Diabetes Mellitus - type 2

Prescribing Notes:

BMI and treatment choice

• Metformin is the first choice oral hypoglycaemic drug for people with BMI* greater than 25kg/m² presenting with ‘typical’ type 2 diabetes [*a lower BMI cut-off of 23kg/m² may be more appropriate for members of minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population].
• If BMI* is less than 25kg/m² reconsider if the diagnosis of type 2 diabetes is correct. Seek advice from secondary care if there is uncertainty about the cause of diabetes.
• Provided that type 1 diabetes has been excluded. Treatment options for type 2 diabetes in people with a BMI* less than 25kg/m² include oral gliclazide or subcutaneous insulin. Refer to the Diabetes Type 1 insulin pathways for product choice.

Biguanides - metformin

• Metformin is proven to improve survival. It does not need to be limited to overweight patients.
• Metformin may cause gastro-intestinal adverse effects; it should be started at low dose and taken with or after meals, and the dose gradually increased if tolerated. Hypoglycaemia is not a problem with metformin monotherapy.
• Metformin modified release tablets may be helpful in patients who are unable to tolerate immediate release metformin.
• Metformin oral solution should be restricted to patients unable to swallow tablets.
• Due to the rare but serious risk of lactic acidosis, metformin must be avoided in patients with: significant renal impairment (estimated glomerular filtration rate (eGFR) less than 30mL/min); alcoholism with previous pancreatitis; severe cardiac/respiratory disease producing tissue hypoxia; severe liver disease with potential for hepatic failure. Sick day rules apply to metformin. Supply the patient with appropriate advice.
• The precipitant of a lactic acid crisis is often in the eGFR range 30 to 45mL/min when the patient develops what would have been a trivial illness (such as diarrhoea and vomiting) which compromises renal function and causes acute renal failure. This is compounded if the patient is also taking diuretics and/or ACE inhibitors in combination with metformin. Unlike acute illnesses in type 1 diabetes (where insulin treatment MUST be continued) stopping the drugs for a day or two will NOT cause any immediate problem for the patient and will protect renal function until the patient improves. Blood glucose estimation should be used to assess any glycaemic deterioration. In circumstances where renal impairment is suspected, NSAIDs should NOT be used as they can further compromise renal function.

SGLT-2 Inhibitors - Dapagliflozin and Empagliflozin

• NICE Multiple Technology Appraisal 390 recommends that dapagliflozin and empagliflozin are suitable for monotherapy. Healthcare Improvement Scotland notes that NICE MTA 390 superseded previous SMC advice not recommending empagliflozin for monotherapy. SGLT-2 inhibitors can be used when metformin is contraindicated or not tolerated and a sulphonylurea is not appropriate.
• Sodium-glucose co-transporter 2 (SGLT2) inhibitors reversibly inhibit sodium-glucose co-transporter 2 in the kidneys to reduce glucose reabsorption and increase glucose excretion.
• Risk of euglycaemic ketoacidosis with SGLT2 inhibitors; provide clear guidance to stop treatment if intercurrent dehydrating illness. A 'sick day' guidance leaflet for patients is available.
• Patients on SGLT2 inhibitors should be given advice on genitourinary infections.
• The glucose lowering efficacy of dapagliflozin and empagliflozin is dependent on renal function, and is reduced in patients with eGFR < 45 mL/min/1.73m² and is likely absent in patients with severe renal impairment. Therefore, if eGFR falls below 45 mL/min/1.73m², additional glucose lowering treatment should be considered in patients with type 2 diabetes mellitus.
• Dapagliflozin is the preferred SGLT2i. Empagliflozin is an alternative for patients with eGFR > 60 mL/min/1.73m² and no microalbuminuria. There is limited experience with initiating treatment with dapagliflozin in patients with eGFR < 25 mL/min/1.73m², seek specialist advice from the renal team.
• For guidance on empagliflozin dosing for eGFR <60mL/min/1.73m² refer to product information.
• SGLT2 inhibitors should be used with caution in patients with a past history of recurrent genito-urinary tract infection.
• If considering initiation of an SGLT2 for a patient with co-morbid heart failure see formulary recommendations for heart failure.
• If considering initiation of an SGLT2 for a patient with co-morbid chronic kidney disease see formulary recommendations for kidney disease.

Sulfonylureas - gliclazide

• Gliclazide is a potent anti-diabetic agent that stimulates endogenous insulin production. It is associated with weight gain and hypoglycaemia; it is not associated with a reduction in cardiovascular disease. It remains very useful in the following situations:
  • individuals with BMI* <25kg/m² (providing type 1 diabetes has been excluded)
  • significant hyperglycaemia at the time of diagnosis of T2D (providing type 1 diabetes has been excluded)
  • steroid-induced diabetes or where pre-existing diabetes worsened by steroids
  • individuals with significant liver or kidney disease
  • certain rare genetic forms of diabetes
• Sulfonylureas should be taken before meals.
• Patients should be informed that sulfonylureas can cause hypoglycaemia.  The risk of hypoglycaemia increases with age.

Prescribing Notes:

• Sodium-glucose co-transporter 2 (SGLT2) inhibitors reversibly inhibit sodium-glucose co-transporter 2 in the kidneys to reduce glucose reabsorption and increase glucose excretion.
• Review treatment at 3-6months, if not reaching target review adherence then move to 3rd line medicines treatment.
• Risk of euglycaemic ketoacidosis with SGLT2 inhibitors; provide clear guidance to stop treatment if intercurrent dehydrating illness. A 'sick day' guidance leaflet for patients is available.
• Patients on SGLT2 inhibitors should be given advice on genitourinary infections.
• SGLT2 inhibitors should be used with caution in patients with a past history of recurrent genito-urinary tract infection.
• The glucose lowering efficacy of dapagliflozin and empagliflozin is dependent on renal function, and is reduced in patients with eGFR < 45 mL/min/1.73m² and is likely absent in patients with severe renal impairment. Therefore, if eGFR falls below 45 mL/min/1.73m², additional glucose lowering treatment should be considered in patients with type 2 diabetes mellitus.
• Dapagliflozin is the preferred SGLT2i. Empagliflozin is an alternative for patients with eGFR > 60 mL/min/1.73m² and no microalbuminuria. There is limited experience with initiating treatment with dapagliflozin in patients with eGFR < 25 mL/min/1.73m², seek specialist advice from the renal team.
• For guidance on empagliflozin dosing for eGFR <60mL/min/1.73m² refer to product information.
• In patients with moderate renal impairment (eGFR < 60 mL/min/1.73m²), a higher proportion of patients treated with dapagliflozin had adverse reactions of increase in parathyroid hormone (PTH) and hypotension, compared with placebo.
• If considering initiation of an SGLT2 for a patient with co-morbid heart failure see formulary recommendations for heart failure.
• If considering initiation of an SGLT2 for a patient with co-morbid chronic kidney disease see formulary recommendations for kidney disease.
• SGLT-2 inhibitors are to be used with caution in peripheral vascular conditions and those at risk of acute kidney injury due to increased risk of volume depletion. Caution must be exercised when using loop diuretics concomitantly.
• MHRA have issued safety information (June 2015) on the risk of DKA associated with SGLT2 inhibitors, and patients should be advised on how to recognise signs and symptoms of DKA.

Prescribing Notes:

• GLP-1 agonists are currently in short supply refer to the Medicine Supply Alert Notice (MSAN) on the NHS Scotland Publications website.
• NHS Lothian Diabetes MCN Prescribing subgroup have published additional guidance refer to Diabetes MCN > Prescribing information.
• When GLP-1 agonists return to normal supply status the initial choice is oral semaglutide. If adherence to oral administration guidance is difficult, consider a once weekly injectable GLP-1 agonist.
• GLP-1 agonists are approved for use in combination with other antidiabetic medicines. They are not approved for use as monotherapy.
• Concomitant insulin or sulfonylureas may require dose reduction with GLP-1 agonist. Patients being started on GLP-1 agonists must have their gliptins stopped on commencement of the GLP-1.
• GLP-1 agonists are associated with gastro-intestinal side-effects; use with caution if previous pancreatitis.
• Semaglutide can worsen diabetic retinopathy, discuss with local diabetes team if pre-existing retinopathy.
• Oral semaglutide is taken on an empty stomach with a small glass of water avoiding food, drink and other oral medicines for 30mins. Adherence to these instructions is important for efficacy, therefore offer injectable therapy if the patient is unable to comply.
• If glycaemic targets have not been met on oral semaglutide an injectable GLP-1 agonist is likely to be a more effective alternative.
• Prescribers should note that the effect of switching between oral and subcutaneous semaglutide cannot easily be predicted because of high pharmacokinetic variability of oral semaglutide. Clinical effectiveness should be considered when making switching decisions between formulations. Refer to product literature for more information, seek advice from secondary care if no prior experience.
• Semaglutide has been shown to be more cost effective than liraglutide, however some patients may prefer a daily preparation. As an alternative to 1.8mg liraglutide daily, a switch to semaglutide could be considered. Liraglutide 1.8mg is significantly more expensive and is no more effective than semaglutide.
• Semaglutide injection is administered once weekly, at any time of the day, with or without meals. The day of weekly administration can be changed if necessary. If the dose is more than 5 days late, the missed dose should not be taken and the next dose should be administered at the normal time.
• Semaglutide is first choice glucagon-like peptide (GLP-1) agonist weekly injection on account of the preferable cardiac profile. Dulaglutide, however, employs a simple injection pen, the use of which can be taught remotely and it may therefore be preferred for this reason.
• Dulaglutide is administered once weekly. The injection device is considered to be superior in that the needle is preloaded and hidden. The needle retracts after administration. This may make it a more appropriate choice for district nurse administration, people with a needle phobia or significant dexterity issues.
• Gastric emptying may be delayed, therefore the rate and extent of absorption of other oral drugs administered at the same time may be affected. For oral drugs that require threshold concentrations for efficacy, patients should take these medicines at least one hour before.
• Patients should be reviewed at 6 months and only continue therapy in those with a ≥5 mmol/mol reduction in HbAlc and/or ≥3% reduction in body weight.
• Upper gastro-intestinal side effects are common with incretin mimetics. Acute pancreatitis has been associated with GLP-1 agonists, patients should be informed of the warning signs to look for.
• There is an increased risk of hypoglycaemia when GLP-1 agonists are combined with a sulfonylurea.
• Tirzepatide is long-acting dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) receptor agonist, and first in its class.

Prescribing Notes:

Consider seeking advice or a referral to secondary care if patient has suboptimal glycaemic control despite maximum tolerated oral therapy. Then guided by patient profile, add additional agent(s) from 4th line options.

Sulfonylureas - gliclazide

• Gliclazide is a potent anti-diabetic agent that stimulates endogenous insulin production. It is associated with weight gain and hypoglycaemia; it is not associated with a reduction in cardiovascular disease. It remains very useful in the following situations:
  • individuals with BMI <25kg/m² (providing type 1 diabetes has been excluded)
  • significant hyperglycaemia at the time of diagnosis of T2D (providing type 1 diabetes has been excluded)
  • steroid-induced diabetes or where pre-existing diabetes worsened by steroids
  • individuals with significant liver or kidney disease
  • certain rare genetic forms of diabetes
• Sulfonylureas should be taken before meals.
• Patients should be informed that sulfonylureas can cause hypoglycaemia. The risk of hypoglycaemia increases with age.

Dipeptidyl-peptidase 4 (DPP4) or ‘Gliptins’ - sitagliptin

• Gliptins are weak anti-diabetic agents. They are weight neutral and do not reduce cardiovascular disease. They have a low side effect profile and do not cause hypoglycaemia; therefore, sitagliptin has a place in the management of frail individuals, where a modest reduction in hyperglycaemia may improve osmotic symptoms. Sitagliptin may be useful for individuals with contra-indications to multiple anti-diabetic agents.
• There are five DPP-4 inhibitors available, they differ in which of their licensed indications are approved for use by the Scottish Medicines Consortium.
• Sitagliptin is approved for use:
  • in combination with metformin, where the addition of a sulfonylurea is not appropriate
  • in combination with a sulfonylurea, where the addition of metformin is not appropriate
  • in combination with metformin and a sulfonylurea
  • as monotherapy, where metformin or a sulfonylurea are not appropriate.
  • in combination with insulin (with or without metformin).
• DPP-4 inhibitors have been shown to reduce HbAlc levels, but there is no data on morbidity, mortality or long-term adverse effects.
• DPP-4 inhibitors are considered to be weight neutral.
• There have been reports of acute pancreatitis associated with DPP-4 inhibitors. Patients should be informed of the characteristic symptoms of pancreatitis – persistent, severe abdominal pain (sometimes radiating to the back) – and encouraged to inform their healthcare professional if they experience these symptoms. If pancreatitis is suspected, the DPP-4 inhibitor and other potentially suspect medicines should be discontinued.

 Thiazolidinediones or ‘Glitazones’ - pioglitazone

• Pioglitazone is reserved for individuals with contra-indications or intolerance to multiple anti-diabetic agents and where insulin therapy is not desirable. Pioglitazone is preferred in insulin resistant younger patients. i.e. younger overweight or obese patients.
• Pioglitazone can cause significant weight gain and fluid retention. It must not be used in patients with heart failure or history of heart failure. Macular oedema has also been associated with its use.
• Pioglitazone should not be used in patients with current or a history of bladder cancer or in patients with uninvestigated macroscopic haematuria. Use with caution in patients with other cardiovascular disease, in the elderly and those on insulin.
• Due to a reduction in bone mineral density in post-menopausal women with a subsequent increase in fracture risk, pioglitazone should be avoided in elderly women with high fracture risk, irrespective of cardiovascular risk.
• Liver function should be checked before initiating pioglitazone and periodically thereafter based on clinical judgement. It should not be initiated in anyone with ALT >2.5 times the upper limit of normal or with other evidence of liver disease.
• The balance of risks and benefits should be considered both before initiating and during treatment. Prescribers should review patients after three to six months (and regularly thereafter) to ensure only patients who are benefiting from treatment continue.
• Pioglitazone can be used in combination with insulin in patients with type 2 diabetes mellitus, who have insufficient glycaemic control on insulin, in whom metformin is inappropriate because of contraindications or intolerance.
• There is an increased risk of hypoglycaemia when pioglitazone is combined with a sulfonylurea.

Prescribing Notes:

Addition of insulin for patients with type two diabetes should be undertaken by a specialist. Consider referring patient for advice and treatment by secondary care.

Refer/seek advice from secondary care if patient has suboptimal glycaemic control despite maximum tolerated oral therapy. Then guided by patient profile, add insulin.

• Choice depends on the particular needs of the individual patient, taking into account lifestyle, age, preference and capabilities. Patients should not be changed from the insulin that they are currently receiving without advice from a specialist or a clinician with the appropriate skills and expertise.
• Type of insulin, device and needle gauge and length should be specified. Care should be taken to write the brand name in full to avoid errors such as, for example, administration of Humalog in place of Humalog Mix25 or Humalog Mix50. In order to avoid dosing errors, when writing prescriptions for insulin the dose should always be written as ‘units’. Abbreviations such as ‘U’ or ‘IU’ should be avoided.
• Insulin is available in 3ml cartridges, 10ml vials, 3ml disposable pens. Not all insulin cartridges fit all pens, see Diabetes UK Meds + Kit information.
• Remind patients to rotate injection sites within the same body region. Cutaneous amyloidosis at the injection site has been reported in patients using insulin and this may affect glycaemic control. For further advice, see MHRA Drug Safety Update September 2020.
• Insulin should not be withdrawn from cartridges/penfills for administration. Insulin should be administered from 10ml vial, prefilled pen or from cartridge-loaded pen as appropriate for individual patients.
• September 2024 Tresiba (insulin degludec) FlexTouch 100units/ml solution for injection 3ml pre-filled pens are currently in short supply refer to the Medicine Supply Alert Notice (MSAN) on the NHS Scotland Publications website.

Prescribing Notes:

General prescribing notes

• Seek specialist advice for the management of type 2 diabetes in children.
• Patients with type 2 diabetes who cannot be managed on metformin and/or sulphonylureas will be discussed with adult diabetes services.
• Individuals with type 2 diabetes may require treatment with insulin, in combination with oral agents.
• Seeking advice or refer to secondary care if patient has suboptimal glycaemic control despite maximum tolerated oral therapy.
• Seek specialist advice for the management of type 2 diabetes and MODY (Maturity Onset Diabetes of the Young) in children. Further information can be found on the Diabetes Genes website.

BMI and treatment choice

• Metformin is the first-choice oral agent for children with type 2 diabetes. Metformin is the first-choice oral hypoglycaemic drug for people with BMI* greater than 25kg/m² presenting with ‘typical’ type 2 diabetes [*a lower BMI cut-off of 23kg/m² may be more appropriate for members of minority ethnic groups known to be at equivalent risk of the consequences of obesity at a lower BMI than the white population].
• If BMI* is less than 25kg/m² reconsider if the diagnosis of type 2 diabetes is correct. Seek advice from secondary care if there is uncertainty about the cause of diabetes.
• Provided that type 1 diabetes has been excluded. Treatment options for type 2 diabetes in people with a BMI* less than 25kg/m² include oral gliclazide or subcutaneous insulin. Refer to the Diabetes Type 1 insulin pathways for product choice.

Biguanides - metformin

• Metformin is proven to improve survival. It does not need to be limited to overweight patients.
• Metformin may cause gastro-intestinal adverse effects; it should be started at low dose and taken with or after meals, and the dose gradually increased if tolerated. Hypoglycaemia is not a problem with metformin monotherapy.
• Metformin modified release tablets may be helpful in patients who are unable to tolerate immediate release metformin.
• Metformin oral solution should be restricted to patients unable to swallow tablets.
• Due to the rare but serious risk of lactic acidosis, metformin must be avoided in patients with: significant renal impairment; alcoholism with previous pancreatitis; severe cardiac/respiratory disease producing tissue hypoxia; severe liver disease with potential for hepatic failure. Sick day rules apply to metformin. Supply the patient with appropriate advice.
• A lactic acid crisis may occur in patients with underlying moderate renal impairment when the patient develops what would have been a trivial illness (such as diarrhoea and vomiting) which compromises renal function and causes acute renal failure. This is compounded if the patient is also taking diuretics and/or ACE inhibitors in combination with metformin. Unlike acute illnesses in type 1 diabetes (where insulin treatment MUST be continued) stopping the drugs for a day or two will NOT cause any immediate problem for the patient and will protect renal function until the patient improves. Blood glucose estimation should be used to assess any glycaemic deterioration. In circumstances where renal impairment is suspected, NSAIDs should NOT be used as they can further compromise renal function.

SGLT-2 Inhibitors – Dapagliflozin

• SGLT-2 inhibitors (dapagliflozin) can be used as monotherapy when metformin is contraindicated or not tolerated and a sulphonylurea is not appropriate.
• Sodium-glucose co-transporter 2 (SGLT2) inhibitors reversibly inhibit sodium-glucose co-transporter 2 in the kidneys to reduce glucose reabsorption and increase glucose excretion.
• Risk of euglycaemic ketoacidosis with SGLT2 inhibitors; provide clear guidance to stop treatment if intercurrent dehydrating illness. A 'sick day' guidance leaflet for patients is available.
• Patients on SGLT2 inhibitors should be given advice on genitourinary infections.
• The glucose lowering efficacy of dapagliflozin is dependent on renal function and is reduced in patients with moderate renal impairment and is likely absent in patients with severe renal impairment. Therefore, if renal function is impaired seek specialist advice with consideration to the addition of alternative anti-diabetic agents for glucose lowering treatment.
• SGLT2 inhibitors should be used with caution in patients with a past history of recurrent genito-urinary tract infection.
• SGLT-2 inhibitors are to be used with caution in peripheral vascular conditions and those at risk of acute kidney injury due to increased risk of volume depletion. Caution must be exercised when using loop diuretics concomitantly.
• MHRA have issued safety information on the risk of DKA associated with SGLT2 inhibitors, and patients should be advised on how to recognise signs and symptoms of DKA.

Glucagon like peptide 1 receptor agonist (GLP-1 agonist) or Incretin mimetic

• GLP-1 agonists are currently in short supply refer to the Medicine Supply Alert Notice (MSAN) on the NHS Scotland Publications website.
• NHS Lothian Diabetes MCN Prescribing subgroup have published additional guidance refer to Diabetes MCN > Prescribing information.
• GLP-1 agonists are approved for use in combination with other antidiabetic medicines. They are not approved for use as monotherapy.
• Concomitant insulin or sulfonylureas may require dose reduction with GLP-1 agonist. Patients being started on GLP-1 agonists must have their gliptins stopped on commencement of the GLP-1.
• GLP-1 agonists are associated with gastro-intestinal side-effects; use with caution if previous pancreatitis.
• Dulaglutide is administered once weekly.
• Gastric emptying may be delayed, therefore the rate and extent of absorption of other oral drugs administered at the same time may be affected. For oral drugs that require threshold concentrations for efficacy, patients should take these medicines at least one hour before.
• Patients should be reviewed at 6 months and only continue therapy in those with a ≥5 mmol/mol reduction in HbAlc and/or ≥3% reduction in body weight.
• Upper gastro-intestinal side effects are common with incretin mimetics. Acute pancreatitis has been associated with GLP-1 agonists, patients should be informed of the warning signs to look for.
• There is an increased risk of hypoglycaemia when GLP-1 agonists are combined with a sulfonylurea.

Prescribing Notes:

• Insulin choices in Type 2 Diabetes align with those in the Type 1 diabetes pathways.