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Diabetic microvascular complications – screening, diagnosis and prevention Abstract This article hopes to update primary care teams about diabetic microvascular complications, to provide an overview of important scientific evidence, and to focus on aspects of screening, diagnosis and prevention with a special emphasis on NICE recommendations. Keywords Retinopathy, nephropathy, neuropathy, Diabetes Control and Complications Trial (DCCT), United Kingdom Prospective Diabetes Study (UKPDS), National Institute for Health and Clinical Excellence (NICE), Diabetic Retinopathy Candesartan Trial (DIRECT), Diabetic macular edema (DME), Non-proliferative diabetic retinopathy (NPDR), Proliferative diabetic retinopathy (PDR), Albumin/Creatinine Ratio (ACR), Distal symmetrical sensory-motor polyneuropathy (DSP). Introduction The microvascular complications of diabetes include retinopathy, nephropathy and neuropathy. Their impact on quality of life and survival of a person with diabetes can be devastating. Hyperglycaemia is central to the development of microvascular complications. There is a well-established association between the likelihood of developing microvascular complications and the duration and severity of hyperglycemia. Crucially both the Diabetes Control and Complications Trial (DCCT) in Type 1 diabetes (T1D) and UK Prospective Diabetes Study (UKPDS) in Type 2 diabetes (T2D) have proven beyond doubt that intensive glycaemic control substantially reduces the risk of developing these complications. Intensive glucose control may also slow the progression of early stage complications but recent data suggest that reversing the tissue damage associated with more established microvascular complications is more difficult. Primary care teams are assuming a greater role in diabetes management. Recent clinical trials in both T1D and T2D have highlighted the importance of achieving optimal glucose control as soon as possible after diagnosis and maintaining it for as long as possible. This approach is believed to result in a ‘legacy benefit’, whereby the protective benefits of early optimal glucose control continue to be seen later in the disease even if glucose Dr N Hewapathirana SpR Diabetes/Endocrinology Nottingham University Hospitals NHS Trust Dr Simon Page Consultant Physician and Endocrinologist Nottingham University Hospitals NHS Trust Correspondence: Dr Simon Page Nottingham University Hospitals NHS Trust QMC campus, Derby Road, Nottingham NG7 2UH Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 177 Diabetic microvascular complications – screening, diagnosis and prevention control deteriorates over time. Primary care teams also have a pivotal role in ensuring that effective screening takes place to detect microvascular complications at a more treatable stage. Annual retinal screening with timely referral for ophthalmic assessment and treatment, screening for microalbuminuria and the early use of an ACE inhibitor or angiotensin receptor blocker (ARB) where the albumin creatinine ratio (ACR) is persistently raised, and assessment for neuropathy using a 10-g filament to identify patients at increased risk for foot ulcers are key aspects of screening for microvascular complications. Diabetic Retinopathy Diabetic retinopathy remains the commonest cause of blindness in people of working age.1 Epidemiological studies suggest that 5 years after diagnosis of T1D approximately one in four patients have developed retinopathy; after 20 years over 95% will have some retinopathy.2 In T2D, because abnormal glucose regulation is often present for several years before clinical diagnosis, approximately one in four patients has retinopathy at diagnosis. After 20 years approximately 60% will have some degree of retinopathy and in over one in three patients this will be sightthreatening.2 The duration and severity of hyperglycaemia are major risk factors for the development and progression of retinopathy in both T1D3 and T2D.4 Hypertension5 and proteinuria are other important predictors for retinopathy progression. Gross proteinuria is associated with a 95% increased risk of developing diabetic macular edema (DME) among subjects with T1D.6 Recent clinical trial data also suggests that dyslipidaemia is associated with an increased risk of developing retinopathy, in particular DME. Pathophysiology One of the earliest signs of retinopathy is loss of pericytes from the retinal capillary bed. These contractile cells play a role in controlling retinal blood flow. Other early features include thickening of the capillary basement membrane and the development of micro aneurysms in retinal capillaries which are responsible for the ‘dot’ appearances on retinal screening images. Rupture of these micro aneurysms leads to ‘blot’ haemorrhages. Dot and blot haemorrhages and hard exudates (see below) are cardinal features of non-proliferative diabetic retinopathy (NPDR). Two main types of sight-threatening retinopathy are recognised. In proliferative diabetic retinopathy (PDR), capillary damage and closure results in the development of areas of retinal ischaemia. Soft exudates (also known as cotton wool spots) are retinal infarcts and are an important finding on screening images since they are associated with an increased risk of developing PDR. The resulting retinal ischaemia stimulates the production of growth factors such as vascular endothelial growth factor (VEGF) which, over time promotes the growth of new blood vessels from the optic disc and retina (Figure 1). From a screening perspective it is important to appreciate that new vessels are symptomless unless a haemorrhage occurs into the vitreous, at which point a patient will experience acute uni-ocular visual loss, and also that laser Figure 1: Extensive new vessel formation both on the optic disc and the peripheral retina together with background dot and blot changes of background retinopathy. A small sub-hyaloid haemorrhage is seen in the top right of the retina at 12 o clock relative to the optic disc. 178 Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 Diabetic microvascular complications – screening, diagnosis and prevention therapy is an effective treatment which significantly reduces the risk of visual loss associated with PDR. In DME the integrity of the blood retinal barrier breaks down leading to increased capillary permeability. Hyperglycaemia is associated with increased retinal capillary blood flow and this, coupled with pericytes loss and a breakdown of capillary auto-regulation, causes increased leakage and exudation into the retina. The principle clinical manifestation of DME is the appearance of hard exudates–discrete well defined whitish spots seen in the retina which are believed to reflect lipid accumulation. Hard exudates involving the macular region, (the area of the retina within 2 disc diameters of the fovea), commonly form circinate rings which suggest the presence of focal capillary leakage. Patients with these retinal features are at increased risk of slowly progressive visual loss (Figure 2). Screening It is crucial to appreciate that early stage retinopathy is asymptomatic. Identifying patients with potentially treatable early-stage disease is a central objective of the comprehensive screening programmes in the UK and other countries. Patients should be educated about the importance of attending for eye screening appointments even though they are likely to have no symptoms. It is known that non participation in retinal screening programmes is associated with worse visual outcomes,7 a fact that may be persuasive for some patients. Recommendations in the National Service Framework for Diabetes (2001) led to the establishment of the English National Screening Programme for Diabetic Retinopathy (ENSPDR: www.retinalscreening.nhs.uk). This organisation provides advice, support and facilitation to Strategic Health Authorities (SHAs), Primary Care Trusts (PCTs) and local programmes. In outline, 2-field mydriatic retinal photography is the preferred screening method, with 2 or 3 levels of grading for retinal images. ENSPDR provide various guidance documents, fact sheets and information which can be useful in patient care.8 Whilst acknowledging significant overlap, the National Institute for Health and Clinical Excellence (NICE) have published guidelines for retinopathy screening in both T1D (CG15)9 and T2D (CG66).10 Annual eye screening for all T1D patients over the age of 12 years and for all patients with T2D from diagnosis is recommended. Patients identified as having sight-threatening retinopathy as a result of screening should be referred for ophthalmological assessment as an integral part of the screening programme. Time lines for referral vary with the severity of the finding. Occasionally a patient may present outside of a screening programme with visual symptoms such as acute uni-ocular loss of vision, suggesting a vitreous haemorrhage, or sudden onset of flashing lights or floaters suggesting a possible retinal detachment. Urgent referral to ophthalmology services is advised. Primary Prevention Optimal control of glycaemia, blood pressure and lipids are all important in preventing retinopathy and in slowing the progression of established disease. Glucose control The DCCT trial3 enrolled 1441 T1D subjects with either no retinopathy (primary prevention cohort) or Figure 2: Areas of confluent hard exudates centered around the macular region consistent with diabetic maculopathy. Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 179 Diabetic microvascular complications – screening, diagnosis and prevention early retinopathy (secondary prevention cohort). Subjects were randomised into intensive and conventional insulin management arms who achieved mean HBA1c concentrations of 7.2% and 9.2% respectively over 6 years). The greatest benefit was seen in the primary prevention cohort who achieved a 76% reduction in newonset retinopathy compared with the conventional arm. In the secondary intervention cohort, although the intensive group had a higher cumulative incidence of sustained progression during the 1st year, by 36 months this was significantly lower than the conventional group with a 54% reduction in the risk of progression. These benefits extended across all subgroups. An early deterioration in pre-existing retinopathy associated with improved glycaemic control has been reported in other trials from Scandinavia. A practical implication of this phenomenon is the need to monitor retinal appearances in each trimester in women with diabetes whose control typically improves during the course of a pregnancy. The Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group followed the DCCT patient cohorts for a further 6 years after the conclusions of the trial and found that the benefits of intensive glucose control persisted even though HBA1c levels rose over this time (mean HbA1c increased from 7.2 to 7.9%). Importantly patients in the conventional insulin management group, whose control improved during the course of EDIC did not see any reduction in their rate of retinopathy progression.11 The UKPDS studied newly diagnosed T2D subjects. Over the 15 years of the trial the majority of the benefits of tight glucose control (intensive group HBA1c 7% vs conventional group HBA1c 7.9%) were seen in a 25% reduction in microvascular end points including retinopathy and the need for retinal photocoagulation.4 More recent trials have investigated whether improving diabetes control in T2D at a later stage in the disease (approximately 10 years after diagnosis) has any benefits. The ACCORD trial12 reported a significant 33% relative reduction in the risk of progression of retinopathy associated with intensive glucose management. Interestingly there was a 40% reduction in retinopathy progression associated with an intensive lipid management arm using fenofibrate and a non-significant 13% reduction with intensive blood pressure control. In contrast in the ADVANCE trial,13 although intensive glucose control (target HBA1c < 6.5%) was associated with a reduction in microvascular complications, this was largely due to a reduction in nephropathy with only a non-significant 5% reduction in the onset or progression of retinopathy. From these and other publications it is clear that a crucial objective in diabetes management is to help patients achieve and maintain glucose levels as near to normal as soon as possible after diagnosis. The risks of tight glucose control such as hypoglycaemia must always be borne in mind however, and treatments should be individualized with special consideration given to children, pregnant women, and the elderly. In general the presence of retinopathy 180 should not influence the choice of medication used to optimise glucose control with the proviso that there have been reports of worsening macular oedema in patients treated with pioglitazone. This is generally reversible on withdrawal of the drug but care should be taken in using this particular agent in patients with known DME. Blood pressure control There is a strong link between hypertension and the development and progression of retinopathy. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) reported progression of retinopathy to be associated with higher diastolic blood pressure14 and with a higher incidence of DME among older-onset patients.15 Of the randomized controlled clinical trials the UKPD38 reported a 34% relative risk reduction in progression of retinopathy associated with intensive blood pressure control (target <150/85). After 9 years the risk of moderate visual loss was reduced by 47% and the need for laser therapy by 35% compared with the less tight control group (BP target <180/105). These benefits were independent of the type of blood pressure medication. The UKPDS blood pressure targets are largely of historical interest since more recent trials have confirmed substantial benefits of aiming for lower targets in reducing complications. Current recommendations are for a BP target of < 140/80 for most patients with T2D but to aim for a lower target of < 130/80 for those with evidence of complications including retinopathy (NICE CG 66).10 There has been much debate about whether drugs that block the renin-angiostensin-aldosterone system (RAAS), principally ACE-inhibitors (ACEI) and angiotensinreceptor blockers (ARBs), have any specific advantage over other anti-hypertensive therapies in diabetic retinopathy. This is partly based on evidence suggesting there is a locally acting RAAS within the retina. The EUCLID trial16 reported a 50% relative risk reduction in the progression of retinopathy in normotensive patients with T1D treated with lisinopril. Retinopathy was, however a secondary end-point in a trial investigating progression to microalbuminuria. A more recent trial, RASS (2008),17 reported reduced retinopathy progression in T1D from RAAS blockade with both the ARB losartan and the ACEI enalapril. More recently the Diabetic Retinopathy Candesartan Trial (DIRECT)18,19 investigated whether treatment with the ARB candesartan (32mg od) would reduce the development and progression of retinopathy in T1 and T2 diabetic subjects. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAAS blockade. These data support a central role for RAAS blocking drugs in the management of hypertension in diabetes as a means of reducing retinopathy risk. RAAS blockade is also of crucial importance in diabetic nephropathy treatment – see below. It is interesting to note that the event rate in the DIRECT trial was lower than that expected from initial power calculations and the trial was extended for a further year as a result. This suggests that modern intensive Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 Diabetic microvascular complications – screening, diagnosis and prevention diabetes management may be impacting beneficially on the risk of developing retinopathy. Blood lipids There is observational evidence that elevated lipids are associated with an increase in retinal hard exudates and in the severity of retinopathy. As discussed earlier the ACCORD12 trial reported benefits of intensive control of blood lipids with respect to slowing retinopathy progression. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)20 trial involving over 9000 patients with T2D the use of fenofibrate was associated with a 31% reduction in the requirement for first laser therapy for all retinopathy. The significance of this observation, a secondary end-point in the FIELD trial, remains uncertain. Retinopathy treatment Laser photocoagulation remains the treatment of choice for sight threatening diabetic retinopathy. Pan-retinal photocoagulation is used for PDR. In this procedure the peripheral retina is treated with multiple laser burns with the intention of reducing oxygen demand from retinal tissue. This in turn leads to a reduction in growth factors such as VEGF which results in stabilisation and eventual regression of new vessel formation. The Diabetic Retinopathy Study21 reported a 50% reduction in visual loss in treated eyes with new vessels at the optic disc. Laser therapy for macular oedema is generally more limited in extent, but has a similar 50% reduction in risk of visual deterioration. For patients with progressive DME despite laser therapy other options can be considered. A Cochrane Database Review22 in 2008 concluded that intra-vitreal steroid injections have some utility in the treatment of resistant DME. More recent research is focussing on the combination of laser plus intravitreal steroids to determine if outcomes can be improved. A second line of therapy involves the use of biological therapies which block the effects of VEGF. These therapies are expensive, require repeated ocular injections and have not, to date, been approved for use in DME. Two agents, pegaptanib and raniibizumab are currently being reviewed by NICE. Vitrectomy, the surgical removal of the vitreous, is an important treatment option in patients with PDR who have suffered a vitreous haemorrhage. Restoration of sight is usually achieved and the procedure also allows for pan-retinal endo-laser therapy to be completed reducing the risk of future haemorrhages. Retinopathy, laser therapy and driving Laser therapy is essentially a destructive process which may impact on visual acuity and peripheral visual fields. Visual criteria for driving are available on the DVLA website (www.dvla.gov.uk). Patients who have had laser therapy are required to notify the DVLA and will be asked to undertake an acuity and visual field assessment at a registered ophthalmic practitioner in order to confirm that their vision meets current requirements. Acute monocular visual loss, for example associated with a vitreous haemorrhage, should also be notified to the DVLA and driving should cease until the ocular pathology is fully evaluated. Persistent monocular visual loss precludes a patient from holding a Class 2 licence. Nephropathy Diabetic nephropathy is the leading cause of chronic kidney disease in patients starting renal replacement therapy and is associated with increased cardiovascular mortality.23 Between 20% and 40% of patients with T1D ultimately develop nephropathy, although the reason why only a proportion develops this complication is unknown. Genetic factors have been implicated. The UKPDS trial provided valuable information about the natural history of nephropathy in T2D. Annual conversion rates of approximately 2% between normo-albuminuria and micro-albuminuria and microalbuminuria and established proteinuria were seen.24 Importantly there was a significant increase in mortality with worsening nephropathy rising from 1.4% per annum in those with normal albumin excretion, to 4.6% in those with established proteinuria and to 19.2% in those with renal failure. Five stages in the progression of classical diabetic nephropathy have been described: Stage 1 Hyperfiltration with renal hypertrophy and increased glomerular filtration Stage 2 Early glomerular changes including basement membrane thickening and mesangial expansion – albumin excretion is normal. Stage 3 Microalbuminuria and early hypertension Stage 4 Overt proteinuria Stage 5 End stage renal disease The situation in respect of renal disease is not quite as clear cut in T2D as it is in T1D where diabetic nephropathy accounts for most cases of renal failure. In contrast it only accounts for about one third of cases in T2D because patients are older and are more likely to have other causes of progressive renal failure. These include reno-vascular and hypertensive disease, obstructive uropathy, renal stone disease, polycystic kidney disease and myeloma. Clinical clues which may point to an alternative cause of deteriorating renal function in a patient with diabetes are shown in Table 1. Microalbuminuria is the earliest clinically detectable indication of diabetic renal involvement. It is defined as a urinary albumin excretion of 30-299 mg/24hrs (20200mcg/min). Without intervention, 80% of people with T1D and microalbuminuria will progress to overt nephropathy (i.e. proteinuria characterized by >300 mg albumin excreted daily). Like all other microvascular complications of diabetes, there are strong associations between poor glycaemic control and the risk of developing diabetic nephropathy.25 Primary prevention of diabetic nephropathy is based on treatment of known risk factors including hypertension, hyperglycaemia, smoking, Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 181 Diabetic microvascular complications – screening, diagnosis and prevention Table 1: Features present in non-diabetic deteriorating kidney function. Suspect renal disease, other than diabetic nephropathy and consider further investigation or referral when the ACR (albumin-creatinine ratio) is raised and any of the following apply: • There is no significant or progressive retinopathy. • Blood pressure is particularly high or resistant to treatment. • Had a documented normal ACR and develops heavy proteinuria (ACR >100 mg/mmol). • Significant haematuria is present. • The glomerular filtration rate has worsened rapidly. • The person is systemically ill. and dyslipidaemia. Primary care team are well placed to coordinate this multifactorial approach to diabetes management. Pathophysiology Diabetic nephropathy is primarily a disease of the glomerulus, the fundamental filtration units of the renal cortex. The underlying mechanisms of injury in early stage disease are similar to that seen in diabetic retinopathy with increased glomerular basement membrane thickness and micro-aneurysm formation.25 Mesangial expansion may compromise to a degree glomerular filtration. Podocytes are specialised cells which determine the size of the filtration pores between the glomerular capillaries and Bowman’s capsule. As a result of metabolic injury to podocytes these pores increase in size allowing relatively small protein molecules such as albumin to ‘leak’ into the renal tubular system resulting in the onset of microalbuminuria. Glycation of the glomerular basement membrane alters its electrical charge which enables negatively charges molecules like albumin to be more easily filtered. Finally glomerular capillary filtration pressure is believed to be increased in diabetic nephropathy, partly as a result of increased vasoconstriction of the efferent arteriole. This aspect of glomerular capillary function is under the regulatory control of the RAAS system. In fact, one of the suggested ways in which ACE-inhibitors and ARBs provide specific renoprotection is by lowering glomerular filtration pressure through inhibiting angiotensinmedicated efferent arteriolar constriction. As renal dysfunction progresses glomerular capillary architecture and the supporting mesangial tissues become progressively sclerosed with the formation of classical mesangial nodules, the Kimmelsteil-Wilson body. The progression of structural glomerular damage is not uniform. At any time point there is a wide range of glomerular histological appearances ranging from normal to severe scarring. Glomeruli which are less severely affected are able to adapt to the increased filtration and reabsorption demands for a time, but with disease progression, the ultimate outcome is near complete loss 182 of renal filtration capacity associated with the fluid and electrolyte imbalances seen with end-stage renal failure. As renal function declines and reaches stage 4 CKD (eGFR < 30 ml/min), other factors need to be considered. These are summarised in the NICE guidelines on the management of Chronic Kidney Disease 2008.26 Patients may develop anaemia, often related to iron deficiency. This requires regular monitoring and, where appropriate oral or intravenous iron therapy. If the haemoglobin remains below 11 g/dl referral to a renal physician for erythropoietin replacement therapy should be considered.27 Disturbances of calcium homeostasis become more problematic as renal function declines. Since the kidneys are involved in the synthesis of active di-hydroxy-vitamin D, progressive renal failure commonly leads to vitamin D deficiency. Serum calcium levels are then maintained by a rising concentration of parathyroid hormone at the expense of skeletal calcium. The long term consequences are the development of renal bone disease, an increased fracture risk, and ultimately the development of tertiary hyperparathyroidism. Monitoring of bone parameters and parathyroid hormone levels when stage 4 CKD has developed allows timely intervention with pharmacological vitamin D replacement. 1 alfa-calcidol is preferred since this does not require 1 hydroxylation in the kidney to become biologically active. Finally it is vitally important to treat cardiovascular risk factors at all stages in the progression of diabetic nephropathy because of the strong association with increased cardiovascular morbidity and mortality. Screening and Diagnosis; Current Guidelines NICE (CG66)10 have published helpful recommendations for screening for diabetic nephropathy – Table 2. It is now appreciated that raised ACRs do not always progress. They may be an intermittent finding, or they may remain raised but at a low and non-progressive level over time. Reversion of previously raised levels to normal has been reported in up to one third of cases.28 Hence it is important not to over-interpret a single raised ACR result. Long term trends are more important in guiding therapeutic decisions. Current guidelines recommend that Table 2: NICE Recommendations (CG 66) for screening for Diabetic nephropathy10 Annual measurement of • Albumin/creatinine ratio (ACR) or protein/creatinine ratio (PCR) (if the urine sample is ‘dipstick positive’ for protein) in a first pass urine sample** (exclude urinary tract infection (UTI) and repeat if UTI present after treatment). • Serum creatinine and eGFR * Screening in T1D should start from 12 years of age ** If a first pass sample is not available make the ACR/ PCR measurement on a spot sample. If this result is abnormal a first pass sample should be checked. Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 Diabetic microvascular complications – screening, diagnosis and prevention if an ACR is abnormal it should be repeated on at least two further occasions within 3–4 months. Microalbuminuria is diagnosed if 2 or 3 ACR readings on different samples are increased above the reference ranges for men (< 2.5 mg/mmol) or women (< 3.5 mg/mmol). ACE inhibitors (or ARBs if not tolerated) are recommended as first line therapy in all patients with microalbuminuria. The usual monitoring precautions should apply but, having started treatment the therapeutic objective should be to titrate to full or maximally tolerated dose over a few weeks. Monitoring the response of the ACR to starting RAAS blockade can be rewarding and provide positive feedback of benefit since it often falls significantly and may return to normal. In pre-menopausal women ACE inhibitors should be used with caution if there is any prospect of pregnancy and only after full discussion with the patient. Prevention Optimal glycaemic control has an established role in preventing the onset of microalbuminuria in both T1D and T2D. In the DCCT trial3 in T1D, intensive glycaemic control reduced the incidence of microalbuminuria by 39%. It is interesting to note that patients randomized to strict glycaemic control had a long-lasting reduction of ~40% in the risk for development of microalbuminuria 7–8 years after the end of the DCCT,11 a result of the so called legacy benefit of early good glucose control. In T2D the UKPDS4 reported a 30% risk reduction for the development of microalbuminuria in the group intensively treated for hyperglycaemia. The role of anti-hypertensive therapy, in particular ACE inhibitors or ARBS, in preventing the development of microalbuminuria in T1D is uncertain. Since only 4 in 10 patients with T1D at most will ever be at risk of developing nephropathy, the use of these drugs in all patients with T1D would mean that the majority would take them unnecessarily. Furthermore clinical studies in T1D such as the EUCLID16 trial have also cast doubt on whether ACEinhibitors can prevent microalbuminuria. The preferred management in patients with T1D is to start treatment with an ACE-inhibitor (or ARB if not tolerated) once microalbuminuria has been diagnosed through effective ACR screening. In T2D over 70% of patient have co-existent hypertension which requires treatment in its own right. In addition to reducing risk of stroke and heart failure there is good data to show benefit in nephropathy prevention. In the UKPDS a reduction from 154 to 144 mmHg in the intensive blood pressure sub-study was associated with a 29% reduction in the risk of developing microalbuminuria.5 Treatment of established nephropathy Once persistent microalbuminuria has developed a patient is at increased risk of progression to overt proteinuria, an accelerated decline in GFR and increased risk of cardiovascular disease. Treatments should be geared to reducing these risks and this requires a multi-factorial approach. The evidence that strict glucose control is effective in reducing disease progression in patients who have already developed microalbuminuria is conflicting. Neither the DCCT29 nor the Microalbuminuria Collaborative Study Group30 reported any reduction in the progression to overt proteinuria associated with intensified glucose control in patients with T1D. In contrast the recently reported ADVANCE13 trial reported reno-protective benefits of tight glucose control in T2D patients with more advanced disease. Rising systemic blood pressure is a cardinal feature of diabetic nephropathy. In T1D, 24 hr ambulatory monitoring studies have demonstrated that blood pressure is higher in patients with microalbuminuria than in patients with normal albumin excretion. As microalbuminuria progresses to more established renal disease blood pressure rises inexorably. Many clinical trials have demonstrated that renal function declines more rapidly if hypertension is poorly controlled and, in later stage disease control of blood pressure is the single most important clinical intervention to preserve remaining renal function. Drugs that block the RAAS system, used at maximum or maximally tolerated doses play a central role in the management of diabetic nephropathy. The evidence base for this recommendation is strong. A meta-analysis of 12 trials evaluating 698 nonhypertensive micro-albuminuric T1D subjects found a 60% reduction in progression to macro-albuminuria associated with the use of ACE inhibitors.31 In T2D the MICRO-HOPE32 (Heart Outcomes Prevention Evaluation) study, ramipril (10 mg/day) decreased the risk of overt nephropathy by 24% and the risk of cardiovascular death by 37% in T2D subjects who were >55 years of age with one additional cardiovascular risk factor by 37%. ARBs have also been shown to be effective. Irbesartan (300 mg/day) reduced the risk of progression to overt diabetic nephropathy by 70% in a 2-year follow-up study of 590 hypertensive micro-albuminuric T2D subjects.33 Since ACE-inhibitors and ARB drugs block the RAAS system at different levels clinical trials have been undertaken to determine if combination therapy would offer additional benefits. Several small trials showed promising results. A recent large scale multicentre trial (ONTARGET)34 enrolled enrolled 25,620 patients with coronary heart disease or diabetes plus additional risk factors who were over the age of 55 years of age but did not have evidence of heart failure. Patients were randomized to receive ramipril 10 mg per day, telmisartan 80 mg a day, or the combination of the two. Mean duration of followup was 55 months. There were no significant differences in the primary end point (a composite of cardiovascular death, MI, stroke, or hospitalization for heart failure) between all three patient groups. Compared with the ramipril group, telmisartan patients had lower rates of cough and angioedema and a higher rate of hypotensive symptoms. Patients who received combination therapy Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 183 Diabetic microvascular complications – screening, diagnosis and prevention Figure 3: Current NICE guidance on Blood Pressure management in T2D. had higher rates of hypotensive symptoms, syncope, renal dysfunction, and hyperkalemia, with a trend toward an increased risk of renal function requiring dialysis. The authors concluded that there was no additional advantage (and some harm) from the combination of telmisartan and ramipril used in full doses, as compared with ramipril alone. In view of this outcome combination of ACE-inhibitor and ARB is not generally recommended other than in particular circumstances of persistent heavy (nephrotic 184 range) proteinuria where there is some evidence in support of this approach, albeit with close biochemical and clinical surveillance. Current UK guidelines recommend a blood pressure target of < 130/80 for patients with complications including nephropathy, whilst the American Joint National Committee group (JNC7) advocate a lower target of < 125/75 for patients with heavy proteinuria (> 1g per 24hrs). To achieve this combination antihypertensive therapy Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 Diabetic microvascular complications – screening, diagnosis and prevention Figure 4: Microvascular benefits of intensive multifactorial intervention in high risk patients with T2D and microalbuminuria. is usual with 3-4 different classes of agent typically being required. The current NICE guideline summarising hypertension management in diabetes is shown in Figure 3. A discussion of the extensive evidence base which underpins these recommendations is beyond the scope of this article. Modification of cardiovascular risk factors beyond glucose and blood pressure is important in improving outcomes in subjects with nephropathy. Current recommendations in respect of total and low density lipoprotein (LDL)-cholesterol are to aim for levels of 4 and 2 mmol/l respectively. There is some evidence that, in addition to the undoubted cardiovascular benefits associated with these targets, there may be additional renoprotective benefits.35 In the Heart Protection Study36 for example 40mg simvastatin reduced the GFR decline in patients with diabetes, independent of cholesterol levels at baseline, by 25%. A multi-factorial approach Patients with early stage nephropathy are a high risk group who require intensive risk factor modification to reduce their risk of cardiovascular and renal morbidity and mortality. The Steno-2 study37 investigated the benefits of such an approach in 160 T2D subjects with microalbuminuria. Therapeutic targets were blood pressure levels <130/80 mmHg, fasting cholesterol <4.5 mmol/l, fasting triglycerides <1.7mmol/l, and HBA1c <6.5%. The multifactorial intervention comprised a stepwise lifestyle changes programme including a lowfat diet, a three to five times a week light-to-moderate exercise programme and a smoking cessation program. Pharmacological interventions included ACE inhibitors or ARBs and aspirin plus other agents in order to achieve targets. The intensively treated group had a 61% reduction in the risk of developing macroalbuminuria and a 58% and 63% reduction in the risk of retinopathy and autonomic neuropathy, respectively (Figure 4). Most importantly, a 55% reduction in the risk for the development of a composite end point consisting of death from cardiovascular causes, nonfatal myocardial infarction, revascularization procedures, nonfatal stroke, and amputation was also observed in the multifactorial intervention group. In summary annual screening for microalbuminuria (ACR), measurement of serum creatinine and eGFR, and regular BP monitoring are important aspects of screening for early diabetic renal disease. An intensive multifactorial approach to improving glycaemic control and aggressive antihypertensive treatment aiming at target blood pressure <130/80 mmHg, with the use of ACE inhibitors or ARBs will slow the rate of progression of nephropathy and other diabetic microvascular (and macrovascular) complications. Early referrals to diabetes and renal specialists are important and should be in accordance with local guidelines. Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 185 Diabetic microvascular complications – screening, diagnosis and prevention Neuropathy Between 10 and 20% of patients with newly diagnosed T2D have clinical symptoms and signs of diabetic neuropathy and this figures rises to 50% after 15 years of disease duration. As with other microvascular complications, risk of developing diabetic neuropathy is proportional to both the severity and duration of hyperglycemia. Also it is being suggested that some individuals are genetically at higher risk of developing neuropathic complications. There are several forms of neuropathy associated with diabetes but chronic distal symmetrical sensory-motor polyneuropathy (DSSP) is the most common. The other varieties include focal/multifocal sensory or motor neuropathies and autonomic neuropathies. In addition to chronic unpleasant symptoms which have a marked impact on quality of life the most important consequence of DSSP is an increased risk of foot ulceration and amputation. It is important not to assume neuropathy is due to diabetes but exclude other causes such as chronic inflammatory polyneuropathy, vitamin B12 deficiency, hypothyroidism, and uremia. Published estimates vary widely but around 10% or patients with diabetes and neuropathy may have another cause of neuropathy which may be amenable to treatment. Pathophysiology The pathophysiology of diabetic symmetrical polyneuropathy remains incompletely understood. Two main mechanisms are suggested. Firstly, a metabolic hypothesis in which disturbances of cellular metabolic pathways as a result of persistent hyperglycaemia lead to increased polyol flux, accumulation of advanced glycation end products, oxidative stress, and lipid alterations among other metabolic abnormalities. Secondly a vascular hypothesis in which microvascular damage to the capillary network in the vasa nervorum, the delicate network of vessels which delivers oxygen to nerves results in nerve hypoxia. More recently evidence of involvement of the spinal cord and higher centres in the brain in patients with DSSP has been reported which are the focus of ongoing research. Data from a European Collaboration has demonstrated significant associations between diabetic neuropathy and well known cardiovascular risk factors.38 Diabetes is also associated with other neuropathies including those which affect single nerves such as femoral neuropathy, radiculopathy and ocular palsies of the 3rd and 6 nerves.39 The pathogenesis is less clear in these cases but their acute onset and tendency to slow recovery suggests acute vascular insufficiency may play an important role. Screening The main purpose of screening patients for neuropathy is to identify those at increased risk of foot ulceration as a result of neuropathic or vascular compromise. Patients should be asked about symptoms of diabetic neuropathy. Typically patients report pins and needles type parasthesiae, 186 Table 3: Essential components of annual foot examination in diabetic patients. Key aspects of annual foot examination • Testing of foot sensation using a 10g monofilament or vibration (using a biothesiometer or calibrated tuning fork) • Palpation of the foot pulses (dorsalis pedis and tibialis posterior) • Inspection of the foot for any deformity • Inspection of footwear burning pains, electric shock like shooting pains and increased sensitivity of the skin of the feet, variably extending up the calf. Symptoms tend to be worse at night and can disturb sleep resulting in chronic fatigue and mood changes. These are so called ‘positive pain symptoms’. More commonly a patient will not complain of any symptoms since their feet have become numb and incapable of feeling anything. Regarding examination, NICE guidelines40 recommend regular (at least annual) visual inspection of patients’ feet, assessment of foot sensation, and palpation of foot pulses by trained personnel as an important means of identifying patients who are at higher risk of future foot ulceration. The essential components of foot examination are shown in Table 3. This will enable classification into four groups • low current risk (normal sensation, palpable pulses) • at increased risk (neuropathy or absent pulses or other risk factor) • at high risk (neuropathy or absent pulses + deformity or skin changes or previous ulcer) • ulcerated foot All patients should receive advice and education on good foot care but those at increased or high risk should be referred for additional care from podiatry and/or orthotic services or to the local multi-disciplinary foot care team (MDT). All patients with active foot ulceration should be referred to a local foot care MDT for urgent assessment. Prevention As with other microvascular complications optimizing glucose control is central to preventing the development and progression of diabetic neuropathy. This was clearly demonstrated in both the DCCT3 and UKPDS4 trials. As with retinopathy and nephropathy there is evidence of a ‘legacy benefit’ from early intensive glucose control in neuropathy. Intensive therapy was associated with a 51% and 43% reduction in the symptoms and signs of neuropathy respectively 8 years beyond the end of the DCCT trial.41 The UKPDS study also suggests that other factors, including dyslipidaemia and hypertension as part of the metabolic syndrome, are instrumental in the onset and progression of diabetic neuropathy in patients with T2D and it is interesting to note the previously mentioned benefits reported in the Steno 2 trial37 in respect of reduced autonomic neuropathy associated with an intensive multi-factorial approach. Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 Diabetic microvascular complications – screening, diagnosis and prevention Figure 5: Algorithm for the pharmacological management of painful diabetic neuropathy: Adapted from NICE neuropathy management guidelines 2011. Several other interventions including a number of aldose reductase inhibitors and alpha lipoic acid and have been studied over the years but none has been shown to have consistent clinical benefits. Thus, other than helping patients to improve their glycaemic control, medical management of peripheral neuropathy is aimed mainly at symptom control, particularly pain. Painful neuropathy This can be a very distressing symptom for patients and loved ones alike. It is associated with significant reductions in quality of life and may be associated with the development of depressive symptoms. Recently published guidelines on the management of neuropathic pain have recommended that duloxetine is the drug of 1st choice.40 See Figure 5 for a summary of the current management guidelines Copyright © 2012 Rila Publications Ltd. Clinical Focus Primary Care 2012, 6 (3): 177–191 187 Diabetic microvascular complications – screening, diagnosis and prevention Other presentations of neuropathy Acute painful neuropathy Table 4: Clinical manifestations of diabetic autonomic neuropathy. This is an uncommon but severe manifestation of painful neuropathy. The cause is unclear. Sometimes termed insulin neuritis, is typically presents in a patient who has experienced a sudden change in glucose control often in association with the introduction of insulin therapy. It can occur within weeks of starting insulin in a patient with newly diagnosed diabetes, or in the situation of rapidly improving glycaemic control at any stage. The pain can be more generalised than with typical diabetic peripheral neuropathy and is typically very severe. Combination therapy with neuropathic analgesics and sometimes opioids are needed to achieve pain control. Anecdotally the condition can be helped by recommending that patients let their sugar levels increase temporarily and patients should be reassured that the condition tends to resolve after a few months. Autonomic system Symptoms and signs Cardiac Resting tachycardia Postural hypotension Sudden cardiac death Gastroparesis Easy satiety Abdominal distension Nausea and intermittent vomiting Epigastric discomfort and fullness Unstable diabetes control Weight loss Eructation and halitosis Colonic Altered bowel habit Diarrhoea – intermittent, often nocturnal Constipation - variable Genitourinary Urinary retention Increased risk of cystitis Erectile dysfunction Sweating Uncontrolled sweats – often precipitated by eating (gustatory sweating) Metabolic Hypoglycaemia unawareness Diabetic femoral neuropathy This describes an uncommon, unpleasant and sometimes disabling condition which is typically seen in older males with T2D. It presents over a few weeks with severe unrelenting pain in the thigh associated with progressive weakness. This can be so severe as to prevent patients from climbing stairs or getting out of a chair. Examination findings include weakness and wasting of the quadriceps muscle, combined with loss of the knee jerk on the affected side. Pain control is the cornerstone of management. Anecdotally tightening of glucose control with a transfer to insulin therapy is suggested as a means of hastening recovery. Patients should be reassured that the prognosis is generally good with most making a complete or near complete recovery in 12-18 months. Ocular nerve palsies Acute onset of 3rd or 6th nerve palsies is seen in patients with diabetes, and is generally self-limiting over a 3-6 month period. It is thought to be related to microvascular damage to the vascular supply to the relevant nerve. Investigations to exclude other intra-cranial causes of ocular palsies are sometimes required depending on clinical circumstances. Compression neuropathies Patients with diabetes are more likely to develop a carpal tunnel syndrome, often bilaterally. It is important to recognise the typical symptoms and refer for assessment and carpal tunnel decompression rather than assuming all the symptoms are a result of DSSP. Foot drop as a result of localised pressure or trauma to the common peroneal nerve as it passes by the head of the fibula is also more common in diabetes, but is not generally amenable to surgical intervention. 188 Autonomic neuropathy Fortunately this is a rare but potentially devastating microvascular complication. Clinical manifestations are summarised in Table 4. A detailed discussion of the investigation and management of autonomic neuropathy in all its various manifestations is beyond the scope of this article. Conclusions The microvascular complications of diabetes can be associated with significant morbidity and mortality. Prevention, early diagnosis and early treatment are of paramount importance. The management of microvascular complications may require the input of various health care disciplines and the primary care team involvement plays a central coordinating role to ensure patients receive appropriate and timely screening. There is a wealth of information available and it is important for Primary Care teams to become familiar with the current NICE standards for screening, prevention and referral criteria as illustrated throughout this article. The importance of optimizing glycaemic control as a means of preventing microvascular complications cannot be overstated. However, a wider multi-factorial approach incorporating good control of blood pressure, Copyright © 2012 Rila Publications Ltd. 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