Diabetic neuropathy

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

diabetic peripheral neuropathy

1st line – glycaemic control and supportive measures

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1st line –

glycaemic control and supportive measures

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy in type 1 diabetes reduced the incidence of neuropathy by 60% over a 5-year period in patients without baseline neuropathy.[17][114] Patients receiving intensive insulin therapy - via multiple daily injections or continuous subcutaneous insulin infusion (insulin pump therapy) - were compared with those receiving conventional insulin treatment (one or two daily injections without stringent glucose targets). Intensive therapy significantly reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) at the end of the trial. This benefit extended through the long-term follow-up, with persistently lower rates of both DPN and CAN in the intensive group.[115]

In type 2 diabetes, some data suggest reduced DN risk with optimal glycaemic control achieved using multiple daily insulin injections, but the evidence is not as strong as for type 1 diabetes.[29] A 2014 review reinforced the importance of early, sustained glycaemic control in type 1 diabetes, particularly for preventing CAN, whereas in type 2 diabetes, the effects of glycaemic control on DPN or CAN were less clear, with benefits more likely when control was initiated earlier in the disease course, and in patients with fewer comorbidities.[60]

The type of glucose-lowering approach may also influence DPN development or progression. Among more than 2000 patients with type 2 diabetes followed for up to 4 years in the BARI 2D trial, glycaemic control therapy with insulin sensitisers (metformin and/or a thiazolidinedione) significantly reduced the incidence of DPN compared with insulin-providing therapies (sulfonylureas, meglitinides, and/or insulin), especially in men.[21] Pancreatic transplantation appears to halt the progression of DN, and two studies have reported improvement in corneal nerve parameters following simultaneous pancreas-kidney transplantation.[106][117][118][119]

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DPN in both type 1 and type 2 diabetes, as well as other microvascular complications such as retinopathy and nephropathy.[34][121][122][123][124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

All patients with diabetes require regular foot inspection and care. This is especially important for those with DPN, who are at higher risk for painless injuries. Effective foot care starts with patient education.[127] Patients at risk should be counselled about the consequences of foot deformities, loss of protective sensation, and peripheral arterial disease.[34] Education should include guidance on proper foot hygiene and the importance of daily self-examinations to detect early signs of injury or infection.[34] Offloading footwear is recommended for high-risk patients, particularly those with loss of protective sensation (severe peripheral neuropathy), as it can help can prevent the development or progression of foot ulcers.[34][128][129] Patients with diabetes-related foot disease, including ulcers and infections, may require debridement and antibiotic therapy (although minor non-infected wounds without evidence of soft-tissue or bone infection do not require antibiotic treatment).[34][128][129] More serious problems are best handled in consultation with specialists in diabetic foot care.[194][195] Guidelines on the prevention and management of diabetes-related foot disease vary between countries. See Diabetes-related foot disease.

It is important to assess patients for comorbid mood disorders, particularly depression and anxiety, and sleep disorders.[63][97][98][99][101][102] The presence of sleep or mood disorders can affect perception of pain; treatment of these conditions may help to reduce pain and improve quality of life.[63]

with pain

Consider – systemic pharmacotherapy

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Consider –

systemic pharmacotherapy

Additional treatment recommended for SOME patients in selected patient group

Approximately 30% of individuals with diabetic peripheral neuropathy (DPN) will experience painful symptoms that will require pharmacological and other treatments.[113] Although painful DPN may occur in all age-groups, it is more common in older patients.[113] Painful DPN significantly impairs quality of life and should be treated appropriately. If pharmacologic intervention is required, patients should be advised that treatment can reduce - but may not completely eliminate - their pain.[63] Setting realistic expectations is important as it can increase the likelihood of treatment satisfaction and improve adherence.[63] Antidepressant treatment options for painful neuropathy may have beneficial effects on mood disorders; presence of mood disorders should therefore be taken into account when selecting regimens.

The American Academy of Neurology (AAN) and American Diabetes Association (ADA) recommend initiating treatment with an oral agent from one of the following classes: gabapentinoids (e.g., pregabalin, gabapentin); serotonin-noradrenaline reuptake inhibitors (SNRIs; e.g., duloxetine, venlafaxine, desvenlafaxine); tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline, desipramine); sodium-channel blockers (e.g., valproic acid, carbamazepine).[34][63] In one systematic review and meta-analysis, the AAN found these drug classes to be comparable in their ability to reduce pain.[63] Therefore, treatment choice should consider adverse effect profiles, comorbidities, and patient preference. Pregabalin, gabapentin, duloxetine, and amitriptyline are considered first-line options.[1][34] Only pregabalin and duloxetine are approved in the US for this indication. Licensing status may vary in other countries. Gabapentinoids may be considered controlled (scheduled) drugs in some countries.

In the UK, the National Institute of Health and Care Excellence (NICE) takes a more restrictive approach than the AAN/ADA, recommending one of the following specific agents as initial therapy: amitriptyline; duloxetine; gabapentin; pregabalin. NICE recommends against initiating venlafaxine for neuropathic pain unless advised by a consultant to do so.[130] NICE advises carrying out an early clinical review after initiating or adjusting treatment to assess tolerability and adverse effects.[130] Specialist referral (to a pain management or diabetes service) should be considered at any stage for severe pain, functional impairment, or deterioration in glycaemic control.[130]

Pregabalin modulates voltage-gated calcium channels and is more potent at this site than gabapentin; randomised controlled trials show reduced mean pain versus placebo, with a dose-dependent effect.[113][131] [ ] It is excreted virtually unchanged in the urine; use caution in patients with impaired renal function (especially eGFR <45 mL/min/1.73 m²), a dose adjustment may be necessary.[113] Common adverse effects include drowsiness, dizziness, peripheral oedema, and gait disturbance, with higher risk at higher doses and in older adults; a ‘start low-go slow’ mitigates this.[113] Because pregabalin also has anxiolytic activity, it may be particularly helpful in individuals with marked anxiety, which is not uncommon among people experiencing neuropathic pain.[113]

Gabapentin has been found to improve pain in people with DN, with 38% of participants in one meta-analysis reporting substantial benefit (at least 50% pain relief) from gabapentin compared with placebo.[132] [ ] As with pregabalin, gradual up-titration is recommended. Clinical trials indicate that most patients require 1800 mg/day to achieve pain relief, with some needing up to 3600 mg/day. Dose adjustments are necessary for patients with impaired renal function (reduced eGFR).[113] Adverse effects that may require discontinuation of therapy include drowsiness, dizziness, peripheral oedema, and gait disturbance.[132] [ ]

Duloxetine is safe and effective, with comparative data showing no significant efficacy/safety difference versus gabapentin.[133][134] Nausea is common but can be minimised by taking the drug with food and by gradual titration; drowsiness/dizziness may also occur.[113][135] Because duloxetine is also an antidepressant, it may be particularly helpful in people with painful DPN who also have depressive symptoms.[113]

Tricyclic antidepressants have long been used for neuropathic pain and may be effective in some patients.[113][63][141] The AAN advises that tricyclic antidepressants are possibly more likely than placebo to improve pain, but this is based solely on studies of amitriptyline.[63] They are usually given in the early evening due to sedation.[113] They act across multiple neurotransmitter pathways and are therefore associated with more adverse effects than other antidepressants.[142] Cochrane reviews do not support tricyclic antidepressants as first-line option because of methodological limitations in trials.[143][144][145][146] Anticholinergic effects (e.g., dry mouth, urinary retention, drowsiness) are common; up to one third of patients cannot tolerate even low-dose amitriptyline.[113] These adverse effects may be particularly problematic for individuals with pre-existing constipation, urinary retention, or orthostatic hypotension.[63] Among commonly used tricyclic antidepressants, the likelihood of anticholinergic adverse effects is generally ranked from highest to lowest as follows: amitriptyline; imipramine; nortriptyline; and desipramine.[147] Use lower doses in older adults and take extra care in patients with ischaemic heart disease due to the potential for cardiovascular adverse effects.[113]

SNRIs are another option. One 2015 Cochrane review found little compelling evidence to support the use of venlafaxine in neuropathic pain. However, US guidelines advise that it may be effective in some patients.[34][63][138] Unlike venlafaxine, desvenlafaxine is not subject to significant metabolism by CYP2D6, and so may be preferred in people with drug-drug interactions and genetic polymorphisms that affect this enzyme.[139] However, it is rarely used.

Sodium-channel blockers may be effective in some patients.[63] One Cochrane review found only limited evidence to suggest that valproic acid or sodium valproate reduce pain in DN, and did not recommend these treatments as first-line therapy for neuropathic pain.[148] Valproic acid should not be prescribed for painful DN unless multiple other treatments have failed, due to its association with serious adverse events, including hepatotoxicity, pancreatitis, hyponatraemia, and pancytopenia.[63] Valproic acid and its derivatives must not be used in female patients of child-bearing potential unless other options are unsuitable, there is a pregnancy prevention programme in place, and certain conditions are met. Precautionary measures may also be required in male patients.

If pain persists despite optimised pharmacotherapy, is complicated by comorbidities, or is associated with severe symptoms, functional impairment, or worsening diabetes control, consider referral to a pain management or diabetes consultant at any stage.[130]

Primary options

pregabalin: 50 mg orally (immediate-release) three times daily initially, increase gradually according to response, maximum 300-600 mg/day; 165 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 330 mg/day

gabapentin: 100-300 mg orally (immediate-release) once to three times daily initially, increase gradually according to response, maximum 3600 mg/day

duloxetine: 30-60 mg orally once daily initially, increase gradually according to response, maximum 60-120 mg/day

amitriptyline: 25 mg orally once daily at bedtime initially, increase gradually according to response, maximum 150 mg/day

Secondary options

venlafaxine: 37.5 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 225 mg/day

desvenlafaxine: 50-100 orally once daily initially, increase gradually according to response, maximum 200 mg/day

imipramine: 50 mg orally once daily initially, increase gradually according to response, maximum 150 mg/day given in 1-2 divided doses

nortriptyline: 10-25 mg orally once daily at bedtime initially, increase gradually according to response, maximum 150 mg/day given in 1-2 divided doses

desipramine: 12.5 mg orally once daily at bedtime initially, increase gradually according to response, maximum 250 mg/day given in 1-2 divided doses

Tertiary options

carbamazepine: 100 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 1200 mg/day

valproic acid: consult specialist for guidance on dose

Consider – topical pharmacotherapy

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Consider –

topical pharmacotherapy

Additional treatment recommended for SOME patients in selected patient group

Some patients with painful diabetic peripheral neuropathy (DPN) may prefer topical therapies, although evidence remains limited.[63] They can also be used in combination with systemic therapies to potentially enhance pain relief and overall efficacy.[113] Their use may improve overall pain control, reduce required drug doses of systemic treatments, and minimise adverse effects.[113]

A number of topical therapies have been proposed for the treatment of painful DPN over the years but are not widely used because the area of neuropathic pain can be extensive, involving not only both feet, but also the lower limbs, generally below the knee.[113]

A few small studies have demonstrated the effectiveness of topical capsaicin in pain control and improvement in daily activities.[157] [ ] US guidelines advise that it may be effective in some patients when used alone or in combination with other therapies.[34][63] Capsaicin cream has been shown to cause a loss of intra-epidermal nerve fibres and thermal sensation, which typically does not recover for approximately 150 days.[156] In the UK, National Institute of Health and Care Excellence (NICE) guidelines state that capsaicin cream may be considered in a specialist setting for patients with localised neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments.[130] A capsaicin cutaneous patch is approved in some countries for neuropathic pain associated with DPN of the feet. Its use may cause significant pain at the application site.[113] It must therefore be applied under the supervision of a healthcare professional in a medical setting and should be avoided in patients with active skin lesions.[113] Poor adherence is common due to the need for frequent applications, an initial exacerbation of symptoms, and frequent burning and redness at the application site.[141]

Glyceryl trinitrate spray is included in the American Academy of Neurology (AAN) guidelines as an option for topical treatment as it is possibly more likely than placebo to improve pain.[63] Evidence from one small randomised controlled trial suggested that glyceryl trinitrate spray may have some efficacy when used alone and in combination with sodium valproate.[63][158]

A lidocaine topical patch is available in some countries for the management of post-herpetic neuralgia. There are limited data supporting the off-label use of lidocaine topical patches in DPN. The American DIabetes Association (ADA) advises that they may be considered in individuals with nocturnal neuropathic foot pain; however, they are unlikely to be effective if there is a more widespread distribution of pain.[34][159] Lidocaine patches cannot be used for more than 12 hours within a 24-hour period.[113]

Primary options

capsaicin topical: (0.025% or 0.075%) apply to the affected area(s) up to four times daily when required; (8% patch) apply patch to most painful area(s) for 30 minutes and remove, maximum 4 patches per application, may repeat treatment after 3 months (do not apply more frequently than every 3 months)

Secondary options

glyceryl trinitrate: (0.4 mg/dose spray) consult specialist for guidance on dose

lidocaine topical: (5% patch) apply patch to most painful area(s) for up to 12 hours per day, maximum 3 patches per application

Consider – non-pharmacological therapies

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Consider –

non-pharmacological therapies

Additional treatment recommended for SOME patients in selected patient group

Some patients with painful diabetic peripheral neuropathy (DPN) may prefer the option of non-pharmacological interventions, although evidence for these therapies remains limited.[63] Non-pharmacological treatments can also be used in combination with pharmacotherapy to potentially enhance pain relief and overall efficacy.[113] Their use may improve overall pain control, reduce required drug doses, and minimise adverse effects.[113]

Transcutaneous electrical nerve stimulation (TENS) or acupuncture may be added to existing therapy or used alone in refractory cases.[141][160] TENS is a non-invasive therapy using low-voltage electrical currents delivered through electrodes placed on the skin. In a controlled study, it was more effective than sham treatment in reducing pain in patients with DN.[161] In uncontrolled studies, TENS and acupuncture have been reported to decrease pain in >75% of patients with DN.[162][163] A 2010 report by American Academy of Neurology (AAN), which was reaffirmed in 2024, concluded that TENS may have some effectiveness for reducing pain caused by DPN.[160]

Percutaneous electrical nerve stimulation (PENS) is a minimally invasive technique in which fine needles are inserted through the skin to deliver electrical stimulation directly to deeper nerve structures. The UK National Institute for Health and Care Excellence (NICE) found evidence of short-term efficacy of PENS for refractory neuropathic pain with no major safety concerns. It recommends that PENS should be provided only by specialists in pain management.[164]

The AAN includes cognitive behavioural therapy (CBT) and mindfulness as potential options for patients with painful DPN.[63] Evidence for CBT in this context is limited, although it has been shown to be efficacious in other types of chronic pain.[63]

with pain partially responsive or unresponsive to initial treatments, or initial therapy not tolerated

Consider – switch to different drug or combination therapy

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Consider –

switch to different drug or combination therapy

Additional treatment recommended for SOME patients in selected patient group

Clinicians should counsel patients that multiple drugs may need to be tried to identify the treatment that most benefits patients with painful diabetic peripheral neuropathy (DPN).[63] According to the American Academy of Neurology (AAN), a treatment may be considered unsuitable for an individual patient if it does not provide meaningful relief after 12 weeks or is associated with adverse effects that are difficult to tolerate.[63] In this situation, it is appropriate to trial a drug from a different effective drug class.[63] When withdrawing or switching treatment, a gradual taper - based on dose and treatment duration - should be used to reduce the risk of withdrawal symptoms.[130]

When first-line therapy yields only partial relief, the AAN recommends switching to an agent from a different effective drug class or initiating combination therapy by adding an agent from another effective drug class.[63] Adding a second drug from a different drug class may provide combined efficacy greater than that provided by each drug individually.[63]

The COMBO-DN study was a multicenter, double-blind, parallel-group trial that evaluated whether combination therapy with duloxetine and pregabalin was superior to escalation to maximum-dose monotherapy in patients with painful DPN who did not respond to standard-dose monotherapy. During an 8-week treatment period, nonresponders to monotherapy (n = 339) were randomized to receive either high-dose duloxetine, a combination of standard doses of duloxetine and pregabalin, or high-dose pregabalin. Both monotherapy and combination regimens were well tolerated. Although combination therapy was not significantly superior to high-dose monotherapy, it was considered effective, safe, and well tolerated.[152] A subanalysis of COMBO-DN suggested that combination therapy with pregabalin and duloxetine may be more effective for moderate-intensity neuropathic pain, whereas high-dose monotherapy may be more suitable for severe pain.[153]

In the OPTION-DM study, a multicenter, randomized, double-blind, crossover trial, 130 participants were included in the primary analysis and were titrated to the maximum tolerated doses of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin. Participants were assigned to test all three treatment pathways in a randomised order, including an initial titration period followed by 16 weeks of treatment.[154] Seven-day mean pain scores improved with monotherapy and subsequently improved further with combination therapy. No significant difference was found between the three pathways, but combination therapy resulted in more participants achieving 50% pain reduction or a pain score under 3.[154]

In another randomised controlled trial, combination therapy with imipramine and pregabalin significantly lowered pain scores compared with either agent alone, but was associated with a higher dropout rate and a greater frequency and severity of adverse effects.[155]

severe painful diabetic neuropathy refractory to all other treatments

Consider – spinal cord stimulation

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Consider –

spinal cord stimulation

Additional treatment recommended for SOME patients in selected patient group

Spinal cord stimulation should be considered in patients refractory to all other treatment options for severe painful DN.[165][166]

One meta-analysis found that spinal cord stimulation is an effective therapeutic adjunct to best medical therapy in reducing pain intensity and improving health-related quality of life in patients with painful DN.[167]

One subsequent network meta-analysis found that adding spinal cord stimulation to conventional management provided meaningful pain relief and quality of life benefits in patients with painful DN.[168] Greater pain reductions were seen in those who received high-frequency spinal cord stimulation compared with those receiving low frequency stimulation.

cranial neuropathies

1st line – glycaemic control and supportive measures

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1st line –

glycaemic control and supportive measures

There is no specific treatment, although gradual recovery typically occurs.

Treatment strategies for diabetic neuropathy (DN) in general may be divided into those targeting the underlying pathogenic mechanisms, and those targeting the relief of symptoms. Addressing the pathogenic mechanisms remains particularly challenging; to date, tight glycaemic control is the only strategy convincingly shown to prevent or delay the development of DN in patients with type 1 diabetes, and to slow the progression of neuropathy in some patients with type 2 diabetes.[60] The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy in type 1 diabetes reduced the incidence of neuropathy by 60% over a 5-year period in patients without baseline neuropathy compared with conventional insulin therapy.[17][114] In type 2 diabetes, some data suggest reduced DN risk with optimal glycaemic control achieved using multiple daily insulin injections, but the evidence is not as strong as for type 1 diabetes.[29]

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

It is important to assess patients for comorbid mood disorders, particularly depression and anxiety, and sleep disorders.[63][97][98][99][101][102] The presence of sleep disorders or mood disorders can affect perception of pain; treatment of these conditions may help to reduce pain and improve quality of life.[63]

limb or truncal mononeuropathies

1st line – glycaemic control and supportive measures

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1st line –

glycaemic control and supportive measures

There is no specific treatment for abrupt limb mononeuropathies, though some have advocated immunomodulatory therapy when there is multi-nerve involvement.

Once structural abnormalities have been ruled out, treatment for diabetic truncal mononeuropathy consists of pain management. Improvement is generally gradual.

Treatment strategies for diabetic neuropathy (DN) in general may be divided into those targeting the underlying pathogenic mechanisms, and those targeting the relief of symptoms. Addressing the pathogenic mechanisms remains particularly challenging; to date, tight glycaemic control is the only strategy convincingly shown to prevent or delay the development of DN in patients with type 1 diabetes, and to slow the progression of neuropathy in some patients with type 2 diabetes.[60] The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy in type 1 diabetes reduced the incidence of neuropathy by 60% over a 5-year period in patients without baseline neuropathy.[17][114] There is some evidence for a reduction in risk of DN with optimal blood glucose control achieved using multiple insulin injections in people with type 2 diabetes, but the evidence is not as strong as that for type 1 diabetes.[29]

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

All patients with diabetes require regular foot inspection and care. This is especially crucial for those with DN affecting the feet, as they are at higher risk for painless injuries. Effective foot care starts with patient education.[127] Patients at risk should be counselled about the consequences of foot deformities, loss of protective sensation, and peripheral arterial disease.[34] Education should include guidance on proper foot hygiene and the importance of daily self-examinations to detect early signs of injury or infection.[34] Offloading footwear is recommended for high-risk patients, particularly those with loss of protective sensation, as it can help can prevent the development or progression of foot ulcers.[34][128][129] Patients with diabetes-related foot disease, including ulcers and infections, may require debridement and antibiotic therapy (although minor non-infected wounds without evidence of soft-tissue or bone infection do not require antibiotic treatment).[34][128][129] More serious problems are best handled in consultation with specialists in diabetic foot care.[194][195] Guidelines on the prevention and management of diabetes-related foot disease vary between countries. See Diabetes-related foot disease.

diabetic amyotrophy

1st line – glycaemic control and supportive measures

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1st line –

glycaemic control and supportive measures

Typically, no treatment is given for diabetic amyotrophy, other than improving glycaemic control.

However, patients with inflammatory changes on biopsy may respond to immunomodulation.[169]

To date, tight glycaemic control is the only strategy convincingly shown to prevent or delay the development of DN in patients with type 1 diabetes, and to slow the progression of neuropathy in some patients with type 2 diabetes.[60] When treating patients with painful neuropathy, maintaining stable blood glucose levels may also provide symptom relief.[120] The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy in type 1 diabetes reduced the incidence of neuropathy by 60% over a 5-year period in patients without baseline neuropathy.[17][114] In type 2 diabetes, some data suggest reduced DN risk with optimal glycaemic control achieved using multiple daily insulin injections, but the evidence is not as strong as for type 1 diabetes.[29]

diabetic autonomic neuropathy

orthostatic hypotension

1st line – non-pharmacological therapies

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1st line –

non-pharmacological therapies

Treating orthostatic hypotension (OH) is challenging. The therapeutic goal is to minimise postural symptoms rather than to restore normotension.[34]

Simple non-pharmacological measures should be recommended for all patients. Simple measures include: avoiding sudden changes in body posture to the head-up position; avoiding drugs that aggravate hypotension; eating small, frequent meals; avoiding a low-salt diet; ensuring adequate fluid intake; and avoiding activities that involve straining.[34]

Elevating the head of the bed by 45 cm (18 inches) at night improved symptoms in a small series of patients with OH from various causes.[172]

Case reports suggest that a compressive garment over the legs and abdomen may be of benefit.[173][174][175][176] An inflatable abdominal band was effective in a study of 6 patients with OH.[177]

Using a low portable chair as needed for symptoms was found to be effective in one study.[178] Several physical counter-manoeuvres, such as leg crossing, squatting, and muscle pumping, can help maintain BP.[179]

Physical activity and exercise should be encouraged to avoid deconditioning, which is known to exacerbate OH.[34]

See Orthostatic hypotension.

Plus – glycaemic control and supportive measures

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Plus –

glycaemic control and supportive measures

Treatment recommended for ALL patients in selected patient group

Control of hyperglycaemia has been shown to delay the onset and progression of autonomic neuropathy in patients with type 1 diabetes, and possibly in those with type 2 diabetes.[17][114][170][171] Studies have shown that implementing tight glucose control as early as possible in the treatment of type 1 diabetes prevents early development of cardiovascular autonomic neuropathy (CAN) and confers long-term protection against CAN.[60] However, the impact of glycaemic control on CAN in type 2 diabetes is less well established.[60]

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

2nd line – pharmacotherapy

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2nd line –

pharmacotherapy

Patients with severe orthostatic hypotension (OH) who remain symptomatic despite adherence to non-pharmacological therapies should be considered for pharmacological treatment, which includes pressor agents (e.g., midodrine, droxidopa) and agents that expand extracellular fluid volume (e.g., fludrocortisone).[180] Midodrine and droxidopa are the only drugs approved in the US for neurogenic OH. Because long-term safety is uncertain, pharmacological treatment should be prescribed cautiously; referral to a specialised unit is advisable, particularly for patients with multimorbidity or when symptoms persist despite non-pharmacological strategies and a single drug.[180] Choice of drug should be guided by patient preference, comorbidities, adverse effects, and therapeutic response.[180]

Supine hypertension is present in up to 50% of patients with neurogenic OH.[181] Proposed mechanisms include residual sympathetic activity, elevation of angiotensin II, and inappropriate mineralocorticoid receptor activation.[181] Since the harms of symptomatic OH can exceed those of supine hypertension, and the latter may not mirror essential hypertension, management should prioritise symptom relief and accept moderate supine hypertension when necessary.[180] Severe supine hypertension, however, is linked to increased cardiovascular risk and reduced survival; if substantial supine hypertension persists despite head-up sleeping and avoidance of long-acting pressor agents, a short-acting antihypertensive at bedtime can be considered, recognising it may aggravate nocturnal orthostatic symptoms if the patient rises during the night.[180]

See Orthostatic hypotension.

Plus – glycaemic control and supportive measures

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Plus –

glycaemic control and supportive measures

Treatment recommended for ALL patients in selected patient group

Control of hyperglyacemia has been shown to delay the onset and progression of autonomic neuropathy in patients with type 1 diabetes, and possibly in those with type 2 diabetes.[17][114][170][171] Studies have shown that implementing tight glucose control as early as possible in the treatment of type 1 diabetes prevents early development of cardiovascular autonomic neuropathy (CAN) and confers long-term protection against CAN.[60] However, the impact of glycaemic control on CAN in type 2 diabetes is less well established.[60]

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

diabetic gastroparesis

1st line – dietary modification and drug history review and glycaemic control

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1st line –

dietary modification and drug history review and glycaemic control

All patients should receive dietary advice, with dietary modification the initial approach for mild gastroparesis.[182] Patients should limit spicy, acidic, and high-fat foods and avoid carbonated beverages, alcohol, and smoking, which can worsen symptoms.[182] As part of a multidisciplinary plan, involve a dietitian to guide small, frequent meals (e.g., four to five per day) that are low in fat and fibre, minimising high-fibre items such as whole grains, beans, and legumes.[182] Overall, meal plans should be low fat, low fibre, and low residue to reduce gastric workload.[182]

In more severe cases, nutritional support may be required. Oral intake is preferred; if solids are not tolerated, use homogenised or liquid meals.[182] If weight loss or malnutrition persists, escalate to enteral nutrition (preferably jejunal), reserving parenteral nutrition for situations in which enteral feeding is not feasible.[182] Because electrolyte and micronutrient deficiencies are common, provide supplemental hydration, electrolytes, and vitamins with monitoring.[182]

Withdrawing drugs with adverse effects on gastrointestinal motility, including opioids, anticholinergics, tricyclic antidepressants, glucagon-like peptide-1 (GLP-1) receptor agonists, and pramlintide, may improve intestinal motility.[34] The American Diabetes Association (ADA) caveats that the risk of withdrawing GLP-1 receptor agonists should be balanced against their potential benefits.[34]

Patients should aim to optimise glycaemic control, although this can be challenging because unreliable nutrient absorption often misaligns with endogenous insulin secretion and exogenous insulin dosing.[182] For patients using rapid- or short-acting prandial insulin, post-meal dosing may better match the delayed post-prandial glucose rise caused by impaired gastric emptying.[182] UK National Institute for Health and Care Excellence (NICE) guidelines recommend considering insulin pump therapy for adults with type 1 diabetes who have gastroparesis.[183] Although improved glycaemic control reduces the risk of microvascular complications, evidence that long-term glycaemic optimisation alleviates gastroparesis symptoms or restores normal gastric emptying remains limited.[182]

See Gastroparesis.

2nd line – pharmacotherapy

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2nd line –

pharmacotherapy

Pharmacological therapy should be considered for those who experience recurrent symptoms despite dietary modifications and glycaemic control.[182]

Metoclopramide, a prokinetic agent, is the only drug approved in the US for the treatment of diabetic gastroparesis.[34] However, evidence for its benefit is limited, and because of the risk of serious extrapyramidal adverse effects (including acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia), treatment beyond 12 weeks should be avoided, except in rare cases and using particular caution in older adults (with dose reduction as appropriate).[34][184] The American Diabetes Association (ADA) states that metoclopramide should be reserved for severe cases that are unresponsive to other therapies.[34]

Domperidone remains controversial due to safety concerns. In the US it is available only through an expanded-access investigational new drug (IND) programme for patients ≥12 years with gastroparesis who have not responded to standard therapies.[185] Domperidone is available in other countries.

Erythromycin (a motilin agonist) is another option, but is generally limited to short-term use (up to 4 weeks) because of tachyphylaxis.[34]

Antiemetics may be added for nausea and vomiting but do not accelerate gastric emptying.[182][184]

See Gastroparesis.

Plus – dietary modification and drug history review and glycaemic control

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Plus –

dietary modification and drug history review and glycaemic control

Treatment recommended for ALL patients in selected patient group

Patients should limit spicy, acidic, and high-fat foods and avoid carbonated beverages, alcohol, and smoking, which can worsen symptoms.[182] As part of a multidisciplinary plan, involve a dietitian to guide small, frequent meals (e.g., four to five per day) that are low in fat and fibre, minimising high-fibre items such as whole grains, beans, and legumes.[182] Overall, meal plans should be low fat, low fibre, and low residue to reduce gastric workload.[182]

See Gastroparesis.

3rd line – non-pharmacological therapies

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3rd line –

non-pharmacological therapies

Non-pharmacological methods (gastric electrical stimulation [GES; also known as gastric pacing] and surgery) have been used to treat diabetic gastroparesis in patients unresponsive to pharmacotherapy. Such patients should be referred for consultant advice.[183]

GES, using a surgically implantable device, is available in specialised centres for patients with refractory nausea and vomiting who have failed standard therapy; it carries an Food and Drug Administration (FDA) humanitarian device exemption and may improve symptoms and nutritional status, but overall evidence remains limited, so routine use is not recommended.[34][184] Patients who need this device should be referred to centers with expertise in its implantation. In the UK, the National Institute for Health and Care Excellence (NICE) has made similar recommendations regarding use of GES for gastroparesis.[186]

Surgical and endoscopic options are reserved for persistent, disabling symptoms despite maximal medical therapy (and, where tried, GES). Choices include pyloroplasty/pyloromyotomy or gastric per oral endoscopic pyloromyotomy (G-POEM) in appropriately selected patients, feeding jejunostomy to bypass an atonic stomach when vomiting persists, and partial/total gastrectomy only rarely as a last resort.[184][187]

See Gastroparesis.

Plus – dietary modification and drug history review and glycaemic control

Back

Plus –

dietary modification and drug history review and glycaemic control

Treatment recommended for ALL patients in selected patient group

See Gastroparesis.

diabetic diarrhoea

1st line – broad-spectrum antibiotics

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1st line –

broad-spectrum antibiotics

Broad-spectrum antibiotics are commonly used to treat diabetic diarrhoea, either when the hydrogen breath test is positive or as an empirical trial.[95]

An early double-blind study, involving a single patient, found that diarrhoea subsided when the patient was treated with an oral antibiotic, then recurred when placebo was substituted.[188]

Several different regimens have been advocated. Caution must be used because long-term use of metronidazole can lead to neuropathy.

Primary options

metronidazole: 500 mg orally four times daily for 3 weeks; or 750 mg orally three times daily for 3 weeks

tetracycline: 250 mg orally three to four times daily for 14 days

amoxicillin/clavulanate: 875 mg orally twice daily for 14 days

Plus – glycaemic control and supportive measures

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Plus –

glycaemic control and supportive measures

Treatment recommended for ALL patients in selected patient group

To date, tight glycaemic control is the only strategy convincingly shown to prevent or delay the development of diabetic neuropathy (DN) in patients with type 1 diabetes, and to slow the progression of neuropathy in some patients with type 2 diabetes.[60] The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy in type 1 diabetes reduced the incidence of neuropathy by 60% over a 5-year period in patients without baseline neuropathy compared with conventional insulin therapy.[17][114] In type 2 diabetes, some data suggest reduced DN risk with optimal glycaemic control achieved using multiple daily insulin injections, but the evidence is not as strong as for type 1 diabetes.[29]

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

2nd line – colestyramine

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2nd line –

colestyramine

Colestyramine can be used in an attempt to chelate bile salts if the hydrogen breath test is normal, or if an empirical trial of broad-spectrum antibiotics is unsuccessful.

Primary options

colestyramine: 2-4 g/day orally initially given in 1-4 divided doses, increase gradually according to response, maximum 24 g/day

Plus – glycaemic control and supportive measures

Back

Plus –

glycaemic control and supportive measures

Treatment recommended for ALL patients in selected patient group

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

3rd line – octreotide

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3rd line –

octreotide

Octreotide was effective in a case report of a single patient with diabetic diarrhoea.[192]

In healthy volunteers, octreotide improved gastric, small bowel, and colonic transit, as well as colonic motility and tone.[193] Octreotide may be considered for the management of diabetic diarrhoea when other approaches have failed.

Primary options

octreotide: 50 micrograms subcutaneously/intravenously two to three times daily initially, increase gradually according to response, maximum 500 micrograms/dose or 1500 micrograms/day

Plus – glycaemic control and supportive measures

Back

Plus –

glycaemic control and supportive measures

Treatment recommended for ALL patients in selected patient group

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

bladder dysfunction

1st line – bethanechol

Back

1st line –

bethanechol

Bethanechol, a parasympathomimetic agent, may be helpful for people with symptoms of bladder dysfunction.

Primary options

bethanechol: 10-50 mg orally three to four times daily

Plus – glycaemic control and supportive measures

Back

Plus –

glycaemic control and supportive measures

Treatment recommended for ALL patients in selected patient group

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

Consider – bladder hygiene techniques

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Consider –

bladder hygiene techniques

Additional treatment recommended for SOME patients in selected patient group

Bladder training techniques, such as scheduled voiding, may be used particularly for managing urge incontinence.

The Crede manoeuvre may also be used to assist bladder emptying when the bladder is weak and flaccid. This technique involves the patient applying gentle, steady pressure on the abdomen with their hand, moving downwards from the umbilicus towards the bladder.[95]

erectile dysfunction

1st line – glycaemic control and supportive measures

Back

1st line –

glycaemic control and supportive measures

In addition to good glycaemic control, treatment of other modifiable risk factors (e.g., obesity, dyslipidaemia, and hypertension), alongside healthy lifestyle habits (diet and exercise), may help to prevent progression of DN in both type 1 and type 2 diabetes, as well as other microvascular complications of diabetes such as retinopathy and nephropathy.[34][121][122][123] Lifestyle interventions (diet and exercise) may improve neuropathic symptoms and intra-epidermal nerve fibre density in patients with neuropathy and impaired glucose tolerance.[124][125] Data from the UK Biobank cohort study (18,092 individuals with type 2 diabetes) showed that even modest levels of leisure-time physical activity - equivalent to under 1.5 hours of walking per week - were linked to a reduced risk of neuropathy.[126]

Consider – pharmacotherapy or non-pharmacological therapies

Back

Consider –

pharmacotherapy or non-pharmacological therapies

Additional treatment recommended for SOME patients in selected patient group

Treatments for erectile dysfunction (ED) may include phosphodiesterase-5 (PDE5) inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses.[34] These interventions do not change the underlying pathology and natural history of the disease process but may improve a person’s quality of life.[34]

If suspected, hypogonadism should be investigated and treated as necessary.[34] Removal of drugs that may be exacerbating ED, management of associated comorbidities, and lifestyle modifications are essential in all patients.

Given the impact of both ED and diabetes on male self-esteem, as well as their association with depression and anxiety, psychological assessment and appropriate intervention are also likely to be beneficial.

See Erectile dysfunction.

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Diabetic neuropathy

Treatment algorithm

diabetic peripheral neuropathy

glycaemic control and supportive measures

systemic pharmacotherapy

Primary options

Secondary options

Tertiary options

topical pharmacotherapy

Primary options

Secondary options

non-pharmacological therapies

switch to different drug or combination therapy

spinal cord stimulation

cranial neuropathies

glycaemic control and supportive measures

limb or truncal mononeuropathies

glycaemic control and supportive measures

diabetic amyotrophy

glycaemic control and supportive measures

diabetic autonomic neuropathy

non-pharmacological therapies

glycaemic control and supportive measures

pharmacotherapy

glycaemic control and supportive measures

dietary modification and drug history review and glycaemic control

pharmacotherapy

dietary modification and drug history review and glycaemic control

non-pharmacological therapies

dietary modification and drug history review and glycaemic control

broad-spectrum antibiotics

Primary options

glycaemic control and supportive measures

colestyramine

Primary options

glycaemic control and supportive measures

octreotide

Primary options

glycaemic control and supportive measures

bethanechol

Primary options

glycaemic control and supportive measures

bladder hygiene techniques

glycaemic control and supportive measures

pharmacotherapy or non-pharmacological therapies