Prevention and early detection of vascular complications of diabetes

Macrovascular disease

Excess mortality from cardiovascular disease is seen in all age groups, particularly in young people with type 1 diabetes (box 2), and is exacerbated by social deprivation (table).^w3 Premenopausal women with diabetes lose their protection against macrovascular disease (fig A on bmj.com).2 ^{w4 w5} In type 2 diabetes, the risk of myocardial infarction and stroke is two to five times higher than in the general population.

Retinopathy

The World Health Organization estimates that diabetic retinopathy is the cause of blindness in 5% of blind people worldwide.3 Almost everyone with diabetes has some degree of retinopathy after 20 years (see appendix on bmj.com for the grading of diabetic retinopathy), but only 20-50% of patients develop sight threatening disease. In some centres the cumulative incidence of sight threatening retinopathy is falling.4 ^{w6 w7}

Nephropathy

About half of patients with diabetes develop microalbuminuria at some point. Approximately one third will progress to proteinuria, one third will remain microalbuminuric, and one third will revert to normal albumin excretion (fig 1).^w8 Microalbuminuria and proteinuria are more common in ethnic minorities worldwide.^{w9 w10} Once proteinuria is present, progression to end stage renal disease is inevitable. From 20% to 50% of patients who start renal replacement therapy have diabetes.5 ^w11 The rapid increase in the numbers of patients with diabetes requiring renal replacement in Europe in recent years is due mainly to the rise in the number of patients with type 2 diabetes (fig B on bmj.com).6

Fig 1

Development of nephropathy

• Download figure
• Open in new tab
• Download powerpoint

Neuropathy

Patients with diabetes have a 30-50% lifetime risk of developing chronic peripheral neuropathy (box 3), and 10-20% of patients develop severe symptoms.7 ^{w12 w13} Peripheral neuropathy contributes to foot ulceration and amputation of lower limbs.8 Erectile dysfunction occurs in up to 50% of men over 50 years, compared with 15-20% of men without diabetes. Other neuropathies are rare but have a major impact on quality of life and life expectancy.

Glucose control

The diabetes control and complications trial (DCCT) in type 1 diabetes and the UK prospective diabetes study (UKPDS) in type 2 diabetes showed that the lower the glycated haemoglobin achieved the lower the risk of microvascular complications.¹¹¹² During the eight year open follow-up of the DCCT cohort, glycated haemoglobin values were similar in patients who had previously been managed intensively or conventionally.^{1314 w17} Despite this, patients who had previously been in the intensively managed group were less likely to have microvascular complications (fig 3). Thus, a period of good glycaemic control reduces the risk of complications for longer than the duration of tight control, a phenomenon known as metabolic memory.

Fig 3

Prevalence of complications at open follow-up of patients who completed the diabetes control and complications trial. Prevalence of progression at *four years and †eight years

• Download figure
• Open in new tab
• Download powerpoint

Blood pressure

In UKPDS, tight control of blood pressure (144/82 v 154/87 mm Hg) reduced the incidence of a microvascular event by 37%.16 A reduction in systolic blood pressure of 10 mm Hg was associated with a 13% reduction in risk for a microvascular event and an 11% reduction for myocardial infarction.^w19 Other studies have shown that the reduction in relative risk is at least as great in the diabetic population as in the non-diabetic population, so that the absolute benefits of a reduction in blood pressure are greater.¹⁷¹⁸

The choice of initial antihypertensive drug is less important than reducing blood pressure. Tight targets (< 130/80 mm Hg) are difficult to reach and require at least three antihypertensive drugs. Drugs that are taken once daily and that have good 24 hour cover should be used.

A Cochrane review suggests that angiotensin converting enzyme inhibitors are the best drugs to prevent microalbuminuria and nephropathy.19 ^w20 A recent meta-analysis that did not support this conclusion has been criticised for many reasons.^w21

Lipids

Two placebo controlled trials have shown that treatment with statins reduces the risk of a major cardiovascular event by 37% in patients with type 2 diabetes without clinically apparent cardiovascular disease.²⁰²¹ The reduction in relative risk is as great in the diabetic population as in the non-diabetic population, so that the absolute benefit is greater.22 Thus, all patients with diabetes aged 40 years or more should be offered statins. Younger patients have a high lifetime risk of cardiovascular disease even though their 10 year risk is relatively low. Statins should be offered to those at particularly high risk (box 4).

When fibrates should be prescribed is unclear. In a recent large, randomised, controlled trial, fenofibrate did not reduce the risk of primary coronary events in type 2 diabetes.23 Despite the lack of robust evidence, however, once low density lipoprotein-cholesterol and control of blood glucose are optimal, clinicians should consider adding a fibrate to statin therapy if triglycerides are still greater than > 2.3 mmol/litre.

Smoking

It is essential that patients stop smoking to reduce the risk of cardiovascular disease and probably the risk of microvascular complications.

Aspirin

Although no studies have been performed on primary prevention of cardiovascular disease in diabetes, low dose aspirin is usually recommended, even in the absence of overt cardiovascular disease.

Macrovascular disease

Screening for macrovascular disease rests on symptoms of angina or claudication and with a low threshold for investigation. Routine exercise tolerance testing or stress echocardiography are not recommended. A 12 lead resting electrocardiogram has low sensitivity and specificity, although it does provide a useful baseline.

Retinopathy

Corrected visual acuity should be measured and retinopathy assessed. Retinal photography, usually through dilated pupils and performed and interpreted by trained healthcare professionals, is the preferred method. Sensitivity and specificity must be acceptable, there must be an ongoing quality assurance programme, and the number of images that cannot be graded must be low.^w22 Screening with static or “mobile” cameras can be performed in the community; the retinal images are read on site or at a distant centre.

Nephropathy

Urine albumin and serum creatinine should be measured annually (fig 4). Positive urine samples should be repeated at least twice. Trends in albumin excretion with time are important. An estimated glomerular filtration rate is a better reflection of glomerular filtration than serum creatinine. Laboratories in the United Kingdom now do such estimations automatically, and web based calculators are available. Table 2 shows the agreed classification of renal disease based on estimated glomerular filtration rate.

Fig 4

Screening for diabetic nephropathy

• Download figure
• Open in new tab
• Download powerpoint

Neuropathy and peripheral arterial disease

Box 5 shows what needs to be done to identify the four classic risk factors for developing diabetic foot problems (deformity, neuropathy, ischaemia, and infection).24 Questions should be asked about erectile function. Tests of autonomic function are not performed routinely.

General

Tight control of blood glucose and blood pressure reduces the risk of progression of background diabetic retinopathy to sight threatening disease and the progression of neuropathy.¹¹¹²¹⁶ The effect of glucose control on progression of nephropathy is less certain. Blood pressure and lipid control are extremely important.

Cardiovascular disease

Most importantly, all patients with symptoms that might reflect vascular disease, particularly ischaemic heart disease, should be investigated. The absolute benefits of treatment with statins in secondary prevention of vascular disease are greater in people with diabetes.22

Retinopathy

Frequent retinal examination may be required, with referral to the ophthalmology department when sight threatening disease is apparent (table 3).

Nephropathy

All patients should be prescribed a long acting, once daily angiotensin converting enzyme inhibitor or angiotensin receptor blocker titrated up to the maximum recommended or tolerated dose.^w23-w26 Additional antihypertensives should be used to achieve tight control of blood pressure. A target of 125/75 mm Hg is recommended for patients with proteinuria or an estimated glomerular filtration rate less than 60 ml/min/1.73 m², although these guidelines are not evidence based. Combining an angiotensin converting enzyme inhibitor with an angiotensin receptor blocker or adding an aldosterone antagonist further reduces urine albumin excretion and blood pressure in the short term.^w27-w29 However, long term benefits are unclear. Box 6 lists the indications for referral to the nephrology department.

Neuropathy and peripheral arterial disease

Patients whose feet have a high risk of ulceration or gangrene need support and education about foot care; they also need to be given prophylactic foot care and special footwear.24 These measures can reduce amputation rates by 30-50%.^{w30 w31} Early referral of patients with ulcers (and those who have had ulcers in the past) to a specialist multidisciplinary team is essential.

Support and counselling should be available for men with erectile dysfunction. Investigations to exclude other causes (measurement of prolactin, follicle stimulating hormone, luteinising hormone, testosterone, and sex hormone binding globulin) may be necessary. Oral phosphodiesterase type 5 inhibitors are effective in about 60% of men with diabetes, less than in the non-diabetic population. Alternatives include sublingual apomorphine, intraurethral drugs, intracavernosal drugs, vacuum devices, and penile prostheses.

The importance of multifactorial care

A small randomised controlled trial of patients with type 2 diabetes, microalbuminuria, and hypertension showed the importance of a structured, protocol driven, multifactorial approach to managing the complications of diabetes.25 The intensively managed group received lifestyle advice, aspirin, and angiotensin converting enzyme inhibitors, with tight targets for glucose, blood pressure, and lipids in a specialist setting. The conventionally managed group received usual structured care in a primary care setting. Over eight years, the risks of progression of microvascular and macrovascular disease were reduced by 40-60% in the intensively managed group (table 4).