ByDr. Hani A. AbdelWahab,

M.D.Consultant cardiologist,

AFHJ(June/ 2nd /2016)

Cardiovascular risk in Cardiovascular risk in patients with Diabetes patients with Diabetes

MellitusMellitus

IntroductionIntroduction

DM is considered as a CAD equivalent

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.

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.

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

The pathological The pathological continuumcontinuum

Normal glucose tolerance

Impaired fasting glucose

Impaired glucose tolerance

T2DMT2DM

PREDIABETES

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Impact of diabetes on Impact of diabetes on CVD:CVD:

Both T1DM and T2DM confer significantly elevated risks (2-5 folds) of:

CAD, ACS, post MI complications.Heart failure.Sudden cardiac death.PAD.StrokeEnd stage renal failure.

Diabetes as a CHD Risk Equivalent: Diabetes as a CHD Risk Equivalent: Type 2 DM and CHD Type 2 DM and CHD

7-Year Incidence of Fatal/Nonfatal MI 7-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-ye

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CHD=coronary heart disease; MI=myocardial infarction; DM=diabetes mellitus

Haffner SM et al. N Engl J Med. 1998;339:229-234.

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.”

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.

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.

DMDM

AtherogenicAtherogenic ThromboticThrombotic

DyslipidemiaDyslipidemiaThis 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.

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.

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).

HypertriglyceridemiaHypertriglyceridemiaElevated 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.

HypertensionHypertensionThe 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.

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.

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.

TobaccoTobacco There is evidence that smokers with diabetes have a markedly increased risk of:

M.I. PAD. Dyslipidemia.

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.

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.

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 medicationsincluding metformin and the glucagon like peptide (GLP) analogs).

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.

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.

Metabolic syndrome

DMDM

AtherogenicAtherogenic ThromboticThrombotic

Role of DM in the pathology of Role 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.

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.

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.

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).

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.

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).

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 autonomic dusfunctiondusfunction).

Vascular Complications of Vascular Complications of DMDM

MicrovasculMicrovascular:ar:•Neuropathy.•Nephropathy.•Retinopathy.Macrovascular:Macrovascular:

•Coronary heart diease.•Cerebrovascular disease.•Peripheral vascular disease.

MICROVASCULAR TRIALSMICROVASCULAR TRIALSThe 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.

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.

MACROVASCULAR TRIALSMACROVASCULAR TRIALSDespite 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.

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

The ADVANCE ADVANCE 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%

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

The ACCORD trial The 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%

ACCORD was discontinued at a ACCORD was discontinued at a mean follow-up of 3.5 years due mean follow-up of 3.5 years due to an increased risk of death in to an increased risk of death in the intensive treatment arm.the intensive treatment arm.

Hypoglycemia requiring medical attention and weight gain > 10 kg were both more common in the intensive therapy group.

Trials Show No Reduction in CV Events with Trials Show No Reduction in CV Events with More Intensive Glycemic ControlMore Intensive Glycemic Control

1ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.2ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

Number at RiskIntensive 5570 5369 5100 4867 4599 1883Standard 5569 5342 5065 4808 4545 1921

25

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Months of follow-up

Standard therapyIntensive therapy

ADVANCE: Primary Outcome

Number at RiskIntensive 5128 4843 4390 2839 1337 475 448Standard 5123 4827 4262 2702 1186 440 395

Patie

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eve

nts

(%)

0 1 2 3 4 5 6

25

20

15

10

5

0

Years

Standard therapyIntensive therapy

ACCORD: Primary Outcome

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.

The 2009 ACC/AHA Scientific Statement supports a goal HbA1c a goal HbA1c of ≤ 7 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.

Diabetic CardiomyopathyDiabetic CardiomyopathyOne 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.

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.

Guide to Guide to Comprehensive Comprehensive

Risk Reduction for Risk Reduction for Patients With Patients With Coronary and Coronary and

Other Vascular Other Vascular Disease Who Have Disease Who Have

DiabetesDiabetes

Lifestyle Modifications for Lifestyle Modifications for primary and secondary primary and secondary prevention of CADprevention 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

Weight Weight ManagementManagement

Smoking Cessation Smoking Cessation Strongly encourage patient and family to stop smoking.

Provide counseling, nicotine replacement, and formal cessation programs as appropriate.

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

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.

DyslipidemiaDyslipidemia

Glucose ControlGlucose ControlFirst-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.

Novel TherapiesNovel Therapies

Islet cell transplantation.

Stem cell therapy.

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

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