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Slide notes: The major chronic complications of diabetes mellitus are described here. Among these, microvascular complications have an important role. They comprise microangiopathy, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. The current presentation will talk about specific issues relating to microvascular complications.

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Slide notes: Diabetic retinopathy is a leading cause of visual impairment in working-age adults and is a common microvascular complication of diabetes; it is one of the leading causes of blindness worldwide. During the first two decades of disease, nearly all patients with type 1 diabetes and over 60% with type 2 diabetes develop retinopathy. Duration of diabetes and severity of hyperglycaemia are the major risk factors for diabetic retinopathy. Others include age, type of diabetes, clotting factors and renal disease. Sources/references: Yam and Kwok. Hong Kong Med J 2007;13:46–60. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. Am Acad Ophthalmol 2014; available at: http://www.aao.org/ppp

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Slide notes: A table describing the features of the different levels of NPDR and PDR is shown on the next slide. Sources/references: Yam and Kwok. Hong Kong Med J 2007;13:46–60. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. Am Acad Ophthalmol 2014; available at: http://www.aao.org/ppp

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Slide notes: The earliest stage of diabetic retinopathy is NPDR, which is graded as mild, moderate, severe or very severe, depending on the presence and extent of lesions: • The earliest stage of NPDR is characterised by retinal vascular abnormalities

including microaneurysms, intraretinal haemorrhages and cotton-wool spots, which are nerve fibre layer infarctions

• As diabetic retinopathy progresses, the retinal vessels gradually close, which results in retinal ischaemia. This manifests as venous abnormalities (beading, loops), intraretinal microvascular abnormalities, and increasing retinal haemorrhage and exudation.

The more advanced stage of diabetic retinopathy is PDR, which involves the formation of new blood vessels, induced by the retinal ischaemia, which spreads out either from the disc (NVD) or from elsewhere in the retina (NVE): • New vessels extending into the vitreous can cause vitreous haemorrhage, and

tractional retinal detachments • Ghost cell glaucoma resulting from vitreous haemorrhage can occur • Late in the course of diabetic retinopathy, neovascular glaucoma can result

from new vessels growing on the iris and anterior chamber angle structures • The extent and location of neovascularisation determines the level of PDR. Source/reference: Adapted from Yam and Kwok. Hong Kong Med J 2007;13:46–60.

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Slide notes: The first step toward preventing or delaying the onset of DR is maintaining tight blood pressure and blood sugar control. The protective effect of glycaemic control on microvascular complications has been confirmed for patients with T1DM and T2DM. The UKPDS has shown that maintaining blood pressure at <150/85 mmHg reduces the rate of progression of retinopathy. However, because patients at risk for retinopathy are also at risk for nephropathy, maintaining a blood pressure of <130/80 mmHg is advised. Comprehensive eye examinations on a yearly basis will help the physician and patient identify any clinical signs of retinopathy prior to the patient developing symptoms. Sources/references: Yam and Kwok. Hong Kong Med J 2007;13:46–60. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. Am Acad Ophthalmol 2014; available at: http://www.aao.org/ppp

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Slide notes: In addition to tight glycaemic and blood pressure control, regular eye examinations and treatment are necessary. Mild NPDR is characterised by increased vascular permeability, microaneurysms and intraretinal haemorrhages. DMO can be present at this stage, and clinically significant DMO occurs when oedema threatens the centre of vision or is within 500 m of the fovea. • If clinically significant DMO is present, colour fundus photography can be used to

determine the extent of DMO • Fluorescein angiography can be used to identify lesions, and focal

photocoagulation used to reduce the risk of vision loss • Decision to treat clinically significant DMO in patients with mild NPDR should be

discussed. If photocoagulation is not performed the patient should be carefully monitored and examined approximately every 3 months for progression.

Patients with moderate NPDR experience gradual retinal ischaemia, venous calibre abnormalities, intraretinal microvascular abnormalities and, possibly, clinically significant DMO. • Patients at this stage of retinopathy without clinically significant DMO should have

ophthalmic examinations every 6–12 months to monitor disease progression • If DMO is present, colour fundus photography is used to document the extent of

oedema, fluorescein angiography is used to locate leaking blood vessels and photocoagulation to seal the vessels.

Sources/references: Yam and Kwok. Hong Kong Med J 2007;13:46–60. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. Am Acad Ophthalmol 2014; available at: http://www.aao.org/ppp

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Slide notes: Severe to very severe NPDR is characterised by even more extensive haemorrhage and microaneurysms. The microvasculature of the retina begins to deteriorate, resulting in retinal ischaemia. • Patients at this stage of retinopathy should be evaluated every 3–4 months for

progression to PDR • Panretinal or “scatter” laser photocoagulation can be considered to shrink

abnormal blood vessels • If clinically significant diabetic macular oedema (DMO) is present, the same

methods of treatment can be used as for moderate NPDR. Clinically significant DMO should be treated prior to performing scatter photocoagulation.

PDR should be managed with panretinal laser photocoagulation, colour fundus photography, and follow-up every 3–4 months to monitor treatment success. • Vitrectomy should be considered when there is substantial amount of

haemorrhaging in the vitreous fluid, and when neovascularisation causes retinal traction or retinal detachment. Clinically significant DMO is treated in the same manner as described for severe NPDR.

Sources/references: Yam and Kwok. Hong Kong Med J 2007;13:46–60. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. Am Acad Ophthalmol 2014; available at: http://www.aao.org/ppp

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Slide notes: Diabetic nephropathy represents the major cause of end-stage renal disease in western societies. One of the hallmarks of diabetic nephropathy is the development of proteinuria, which is usually followed by a progressive decline in renal function. The development of diabetic nephropathy is also a major risk factor for cardiovascular disease. From an epidemiological, pathophysiological and clinical perspective, hypertension and poor glycaemic control are usually associated with this condition. Diabetic nephropathy is generally defined as a rise in urinary albumin excretion and reduced renal function, as reflected by raised plasma creatinine concentration, reduced calculated creatinine clearance or decreased glomerular filtration rate. Sources/references: Ritz E and Orth SR. N Engl J Med 1999;341:1127–1133. Adler AI, et al. BMJ 2000;321:412–419. Stratton IM, et al. BMJ 2000;321:405–412. Fineberg D, et al. Nat Rev Endocrinol 2013;9:713–723.

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Slide notes: There are many potential contributors to the progression of diabetic nephropathy in patients with diabetes, as listed on the slide. Source/reference: Fernandez-Fernandez B, et al. Nat Rev Nephrol 2014;10:325–346.

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Source/reference: Fineberg D, et al. Nat Rev Endocrinol 2013;9:713–723.

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Slide notes: Treatment of diabetic nephropathy must be done early to prevent progression of the disease. Treatment to control blood pressure dramatically reduces the risk of cardiovascular and microvascular events. Multifactorial intervention, such as renin–angiotension system blockers, blood pressure control and dyslipidaemia treatment, as well as better nutrition, smoking cessation and increased physical activity, has been shown to be effective in slowing the progression of diabetic nephropathy.

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Slide notes: The control of protein in the diet (restricted to 0.6–0.8 g/day of protein) should only be recommended for patients with established nephropathy. As soon as hypertension is diagnosed, RAS blockade with ACE inhibitors should be started for patients with T1DM and T2DM. RAS blockade with ACE inhibitors or ARBs has the advantage of additional benefit on renal function, independent of blood pressure reduction.

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Slide notes: Peripheral neuropathy is characterised by diffuse damage to the peripheral nerve fibres. The commonest cause of peripheral neuropathy is diabetes, and 30–90% of patients with diabetes have peripheral neuropathy. Diabetic sensorimotor polyneuropathy, the most common type of diabetic neuropathy, is associated with impaired quality of life, significant morbidity and increased healthcare costs. 16–34% of patients with diabetes report painful neuropathic symptoms and the prevalence is greater in T2DM, women and South Asians. The symptoms of painful diabetic neuropathy can be debilitating, cause sleep disturbances and anxiety, and interfere with physical functioning. Sources/references: Javed S, et al. Ther Adv Chronic Dis 2015;6:15–28. Callaghan B, et al. Lancet Neurol 2012;11:521–534. Galer B, et al. Diabetes Res Clin Pract 2000;47:123–128.

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Slide notes: The mechanisms by which diabetic neuropathy develops are still being researched. It is thought that neuropathy can be caused or aggravated by metabolic factors, ischaemia or impaired nerve fibre repair mechanisms. High blood glucose levels have been correlated to increased risk of diabetic neuropathy, and there are several theories as to why this occurs. Patients with diabetes have increased levels of serum advanced glycation end products (AGEs). AGEs form when excess blood glucose combines with amino acids to form, initially, early reversible glycation products. Later, irreversible AGEs are formed. AGEs are thought to contribute to blood vessel injury due to their effects on increasing vascular permeability, blood coagulation and collagen. Glucose entering the cells is partially metabolised into sorbitol – this occurs even more so with hyperglycaemia. Excess sorbitol leads to problems with cell metabolism, and could contribute to nerve damage in this way. Nerve ischaemia, or reduced nerve blood flow, is involved in the pathogenesis of diabetic neuropathy. Evidence of vascular occlusions and thickened endoneural blood vessel walls have been found in patients with diabetic neuropathy. Finally, the nerve fibre repair mechanisms present in persons without diabetes are impaired in those with diabetes. Nerve growth factor and other neurotrophic factors are decreased in diabetes, which leads to a decreased ability to repair damaged nerves.

Slide notes: There are several neuropathies associated with diabetes mellitus; the most common are listed on the slide. Source/reference: Russell JW and Zilliox LA. Continuum (Minneap Minn) 2014;20(5 Peripheral Nervous System Disorders):1226–40.

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Slide notes: Symmetric polyneuropathy is the most common form of neuropathy seen in diabetic patients and approximately half of all patients with diabetes will show signs. It is typically slowly progressive and symptoms generally begin distally in the toes and feet and move upward towards the calf. It is not uncommon for symptoms to also begin to appear in the hands, and the patient develops what is known as “stocking-glove” sensory loss. Symptoms include pain, abnormal sensation in the affected areas (typically a burning, itching, tingling sensation), numbness and loss of vibratory sensation. Touch and thermal sensations are also affected. Source/reference: Russell JW and Zilliox LA. Continuum (Minneap Minn) 2014;20(5 Peripheral Nervous System Disorders):1226–40.

Slide notes: The Toronto Expert Panel on Diabetic Neuropathy has provided criteria for the diagnosis of diabetic neuropathy (2010–2011). Sources/references: Russell JW and Zilliox LA. Continuum (Minneap Minn) 2014;20(5 Peripheral Nervous System Disorders):1226–40. Dyck PJ, et al. Toronto Expert Panel on Diabetic Neuropathy. Diabetes Metab Res Rev 2011;27:620–8. Tesfaye S, et al. Diabetes Care 2010;33:2285–93.

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Slide notes: Symmetric polyneuropathy is treated with glycaemic control, treatment of pain and foot care. The DCCT and other studies provide evidence that intensive glucose control is effective in both preventing the development of neuropathy and, to a lesser degree, improving neuropathic symptoms. Pain can be treated with tricyclic antidepressants such as amitriptyline or desipramine. These drugs are contraindicated in patients with cardiac disease, and in these cases doxepin, trazodone or paroxetine can be substituted. Nortriptyline can be substituted if cholinergic side-effects are present. Topical pain relievers such as capsaicin cream can be added to the antidepressant regimen if pain persists. Anticonvulsants such as carbamazepine, gabapentin and lamotrigine can be added to the pain relief regimen if the above remedies do not successfully alleviate pain. Foot care is not only important in the treatment of diabetic neuropathy, it is necessary to prevent amputation.

Slide notes: Microvascular complications are very prevalent in patients with diabetes mellitus and there are several known mechanisms related to the appearance of such events. The pathophysiology of microvascular complications in patients with type 1 and type 2 diabetes appears to be similar. Long-term hyperglycaemia is a major initiator of microvascular complications of diabetes, such as neuropathy, nephropathy and retinopathy. Strong evidence indicates that good glycaemic control, in addition to associated comorbidities, is accompanied by preventing or delaying the onset of these conditions.

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