Patients with long-standing diabetes may develop complications affecting the eyes, kidneys or nerves (microvascular complications) or major arteries. The major arteries are affected in people with diabetes, causing a substantial increase in both in coronary artery disease and strokes as well as peripheral vascular disease. The greatest risk of large vessel disease occurs in those diabetic patients who develop proteinuria or microalbuminuria, which are associated with widespread vascular damage. These complications are often discovered at presentation in Type 2 diabetic patients who must have had diabetes for many years before it has been diagnosed. Issues concerning macrovascular complications are described in site.
During the last two decades, there has been a considerable increase in understanding the mechanisms underlying the development of the long-term diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular disease, accompanied by major developments in preventing them. The United Kingdom Prospective Diabetes Survey (UKPDS) in particular demonstrated quantitatively the long-term harmful effects of hyperglycaemia and hypertension in the development of both microvascular and macrovascular complications in Type 2 diabetes. Both UKPDS and the Diabetes Complications and Control Trial (DCCT) of Type 1 diabetes demonstrated the benefits of optimal control.
Causes and prevention of complications
Major advances in recent years have resulted in an actual decrease of some complications, notably nephropathy. Primary prevention of diabetic complications, together with retardation of their progression, is now possible, chiefly by tight control of the diabetes and of hypertension, together with reduction of other “risk factors” detailed in site. Even when the complications are established, their progression leading to serious damage can be delayed.
Although many attempts have been made to develop specific pharmacological agents to alter the course of diabetic complications, and although many trials are in progress at the present time, none have proved unequivocally successful and none are licensed. There is at present intense interest in and optimism for the use of protein kinase-C inhibitors.
Two major studies
DCCT: a multicentre study of 1441 Type 1 diabetic patients in the United States examining the effects of tight control on the development of microvascular complications, terminated after nine years because of highly significant benefits reported in 1993. The benefits on the microvascular complications were considerable.
UKPDS: a multicentre study of 5102 Type 2 diabetic patients co-ordinated from Oxford, assessed both the harmful effects of persistent hyperglycaemia and hypertension on the development of microvascular and macrovascular complications, and also demonstrated the benefits of 10 years of better, compared with less satisfactory, control of both glycaemia and blood pressure reported in 1998. Benefits were achieved regardless of the drugs used to reach the required standards of either blood glucose or blood pressure control.
The long-term effects of treatment in the two studies are shown in the two figures demonstrating the stable control in Type 1 diabetes (DCCT) compared with the deteriorating control in Type 2 diabetes as the disease progresses (UKPDS).
Persistent hyperglycaemia
Over many years this is the principal underlying cause of the microvascular complications of diabetes. It is also an independent risk factor for the development of macrovascular coronary artery disease and cataract formation. The UKPDS showed precisely the increasing hazard in relation to continuously rising HbAlc levels, without any specific threshold point, and then demonstrated the benefits of tight control. Once complications are established additional factors, notably hypertension, may accelerate their progression (for further details see chapters on specific complications).
For every 1 % increase in HbA1C:
• microvascular complications increased by 37%
• any end point (micro and macrovascular) related to diabetes increased by 21%
• deaths related to diabetes increased by 21%.
(Microvascular complications are here defined as retinopathy requiring photocoagulation, vitreous haemorrhage, and fatal or non-fatal renal failure.)
The progression of neuropathy assessed in a group of Type 1 diabetic patients in a prospective 14-year study conducted in Dusseldorf has also shown clearly that the decline of numerous measurements of nerve function occurs almost exclusively in those with poor glycaemic control.
The effect of better blood glucose control on the microvascular complications was as follows:
• reduction of microvascular complications (chiefly the need for photocoagulation) by 25%
• reduction of any diabetes end point by 12%
• reduction of any diabetes related death by 10%.
Glycaemic control was also shown to reduce the evolution of microalbuminuria after nine years, and the loss of vibration perception after 15 years of the study. Tight blood glucose control had a non-significant effect on reduction of myocardial infarction, and none on diabetes related mortality.
The DCCT (Type 1 diabetes) demonstrated that primary prevention and retardation of progression of diabetic complications can be achieved over a decade if tight diabetic control is achieved. Retinopathy, nephropathy, and neuropathy were reduced by 35-70% if HbA1C was maintained around 7%. Maintaining tight control requires optimisation of insulin regimen and diet, careful blood glucose monitoring, and substantial professional support.
Five years after termination of the DCCT, the EPIC study showed that, despite lapse of the earlier tight blood glucose control, the benefits with regard to amelioration of complications persisted.
Hypertension
This is the principal underlying risk factor for the development of coronary artery disease leading to myocardial infarction, and increases the risk of strokes and heart failure as well.
It also exacerbates the progression of retinopathy, the evolution of proteinuria, and probably the deterioration of nerve function as well.
The UKPDS (Type 2 diabetes) has shown that for every 10 mm Hg increase in systolic blood pressure:
• any complication related to diabetes is increased by 12%
• deaths related to diabetes are increased by 15%
• myocardial infarction is increased by 11%
• microvascular complications are increased by 13%.
By achieving a mean blood pressure of 144/82, representing a reduction of systolic blood pressure of 10 mm Hg compared with the less intensively treated group, microvascular end points (chiefly the need for photocoagulation) were reduced by 37%, and risk of vision declining by three lines on the Snellen chart was reduced by 47%, chiefly by protection from the development of macular disease.
Better control of blood pressure also resulted in a 32% reduction in deaths related to diabetes, and a 44% reduction in strokes; there was a non-significant reduction in myocardial infarction.
Further details on the benefits of good blood pressure control in general and on established nephropathy in particular are described in site.
Smoking
This exacerbates all the complications of diabetes, both microvascular and macrovascular.
Dyslipidaemias
These increase the propensity to macrovascular disease: targets for control are described in site.
The presence of the above factors in combination additively increases the risks of developing complications.
The benefits of controlling glycaemia required persistently good control over a decade; benefits of successful blood pressure control were witnessed after approximately 4 to 5 years
Targets for control and reduction of risk factors
Blood glucose
The facility for patients to measure their own blood glucose empowers them to achieve optimal control by their own interventions. The aims are as follows:
• Type 1 diabetes: achieve preprandial blood glucose readings mainly in the range 4.5-7.7 mmol/1, postprandial readings in the range 6.0-9.0 mmol/1, and 7.0-9.0 mmol/l at bedtime, and preferably never below 4.0 mmol/1 to avoid blunting of hypoglycaemic awareness.
• Type 2 diabetes: fasting < 5.5 mmol/1;
postprandial < 9.0 mmol/1.
Glycated haemoglobin
Aim for an HbAlc< 6.5% (normal value 4.0-6.0%) as an ideal, since values > 7% are increasingly associated with development of all microvascular and macrovascular complications, and reduction of HbA1C has been shown to diminish microvascular complications substantially (see below). Values up to 8% are acceptable in those who cannot readily achieve the ideal (and there are many). When HbA1C values exceed 9%, additional education and counselling should be attempted although even then patients may not succeed, and some show no inclination to do so.
Blood pressure
Targets for control are described in site.
| Targets for glycaemic control suggested by the European Diabetes Policy Grout | |||
| Low risk | Arterial risk | Micro vascular risk | |
| HbA1C %
Venous plasma glucose Fas ting/prepran dial mmol/1 mg/dl |
≤6.5
≤6.0 <110 |
>6.5
>6.0 ≥110 |
>7.5
>7.0 >126 |
| Self-monitored blood glucose*
Fasting/preprandial mmol/1 mg/dl |
≤5.5
<100 |
>5.5
≥100 |
>6.0
≥110 |
| Postprandial or peak
mmol/1 mg/dl |
<7.5
<135 |
≥7.5
≥135 |
>9.0
>160 |
* Fasting capillary blood glucose is about 1.0 mmol/1 (18 mg/dl) lower than venous plasma blood glucose. Postprandial capillary blood glucose is about the same as venous plasma blood glucose
Weight
Body mass index < 25 is ideal; 27 acceptable; greater than 30 represents obesity.
Lipids
Targets for control are described in site.
Smoking
Aim: to stop smoking.
Complications screening programme
Detection of the earliest signs of diabetic complications is an essential requirement of diabetes care leading to early preventive and treatment strategies which can abort progression of some of the most serious consequences.
Screening is ideally performed as a structured service undertaken by nurses and technicians outside the process of professional consultation, which should be informed by printed results from the screening programme. Screening should be performed at onset and then annually, from the onset of diabetes in all diabetic patients. Complications in Type 1 diabetes, however, are unlikely to develop during the first five years after diagnosis, so that the complete annual screening protocol can be deferred for a short time. The screening programme can be performed wherever appropriate facilities exist. Once complications are present and established, more frequent screening or treatment, or both may be needed.
Eye screening requires specialist equipment and is often undertaken as a community responsibility, and there are strong representations that there should be a national screening programme. Detection and prevention of foot problems linked to delivery of adequate community podiatry services is also crucial and highly effective in preventing serious foot disorders.
The annual complications screening programme
This comprises:
• weight (height): body mass index
• blood pressure
• eye examination (visual acuity, fundoscopy, and photography)
• foot examination:
check for deformities, abrasions and ulcers
sensation (monofilament tests, and other sensory modalities if available, see pages 52 and 63)
palpate foot pulses
• blood tests: HbA1C; lipid profile; creatinine
• urine tests: strip tests for proteinuria or microalbuminuria (if either of these are positive, total 24 hour proteinuria or the albumin creatinine ratio (ACR) should be measured, preferably on an early morning urine sample)
• assessment of smoking status.
Other complications
Necrobiosis lipoidica diabeticorum
Necrobiosis is an uncommon and unsightly blemish of the skin which chiefly affects diabetic women. It is unrelated to microvascular complications. The shin is the most common site. The lesions show rather atrophic skin at the centre with obviously dilated capillaries (telangiectasis) and a slightly raised pinkish rim; ulceration sometimes occurs. The lesions are indolent and rarely resolve. There is no effective treatment although steroid applications and even injection have been attempted.
Cheiroarthropathy
The development of tight, waxy skin, probably as a result of glucose related alteration of collagen structure, leads to some limitation of joint mobility. A relatively common yet symptomless consequence of these skin changes is the development of some fixed curvature of the fingers which may typically be seen in some patients with long-term diabetes. Those affected are unable to place the palm of the hand on a flat surface. The characteristic appearance is shown in the illustration on the right.