Microvascular complications: pathophysiology and management

Management

Pan-retinal photocoagulation, introduced in the early 1970s, is the treatment of choice for proliferative and pre-proliferative retinopathy. This procedure coagulates the ischaemic retina which acts as the driving factor for new vessel formation (presumably by reducing vascular endothelial growth factor. Focal laser treatment is also used in macular oedema to reduce vascular leakage. Laser treatment can bring down the five-year incidence of blindness from 50% to 5%,¹⁴ but at the expense of losing up to 50% of peripheral vision¹⁰ – with possible implications for driving licence holders.

Microalbuminuria

Increased glomerular filtration pressures result in albuminuria, a driver for ongoing renal damage.¹⁶ Microalbuminuria (Fig 1) is the first step towards developing overt proteinuria, but only 20% of patients with the condition progress towards proteinuric nephropathy.¹⁵ Proteinuric nephropathy continues to have a poor prognosis, with most patients dying from cardiac disease or progressing to end-stage renal failure. Furthermore, proteinuria is a marker of vascular endothelial dysfunction and there is a good correlation between cardiovascular risk and degree of albuminuria. The presence of microalbuminuria should therefore prompt clinicians to manage all cardiovascular risk factors aggressively. Criteria for referrals to nephrology services need to be defined so that these patients can be referred in a timely manner and their care optimised.

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Fig 1.

Progression of nephropathy

Management

Aggressive blood pressure reduction is of vital importance in managing diabetic nephropathy. Individuals with microalbuminuria need to have BP ≤=125/75.¹⁸ Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are first line agents for treating hypertension with numerous trials showing their effectiveness in reducing proteinuria and deterioration of renal function,^19–21 but often multiple blood pressure lowering agents are required. Early studies suggested that combining ACEIs and ARBs was superior to monotherapy in reducing proteinuria,²²but recent evidence highlights increased side effects (hyperkalemia and renal impairment) of combination therapy with quite modest outcome benefits.^23,24 Both the UKPDS and the DCCT have demonstrated the importance of glycaemic control in retarding progression of nephropathy, whereas the evidence for positive outcomes with low-density lipoprotein (LDL) cholesterol reduction appears less clear. Patients with worsening proteinuria or deteriorating renal function will need to be seen by nephrologists to ensure that renal replacement therapy can be planned appropriately.

Management

The management of neuropathy is predominantly supportive. Good glycaemic control can reduce its progression. However, once neuropathy has been established glycaemic control has little influence in controlling pain which is the main symptom. Simple analgesics suffice in mild cases of painful neuropathy, but opiates may be required in more severe cases. Amitriptyline, duloxetine, gabapentin and pregabalin all have evidence of being superior to placebo.²⁵ Tricyclic antidepressants such as amitriptyline are first-line agents but pregabalin is particularly useful as therapeutic benefits are seen early. Clinicians need to have empathy with a holistic approach when dealing with these patients and often high doses of analgesics are needed. Patients with neuropathy need to be told of the importance of paying attention to foot care and wearing appropriate footwear as they are at high risk of developing ulcers. Patients also need to have access to podiatry and chiropody services for regular assessment of their feet.

Severe symptoms. Autonomic neuropathy can have devastating effects on patients' lives. Postural hypotension increases the risk of falling. Standard treatments such as fludrocortisone are usually not possible due to coexisting hypertension. Gastroparesis can cause intractable nausea and vomiting in severe cases. Delays in food absorption in mild cases cause severe problems in insulin treated patients where erratic food absorption causes fluctuations in blood glucose levels that are difficult to control with conventional basal bolus regimens. In fact, a large proportion of patients with ‘brittle diabetes’ have some degree of underlying gastroparesis. Mild cases can be managed with prokinetic agents such as metoclopramide, domperidone, erythromycin and dietary modification. More severe cases may require gastric electrical stimulation where implanted electrodes act as a form of gastric pacemaker and stimulate gastric contractions. Unfortunately, this procedure is performed only in specialist centres. Erectile dysfunction affects up to 50% of men with diabetes and is often multifactorial (a combination of neuropathy, small vessel disease, medication and psychological), requiring a holistic approach.

Risk factors

The prevention of microvascular disease involves paying attention to aggravating risk factors and implementing screening programmes to improve early detection. Both the UKPDS and DCCT have clearly demonstrated that progression of retinopathy and nephropathy is linked to glycaemic control and that it is crucial that patients maintain HbA_1c less than or equal to 6.5% to minimise disease progression. In contrast, the association between glycaemic/BP control and neuropathy progression is more tenuous.

Blood pressure

BP needs to be kept below 140/80 mmHg to prevent microvascular disease, but once this has been established it needs to be more aggressively treated with targets below 125/75 mmHg.²⁶

Angiotensin-converting enzyme inhibitors (ACEIs)

ACEIs and angiotensin receptor antagonists are first-line agents. Many clinical trials have demonstrated their efficacy in reducing proteinuria and delaying progression of renal failure. In the Heart Outcomes Prevention Evaluation (HOPE) study ramipril reduced overt nephropathy by 24%.¹⁹ In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial there was a 25% reduction in retinopathy progression and the risk of end-stage renal disease was reduced by 28%.²⁰ Angiotensin blockade with ACEI also has a useful role in preventing retinopathy and reducing its progression by 50%.²⁷However, these agents are potentially teratogenic which needs to be considered when prescribing them to women of reproductive age.

Statins

Statins are useful in reducing the progression of nephropathy. They reduce proteinuria and have modest effects in improving renal function.²⁸ Patients with nephropathy need to have their low-density lipoprotein cholesterol levels brought below 2 mmol/l. Statins also have benefits in ameliorating retinopathy in animal models,^29,30 though the evidence in clinical trials is less robust. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial has shown some positive effects of fibrate therapy on retinopathy.³¹

Screening

Microvascular disease needs to be identified early by robust screening methods. Nationwide screening for retinopathy started in the 1990s and has played a central role in reducing diabetes-related visual loss.³² Patients with significant retinopathy need to be referred according to national guidelines (Table 3). Nephropathy can be picked up early by testing for microalbuminuria, and neuropathy detected by detailed foot examination during annual review of the diabetic patient.