Much of the increased mortality and morbidity seen in diabetic patients is the result of complications mat develop with increasing duration of disease, particularly when glycaemic control is poor. Such complications may originate from increased glycation of proteins and other biological macromolecules in the hyperglycaemic environment, pathological activation of protein kinase C, or from increased accumulation of sorbitol and other polyols via the aldose reductase pathway, but other factors play an important role in determining susceptibility. At the macrovascular level, diabetics are prone to hypertension and ischaemic heart disease, and heart disease is a major cause of death control of blood pressure is now seen as being as important as glycaemic control in patients with type 2 diabetes. Microvascular tissue damage is an important factor in the development of diabetic nephropamy and retinopathy it may also contribute to the other major complication, diabetic neuropathy. Collagen abnormalities are also seen. Diabetics with poor glycaemic control also have an increased liability to severe bacterial or fungal infection. Sometimes several factors may interact thus neuropathy, infection, and impaired blood flow due to macro- or microvascular disease may all play a role in the development of diabetic foot disease, a complication which can ultimately lead to amputation.
Prevention of diabetic complications
Much attention has been focused on whether strict or tight glycaemic control can modify the development or progression of diabetic complications. In general, the longer-term studies have provided more encouraging results man initial results indicated, and meta-analysis of such studies has suggested mat intensive regimens may prevent microvascular complications.
The Diabetes Control and Complications Trial (DCCT) confirmed mis view in type 1 diabetes. It compared in selected patients the effects of conventional insulin therapy with those of continuous subcutaneous insulin infusion or multiple-injection regimens, on the development and progression of complications. The intensive treatment was aimed at keeping preprandial blood-glucose concentrations between 3.9 and 6.7mmol/litre, postprandial concentrations at less man 10 mmol/litre, a weekly 3 a.m. measurement at greater than 3.6 mmol/litre, and the monthly glycosylated haemoglobin measurement at less man 6.05%. Intensive insulin therapy reduced the development and progression of retinopamy it also reduced the occurrence of microalbuminuria, albuminuria, and clinical neuropathy. The major disadvantage of intensive insulin therapy was a threefold greater risk of hypoglycaemia weight gain was also significantly greater.
While it is accepted mat some patients will benefit from intensive insulin regimens, this approach requires caution in patients at risk of hypoglycaemia. Also such intensive treatment may not always be necessary, for example in patients known to maintain good control by conventional dosage schedules, or where improvement can be obtained by setting achievable targets and improving patient education. However, intensive therapy can help sustain endogenous insulin secretion in type 1 diabetes, which is associated with improved metabolic control mis would favour starting intensive insulin therapy at an early stage. After the DCCT finished the patients returned to their own healm care providers for diabetes care, but were followed in a cohort study for a further 11 years. Although more man 90% of all patients went on to use intensive therapy, and glycosylated haemoglobin values became very similar for bom groups during this time, mere were fewer cardiovascular events and less microalbuminuria and albuminuria in the group that had received intensive treatment during the original DCCT, showing mat the beneficial effects of intensive therapy were maintained long term.
The reports of the UK Prospective Diabetes Study (UKPDS) have provided similar evidence in patients with type 2 diabetes. This study has examined the benefits of intensive therapy, using a variety of tings with diet and exercise. Intensive therapy, which aimed at producing fasting plasma-glucose concentrations of below 6 mmol/lilre, substantially decreased the risk of microvascular complications (particularly retinopathy). There was no difference in benefit between intensive merapy with sulfonylureas and with insulin. Metformin also produced benefit in the overweight patients who received it. The UKPDS did not provide unequivocal evidence of a reduction in macrovascular disease with improved glycaemic control, although there was some suggestion of a reduction in risk of myocardial infarction (in line with a small earlier Japanese study). However, it did show that vigorous control of blood pressure, using captopril or atenolol as the first-line drugs, reduced the risk of both macrovascular and micro-vascular complications, suggesting mat mis should have a high priority in the treatment of type 2 diabetes. A subsequent study has confirmed the importance of a multifactorial approach in reducing cardiovascular events. It has been suggested that miazolidinediones may have beneficial effects in addition to their hypoglycaemic effect, and a study in patients with type 2 diabetes and extensive macrovascular disease found that pioglitazone improved cardiovascular outcome and reduced the need to add insulin. There has, however, been some concern about possible adverse cardiovascular effects of rosiglitazone.
Diabetic eye disease
Diabetic patients are prone to potentially blinding eye disease, usually in the form of cataract or diabetic retinopathy. Cataract generally requires surgical extraction, particular care being taken to avoid infection. Diabetic retinopathy may take a ‘background’, non-proliferative form, or become a more serious proliferative retinopathy associated with neovascularisation, vitreous haemorrhage and retinal detachment. Macular oedema, characterised by retinal thickening from leaky blood vessels, can develop at any stage.
Aggressive glycaemic and blood pressure control are the main methods of prevention. However, once proliferative retinopathy has developed, glycaemic control is not adequate to prevent worsening. Moreover, transient early worsening may occur in patients transferred to more intensive glycaemic regimens.
Once severe nonproliferative or proliferative retinopathy has developed, photocoagulation using an argon laser or a xenon arc is effective in limiting progression, while vitrec-tomy may be helpful for vitreous haemorrhage and retinal detachment.
Numerous tings have been tried for the prevention or retardation of diabetic eye disease, mostly with indifferent results. Aldose reductase inhibitors such as sorbinil, aspirin, statins, oxygen (and conversely, the antoxidant vitamin E), ACE inhibitors, angiotensin II receptor antagonists such as losartan, interferon alfa-2a, and the matrix metalloproteinase inhibitor prinomastat, have all produced either minor benefit or no benefit at all, while the non-specific kinase inhibitor PKC-412 has produced some benefit but accompanied by significant adverse effects. Other drugs for which benefit has been claimed include ticlopidine, epoetin, and danaparoid sodium. Ongoing studies include those with the somatostatin analogue octreotide, the specific protein kinase C inhibitor ruboxistaurin mesilate, and the growth factor antagonist pegaptanib. Intravitreal injection of the corticosteroid triamcinolone acetonide may be useful for diabetic macular oedema.
Diabetic nephropathy
Nephropathic changes associated with microvascular disease develop in up to 30% of patients with type 1 diabetes and up to 40% of those with type 2 disease diabetic nephropathy, of which the first clinical sign is albuminuria, is one of the major causes of end-stage renal disease (see Chronic Renal Failure).
Results from the DCCT indicate that strict glycaemic control reduces the incidence of microalbuminuria in type 1 diabetes, (with long-term renal benefits) and a smaller reduction was seen in the UKPDS in patients with type 2 diabetes. However, while good control may prevent development of the initial lesion, it is not clear whether it can prevent progression in patients who are already microalbuminuric. Some studies, including the DCCT, have suggested mat mis is the case others have failed to confirm it. Dietary protein restriction (see Renal Failure), which appears from a number of small studies to have a beneficial, although small, effect on disease progression, has been recommended in patients with overt nephropathy.
The most important approach to slowing the progression of diabetic nephropathy is aggressive antihypertensive control. Although most patients will require combination merapy, first-line use of ACE inhibitors has been particularly recommended, as they have been suggested to reduce proteinuria to a greater extent than other anti-hypertensives. However, results from the UKPDS showed no difference between the effects of an ACE inhibitor and a beta blocker in reducing microalbuminuria in type 2 diabetics with hypertension, and a systematic reviewfound limited evidence to support a specific renoprotective action in diabetics, independent of their effect on blood pressure. Another systematic review found ACE inhibitors to be effective for the primary prevention of developing microalbuminuria. The authors noted that although data were limited this effect appeared independent of baseline blood pressure, renal function, and type of diabetes. Beneficial effects have also been reported when ACE inhibitors are given to patients with microalbuminuria but without hypertension, and it has been recommended that such patients receive ACE inhibitors, initially in small doses, to slow the progression of renal disease. Some consider that small decreases in blood pressure associated with such therapy may be responsible for the benefit.ACE inhibition also had a modest renal protective effect in normotensive diabetics with normal urinary albumin excretion, and such use requires further study.
Angiotensin II receptor antagonists have also been shown to reduce the progression of renal disease in type 2 patients with both microalbuminuria and macroalbuminuria, and US recommendations consider mem an equal first choice with ACE inhibitors UK guidelines suggest they may be used in those unable to tolerate ACE inhibitors. Although a systematic review failed to find evidence mat the two classes were equivalent in their effects on survival,their effects on progression of nephropathy appear equivalent.
The aldose reductase inhibitors have been investigated for their effects on nephropathy, but results have been, at best, ambiguous a study in microalbuminuric patients given tolrestat (now withdrawn worldwide) did show a decrease in urinary albumin excretion but mere was also a decrease in the (initially raised) glomerular filtration rate. Pimagedine, which inhibits the formation of glycosylated end products, is also under investigation.
Diabetic neuropathy
Peripheral neuropathies are common complications of diabetes mellitus. The intensity and extent of neurological abnormalities are proportional to the degree and duration of hyperglycaemia. Neuropathic symptoms include symmetrical sensory loss, particularly in the feet and lower limbs features of autonomic neuropathy such as gastroparesis, orthostatic hypotension, erectile dysfunction, and gustatory sweating pain and cranial nerve palsy associated with mononeuropathies and acute, painful, sensory neuropathy.’
Results from the DCCT indicated that strict glycaemic control could substantially reduce the occurrence of clinical neuropathy in patients with type 1 diabetes, a result which was not duplicated in the UKPDS in patients with type 2 diabetes.
Although some studies have suggested mat aldose reductase inhibitors such as epalrestat can reduce the severity of diabetic neuropathy, larger scale analysis has apparently failed to show any benefit. However, studies with some newer members of the class such as fidarestat are still ongoing. Interesting preliminary results have suggested that ACE inhibitors may also have benefits in diabetic neuropathy. An analysis of 4 studies using the antoxidant thioctic acid found variable results, but an overall benefit, in symptomatic diabetic polyneuropamy. Results from another study have suggested some improvement in cardiac autonomic neuropathy. Inhibition of protein kinase C with ruboxistaurin is also under investigation.Other management of diabetic neuropathy is essentially symptomatic. The pain, which can be severe, may be managed with tricyclic antidepressants duloxetine, mexil-etine, antiepileptics including carbarn azepine, and topical capsaicin or lidocaine may also be tried, as discussed on site.
Diabetic gastroparesis may respond to prokinetic drugs such as metoclopramide, cisapride, domperidone, or eiythromycin, but their effects can be variable and long-term use may be limited by adverse effects. Endoscopic or surgical interventions may be needed when symptoms cannot be controlled. Diarrhoea may respond to tetracycline (see below), while orthostatic hypotension should be managed conventionally (see under Fludrocortisone) although care may be required in the use of elastic stockings in patients with impaired blood flow to the feet. For the management of erectile dysfunction.
Diarrhoea
Diabetic patients may develop intermittent bouts of watery diarrhoea, sometimes alternating with constipation autonomic neuropathy and abnormalities of digestion and bowel flora may play a role. Clonidine has been suggested for severe cases, and octreotide has been tried, but conventional management with antidiarrhoeal drugs is otherwise used a broad spectrum antibacterial (especially tetracycline) may also be effective. The mechanism of action of tetracycline in diabetic diarrhoea is uncertain, but it has been suggested mat one or two doses of tetracycline should be the first line of treatment.
Foot disease
Peripheral arterial disease, neuropathy, collagen changes, and increased susceptibility to infection may contribute to the foot lesions to which diabetics are prone. Ulceration and tissue necrosis at pressure-points may be followed by infection, gangrene, and sepsis. Management involves drainage and debridement of dead and infected tissue, and the use of antibacterials if necessary:broad spectrum cover should be given intravenously if there is severe infection, and adapted once the results of bacteriological culture are available. Local antiseptic therapy may be helpful, especially for infections with Pseudomonas or Proteus spp. Neuropathic skin ulcers of the lower extremities have responded to a platelet-derived growth factor, becaplermin. Granulocyte colony-stimulating factors have been used as adjunctive therapy with antibacterials in severe foot infections. Strict control of blood glucose is important and insulin should be given as required. Effective pain relief and bed rest may be needed, and surgical reconstruction to improve blood supply may be helpful in some cases. Ultimately, some patients require amputation of all or part of the foot. Preventive care, with regular visits to a chiropodist, is therefore particularly important.
Heart disease
Cardiovascular disease (heart failure, ischaemic heart disease, and stroke) is a major cause of morbidity and death in patients with diabetes, who are at greatly increased risk of such disorders, often have a worse prognosis when they occur, and who may be undertreated for cardiovascular complications. Conventional risk factors such as obesity, hypertension, and hyperlipidaemias tend to be common in diabetic patients, but other factors, including hyperglycaemia itself (and particularly postprandial hyperglycaemia), may play a role.
Management of cardiovascular disease in diabetic patients should be essentially the same as in other patients there have been concerns about the use of individual drug classes — beta blockers, aspirin (which may need to be given in higher than usual doses), and calcium-channel blockers — but in general the benefits of intensive treatment are seen to outweigh the risks. Treatment should also include strict glycaemic control: it has been shown that insulin-glucose infusion after myocardial infarction, followed by subcutaneous insulin for at least 3 months, improves long-term survival in patients with bom type 1 and type 2 diabetes.
Primary prevention of cardiovascular disease with lipid-lowering drugs (see also Hyperlipidaemias, below) is an increasingly important part of management in high-risk patients. It has proved hard to demonstrate that good glycaemic control also plays a role in reducing cardiovascular risk (see Prevention of Complications, above) however, mere is evidence from a study in patients with impaired glucose tolerance but not diabetes that decreasing postprandial hyperglycaemia with acarbose reduced the risk of hypertension and cardiovascular events such as myocardial infarction.
Diabetics may also develop a form of restrictive cardiomyopathy in the absence of ischaemic heart disease. Again, the condition is managed similarly to cardiomyopathy in non-diabetic patients.
Cardiac autonomic neuropathy has been reported to be improved by thioctic acid (see Diabetic Neuropathy, above).
Hyperlipidaemias
Insulin plays an important role in lipid metabolism and deficient insulin action means that diabetics are prone to hypertriglyceridaemia and have a blood-lipid profile associated with an increased risk of atherosclerosis, and hence of macrovascular complications (see also Cardiovascular Risk Reductionand Hyperlipidaemias). The American Diabetes Association recommends mat LDL cholesterol concentrations should be below 2.6 mmol/litre, HDL cholesterol concentrations more than 1.15 mmol/litre, and triglyceride concentrations less man 1.7 mmol/litre.
Where drug therapy is needed, statins, in at least moderate doses, are the lipid-lowering drugs of choice for bom secondary and primary prevention of cardiovascular events in type 2 diabetes studies have shown benefit with atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, and mere is no clear evidence to favour one statin over another in these patients. Fibrates such as gemfibrozil may be an alternative, particularly for secondary prevention in patients with low levels of bom LDL and HDL cholesterol. Nicotinic acid has been used to raise HDL cholesterol concentrations, but high doses can have an adverse effect on glycaemic control.
Hypertension
Hypertension is twice as common in the diabetic as in the non-diabetic population, and is associated with both macrovascular complications and microvascular disease (especially diabetic nephropathy). Management of hypertension in diabetics follows the same principles as in the general population, but it should be treated aggressively with a view to retarding development of complications, and the threshold for drug treatment and the treatment goal are lower than in non-diabetic patients (see Hypertension). All of the main groups of antihypertensive drugs may be used although an ACE inhibitor, such as ramipril, an angiotensin II receptor antagonist, or a beta blocker may be effective in reducing complications. Low-dose diuretic therapy has also been shown to be beneficial. Results with calcium-channel blockers have been variable, and there has even been a suggestion that they may increase cardiovascular adverse effects (see Diabetes Mellitus under Precautions of Nifedipine). However, a review of randomised studies concluded that they were safe and effective in this population, although possibly less so man other antihypertensive tings. In the UK, guidelines recommend that long-acting calcium-channel blockers may be used as second-line treatment or as part of combination therapy.