Tayside Diabetes MCN Handbook
Pharmacological management of glycaemic control in people with Type 2 diabetes

 

Aims of Drug Treatment  
When to consider tablets Sulphonylureas
Drug Mechanisms, indications and recommendations Thiazolidinediones (Glitazones)
Algorithm for Oral Hypoglycaemic Agents                                                                   Acarbose
Rough Guide to HbA1c Targets Incretin mimetics/DPP-4 inhibitors
Empagliflozine (and other SGLT2 Inhibitors)        Prescribing in renal impairment
Metformin  

Aims of Drug Treatment

  • to alleviate hyperglycaemic symptoms, improve control of glucose, and reduce microvascular complications
  • to minimise hypoglycaemia and weight gain
  • to reduce or avoid aggravating cardiovascular risk (BP, cholesterol, events i.e. MI, stroke)

 

When to Consider Tablets

  • in type 2 diabetes with inadequate glycaemic control after 12 weeks diet and lifestyle advice
  • sooner if severe symptoms or adequate control unlikely to be achieved with non-pharmacological measures
  • metformin is now considered as a treatment option in pregnancy and gestational diabetes.

Tablets should be replaced by insulin in the presence of severe intercurrent illness, especially if ketosis is present or if usual tablet treatment is stopped temporarily e.g. metformin due to renal impairment, insulin may also be needed.

 

Dosage Alteration

 

For any therapy, changes in dosage should usually be gradual i.e. intervals of 8-12 weeks

 

Drug Mechanisms, Indications and Recommendations

 

This is an exciting time for the treatment of type 2 diabetes, with the increasing availability of new therapies. However, this also makes it less clear how these drugs should be used and in what order of preference. Any recommendations are made on the basis of current evidence and considered opinion at the time of writing and will be reassessed when new evidence or guidance becomes available.

Current Tayside guidelines are based on SIGN 116 Management of Diabetes

 

Algorithm for Use of Oral Hypoglycaemic Agents

 

Click here for a pdf version which can be enlarged

Rough Guide to HbA1c Targets

 

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Empagliflozin (and other SGLT2 Inhibitor drugs)

  • Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new group of oral glucose lowering agents only licenced for use in Type 2 Diabetes at this time. They act primarily by inhibiting glucose re-absorption in the kidney resulting in glycosuria.
  • Empagliflozin is the NHS Tayside drug of first choice in the SGLT2 Inhibitor class of oral glucose lowering drugs.
  • 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 total tablet count, 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 incidence of genital candidiasis – this is easily treated with topical clotrimazole and does not usually recur.
  • 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 and 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.

 

 

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 (eg atypical for DKA. This atypical presentation could delay diagnosis and treatment.

N.B. Therefore inform patients commencing an SGLT2I of the signs and symptoms of DKA (eg nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness) and 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 these medicines 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.

 

Metformin

 

Metformin is weight neutral, and in some studies was associated with weight loss. In the UKPDS, all cause and cardiovascular mortality was reduced in those achieving intensive control of glycaemia with metformin compared to patients receiving conventional management with other agents. It acts primarily to decrease liver glucose production but also it decreases gut glucose absorption and may increase peripheral glucose disposal.

  • Metformin should be considered as the drug of first choice in overweight or obese individuals with type 2 diabetes. There is no evidence that metformin is ineffective in non-overweight individuals so it should be considered in this group, although sulphonylureas would be a reasonable alternative.
  • It can be used alone or if necessary with any other diabetes therapy. It carries a low risk of hypoglycaemia.
  • GI side effects are experienced in up to 25% of patients, although only 5% cannot tolerate it. Metformin should be started in low dose and built up gradually in 2 or 3 divided doses to a dose 1g bd or 850mg bd with or after food, to a usual maximum of 2g/day. 
  • Slow release preparations of metformin are approved by SMC. There is some evidence to suggest that in those intolerant of standard formulations of metformin, slow release formulations are better tolerated. A trial of metformin MR (Glucophage SR) could therefore be considered in those patients with severe GI side effects who would otherwise discontinue immediate release metformin. If no benefit in GI side effect is seen within 6 months, metformin MR should be stopped and an alternative agent commenced.
  • Metformin oral solution can be used in those unable to swallow the solid tablet.
  • Metformin is renally excreted and accumulation may precipitate lactic acidosis. The dose of metformin should be reduced to 500 mg bd when the eGFR falls below 45mls/min. Metformin should be stopped when the eGFR falls below 30ml/min. For further information see Section on Screening and Management of Kidney Complications. Patients with deteriorating renal function should be monitored closely. It is generally advised for patients with impaired renal function to stop metformin temporarily if they are unwell as many of these patients are also on ACE Inhibitors and ARBs.  Other glucose lowering treatment may be needed.
  • Hepatic impairment, severe infection, trauma, dehydration, and heavy alcohol use, are also contraindications to metformin use.
  • Metformin is classically contraindicated in heart failure due to an increased risk of lactic acidosis and should be avoided where there is a suspected risk of tissue hypoxia. However, clinical trials are now in progress examining its effect in stable congestive heart failure patients and there is epidemiological evidence to suggest no adverse effects of metformin in stable heart failure.
  • Metformin should be stopped in patients admitted with severe infection or undergoing major surgery; in this situation, hyperglycaemia should be managed with insulin. For further information see Perioperative Guidelines
  • Metformin should also be stopped prior to any procedures which involve use of iodinated contrast. For further information see Preparations Prior to Procedures.

 

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Sulphonylureas

 

These agents act by augmenting insulin release by the pancreas, so some capacity to produce insulin must be retained.  Sulphonylureas cause a significant risk of hypoglycaemia.  Sulphonylureas are associated with on average a 1-2kg weight gain.  Epidemiological evidence suggests that sulphonylureas are assocaited with higher rates of cardiovascular disease than with metformin.  Sulphonylureas should be considered second line in combination with metformin when glycaemia is above target; or in place of metformin if this cannot be tolerated.

  • Shorter acting sulphonylureas such as gliclazide and glimepride are most commonly used.  Gliclazide is entirely metablosed in the liver, so it is safe in renal failure but contraindicated in liver failure.  Gliclazide doses start at 40-80mg daily, then 160mg daily or in two divided doses, up to a mximum of 160mg twice daily.  Therapeutic benefit over 80mg twice daily is small.  Occassionally 40mg of gliclazide may be sufficient, especially in the elderly.
  • Sulphonylureas can be used with all other oral agents and insulin.
  • Longer acting sulphonylureas (glibenclamide, chlorpropamide) are not used routinely. In patients established on these agents their use should be reviewed in the elderly due to decreased renal excretion and subsequent increased risk of hypoglycaemia and should also be avoided in renal impairment (eGFR < 50ml/min).
  • Glibenclamide may be used in gestational diabetes but only under the supervision of the specialist diabetes antenatal clinic.
  • A sustained-release formulation of gliclazide is available (Diamicron-MR) and may be useful to increase concordance in patients who frequently omit their teatime dose(s). However, the tablet burden is not lessened and care should be taken in prescribing and explanation as 30mg of Diamicron-MR is equivalent to 80 mg of the standard formulation (i.e. maximum dose 120mg daily).

Repaglinide and nateglinide were introduced as a different class of drug – “Prandial glucose regulators” yet they work via the sulphonylurea receptor and are essentially short acting sulphonylureas designed to be taken with meals to promote prandial insulin release. These agents are not routinely used in Tayside but could be used in place of traditional sulphonylureas.

 

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Thiazolidinediones (Glitazones)

 

These are insulin sensitising drugs that activate the transcription factor PPARgamma. Transcription factors regulate expression of a number of other genes. Pioglitazone is the only one of this class to be recommended by the Tayside team, following the suspension of rosiglitazone by the European Medicines Agency (see below).

 

The manufacturers of Pioglitazone have highlighted a small increased risk of bladder cancer in patients using pioglitazone.  Pioglitazone is now contraidicated in patients with current bladder cancer, a history of bladder cancer, or uninvestigated macroscopic haematuria.  Pioglitazone is already contraindicated in patients with a history of any stage of heart failure (NYHA stages 1-1V) and is recognised as increasing the risk of small bone fractures in women.  In addition, new Scottish data (as yet unpublished) indicates that there may be a small increased risk of hip fracture.  This appears to affect both men and women and be related to length of exposure to pioglitazone.  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 in those over 65.  More detailed Tayside guidance on pioglitazone is available here.  Prescribers should also read the Risk Minimisation Advice in the Prescribers Guide by Takeda.

  • The main effect of glitazones is to increase insulin sensitivity by promoting differentiation of pre-adipocytes to adipocytes.  This has the adverse effect of increasing fat mass with an average weight gain of 3-4 kg.
  • In the 2008 NICE guidelines,  glitazones are recommended second line only in patients intolerant of sulphonylureas or where hypoglycaemia with sulphonylureas is an issue.  In patients treated with sulphonylureas and metformin, thiazolidinediones should be considered as an alternative to insulin only when there is fear of insulin, the use of insulin would affect employment or it is anticipated that large insulin doses would be required.
  • Pioglitazone is available as a fixed-dose combination tablet with metformin (Competact) which may be used in decreasing tablet burden and improving concordance with therapy.
  • A key side effect of this agent is fluid retention causing ankle oedema and an increase in hospital admissions with heart failure.  Although the glitazones do not diminish left ventricular contractility, they are contraindicated in patients with heart failure/LVdysfunction (echocardiography recommended where there is clinical uncertainty)
  • Pioglitazone is licensed in the UK for use with insulin but because of the risk of fluid retention this should only occur in exceptional cases and under close specialist supervision.
  • Following new evidence from the MHRA and the subsequent recommended suspension by the EMA, we recommend that in Tayside, patients who are currently treated with rosiglitazone should be changed to pioglitazone.  Those on rosiglitazone 4mg should change to pioglitazone 30mg; those on 8mg rosiglitazone should convert to 45mg pioglitazone; those  on 'Avandamet' should change to 'Competact' but be aware that a small reduction in metformin dose  will result.
  • Following new evidence from the MHRA, patients with active bladder cancer or with a history of bladder cancer, and those with uninvestigated haematuria, should not receive pioglitazone.
  • 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 glycoslated haemoglobin HbA1c).
  • Before starting pioglitazone, the following known risk factors for development of bladder cancer should be assessed in individuals: age; current or past history of smoking; exposure to some occupational or chemotherapy agents such as cyclophosphamide; or previous irritation of the pelvic region.
  • Use in elderly patients should be considered carefully before and during treatment because of the risk of bladder cancer increases with age.  Elderly patients should start on the lowest possible dose and be regularly monitored because of the risks of bladder cancer and heart failure associated with pioglitazone.
  • Further information available from the MHRA
  • Thiazolidinediones have been associated with an increased risk of fracture in women.  Although the numbers experiencing fractures in the trials is very small, it is recommended that these drugs are avoided in those with high fracture risk.  In general that means we do not recommend starting someone aged over 65 years on pioglitazone, and those who are already taking pioglitazone should have their risk / benefit reassessed ( see Tayside guidance)
  • Because of fatal hepatotoxicity with a previously-available glitazone (troglitazone), initial licensing of glitazones required regular monitoring of LFTs.  This has since been relaxed as there appears to be no concern with pioglitazone.

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Acarbose

 

This is an inhibitor of intestinal alpha glucosidase. It delays digestion of starch and sucrose and hence reduces the increase in blood glucose levels following a carbohydrate rich meal. It can cause flatulence and diarrhoea and although popular in the Far East is now little used in patients on Western diets. Acarbose can be used with all other oral agents.

 

Incretins 

The incretin hormones (GLP-1, 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; GLP-1 receptor agonists and DPP-4 inhibitors.

 

The following GLP-1 receptor agonists are licensed and approved by SMC:

  • Liraglutide - once daily injection
  • Lixizenatide - once daily injection
  • Exenatide - twice daily injection
  • Exenatide LAR (Bydureon) - once weekly injection requiring reconstitution by the patient prior to administration
  • Dulaglutide - once weekly injection
  • Albiglutide - once weekly injection
  • All improve HbA1c and cause weight loss.
  • In a head to head comparison liraglutide was more effective at lowering HbA1c and was associated with less nausea than exenatide. Liraglutide is also slighlty more effective at lowering HbA1c than Bydureon, although Bydureon has less associated nausea.  Liraglutide is approved  as the first line GLP-1 receptor agonist in Tayside and is approved for use as a third-line agent, in combination with metformin and a sulphonylurea, or metformin and a thiazolidinediones, as an alternative to insulin therapy in those who are obese (BMI >=30kg/m2) and in whom weight loss is desirable. Liraglutide is not licensed for use with moderate renal impairment (eGFR < 50ml/min).
  • Lixizenatide can be used in moderate renal impairment but not severe renal impairmnet (eGFR>30ml/min).  Lixizenatide has also been approved by SMC for use with basal insulin.  Lixizenatide is the second line GLP-1 receptor agonist in Tayside. 
  • As with all therapies other than metformin, GLP-1 receptor agonists should be stopped if adequate glycaemic control is not achieved within 3-5 months (at least 1% (11mmol/mol).

The following DPP-4 inhibitors are approved for use within Scotland.

  • Sitagliptin
  • Alogliptin
  • Vildagliptin
  • Saxagliptin
  • Linagliptin

 

  • DPP-IV breaks down GLP-1 in vivo, so these drugs enhance the effect of naturally produced GLP-1. 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 these agents, although they are weight neutral. 
  • All are available as combination tablets with metformin. The gliptins have been approved by SMC for restricted use in patients when the addition of a sulphonylurea to metformin is not appropriate and are an alternative to thiazolidinediones. Currently alogliptin is first line DPP-4 on Tayside formulary; sitagliptin is also listed.  Vildagliptin, Linagliptin and saxagliptin are non-formulary.  Other combinations currently approved for use in Scotland are outlined below

 

Added to

 

 

 

 

 

 

Metformin (M)

Sulphonylurea (SU)

M+SU

M+TZD

Combination tablet with metformin?

Monitoring?

Sitagliptin

yes

yes

yes

no

yes

no

Vildagliptin

yes

yes

no

no

yes

LFTs 3 monthly for 1 year

Saxagliptin

yes

no

yes

no

yes

no

 Linagliptin

 yes

 no

 yes

 no

 yes

no 

 Alogliptin

yes

yes

no

yes

yes

no

  • Vildagliptin should be used cautiously in NYHA I & II heart failure, and is contraindicated in NYHA III & IV heart failure (due to limited data on these groups). Also, vildagliptin should not be used in moderate to severe renal impairment (i.e. CKD stages 4 and 5). Sitagliptin does not require liver function monitoring and use in heart failure is not contraindicated.  Sitagliptin can be used in moderate to severe renal impairment (50mg daily should be prescribed when the eGFR falls below 50ml/min; 25mg should be prescribed when the eGFR < 30ml/min down to and including ESRD requiring dialysis.  Saxagliptin also has a licence for use in moderate and severe renal impairment, when the 2.5mg tablets should be used.  In a Cochrane systematic review the HbA1c reduction seen with these agents was 0.6 – 0.7%, less than is seen with metformin or sulphonylureas. They represent an alternative to other agents such as the glitazones.
  • Recent reports in the British Medical Journal have highlighted potential significant side effects from DPPIV inhibitors and GLP-1 Receptor Agonist medications - specifically that these medications may be associated with an increased risk of pancreatitis and pancreatic cancer.  Guidance and patient information was issued by the MCN in June 2013. 
  • With the current available evidence we advise:

    1.    All patients treated with DPP4 inhibitors (gliptins) or GLP1 Agonists:

    a) should be informed of the characteristic symptoms of acute pancreatitis – persistent, severe abdominal pain (sometimes radiating to the back) – and encouraged to tell their GP if they have such symptoms. (MHRA Advice for Healthcare Professionals September 2012)

    b) If pancreatitis is suspected the agent should be discontinued and the ‘suspected adverse reaction’ reported through the Yellow Card Scheme — www.mhra.gov.uk/yellowcard.

    2)    For patients already established on DPP4 inhibitors (gliptins) or GLP1 Agonists, at the time of their next diabetes assessment:

    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 DPP4s (gliptins), an HbA1c reduction in the 6 months after initiation of ≥ 5.5 mmol/mol (0.5%). For GLP1 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 .

    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.

    c) If there has been an appropriate improvement in HbA1c or weight, then an individual discussion should be had with the patient focusing on 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.

     

    3)    Patients who might benefit from initiation of DPP4 inhibitors (gliptins) or GLP1 Agonists, in line with the current 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:

    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,  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.

    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.

    c) that during this initial 6 month assessment period the risks are likely to be very low.

 

 Prescribing in Renal Impairment

 

 

Mild

(eGFR 50-80)

Moderate (eGFR 30-50)

Severe

(eGFR 19-30)

End stage/Dialysis

Metformin

yes

yes

(half maximal dose below eGFR 45ml/min)

no

 no

Gliclazide

yes

yes

Not licensed but as only 5% of Gliclazide is excreted in urine gliclazide is often used without problem in severe renal impairment within the specialist service

no

Pioglitazone

yes

yes

yes

yes (eGFR>4ml/min)

Alogliptin

yes (reduce to 12.5mg od)

yes (reduce to 6.25 mg od)

Use with caution

no

Sitagliptin

yes

yes

(reduce to 50mg od)

 yes

(reduce to 25mg od)

 yes

(reduce to 25mg od)

Lixizenatide

yes

yes

no

no

Liraglutide

yes

yes

no

no

Bydureon

yes

yes

no

no

Dulaglutide

yes

yes

no

no

 Empagliflozin

yes(>60 at initiation,> 45 to continue)

off licence medication <45

no

no

Dapagliflozin

yes

 no

no

no

 For further information on the prescribing of oral hypoglycaemic drugs see:

 BNF Section 6.1.2 Antidiabetic Drugs

Tayside Area Formulary Section 6 Endocrine System