Section 1 – Lisa

Lisa is a 47-year-old lady who has just received a diagnosis of type 2 diabetes. She has no comorbid conditions. There is a family history of type 2 diabetes.

• Blood pressure 145/82 mmHg.
• BMI 28.7 kg/m².
• HbA_1c 58 mmol/mol (7.5%).
• eGFR 87 mL/min/1.73 m².
• LFTs normal.
• Non-HDL cholesterol 3.7 mmol/L.

Possible lifestyle changes that might benefit glucose regulation and cardiovascular risk have been discussed with Lisa, and she has agreed to be referred to the NHS Type 2 Diabetes Path to Remission Programme.

What initial diabetes medication would you recommend for Lisa?

Section 2

For many years the starting point for pharmacological treatment of type 2 diabetes has been metformin. The recently updated NICE NG28 guideline, however, now recommends dual therapy with modified-release (M/R) metformin and an SGLT2 inhibitor from the point of diagnosis of type 2 diabetes in nearly all circumstances, including for people like Lisa who have no accompanying comorbidities (NICE, 2026).

Why do you think modified-release metformin is recommended ahead of standard-release?

Section 3

NICE (2026) indicates that, compared with the standard-release formulation, metformin M/R has:

• Better gastrointestinal tolerance.
• Better adherence.
• Equivalent HbA_1c and weight benefits.
• Similar safety results in terms of hypoglycaemia.
• No increased expense.

However, standard-release metformin is still recommended if the person has swallowing difficulties and needs to crush tablets or use liquid preparations.

What are the reasons for introducing SGLT2 inhibitors alongside metformin as initial glucose-lowering therapy in type 2 diabetes?

Section 4

Benefits provided by SGLT2 inhibitors include:

• Effective improvement in HbA_1c.
• Facilitation of weight loss.
• Low risk of hypoglycaemia.
• Reductions in risk of adverse cardiovascular and renal outcomes.

It is really the increasing evidence of cardiorenal benefits from double-blind, randomised controlled trials that has elevated SGLT2 inhibitors to first-line therapy. Crucially, SGLT2 inhibitors can reduce the risk of:

• Cardiovascular death, non-fatal myocardial infarction and stroke for those with pre-existing cardiovascular disease (angina, myocardial infarction, stroke, transient ischaemic attack or peripheral artery disease), and those at high risk of cardiovascular events. The best evidence is for empagliflozin (Zinman et al, 2015), canagliflozin (Neal et al, 2017) and dapagliflozin (Wiviott et al, 2019).
• Hospitalisation from heart failure: best evidence for dapagliflozin (McMurray et al, 2019; Solomon et al, 2022) and empagliflozin (Packer et al, 2020; Anker et al, 2021).
• Renal complications in those with chronic kidney disease: best evidence for canagliflozin (Perkovic et al, 2019), dapagliflozin (Heerspink et al, 2020) and empagliflozin (Herrington et al, 2023).

NICE strongly emphasises that socioeconomically disadvantaged groups are especially likely to benefit from initial dual therapy with metformin and an SGLT2 inhibitor.

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Lisa is commenced on metformin M/R and dapagliflozin 10 mg once daily.

Are there any reasons to choose dapagliflozin as the preferred SGLT2 inhibitor for Lisa?

Section 5

The dapagliflozin patent is, subject to legal issues, due to expire, allowing generic production and likely cost reduction, making it the most cost-effective option for an SGLT2 inhibitor. As previously stated, there is robust evidence that dapagliflozin provides cardiorenal benefits.

How would you go about introducing Lisa’s metformin M/R and dapagliflozin?

Section 6

The metformin and dapagliflozin should be introduced in a stepwise manner so that adverse events can be accurately identified.

Start with metformin M/R 500 mg once daily, and gradually build the dose, typically at weekly intervals, checking for tolerability. Aim for a dose of 1 g twice daily but be prepared to accept a lower maintenance dose should gastrointestinal side-effects occur.

Once Lisa’s dose of metformin has been stabilised, add the dapagliflozin without further measurement of HbA_1c.

If Lisa was unable to tolerate metformin M/R at any dose, how would you proceed?

Section 7

Offer dapagliflozin as monotherapy. If HbA_1c reduction proves insufficient, further medication for hyperglycaemia can be added at a later date.

What side-effects of SGLT2 inhibitors do you need to be aware of?

Section 8

Here is a short list. Ensure people are adequately counselled.

• Genital fungal infection – common.
• Increased risk of urinary tract infection.
• Volume depletion side-effects (e.g. postural hypotension).
• Diabetic ketoacidosis (DKA) – rare but serious.
• Fournier’s gangrene – rare but serious.

To minimise the risk of DKA, check the following:

• The person is not following a low-carbohydrate or ketogenic diet.
• The person has no previous history of DKA.
• The person is aware to temporarily discontinue their SGLT2 inhibitor in situations of acute illness and dehydration – to avoid both DKA and acute kidney injury.

Modifiable risks of DKA should be addressed before starting the SGLT2 inhibitor.

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This ends Lisa’s case study.

Section 9 – Deepak

Deepak is a 53-year-old man of South Asian ethnicity. He recently suffered a myocardial infarction requiring coronary artery stenting. During his hospital admission, Deepak was found to have hyperglycaemia, later confirmed as type 2 diabetes.

Current medications: Aspirin, clopidogrel, ramipril, bisoprolol, atorvastatin.

Results: HbA_1c 71 mmol/mol (8.6%), eGFR 78 mL/min/1.73 m².

What would you offer Deepak as initial therapy for his type 2 diabetes?

Section 10

Deepak should be commenced on the combination of metformin and an SGLT2 inhibitor in the manner described previously. Both of these treatments offer Deepak secondary prevention against further cardiovascular events (NICE, 2026).

Are there any other diabetes medications that you could offer Deepak for additional cardiovascular protection?

Section 11

The following incretin mimetics have been demonstrated in randomised controlled trials to provide cardiovascular protection for people with type 2 diabetes and pre-existing or high risk of cardiovascular disease:

• GLP-1 receptor agonists (GLP-1 RAs): liraglutide (Marso et al, 2016a), dulaglutide (Gerstein et al, 2019), subcutaneous semaglutide (Marso et al, 2016b) and oral semaglutide (McGuire et al, 2025).
• Dual GIP/GLP-1 RA: tirzepatide (Nicholls et al, 2025).

NICE (2026) has recommended offering subcutaneous semaglutide up to a dose of 1 mg once weekly, alongside metformin and an SGLT2 inhibitor, as initial triple therapy for people with type 2 diabetes and established atherosclerotic cardiovascular disease.

It is important to note that the cardiovascular outcome trial of tirzepatide was not available at the time of the recent guideline review, and so no specific recommendation to use it in atherosclerotic cardiovascular disease has yet been made by NICE.

If subcutaneous semaglutide is being considered, what side-effects should Deepak be made aware of?

Section 12

• Gastrointestinal side-effects: nausea, vomiting, diarrhoea or constipation (Manne-Goehler and Franco, 2025). Advise slow upward dose titration of semaglutide.
• Upper abdominal pain (Monami et al, 2017) – could represent biliary problems due to cholesterol gallstones or acute pancreatitis. Advise to report any severe upper abdominal pain.
• Risk of loss of skeletal muscle mass (Wilding et al, 2021). Encourage adequate protein intake and resistance exercises (see Green, 2026, for more information).
• Risk of sudden worsening of diabetic retinopathy (Bain, 2021). Need to identify people at high risk (see Section 15). If it is possible diabetes may have been present for a prolonged period before diagnosis, it would be preferable to delay semaglutide until the retinal screening result is known.

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When the benefits, risks and side-effects of semaglutide are explained to Deepak, he decides to stick with the dual therapy of metformin and dapagliflozin, as he feels he has very quickly progressed to multiple medications and would like to get used to these, leaving semaglutide as a possible future option.

Under what circumstances might you re-offer Deepak the option of subcutaneous semaglutide?

Section 13

If Deepak’s individualised glycaemic target is not reached on dual therapy with metformin and dapagliflozin (an HbA_1c of 53 mmol/mol would be a reasonable target for Deepak), he could be re-offered semaglutide. In addition to improving glycaemic control, important benefits for Deepak would be cardiovascular protection and weight loss.

If semaglutide were added to Deepak’s regimen, what issues need to be covered?

Section 14

Initiation of semaglutide could take place in primary care, or via referral to the Diabetes Specialist Nurse or Diabetes Specialist Team. Important issues to cover with Deepak include:

• Potential side-effects (see Section 12 previously).
• Retinal screening status (see Section 15).
• Demonstration of the pen injection device.
• Injection site rotation, sharps disposal.
• Advice on dose titration.
• Strategies to maintain muscle mass (see Green, 2026, for more information).
• Sick day rules – temporarily withdraw treatment if dehydration, in order to avoid acute kidney injury.
• Follow-up arrangements and point of contact if problems.

How would retinal screening results direct your decision to start semaglutide?

Section 15

If pre-proliferative retinopathy, proliferative retinopathy or diabetic maculopathy have been identified, discussion with the specialist ophthalmological team is advised if semaglutide (or any other incretin mimetic) is being considered (Bain, 2021; Bain, 2024). Semaglutide is associated with a small risk of sudden deterioration in vision in such cases (Marso et al, 2016b).

It is, however, reasonable to start semaglutide in the situation of background retinopathy.

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This ends Deepak’s case study.

Section 16 – Soma

Soma is a 38-year-old lady of South Asian ethnicity who has just been diagnosed with type 2 diabetes.

There is a strong family history of type 2 diabetes. Autoantibody tests for type 1 diabetes are negative and C-peptide levels (a measure of insulin reserve) are adequate. Early-onset type 2 diabetes (age <40 years) is diagnosed.

• BMI 32.4 kg/m².
• HbA_1c 75 mmol/mol (9.0%).

What is recommended as initial therapy for Soma?

Section 17

Early-onset type 2 diabetes is an aggressive condition which carries a high risk of cardiovascular and renal disease. Early intervention with medications providing cardiorenal protection can reduce the risk of cardiovascular disease and end-stage renal failure.

If following NICE (2026) advice, you could offer metformin M/R and an SGLT2 inhibitor, and also consider starting a GLP-1 RA, such as semaglutide, or the dual GIP/GLP-1 RA tirzepatide alongside these.

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This ends Soma’s case study.

Section 18 – Mark

Mark is a 68-year-old man with known chronic kidney disease (CKD) with albuminuria. He has developed type 2 diabetes.

• Estimated glomerular filtration rate (eGFR) 48 mL/min/1.73 m².
• Urinary albumin:creatinine ratio (uACR) 23 mg/mmol.
• HbA_1c 57 mmol/mol (7.4%).

Current medications: losartan, atorvastatin, amlodipine.

What would be your initial glucose-lowering therapy for Mark?

Section 19

Again, start with metformin M/R and an SGLT2 inhibitor (NICE, 2026). The strongest evidence for renoprotection lies with canagliflozin (Perkovic et al, 2019), dapagliflozin (Heerspink et al, 2020) and empagliflozin (Herrington et al, 2023).

How might you adjust the dose of metformin in the face of falling eGFR?

Section 20

• If eGFR is <45 mL/min/1.73 m², consider reducing the dose of metformin from 1 g twice daily.
• If eGFR is <30 mL/min/1.73 m², discontinue metformin altogether to reduce the risk of lactic acidosis (NICE, 2026).
• If eGFR is <30 mL/min/1.73 m² at the outset, avoid metformin. In this situation, a DPP-4 inhibitor (e.g. linagliptin) may be added to an SGLT2 inhibitor as initial dual therapy (NICE, 2026).

Are GLP-1 RAs useful in CKD?

Section 21

There is consistent evidence from the cardiovascular outcome trials that GLP-1 RAs are useful in managing CKD in type 2 diabetes, predominantly by reducing albuminuria. More recently, a double-blind, randomised controlled trial with a composite renal outcome as the primary outcome demonstrated reduced decline in eGFR and improvements in albuminuria with semaglutide versus placebo (Perkovic et al, 2024).

Despite the above findings, NICE has judged that initial treatment with GLP-1 RA therapy in people with type 2 diabetes and CKD is not a cost-effective option (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 CKD.

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This ends Mark’s case study. For a summary of NICE recommendations for initial therapy for type 2 diabetes depending on clinical circumstances, see Section 22. A quick summary of the updated NG28 guidance is available in this journal (Brown and Diggle, 2026).

Section 22

A summary of NICE recommendations for initial therapy for type 2 diabetes depending on clinical circumstances is summarised in the table below.

Table. Initial therapy for people with type 2 diabetes recommended in NICE NG28.

eGFR in mL/min/1.73 m².