This document discusses cardiovascular risk in patients with diabetes mellitus. It notes that diabetes is considered a coronary artery disease equivalent and is a major risk factor for cardiovascular events. Patients with diabetes have significantly higher risks of coronary artery disease, heart failure, stroke and other vascular complications compared to those without diabetes. The document outlines the various modifiable and non-modifiable risk factors that further increase cardiovascular risk in patients with diabetes, including dyslipidemia, hypertension, obesity, and smoking. It summarizes the results of major clinical trials investigating the effects of intensive glycemic control on microvascular and macrovascular outcomes.

1. By
Dr. Hani A.AbdelWahab, M.D.
Consultant cardiologist,AFHJ
(June/ 2nd
/2016)
Cardiovascular risk inCardiovascular risk in
patients with Diabetespatients with Diabetes
MellitusMellitus

2. IntroductionIntroduction
DM is considered as a CAD equivalent

3. It is also considered as a worldwide
epidemic and one of the most common
chronic diseases in both developed and
developing nations.
CAD accounts for as many as 80% of deaths
among individuals with DM compared
with 30% in those without DM.

5. The prevalence of T2DM which correlates
closely with obesity has shown a sharp rise
over recent decades. Consequently the
management of DM & other CAD risk factors is
the main focus in the primary and secondary
prevention of cardiovascular events.

6. Diabetes is a huge and growing problem, and the costs to
society are high and escalating
382 million people have
diabetes
By 2035, this number will
rise to 592 million
IDF ,Global burden of
diabetes , 2013

9. The pathological continuumThe pathological continuum
Normal glucose tolerance
Impaired fasting glucose
Impaired glucose tolerance
T2DMT2DM
PREDIABETES
COMPLICATIONS

10. Impact of diabetes on CVD:Impact of diabetes on CVD:
Both T1DM and T2DM confer significantly
elevated risks (2-5 folds) of:
CAD, ACS, post MI complications.
Heart failure.
Sudden cardiac death.
PAD.
Stroke
End stage renal failure.

12. Diabetes as a CHD Risk Equivalent:Diabetes as a CHD Risk Equivalent:
Type 2 DM and CHDType 2 DM and CHD
7-Year Incidence of Fatal/Nonfatal MI7-Year Incidence of Fatal/Nonfatal MI
(East West Study)(East West Study)
No Diabetes Diabetes
3.5%
18.8%
20.2%
45.0%
P<0.001 P<0.001
7-yearincidencerateofMI
CHD=coronary heart disease; MI=myocardial infarction; DM=diabetes mellitus
Haffner SM et al. N Engl J Med. 1998;339:229-234.

13. In the Framingham Heart Study, the risk of
CAD is doubled in men and tripled in women
with diabetes, compared with age-matched
subjects without diabetes.
Patients with diabetes present differently from
those without diabetes and are much more
likely to experience an acute coronary
syndrome without chest pain known as “silent
ischemia.”

14. Indeed, there are multiple studies
suggesting poorer outcomes following
cardiovascular events, even with
revascularization, for individuals with
diabetes compared with those without.
Cardiogenic shock is more common and
more severe in post-MI patients with
diabetes.

15. Risk factors for CAD in patients
with DM
 The risk factors that predispose individuals
with diabetes to develop cardiovascular
disease are the same as those that raise
cardiovascular risks in those without
diabetes.
However, the prevalence of known major
risk factors for CAD is generally amplified
among persons with diabetes.

16. DMDM
AtherogenicAtherogenic ThromboticThrombotic

18. DyslipidemiaDyslipidemia
This is one of the most profound risk factors
among individuals with diabetes.
Diabetes is associated with:
Small, dense low-density lipoprotein (LDL)
particle composition.
Increased levels of apolipoprotein B and E.
Low levels of high-density lipoprotein (HDL)
cholesterol.
High triglyceride (TG) levels.

20. Lipid-lowering therapy is now a
cornerstone of T2DM management.
In the Scandinavian Simvastatin Survival
Study (4S4S), there was a 55% reduction in
cardiovascular events among subjects with
diabetes, a 25% reduction in the CARECARE trial
and 24% reduction in the LIPIDLIPID trial with
pravastatin.

21. In the Collaborative AtoRvastatin Diabetes
Study (CARDSCARDS), atorvastatin 10 mg reduced
LDL-C by 40% on average. Results at 4 years
showed a 37% relative risk reduction (p
<0.001) in the primary endpoint & 27%
relative risk reduction in the secondary
endpoints (p=0.05).

22. HypertriglyceridemiaHypertriglyceridemia
Elevated fasting TG levels are characteristic
of the lipid panel in diabetes and constitute
an independent cardiovascular risk factor.
Hypertriglyceridemia correlates with
abdominal adiposity.
Fibrates have traditionally been considered
an appropriate therapy to target
hypertriglyceridemia and have often been
added to statin therapy for this indication.

23. HypertensionHypertension
The prevalence of hypertension is increased
in individuals with diabetes compared with
those without.
In the UKPDS, lowering the blood pressure
to a mean of 144/82 mm Hg (compared with
154/87 mm Hg) significantly reduced
strokes, diabetes related deaths, and heart
failure, as well as microvascular
complications.

24. Several trials have demonstrated the renal
protective effects of angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin
receptor antagonists (ARBs) over alternate
agents, which has firmly established them as
the first-line antihypertensives in diabetes.
There is currently insufficient evidence to
recommend ACE inhibitors in normotensive
patients with diabetes without
microalbuminuria.

25. Major guidelines suggest a target blood
pressure in patients with diabetes of < 130/80
mmHg.
The ACCORD trial randomized subjects with
diabetes to a target systolic blood pressure of <
120 mmHg or < 140 mmHg. The lower target
group showed no difference in the primary
cardiovascular outcomes end point but did
have a significantly lower stroke rate; however,
this was at the expense of significantly more
adverse drug events and an increased risk of a
creatinine rise of> 1.5 mg/dL.

26. TobaccoTobacco
 There is evidence that smokers with
diabetes have a markedly increased risk of:
M.I.
PAD.
Dyslipidemia.

27. ObesityObesity
 Obesity and overweight are typically
defined in terms of body mass index (BMI),
with:
Overweight being 25 to 30 kg/m2
Class I obesity 30 to 35 kg/m2
Class II obesity 35 to 40 kg/m2
Class III obesity > 40 kg/m2
.

28. Waist circumference and waist-to-hip ratio
better reflect abdominal adiposity and are
more reliable predictors of CAD outcomes
than BMI.
T2DM correlates closely with obesity,
especially central obesity.
Caloric restriction, behavior modification,
and increased physical activity form the
basis of weight management programs.

29. Drugs for weight loss:
Sibutramine
Ephedrine and ephedra alkaloids
Phentermine and diethylpropion
Orlistat (pancreatic lipase inhibitor)
Others (antidepressants such as fluoxetine,
sertraline, bupropion & anti-epileptics such as
topiramate and zonisamide; and diabetes
medications
including metformin and the glucagon like
peptide (GLP) analogs).

30. There is growing evidence regarding the
beneficial effects of significant weight loss
achieved by bariatric surgery on glucose
metabolism.
 Bariatric surgery is generally restricted to
individuals with BMI >40 kg/m2
or BMI 35
to 40 kg/m2
with co-existing medical
conditions such as diabetes.

31. Bariatric surgery options include :
Malabsorptive procedures such as the
Roux-en-Y gastric bypass.
Restrictive procedures such as
laparoscopic adjustable gastric bands and
sleeve gastrectomy.

32. Metabolic syndrome

33. DMDM
AtherogenicAtherogenic ThromboticThrombotic

34. Role of DM in the pathology ofRole of DM in the pathology of
atherosclerosisatherosclerosis
Diabetes accelerates the atherosclerosis
process & endothelial dysfunction.
Autopsy series have revealed more diffuse
coronary involvement, greater severity of
vessel stenosis, and more severe left main
disease in persons with diabetes, compared
with those without.

35. NONO is among several key substances that
maintain healthy endothelial function,
which includes freedom from adhesion
molecule activation, leukocyte diapedesis,
platelet aggregation, and activation of
thrombosis.

36. Current research reveals the impact of
excessive oxidative stress (which can he
induced by hyperglycemia, fatty acids, or
insulin resistance) on NONO production and
also on the generation of advanced glycation
end products (AGEPsAGEPs), which are suspected
to mediate various negative cellular effects
in diabetes.

37. DMDM
 Reactive oxygen substances (ROS).
Hyperglycemia :  NO by:
 NO synthetase.
 Its degradation by formation of ROS
through protein kinase C, NADPH oxidases
and AEGs (Advanced End Glycation
Products).

38. Free Fatty Acids (FFA) :Free Fatty Acids (FFA) :
 O2 free radicals.
 PKC which leads to :
 Cytokines (proinflammatory).
 Proliferation of vascular cell wall.
ECM accumulation & atherosclerosis.
 TG,  HDL,  LDL.

39.  vascular inflammation by  nuclear
factor (NF) & activator proteins (AP)  
cytokines, chemokines, adhesion molecules
(ICAM & VCAM) & TNF alpha   MMPs &
TF   plaque instability.plaque instability.
 PAI-1 (plasminogen activator inhibitor)
(antifibrinolytic action).

40. Platelet function is also abnormal in
diabetes, with overexpression of the
glycoprotein IIb/IIIa receptor promoting
inappropriate platelet adhesion and
activation.
 Vasoconstriction by:
 Endothelin-1 ,  Angiotensin II &
prostanoids ,  V.C. response to
catecholamines (autonomic dusfunctionautonomic dusfunction).

42. Vascular Complications ofVascular Complications of
DMDM
Microvascular:Microvascular:
•Neuropathy.
•Nephropathy.
•Retinopathy.
Macrovascular:Macrovascular:
•Coronary heart diease.
•Cerebrovascular disease.
•Peripheral vascular disease.

43. MICROVASCULAR TRIALSMICROVASCULAR TRIALS
The role of tight control of glycemia was
firmly established in the 1990s with the
publication of two large trials demonstrating
decreases in microvascular complications
nephropathy and retinopathy with lower
glucose goals.

44. In summary,
The two large trials published in the 1990s,
DCCT and UKPDS,DCCT and UKPDS, showed significant
improvements in microvascular outcomes
with tighter glycemic control in T1DM or
T2DM.

45. MACROVASCULAR TRIALSMACROVASCULAR TRIALS
Despite the convincing evidence for a
reduction in microvascular complications,
the relationship between glycemia and
cardiovascular events remained unclear,
with neither DCCT nor UKPDS showing a
definitive advantage in terms of
cardiovascular outcomes or mortality.

46. Three further large trials added additional
information regarding the potential
relationship between glycemic control and
cardiovascular outcomes.

47. The ADVANCEADVANCE trial (Action in Diabetes and
Vascular Disease: Preterax and Diamicron Modified
Release Controlled Evaluation) randomized 11,140
patients with T2DM to standard versus
intensive glucose control.
 Intensive control was achieved with the use
of gliclazide (a sulfonylurea) plus other
agents as necessary to achieve a HbAlc 6.5%

48. There was a decrease in the incidence of
microvascular events (primarily
macroalburninuria) but no significantno significant effect
of the type of glucose control on major
macrovascular events.

49. The ACCORD trialThe ACCORD trial (Action to Control
Cardiocascular Risk in Diabetes) also tested the
effects of tight glucose control, recruiting a
total of 10,251 T2DM patients who were
randomized to a target HbAlc of < 6% versus
7.0% to 7.9%

50. ACCORD was discontinued at a meanACCORD was discontinued at a mean
follow-up of 3.5 years due to an increasedfollow-up of 3.5 years due to an increased
risk of death in the intensive treatment arm.risk of death in the intensive treatment arm.
Hypoglycemia requiring medical attention
and weight gain > 10 kg were both more
common in the intensive therapy group.

51. Trials Show No Reduction in CV Events withTrials Show No Reduction in CV Events with
More Intensive Glycemic ControlMore Intensive Glycemic Control
1
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.
2
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.
Number at Risk
Intensive 5570 5369 5100 4867 4599 1883
Standard 5569 5342 5065 4808 4545 1921
25
20
15
10
5
0
0 12 24 36 48 60
Cumulativeincidence(%)
Months of follow-up
Standard therapy
Intensive therapy
ADVANCE: Primary Outcome
Number at Risk
Intensive 5128 4843 4390 2839 1337 475 448
Standard 5123 4827 4262 2702 1186 440 395
Patientswithevents(%)
0 1 2 3 4 5 6
25
20
15
10
5
0
Years
Standard therapy
Intensive therapy
ACCORD: Primary Outcome

52. In the VADTVADT (Veterans Affairs Diabetes Trial)
there was no significant difference observed
between the two groups in any component
of the primary outcome or in all-cause
mortality.

54. The 2009 ACC/AHA Scientific Statement
supports a goal HbA1c of ≤ 7a goal HbA1c of ≤ 7 with
acknowledgment of the benefits of tight
control in terms of microvascular disease,
but recognizes the paucity of evidence for a
cardiovascular benefit.

55. Diabetic CardiomyopathyDiabetic Cardiomyopathy
One reason for the poor prognosis in
patients with both diabetes and ischemic
heart disease seems to be an enhanced
myocardial dysfunction leading to
accelerated heart failure.
Thus, patients with diabetes are unusually
prone to congestive heart failure.

56. Several factors probably underlie diabetic
cardiomyopathy:
Accelerated coronary atherosclerosis.
Prolonged hypertension.
Chronic hyperglycemia, microvascular
disease, endothelial dysfunction, altered
calcium handling, accumulation of AGEPs
and FFAs, glycosylation of myocardial
proteins, and autonomic neuropathy.

57. Guide toGuide to
Comprehensive RiskComprehensive Risk
Reduction forReduction for
Patients WithPatients With
Coronary and OtherCoronary and Other
Vascular DiseaseVascular Disease
Who Have DiabetesWho Have Diabetes

58. Lifestyle Modifications for primaryLifestyle Modifications for primary
and secondary prevention of CADand secondary prevention of CAD
5-Avoid tobacco
(JNC VI. Arch Intern Med. 1997)
1- Reduce weight 3-Moderate consumption
of:
• Sodium (6gm/day)
• saturated fat
• cholesterol
2-Increase
physical
activity
(30-40
min/day)
4-Maintain adequate intake of dietary:
• potassium
• calcium
• magnesium

59. Weight ManagementWeight Management

61. Smoking CessationSmoking Cessation
Strongly encourage patient and family to
stop smoking.
Provide counseling, nicotine replacement,
and formal cessation programs as
appropriate.

62. Blood pressure controlBlood pressure control
Initiate lifestyle modification, weight
control, physical activity, alcohol and
smoking cessation, and moderate sodium
restriction in all patients with blood
pressure > 130 mm Hg systolic or 85 mm Hg
diastolic.
Goal: ≤ 130/85 mm HgGoal: ≤ 130/85 mm Hg

63. Add blood pressure medication according
to other patient requirements and
characteristics (i.e. age, race, compelling
indications) if:
BP is not < 140 mm Hg systolic or < 90 mm
Hg diastolic in 3 months or if initial BP is >
160 mm Hg systolic or > 100 mm Hg
diastolic.

64. DyslipidemiaDyslipidemia

65. Glucose ControlGlucose Control
First-step therapy: weight reduction and
exercise.
Second-step therapy: oral hypoglycemic
agents (sulfonylureas and/or metformin;
ancillary: acarbose, pioglitazone, Dipeptidyl
peptidase DPP-4 inhibitors).
Third-step therapy: insulin therapy.

66. Novel TherapiesNovel Therapies
Islet cell transplantation.
Stem cell therapy.

67. AntiplateletsAntiplatelets
Some authorities recommend aspirin 80 to
325 mg/day if not contraindicated for
primary prevention in high-risk diabetic
patients.

68. Take Home MessageTake Home Message