Download Diabetic microvascular complications

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.
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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.
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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
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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
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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,
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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.
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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
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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.
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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,
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Diabetic microvascular complications – screening,
diagnosis and prevention
dyslipidaemia and lifestyle related risk factors such as
smoking and obesity is also likely to pay dividends.
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