Section 1: Susan

Susan is a 46-year-old nurse diagnosed with type 2 diabetes three years ago. Achieving satisfactory glycaemic control is proving to be challenging. She attends the primary care diabetes clinic.

Current medication: Metformin 1 g twice daily, empagliflozin 25 mg once daily, gliclazide 160 mg twice daily, atorvastatin 20 mg once daily, ramipril 10 mg once daily.

Diabetes complications: Hypertension, dyslipidaemia.

Social history: Married, two children. Non-smoker, alcohol <10 units/week.

Results: HbA_1c 74 mmol/mol (8.9%); eGFR 75 mL/min/1.73 m²; uACR <3 mg/mmol; non-HDL cholesterol 2.7 mmol/L; LFTs satisfactory.

Clinic measurements: Blood pressure 136/85 mmHg; BMI 36.7 kg/m².

What target HbA_1c would you advise Susan to aim for?

Section 2

Susan is a relatively young person with type 2 diabetes and at an early stage in her diabetes trajectory, so we should be aiming for tight glucose control to reduce the risk of future diabetes complications. As she is on multiple diabetes medications, including a sulfonylurea which increases her risk of hypoglycaemia, an HbA_1c of 53 mmol/mol (7.0%) would seem a reasonable glycaemic target (NICE, 2022).

Despite triple oral antidiabetes therapy, Susan remains well above her target HbA_1c.

What might you offer to discuss first with Susan to help improve her HbA_1c?

Section 3

Lifestyle issues are central to management of type 2 diabetes, so offer to discuss these with Susan. Diet, exercise and weight loss are all important areas to cover and, if appropriate, Susan could be referred for lifestyle management, including the NHS Type 2 Diabetes Path to Remission Programme (Bakhai, 2023). As she has diabetes and a BMI >30 kg/m², she could alternatively be signposted to the NHS Digital Weight Management Programme, a 12-week online behavioural and lifestyle programme available via smartphone or computer, accessible via GP or community pharmacist referral.

Remember that any goals set should be agreed with Susan and, importantly, be achievable and sustainable.

It is also important to check that Susan is tolerating her diabetes medications and taking them correctly.

What further pharmacological options might you consider for managing Susan’s glucose control?

Section 4

Beyond Susan’s current triple oral therapy for hyperglycaemia, there would be the option of adding in pioglitazone. This, however, would be likely to lead to further weight gain and would be unlikely to achieve the necessary improvement in HbA_1c. Further concerns with pioglitazone include an increased risk of heart failure, a possible increased risk of bladder cancer and an association with osteoporosis (Miller, 2024).

Injectable therapy for diabetes should be considered. The choice lies between an incretin-based agent – a GLP-1 receptor agonist or a GIP/GLP-1 receptor agonist – or insulin.

What are the advantages of choosing an incretin-based agent over insulin for Susan?

Section 5

There is strong evidence that incretin-based agents are at least as effective as the addition of a basal insulin in reducing HbA_1c (Singh et al, 2017), and indeed, the newer agents semaglutide and tirzepatide outperform basal insulin in this regard (Aroda et al, 2017; Del Prato et al, 2021).

The incretin-based agents facilitate weight loss and carry a low risk of hypoglycaemia, whereas insulin is associated with weight gain and carries a high risk of hypoglycaemia. Some incretin agents (tirzepatide, semaglutide, dulaglutide and exenatide once weekly) are available as once-weekly injections, rather than the daily injections required for insulin, and they avoid the intensive glucose monitoring requirements of insulin.

GLP-1 and GIP/GLP-1 receptor agonists should, therefore, be considered as the first-choice injectable agent in type 2 diabetes, unless there are contraindications or there is evidence supporting a state of insulin deficiency (e.g. the person has low/normal BMI, osmotic symptoms or a personal/family history of autoimmune disease, or if HbA_1c is very high: >97 mmol/mol) (ADA Professional Practice Committee, 2025a).

Which incretin-based agent would you choose for Susan, and why?

Section 6

The evidence indicates that semaglutide is the most powerful glucose-lowering GLP-1 receptor agonist, ahead of liraglutide and dulaglutide, followed by exenatide once weekly and then exenatide twice daily and lixisenatide (Htike et al, 2017; Nauck and Meier, 2021). Semaglutide is also the most powerful GLP-1 receptor agonist in facilitating weight loss (Andreadis et al, 2018).

Tirzepatide is the first dual GIP/GLP-1 receptor agonist to be licensed for the treatment of type 2 diabetes and is available as a once-weekly subcutaneous injection (Bain, 2024). Tirzepatide has been demonstrated to provide greater improvements in both glycaemic control and weight loss than semaglutide in a head-to-head trial (Frías et al, 2021).

Susan is referred to the Diabetes Specialist Nurse team with a view to commencing tirzepatide. She is advised to continue her metformin and dapagliflozin treatment but to reduce her gliclazide dose to 80 mg twice daily, to reduce the risk of hypoglycaemia and to help with weight loss. Susan is also advised to carefully monitor her blood glucose readings.

Who SHOULD NOT receive a GLP-1 or a GIP/GLP-1 receptor agonist?

Section 7

Reasons to avoid incretin-based agents include:

• Type 1 diabetes.
• Pregnant and breastfeeding women (check for adequate contraception in women of child-bearing age), and women who are trying to conceive.
• Severe gastrointestinal disease (e.g. inflammatory bowel disease).
• Diabetic gastroparesis.
• History of pancreatic cancer, medullary thyroid cancer or multiple endocrine neoplasia (MEN) type 2.
• Caution if high risk of pancreatitis (e.g. gallstones, alcohol excess, hypertriglyceridaemia).
• Caution if gastro-oesophageal reflux disease or irritable bowel syndrome.
• Caution if advanced retinopathy, especially if there is poor glycaemic control and/or the person is taking insulin. It is important to ensure that people are up to date with retinal screening.

The evidence is, in fact, reassuring over the risks of pancreatitis and pancreatic cancer with use of GLP-1 receptor agonists; however, a significant increased risk of cholelithiasis with gallbladder and biliary diseases has been identified, notably associated with higher doses and longer duration of use (Monami et al, 2017; Storgaard et al, 2017; He et al, 2022).

Following the finding of a significant increase in adverse retinal outcomes in the cardiovascular outcomes trial of (once-weekly injectable) semaglutide (Marso et al, 2016a), caution should be exercised over the use of GLP-1 and GIP/GLP-1 receptor agonists (both injectable and oral) in people with pre-proliferative or proliferative retinopathy, or maculopathy. Discussion with the specialist ophthalmology team is advised prior to initiation of incretin-based treatment (Bain, 2021; Bain, 2024; Brown, 2025a).

For people without significant retinopathy (including those with background retinopathy), use of a GLP-1 or GIP/GLP-1 receptor agonist is reasonable, including in those with poor glycaemic control or using insulin.

What side-effects from tirzepatide should Susan be warned about?

Section 8

Susan should be warned about gastro-intestinal symptoms – nausea, vomiting and diarrhoea – which are the most prominent side-effects with incretin-based agents (Bettge et al, 2017). These problems, which are dose-dependent, can be mitigated by gradual dose uptitration and by keeping portion sizes small.

Advise Susan that, in the situation of dehydration (e.g. diarrhoea and vomiting), she should maintain a good fluid intake to reduce the risk of acute kidney injury, and in severe episodes she should temporarily pause her tirzepatide.

Encourage Susan to maintain a good protein intake and to undertake physical exercise, notably resistance exercise, to maintain muscle mass. Weight loss induced by incretin-based agents is not exclusively fat; up to 40% of the weight lost can comprise lean mass (Brown, 2025b).

How would you explain to Susan how tirzepatide works?

Section 9

It may be helpful for Susan to know that tirzepatide mimics two natural hormones produced in the body, GIP and GLP-1, which act to lower blood glucose levels by:

• Stimulating insulin release (from pancreatic beta-cells).
• Inhibiting glucagon release (from pancreatic alpha-cells).
• Slowing gastric emptying.

A further action of tirzepatide is to induce satiety, reducing appetite and calorie intake, thus facilitating weight loss.

It is worth advising Susan that the greatest weight loss occurs in the first few months and subsequently tapers off. This tapering is expected and does not indicate treatment failure. Setting this expectation helps improve adherence and supports the need to sustain lifestyle changes.

What important educational points about using an injectable GLP-1 or GIP/GLP-1 receptor agonist need to be covered at initiation?

Section 10

Education on the use of GLP-1 and GIP/GLP-1 receptor agonists should be provided at initiation, including:

• Potential side-effects.
• Demonstration of the device – drawing up and injecting the GLP-1 receptor agonist.
• Injection site rotation, needle changes and disposal.
• Advice on dose titration.
• Blood glucose monitoring (if appropriate).
• Sick day rules.

A general principle of using incretin-based agents is to initiate at a low dose and gradually uptitrate the dose, monitoring for side-effects and for desired response.

Apart from pharmacological interventions, does Susan have any other treatment options?

Section 11

Bariatric surgery would be an option for Susan. Referral can be expedited for people with type 2 diabetes and BMI >30 kg/m²; Susan would need to be referred to a Tier 3 weight management service for assessment and support (NICE, 2025).

Susan is, however, keen to try an injectable treatment at this stage.

This ends Susan’s case study.

Section 12: Ravi

Ravi is a 55-year-old man of Indian ethnicity with type 2 diabetes of 7 years’ duration. He is reviewed in the GP diabetes clinic.

Current medication: Metformin 1 g twice daily, dapagliflozin 10 mg once daily, linagliptin 10 mg once daily, atorvastatin 20 mg once daily, ezetimibe 10 mg once daily, losartan 50 mg once daily.

Social history: Married, three children. Taxi driver. Non-smoker, no alcohol consumption.

Diabetes complications: Hypertension, dyslipidaemia, background retinopathy, diabetic nephropathy.

Results: HbA_1c 64 mmol/mol (8.0%); eGFR 58 mL/min/1.73 m²; uACR 38 mg/mmol; non-HDL cholesterol 2.4 mmol/L.

Clinic measurements: Blood pressure 146/70 mmHg; BMI 29.5 kg/m²; waist-to-height ratio 0.58.

What clinical problems related to diabetes does Ravi have that need attention?

Section 13

Ravi’s problem list includes:

• Elevated HbA_1c.
• Raised blood pressure.
• Diabetic kidney disease (DKD) – reduced eGFR and raised urinary ACR (KDIGO classification G3aA2).
• Raised waist:height ratio, indicating central adiposity – a measure of visceral fat (NICE, 2025).

The diagnosis of DKD places Ravi at high risk of cardiovascular events (no need to use QRISK score) and progression to end-stage renal failure. What medication do we already have in place for Ravi to counter this risk?

Section 14

ACE inhibitors/angiotensin receptor blockers and SGLT2 inhibitors offer cardiorenal protection in albuminuric DKD (see previous interactive case study; Morris, 2025). Thus, losartan and dapagliflozin are key medications for Ravi. Metformin also offers a degree of cardioprotection.

Ravi’s lipid profile is well controlled on atorvastatin and ezetimibe.

What would be your HbA_1c and blood pressure targets for Ravi?

Section 15

An HbA_1c target of 53 mmol/mol (7.0%) would be appropriate given Ravi’s age, duration of diabetes, and medical and social histories (NICE, 2022).

His systolic blood pressure target should be <140 mmHg according to NICE NG203 and NG136 guidelines (NICE, 2021; NICE, 2023), with <130 mmHg advised by the American Diabetes Association (ADA Professional Practice Committee, 2025b). For home and ambulatory recordings, blood pressure targets are 5 mmHg lower than those in the clinic.

What would you do next to improve Ravi’s glycaemic control?

Section 16

We would ideally lower glucose levels with a medication that does not induce hypoglycaemia, given that Ravi drives for a living. It would also be very desirable to choose an agent that offers further cardiorenal protection. A weight-losing treatment would be preferable to address visceral fat, a key determinant of insulin resistance (NICE, 2025).

Incretin-based agents can provide all of these benefits.

What incretin-based agent would you choose, and why?

Section 17

Cardiovascular outcome trials of liraglutide, dulaglutide and semaglutide have all demonstrated improved cardiovascular outcomes compared to placebo in people with type 2 diabetes with established atherosclerotic cardiovascular disease or with risk factors for this, including DKD (Marso et al, 2016a; Marso et al, 2016b; Gerstein et al, 2019).

The recent FLOW trial in people with type 2 diabetes and chronic kidney disease – the first randomised controlled trial with a dedicated renal outcome for a GLP-1 receptor agonist – demonstrated that semaglutide improved the primary composite renal outcome and reduced cardiovascular events compared with placebo (Perkovic et al, 2024). Improvements in both uACR and rate of eGFR decline were identified. Secondary outcomes also favouring semaglutide included reductions in cardiovascular events and all-cause mortality versus placebo.

Whilst tirzepatide brings even greater responses than semaglutide in terms of glucose and weight lowering, we currently await results of the tirzepatide cardiovascular outcomes trial and, as yet, have renal outcomes only as a secondary measure in trials. Thus, semaglutide is the incretin-based agent with the strongest evidence of cardiorenal benefit.

Ravi is commenced on once-weekly semaglutide injections to improve glycaemic control, strengthen cardiorenal protection and induce weight loss whilst minimising risk of hypoglycaemia. His linagliptin is stopped on initiation of the semaglutide, as this is not considered to provide additional benefit in the presence of a GLP-1 receptor agonist. Metformin and dapagliflozin are continued.

What other medication changes could you make to address Ravi’s hypertension and to optimise cardiorenal protection?

Section 18

With the presence of albuminuria, Ravi’s losartan should be titrated up to maximum dose, to optimise cardiorenal protection and to reduce blood pressure. If systolic blood pressure remains above 140 mmHg, a further antihypertensive agent should be added.

Ravi’s losartan dose is increased to 100 mg once daily. The dose is well tolerated and repeat electrolytes and renal function are satisfactory. His systolic blood pressure is now below 140 mmHg.

This ends Ravi’s case study.

Section 19: Simon

Simon is a 67-year-old man who has had type 2 diabetes for 10 years.

Current medication: Metformin 1 g twice daily, gliclazide 160 mg twice daily, dapagliflozin 10 mg once daily, aspirin 75 mg once daily, atorvastatin 80 mg once daily, ramipril 10 mg once daily, bisoprolol 5 mg once daily, amlodipine 5 mg once daily, nitrolingual spray.

Diabetes complications: Hypertension, dyslipidaemia, angina, previous myocardial infarction, background retinopathy.

Social history: Retired, lives with partner. Ex-smoker. Severe needle phobia.

Results: HbA_1c 68 mmol/mol (8.4%); eGFR 52 mL/min/1.73 m²; uACR 8 mg/mmol; non-HDL cholesterol 2.4 mmol/L, LFTs normal.

Clinic measurements: Blood pressure 131/66 mmHg; BMI 33.7 kg/m²; waist-to-height ratio 0.65.

With his cardiovascular history in mind, how might you go about improving Simon’s glycaemic control?

Section 20

A GLP-1 receptor agonist with proven efficacy in reducing cardiovascular events would be a good choice to improve glycaemic control. Additional benefits for Simon would include weight loss and renoprotection.

What GLP-1 receptor agonist would you choose for Simon?

Section 21

Given Simon’s needle phobia, we could consider oral semaglutide, an effective agent for reducing HbA_1c and facilitating weight loss. Oral semaglutide is co-formulated with an absorption enhancer, which facilitates entry of semaglutide into the circulation with a bioavailability of 1% (Buckley et al, 2018). Stringent administration conditions are required (see next section).

The recently reported SOUL study examined cardiovascular outcomes with use of oral semaglutide in people with type 2 diabetes at high cardiovascular risk – including atherosclerotic cardiovascular disease, chronic kidney disease or both. A reduction in cardiovascular events was observed with oral semaglutide versus placebo, driven largely by a lower incidence of non-fatal myocardial infarction (McGuire et al, 2025).

How would you advise Simon to take oral semaglutide?

Section 22

Simon should take oral semaglutide first thing in the morning with a sip of water, after which he should wait at least 30 minutes before eating or drinking or taking any other medication. If there are any other medications due to be taken after an overnight fast (e.g. bisphosphonate, levothyroxine), they will need to be rescheduled.

Simon is prescribed oral semaglutide 3 mg once daily, with a view to increasing the dose to 7 mg after one month. To reduce the risk of hypoglycaemia, his gliclazide is discontinued.

This ends Simon’s case study.

Can you try to summarise circumstances where consideration of incretin-based agents could be prioritised in type 2 diabetes?

Section 23

Situations in which consideration of incretin mimetics could be prioritised for use in people with type 2 diabetes are summarised in the Table below (NICE, 2022; ADA Professional Practice Committee, 2025a). The ADA recommends that GLP-1 and GIP/GLP-1 receptor agonists could, under these circumstances, be considered as a second- or third-line agent after metformin. Choice of treatment should, as always, be individualised and take account of patient choice.