The advice in this Section is based on SIGN 154 - Pharmacological management of glycaemic control in people with type 2 diabetes (pub. 2017), the NHS Scotland Quality Prescribing for Diabetes, a Guide for Improvement 2018-2021  and the Tayside Area Formulary (Chapter 6).

 

General Prescribing Principles:

High quality prescribing involves:

  • The appropriate selection of therapies for an individual patient.
  •  Review of dosage and side effects.
  •  Consideration of when a treatment is no longer effective or appropriate and should be stopped. (A trial of stopping a medicine, with careful monitoring, should be considered when there are doubts regarding the continuing benefit to the patient.)
  • Clarity about the advantages and disadvantages of any treatment.

 

Key Recommendations:

  • Clinicians should…

    Develop a clear management plan collaboratively with patients, including regular review dates, realistic targets and treatment goals. Expectations should be addressed and clarified. The plan should focus on what matters to you

     

    Pursue non-pharmaceutical approaches wherever possible, either alone or in conjunction with medicines. Self-management should be actively encouraged, supported and included in the management plan.

     

    Follow a clinically appropriate approach to initiation of medication, discussing risks and benefits and incorporating agreed criteria for stopping/continuing medication.

     

    Review effectiveness, tolerability and adherence on a regular basis. Medicine burden should be reduced where possible, in line with Polypharmacy Guidance  The SCI-Diabetes Prescribing Timeline Function is a useful tool to inform reviews.

     

 

There are three key principles which prescribers should follow:

  • The approach should assist the patient to achieve goals which have been identified and developed in partnership through the what matters to me principle   The management plan will be individual to each patient and should place the patient at the centre.
  • Prescribers should work with patients to develop an understanding of the importance of self-management to the successful achievement of goals. Self-management does not mean that the patient is expected to deal with matters on their own – rather it is about developing skills and knowledge so that they can be confident to manage their condition. This would include aspects such as Sick Day Rule guidance  and lifestyle changes.
  • Difficult and honest conversations may be required to communicate the importance of self-management and the benefits of lifestyle changes, which can often be of similar or greater benefit than medication, in treating type 2 diabetes. The importance of the patient’s psychological state and willingness to change should not be underestimated.

 

Lifestyle advice should be given to all people with type 2 diabetes. This can help minimise the risk of developing complications. The recommended lifestyle advice includes:

  • Eating a healthy, balanced diet following advice from clinicians, which may include:
  • Replacing refined carbohydrates with wholegrain foods
  •  Increasing intake of vegetables and other foods high in dietary fibre
  •  Reducing the amount of saturated fat and sugar in the diet

[Advice for patients is available from Diabetes UK  and British Dietetic Association websites].

  • Losing weight to achieve and maintain a healthy body mass index.
  • Drinking alcohol only in moderation. [Advice on the alcohol, sugar and calorie content of alcoholic drinks, which can be helpful for patients with diabetes, is available from Drink Aware
  • Taking plenty of regular exercise, for adults two and a half hours each week of moderate to vigorous physical activity, adding in muscle strengthening activity twice a week.
  • All patients who smoke should be advised to stop and offered support.

 

 

Algorithm for Glucose Lowering (SIGN 154):

 

  

 

Therapeutic Inertia.

Therapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner according to evidence-based clinical guidelines, is a key reason for uncontrolled hyperglycaemia in patients with type 2 diabetes. Systematic Reviews have demonstrated that the median time to treatment intensification after a glycated haemoglobin (HbA1c) measurement above target was more than 1 year (range 0.3 to >7.2 years). Therapeutic inertia increased as the number of antidiabetic drugs rose and decreased with increasing HbA1c levels. For this reason, it is important that clinical teams follow the NHS Tayside review intervals guidance (6 monthly if at Target & 3-4 monthly if not at target) and intensify therapy as appropriate and according to the SIGN Algorithm.

 

Rough Guide to HbA1c Targets

 

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Antidiabetic Drugs

The therapeutic use of antidiabetic drugs must be supported by the consumption of a healthy diet for people with diabetes and appropriate physical activity. In addition, the greater importance of lipid lowering and blood pressure control, when required, should be recognised.

Metformin.

Metformin is a small molecule from the biguanide family that has been used as a glucose-lowering agent for around 60 years. Actions at a molecular level are complex but effects on physiology include reduced production of glucose by the liver, weight loss or stabilisation, and improved insulin sensitivity.

Key Information Metformin
Efficacy Moderate
CV benefit Yes
Hypoglycaemia risk Low
Weight Reduction
Main adverse events Gastrointestinal
In CKD stage 3A (eGFR 45-59) Maximum 2 grams per day
Cost for 28 days treatment £3.44 - £10.64

 

Metformin should be the first-line agent due to its proven evidence of survival advantage.

Metformin should be taken with or immediately after a meal. It should be introduced in low dose, with gradual escalation (e.g.500 mg once daily for one week, 500 mg twice daily in week two and 1 g twice daily in week four). Despite being licensed in doses up to 3g per day and for three times daily dosing, in NHS Tayside, twice daily dosing and a maximum daily dose of 2 g (so 1g BD) is the usual recommendation. Some individuals may not tolerate higher doses, in which case dose reduction is appropriate. Nausea, diarrhoea, and abdominal pain are the most common adverse effects. People should be informed that these side effects often improve after a few days of continued therapy, or with a small dose reduction.

A modified-release preparation (metformin MR) is also available. Some individuals otherwise intolerant of metformin may find this more acceptable. It should be started once-daily but may be intensified to split daily doses (BD).

Metformin should be discontinued during a severe illness (e.g. myocardial infarction, pneumonia, severe infection and/or dehydration) as it may aggravate tissue hypoxia and accumulate when renal function is impaired. The maximum recommended dose when eGFR >45ml/min is 1g twice daily and 500mg twice daily when eGFR is 30 – 44ml/min. Metformin is contraindicated when eGFR <30ml/min. In these circumstances, it may be appropriate to use other glucose lowering therapies, including insulin, in which case admission to hospital may be required.

As iodine-containing contrast media may cause acute deterioration of renal function, local arrangements are in place for discontinuation of metformin prior to either i) intra-arterial radiological or cardiology investigations/interventions when eGFR is lower than 45, or ii) intravenous or intra-arterial procedures when eGFR is deteriorating due to illness (LINK to local Guidance).

Fasting presents little hazard in people who take only metformin to manage glucose levels. For those fasting during Ramadan, for example, if a dose is usually taken at lunchtime it can be omitted or taken with the sunset meal instead.

 

Sulphonylureas.

Sulphonylureas increase endogenous release of insulin from pancreatic β-cells.

Key Information Sulphonylureas
Efficacy High
CV benefit No
Hypoglycaemia risk High
Weight Gain
Main adverse events Hypoglycaemia
In CKD stage 3A (eGFR 45 - 59) Careful monitoring (consider dose reduction)
Cost for 28 days treatment £4.12 - £6.56

 

Sulfonylureas are recognised by SIGN 154 as a first-line agent for those who are intolerant of, or have contra-indications to, metformin, or as a second line agent option in other patients. These agents, most commonly gliclazide in NHS Tayside, act by augmenting insulin release by the pancreas, so some capacity to produce insulin must be retained. They should ideally be taken 30 minutes before food. They are particularly useful for rapid control of blood glucose and relief of osmotic symptoms including thirst, polyuria and weight loss. They are more effective early in the management of type 2 diabetes.

They have a particularly important role in the initial management in primary care of newly diagnosed patients presenting with osmotic symptoms who do not have raised blood or urinary ketones.  Handbook

Their main side effects are hypoglycaemia and weight gain. The warning signs of hypoglycaemia, which should be outlined to people taking these agents, include (early signs) tremor, sweating, shaking, irritability, and (later signs) lack of concentration and co-ordination. People prescribed sulphonylureas should be prescribed adequate supplies of blood glucose test strips as per the local formulary. The risk of hypoglycaemia is higher in older age groups, and in those with renal impairment and/or liver disease; this risk may be underestimated by RCTs.

Although doses of gliclazide up to 320mg /day (160mg bd) are licensed, in NHS Tayside it is recommended that the usual maximum dose is 80mg bd as above this the risk-benefit ratio is unfavourable.

In clinical trials, the glucose lowering effects of sulphonylureas begin to reduce after a shorter period of use than some other second-line agents (the ‘Nike Tick’ effect).

The Driver and Vehicle Licensing Agency (DVLA) requires holders of group 2 licenses (bus and lorry drivers) to notify them when using any glucose-lowering medication. Those taking sulphonylureas must be able to provide evidence of checking blood glucose at least twice per day and at times relevant to driving. Holders of group 1 licenses (car drivers and motorcyclists) need not notify the DVLA provided they have experienced no more than one episode of severe hypoglycaemia in the last 12 months and, if needed, check blood glucose at times relevant to driving and are under regular review. Detailed guidance can be found here:

Gliclazide is available in an MR preparation. This permits once-daily dosing even when higher doses are required. Prescribers should be aware that gliclazide MR 30 mg is therapeutically equivalent to standard gliclazide 80 mg (maximum dose therefore 120 mg once daily rather than 160 mg twice daily).

Individuals using gliclazide should not be prescribed the antifungal miconazole due to an increase in the hypoglycaemic effect.

Individuals taking a short-acting sulphonylurea, (e.g. gliclazide) who are fasting, for example during Ramadan, may be advised to take the largest dose with their evening meal and, if necessary, to halve their morning dose. Longer-acting sulphonylureas, such as glimepiride, are more hazardous and should be avoided while fasting.

People taking sulphonylureas in the longer term should also be advised of their propensity to cause weight gain.

Sulfonylureas in frail patients are recognised as a potential risk. The key issues are of frailty, weight loss, impaired renal function and cognitive decline all of which increase the risk of side effects. One of the key considerations when treating type 2 diabetes in frail patients needs to be the avoidance of hypoglycaemia. Hypoglycaemic episodes can exacerbate dementia and confusion and can increase the likelihood of falls and cardiac arrhythmias. This can lead to emergency hospital admissions. These patients should be reviewed and where possible prescribed medications less likely to cause hypoglycaemia.

  

Pioglitazone.

Thiazolidinediones (TZDs) increase whole-body insulin sensitivity by activating nuclear receptors and promoting esterification and storage of circulating free fatty acids in subcutaneous adipose tissue. Pioglitazone is now the only TZD with a marketing authorisation in the UK.

 

Key Information Pioglitazone
Efficacy Moderate
CV benefit Probable (but fluid retention)
Hypoglycaemia risk Low
Weight Gain
Main adverse events Oedema / Fractures / Bladder Cancer
In CKD stage 3A (eGFR 45 - 59) Dose unchanged
Cost for 28 days treatment £0.87

 

 

Pioglitazone is an alternative second or third-line agent, but use is associated with weight gain.

Pioglitazone is available as a fixed-dose combination tablet with metformin (Competact®) which may be used to decrease tablet burden and improve concordance with therapy.

The European Medicines Agency has previously advised of a small increased risk of bladder cancer associated with pioglitazone use. However a large pooled multi-population analysis was published in 2014, concluding that the cumulative use of pioglitazone was not associated with an increased incidence of bladder cancer. People prescribed pioglitazone should however be counselled to seek medical advice if they experience haematuria, dysuria or pelvic pain. It remains contraindicated in patients with current bladder cancer, a history of bladder cancer, or un-investigated macroscopic haematuria.

Pioglitazone is contraindicated in patients with a history of any stage of heart failure (NYHA stages 1-1V).

People prescribed pioglitazone should be advised that they might experience ankle oedema. Where this occurs, discontinuation is usually appropriate.

Pioglitazone is associated with an increased risk of bone fractures, particularly in women. These are predominantly distal limb fractures and often do not occur until after at least a year of treatment. Although the absolute fracture risk is low, the risk is doubled by the use of pioglitazone which equates to an excess fracture rate of 0.5-1 fractures/100 patient years. The increased risk of hip fracture should also be considered during long term treatment.

In light of age related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in those over age 65. MHRA recommends that liver enzymes should be checked prior to initiation of pioglitazone – therapy should not be initiated in patients with elevated baseline liver enzyme levels or with any other evidence of liver disease. Periodic liver enzyme monitoring is also recommended, based on clinical judgement. The official recommendations are now that in light of age related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment.

Prescribers should review the safety and efficacy of pioglitazone in individuals after 3–6 months of treatment to ensure that only patients who are deriving benefit continue to be treated. Pioglitazone should be stopped in patients who do not respond adequately to treatment (e.g., reduction in HbA1c)

 

No changes to pioglitazone regimens are required during fasting including Ramadan.

 

 

Empagliflozin (and other SGLT2 Inhibitor drugs)

Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce renal glucose re-absorption resulting in increased glucose excretion equivalent to a net loss of 200–300 kcal/day. Their glucose-lowering effect is therefore independent of pancreatic β-cell function. Three drugs are currently licensed in this class; canagliflozin, dapagliflozin and empagliflozin. Empagliflozin is NHS Tayside’s drug of first choice in the SGLT2 Inhibitor class of oral glucose lowering drugs.

 

Key Information SGLT-2 Inhibitors
Efficacy Moderate
CV benefit Yes (specific agents)
Hypoglycaemia risk Low
Weight Loss
Main adverse events Genital mycotic
In CKD stage 3A (eGFR 45 - 59) Do not initiate (see BNF, specific agents can be continued at reduced dose)
Cost for 28 days treatment £36.69

 

Patients successfully established on the other agents in the class (dapagliflozin & canagliflozin) should not routinely be changed to empagliflozin.

 

The SGLT2 Inhibitors cause modest reductions in HbA1c, blood pressure and weight.

Of the two available strengths, there are no significant additional benefits in using 25mg compared with 10mg, so the 10mg daily dose is recommended in NHS Tayside.

 

A fixed combination empagliflozin/metformin preparation is available (Synjardy® - 5mg empagliflozin plus 850mg or 1000mg metformin) which can be used to reduce tablet burden, aid compliance and reduce overall cost.

 

The EMPA-REG OUTCOME Trial reported in September 2015. It studied the effect of empagliflozin .v. placebo on 7020 patients with Type 2 Diabetes and existing cardiovascular disease and showed a 38% reduction in CV death, 32% reduction in all-cause mortality and 35% reduction in heart failure hospitalization.

Due to the importance of these Trial findings, it is recommended in NHS Tayside that:

 

  • all suitable (see below) patients with Type 2 Diabetes and CVD (prior MI; coronary artery disease; stroke; unstable angina or occlusive peripheral arterial disease) who are on any glycaemic therapy regime and whose HbA1c level is 53 mmol/mol or higher should be considered for the addition of empagliflozin to their current glycaemic therapy regime. A flow-chart, below, has been developed to help prescribers navigate through the necessary considerations
  • empagliflozin can also be considered as an option for add-on to metformin in all suitable patients failing to achieve glycaemic targets on metformin alone.

 

Empagliflozin:

  • is only licensed for use in Type 2 Diabetes at this time.
  • due to its mechanism of action, patients taking empagliflozin will test positive for glucose in their urine.
  • causes a small increased risk of developing a genital yeast or fungal infection (most commonly thrush in women) when taking SGLT2 inhibitors due to more glucose being excreted in the urine. These infections are easily treated with over-the-counter treatments. The prescribing doctor should be informed as treatment may need to be changed if infections recur. People taking these medications should be advised of the need for scrupulous personal hygiene to try to reduce the risk of these infections.
  • causes an osmotic diuresis. Patients may notice a modest increase in urinary frequency, equivalent to one extra void per day.
  • caution should be exercised in patients for whom an empagliflozin-induced drop in blood pressure could pose a risk.
  • should be temporarily discontinued in conditions that may lead to fluid loss e.g. gastrointestinal illness. (‘Sick Day’ Rules), in particular for those on concomitant diuretic therapy.
  • initiation in patients with an eGFR
  • in patients without CVD on empagliflozin whose eGFR falls persistently below 45 continued use is an off licence indication.
  • in patients with CVD on empagliflozin whose eGFR falls persistently below 30, continued use is an off licence indication.
  • is not recommended for initiation in patients over the age of 85 in those aged 75 years and older with an increased risk of volume depletion should be taken into account.
  • when added to insulin or a sulphonylurea, it may contribute to hypoglycaemia, so a reduction in insulin or SU dose and additional blood glucose monitoring should be considered.
  • can, rarely, be associated with diabetic ketoacidosis (DKA) – see specific advice about this below.
  • For those who are fasting, for example, during Ramadan, no change in SGLT2 inhibitor dose is required, although individuals should be reminded to stay adequately hydrated (at least two litres of water per day).

 

 

 

 

SGLT2 Inhibitors and Diabetic Ketoacidosis (DKA)

Rare (affecting up to 1 in 1,000 patients) but serious and life-threatening cases of DKA have been reported in some patients with Type 2 Diabetes taking SGLT2 inhibitors (canagliflozin, dapagliflozin or empagliflozin). Most cases occurred in patients also on insulin therapy. Half of the cases occurred during the first 2 months of treatment. Some cases occurred shortly after stopping the SGLT2 inhibitor. This complication may be more likely in those who are slimmer and so for whom reduced insulin secretion is more predominant.

In several cases, blood glucose levels were only moderately elevated (e.g. atypical for DKA. This atypical presentation could delay diagnosis and treatment.

 

N.B. Although DKA is uncommon with SGLT2 inhibitors, those who are prescribed them should be made aware of the risk and how to recognise the symptoms, including rapid weight loss, nausea or vomiting, stomach pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odour to urine or sweat. In this situation, the SGLT2 inhibitor should be stopped and urgent medical attention sought. It is important to test for raised ketones in patients with these signs and symptoms.

 

When treating patients who are taking an SGLT2 inhibitor (canagliflozin, dapagliflozin or empagliflozin):

  • test for raised ketones in patients with symptoms of acidosis, even if blood sugar levels are not high; omitting this test could delay diagnosis of DKA.
  • if you suspect DKA, stop SGLT2 inhibitor treatment.
  • if DKA is confirmed, take appropriate measures to correct the DKA and to monitor glucose levels – seek specialist advice and probable admission.
  • in such cases, SGLT2Is should not normally be re-started.
  • inform patients of the symptoms and signs of DKA (see above); advise them to get immediate medical help if these occur.
  • temporarily stop SGLT2 inhibitors in patients who are undergoing major surgery or are in hospital due to serious illness.
  • be aware that SGLT2 inhibitors are not approved for treatment of type 1 diabetes.
  • please continue to report suspected side effects to SGLT2 inhibitors or any other medicines on a Yellow Card

 

The benefits of SGLT2 Inhibitors continue to outweigh the risks in the treatment of type 2 diabetes.

Click here for an information leaflet which can be given to patients on SLGT2 Inhibitors and DKA.

Click here for the European Medicines Agency (EMA) recommendations to minimise the risk of DKA in patients taking SGLT2 inhibitors.

Further information on prevention and immediate management of this risk is available from the Association of British Clinical Diabetologists position statement.

 

Incretin Therapies

The incretin hormones (GLP1, GIP) are produced by the small intestine in response to a nutrient stimulus (meal). They act on the pancreas to promote insulin secretion in a glucose–regulated manner.  So in effect they are like sulphonylureas, except that they only promote insulin secretion when the glucose is high.  The incretins also act centrally to decrease appetite, and they slow gastric emptying causing early satiety.

Two types of new drug utilise this pathway; DPP-4 inhibitors (gliptins) and GLP-1 receptor agonists.

 

Alogliptin (and other DPP4 Inhibitor drugs – also known as ‘gliptins’)

 

Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral agents that inhibit the activity of the enzyme DPP-4 and hence prolong the actions of endogenous GLP-1. Five DPP-4 inhibitors are currently available: alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin. Alogliptin is the Tayside Formulary choice in this Class.  It is as efficacious as other gliptins (e.g./ sitagliptin) but significantly less expensive.

 

Key Information DPP-4s
Efficacy Low / moderate
CV benefit No
Hypoglycaemia risk Low
Weight Neutral
Main adverse events Few
In CKD stage 3A (eGFR 45 -59) Reduce dose (see BNF, no dose reduction for linagliptin)
Cost for 28 days treatment £26.20 - £33.35

 

DPP-4 inhibitors are alternative second or third-line agents. They have a neutral effect on weight and no increased risk of hypoglycaemia.

Their advantage over GLP-1 receptor agonists is their oral bioavailability; however they are less potent at lowering glucose and do not have the beneficial weight effects seen with GLP-1 receptor agonists, although they are weight neutral.

A fixed combination alogliptin/metformin preparation is available (Vipdomet = 12.5mg alogliptin plus metformin 850 or 1000mg twice daily) which can be used to reduce total tablet count, aid compliance and reduce overall cost.

 

Alogliptin is not currently licensed for monotherapy or as triple therapy when used in combination with metformin + sulfonylurea. However, in line with systematic review evidence1 showing similar efficacy and safety for all DPP-4 inhibitors as treatment for type 2 diabetes, either as monotherapy or combination therapy, and with the recommendations of SIGN 154, which does not differentiate between different agents in the class, NHS Tayside Diabetes MCN recommends that alogliptin should be the preferred DDP-4 inhibitor in all situations where a DPP-4 inhibitor is considered clinically appropriate. (Reference: Craddy, P et al. Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison. Diabetes Ther.  2014 Jun; 5(1): 1–41.)

Although DPP-4 inhibitors have few adverse events associated with their use, in 2012 the MHRA gathered reports of acute pancreatitis and issued the following advice: “Patients treated with DDP-4 inhibitors should be informed of the characteristic symptoms of acute pancreatitis – persistent, severe abdominal pain (sometimes radiating to the back) – and encouraged to tell their healthcare provider if they have such symptoms. If pancreatitis is suspected, the DPP-4 inhibitor and other potentially suspect medicines should be stopped.”

There is limited experience with use of DPP-4 inhibitors in patients with moderate or severe heart failure therefore use with caution is recommended in these patients.

They may be useful if ongoing glucose-lowering therapy is required during periods of fasting, for example Ramadan.

There is no evidence to support the concurrent use of DPP-4 Inhibitors and the GLP1 Agonists.

 

Glucagon-like peptide (GLP)-1 Receptor Agonists

Glucagon-like peptide (GLP)-1 is one of the key ‘incretin’ hormones. These are a group of rapidly metabolised peptides, secreted from the gut in response to food, which augment secretion of insulin from pancreatic β-cells and inhibit inappropriate glucagon secretion. GLP-1 has a circulating half-life of less than two minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4. GLP-1 also slows gastric emptying, resulting in slower absorption of glucose following meals, enhances satiety and reduces appetite.

GLP-1 receptor agonists mimic endogenous GLP-1 activity but are resistant to breakdown by the DPP-4 enzyme, resulting in prolonged action.

GLP-1 agonists are alternative third-line antidiabetic agents that are injected subcutaneously.

On initiation, people with diabetes should be informed that their injections are not insulin as this can lead to confusion in interactions with other health professionals.

Five GLP-1 receptor agonists are currently available, all in injectable formulations: albiglutide (once-weekly, to be discontinued in July 2018), dulaglutide (once weekly), exenatide (twice daily or once weekly), liraglutide (once daily) and lixisenatide (once daily).

 

Key Information GLP-1 agonists
Efficacy High
CV benefit Yes (liraglutide)
Hypoglycaemia risk Low
Weight Loss
Main adverse events Gastrointestinal
In CKD stage 3A (eGFR 45 -59) Dose unchanged (caution with exenatide when eGFR <50ml/min/1.73)m2)    
Cost £57.93 - £117.72

 

GLP-1 receptor agonists are initiated by the Specialist Diabetes Service.

GLP-1 receptor agonist therapy should be considered as an alternative to insulin in people for whom treatment with combinations of oral glucose-lowering drugs has been inadequate.

 

Once daily liraglutide, usually at a dose of up to 1.2mg/day, is the agent of choice in NHS Tayside.  For patients who would prefer a once weekly injection, exenatide MR (Bydureon) can be considered.

They may help weight-loss and are not associated with increased risk of hypoglycaemia.

They should be considered in people with a body mass index of ≥30 kg/m2 (or ethnicity-adjusted equivalent) in combination with oral glucose-lowering drugs or basal insulin (or both) as third or fourth-line treatment, when adequate glycaemic control has not been achieved with these drugs.

 

For individuals with type 2 diabetes and established cardiovascular disease, GLP-1 receptor agonist therapies with proven cardiovascular benefit (currently liraglutide) should be considered. The recent LEADER study, randomised and large scale, on liraglutide demonstrated cardiovascular benefit to those at high cardiovascular risk.

 

They should be avoided in severe gastrointestinal disease or gastroparesis, pancreatitis, or cholecystitis. In 2009 the MHRA highlighted the risks of severe pancreatitis and renal failure with exenatide.

Liraglutide is available as a combination product with insulin degludec (Xultophy®) for use where the combination of basal insulin and GLP-1 receptor agonist is appropriate as directed by the specialist Diabetic team/Diabetes clinic.

There are no guidelines that support the combined use of a GLP-1 agonist and a DPP-4 inhibitor. Without any studies demonstrating clear benefits of this combination, it is not currently recommended. If a GLP-1 agonist is indicated then any current treatment with a DPP-4 should be stopped.

GLP-1 receptor agonist therapy should only be continued if there is a beneficial metabolic response (a reduction of HbA1c by at least 11mmol/mol and a weight loss of at least 3% of initial body weight in 6 months)

 

Risk-Benefit Informed Approach to Prescribing of Incretin Therapies:

 

1) For patients already established on DPP-4 inhibitors (gliptins) or GLP-1 Agonists, at the time of their next diabetes assessment:

  1. a) an active decision should be made about the benefits and risks of continuing this therapy. In particular it should be noted whether in the first 6 months after the agent was commenced there was a satisfactory clinical response to the therapy. As a general rule, for DPP-4 inhibitors, an HbA1c reduction in the 6 months after initiation of ≥ 5.5 mmol/mol (0.5%). For GLP-1 Receptor Agonists, an HbA1c reduction in the 6 months after initiation of ≥ 11 mmol/mol (1.0%) without weight gain OR a significant weight loss of ≥ 10% of weight at initiation with no increase in HbA1c. For most patients whose HbA1c or weight has responded to these levels, the benefits are likely to outweigh the risks of ongoing treatment.
  2. b) If there has been no significant improvement in HbA1c or weight (as above), then the drug should usually be stopped and alternative glycaemic control options considered.
  3. c) If there has been an appropriate improvement in HbA1c or weight, then an individual discussion should be had with the patient focusing on
  4. i) the small increased risk of acute pancreatitis (‘background risk’ in Type 2 DM = 1/200 [~0.5% per year]. Potential risk on incretin therapies = 1/100, i.e. 1 extra case in 200 patient years of treatment) + the very small potential risk of cancer

                        (ii)  the likely cardiovascular benefits of incretins and the microvascular benefits of good glycaemic control  and

                        (iii) the options and potential drawbacks of alternative therapies.

 

2) For patients who might benefit from initiation of DPP-4 inhibitorsor GLP-1 Receptor Agonists, in line with the current NHS Tayside MCN Treatment Algorithm, should be enabled to contribute to an informed decision about whether or not to commence such therapy, by an explanation of the potential risks and benefits of these agents, including:

  1. a) i) the small increased risk of acute pancreatitis (‘Background risk’ in Type 2 DM = 1/200 [~0.5% per year]. Potential risk on incretin therapies = 1/100, e. 1 extra case in 200 patient years of treatment) + the very small potential risk of cancer

(ii) the likely cardiovascular benefits of incretins and the microvascular benefits of good glycaemic control  and

(iii) the options and potential drawbacks of alternative therapies.

  1. b) that this will be a therapeutic trial for approximately 6 months, at which time the benefits of continuing with the agent will be re-assessed.
  2. c) that during this initial 6 month assessment period the risks are likely to be very low.

 

Insulin

Type 2 diabetes can progress and require a third-line agent for glycaemic control.

For most non-obese patients (BMI <30), insulin remains the preferred third-line therapy following optimal use of first and second-line agents.

 

Key Information Basal Insulin
Efficacy High
CV benefit Low
Hypoglycaemia risk Highest
Weight Gain
Main adverse events Hypoglycaemia
In CKD stage 3A (eGFR 45 - 59) Dose unchanged
Cost Variable

 

Insulins are initiated by the Specialist Diabetes Service.

Careful clinical judgement must be applied to ensure insulin therapy is not delayed inappropriately and that patients are referred in a timely manner.

SIGN advises that when commencing insulin therapy, human intermediate acting insulins should be initiated in the first instance, normally a once-daily bedtime NPH insulin regime.

Oral metformin therapy should be continued when insulin therapy is initiated to maintain or improve glycaemic control.

In contrast to GLP-1 receptor agonists insulin is associated with weight gain and hypoglycaemia.

Insulin analogues may be considered according to hypoglycaemic risk. Analogue insulins are biological medicines which should be prescribed and dispensed by brand name. Where a clinical decision is made that an analogue insulin is appropriate for a patient with type 2 diabetes then it should therefore be prescribed by brand name. There are now biosimilar preparations available for insulin glargine and it is therefore important that the patient receives the product intended by the prescriber.

 Acarbose (alpha-glucosidaseinhibitors)

 

Following the results of the Acarbose Cardiovascular Evaluation (ACE) trial which showed no differences between participants taking acarbose and placebo for any cardiovascular outcomes, but significantly more adverse effects with acarbose, this agent is not routinely used in NHS Tayside.

 Prescribing for High Risk Groups

Clinical judgement must be utilised when prescribing for high risk patients i.e. frail, women of childbearing age, renal impairment, hepatic impairment, patients unable to self-care, patients with existing cardiovascular disease. Clinicians should be aware of the need to adjust prescribing in patients with diabetes and chronic kidney disease. Refer first to BNF and SPCs. The table below provides guidance:

 

 

 

 

 

Careful consideration should be given when prescribing for women who are planning a pregnancy or may become pregnant. Comprehensive information on managing medicines in women with diabetes planning a pregnancy is contained within SIGN 116. Tight glycaemic control may increase the risk of hypoglycaemia. In frail patients, especially those with co-morbidities, it will often be appropriate to adjust the target HbA1c. Clinicians should take care when prescribing for frail patients. The key issues surround weight loss, renal function and cognitive decline, which increase the risk of side effects. The benefits of preventative cardiovascular medicine in this group should be carefully considered as time to derive clinical benefit from tight glycaemic control may be unrealistic. Clinicians should refer to Polypharmacy Guidance  when prescribing.

 

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