Clinical review

Vascular complications of diabetes

Richard Donnelly,  Alistair M Emslie-Smith,  Iain D Gardner,  Andrew D Morris. 

Adults with diabetes have an annual mortality of about 5.4% (double the rate for non-diabetic adults), and their life expectancy is decreased on average by 5-10 years. Although the increased death rate is mainly due to cardiovascular disease, deaths from non-cardiovascular causes are also increased. A diagnosis of diabetes immediately increases the risk of developing various clinical complications that are largely irreversible and due to microvascular or macrovascular disease. Duration of diabetes is an important factor in the pathogenesis of complications, but other risk factorsfor example, hypertension, cigarette smoking, and hypercholesterolaemiainteract with diabetes to affect the clinical course of microangiopathy and macroangiopathy.

	Microvascular complications

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A continuous relation exists between glycaemic control and the incidence and progression of microvascular complications. Hypertension and smoking also have an adverse effect on microvascular outcomes. In the diabetes control and complications triala landmark study in type 1 diabetesthe number of clinically important microvascular endpoints was reduced by 34-76% in patients allocated to intensive insulin (that is, a 10% mean reduction in glycated haemoglobin (Hb_A1c) concentration from 8.0% to 7.2%). However, these patients also had more hypoglycaemic episodes. Similarly, in the UK prospective diabetes study of patients with type 2 diabetes, an intensive glucose control policy that lowered glycated haemoglobin concentrations by an average of 0.9% compared with conventional treatment (median Hb_A1c 7.0% v 7.9%) resulted in a 25% reduction in the overall microvascular complication rate. It was estimated that for every 1% reduction in Hb_A1c concentration there is a 35% reduction in microvascular disease.

View larger version (34K): [in this window] [in a new window]   Relation between glycaemic control (HbA1c) and risk of progression of microvascular complications (retinopathy) and severe hypoglycaemia in patients with type 1 diabetes. Data from the diabetes control and complications trial. Dotted lines represent 95% confidence intervals

Retinopathy
Diabetic retinopathy is a progressive disorder classified according to the presence of various clinical abnormalities. It is the commonest cause of blindness in people aged 30-69 years. Damage to the retina arises from a combination of microvascular leakage and microvascular occlusion; these changes can be visualised in detail by fluorescein angiography. A fifth of patients with newly discovered type 2 diabetes have retinopathy at the time of diagnosis. In type 1 diabetes, vision threatening retinopathy almost never occurs in the first five years after diagnosis or before puberty. After 15 years, however, almost all patients with type 1 diabetes and two thirds of those with type 2 diabetes have background retinopathy.

View larger version (108K): [in this window] [in a new window]   Background retinopathy showing microaneurysms and small blot haemorrhages

View larger version (93K): [in this window] [in a new window]   Diabetic maculopathy

View larger version (37K): [in this window] [in a new window]   Effect of antihypertensive treatment ( blockers and diuretics) on mean arterial pressure, glomerular filtration rate, and albuminuria in patients with type 1 diabetes and nephropathy. Reproduced with permission from Mogensen, Diabetic Med 1995;12:756-9.

Nephropathy
Diabetic nephropathy is characterised by proteinuria >300 mg/24 h, increased blood pressure, and a progressive decline in renal function. At its most severe, diabetic nephropathy results in end stage renal disease requiring dialysis or transplantation, but in the early stages overt disease is preceded by a phase known as incipient nephropathy (or microalbuminuria), in which the urine contains trace quantities of protein (not detectable by traditional dipstick testing). Microalbuminuria is defined as an albumin excretion rate of 20-300 mg/24 h or 20-200 µg/min in a timed collection and is highly predictive of overt diabetic nephropathy, especially in type 1 diabetes.

View larger version (26K): [in this window] [in a new window]   Data from WHO multinational study of vascular disease in diabetes showing survival in patients with type 1 and type 2 diabetes according to degree of proteinuria (none, slight, or heavy) at baseline. Reproduced with permission from Stephenson et al, Diabetic Med 1995;12:149-55

Neuropathy
The diabetic neuropathies present in several ways. The commonest form is a diffuse progressive polyneuropathy affecting mainly the feet. It is predominantly sensory, often asymptomatic, and affects 40-50% of all patients with diabetes. Reduced sensation can be detected with a monofilament, and patients with sensory neuropathy as well as other high risk features need advice on foot care to minimise the risk of ulceration. Neuropathic foot ulcers can be distinguished from vascular ulcers, although a mixed aetiology is common.

	Macrovascular complications

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Atherosclerotic disease accounts for most of the excess mortality in patients with diabetes. In the UK prospective diabetes study, fatal cardiovascular events were 70 times more common than deaths from microvascular complications. The relation between glucose concentrations and macrovascular events is less powerful than for microvascular disease; smoking, blood pressure, proteinuria, and cholesterol concentration are more important risk factors for atheromatous large vessel disease in patients with diabetes.

View larger version (35K): [in this window] [in a new window]   Estimated hazard ratios for significant risk factors for coronary heart disease occurring in 335 out of 3055 patients with type 2 diabetes. Reproduced from Turner et al, BMJ 1998;316:823-8.

Hyperlipidaemia is no more common in patients with well controlled type 1 diabetes than it is in the general population. In patients with type 2 diabetes, total and low density lipoprotein cholesterol concentrations are also similar to those found in non-diabetic people, but type 2 diabetes is associated with a more atherogenic lipid profile, in particular low concentrations of high density lipoprotein cholesterol and high concentrations of small, dense, low density lipoprotein particles.

Hypertension affects at least half of patients with diabetes. In the UK prospective diabetes study tight blood pressure control (mean 144/82 mm Hg) achieved significant reductions in the risk of stroke (44%), heart failure (56%), and diabetes related deaths (32%), as well as reductions in microvascular complications (for example, 34% reduction in progression of retinopathy). One third of patients required three or more antihypertensive drugs to maintain a target blood pressure <150/85 mm Hg. In another recent study (hypertension optimal treatment study) rates of cardiovascular events in patients with type 2 diabetes were reduced even further when combination treatment was used to aim for target diastolic blood pressures <80 mm Hg.

Coronary heart disease
The incidence and severity of coronary heart disease events are higher in patients with diabetes, and several clinical features are worth noting. The diabetes subgroups in the major secondary prevention studies of cholesterol reduction (Scandinavian simvastatin survival study (4S) and cholesterol and recurrent events (CARE) trial) show a beneficial effect of statins.

View larger version (21K): [in this window] [in a new window]   Rates of serious cardiovascular events according to target diastolic blood pressure in 1500 patients with hypertension and type 2 diabetes. Drawn from Hansson et al, Lancet 1998;351:1755-62.

Peripheral vascular disease
Atheromatous disease in the legs, as in the heart, tends to affect more distal vesselsfor example, the tibial arteriesproducing multiple, diffuse lesions that are less straightforward to bypass or dilate by angioplasty. Medial calcification of vessels (Mönckeberg's sclerosis) is common and can result in falsely raised measurements of the ankle brachial pressure index. This index is therefore less reliable as a screening test in patients with diabetes and intermittent claudication.

Stroke
Roughly 85% of acute strokes are atherothrombotic, and the rest are haemorrhagic (10% primary intracerebral haemorrhage and 5% subarachnoid haemorrhage). The risk of atherothrombotic stroke is two to three times higher in patients with diabetes, but the rates of haemorrhagic stroke and transient ischaemic attacks are similar to those of the non-diabetic population. Patients with diabetes are probably more prone to irreversible rather than reversible ischaemic brain damage, and small lacunar infarcts are common. Stroke patients with diabetes have a higher death rate and a poorer neurological outcome with more severe disability. Maintaining good glycaemic control immediately after a stroke is likely to improve outcome, but the long term survival is reduced because of a high rate of recurrence. Antihypertensive treatment is effective in preventing stroke.

View larger version (22K): [in this window] [in a new window]   Kaplan-Meier plot of proportions of patients who developed fatal or non-fatal stroke, according to blood pressure control. Reproduced from Turner et al, BMJ 1998;317:703-13.

Erectile dysfunction
Erectile dysfunction is a common complication of diabetes, occurring in up to half of men aged over 50 years (compared with 15-20% in age matched non-diabetic men), although the exact prevalance is unknown because of likely underreporting. The underlying pathogenesis is multifactorial, with autonomic neuropathy, vascular insufficiency, and psychological factors contributing to the clinical picture. The condition causes appreciable social and psychological problems for many patients, and its importance should not be underestimated. The recent introduction of sildenafil, which is reported to have a 50-70% success rate in patients with diabetes, is an important advance.

View larger version (33K): [in this window] [in a new window]   Transition from normal renal function through to end stage renal disease requiring dialysis or transplantation. Increasing proteinuria and renal impairment is associated with an increasing risk of fatal or non-fatal coronary heart disease, especially in older patients with type 2 diabetes and other risk factors

	Surveillance and management in general practice

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Screening for diabetes
Up to half of people with type 2 diabetes have vascular complications at the time of diagnosis. Early detection of diabetes is therefore essential. Screening (by measuring fasting blood glucose concentration) should be considered for high risk patients, especially those who are middle aged and obese, are of Asian or Afro-Caribbean origin, have a history of gestational diabetes, or have a family history of diabetes.

Eye screening
The small number of patients with retinopathy in any one practice (about 50 patients per 10 000 practice list) does not allow most general practitioners to develop and maintain their funduscopic skills. Innovative approaches, including the use of trained community optometrists and mobile retinal photography units that visit practices annually, can provide a high standard of retinal screening in the community.

Cardiovascular risk prediction
Identification of patients at highest risk of developing cardiovascular events allows efforts and resources to be channelled most effectively. Coronary risk prediction charts and computer programs such as that recently produced as part of the joint British recommendations on prevention of coronary heart disease in clinical practice will help general practitioners to implement the findings of recent major clinical trials.

Annual complications assessment
All patients with diabetes should be offered an annual clinical assessment concentrating on the prevention, detection, and management of macrovascular and microvascular complications.

Areas of debate in surveillance of diabetes complications
The value of routine measurements of microalbuminuria in patients with type 2 diabetes is less clear than in type 1 diabetes. Arrangements to allow the testing of microalbuminuria in general practice are not universally available.

View larger version (94K): [in this window] [in a new window]   Neuropathic ulcer is a common complication in patients with diabetes

View larger version (106K): [in this window] [in a new window]   Use of monofilament to detect impaired sensation during annual assessment

Team approach to integrated diabetic care
The ongoing care of patients with diabetes, in particular once they have developed vascular complications, includes a wide spectrum of healthcare professionals. A systematic, integrated, and collaborative approach must be developed at a regional level, with clear lines of communication and the adoption of locally agreed guidelines for treatment and referral based on national guidelinesfor example, those from the Scottish Intercollegiate Guideline Network (www.show.scot.nhs.UK/sign/home.htm).

View larger version (71K): [in this window] [in a new window]   Mobile eye screening unit

	Footnotes

Alistair M Emslie-Smith is general practitioner, Tayside Centre for General Practice, Dundee; Iain D Gardner is consultant ophthalmologist, Derbyshire Royal Infirmary, Derby; and Andrew D Morris is senior lecturer in medicine and diabetes, Ninewells Hospital and Medical School, Dundee.

The ABC of arterial and venous disease is edited by Richard Donnelly, professor of vascular medicine, University of Nottingham and Southern Derbyshire Acute Hospitals NHS Trust (richard.donnelly{at}nottingham.ac.uk) and Nick J M London, professor of surgery, University of Leicester, Leicester (sms16{at}leicester.ac.uk). It will be published as a book later this year.