DIABETES AND

CARDIOVASCULAR DISEASE

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 sixfoldincreased 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

ROLE OF ADIPONECTIN

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 fibrinolyticsystems 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 revascularizeOccluded 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 peronealarteries, 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 claudicationby more than 3-fold in men and more than 8-fold in women.

Diabetes is the most common cause of nontraumaticamputations in the United States.

DIABETIC DYSLIPIDEMIA

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;364:685Diabetes Care 2006;29:1220Lancet 2003;361:2005Diabetes Care 2006;7:1478Diabetes Care 1997;20:614

*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 statinmonotherapy.

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 statinmonotherapy when patients do not achieve therapeutic targets (noting some increased myopathyrisk).

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 statintherapy, 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 statinmonotherapy 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.

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-AldosteroneSystem (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 subanalysisof 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 clopidogrelin 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

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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.

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 REDUCTIONFOR 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 epicardialvessels,

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<0.001P<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 restenosisand 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 glycemiccontrol 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

10.211.6

%

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

SYNTAXTrial 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

CABG v/s PCI in Diabetics

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% vs12.2% (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.

RECOMMENDATIONS OF OTHERS

The 2011 ACC/AHA guideline for coronary artery bypass graft surgery (CABG) made a weak recommendation to prefer CABG to percutaneous coronary intervention (PCI) in patients with multivessel disease with diabetes [94].

This recommendation was made prior to the publication of the FREEDOM trial. (See 'Stenting versus CABG in multivessel disease' above.)

Our recommendations for coronary revascularization in patients with diabetes are similar to those found in the 2013 European Society of Cardiology/EuropeanAssociation for the Study of Diabetes guidelines on diabetes, pre-diabetes, and cardiovascular diseases [95].

IMPACT OF LATE-ONSET HEART FAILURE

Although the unfavorable long-term prognosis after revascularization in diabetics has been ascribed to progressive atherosclerotic disease, plaque instability, and a higher restenosis rate, progressive heart failure may be another factor.

This was illustrated in a report of 363 patients who were followed for 13 years after balloon angioplasty or coronary artery bypass graft surgery (CABG) [96].

The cumulative incidence of hospitalizations for heart failure was higher in diabetics (25 versus 11 percent for nondiabetics), with a rapidly increasing incidence after five years [96].

Both long-term survival (43 versus 78 percent) and survival free of heart failure (33 versus 71 percent) were reduced in patients with diabetes. (See "Heart failure in diabetes mellitus".)

STRATEGIES TO IMPROVE OUTCOMES

Regardless of the procedure chosen, all patients with diabetes and coronary artery disease should be treated with aggressive risk factor reduction including blood pressure control, statintherapy, exercise, and smoking cessation when indicated.

In addition, as mentioned above, strict glycemic control (HbA1c ≤7 percent) may lower the rate of target vessel revascularization after percutaneous coronary intervention (PCI) [56,97

The multiple benefits associated with multifactorial risk factor reduction were demonstrated in the Steno-2 trial. The details of the protocol and overall results of this study are discussed elsewhere. (See "Overview of medical care in adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

For those patients undergoing coronary artery bypass graft surgery (CABG), maintenance of strict glycemic control (serum glucose <200 mg/dL [11.1mmol/L]) with a continuous insulin infusion during the perioperative period is useful [76,77].

In addition to improving cardiac outcomes [76,77], a continuous insulin infusion also may reduce the rate of postoperative mediastinitis [36]. (See 'Perioperative glycemic control' above.)

In addition, the use of arterial conduits, preferably internal thoracic grafts, particularly to anastomoses to the left anterior descending artery are advantageous.

As noted above, the improved outcomes with CABG in BARI were only seen in patients receiving at least one internal thoracic graft [26].

Long-term internal thoracic artery graft patency may contribute to this benefit by reducing the mortality from late myocardial infarctions by providing a better alternative source of perfusion in hypoperfused areas.

SUMMARY AND RECOMMENDATIONS

Outcomes after revascularization are generally worse in patients with diabetes than those without. However, the approach to revascularization is for the most part similar, including a preference for medical therapy to revascularization therapy unless it will improve survival or lessen unacceptable symptoms. (See "Bypass surgery versus percutaneous intervention in the management of stable angina pectoris: Recommendations" and 'Medical therapy versus revascularization' above.)

For patients with diabetes and stable angina that is not significantly interfering with the quality of life and who do not have silent myocardial ischemia involving at least a moderate sized territory or an indication for revascularization associated with mortality benefit, we suggest intensive medical therapy as initial strategy rather than immediate revascularization (Grade 2B). (See 'Medical therapy versus revascularization' above.)

For patients with diabetes and multivessel disease who require revascularization, we recommend coronary artery bypass graft surgery (CABG) rather than percutaneous coronary intervention (PCI) (Grade 1A). (See 'PCI versus CABG' above.)

For patients with diabetes undergoing CABG, we suggest placement of bilateral, rather than single, internal thoracic artery (ITA) grafts (Grade 2C). It is reasonable to not perform bilateral ITA grafting in individuals older than 70 to 75 years, as the survival benefit from bilateral ITA may be small in older individuals. (See 'Internal thoracic artery grafts' above.)

For diabetic patients with recurrence of unacceptable angina after CABG, we suggest repeat revascularization with PCI for appropriate lesions (Grade 2B). (See 'Post-CABG angina' above.)

Irrespective of the method of revascularization chosen, all patients should receive non-revascularization therapies known to be associated with better outcomes in patients with diabetes and coronary artery disease. (See 'Strategies to improve outcomes' above.)

The early glucometabolic impairment is characterized by a progressive decrease in insulin sensitivity and increased glucose levels that remain below the threshold for a diagnosis of T2DM, a state known as IGT.

The pathophysiological mechanisms supporting the concept of a ‘glycaemic continuum’ across the spectrum of IFG, IGT, DM and CVD will be addressed in the following sections.

The development of CVD in people with IR is a progressive process, characterized by early endothelial dysfunction and vascular inflammation leading to monocyte recruitment, foam cell formation and subsequent development of fatty streaks.

Over many years, this leads to atherosclerotic plaques, which, in the presence of enhanced inflammatory content, become unstable and rupture to promote occlusive thrombus formation.

Atheroma from people with DM has more lipid, inflammatory changes and thrombus than those free from DM.

These changes occur over a 20–30 year period and are mirrored by the molecular abnormalities seen in untreated IR and T2DM.

Pathophysiology of insulin resistance in type 2 diabetes mellitus

Insulin resistance has an important role in the pathophysiology of T2DM and CVD and both genetic and environmental factors facilitate its development.

More than 90% of people with T2DM are obese, and the release of free fatty acids (FFAs) and cytokines from adipose tissue directly impairs insulin sensitivity (Figure 6).

In skeletal muscle and adipose tissue, FFA-induced reactive oxygen species (ROS) production blunts activation of insulin receptor substrate 1 (IRS-1) and PI3K-Akt signalling, leading to downregulation of insulin responsive glucose transporter 4 (GLUT-4).

Endothelial dysfunction, oxidative stress and vascular inflammation

FFA-induced impairment of the PI3K pathway blunts Akt activity and phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser, resulting in decreased production of nitric oxide (NO), endothelialdysfunction, and vascular remodelling(increased intima-media thickness), important predictors of CVD.

In turn, accumulation of ROS activates transcription factor NF-kB, leading to increased expression of inflammatory adhesion molecules and cytokines.

Chronic IR stimulates pancreatic secretion of insulin, generating a complex phenotype that includes progressive beta cell dysfunction, decreased insulin levels and increased Plasm Glucose.

Evidence supports the concept that hyperglycaemiafurther decreases endothelium-derived NO availability and affects vascular function via a number of mechanisms, mainly involving overproduction of ROS (Figure 6)

The mitochondrial electron transport chain is one of the first targets of high glucose, with a direct net increase in superoxide anion(O2) formation.

A further increase in O2 production Is driven by a vicious circle involving ROS-induced activation of protein kinase C (PKC).

Activation of PKC by glucose leads to up-regulation of NADPH oxidase, mitochondrial adaptor p66Shc and COX-2 as well as thromboxane production and impaired NO release (Figure 6)

Mitochondrial ROS, in turn, activate signallingcascades involved in the pathogenesis of cardiovascular complications, including polyol flux, advanced glycation end-products (AGEs) and their receptors (RAGEs), PKC and hexosamine pathway (HSP) (Figure 6).

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.

ROS-driven epigenetic changes are particularly involved in this process

Macrophage dysfunction

The increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation and IR.

In addition, the insulin-resistant macrophage increases expression of the oxidized low-density lipoprotein (LDL) scavenger receptor B (SR-B), promoting foam cell formation and atherosclerosis.

These findings are reversed by peroxisomeproliferator activated receptor gamma (PPARg) activation, which enhances macrophage insulin signalling (Figure 6).

In this sense it seems that macrophage abnormalities provide a cellular link between DM and CVD by both enhancing IR and by contributing to the development of fatty streaks and vascular damage.

Atherogenic dyslipidaemia

Insulin resistance results in increased FFA release to the liver due to lipolysis.

Therefore, enhanced hepatic very low-density lipoprotein (VLDL) production occurs due to increased substrate availability, decreased apolipoprotein B-100 (ApoB) degradation and increased Lipogenesis .

In T2DM and the metabolic syndrome, these changes lead to a lipid profile characterized by high triglycerides (TGs), low high-density lipoprotein cholesterol (HDL-C), increased remnant lipoproteins, apolipoprotein B (ApoB) synthesis and small, dense LDL particles.

This LDL subtype plays an important role in atherogenesisbeing more prone to oxidation.

On the other hand, recent evidence suggests that the protective role of HDL may be lost in T2DM patients due to alterations of the protein moiety, leading to a pro-oxidant, inflammatory phenotype.

In patients with T2DM, atherogenic dyslipidaemia is an independent predictor of cardiovascular risk, stronger than isolated high triglycerides or a low HDL cholesterol.

Coagulation and platelet function In T2DM patients, IR and hyperglycaemia participate to

the pathogenesis of a prothrombotic state characterized by increased plasminogen activator inhibitor-1 (PAI-1), factor VII and XII, fibrinogen and reduced tissue plasminogen activator (tPA) levels.

Among factors contributing to the increased risk of coronary events in DM, platelet hyper-reactivity is of major relevance.

A number of mechanisms contribute to platelet dysfunction, affecting the adhesion and activation, as well as aggregation, phases of platelet mediated thrombosis.

Hyperglycaemia alters platelet Ca2+ homeostasis, leading to cytoskeleton abnormalities and increased secretion of proaggregant factors.

Moreover, hyperglycaemia-induced upregulation of glycoproteins (Ib and IIb/IIIa), P-selectin and enhanced P2Y12 signalling are key events underlying atherothrombotic risk in T1DM and T2DM

Diabetic cardiomyopathy

In patients with T2DM, reduced IS predisposes to impaired myocardial structure and function and partially explains the exaggerated prevalence of heart failure in this population.

Diabetic cardiomyopathy is a clinical condition diagnosed when ventricular dysfunction occurs in the absence of coronary atherosclerosis and hypertension.

Patients with unexplained dilated cardiomyopathy were 75% more likely to have DM than age-matched controls.

Insulin resistance impairs myocardial contractility via reduced Ca2+ influx through L-type Ca2+ channels and reverse mode Na2+/Ca2+ exchange.

Impairment of phosphatidylinositol 3-kinases (PI3K)/Aktpathway subsequent to chronic hyperinsulinaemia is critically involved in cardiac dysfunction in T2DM.

Together with IR, hyperglycaemia contributes to cardiac- and

structural abnormalities viaROSaccumulation,AGE/RAGEsignalling

and hexosamine flux.84,86 Activation of ROS-driven pathways affects

the coronary circulation, leads to myocardial hypertrophy and fibrosis

with ventricular stiffness and chamber dysfunction

The metabolic syndrome

The metabolic syndrome (MetS) is defined as a cluster of risk factors for CVD and T2DM, including raised blood pressure, dyslipidaemia (high triglycerides and low HDL cholesterol), elevated PG and central obesity.

Although there is agreement that the MetS deserves attention, there has been an active debate concerning the terminology and diagnostic criteria related to its definition.

However, the medical community agrees that the term ‘MetS’ is appropriate to represent the combination of multiple risk factors.

Although MetS does not include established risk factors (i.e. age, gender, smoking) patients with MetShave a two-fold increase of CVD risk and a five-fold increase in development of T2DM.

Endothelial progenitor cells and vascular repair

Circulating cells derived from bone marrow have emerged as critical to endothelial repair.

Endothelial progenitor cells (EPCs), a subpopulation of adult stem cells, are involved in maintaining endothelial homeostasis and contribute to the formation of new blood vessels.

Although the mechanisms whereby EPCs protect the cardiovascular system are unclear, evidence suggests that impaired function and reduced EPCs are features of T1DM and T2DM.

Hence, these cells may become a potential therapeutic target for the management of vascular complications related to DM.

PREVENTION OF CARDIOVASCULAR

DISEASE IN PATIENTS WITH DIABETES

Lifestyle

Smoking

Smoking increases the risk of T2DM,148 CVDandpremature death, and should be avoided.

Stopping smoking decreases risk of CVD.150

People with DM who are current smokers should be offered a structured smoking cessation programmeincluding pharmacological support with, for example, buproprion and varenicline if needed.

Detailed instruction on smoking cessation should be given according to the five A principles

Glucose control

Randomized controlled trials provide compelling evidence that the microvascular complications of DM are reduced by tight glycaemic control, which also exerts a favourable, although smaller, influence on CVD that becomes apparent after many years.

However, intensive glucose control, combined with effective blood pressure control and lipid lowering, appear to markedly shorten the time needed to make improvements in the rate of cardiovascular events

Microvascular disease (retinopathy, nephropathy and neuropathy)

Intensified glucose lowering, targeting an HbA1c of 6.0–7.0%, (42– 53 mmol/mol),has consistently been associated with a decreased frequency and severity of microvascularcomplications.

This applies to both T1DM and T2DM, although the outcomes are less apparent in T2DM with established complications .

Analyses from the Diabetes Control and Complications Trial (DCCT) and the UKPDS demonstrated a continuous relationship between increasing HbA1c and microvascularcomplications, without an apparent threshold.

In the DCCT, a decrease in HbA1c of 2% (21.9 mmol/mol) significantly lowered the risk of the development and progression of retinopathy and nephropathy, although the absolute reduction was low at HbA1c ,7.5% (58 mmol/mol).

The UKPDS reported a similar relationship in people with T2DM.

Macrovascular disease (cerebral, coronary and peripheral artery disease)

Although there is a strong relationship between glycaemia and microvascular disease, the situation regarding macrovasculardisorders is less clear.

Hyperglycaemia in the high normal range, with minor elevations in HbA1c, has been associated with increased cardiovascular risk in a dose-dependent fashion.

However, the effects of improving glycaemia on cardiovascular risk remain uncertain and recent RCTs have not provided clear evidence in this area.

The reasons, of which there are several, include the presence of multiple comorbidities in long-standing T2DM and the complex risk phenotype generated in the presence of IR.

Medium-term effects of glycaemic control

Action to Control Cardiovascular Risk in Diabetes (ACCORD)

A total of 10 251 T2DM participants at high cardiovascular risk were randomized to intensive glucose control achieving an HbA1c of 6.4% (46 mmol/mol), or to standard treatment achieving an HbA1c of 7.5% (58 mmol/mol).

After a mean follow-up of 3.5 years the study was terminated due to higher mortality in the intensive arm (14/1000 vs. 11/1000 patient deaths/year), which was pronounced in those with multiple cardiovascular risk factors and driven mainly by cardiovascular mortality.

As expected, the rate of hypoglycaemia was higher under intensive treatment and in patients with poorer glycaemic control, although the role of hypoglycaemia in the CVD outcomes is not entirely clear.

Further analysis revealed that the higher mortality may have been due to fluctuations in glucose, in combination with an inability to control glucose according to target, despite aggressive glucose lowering treatment

Long-term effects of glycaemic control

Diabetes Control andComplications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC).

In DCCT, the rate of cardiovascular events was not significantly altered in the intensive-treatment group.

After termination of the study, 93% of the cohort were followed for an additional 11 years under EDIC, during which the differences in HbA1 disappeared. During the combined 17-year follow-up, the risk of any cardiovascular event was reduced in the intensive group by 42% (9–63%; P , 0.01).

COMPLICATIONS OF DIABETES

Microvascular Complications Renal Nephropathy occurs in 40 percent of patients with type 1

and type 2 diabetes. Risk factors include poor glycemic control, hypertension,

and ethnicity (blacks, Mexicans, Pima Indians).32

Table 90–5 summarizes the key points for the assessment of renal status in a diabetic patient.

The earliest clinical finding of diabetic kidney disease is microalbuminuria, which may occur at a time when renal histology is essentially normal (Fig. 90–5).

The Diabetes Control and Complications Trial (DCCT) and the UKPDS showed that the development and progression of microalbuminuria can be prevented through strict glycemic control.

United Kingdom Prospective Diabetes Study (UKPDS). Although a clear reduction in microvascular complications

was evident, the reduction in MI was only 16% (P ¼ 0.052).

In the extension phase of the study, a risk reduction in MI remained at 15%, which became significant as the number of cases increased.

Furthermore, the beneficial effects persisted for any DM-related end point; MI and death from any cause was reduced by 13%.

It should be noted that this study was performed when lipid lowering and blood pressure were less effectively managed, partially due to the lack of availability of potent, currently available drugs.

Thus UKPDS was performed when other important parts of a multifactorial management were less efficient.

One may speculate that it may have been easier to verify a beneficial effect of glucose-lowering agents at that time, than in subsequently performed trials.

Conclusion. DCCT and UKPDS showed that, in T1DM and T2DM:

(i) glycaemic control is important for reducing long-term macrovascular complications;

(ii) a very long follow-up period is required to demonstrate an effect and

(iii) early glucose control is important (metabolic memory).

Glycaemic targets

An HbA1c target of < 7.0% (< 53 mmol/mol) to reduce microvascular disease is a generally accepted level.

The evidence for an HbA1c target in relation to macrovascular risk is less compelling, in part due to the complexities surrounding the chronic, progressive nature of DM and the effects of metabolic memory.

Consensus indicates that an HbA1c of ≤7% should be targeted, but with acknowledgement of the need to pay attention to the individual requirements of the patient.

Ideally, tight control should be instigated early in the course of the disorder in younger people and without attendant co-morbidities.

Fasting plasma glucose (FPG) should be < 7.2 mmol/L (< 120 mg/dL) and post-prandial ,9–10 mmol/L (< 160–180 mg/dL) on an individualized basis.

Successful glucoselowering therapy is assisted by self-monitoring of blood glucose, most notably in patients with insulin-treated DM.

When near normoglycaemia is the objective, post-prandialglycaemia needs to be taken into account in addition to fasting glycaemia.

However, although post-prandial hyperglycaemia is associated with an increased incidence of CVD events

it remains controversial as to whether treatment targets addressing post-prandial hyperglycaemia are of added benefit to CVD outcomes