VASCULAR COMPLICATIONS OF DIABETES - PART 4 pot

treat-Peripheral vascular disease The Wisconsin Epidemiological Study of Diabetic Retinopathy WESDRincluded nearly 3,000 people with diabetes 1,200 type 1 patients diagnosedunder 30 year

Fig 7.1 Effects of ramipril on cardiovascular outcomes in people with diabetes –

Urgent revascularization is usually undertaken in refractory unstable anginathat fails to settle despite optimum medical therapy In 90–95% medicaltherapy stabilizes the situation However, early intervention, with angiogra-phy and angioplasty where appropriate, has now been shown to be superior

to medical treatment alone One study compared thrombolysis within 30minutes of admission with primary angioplasty within 90 minutes After sixmonths of follow-up, patients in the angioplasty group fared better on allmeasures: the mortality rate was 6.2%, compared with 7.1% for TPA; the rate

of recurrent ACS was 5.3%, compared with 10.6% for TPA; and the strokerate was 2.2%, compared with 4% for TPA Length of time in hospital alsowas shorter for the angioplasty group: 4.5 days compared with 6 days forthose who received TPA These differences, though small, represent signifi-cant improvements in outcome When available and performed by experi-enced operators at high-volume centers, primary percutaneous coronaryintervention (PPCI) saves 20 lives and results in 60 fewer events for every1,000 patients treated ‘Time is muscle’ and most hospitals do not have thesefacilities, so unless transfer and urgent PPCI can be achieved within 90 min-utes, thrombolysis remains the treatment of choice

Surgery and angioplasty have similar results – vein grafting only improvesprognosis in patients with triple vessel disease or LV dysfunction There is noevidence that diabetics need an alternative strategy except that the BypassAngioplasty Revascularization Investigation (BARI) study suggested thatpeople with diabetes did less well with angioplasty – this remains to be con-firmed The BARI 2 Diabetes (BARI 2D) trial has not yet reported but willcompare whether attenuation of insulin resistance can arrest or retard pro-gression of coronary artery disease compared with treatment targeted to thesame level of glycaemic control with an insulin-providing approach It isdesigned also to determine whether early revascularization reduces mortalityand morbidity in patients with type 2 diabetes whose cardiac symptoms aremild and stable The role of other antiplatelet agents such as clopidogrel, orangioplasty followed by drug-eluting stents remains uncertain Comparisons

of restenosis after angioplasty have shown slightly higher rates in people withdiabetes compared to non-diabetics This difference is probably explained bythe older ages of those with diabetes in these studies

anti-Several clinical trials have now looked at the effect of initiating a statin

with-in hours and days of a coronary event and the fwith-indwith-ings suggest there may be nificant benefits The RECIFE (Reduction of Cholesterol in Ischaemia andFunction of the Endothelium) trial looked at the effect of rapidly lowering cho-lesterol on endothelial function days after a coronary event Patients admittedwith MI or unstable angina were randomized to placebo or pravastatin 40mgwithin 10 days Endothelial function was assessed by measuring flow-mediateddilatation of the brachial artery, which increased by 42% with pravastatin com-pared with placebo More excitingly, other short-term studies with pravastatin40mg and atorvastatin 80mg initiated within four days have shown significantreductions in coronary events in as little as 16 weeks Larger trials are on-goingwhich will help to determine if these preliminary findings are confirmed and ifthis is a class effect Not all statins have been demonstrated to lower CRP, andsmooth muscle cell proliferation (which may help stabilize plaques) is inhibit-

sig-ed by some statins in vivo but not by pravastatin

Potential but unproven interventions such as use of antioxidants, ment of homocysteinaemia (with folic acid) or hypertriglyceridaemia remainuntested In the HOPE study vitamin E conferred no benefit

treat-Peripheral vascular disease

The Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR)included nearly 3,000 people with diabetes (1,200 type 1 patients diagnosedunder 30 years) and showed an association between rising HbA1Cand risk oflower limb amputation However, neither DCCT nor UKPDS were powered

to look at PVD or an amputation as an end-point – DCCT patients wereyoung and few had macrovascular events; UKPDS patients with significantperipheral vascular disease at diagnosis were excluded from the study Therewas a non-significant (16%) reduction in fatal and non-fatal MIs in the inten-sively treated group after 15 years and there was no difference between theintensive and conventional treatment groups in the proportion of patientswho had evidence of peripheral vascular disease by Doppler blood pressure orabsent peripheral pulses No controlled trials have been undertaken with dia-betic patients to assess the effects of risk factor modification on the regression

of vascular disease, however, smoking cessation is associated with ment of symptoms in non-diabetics Among patients with symptomatic PVD,continued smoking is associated with worsening claudication, limb-threaten-ing ischaemia and amputation, and the need for revascularization Patencyrates are lower following revascularization in patients who continue to smokeand survival is reduced The effects of management of hyperlipidaemia andhypertension on the progression of PVD has not been fully evaluated but ananalysis of the Scandinavian Simvastin Survival Study (4S) study showed thatthe incidence of ‘new or worsening claudication’ was significantly lower in

improve-CHD patients treated with simvastatin (Fig 7.2) In the Physician’s Health

study, low doses of aspirin resulted in a 54% reduction in the risk of eral arterial surgery, compared with placebo, but no study has shown anyimprovement in claudication symptoms with antiplatelet agents Drug treat-ment for claudication has generally been disappointing but a new agent,cilostazol, (a phosphodiesterase III inhibitor with antiplatelet, antithrombot-

periph-ic and vasodilatory effects), looks promising Phase III studies involving justover 2,000 patients (approximately 25% with diabetes) using doses ofbetween 50 and 100 mg twice daily, showed improvement in maximal walkingdistance in most but not all studies Pain-free walking distance and quality oflife were improved and cilostazol was significantly better than both placebo

and oxpentifylline 400 mg tid (Fig 7.3).

Peripheral vascular disease is a contributory factor in most diabetic footulcers, and evidence exists that a combination of a dedicated multidisciplinaryfoot service and the utilization of specialist footwear can reduce both ulcerationand amputation rates

Cerebrovascular disease

In UKPDS each 1% reduction in HbA1Cwas associated with a 37% decrease inrisk for microvascular complications and a 21% decrease in the risk of any dia-betes related end-point or death The association with glycaemia was less steep

for stroke and heart failure (Fig 7.4), for which hypertension is a much more

important contributory factor but nevertheless improved glycaemia reduced

Fig 7.2 Effect of simvastatin on incidence of ‘new or worsening’ intermittent

claudication in the Scandinavian Simvastatin Survival (4S) study Am J Cardiol

the incidence of stroke Unfortunately, acute stroke management in the personwith diabetes is based on extrapolation of the data from non-diabetics as thereare, as yet, no prospective studies of stroke management in diabetics Trialshave shown that thrombolytic therapy started within six hours of the onset ofsymptoms of ischaemic stroke reduces the proportion of patients who die orremain dependent on others, up to six months later, (61.5% vs 68% of controlpatients not given thrombolysis) Results were more impressive if treatmentwas started within three hours (56.6% vs 70.7%) Alteplase seemed superior tostreptokinase but overall there was an increased risk of symptomatic intracra-nial haemorrhage (9.6% vs 2.6%) Overall, the risk of dying within two weekswas increased in those receiving thrombolytic therapy (20.9% vs 11.9%) despitethe improvement 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.

Hyperglycaemia on admission is associated with a worse outcome andalthough the benefits of treatment of hyperglycaemia in this situation areunknown, a DIGAMI-style glucose and insulin infusion would seem sensible(trials are ongoing)

Fig 7.3 Maximal walking distance in patients with claudication treated with cilostazol

or oxpentifylline or placebo Circulation 1998; 98 (Suppl 1): 1012, Abstract 58.

70

(Mean ± 95% confidence interval)

Cilostazol 100 mg bid Oxpentifylline 400 mg tid Placebo

Secondary prevention data is based entirely on general population studieswith none having been conducted in people with diabetes alone Targets sim-ilar for those of diabetic patients with CHD are appropriate The dose ofaspirin required is uncertain The European Stroke Prevention Study showedthat, in the general population, aspirin and sustained-release dipyridamoleare an equally effective secondary prevention in reducing the risk of stroke

Fig 7.4 Hazard ratios (with 95% confidence intervals) showing association between

mean HbA1Cand various micro- and macrovascular complications in the UKPDS trial.

BMJ 2000; 321: 405–441, with permission.

10

P<0.0001

12% decrease per 1% reduction in HbA1c

14% decrease per 1% reduction in HbA1c

19% decrease per 1% reduction in HbA1c37% decrease per

1% reduction in HbA1c

16% decrease per 1% reduction in HbA1c43% decrease per

1% reduction in HbA1c

Fatal and non-fatal myocardial infarction

Fatal and non-fatal stroke

Amputation or death from peripheral vascular disease

and/or death However, doubts exist because of the relatively low dose ofaspirin used and the exclusion of one centre from the study because of scien-tific fraud In the Clopidogrel versus Aspirin in Patients at Risk of IschaemicEvents (CAPRIE) study, 7.2% of those treated with clopidogrel 75 mg/day had

an event compared with 7.7% of patients receiving aspirin 325 mg/day So, ifthe patient has a cerebrovascular incident whilst on aspirin, addition ofdipyridamole may be justified; where patients have a true aspirin allergyclopidogrel is probably the most appropriate choice

There are a number of studies where stroke prevention has been a cant secondary end-point The UKPDS hypertension study, in which the tar-get for tight blood pressure control was <150/85, showed a 44% reduction instrokes compared to the less tight blood pressure control group (target blood

signifi-pressure <180/105) (Fig 7.5)

Ramipril 10 mg daily in the diabetic sub-group (Micro-HOPE) of theHOPE study reduced the number of strokes from 6.1% to 4.2% (a 33% rela-tive risk reduction) in a cohort of patients most of whom had establishedCHD The difference in blood pressure between the ramipril and placebogroups at the end of the study was only 2.5/1.0 Some commentators say this

is insufficient to account for the difference in stroke rates, but as these werebased on casual readings rather than 24-hour profiles it remains uncertainwhether the benefit is due to blood pressure lowering or a different mode ofvascular protection by ACE-Is

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

Nephropathy

The DCCT showed a 39% reduction in the occurrence of microalbuminuriaand a 54% reduction in albuminuria in the intensive therapy arm for bothadults and adolescents with type 1 diabetes Similarly, the UKPDS showed aslowing of renal decline in the tight glycaemic control group with type 2 dia-

betes (Fig 7.6) Type 2 patients with microalbuminuria or proteinuria are less

likely to progress to ESRF but, as with type 1 diabetes, blood pressure ment is the mainstay of treatment to reduce the decline in renal function.ACE-Is are indicated in type 1 patients with persistent microalbuminuria or

manage-proteinuria, irrespective of initial blood pressure (Fig 7.7) and are first line

agents in type 2 diabetes if microalbuminuria or proteinuria is present, thoughlowering blood pressure is the priority Renoprotection by ACE-Is is probably

a class effect Angiotensin receptor antagonists (ARAs) achieve similar tions in blood pressure and proteinuria as ACE-Is There have been only threerandomized double-blind studies lasting more than one year using ARAs as

reduc-anti-hypertensive treatment for people with diabetes None showed a cant reduction in total or cardiovascular mortality In the RENAAL studythere was a statistical reduction in progression to end-stage renal failure inthose that were treated with ARAs but the placebo group had higher bloodpressure throughout the study which may account for the worse outcomes

signifi-Fig 7.5 Hazard ratios (with 95% confidence intervals) showing association between

mean systolic blood pressure and various micro- and macrovascular complications in

the UKPDS study BMJ 2000; 321: 413–417, with permission.

10

P<0.0001

12% decrease per 10mmHg reduction in systolic blood pressure

13% decrease per 10mmHg reduction in systolic blood pressure

16% decrease per 10mmHg reduction in systolic blood pressure

19% decrease per 10mmHg reduction in systolic blood pressure

12% decrease per 10mmHg reduction in systolic blood pressure

Fatal and non-fatal myocardial infarction

Fatal and non-fatal stroke

Amputation or death from peripheral vascular disease

To achieve a target blood pressure of <130/80 for patients withnephropathy may require several anti-hypertensive agents and for youngpeople blood pressure targets may be set even lower to achieve a blood pres-sure < 90thcentile for age

Fig 7.7 Effect of captopril on progression of microalbuminuria in normotensive

patients with type 1 diabetes Diabetologia 1996; 39: 587–593

9

98 96

12

91 90

15

86 89

21

69 77

18

78 85

24

40 41

The DCCT demonstrated beyond doubt that good glycaemic control

retard-ed the onset of microvascular complications and delayretard-ed progression of thosecomplications already present Almost a half of patients in the intensive treat-ment arm achieved an HbA1Cof 6.1% or less at least once during the study,giving a mean of approximately 7% for the duration of the study From fiveyears into the study there was a 50% reduction in the cumulative incidence ofretinopathy in the primary prevention cohort and a 54% reduction in pro-gression in the secondary prevention arm compared to the conventionaltreatment group (mean HbA1C 8.9%) (Figs 7.8 & 7.9) Intensive therapy

reduced the risk of pre-proliferative and proliferative retinopathy by 47% andthe need for photocoagulation by 56%

In the UKPDS, hypertensive patients were assigned to either tight or erate blood pressure control over nine years The group randomized to tightblood pressure control (mean 144/82 mmHg) experienced a 47% reduction inthe risk of losing three lines of vision compared to the group with standard

mod-Fig 7.8 Cumulative incidence of sustained change in retinopathy in patients with

IDDM receiving intensive or conventional therapy in the primary prevention arm of

the DCCT Year of study refers to sample sizes at different years of the study NEJM

4 Year of study 5

220 202

79 78

8 9

52

49

blood pressure control (mean BP 154/87 mmHg) There was also a 34% tion in the risk of progression of retinopathy status The EURODIABControlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus(EUCLID), also comparing tight with moderate blood pressure control, pro-duced similar results, i.e a significantly reduced risk of blindness and reducedrate of progression of retinopathy in those patients randomized to moreintensively controlled blood pressure Use of an ACE-I may reduce the pro-gression of retinopathy, independently of blood pressure reduction, especial-

reduc-ly in normotensive type 1 diabetics

Neuropathy

In the primary prevention cohort of the DCCT, intensive therapy delayed theappearance of neuropathy at 5 years by 69% Ten per cent of the conventionaltreatment group developed neuropathy compared to 3% in the conventionalgroup Progression (as judged by clinical findings and nerve conduction stud-ies) was reduced by 59%

Fig 7.9 Cumulative incidence of sustained change in retinopathy in patients with

IDDM receiving intensive or conventional therapy in the secondary prevention arm of

the DCCT Year of study refers to sample sizes at different years of the study NEJM

4 Year of study 5

324 335

128 136

8 9

79 93