VASCULAR COMPLICATIONS OF DIABETES - PART 3 potx

The benefit was greater for microvascular com-plications but a significant reduction in macrovascular events was also seen.The previous fears raised by the University Group Diabetes Prog

CHAPTER 4 • CORONARY HEART DISEASE AND DIABETES

negative interaction between aspirin and intravenous enalapril (an 11%increase in mortality in the enalapril group) However, in this studyhypotension and severe cardiac failure at the time of randomization werenot exclusion criteria GISSI-3, using lisinopril, showed a 44% and 27%reduction in 6-week mortality in type 1 and type 2 diabetics respectively

The large Heart Outcomes Prevention Evaluation (HOPE) study domized patients with CHD but clinically normal left ventricular (LV) func-tion to ramipril 10 mg or placebo, with or without vitamin E The diabeticsubgroup (Micro-HOPE) of 3,577 patients were followed for a mean of 4.5years and treatment with ramipril was associated with a 24% reduction inall-cause mortality, a 22% reduction in the rate of MI and a 33% reduction

ran-in the rate of stroke (Fig 4.6) Vitamran-in E had no benefit

Does improving glycaemic control reduce cardiovascular risk?

The Diabetes Complications and Control Trial (DCCT) of conventional vs.intensive glycaemic control in type 1 diabetes was underpowered to answer thisquestion as the cohort was relatively young and therefore the number of eventswas low There was a trend towards a reduction in cardiovascular events in theintensively treated group The UK Prospective Diabetes Study (UKPDS) trial

41

Fig 4.5 Effects of simvastatin 20–40 mg on fatal and non-fatal cardiovascular

events in patients with diabetes and non-diabetics with known CHD:

Scandanavian Simvastatin Survival Study (4S).

DM, simvastatin

DM, placebo

Non-DM, simvastatin Non-DM, placebo

also had a non-significant (16%) reduction in fatal and non-fatal MIs in theintensively treated group after 15 years Again, this may be because of the rela-tively low event rate in a group of patients who were recruited at diagnosis andwere relatively young Additionally, the trial had as exclusion criteria diagnosessuch as severe peripheral vascular disease and existing CHD However, furtheranalysis of the UKPDS data showed that irrespective of the treatment arm, thelower the HbA1C, the lower the event rate for both micro and macrovascularcomplications There was a 21% decrease in all diabetes related end-points foreach 1% decrement in HbA1C The benefit was greater for microvascular com-plications but a significant reduction in macrovascular events was also seen.The previous fears raised by the University Group Diabetes Program (UGDP)

in the 1970s that sulphonylureas were associated with increased cardiovascularmortality was not realized and there appeared to be no difference between

insulin and sulphonylureas as long-term therapy, in this regard Nevertheless,

there remains uncertainty about their use in the acute setting (e.g acute MI orangioplasty etc.) where there is some evidence that there is loss of protectiveischaemic pre-conditioning, possibly due to their inhibitory effect on the ATPsensitive K+ channel

However, in the UKPDS, metformin used as monotherapy in the obesepatient was associated with a significant reduction in CV deaths compared toinsulin or sulphonylureas There is no long-term data on thiazolidenedionederivatives or the newer sulphonylureas

Fig 4.6 Micro-HOPE Study: Effects of Ramipril or placebo on cardiovascular death in

3,577 diabetics with normal left ventricular function Lancet 2000; 355: 253–259

Cumulative mortality Kaplan-Meier rates

RRR = 37% (21-51) P = 0.0001

CHAPTER 4 • CORONARY HEART DISEASE AND DIABETES

Anti-platelet therapy

There have been no specific trials of aspirin in acute MI in people with betes but secondary prevention studies demonstrate a 25% reduction in car-diovascular events and a 15% reduction in mortality with apparently similarresults in people with diabetes The optimal dose of aspirin remains uncertainbut lower doses are associated with fewer haemorrhagic complications.Evidence of benefit of aspirin in people with diabetes for primary preventionmust be extrapolated from trials in non-diabetics (mostly male) which havesuggested that there is a reduction in non-fatal cardiovascular and cere-brovascular events These trials have also shown that 75 mg is probably aseffective as 500 mg and is not associated with an increased risk of cerebralhaemorrhage in patients with controlled hypertension There was a non-sig-nificant reduction in fatal and non-fatal MI in the Early Treatment ofDiabetic Retinopathy Study using 325 mg aspirin

dia-Lipid-lowering therapy

Statins will reduce mortality, the need for revascularization and cardiovascularand cerebrovascular events, but the optimum dose and lipid targets remainuncertain The British and Europeans recommend achieving a total cholesterol

<5 mmol/l, and LDL <3 mmol/l, whilst the American Diabetes Association gests an LDL target <2.6mmol/l, HDL >1.15mmol/l and triglycerides <2.3mmol/l Improved glycaemic control will enhance the lipid profile, though gli-tazones (more so rosiglitazone) cause a 12% increase in LDL (compensated inpart by an increase in HDL) These LDL particles are less dense and theoreti-cally less atherogenic though there are no long-term outcome studies yet com-pleted Fibrates have little effect on LDL but increase HDL and lower triglyc-erides Only gemfibrozil has been shown to reduce cardiovascular mortality –which in the Veterans Affairs–High density Lipoprotein Intervention Trial(VA-HIT) study resulted in a 22% reduction in CHD deaths or non-fatal MIs.This study included 25% diabetics and so for patients intolerant of statins, gem-fibrozil 600mg twice daily is a suitable alternative

sug-Diabetic patients presenting with non-ST segment elevation (NSTE) acutecoronary syndrome have a higher risk profile for subsequent events and somestudies suggest they derive greater benefit when managed with rapid initiation ofintensive management together with early angiography and revascularization.For most parts of the world, such aggressive reperfusion strategies remainbeyond reach Nevertheless, intensive multiple risk factor treatment in highrisk patients (such as a patient with type 2 diabetes and microalbuminuria)has been shown to reduce cardiovascular events by as much as 53% (CI 27–76)over an 8-year period when compared to a less intensive strategy

43

People with diabetes may not always be suitable for revascularization dures as their atherosclerotic disease is often severe and widespread Long-termsurvival following CABG is less good in diabetic patients The BypassAngioplasty Revascularization Investigation (BARI) trial suggested that 5-yearoutcomes from angioplasty were inferior to CABG in diabetic patients Thoughwith improved techniques, routine use of GPIIb/IIIa inhibitors, and drug-elut-ing stents, percutaneous intervention may become a more desirable option indiabetic patients with multivessel disease.

proce-FURTHER READING

Hales CN, Barker DJP, Clark PMS et al Fetal and infant growth and impaired glucose

tolerance at age 64 BMJ 1991; 303: 1019–22.

Malmberg K, Ryden L, Efendic S et al on behalf of DIGAMI Study Group A randomised trial

of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic

patients with acute MI (Oigami Study): effects on mortality at 1 year J Am Coll Cardiology

1995; 26: 57–65.

Laing, S P Swerdlow, A J Slater, S D Bothat, J l Burden, A C Waugh, N R Smith,

A W M Hill, R.D Bingley, P J Patterson, C C Qiao, Z Keen, H The British Diabetic

Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes

mellitus; Diabet Med 1999; 16: 459–465.

CHAPTER 5

DIABETES AND CEREBROVASCULAR DISEASE

Adrian R Scott MD, FRCP 45

INTRODUCTION

The great disabler of all the macrovascular complications – stroke – is, as one

might expect, more frequent in people with diabetes and the outcome worse

than in non-diabetics The prevalence of cerebral infarcts, especially lacunar

infarcts, is increased but the prevalence of subarachnoid haemorrhage,

cere-bral haemorrhage, and transient ischaemic attacks are decreased, despite

hypertension being so common in the diabetic patient The presence of

dia-betic nephropathy and coronary and peripheral vascular disease are risk

fac-tors for stroke in the diabetic patient Afro-Caribbeans and Afro-Americans

with diabetes are particularly at risk

A higher prevalence of stroke is found in the patient with both diagnosed

and undiagnosed diabetes and glucose intolerance and, as with myocardial

infarction (MI), most studies show that individuals with admission serum

glucose of >6.6 mmol/l have a higher morbidity and mortality

EPIDEMIOLOGY

A number of large studies have confirmed the higher prevalence of stroke in

the diabetic population In the Framingham study the fourfold excess in male

diabetics occurred in the 5thand 6thdecades, whereas in females with diabetes

the excess was a decade later Most studies (usually of hospitalized patients)

suggest a relative risk of stroke 2–3 times that of non-diabetics though the

Swedish Gothenburg study put this excess as high as sixfold in men and 13-fold

in women Most studies have not distinguished between insulin requiring and

non-insulin requiring diabetes, but for type 1 the excess may not be so great as

with type 2 Certainly it is not as common as cardiovascular disease – Dekert’s

long term mortality study (1976) of people with diabetes diagnosed before age

30 and followed up for more than 40 years showed a 10% incidence and 7%

mortality from stroke A similar UK study of diabetics dying before their 50th

birthday found a similar mortality from stroke compared to 41% from

coro-nary heart disease (CHD) and 19% from nephropathy

Diabetes mellitus is associated with higher mortality, worse functional

outcome, more severe disability after stroke and a higher frequency of

recur-rent stroke Short- and long-term mortality is increased and in one carefully

matched Finnish study, 5-year mortality was 60% in the non-diabetic

con-trols with stroke compared to 80% in those with diabetes

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition

Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

Cerebral blood flow disturbances, impaired cerebrovascular reactivity, anddamage to large and small extra- and intracranial cerebral vessels have beenfound in humans and animals with diabetes Autopsy studies suggest that dia-betic patients are susceptible to cerebral small-artery disease and lacunarinfarction These strokes result from vascular occlusion of small arteries at thebase of the brain resulting in small deep arterial infarcts usually less than

15 mm in diameter and typically occur in hypertension and diabetes.Embolism from large vessel atheroma and heart (particularly post-infarct) isalso more common In one prospective study, carotid stenoses of >50% werepresent in 8.2% of diabetics compared with 0.7% of age-matched controls.However, only 28% of diabetics with an ischaemic cerebral event had a sig-nificant carotid stenosis suggesting that smaller vessel disease is more impor-tant The precipitant for the occlusion is not clear but appears to be linked toexcessive glycation and oxidation, endothelial dysfunction, increased plateletaggregation, impaired fibrinolysis and insulin resistance Cerebrovascularblood flow has been shown to be abnormal in people with diabetes, both ofauto-regulation and in response to vasodilators such as CO2 Endothelial dys-function with failure to vasodilate in response to nitric oxide has been postu-lated; autonomic neuropathy may also be a factor

Blood glucose on admission correlates both with survival and degree ofrecovery Several studies have demonstrated a worse outcome with a presentingblood glucose >6.6mmol/l Whether hyperglycaemia adversely affects strokeoutcome or primarily reflects stroke severity is not clear – animal studies of acutehyperglycaemia prior to cerebral ischaemia show more severe histological dam-age and a worse outcome but there is no evidence in humans that infarct size islarger Hyperglycaemia might theoretically worsen stroke damage in a number

of ways: the local hypoxia induced by acute cerebral ischaemia results in glucosebeing metabolized anaerobically causing lactic acid to accumulate The resultantlocal acidosis damages vascular, glial and neuronal tissue In addition, ischaemiacauses accumulation of the neurotransmitters, glutamate and aspartate, in theextracellular tissues Usually these neurotransmitters cause stimulation of anerve at a post-receptor site and depolarization When accumulation occurshyperstimulation also occurs, followed by neuronal death, though glial and vas-cular tissue are spared This neural toxicity may result from an increase in intra-cellular calcium following neuronal hyperstimulation

CLINICAL PRESENTATION

Strokes are common and the lack of challenging interventions has oftenmeant that these patients are not always adequately assessed and hence

CHAPTER 5 • DIABETES AND CEREBROVASCULAR DISEASE

receive sub-optimal care Not all acute neurological events are strokes andconsideration must be given to the underlying cause – classically, hypogly-caemia may present with altered consciousness but also with focal neurologyand if missed, permanent neurological sequelae may result There are alsoreports in the literature of focal fits and neurological signs in association withhyperglycaemia but these preceded modern scanning technology so may haverepresented small strokes or transient ischaemic attacks (TIAs) However, it

is important not to overlook the diagnosis of non-ketotic hyperosmolar states(HONK) as the dehydration and elevated viscosity may have led to arterialocclusion causing stroke, MI, or even peripheral gangrene Silent ischaemia isrelatively common and patients may present with a stroke and uncontrolleddiabetes as a complication of an earlier painless MI

EVIDENCE-BASED PRACTICE

The reality is that acute stroke management in the person with diabetes is based

on extrapolation of the data from non-diabetics as there are, as yet, no tive studies of stroke management in diabetics However, there is one proviso:these are high risk patients with a multi-system disorder, whom as a group dobadly, both in terms of survival, and rehabilitation Early interventions must beundertaken promptly as any delay is not likely to improve prognosis

prospec-The role of thrombolysis of acute stroke remains controversial but a tematic review of 12 controlled trials involving 3,435 patients assessed the use ofintravenous thrombolytic therapy (with a number of agents) started within sixhours of the onset of symptoms of ischaemic stroke Thrombolysis reduced theproportion of patients who died or remained dependent on others at the end oftrial follow-up, up to six months later (61.5% vs 68% of control patients notgiven thrombolysis) Results were more impressive if treatment was startedwithin three hours (56.6% vs 70.7%) Alteplase seemed superior to streptoki-nase but overall there was an increased risk of symptomatic intracranial haem-orrhage (9.6% vs 2.6%) Overall, the risk of dying within two weeks wasincreased in those receiving thrombolytic therapy (20.9% vs 11.9%) despite theimprovement in the composite end-point of death or dependency Whetherpeople with diabetes benefit similarly from thrombolysis is not known Use ofanticoagulant therapy with unfractionated or low-molecular weight heparin foracute ischaemic stroke is associated with an increase in haemorrhagic stroke butwith no positive benefit in terms of mortality or dependency

sys-If CT scanning is not immediately available to rule out haemorrhage,administration of aspirin (orally or rectally) should, on balance, be given soon-

er rather than later With the exception of immediate post-stroke hypertensionmanagement (about which little is known but for which avoidance of treatment

is recommended for at least four weeks), correction of other co-morbidities

47

seems logical but lacks the confirmation of randomized-controlled trials Thus,dehydration and hypoxia should be avoided, with administration of antibiotics

if respiratory infection supervenes The benefits of treatment of hyperglycaemia

in this situation are unknown but, as it correlates with a worse outcome, aDIGAMI-style glucose and insulin infusion to maintain near-normoglycaemiawould seem to be a cheap and easily implementable solution Heparin prophy-laxis is best avoided as there appears to be an increased risk of secondary cere-bral haemorrhage but prevention of deep venous thromboses (DVTs) is achiev-able with elasticated thromboembolic stockings

Secondary prevention data is based entirely on general population studieswith none having been conducted in people with diabetes alone Generalmanagement of vascular risk factors using targets similar to those for diabet-

ic patients with CHD would seem logical The dose of aspirin is uncertain andsome authors have suggested that people with diabetes may need higher doses

to achieve the same anti-platelet effects The European Stroke PreventionStudy showed that, in the general population, aspirin and sustained-releasedipyridamole are equally effective secondary prevention in reducing the risk

of stroke and/or death Addition of dipyridamole is justified if the patient has

a cerebrovascular incident whilst on aspirin as this study showed that thecombination was significantly more effective than either alone

Clopidogrel is slightly superior to aspirin at the prevention of recurrentstroke but probably not sufficiently cost-effective to justify widespread use Inthe Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE)study 7.2% of those treated with clopidogrel 75 mg/day had an event com-pared with 7.7% of patients receiving aspirin 325 mg/day It may be moreaffordable if patients with true aspirin allergy are targeted or those who havegastrointestinal intolerance to aspirin but not clopidogrel Reports of throm-botic thrombocytopenic purpura with clopidogrel are worrying but fortu-nately rare

Warfarin should be substituted for antiplatelet therapy if the cause of thestroke is attributable to atrial fibrillation or other emboli from the heart It isprobably safer to wait two weeks after the stroke before making this change Primary prevention of stroke in people with diabetes is of interest becausethere are a number of studies where stroke prevention has been a significantsecondary end-point The UK Prospective Diabetes Study (UKPDS) of hyper-tension, where the target for tight blood pressure control was <150/85, showed

a 44% reduction in strokes compared to the less tight blood pressure controlgroup (target BP <180/105)

Ramipril 10mg daily in the diabetic sub-group of the Heart OutcomesPrevention Evaluation (HOPE) study (Micro-HOPE) reduced the number ofstrokes from 6.1% to 4.2% (a 33% relative risk reduction) in a cohort of patients

CHAPTER 5 • DIABETES AND CEREBROVASCULAR DISEASE

most of whom had established CHD The difference in blood pressure betweenthe ramipril and placebo groups at the end of the study was only 2.5/1.0 – somewould say this was insufficient to account for the difference in stroke rates, sug-gesting a different mode of vascular protection by angiotensin-convertingenzyme inhibitors (ACE-Is) than simply lowering blood pressure However,sub-groups studied with 24 hour blood pressure monitoring suggest that casu-

al blood pressure readings underestimate the difference between the treatedand untreated groups and most experts conclude that blood pressure lowering

is more important than the type of antihypertensive drug used

In both CARE and LIPID (secondary prevention studies in patients withprevious MI or angina) pravastatin 40 mg reduced the risk of fatal and non-fatal cerebrovascular accidents by 31% and 20% respectively The numberswith diabetes, however, were too small to analyse as a separate group

In summary, stroke prevention in people with diabetes is about aggressivemanagement of all vascular risk factors but with an emphasis on tight bloodpressure control and use of antiplatelet therapy, ACE-Is and statins Newdrugs in development offer the possibility of limiting neuronal damage at thetime of the acute event

49

CURRENT ISSUES

• Correction of hyperglycaemia with a glucose and insulin infusion at the

time of the acute stroke is the subject of a randomized controlled trial

Until this is reported, the DIGAMI study of glucose and insulin infusion in

acute myocardial infarction provides sufficient evidence to suggest that

stroke patients are likely to benefit in a similar way, and uncontrolled

hyperglycaemia should not be neglected

• The place of thrombolysis in the management of acute stroke has yet to

be determined and should probably only be undertaken in the context

of randomized controlled trials Current evidence suggests it must be

given within three hours of the onset of symptoms – a goal not

deliverable in most countries

• Neuroprotective therapy remains experimental but a number of agents

are being investigated They include clomethiazole, glycine antagonists,

lubeluzole and magnesium Such treatment, given promptly after stroke

onset, aims to limit ischaemic damage by protecting damaged but

potentially viable neural tissue Animal studies have suggested a

neuroprotective effect of lubelozole but in humans it has not been

shown to reduce neurological disability or mortality

FURTHER READING

Antiplatelet Trialists’ Collaboration Collaborative overview of randomised trials of

antiplatelet therapy – I: Prevention of death, myocardial infarction, and stroke by

pro-longed platelet therapy in various categories of patients BMJ 1994; 308: 81–106.

Counsell C, Sandercock P Anticoagulant therapy compared to control in patients with

acute presumed ischaemic stroke (Cochrane Review) The Cochrane Library, Issue 2, 1998.

Diener HC for the European and Australian Lubelozole Ischaemic Stroke Study Group.

Multinational randomised controlled trial of Lubelozole in acute ischaemic stroke.

Cerebrovasc Dis 1998; 8: 172–181.

Wardlaw JM, Warlow CP, Counsell C Systemic review of evidence on thrombolytic

thera-py for acute ischaemic stroke Lancet 1997; 350: 607–614.

CHAPTER 6

ERECTILE DYSFUNCTION

Adrian R Scott MD, FRCP 51

INTRODUCTION

Diabetes may lead to sexual dysfunction in both men and women For the

purposes of this book it is not possible to consider diabetes-related sexual

dysfunction in women though the causes are similar in both genders For

years the treatment of erectile dysfunction (ED) was complex, unsatisfactory

and disliked by patients and/or their partners Embarrassment lead to a

con-spiracy of silence: ‘I won’t ask if you won’t say’ – and this important and

dis-tressing complication was too often ignored With the advent of oral

thera-pies for ED and the publicity surrounding the launch of Viagra (sildenafil),

there has been much more open discussion Therefore, even though a third

of diabetic men will not respond to sildenafil, the dialogue has begun and

other treatment avenues can be explored This chapter looks at the aetiology

of erectile dysfunction in people with diabetes, the importance of a correct

diagnosis, followed by a look at past, present and future treatments

Sexual function declines with age and it must be remembered that the

range of normal in describing sexual activity is very wide It is estimated that

as many as 25% of men over 65 suffer ED and in the diabetic population this

is much higher Published studies vary, but quoted ranges are between 30 and

60% suffering from partial or complete ED, with ejaculatory abnormalities

such as retrograde ejaculation occurring in a smaller proportion

CLINICAL PRESENTATION

The term ED is preferred to impotence as there are clearly grades of

dysfunc-tion and impotence has such negative connotadysfunc-tions of failure An erecdysfunc-tion

insufficient for intercourse is the usual definition and the skill of the clinician

is to allow the patient to acknowledge there is a problem without

intimidat-ing them with what could be seen as overly intrusive questions Nevertheless,

a clear description of the onset and type of problem is essential if the

appro-priate treatment is to be selected

Intermittent or occasional erectile failure is very common and usually due

to anxiety, alcohol or sexual indifference How the partner copes with this

failure can often determine future function – annoyance, anger or even

ridicule will heighten anxiety on future attempts, leading to ‘performance

anxiety’ and recurrent failure This is perhaps the commonest cause of ED in

the non-diabetic population People with diabetes are not immune to this

type of failure and anxiety may be exacerbated by their awareness of ED as a

complication of diabetes

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition

Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd