Section 1 – Raoul

Raoul is a 49-year-old gentleman of Asian ethnic origin recently diagnosed with type 2 diabetes. He has been seen by one of the Practice Diabetes Nurses and received lifestyle advice along with supportive literature, a link to the Diabetes UK website and referral to a local education course for type 2 diabetes. He has also been referred for eye and foot screening.

At diagnosis, Raoul’s HbA_1c was 73 mmol/mol (8.8%; mean of two measurements). Other findings were:

• eGFR 78 mL/min/1.73 m².
• Normal LFTs and TFTs.
• Total cholesterol 5.7 mmol/L, non-HDL 4.6 mmol/L.
• BMI 27.6 kg/m².
• Blood pressure 138/87 mmHg.

Raoul runs a small IT business and he drives on a daily basis. He is married with three children.

What HbA_1c target would you aim for with Raoul? Would you suggest he start on pharmacological treatment for his diabetes straight away?

Section 2

Raoul is relatively young, without comorbidities, and is at the beginning of his diabetes trajectory, where good glycaemic control provides lasting benefits. An HbA_1c target of 48 mmol/mol (6.5%) is suitable for Raoul (NICE, 2022).

A higher HbA_1c target may be more appropriate in an older person with frailty, longer duration of diabetes, comorbidities and/or limited life expectancy, or in someone using medication that could induce hypoglycaemia.

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Raoul’s HbA_1c level is well above target. He is offered pharmacological treatment immediately, alongside lifestyle measures.

What would be your initial recommendation for therapy for Raoul’s hyperglycaemia, and why?

Section 3

Metformin remains the first-line pharmacological treatment for type 2 diabetes in guidelines across the world, although this may change in the future as evidence emerges on newer treatments and their benefits in certain situations. It is an appropriate choice for Raoul.

In addition to effective HbA_1c lowering, further pragmatic benefits of using metformin include a low risk of hypoglycaemia (thus avoiding the need for capillary glucose monitoring), weight neutrality or possibly small weight loss, and low cost.

Importantly, in the UK Prospective Diabetes Study (UKPDS), metformin was seen to reduce the risk of myocardial infarction and all-cause mortality (UKPDS Group, 1998), a benefit which was maintained at 10-year follow-up (Holman et al, 2008). However, the study size was not large, and other studies and meta-analyses have been inconclusive as to whether metformin reduces cardiovascular disease (CVD) risk in people with type 2 diabetes (Griffin et al, 2017).

How does metformin work and what HbA_1c reduction might you expect?

Section 4

Mechanistically, metformin appears to reduce glucose production and release from the liver, and to improve tissue sensitivity to insulin, allowing increased peripheral glucose uptake. It typically lowers HbA_1c by 11–16 mmol/mol (1.0–1.5%) in type 2 diabetes, improving both fasting and postprandial plasma glucose levels.

How would you advise Raoul to start metformin and what side-effects would you warn him about?

Section 5

A typical regimen for starting standard-release metformin is 500 mg once daily with breakfast, increasing to 500 mg twice daily (at breakfast and the evening meal) after a week, and continuing upward dose titration on a weekly basis, aiming for 1 g twice daily (BNF, 2025). This strategy aims to minimise the gastrointestinal problems (abdominal pain, nausea and diarrhoea) that are common side-effects with metformin (Sanchez-Rangel and Inzucchi, 2017).

How would you approach the use of metformin in someone with chronic kidney disease? In what clinical situations should metformin be withdrawn?

Section 6

Caution is advised when using metformin at eGFR <45 mL/min/1.73 m² and avoidance if eGFR is <30 mL/min/1.73 m² (Inzucchi et al, 2014), in order to reduce the risk of lactic acidosis. It is the author’s practice to reduce the dose of metformin to 500 mg twice daily when eGFR falls below 40 mL/min/1.73 m² and to stop altogether by eGFR of 30 mL/min/1.73 m².

Metformin should also be paused or withdrawn in other situations that predispose to lactic acidosis, including dehydration, sepsis, hepatic impairment and myocardial infarction.

A Cochrane systematic review found the risk of lactic acidosis when using metformin to be very small; however, risk is increased in the situation of acute kidney injury, and it is important in this setting to (temporarily) discontinue the metformin (Salpeter et al, 2010).

There is an association between use of metformin and vitamin B12 deficiency (Aroda et al, 2016), and whilst routine screening for this is not recommended, it would be wise to check vitamin B12 levels in those with anaemia or peripheral neuropathy.

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Raoul starts to build the dose of metformin but, at a dose of 500 mg twice daily, experiences persistent abdominal discomfort and loose stools. He is, therefore, reluctant to continue increasing the dose.

How would you manage Raoul’s problem?

Section 7

To circumvent gastrointestinal problems, Raoul could try a modified-release preparation of metformin, starting with just 500 mg once daily and titrating the dose up gradually over several weeks, again aiming for a total daily dose of 2 g, commonly administered as 1 g twice daily (NICE, 2022). Even if maximum dose is not achieved, a lower dose of metformin is worthwhile. Around 5% of people cannot tolerate metformin even at a low dose (Inzucchi et al, 2017).

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Taking modified-release metformin, Raoul manages to reach 500 mg twice daily, but beyond this his gastrointestinal symptoms return. He manages to lose around 5 lbs in weight over the next 4 months, largely through attention to his diet. A repeat HbA_1c comes back at 61 mmol/mol (7.7%), along with a much improved lipid profile on atorvastatin 20 mg once daily (Raoul’s 10-year QRISK score being >10%).

The need to improve glycaemic control further is explained to Raoul.

What pharmacological treatments might you consider next? Which would you recommend in Raoul’s case, and why?

Section 8

Second-line agents to add to metformin that you could consider are sulfonylureas, DPP-4 inhibitors, pioglitazone and SGLT2 inhibitors (NICE, 2022). If Raoul had been unable to tolerate metformin at all, then any of these treatments would have been options for monotherapy.

Raoul has no specific comorbidities to direct treatment choice. However, weight loss and avoidance of hypoglycaemia are important considerations given his BMI and need to drive. These factors should direct the choice of treatment.

An SGLT2 inhibitor (canagliflozin, dapagliflozin, empagliflozin or ertugliflozin) would be a good choice for Raoul, offering the possibility of an HbA_1c reduction of around 11 mmol/mol (1.0%) and a weight reduction typically of 3–4 kg.

Hypoglycaemia is really only an issue when SGLT2 inhibitors are taken concurrently with sulfonylureas, meglitinides or insulin. Under such circumstances, consideration should be given to reducing the dose of the latter agents when commencing an SGLT2 inhibitor.

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Raoul is prescribed dapagliflozin 10 mg once daily alongside his metformin.

What side-effects of SGLT2 inhibitors might you warn Raoul about?

Section 9

Warn Raoul about the common side-effect of fungal genital infection and, to a lesser extent, an increased risk of urinary tract infection. Increased micturition may be noticed, due to the glycosuric effect of SGLT2 inhibitors. Raoul can be made aware of the symptoms of Fournier’s gangrene (necrotising fasciitis of the perineum): a very rare but serious condition that, if suspected, requires immediate medical review (Morris, 2022).

Raoul should be alerted to the need to temporarily stop his dapagliflozin in situations of hypovolaemia (e.g. diarrhoea and vomiting) or significant acute illness. Under these circumstances, there is a risk of acute kidney injury and of progression to diabetic ketoacidosis (DKA). It is important to note that DKA associated with SGLT2 inhibitor use can occur at relatively low plasma glucose levels (<15 mmol/L) – so-called “euglycaemic DKA”. The key test, if this is suspected, is blood ketones (Rosenstock and Ferrannini, 2015).

It should be noted that canagliflozin has been associated with an increased risk of lower limb amputation and increased fracture risk (Neal et al, 2017). Whilst this association has not been demonstrated with other class members, Raoul should report any new foot ulceration, and consideration should be given to stopping the SGLT2 inhibitor in this event.

What other benefits can SGLT2 inhibitors offer?

Section 10

In addition to the benefits of weight loss and a low risk of hypoglycaemia, SGLT2 inhibitors can bring a small reduction in blood pressure (around 5/3 mmHg) (Morris, 2023). For people with type 2 diabetes, there is strong evidence that SGLT2 inhibitors are effective in the secondary prevention of cardiovascular events, and additionally they can prevent cardiovascular events in people at high risk of CVD (Zinman et al, 2015; Neal et al, 2017; Wiviott et al, 2019).

There is evidence that SGLT2 inhibitors can provide renoprotection (stabilisation of eGFR and slowed progression of albuminuria) and cardioprotection for those with chronic kidney disease (CKD), whether or not diabetes is present (Perkovic et al, 2019; Heerspink et al, 2020; Herrington et al, 2023). Certain SGLT2 inhibitors are also recommended for the treatment of heart failure with or without reduced ejection fraction, again whether or not diabetes is present (Pop-Busui et al, 2022).

The indications (for CKD, heart failure and CVD protection) vary between SGLT2 inhibitors, as do their licences in respect of the eGFR ranges in which they can be used. Thus, it is important to consult the BNF or the Summaries of Product Characteristics of the individual drugs concerned. For a quick guide to the licensed indications, see Brown (2023).

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This ends Raoul’s case study.

Section 11 – Andrew

Andrew attends diabetes clinic having had a repeat HbA_1c level in the diabetic range (55 mol/mol [7.2%]). He was first noted to have raised glucose levels in hospital following a myocardial infarction 2 months previously, from which he has made a good recovery. Andrew has no symptoms of diabetes.

His current medication consists of aspirin 75 mg once daily, clopidogrel 75 mg once daily, atorvastatin 80 mg once daily, ramipril 5 mg once daily and bisoprolol 5 mg once daily. Blood pressure and lipids are satisfactorily controlled.

How would you manage Andrew’s glycaemic medication from this position?

Section 12

The cardiovascular benefits of metformin and SGLT2 inhibitors have already been referred to. With a history of myocardial infarction, Andrew stands to benefit from both of these therapies.

NICE (2022) recommends, as the first line, dual therapy with metformin and an SGLT2 inhibitor with proven cardiovascular benefit in people with type 2 diabetes who have established atherosclerotic CVD (myocardial infarction, angina, ischaemic stroke/transient ischaemic attack or peripheral vascular disease). Should any of these situations arise de novo in a person with existing type 2 diabetes, an SGLT2 inhibitor should be added or switched in for another treatment.

NICE also recommends consideration of this dual first-line therapy for people diagnosed with type 2 diabetes who are at high risk of CVD, as judged by a QRISK score >10% in people over the age of 40 years. If this level of cardiovascular risk develops in a person with existing type 2 diabetes then an SGLT2 inhibitor can be offered.

How would you introduce the metformin and SGLT2 inhibitor for Andrew?

Section 13

Start with metformin at low dose and titrate upwards, as previously discussed, whilst monitoring for gastrointestinal side-effects. Once the metformin dose is established, the SGLT2 inhibitor can be added (without repeating an HbA1c measurement) (NICE, 2022).

Andrew is commenced on metformin and, after a month, when he is established on a dose of 1 g twice daily, empagliflozin 10 mg once daily is added to his regimen.

This ends Andrew’s case study.

Section 14 – Janice

Janice, 57 years old and newly diagnosed with type 2 diabetes, has capillary glucose readings between 15 and 20 mmol/L and reports thirst and increased micturition, although not weight loss. She has a strong family history of type 2 diabetes.

• BMI 32.7 kg/m²
• HbA_1c 87 mmol/mol (10.1%).
• eGFR 82 mL/min/1.73 m² .

How could you quickly improve Janice’s symptoms and glucose control?

Section 15

The diagnosis of type 2 diabetes seems to be clear. Emphasise to Janice the need to keep sugary foods out of her diet and to avoid excessive amounts of longer-acting carbohydrate. You could try a sulfonylurea, which would have the advantage of rapidly reducing glucose levels. Insulin would be an alternative “rescue therapy” but is more complex to initiate (NICE, 2022; Alabraba, 2024).

Janice is commenced on gliclazide 40 mg twice daily and simultaneously started on metformin 500 mg once daily, with instructions to increase the dose of the metformin by 500 mg increments every week. She is provided with glucose monitoring equipment, warned about the possibility of hypoglycaemia and how to correct this should it occur, and advised on precautions around driving.

After a week of treatment, Janice’s capillary glucose readings have fallen to the range 9–16 mmol/L and her symptoms of thirst and polyuria have resolved.

Do you have any concerns about persisting with sulfonylurea treatment for Janice?

Section 16

The risk of hypoglycaemia with a sulfonylurea is relatively high compared with metformin and is particularly concerning because Janice is a driver. Sulfonylureas are associated with weight gain, which would be very unwelcome for Janice. A longer-term disadvantage is that the effectiveness of sulfonylureas tends to fall with time as beta-cell activity declines (these agents operate by stimulating insulin release from pancreatic beta-cells) (Davies et al, 2018).

What would be your future plans for controlling Janice’s hyperglycaemia?

Section 17

Once the metformin dose has been titrated up, consideration could be given to discontinuing gliclazide and, if necessary, replacing this with an alternative agent that does not induce hypoglycaemia or weight gain.

This ends Janice’s case study.

Section 18 – Tom

Tom is a 76-year-old man with longstanding type 2 diabetes who lives alone. Glycaemic control had been reasonably well controlled on metformin 1 g twice daily until recently, but HbA_1c measurements over the last 12 months have drifted steadily upward, such that his last result was 64 mmol/mol (8.0%).

• eGFR 52 mL/min/1.73 m².
• Urinary ACR 1.8 mg/mmol.
• LFTs normal.
• Cholesterol 3.4 mmol/L.
• BMI 27.2 kg/m².
• Blood pressure 144/63 mmHg.

Tom’s other medications are lisinopril 10 mg once daily and atorvastatin 20 mg once daily.

Tom is known to have background retinopathy. His general health is good and he remains physically active.

What target HbA_1c would you consider appropriate for Tom?

Section 19

It is important to have a clear idea of the HbA_1c target for Tom. He is healthy and functionally independent, and potentially with a long life expectancy. It is, therefore, reasonable to aim for an HbA_1c in the range of 53–58 mmol/mol (7.0–7.5%), with the caveat that he avoids medication that carries a high risk of hypoglycaemia (Hambling, 2020).

If Tom had frailty, comorbidities and/or limited life expectancy, it would be appropriate to relax the HbA_1c target.

How would you manage Tom’s hyperglycaemia?

Section 20

In considering add-on therapy to metformin for Tom’s type 2 diabetes, the avoidance of hypoglycaemia is of paramount importance (due to, for example, reduced awareness of hypoglycaemia in the elderly, reduced counter-regulatory hormonal response to hypoglycaemia, consequences of falls and social isolation), so sulfonylureas and meglitinides should be avoided.

SGLT2 inhibitors are an option with a low risk of hypoglycaemia, although their effectiveness in glycaemic lowering does decline in parallel with reduced renal function. However, there are potentially troublesome side-effects (see previously) and, in the absence of cardiovascular problems and albuminuria, they are not a compelling choice for Tom.

Pioglitazone is effective in lowering HbA_1c, carries a low risk of hypoglycaemia, can be used in chronic kidney disease (CKD) and can offer protection against cardiovascular events. However, it is associated with fluid retention and heart failure, especially in the elderly (Dormandy et al, 2005). It is, therefore, not the ideal treatment for Tom.

Bearing in mind the above points and taking on board the presence of CKD (G3aA1), Tom was prescribed linagliptin as add-on therapy to his metformin.

What are the advantages of using a DPP-4 inhibitor in Tom’s situation?

Section 21

Whilst the DPP-4 inhibitors are not powerful glucose-lowering agents (typical HbA_1c reductions of 5–11 mmol/mol [0.5–1.0%]), they do carry the advantages of once-daily oral administration, minimal side-effects, weight neutrality and a low tendency to cause hypoglycaemia (Davies et al, 2018; Buse et al, 2020). They can be used in all stages of renal failure with dose adjustment (no dose change required for linagliptin, which is not renally excreted to any significant degree). See Beba and Baig (2024) for more information.

Cardiovascular outcome trials on the gliptins have mostly demonstrated cardiovascular safety but no benefit, whilst raising concerns over risk of heart failure with saxagliptin and, to a lesser extent, alogliptin (Davies et al, 2018, Buse et al, 2020).

While these trials did not find an association between DPP-4 inhibitor use and pancreatitis, it is probably prudent to avoid these treatments in individuals with a history of pancreatitis.

Section 22 – Building therapy after metformin

Both NICE and ADA guidelines stress the importance of assessing individual factors and the person’s preference when deciding the choice of add-on therapy to metformin to improve glycaemic control (NICE, 2022; ADA Professional Practice Committee, 2025). NICE recommends sulfonylureas, pioglitazone, DPP-4 inhibitors and SGLT2 inhibitors as possible second-line therapies after metformin, while the ADA recommends these treatments and also GLP-1 receptor agonists, GIP/GLP-1 receptor agonists and insulin as options, depending on circumstances. Triple therapy is beyond the scope of this case study but, essentially, involves any two of the above options added to metformin.

Box 1 summarises the factors to consider when choosing add-on treatment to metformin.