Section 1 – Kapil

Kapil, a 47-year-old male of Asian ethnicity, experienced sudden-onset chest pain and was admitted to hospital as an emergency, where a diagnosis of myocardial infarction (MI) was confirmed. During the course of investigations, he was found to have a random blood glucose level of 12.7 mmol/L and an HbA_1c of 61 mmol/mol (7.7%).

Kapil makes a good recovery and, following return home, he arranges an appointment at his GP practice for review.

What do you need to find out at this appointment?

Section 2

• Does Kapil have any ongoing cardiovascular symptoms?
• Are there any abnormalities on cardiovascular examination?
• Is Kapil managing to take his medications satisfactorily or are there any troublesome side-effects?
• Are there any modifiable cardiovascular risk factors?
• What cardiac follow-up has been arranged?

Kapil is not experiencing any chest pain, shortness of breath or palpitations, and he has begun gentle exercise. He is a non-smoker who consumes around 8 units of alcohol per week. It is noted that there is a strong family history of type 2 diabetes. Kapil does not suffer from symptoms of intermittent claudication but has had problems with erectile dysfunction.

Examination: Pulse 64 bpm regular; blood pressure 133/72 mmHg; BMI 26.3 kg/m². No heart murmurs, chest clear, no peripheral oedema.

Current medication: Aspirin 75 mg once daily, bisoprolol 5 mg once daily, ramipril 5 mg twice daily, atorvastatin 80 mg once daily and paracetamol 500 mg as needed. All are well tolerated.

Kapil has been referred for cardiac rehabilitation.

What advice would you offer Kapil regarding his lifestyle and medication? How would you follow up the hospital finding of hyperglycaemia?

Section 3

The consultation is an important opportunity to reinforce lifestyle advice. You could emphasise the importance of a healthy, cardiac-friendly diet, regular exercise, weight loss and healthy sleeping patterns. These issues will be dealt with in detail in the cardiac rehabilitation programme, which Kapil should be encouraged to attend. It would be helpful to explain the function of his medications and the importance of taking this regimen as prescribed.

The likelihood of type 2 diabetes needs to be addressed. Arrangements are made to recheck HbA_1c to confirm the diagnosis of diabetes, and to repeat electrolyte and renal function tests following the introduction of ramipril.

Repeat HbA_1c returns at 59 mmol/mol (7.5%), confirming the diagnosis of diabetes, almost certainly type 2. U+Es and eGFR are within normal range. Lipid results are at target and LFTs are undisturbed.

Kapil is reviewed in the practice diabetes clinic. How would you manage his hyperglycaemia?

Section 4

Lifestyle measures of diet, exercise, weight loss and healthy sleep patterns remain the cornerstone of treatment. Kapil should be referred to the local structured education programme for type 2 diabetes, as well as to online resources for diabetes education. If available, he could be offered referral to the NHS Type 2 Diabetes Path to Remission programme (Bakhai, 2023).

The most recent NICE NG28 guidance advises that a newly diagnosed person with type 2 diabetes who has existing atherosclerotic cardiovascular disease (ASCVD) – MI, angina, stroke or transient ischaemic attack, or peripheral vascular disease – should be offered metformin plus an SGLT2 inhibitor with proven cardiovascular benefit (NICE, 2022).

Apart from improved glycaemic control, what benefits does metformin offer Kapil in this situation?

Section 5

Metformin is widely recommended as the first-line oral treatment in type 2 diabetes based on the evidence that it reduces the risk of myocardial infarction and all-cause mortality (Adler et al, 2024). It is also (at least) weight-neutral and carries a low risk of hypoglycaemia.

What is the basis for recommending SGLT2 inhibitors simultaneously with metformin for Kapil?

Section 6

The cardiovascular outcome trials of empagliflozin (Zinman et al, 2015) and canagliflozin (Neal et al, 2017) established that these treatments are effective in improving cardiovascular outcomes, defined as major adverse cardiovascular events (MACE) – a composite of cardiovascular death, non-fatal MI and non-fatal stroke – in people with type 2 diabetes and established ASCVD. Thus, they would be recommended for secondary prevention of CVD in the case of Kapil, who has had an MI, irrespective of HbA_1c level.

The cardiovascular outcome trial of dapagliflozin, which predominantly recruited people with type 2 diabetes without established ASCVD (i.e. largely a primary prevention cohort), showed a non-significant reduction in MACE versus placebo but also a significant reduction in the combined outcome of cardiovascular death and hospitalisation for heart failure (Wiviott et al, 2019). The ertugliflozin outcome trial, in a population with type 2 diabetes and established ASCVD, established cardiovascular safety but not superiority over placebo (Cannon et al, 2020).

The SGLT2 inhibitors are effective in improving glycaemic control and offer the benefits of weight loss and low risk of hypoglycaemia.

How would you introduce the metformin and SGLT2 inhibitor in practice?

Section 7

Start metformin first and gradually uptitrate the dose, aiming for 1000 mg twice daily. If gastrointestinal side-effects are problematic then the slow-release preparation of metformin may be tried.

Once the highest tolerated dose of metformin is established, the SGLT2 inhibitor can be added, without recourse to re-measuring HbA_1c. If metformin is contraindicated or not tolerated, the SGLT2 inhibitor should be commenced alone (NICE, 2022).

Kapil successfully builds the dose of metformin to 1000 mg twice daily and is then commenced on empagliflozin 10 mg once daily.

The scenario ends here.

Section 8 – Julie

Julie is a 58-year-old Caucasian lady who has had type 2 diabetes for 7 years. She sees her GP with episodic central chest discomfort radiating to her neck and left shoulder, together with shortness of breath that is brought on by exercise and relieved by rest.

Julie is an ex-smoker and consumes around 12 units of alcohol per week. Previous medical history: hypertension, type 2 diabetes. Her father had a myocardial infarction at around the age of 50 years.

Current medication: Metformin 1000 mg twice daily, linagliptin 5 mg once daily, losartan 50 mg once daily.

Examination: BMI 32.7 kg/m²; blood pressure 158/77 mmHg; pulse rate 78 bpm regular; HS normal with no added sounds or murmurs; chest clear; no ankle swelling.

Latest investigations 9 months ago: HbA_1c 57 mmol/mol (7.4%).

What is your assessment of Julie’s problem?

Section 9

Clinically the diagnosis is angina until proven otherwise (NICE, 2016a). Other evidence of ASCVD such as symptoms of peripheral vascular disease (or erectile dysfunction in a male) would strengthen the likelihood of angina.

What risk factors does Julie have for angina?

Section 10

Julie’s risk factors for ischaemic heart disease include her type 2 diabetes, hypertension, dyslipidaemia, smoking history and family history of early CVD.

What investigations might you request?

Section 11

An up-to-date set of bloods are required, including HbA_1c, U+E, LFT, FBC and lipid profile. A resting ECG should also be performed.

What therapeutic interventions might you consider at this stage?

Section 12

It would be reasonable to start aspirin 75 mg once daily for cardiovascular protection (NICE, 2016b). Julie is also provided with a glyceryl trinitrate (GTN) spray to use sublingually when chest pain occurs. If effective, this could help confirm the diagnosis of ischaemic heart disease.

Julie is warned to call for an emergency ambulance should she have persistent chest pain unresponsive to a repeat dose of her GTN spray.

Section 13

A follow-up appointment in 1 week is arranged for Julie. The GTN spray has been helpful in easing chest discomfort when it arises.

Test results: HbA_1c 68 mmol/mol (8.4%); eGFR 63 mL/min/1.73 m²; U+Es and LFTs normal range; cholesterol 6.3 mmol/L, non-HDL cholesterol 5.4 mmol/L. FBC normal range, no anaemia. ECG unremarkable. Blood pressure 152/75 mmHg. Her latest urinary ACR did not show significant albuminuria.

Julie is referred to the rapid-access chest pain clinic for further investigation.

Whilst awaiting her appointment at the chest pain clinic, what could you offer to help prevent symptoms of angina?

Section 14

Beta-blockers (or calcium channel blockers) are a first-line option in stable angina (NICE, 2016b).

Julie is commenced on bisoprolol 2.5 mg once daily for angina prophylaxis, with the future possibility of dose uptitration as necessary.

What would be further steps, in addition to use of aspirin and a beta-blocker, to increase cardioprotection for Julie?

Section 15

Encourage Julie to address lifestyle issues that could reduce cardiovascular risk – diet, exercise, weight loss, healthy sleep patterns and the importance of avoiding smoking should be emphasised.

Julie’s dyslipidaemia needs tackling. A diagnosis of angina should prompt a discussion of benefits and side-effects of statin therapy. In this situation, Julie should ideally be offered atorvastatin 80 mg once daily for secondary prevention of CVD (NICE, 2023a).

ACE inhibitors (or angiotensin receptor blockers) should be considered for cardioprotection in people with type 2 diabetes who have stable angina (NICE, 2016b), so the current use of losartan is appropriate for Julie.

With a diagnosis of angina, Julie’s blood pressure should be controlled to <140/90 mmHg (NICE, 2023b). Uptitration of Julie’s doses of bisoprolol and losartan should help achieve this target.

Julie is asked to record home blood pressure readings and to make a follow-up appointment, at which these could be reviewed along with her angina symptoms.

What changes would you consider to Julie’s glycaemic medication?

Section 16

A choice you should certainly consider here is an SGLT2 inhibitor. SGLT2 inhibitors that offer cardiovascular protection (empagliflozin, canagliflozin, dapagliflozin) are now recommended for people with type 2 diabetes who develop angina or other manifestations of ASCVD, either as an add-on or substitution for existing treatment (NICE, 2022). In Julie’s case, the SGLT2 inhibitor should additionally improve her glycaemic control and facilitate weight loss.

The scenario ends here.

Section 17 – Mark

Mark, a 67-year-old man with type 2 diabetes for 11 years, is seen for his annual review. He is known to have background retinopathy.

Test results: BMI 28.6 kg/m²; blood pressure 128/61 mmHg; HbA_1c 68 mmol/mol (8.4%). eGFR 52 mL/min/1.73 m²; U+Es normal range; cholesterol 3.9 mmol/L, non-HDL cholesterol 2.7 mmol/L; urinary ACR 14.7 mg/mmol (persistent albuminuria).

Medication: Metformin 1000 mg twice daily, gliclazide 160 mg twice daily, lisinopril 20 mg once daily, atorvastatin 20 mg once daily.

How would you assess Mark’s cardiovascular risk?

Section 18

The QRISK calculator can be used to assess the risk of a future cardiovascular event. High risk is defined as having a score of >10% for the next 10 years in a person 40 years or older. Ideally use QRISK3, but if IT systems have not yet had this embedded then the less comprehensive QRISK2 calculator can be used (NICE, 2023a).

Mark’s QRISK3 score turns out to be 27%, which places him in the high-risk category for a cardiovascular event. Key risk factors here are Mark’s age and his diagnoses of type 2 diabetes and chronic kidney disease.

Bearing in mind Mark’s raised cardiovascular risk, what would be your next choice for glycaemic management?

Section 19

For the person with type 2 diabetes at high cardiovascular risk, NICE recommends considering use of an SGLT2 inhibitor with known cardiovascular benefit, for primary prevention (NICE, 2022). Thus, an SGLT2 inhibitor would be a logical choice to improve glycaemia. In Mark’s case, he additionally has chronic kidney disease, as defined by his reduced eGFR and albuminuria, almost certainly due to diabetic nephropathy (as he also has retinopathy), which in itself would be an indicator for use of an SGLT2 inhibitor with renal benefit.

Dapagliflozin 10 mg once daily is added to Mark’s regimen. The dose of gliclazide is reduced to 80 mg twice daily to reduce the risk of hypoglycaemia. Depending on blood glucose readings, the gliclazide dose could be adjusted up or down – Mark is advised to monitor his blood glucose readings carefully and reminded how to respond to these.

If Mark’s HbA_1c had been optimally controlled (HbA_1c ≤48 mmol/mol), how might you have responded to the increased cardiovascular risk?

Section 20

In such a situation, there is no requirement to reduce glycaemic levels but the cardiac and renal benefits from using an SGLT2 inhibitor remain, and the drug should still be considered. To avoid the risk of hypoglycaemia, Mark’s gliclazide should be discontinued. If necessary, it could be recommenced if glycaemic control is not maintained.

It is worth mentioning that although the glucose-lowering potential of SGLT2 inhibitors decreases with falling eGFR, their capacity for cardiovascular and renal protection appears to be maintained even at lower eGFR (Heerspink et al, 2020).

Are you aware of any other classes of diabetes medication that can offer cardiovascular protection?

Section 21

There is evidence from cardiovascular outcome trials to support the use of certain GLP-1 receptor agonists in prevention of cardiovascular events in people with type 2 diabetes and established ASCVD – specifically with liraglutide, semaglutide and dulaglutide (Marso et al, 2016a, Marso et al 2016b; Gerstein et al, 2019). To a lesser extent, there is evidence of cardiovascular benefit from use of GLP-1 receptor agonists in individuals with type 2 diabetes at high cardiovascular risk (without established CVD), with the strongest evidence lying with dulaglutide (Gerstein et al, 2019).

The ADA/EASD consensus report update on management of hyperglycaemia in type 2 diabetes recommends the use of GLP-1 receptor agonists with proven cardiovascular benefit for people with established ASCVD, also advising that individuals with type 2 diabetes and cardiovascular risk factors but not established ASCVD should be considered for these agents, irrespective of HbA_1c levels (Davies et al, 2022).

For triple therapy, in the individual with or at high risk of ASCVD, a logical combination to manage glycaemia would be metformin plus an SGLT2 inhibitor plus a GLP-1 receptor agonist. Further advantages of this regimen are low risk of hypoglycaemia and, for overweight/obese individuals, facilitation of weight loss.

Can you summarise the cardiovascular impact of other diabetes medications?

Section 22

Cardiovascular outcome trials with DPP-4 inhibitors (gliptins) in people with type 2 diabetes and established cardiovascular disease indicated no increased risk of cardiovascular events versus placebo but no benefit either (Nauck et al, 2017).

Whilst pioglitazone can reduce the risk of MI, it is associated with an increased risk of heart failure (Dormandy et al, 2005).

There is no evidence that sulfonylureas or insulin specifically improve cardiovascular outcomes.

The cardiovascular outcome trial on the GIP/GLP-1 dual receptor agonist tirzepatide is awaited with interest.