Diabetes & Peripheral Artery Disease

Diabetes & Peripheral Artery Disease Michael Bottros, MD

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Learning Objectives Describe the clinical features of peripheral artery disease (PAD) in diabetic patients Identify the risk factors associated with PAD in diabetics Describe the diagnostic tools to accurately diagnose PAD and critical limb ischemia (CLI) in diabetic patients Assess treatment options for individuals with PAD

Overview Introduction Epidemiology Clinical Features Pathogenesis Diagnosis Treatment

The Scope of the Problem WHO 2004 report1 – the number of people with diabetes will reach a total of 366 million by as early as 2030

An increase in prevalence is observed among the middle-aged population in developing countries, whereas in developed countries, it is observed in the population aged 65 years and more2

1. The world health report 2004: changing history 2. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047-1053.

The Scope of the Problem (cont’d)

Prevalence of PAD NHANES1

Aged >40 years

1. Selvin E, Erlinger TP. Circulation. 2004;110:738-743.

2. Criqui MH, et al. Circulation. 1985;71:510-515.

3. Diehm C, et al. Atherosclerosis. 2004;172:95-105.

4. Meijer WT, et al. Arterioscler Thromb Vasc Biol. 1998;18:185-192.

5. Hirsch AT, et al. JAMA. 2001;286:1317-1324.

4.3%

San Diego2

11.7%

Mean age 66 years

NHANES1

14.5%

Aged 70 years

Rotterdam3

19.1%

Aged >55 years

Diehm4

19.8%

Aged 65 years

PARTNERS5

29%

Aged >70 years, or 50–69 years with a history diabetes or smoking

0%

5%

10%

15%

20%

25%

30%

35%

Slide adapted from: The Peripheral Arterial Disease Guideline:

Evidence-Based Management of Patients With PAD. Core Curriculum Slide Set

NHANES=National Health and Nutrition Examination Study; PARTNERS=PAD Awareness, Risk, and Treatment: New Resources for Survival [program].

The Scope of the Problem prevalence of Diabetes increases with age

prevalence of PAD increases with age

PAD & “ischemic foot� as one of the main complications of DM

Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

Prevalence  Prevalence of PAD is higher in patients with DM  Framingham study: 3.5- and 8.6-fold excess risk among men and women, of developing PAD with DM  Rochester study: prevalence of PAD at the time of diagnosis of DM was 8% between the years 1945-1969, and10.5% in 1970  Hoorn study: prevalence of ABI < 0.9 in individuals with normal glucose tolerance was 7% and increased to 20.9% in diabetic patients Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Does the Type of Diabetes Affect the Prevalence of PAD?

Prevalence Welborn et al. showed that the type of DM does not affect the prevalence of PAD, identical prevalences being found in patients with Type 1 (DMI) and Type 2 DM (DMII)1 However, Walters et al. found a much higher prevalence of PAD (23.5%) in patients with DMI than in those with DMII (8.7%)2 1. Welborn TA, Knuiman M, McCann V, et al. Clinical macrovascular disease in Caucasoid diabetic subjects: logistic regression analysis of risk variables. Diabetologia 1984; 27: 568–573.

2. Walters DP, Gatling W, Mullee Maet al. The prevalence, detection, and epidemiological correlates of peripheral vascular disease: a comparison of diabetic and non-diabetic subjects in an English community. Diabet Med 1992; 9: 710–715.

Amputation Rate ď&#x201A;§Diabetic patients have increased risk of lowerextremity amputations compared to non-diabetics ď&#x201A;§No evidence that revascularization procedures are effective in preventing amputation ď&#x201A;§Moreover, the severity of PAD in DM assessed angiographically has been associated with major amputations Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Mortality Diabetic patients with PAD have 3- to 4-fold increased mortality compared with healthy individuals Patients with critical limb ischemia and DM have a shorter amputation- free survival period than patients with critical ischemia but without DM The 5-year mortality in diabetic patients with critical limb ischemia is 30% Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Is Peripheral Artery Disease Different in Diabetic Patients?

The Effect of Diabetes on PAD  PAD may be asymptomatic until it reaches an advanced stage  It presents at an earlier age and progresses more rapidly than in nondiabetic patient  It is usually more severe in extent  Often not all patients may be offered a revascularization procedure when needed  Outcome after revascularization procedures is poorer and many patients progress to a major amputation  The presence of PAD is in itself an independent factor for increased mortality due to associated cardiovascular and cerebrovascular disease.  Finally, early detection of PAD helps in risk factor modification, which reduces progression and improves outcome Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Clinical Features Histologically, plaques between diabetics and nondiabetics do not differ Clinically, they consistently differ. In diabetics: –occlusive disease is widespread –anatomical localization is mainly distal –arterial wall calcification is frequently present –occlusion occurs more frequently than stenosis Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

Clinical Features

Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

Clinical Features

1998-2000

2009 Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

Clinical Presentation The majority of diabetic patients with PAD are asymptomatic (up to 75%) when ABI < 0.9 is the criterion for the diagnosis Patients with DM develop more symptomatic forms of PAD such as intermittent claudication, foot ulcers and critical limb ischemia symptoms Diabetic patients with decreased pain perception due to peripheral neuropathy may delay the recognition of PAD Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Peripheral Diabetic Neuropathy Most common form of neuropathy Affects ~50% by 15 years Bilateral Pain, burning, numbness, and autonomic dysfunction (lack of sweating) in the hands and feet in a stocking-glove distribution Tavee J , Zhou L Cleveland Clinic Journal of Medicine 2009;76:297-305

Clinical Presentation Peripheral neuropathy and PAD are known risk factors for foot ulceration 40–60% of diabetic patients with foot ulcers have PAD Dry gangrene is the endstage presentation of PAD Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Risk Factors  Increasing age:

– The Framingham-offspring study showed that for each 10 years of age, the odds ratio of PAD was 2.6

 Gender:

– Framingham and Rochester studies, the incidence of PAD was higher in men than in women – Diabetic women are more likely to have PAD compared with nondiabetic women of similar age – Premenopausal women have relative protection from atherosclerosis due to their hormonal status; DM blunts benefit of the female gender, esp. in elderly Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Fraction of Population With PAD (%)

Risk Factors 10 9 8 7 6 5 4 3 2 1 0

NHW

Black

Hispanic

Asian

Criqui MH, Vargas V, Denenberg JO, et al. Ethnicity and peripheral arterial disease: Slide adapted from: The Peripheral Arterial Disease Guideline: the San Diego Population Study. Circulation. 2005 Oct 25;112(17):2703-7 Evidence-Based Management of Patients With PAD.

Core Curriculum Slide Set

Risk Factors  Glycemic control: – (UKPDS): duration and degree of hyperglycemia associated with increased risk for incident PAD independently of other factors – Each 1% increase in HbA1c was associated with a 28% excess risk for incident PAD at the end of 18 years  Duration of disease: – DMI: Odds ratio of PAD was 28.9 for a DM duration of 20–29 years and 51.1 for > 30 years – DMII: Odds ratio was 3.8 for a DM duration of 10– 19 years and 4.3 for > 20 years  SBP: – Each 10-mmHg increase in SBP associated with a 25% increased risk at end of 18 years – Tight BP control was also associated with lower prevalence of PAD at long-term follow-up in the UKPDS Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Risk Factors

Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Pathogenesis

Pathogenesis: Endothelial Dysfunction Endothelial function impaired by: –Hyperglycemia –Excess circulating free fatty acids –Increased oxidative stress –Inhibition of endothelial nitric oxide (NO) synthase

Thus, there is a decrease in NO and prostacyclin and an increase in endothelin-I and angiotensin-II, which are potent vasoconstrictors.

Marso SP, Hiatt WR. Peripheral arterial disease in patients with diabetes. J Am Coll Cardiol 2006; 47: 921–929.

Pathogenesis: Inflammation  CRP is strongly associated with the development of PAD  CRP is abnormally elevated in patients impaired glucose tolerance and diabetes  In addition to being a marker, CRP may also be a cause for PAD: – CRP binds endothelial cell receptors promoting apoptosis – Colocalizes with oxidized LDL in atherosclerotic plaques – Stimulates endothelial production of procoagulant tissue factor, leukocyte adhesion molecules, and chemotactic substances – Inhibits endothelial cell nitric oxide (NO) synthase (eNOS), resulting in dysregulation of vascular tone – Increases the local production of compounds impairing fibrinolysis, such as plasminogen activator inhibitor (PAI)-1

American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

Pathogenesis: Platelet Dysfunction  Platelets play an integral role in the connection between vascular function and thrombosis  Abnormalities not only promote the progression of atherosclerosis, but also plaque disruption  Hyperglycemia increases oxidative stress and thus increases platelet aggregation.  Platelets in diabetic patients also have increased expression of glycoprotein Ib and IIb/IIIa receptors, which are important in thrombosis via their role in adhesion and aggregation  Calcium hemostasis regulating platelet shape, secretion, aggregation and thromboxane production is disturbed in DM

American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

Pathogenesis: Coagulation Dysfunction Diabetes leads to a hypercoagulable state: –Increased production of tissue factor by endothelial cells and VSMCs, as well as increased plasma concentrations of factor VII –Decreased concentration of antithrombin and protein C –Impaired fibrinolytic function –Excess production of Plasminogen Activtor Inhibitor-1 –Elevation in blood viscosity and fibrinogen American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

Pathogenesis Summary

Creager M, Luscher T. Diabetes and Vascular Disease Pathophysiology, Clinical Consequences, and Medical Therapy: Part I. Circulation 2003;108:1527-1532

Diagnosis

Diagnosis Diagnostic needs differ based on the spectrum of PAD in the diabetic patient: –asymptomatic disease –symptomatic noncritical peripheral disease –critical limb ischemia

Accurate diagnosis of these different clinical pictures is essential for proper treatment and prognosis for limb salvage Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

History & Physical (cont’d) Elicit a thorough walking history Claudication:

–pain after walking a short distance, forcing the patient to stop walking and is only relieved at rest –affects a certain group of muscles according to the level of occlusion: • in aorto-iliac occlusion, the pain affects the gluteal muscles • in femoro-popliteal occlusion, the pain affects the calf muscle • in more distal occlusion, the pain affects the foot muscle • Radiculopathy may be confused with claudication

Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

History & Physical (contâ&#x20AC;&#x2122;d) ď&#x201A;§ Critical limb ischemia: stage of ischemia that may precipitate limb loss within 6 to 12 months

Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

History & Physical (cont’d)  Critical limb ischemia (cont’d)

Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

History & Physical (cont’d) Visually inspect the foot: –Signs of vascular insufficiency include: • dependent rubor • pallor on elevation • absence of hair growth • dystrophic toenails • cool, dry, fissured skin

–The interdigital spaces should be inspected for fissures, ulcerations, and infections American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

History & Physical (cont’d)  Palpation of peripheral pulses: –should include assessment of the femoral, popliteal, and pedal vessels –is a learned skill and has a high degree of interobserver variability, with high false- positive and false-negative rates  The dorsalis pedis pulse is reported to be absent in 8.1% of healthy individuals  The posterior tibial pulse is absent in 2.0%  The absence of both pedal pulses assessed by an experienced individual, strongly suggests the presence of vascular disease American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

The Ankle-Brachial Index (ABI)  The ABI is a reproducible and reasonably accurate, noninvasive measurement for the detection of PAD  Defined as the ratio of the systolic blood pressure in the ankle divided by the systolic blood pressure at the arm  The tools required include: – a hand-held 5-MHz Doppler probe over the popliteal and femoral arteries – an 8-MHz Doppler probe over the pedal arteries – a 10-MHz Doppler probe over the digital arteries – a common sphygmomanometer American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

The Ankle-Brachial Index [ABI] (cont’d)  Place the patient supine for 5 min  Systolic blood pressure is measured in both arms, and the higher value is used as the denominator of the ABI  Systolic blood pressure is then measured in the dorsalis pedis and posterior tibial arteries by placing the cuff just above the ankle. The higher value is the numerator of the ABI in each limb

Khan TH, Farooqui FA, Niazi K. Critical review of the ankle brachial index. Curr Cardiol Rev. 2008 May;4(2):101-6.

The Ankle-Brachial Index [ABI] (contâ&#x20AC;&#x2122;d)

Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds. 2011 Sep;10(3):152-66.

ABI Screening Screening ABI should be performed in patients > 50 years of age who have diabetes If normal, the test should be repeated every 5 year. A screening ABI should be considered in diabetic patients > 50 years of age who have other PAD risk factors (e.g., smoking, hypertension, hyperlipidemia, or duration of diabetes > 10 years) A diagnostic ABI should be performed in any patient with symptoms of PAD American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

Segmental Pressures and PVR  After diagnosis of PAD, the next step would be a vascular laboratory evaluation for segmental pressures and pulse volume recordings (PVRs)  Should also be considered for patients with poorly compressible vessels or those with a normal ABI where there is high suspicion of PAD  Segmental pressures and PVRs are determined at the toe, ankle, calf, low thigh, and high thigh  Segmental pressures help with lesion localization, while PVRs provide segmental waveform analysis, a qualitative assessment of blood flow American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

Treadmill Testing May help in patients with atypical symptoms or a normal ABI with typical symptoms of claudication Patients with claudication will typically exhibit a > 20-mmHg drop in ankle pressure after exercise May also be used as an evaluation of treatment efficacy and as an assessment of physical function American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

Imaging Studies  Duplex ultrasound or MRA may be valuable anatomical localization  Duplex ultrasound can directly visualize vessels and is also useful in the surveillance of post-procedure patients for graft or stent patency  MRA is noninvasive with minimal risk of renal insult. It may give images that are comparable with conventional X- ray angiography, especially in occult pedal vessels, and may be used for anatomical diagnosis

West AM, Anderson JD, Epstein FH, Low-Density Lipoprotein Lowering Does Not Improve Calf Muscle Perfusion, Energetics, or Exercise Performance in Peripheral Arterial Disease. J Am Coll Cardiol. 2011 Aug;58(10):1068-76.

American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care. 2003 Dec;26(12):3333-41.

Hirsch AT, Haskal ZJ, Hertzer NR, et al. Circulation. 2006;21:e463-e654.

Treatments

Lifestyle Modification  Cigarette smoking is the single most important risk factor for the development of atherosclerosis and smoking cessation may halt the progression of disease – Increases the risk and reduces the success of peripheral vascular intervention

 Physical exercise improves exercise tolerance

– Increases cardiovascular fitness, oxidative enzyme activities, NO production and insulin sensitivity – Enhances utilization of fatty acids in calf muscles – Improves walking biomechanics – Leads to modest reductions in BP, cholesterol, and glucose levels Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Glycemic Control  No conclusive evidence to suggest that optimal glycemic control lowers the risk of PAD  However, optimal glycemic control would be sensible in patients with PAD  Medications that improve insulin resistance may have advantages over other hypoglycemic agents, since insulin resistance is a risk factor for PAD –However, metformin was not superior to sulphonylureas or insulin in the prevention of PAD in DM –In the PROACTIVE study only patients without PAD at baseline benefited from treatment with pioglitazone Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Dyslipidemia  Goal is LDL-cholesterol levels  Statins are the treatment of choice in such patients  The 4S-Study: simvastatin reduced claudication in patients with PAD, although there were no specific data regarding diabetic patients  The Heart Protection Study: lowering LDL-cholesterol with simvastatin reduces cardiovascular mortality and morbidity in diabetic patients by almost 25%  Collaborative Atorvastatin Diabetes Study: aggressive treatment with atorvastatin in diabetic patients reduced major cardiovascular events by 37%, irrespective of pretreatment LDL-cholesterol levels Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Hypertension  Goal of 130 ⁄ 80 mmHg reduces stroke and death rates  HOPE study showed that ramipril decreased the rates of MI, stroke, and death in diabetic patients with cardiovascular disease – Reduction of cardiovascular morbidity and mortality was 25%

 A meta-analysis concluded that beta-blockade was not associated with reduced treadmill walking performance in PAD patients with intermittent claudication  Currently, beta-blockers are recommended to be used when indicated, except in patients with critical limb ischemia Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Antiplatelet Therapy Anti-platelet Trialists’ Collaboration: an antiplatelet agent, usually aspirin, reduces cardiovascular deaths by 25% –This reduction was 18% in the subset with intermittent claudication

Aspirin with dipyridamole resulted in the least progression of PAD compared with aspirin alone or placebo –A dose of 325 mg did not show any additional benefit over a dose of 75 mg Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Antiplatelet Therapy (cont’d) Ticlopidine improves clinical outcomes in patients with PAD but not recommended because neutropenia and TTP Clopidogrel has fewer side-effects. The CAPRIE study: clopidogrel decreased the end-point of MI by 19.2% over that of aspirin irrespective of the primary cardiovascular disease Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Drugs for Symptomatic PAD  Two agents for the treatment of intermittent claudication: pentoxifylline and cilostazol  Pentoxifylline reduces blood viscosity, has antiplatelet action, and reduces serum fibrinogen levels – Most studies demonstrated only a modest improvement suggesting it is not justified for routine use – Pentoxifylline may benefit patients with severe claudication symptoms and those in whom exercise and ⁄ or cilostazol is not effective or is contraindicated

 Cilostazol suppresses cAMP degradation. Increased cAMP inhibits thromboxane A2 production and platelet aggregation. Cilostazol induces vasodilation by inhibiting calcium-induced contractions of smooth muscle cells

Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Drugs for Symptomatic PAD ď&#x201A;§Treatment with cilostazol increases pain-free and maximal treadmill walking distances and improves quality of life significantly more than pentoxifylline or placebo ď&#x201A;§Cilostazol is contraindicated in patients with congestive heart failure and severe hepatic or renal impairment ď&#x201A;§These drugs for intermittent claudication are recommended in the event of failure of lifestyle modifications Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Therapeutic Angiogenesis  A novel approach to increase blood flow to ischemic tissues by induction of a collateral vascular network  Achieved by administration of angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF) and nerve growth factor (NGF)  Two modes:

– topical administration of the recombinant growth factor protein – incorporation of genes encoding angiogenic growth factors into a vector (virus or plasmid) to deliver DNA to human cells

 Indication may be for the management of severe limb ischemia not amenable to revascularization surgery

Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Revascularization ď&#x201A;§The number of revascularization procedures for PAD is 8-x to 16-x higher in diabetic compared with nondiabetic patients ď&#x201A;§The choice of a procedure depends on many factors such as site and extent of the disease, distal run off and surgical risk due to associated cardiovascular disease Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.

Summary  PAD is influenced by the co-presence of diabetes  PAD begins earlier, progresses more rapidly, and is more commonly asymptomatic in DM  Distal arterial involvement is the predominant pattern  Lifestyle modifications show benefit  Drug therapy is advised in patients who do not respond to lifestyle modification  Antiplatelet therapy can retard the onset and progression of PAD and reduce cardiovascular events in diabetic patients  Therapeutic angiogenesis represents a promising therapeutic adjunct in the management of PAD and further research is needed Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes--a review. Diabet Med. 2010 Jan;27(1):4-14.