Section 1: Sami

Sami is a 56-year-old man who has a 2-year history of type 2 diabetes and a recent HbA_1c result of 68 mmol/mol (8.4%). He has been unable to tolerate metformin at any dose, including use of the modified-release preparation, because of nausea, diarrhoea and abdominal pain. He continues to take empagliflozin.

Sami’s BMI is 27.2 kg/m²; he has normal urea and electrolytes and liver function tests. He has background diabetic retinopathy but no other comorbidities.

What would you suggest as an HbA_1c target for Sami?

Section 2

Sami has a short history of type 2 diabetes. At this early stage of his diabetes trajectory, good glycaemic control is crucial in preventing future complications. He is free of other comorbidities and not at high risk of hypoglycaemia. Thus, a reasonable target for Sami would be 53 mmol/mol (7.0%) or less (NICE, 2026).

Sami confirms he is taking his empagliflozin as directed. Lifestyle issues are reviewed and the importance of diet and exercise are re-emphasised.

What might you next offer Sami to improve his glycaemic control?

Section 3

In the absence of contraindications or intolerance, nearly all people with type 2 diabetes are recommended by NICE (2026) to start dual therapy with modified-release metformin and an SGLT2 inhibitor. If metformin is not tolerated, as in Sami’s case, then monotherapy with an SGLT2 inhibitor is advised as initial therapy.

Possibilities for additional oral therapy for Sami to lower HbA_1c include a DPP-4 inhibitor, a sulfonylurea, pioglitazone or oral semaglutide (as yet the only oral GLP-1 receptor agonist that is licensed). Of these, NICE recommends a DPP-4 inhibitor as the first-line add-on option for a person with type 2 diabetes without significant comorbidities.

What are the advantages and disadvantages of using DPP-4 inhibitors?

Section 4

Advantages of DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) include:

• Well tolerated – few side-effects.
• Low risk of hypoglycaemia.
• No weight gain.
• Can be used in chronic kidney disease down to an eGFR of 15 mL/min/1.73 m².
• Cardiovascular safety, although not benefit (caution in heart failure; see below) (Sinha and Ghosal, 2019).
• Once-daily medication.

DPP-4 inhibitors are not, however, powerful glucose-lowering agents, achieving an HbA_1c reduction of around 5–11 mmol/mol (0.5–1.0%) (Beba and Baig, 2024).

The use of DPP-4 inhibitors has been linked with acute pancreatitis (Tkáč and Raz, 2017) although other studies have failed to find an association. Warn people that treatment should be stopped and medical advice sought if severe upper abdominal pain occurs.

An increased risk of heart failure was identified in the saxagliptin cardiovascular outcomes trial versus placebo (Scirica et al, 2013). Thus, it is advisable to avoid saxagliptin in a person with a history of heart failure or with risk factors for heart failure, and indeed to use other DPP-4 inhibitors with caution in these situations.

The DPP-4 inhibitors can be used safely in renal failure but dose adjustment is necessary, except in the case of linagliptin, which is minimally renally excreted.

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Linagliptin 5 mg once daily is added to Sami’s empagliflozin.

After 6 months of dual therapy with linagliptin and empagliflozin, Sami’s HbA_1c has fallen to 63 mmol/mol (7.9%) – still above his individualised target. What might you try next to improve glycaemic control?

Section 5

In people who have type 2 diabetes without comorbidities, NICE (2026) recommends choosing from a sulfonylurea (e.g. gliclazide), pioglitazone or an insulin-based treatment for further escalation.

Sami is prescribed gliclazide, initially at a dose of 40 mg twice daily and, because he is a driver, offered fingerprick blood glucose monitoring.

What are the pros and cons of using a sulfonylurea?

Section 6

Advantages of sulfonylureas include:

• Effective HbA_1c
• Quick response of elevated blood glucose levels.
• Inexpensive.
• Well tolerated.

Disadvantages include:

• Risk of hypoglycaemia.
• Weight gain.
• No cardiovascular or renal benefits.

The rapid reduction in glucose levels following introduction of a sulfonylurea makes them useful as a “rescue therapy” for high glucose levels (Khunti et al, 2018; Alabraba, 2025). A sulfonylurea may be helpful as a temporary measure at the outset of type 2 diabetes if glucose levels are very high, buying time for other therapies (e.g. metformin, SGLT2 inhibitors) to achieve full effect.

Sulfonylureas are a first-line treatment for steroid-induced hyperglycaemia and certain forms of MODY (maturity-onset diabetes of the young) (Beba et al, 2023).

How about the pros and cons of using pioglitazone in type 2 diabetes?

Section 7

The problems associated with pioglitazone have limited its use in type 2 diabetes, but it does remain an option recommended by NICE (2026).

Advantages:

• Effective HbA_1c reduction, up to 14 mmol/mol (1.3%) (Miller, 2024).
• Low risk of hypoglycaemia.
• Offers protection against cardiovascular events (myocardial infarction and stroke) (Dormandy et al, 2005).
• Safe to use down to an eGFR of 15 mL/min/1.73 m².
• Benefit in MASLD (metabolic dysfunction-associated steatotic liver disease) – reduced progression to liver inflammation and fibrosis (Vilar-Gomez et al, 2016).
• Inexpensive.

Disadvantages:             

• Oedema, weight gain.
• May precipitate heart failure: contraindicated if previous history (Dormandy et al, 2005).
• Possible small increased risk of bladder cancer (Li et al, 2017).
• Increased risk of fracture (Viscoli et al, 2017).

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This ends Sami’s case.

Section 8 – Linda

Linda is a 64-year-old woman with type 2 diabetes who has developed angina. She is taking modified-release metformin and dapagliflozin for her type 2 diabetes and to provide additional cardiovascular protection. Her remaining medication comprises aspirin, bisoprolol, amlodipine, losartan and atorvastatin.

BMI is 28.7 kg/m²; blood pressure 132/65 mmHg; eGFR 64 mL/min/1.73 m²; HbA_1c 62 mmol/mol (7.8%).

What could you offer Linda to improve glycaemic control and provide additional cardiovascular protection?

Section 9

NICE (2026) recommends offering subcutaneous semaglutide up to 1 mg once weekly, which has been demonstrated in a randomised controlled trial to reduce cardiovascular events compared to placebo in people with type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD) (Marso et al, 2016). Indeed, for someone with established ASCVD like Linda, semaglutide may be offered as part of initial triple therapy, alongside metformin and an SGLT2 inhibitor (NICE, 2026).

If subcutaneous semaglutide is poorly tolerated then other evidence-based options include another GLP-1 receptor agonist, such as dulaglutide (Gerstein et al, 2019), or the dual GIP/GLP-1 receptor agonist tirzepatide (Nicholls et al, 2025) (whose cardiovascular outcomes trial results were not available at the time of NICE guideline formulation). If injectable treatment needs to be avoided, oral semaglutide also has robust evidence of cardiovascular protection (McGuire et al, 2025).

What other favourable characteristics would semaglutide offer Linda?

Section 10

Semaglutide can achieve HbA_1c reductions of up to 20 mmol/mol (1.8%) and should help Linda to lose weight (Pratley et al, 2018). Additionally, semaglutide does not intrinsically induce hypoglycaemia, and thus the triple therapy of metformin, SGLT2 inhibitor and semaglutide carries a low risk of hypoglycaemia – so Linda will not require routine capillary blood glucose monitoring.

How would you advise Linda about the side-effects of semaglutide?

Section 11

Linda should be aware:

• Of possible gastrointestinal side-effects: nausea, vomiting, diarrhoea, constipation. Mitigate these by slow upward dose titration.
• To report any severe upper abdominal pain, which could signal biliary problems or acute pancreatitis (Monami et al, 2017; Chiang et al, 2025).
• Of the need for good protein intake and physical exercise, notably resistance exercises (Mechanick et al, 2025), to counter loss of skeletal muscle mass (which occurs alongside loss of fat) (Wilding et al, 2021). See Green (2026) for more information.
• To report any sudden visual deterioration: semaglutide is associated with a small risk of worsening of diabetic retinopathy, notably in in people with pre-existing pre-proliferative or proliferative retinopathy, or maculopathy (Marso et al, 2016). Check Linda’s retinal screening status for these conditions and, if present, discuss with the specialist ophthalmology team prior to any initiation of semaglutide (Bain, 2021). If Linda does not have significant retinopathy (including background retinopathy), use of semaglutide is reasonable.

If Linda still did not reach her individualised HbA_1c target on a combination of metformin, dapagliflozin and semaglutide, what would be your next option for glycaemic management?

Section 12

Further medication that could be offered include a sulfonylurea, pioglitazone or an insulin-based treatment; often a basal insulin is the first and simplest insulin regimen used (NICE, 2026).

Note that use of a DPP-4 inhibitor is not recommended in combination with a GLP-1 or GIP/GLP-1 receptor agonist because it is unlikely to provide additional glucose-lowering due to overlapping mechanisms of action (ADA Professional Practice Committee for Diabetes, 2026).

If Linda finds that she cannot tolerate semaglutide or other incretin mimetics, what are your options to improve glycaemic control?

Section 13

You could try a DPP-4 inhibitor in this situation. Further options include a sulfonylurea, pioglitazone or an insulin-based treatment.

This ends Linda’s case.

Section 14 – Arthur

Arthur is a 49-year-old man with type 2 diabetes, established on modified-release metformin and dapagliflozin. He is living with obesity (BMI 33.7 kg/m²). His HbA_1c is 70 mmol/mol (8.6%).

What would be your next choice of glucose-lowering medication?

Section 15

A GLP-1 or dual GIP/GLP-1 receptor agonist would be useful in reducing both HbA_1c and weight.

Whilst NICE (2026) does not consider incretin mimetics cost-effective for initial therapy in type 2 diabetes, it does recommend a GLP-1 RA or tirzepatide as an add-on to dual therapy with metformin and an SGLT2 inhibitor for individuals living with obesity, provided they have been taking initial therapy for at least 3 months.

This ends Arthur’s case.

Section 16 – Sunila

Sunila is a 73-year-old lady with type 2 diabetes and diabetic kidney disease with albuminuria (urinary ACR 26 mg/mmol). Her eGFR has been steadily falling and now stands at 27 mL/min/1.73 m². Her current medication is modified-release metformin 500 mg twice daily and dapagliflozin 10 mg once daily.

What medication change is now needed?

Section 17

Now her eGFR has fallen below 30 mL/min/1.73 m², Sunila’s metformin needs to be discontinued in order to reduce the risk of lactic acidosis.

What glucose-lowering medication would you consider adding in?

Section 18

A DPP-4 inhibitor would be useful in maintaining Sunila’s glycaemic control, is safe to use at this eGFR level and is recommended by NICE (2026). The combination of an SGLT2 inhibitor plus a DPP-4 inhibitor is in fact recommended by NICE as initial dual therapy for a person with type 2 diabetes and an eGFR <30 mL/min/1.73 m².

A recent double-blind, randomised controlled trial with a composite renal outcome as the primary outcome demonstrated reduced decline in eGFR and improvements in albuminuria for semaglutide versus placebo (Perkovic et al, 2024). However, NICE has judged treatment with a GLP-1 receptor agonist not to be a cost-effective option in people with type 2 diabetes and chronic kidney disease (NICE, 2026). There may, of course, be other comorbidities that would favour an incretin mimetic, and semaglutide might then be prioritised bearing in mind its effectiveness in attenuating the progress of chronic kidney disease.

This ends Sunila’s case. The following section summarises the add-on medications recommended by NICE (2026) according to clinical circumstances.

Section 19

When initial therapy with modified-release metformin and an SGLT2 inhibitor provide insufficient glycaemic control in people with type 2 diabetes, the following table summarises the add-on medications recommended by NICE (2026) according to clinical circumstances.

ASCVD=atherosclerotic cardiovascular disease; eGFR=estimated glomerular filtration rate; GLP-1 RA=glucagon-like peptide-1 receptor agonist.
eGFR in mL/min/1.73 m².