Cardiac Outcomes
Trial–Blood Pressure Lowering Arm (ASCOT-
BPLA),
 923 patients
 which randomized treatment to amlodipine with
perindopril added as needed versus atenolol with
bendroflumethiazide added as needed,
 The amlodipine-perindopril combination yielded a
significant 13% relative risk reduction (P = 0.028) in
major CVD outcomes in with diabetes, compared
with atenolol-bendroflumethiazide.

 The Avoiding Cardiovascular Events through
Combination Therapy in Patients Living with
Systolic Hypertension (ACCOMPLISH) trial
 the 6946 patients with diabetes
 All patients were treated with benazepril, with
randomization to add-on amlodipine versus add-on
hydrochlorothiazide, treatment with benazepril-
amlodipine versus benazepril-hydrochlorothiazide
was associated with a 21% reduction in CVD
outcomes among (60.4% of the study cohort; P =
0.003).
 Therefore, in combination with thiazide diuretics
and with amlodipine, ACE inhibitors are associated
with improved CVD outcomes, with the combination
with amlodipine proving superior in head-to-head
comparison.

 Likewise, the average systolic blood pressure
achieved in the diabetic subset of HOPE
(139/77 mm Hg) and in the ADVANCE trial
(136/73 mm Hg) provide further support for the
safety and efficacy of such intensified blood pressure
targets in the high-risk population of patients with
DM.

Antihypertensive Therapy Summary
 In summary, five classes of medications have
substantial evidence basis for CVD efficacy in the
setting of diabetes, including ACE inhibitors, calcium
channel blockers, beta blockers, thiazide diuretics,
and ARBs.
 Evidence supports an aggressive blood pressure
target of <130/80 mm Hg for patients with diabetes to
achieve optimal CVD risk mitigation, with most
patients requiring a combination of multiple blood
pressure medications to achieve such targets.

RECOMMENDATIONS FOR BLOOD PRESSURE CONTROL IN
DIABETES

ANTIPLATELET THERAPY
 Patients with diabetes have a number of aberrations
of platelet structure, function, and activity, yielding
in aggregate a prothrombotic milieu.
 Aspirin Therapy
 The ADA/AHA presently recommend daily aspirin
(75 to 162 mg/day) for all patients with diabetes who
have prevalent CVD or for primary prevention in all
patients older than 40 years with additional CVD risk
factors (or younger in the presence of prevalent CVD
risk).

 Absolute or relative aspirin resistance- 40% of
patients with increasing prevalence associated with
poor metabolic control.
 On the basis of this ongoing uncertainty with regard
to the role of aspirin in the setting of primary CVD
risk prevention in type 2 diabetes, two large-scale
randomized clinical trials are currently under way

 A Study of Cardiovascular Events In Diabetes
(ASCEND) plans to enroll 10,000 patients with type 1
or type 2 diabetes without CVD, randomized
factorially to treatment with 100 mg acetylsalicylic
acid (ASA) daily versus placebo or with omega-3 fatty
acid 1 g daily versus placebo, with a primary endpoint
of major adverse cardiovascular events .
 The Aspirin and Simvastatin Combination for
Cardiovascular Events Prevention Trial in
Diabetes (ACCEPT-D) plans to enroll 4700 patients
with type 1 or type 2 diabetes to receive 100 mg ASA
plus simvastatin versus simvastatin alone in a
prospective, open-label, blinded endpoint evaluation
(PROBE) design trial to assess the cardiovascular
efficacy of ASA in primary prevention for patients
with diabetes that has been treated with statins

 Thienopyridines
 The thienopyridines irreversibly bind to P2Y12 ADP
receptors and inhibit ADP-induced activation of
glycoprotein (GP) IIb/IIIa, preventing the binding of
fibrinogen and platelet thrombus formation, thus
yielding more potent antiplatelet effects than
achieved with aspirin alone.

 The CAPRIE trial
 Compared outcomes in patients with NSTEMI ,
ischemic stroke, or established PAD randomized to
treatment with aspirin versus clopidogrel,
 3866 patients with diabetes were enrolled.
 In the subset of patients with diabetes, the 12.5%
reduction in major adverse CVD events with
clopidogrel versus aspirin was comparable to the
effect observed in the overall study cohort.
 Given the incremental expense of clopidogrel and
its associated increment in bleeding risk, however,
this strategy is not routinely recommended over the
use of aspirin alone for most patients.

 Increased prevalence of resistance to clopidogrel, a
prodrug requiring metabolic conversion that appears
to be impaired in diabetes, resulting in decreased
circulating active metabolite.
 These observations have led some investigators to
explore the effects of increased dosing of clopidogrel
in patients with diabetes, with preliminary data
suggesting increased antiplatelet effects with such a
strategy.
 However, the net clinical safety and efficacy of
increased dosing of clopidogrel requires further
evaluation before application in clinical practice.

RECOMMENDATIONSFOR ANTIPLATELET THERAPY IN PATIENTS
WITH DIABETES

GLUCOSE MANAGEMENT
 Drug classes - oral and injectable glucose-
lowering medications approved for clinical
use
 These drugs work by
 Stimulating endogenous insulin release,
 Impairing hepatic glucose production,
 Improving the body's response to insulin, or
 Delaying intestinal carbohydrate absorption.

UKPDS 34, Lancet 352: 854, 1998
UKPDS METFORMIN SUB-STUDY:
CHD EVENTS
Myocardial Infarction
0
5
10
15
20
Incidence
per
1000
patient
years
Conventional
Diet
Insulin
SU’s
Metformin
p=0.01
NS
39%
Reduction
Coronary Deaths
0
2
4
6
8
10 p=0.02
50%
Reduction
Metformin
Conventional
Diet
n= 411 951 342 411 342
#Events 73 139 39 36 16

Cardiovascular Effects of Intensive Glucose Control
Strategies
 UKPDS randomized 5102 patients with newly
diagnosed type 2 diabetes to intensive glucose
control with sulfonylurea or insulin compared with
diet alone; those overweight at study entry (n = 795)
could also be randomized in the intensive arm to
receive metformin.

TYPE 2 DIABETES:
A1C PREDICTS CHD
CHD Mortality Incidence
(%) in 3.5 Years
All CHD Events Incidence
(%) in 3.5 Years
A1C=hemoglobin A1C
*P<0.01 vs lowest tertile
**P<0.05 vs lowest tertile
0
2
4
6
8
10
12
Low
<6%
High
>7.9%
*
Middle
6-7.9%
0
5
10
15
20
25
Middle
6-7.9%
High
>7.9%
**
Low
<6%
Adapted with permission from Kuusisto J et al. Diabetes. 1994;43:960-967.

P=0.03
P<0.01
P<0.01
P=0.05
P=0.02
UKPDS Group. Lancet. 1998;352:837-853.
UKPDS RELATIVE RISK REDUCTION
FOR INTENSIVE VS. LESS INTENSIVE GLUCOSE CONTROL
Over 10 years, HbA1c was 7.0% (6.2-8.2) in the intensive group (n=2,729)
compared with 7.9% (6.9-8.8) in the conventional group (n=1,138).

 Recently, three trials assessing the CVD effects of
more intensive glucose control among patients with
type 2 diabetes at high CVD risk showed no
significant CVD benefit of intensified glucose
control.

 Conclusion.
 A meta-analysis of cardiovascular outcomes based on
VADT, ACCORD and ADVANCE
 HbA1c reduction of 1% was associated with a 15% RRR in
nonfatal MI but without benefits on stroke or all-cause
mortality.
 However, patients with a short duration of T2DM, lower
baseline HbA1c at randomization, and without a history
of CVD seemed to benefit from more-intensive glucose-
lowering strategies.

 Other Glucose-Lowering Medications
 Few data are available with regard to the CVD effects
of other glucose-lowering medications.[46]
 Suggested CVD benefits with insulin derive from
selected trials including both type 2 and type 1
diabetes, but these studies all had limited statistical
power to assess such effects.[4,54] On this backdrop,
and in the wake of increased regulatory scrutiny with
regard to safety and efficacy assessment of drugs
being developed for diabetes,[44] numerous
randomized CVD clinical outcomes trials are
currently under way or in advanced planning.

Acute Coronary Syndromes
 Insulin and Glucose Control
 The myocardium preferentially metabolizes FFA under
physiologic conditions ,but it can also metabolize a
variety of substrates during periods of stress (such as
ischemia), and glucose is principal among these.
 Countering the metabolic switch to glucose metabolism
during ischemia, the myocardium develops a relative
insulin resistance
 Underpinning extensive research into metabolic
modulation of the ischemic myocardium, with insulin as
the primary focus of investigation.

Glucose-Insulin-Potassium Therapy
 The use of insulin for ACS was first described in 1963
by Sodi-Pallares, with the intention of facilitating
potassium flux in the ischemic myocardium, the so-
called polarizing therapy.
 After decades of investigation, this combination of
glucose, insulin, and potassium has become known
as GIK therapy, and the focus of attention has shifted
from the polarizing effects to the direct effects of
insulin

SUMMARY OF SELECTED RANDOMIZED TRIALS ASSESSING
THE EFFECT OF INSULIN INFUSION ON MAJOR ADVERSE
CARDIOVASCULAR OUTCOMES AMONG PATIENTS WITH
ACUTE CORONARY SYNDROME EVENTS
 DIGAMI = Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial
Infarction trial[60]; ECLA = Estudios Cardiol?gicos Latinoam?rica glucose-
insulin-potassium pilot trial[110]; GIPS = glucose-insulin-potassium study[111];
CREATE = Clinical Trial of REviparin and Metabolic Modulation in Acute
Myocardial Infarction Treatment Evaluation[59]; Hi-5 = The Hyperglycemia:
Intensive Insulin Infusion in Infarction study[112]; Pol-GIK = The Poland
glucose-insulin-potassium trial[113]; units/hr = units per hour of intravenous
insulin.

REVASCULARIZATION
 Revascularization in these patients is
challenged by
 Diffuse atherosclerotic involvement of epicardial
vessels,
 higher propensity to develop re-stenosis after PCI
and Saphenous graft occlusion after CABG and
 Unremitting atherosclerotic progression causing
new stenosis.
 Co morbidity ( PVD, CRF )
 Periprocedural complications
 Worse longterm clinical outcones

OUTCOMES COMPARED TO PATIENTS WITHOUT
DIABETES
 Often worse in diabetic patients.
 With PCI —
 Procedural success rates are similar.
 Higher rates of restenosis and lower rates of event-free
survival .

Restenosis
 Diabetic patients –increased restenosis and progression of
coronary disease.
 The following studies illustrate the magnitude of the
increase in restenosis risk:
 In an analysis of 3090 patients who underwent PCI with
BMS, 418 of whom (14 %) had diabetes .
 6 month angiographic follow-up, the rate of restenosis was
significantly higher in the diabetic patients (31 % vs 21 in
non DM patients).

 In an analysis of 10,778 patients in the j-Cypher registry
who underwent PCI with SES, there were 966 patients with
insulin-dependent diabetes, 3404 with noninsulin-
dependent diabetes, and 6378 without diabetes .
 At 3 years - rate of TLR was significantly higher in the
insulin-dependent and noninsulin-dependent groups
compared to those without diabetes (19, 14, and 10 % ,
respectively).

 Predictors of restenosis in diabetic patients
 Smaller vessel caliber
 Greater length of the stented segment
 Lower body mass index
 It is unclear why diabetic patients are more prone to
restenosis after PCI.
 Exaggerated intimal hyperplasia has been demonstrated,
possibly due to the stimulatory effect on vascular smooth
muscle of growth factors, such as insulin-like growth
factor-I .

Event-free survival
 Event-free survival (events such as death or MI) is worse
after revascularization with PCI
 The following observations illustrate the range of findings:
 In a consecutive series of patients with successful stent
placement, comprising 715 patients with DM vs 2839
without DM.

 In the j-Cypher registry - cardiovascular event at 3 years
was significantly greater in the insulin-dependent group
(hazard ratio 1.12, 95% CI 1.03-1.23), but not the noninsulin-
dependent group, compared to those without diabetes .
 The SYNTAX trial compared PCI with drug eluting stents
(DES) versus CABG in patients with complex coronary
artery disease (left main and/or three vessel disease).
 452 patients with DM.
 At 5 year follow-up,
 The rate of repeat revascularization of patients undergoing PCI
(n = 231) was higher in patients with diabetes (29 versus 19 % ).
 Mortality was also increased in the diabetic population (20
versus 12 %)

 With CABG ---
 Procedural success rates are similar
 Follow-up- death and adverse nonfatal outcomes higher in
patients with diabetes
 Mortality
 No affect in-hospital mortality after CABG ,
 short- and long-term survival after CABG are significantly
reduced .
 In different large observational studies, diabetic patients had
higher mortality rates at 30 days (5 versus 2.5 percent) and at
five and ten years (22 versus 12 percent and 50 versus 29 percent,
respectively) .

OUTCOMES AFTER PCI
 The rates of TLR ,MI or survival may be influenced by the
stent type as well as diabetes-related factors.
 Stent type
 DES now preferred to BMS
 Reductions in restenosis and TLR or TVR.

 The individual trials are limited in their ability to compare
two stent designs due to relatively small number of
enrolled patients
 The following summarizes the results of those studies:
 BMS versus first generation stents:
 Significantly lower rates of TLR with first generation stents
compared to BMS in subgroup analyses of major trials such
as SIRIUS , DIABETES, that enrolled only patients with
diabetes , and in a pooled analysis from the first five
TAXUS trials

5.7%
11.8%
52.5%
50.6%
In-Stent In-Segment
%
Sirolimus Control
CYPHER POOLED: DIABETIC SUBGROUP
Angiographic Restenosis
P<0.001
P<0.001
 79%  80%

5.2%
7.4%
33.1%
37.5%
0%
10%
20%
30%
40%
50%
In-stent restenosis In-segment restenosis
Pooled TAXUS Trials (II, IV, VI)
Overall Diabetic Subset: Angiographic Restenosis
 87%
P<0.001
 80%
P<0.001
(n=263) (n=264)

 SES versus PES:
 The DES-DIABETES trial
 400 patient
 Primary endpoint - insegment stenosis
 At 6 months - significantly lower in the SES group (4.0 versus
20.8 percent, respectively) and
 At 9 months - there was no significant difference in the
incidence or MI or death .
 At 4 years - there was no significant difference in the rates of
MACE (11.0 versus 16 percent ) or TVR (7.5 versus 12 percent) .

 ISAR-DIABETES
 250 patients
 125 were randomly assigned to receive PES and 125 to
receive SESs .
 nine-month follow-up period
 The primary end point was in-segment late luminal
loss.
 Secondary end points were angiographic restenosis
and the need for revascularization of the target lesion
 In-segment restenosis - 16.5 percent vs 6.9 percent
(P=0.03).
 TLR - performed in 12.0 vs 6.4 percent (P=0.13).

 Second versus first generation stents:
 SPIRIT IV trial
 3687
 subgroup analysis
 which randomly assigned patients to second generation
everolimus-eluting stents (EES) or PES,
 No significant difference in the primary outcome of target
vessel failure between the EES and PES groups in patients
with diabetes (6.4 versus 6.9 percent, )

 Best available evidence - relative efficacy and safety of the
various DES or BMS comes from a 2012 mixed treatment
comparison analysis of 42 randomized trials with 22,844
patients with years of follow-up.
 Compared to bare metal stents, SES, PES, EES, and ZES
were associated with:
 A significant reduction in TVR, with EES having the
highest probability of being the best (with limited usable
data for the ZES-resolute stent).
 No increased risk of any safety outcome (death, MI,
or probable/definite stent thrombosis).
 For these outcomes, the EES had the highest probability of
being the best stent.

Diabetes-related factors
Nephropathy
 Important predictor of risk after PCI.
 Observational study of 537 diabetic patients in with
proteinuria had a significantly higher two-year mortality
rate following PCI (20 versus 9 percent in those without
proteinuria, adjusted hazard ratio 1.8).

Glycemic control
 Rate of restenosis after PCI - lower if optimal glycemic
control is achieved.
 In a study of 239 patients, 179 with DM, who underwent
elective PCI (67 percent with stenting) after measurement
of glycosylated hemoglobin (HbA1c).
 Preprocedural HbA1c ≤7 percent had a rate TVR at 12
months that was comparable to that in non DM patients (15
versus 18 percent),
 HbA1c >7 percent had a significantly higher rate of target
vessel revascularization (34 percent).

Thiazolidinediones
 Inhibit vascular smooth muscle cell proliferation and migration
and
 Reduce intimal proliferation after vascular injury
 This approach has been evaluated in two, small randomize trials
who underwent PCI with stenting were randomly assigned to
either a thiazolidinedione (pioglitazone or rosiglitazone) or
placebo .
 The rate of angiographic restenosis was lower in the
thiazolidinedione group.
 Further studies are required to confirm the efficacy and safety of
this approach, particularly with the use of drug-eluting stents.

Glycoprotein IIb/IIIa inhibitors
 Reduce the risk of ischemic complications - undergoing
PTCA including those with an ACS & higher-risk patients
with stable angina.
 On the other hand, in lower-risk patients undergoing
elective stenting, a GP IIb/IIIa inhibitor may not provide
any additional benefit if the patient is pretreated
with clopidogrel (600 mg) as shown in the ISAR-REACT
trial

 Indication is more compelling in diabetic patients, since
pooled analyses or meta-analyses of trials of patients
undergoing elective or urgent PCI or those with an acute
coronary syndrome suggested a significant mortality
benefit at 30 days and one year in the subset of patients
with diabetes .

 ISAR-SWEET trial
 701 diabetic patients
 undergoing elective PCI were randomly assigned to
either abciximab plus heparin (70 U/kg) or placebo plus
heparin (140 U/kg).
 All patients were pretreated with 600 mg of clopidogrel at
least two hours before the procedure.
 Patients were treated with balloon angioplasty, bare metal
stents, or drug-eluting stents (10, 80, and 10 percent,
respectively).

 Primary endpoint at one year did not differ between the
two groups (8.3 versus 8.6 percent with placebo)
 No difference in mortality at one year (4.8 versus 5.1
percent).
 Follow-up angiography at 7 months - a reduction in the
rate of angiographic restenosis with abciximab (29 versus
38 % with placebo) and,
 At one year, a significantly lower rate of target lesion
revascularization (23.2 versus 30.4 percent).

OUTCOMES AFTER CABG
Internal thoracic artery grafts
 All patients undergoing CABG, including those with
diabetes, should receive an internal thoracic (mammary)
artery (ITA), to improve survival.
 In addition, prefer bilateral to single ITA grafting for many
patients with diabetes based on two observational studies.

Perioperative glycemic control
 Outcomes are worse in patients with significant
hyperglycemia
 Intensive glycemic control - improve both cardiac and
noncardiac outcomes in diabetic patients after CABG .
 The following observations illustrate the range of
findings:
 In a prospective trial, 141 patients with diabetes who were
undergoing CABG were randomly assigned to tight
glycemic control (125 to 200 mg/dL) with a GIK infusion
or standard therapy with intermittent subcutaneous
insulin .

 Patients treated with GIK had lower mean serum
glucose concentrations in the perioperative period (138
versus 260 mg/dL [7.7 versus 14.4 mg/dL]).
 At two years, GIK patients had significantly lower rates
of wound infections (1 versus 10 percent), recurrent
ischemia (5 versus 19 percent), and mortality (2 versus 10
percent).

PCI VERSUS CABG
 Multivessel or left main coronary artery disease who
require revascularization, the evidence suggests better
outcomes with CABG rather than PCI with stenting.
 Supporting evidence
 Early trials comparing balloon angioplasty to CABG in
patients with diabetes suggested higher rates of
revascularization and mortality with the former
particularly in patients with multivessel disease.
 Early trials of PCI with stenting, including those using
DES, showed similar survival rates but a persistent
increased need for revascularization.

 FREEDOM trial ( Future REvascularization Evaluation in
patients with Diabetes mellitus: Optimal management of
Multivessel disease )
 1900 pts with DM and multivessel CAD (83 percent three-
vessel disease) were randomly assigned to either PCI with
drug-eluting stents (paclitaxel or sirolimus) or CABG.
 Both groups received optimal medical therapies for the
secondary prevention of cardiovascular disease.
 Median follow-up- 3.8 years.

 At one year, there was a higher rate of repeat
revascularization in the PCI group (12.6 versus 4.8
percent; hazard ratio 2.74, 95% CI 1.91-3.89).

 Very early studies evaluated outcomes in patients
treated with either bare metal stents (BMS) or CABG
in patients with diabetes.
 Subset analyses from two smaller randomized trials,
ARTS-I and AWESOME, showed a higher rate of
repeat revascularization with BMS.
 Mortality was not significantly different, but these
studies were severely underpowered to assess
mortality.

 The first evidence comparing DES to CABG was
observational and suggested that DES diminished the
advantage of CABG compared to PCI seen when BMS are
used in diabetic patients.
 ARTS II study, which was a single-arm study of 607
patients (including 159 with diabetes) who were treated
with sirolimus eluting stents; the outcomes were compared
to the CABG arm in the ARTS I trial .
 At 3 years, primary combined endpoint of death, stroke ,MI
and repeat revascularization with DES was not significantly
different from the CABG arm of ARTS I after adjustment
for independent predictors (27.7 versus 17.7 percent for
CABG).

 More evidence comparing DES to CABG came from the
CARDia and SYNTAX trials, which came to similar
conclusions.
 CARDia trial (The Coronary Artery Revascularization in
Diabetes )
 Randomly assigned 510 patients with diabetes and
symptomatic, multivessel, or complex single vessel CAD to
either stenting (31 % were BMS & 69% DES) or CABG .

%
0
5
15
2.0
9.9
20
CARDIA
Trial design: Diabetic patients with multi-vessel disease or complex single-vessel disease,
but not left main disease, were randomized to either CABG or PCI. Clinical outcomes were
compared at 12 months.
(p = 0.63)
CABG
(n = 254)
PCI
(n = 256)
(p = 0.001)
5
10
15
20
10.2
11.6
%
0
Primary endpoint Repeat
revascularization
10

CARDIA
Conclusion -
• Similar incidence of death, MI, or stroke in
diabetics with CABG or PCI
• CABG was associated with fewer repeat
revascularizations compared with PCI
• No difference in death, MI, but trend toward
increased stroke with CABG, as suggested by
other studies

 In subgroup analysis of the 452 patients with diabetes in
SYNTAX, which compared CABG to DES (paclitaxel-
eluting stents ) in patients with multivessel or left main
coronary artery disease

%
0
5
15
5.9
13.7
20
SYNTAX
Trial design: Patients with severe three-vessel disease or left main (LM) disease were
randomized to either CABG or DES-PCI with paclitaxel-eluting stents. Clinical outcomes
were compared at 12 months.
(p = 0.0015)
CABG
(n = 897)
DES-PCI
(n = 903)
(p = 0.0001)
5
10
15
20
12.1
17.8
%
0
MACCE Repeat
revascularization
10

SYNTAX
Conclusion
• CABG was associated with fewer repeat
revascularizations compared with DES-PCI in
patients with LM or three-vessel disease, but a
higher rate of stroke
• No difference in death, MI, or thrombosis
• Diabetics are especially more likely to benefit
with CABG compared with DES-PCI

MEDICAL THERAPY VERSUS REVASCULARIZATION
 In BARI 2D trial
 2368 patients with type 2 DM and stable ischemic
heart disease
 Randomized to receive prompt revascularization plus
intensive medical therapy compared with intensive
medical therapy alone.

 During 5 years - overall mortality rates between the
two groups did not differ significantly—11.7% vs
12.2% (P = 0.97).
 In secondary analyses stratified according to the
mode of revascularization, all cardiovascular
outcomes were statistically similar between the PCI
and medical therapy groups, but CABG compared
with medical therapy was associated with a
significant reduction in major adverse cardiovascular
events (22.4% versus 30.5%; P = 0.01).

 These data provide support for a primary strategy of
intensive medical therapy, as well as additional
suggestion of the benefit of bypass surgery, although
direct comparisons between PCI and CABG are not
possible from this study design.

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