Cardiovascular risk reduction in patients with type 2 diabetes and cardiovascular disease at Leeds Teaching Hospitals NHS Trust

• Aims
• Background
  • Table 1 – Cardiovascular Outcome Trials – SGLT2 inhibitors
  • Table 2 – Cardiovascular Outcome Trials – GLP1 receptor agonists
  • Table 3 – Summary of evidence for cardiovascular benefit in cardiovascular outcomes trials
• Diagnosis
• Investigation
• Treatment/Management
  • Table 4 – Factors favouring SGLT2 inhibitor or GLP-1 receptor agonist therapy
  • Table 5 – Recommended first and second line drugs
  • Table 6 - Initiation and monitoring of SGLT2 inhibitor therapy
  • Table 7 - Initiation and monitoring of GLP1 receptor agonist therapy
• Declarations of Interest

Aims

The combination of type 2 diabetes and cardiovascular disease confers a high risk of cardiovascular events and mortality. Recent cardiovascular outcome trials provide persuasive evidence of reduced cardiovascular events and mortality when a SGLT2 inhibitor or GLP-1 agonist is added to standard care. This guideline provides a practical approach to optimise cardiovascular risk reduction in patients with type 2 diabetes and cardiovascular disease by prioritising prescription of these medications in patients under the care of the cardiology team.

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Background

The combination of diabetes with atherosclerotic cardiovascular disease (CVD) confers a four-fold increase in the risk of mortality and a reduction in life expectancy of around 15 years in a patient of 60 years of age¹. Around one quarter of patients admitted to hospital with acute coronary syndrome have diabetes². In patients with established CVD, individuals with diabetes benefit symmetrically to those without disease from blood pressure reduction, lipid-modification, and anti-platelet therapy³. Despite major advances in overall survival following acute coronary syndrome over time, the gap in mortality between patients with and without diabetes has failed to improve⁴.
Recently, cardiovascular outcome trials have demonstrated that the sodium-glucose cotransporter-2 (SGLT-2) inhibitors empagliflozin, canagliflozin and dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonists liraglutide, dulaglutide and semaglutide reduced the risk of major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction and stroke) when added to standard of care in patients with type 2 diabetes who have or are at risk for cardiovascular disease^5-12 (see Tables 1-2 below). The magnitude of benefit, including reduction in all-cause mortality for some agents, parallels or exceeds that of conventional approaches to risk reduction and is observed in addition to these approaches. Note that inclusion criteria for the cardiovascular outcome trials differ and there are differences in effect on cardiovascular outcomes between agents in each class (Table 3). SGLT2 inhibitors significantly reduced the risk of heart failure hospitalisation across all trials. Only empagliflozin and liraglutide significantly reduced both MACE and all-cause mortality (Table 3). In a more recent trial of patients with heart failure and reduced ejection fraction, dapagliflozin reduced the risk of death or heart failure from cardiovascular causes¹³. Clinical trials with other SGLT2 inhibitors in patients with heart failure are ongoing at the time of writing this guidance.
International guidelines and consensus statements from the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), European Society of Cardiology (ESC), American College of Cardiology (ACC) and the Scottish Intercollegiate Guidelines Network (SIGN) now prioritise SGLT2 inhibitors and GLP-1 agonists to reduce the risk of cardiovascular events in patients with established CVD^14-18. NICE guidelines for diabetes are due to be updated in 2020 and recent guideline updates have not specifically addressed the use of SGLT-2 inhibitors or GLP-1 agonists to reduce the risk of cardiovascular events¹⁹.

Through their experience of managing risk reduction in patients with CVD, members of the cardiology team are ideally positioned to review and optimise diabetes therapy in patients with established CVD, in addition to optimising blood pressure, lipid lowering and anti-platelet therapy, to further reduce cardiovascular risk. This guidance was written jointly by Cardiology, Diabetes and Pharmacy Teams at Leeds Teaching Hospitals NHS Trust (LTHT) to provide a pragmatic algorithm for initiation of drugs with proven cardiovascular disease in patients with CVD and T2DM.

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Table 1 – Cardiovascular Outcome Trials – SGLT2 inhibitors

Results reaching conventional levels of significance are highlighted but should be interpreted with caution in line with hierarchical testing. 3-point MACE (major cardiovascular adverse events) = cardiovascular death, myocardial infarction or stroke. In the DECLARE-TIMI 58 trial, the co-primary efficacy endpoint cardiovascular death or hospitalization for heart failure was significantly reduced (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95). In CANVAS and CANVAS-R an increased risk of amputation was observed (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75).

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Table 2 – Cardiovascular Outcome Trials – GLP1 receptor agonists

Results reaching conventional levels of significance are highlighted but should be interpreted with caution in line with hierarchical testing. 3-point MACE (major cardiovascular adverse events) = cardiovascular death, myocardial infarction or stroke. 4-point MACE (major cardiovascular adverse events) = cardiovascular death, myocardial infarction, stroke or hospitalisation for unstable angina.

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Table 3 – Summary of evidence for cardiovascular benefit in cardiovascular outcomes trials

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Diagnosis

New diagnosis of type 2 diabetes:
Type 2 diabetes should be diagnosed in accordance with UK Department of Health recommendations²⁰. In patients with symptoms suggestive of diabetes, a single measurement of HbA1c 48mmol/mol or higher is diagnostic.  In asymptomatic individuals, a single measurement of HbA1c 48mmol/mol or higher is likely to indicate diabetes, but a second measurement should be taken within two weeks to confirm the diagnosis.

Consider alternative diagnoses (e.g. Type 1 Diabetes, Latent autoimmune diabetes in adults (LADA)) in patients without obesity, history of weight loss or very high glucose levels despite early escalation of hypoglycaemic therapies and discuss with the diabetes team in cases of diagnostic doubt or atypical presentation.  

Pre-diabetes:
In patients with HbA1c 42-47mmol/L, discuss the diagnosis of pre-diabetes and refer to the National Diabetes Prevention Programme – Healthier You (https://preventing-diabetes.co.uk). Recommend monitoring of HbA1c at least annually in primary care.  

Established diabetes:
Around one quarter of patients with clinically manifest CVD have an established diagnosis of Type 2 Diabetes.

Cardiovascular disease:
For the purposes of this guideline, patients presenting to cardiology with cardiovascular disease are considered to be those with a history of myocardial infarction; coronary artery disease or heart failure.

Note - inclusion criteria for EMPA-REG OUTCOME⁵ comprise one or more of the following:  history of myocardial infarction, coronary artery disease (≥50% diameter stenosis or prior revascularization), history of stroke (ischaemic or haemorrhagic), or occlusive peripheral arterial disease (prior revascularisation, limb or foot amputation, ≥50% diameter peripheral artery stenosis, or ankle brachial index <0.9 in ≥1 ankle

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Investigation

• HbA1c should be measured in all patients admitted with a new presentation of coronary artery disease, unless they have established diabetes and a measurement is available within the last three months.
• Renal function should be assessed before initiating new diabetes therapy

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Treatment / Management

Summary of recommendations (refer to algorithm in Summary of Guideline)

1. In patients with type 2 diabetes and CVD, prescribe hypoglycaemic agents proven to reduce the risk of cardiovascular events (SGLT2 inhibitors or GLP1 receptor agonists) in addition to other strategies to reduce CVD risk (lipid modification, blood pressure lowering, anti-platelet therapy).
2. In treatment naïve patients with type 2 diabetes, initiate therapy with metformin (500mg twice daily) if eGFR>30mL/min/1.73m². Consider subsequent addition of SGLT2 inhibitor. Refer to prescribing information in SPC and Leeds Formulary, particularly in relation to renal function thresholds for initiation of SGLT2 inhibitors. If an SGLT2 inhibitor is contra-indicated, consider outpatient initiation of a GLP-1 receptor agonist (liraglutide 0.6mg sc daily or semaglutide 0.25mg sc weekly or dulaglutide 1.5mg sc weekly). Restrict GLP-1 receptor agonist therapy to patients with BMI>30.
3. In patients receiving oral hypoglycaemic therapy, add an SGLT2 inhibitor to current therapy. Consider discontinuing suphonylurea or thiazolidinedione unless HbA1c>58mmol/mol. See algorithm for full details.
4. In patients established on insulin therapy, add an SGLT2 inhibitor to current therapy. Reduce insulin dose by 10-20% unless HbA1c>58mmol/mol. Consider discontinuing one oral agent (preferably sulphonylurea or thiazolidinedione) unless HbA1c>58mmol/mol. Counsel about risk of hypoglycaemia and advise on further decrease in insulin dose if required. Involve the multidisciplinary diabetes team the in management of patients with complex diabetes treatment requirements.

Notes on recommendations in this guidance

General principles
In patients with established CVD and type 2 diabetes, initiation of diabetes therapies proven to reduce the risk of cardiovascular events and mortality should be considered in addition to lifestyle and dietary modification. Involve patients in shared decision making when deciding whether to initiate new medication. Advantages and disadvantages of therapy should be discussed, and the patient’s views taken into account when prescribing. Patients with CVD and type 2 diabetes are more likely to be seen by cardiology teams than by diabetes or endocrinology teams21, providing a valuable opportunity for cardiology teams to initiate therapies for cardiovascular risk reduction15.

Clinical setting
This guidance is designed to be used by secondary care teams to guide cardiovascular risk reduction in patients with T2DM and CVD. In-scope patients include those admitted to LTHT with acute coronary syndromes and those with CVD and T2DM admitted for other reasons or seen in outpatient clinics. Although in-hospital initiation after acute cardiovascular events was not specifically studied in clinical trials, SGLT2 inhibitors and GLP1R-agonists are well tolerated and early initiation after acute coronary syndrome is considered safe by expert opinion¹⁵.  After acute coronary syndrome, initiation should be deferred until the patient is clinically stable (usually in the cardio-metabolic clinic). SGLT-2 inhibitors can lead to a fall in blood pressure and should be used with caution in patients who are hypotensive or volume depleted. The cardio-metabolic follow up clinic will provide the opportunity for review of cardiovascular risk factors and initiation of SGLT2 inhibitor or GLP1R-agonist therapy when appropriate. If therapy is initiated earlier in selected patients before discharge following the index event, treatment will be reviewed in the cardio-metabolic clinic. All patients with acute coronary syndrome will be triaged for follow up as appropriate in the cardiometabolic clinic or post-MI follow up clinic.

Choice between SGLT2 inhibitor and GLP-1 receptor agonist.
Both SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events in patients with CVD and type 2 diabetes, independent of glucose lowering. In this guidance, we recommend an SGLT2 inhibitor first line as SGLT2 inhibitors are oral therapy, readily deliverable by cardiology teams, and supported by evidence for reduction in MACE and heart failure hospitalisation.  Factors favoring the choice of drug class are summarised in Table 4. Out-patient initiation of GLP-1 receptor agonist, if required, can be considered either by primary care or in cardio-metabolic clinic. In most cases, patients selected for GLP-1 receptor agonists will be overweight or obese.

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Table 4 – Factors favouring SGLT2 inhibitor or GLP-1 receptor agonist therapy

Selection of SGLT2 inhibitors or GLP-1 agonists
Recommended drugs for initiation for cardiovascular risk reduction are summarised in Table 5. Empagliflozin and liraglutide are recommended as first choice in each class, in accordance with 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases¹⁷, to reduce the risk of death^5,8.

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Table 5 – Recommended first and second line drugs

Initiation of therapy for type 2 diabetes in drug-naïve patients with CVD
Metformin is well-tolerated with limited evidence for modest reduction in risk of myocardial infarction. Metformin is recommended as first line therapy, in addition to diet and lifestyle modification, in most guidelines for the management of type 2 diabetes. The 2019 European Society of Cardiology Guidelines on diabetes, pre-diabetes, and cardiovascular diseases recommend SGLT2 inhibitors as first line therapy instead of metformin¹⁷. However, this is outside the current marketing authorisation for available SGLT2 inhibitors and the majority of patients in the cardiovascular outcome trials for SGLT2 inhibitors were receiving background therapy including metformin. In this guidance, we recommend initiation of therapy with metformin (note metformin should be avoided if eGFR<30mL/min/1.73m²).  Addition of an SGLT2 inhibitor should be considered on subsequent review.  Although new onset of other types of diabetes (e.g. Type 1 Diabetes, Latent autoimmune diabetes in adults (LADA)) are uncommon in the setting of patients presenting with CVD, cardiology teams should be aware of this possibility and seek advice from the diabetes multidisciplinary team when there is diagnostic uncertainty. 

Adding SGLT2 inhibitors to other background therapy for type 2 diabetes
SGLT2 inhibitor therapy should be prescribed to patients receiving background therapy for type 2 diabetes, unless contraindicated, to confer CVD risk reduction independent of baseline HbA1c. If glycaemic control is satisfactory, it is reasonable to replace one existing oral hypoglycaemic agent – particularly sulphonylurea or thiazolidinedione (pioglitazone) which may be potentially harmful in patients with CVD – with an SGLT2 inhibitor. If glycaemic control is sub-optimal (HbA1c>58mmol/L) an SGLT2 inhibitor should be prescribed in addition to existing therapy. In patients treated with insulin, the dose of insulin should be reduced by 10-20% unless glycaemic control is sub-optimal (HbA1c>58mmol/L). Take into account any history of hypoglycaemic episodes and involve the diabetes multidisciplinary team in decision making when required. Counsel patients on hypoglycaemia awareness and advise that further adjustment of insulin dose may be required after addition of new oral therapies.

Further glycaemic management

If glycaemic control does not improve substantially after initiation of an SGLT2 inhibitor or GLP1 receptor agonist, discuss with the patient the option of continuing therapy anyway for the benefit of cardiovascular risk reduction (which is independent of glycaemic response).

Further out-patient management of glycaemia after the addition of SGLT2 inhibitors or GLP1 receptor agonists to metformin therapy is beyond the scope of this guidance. As a general principal, in patients with CVD, addition of a GLP-1 receptor agonist to an SGLT2 inhibitor should be considered to optimise cardiovascular risk reduction. If oral therapy is preferred, a DPP4 inhibitor, which has a neutral effect on cardiovascular risk, can be added to an SGLT2 inhibitor (avoid saxagliptin in patients with heart failure). DPP4 inhibitors should not be given together with GLP1 receptor agonists. If possible, sulphonylureas should be avoided in patients with CVD due to the risk of hypoglycaemia. The thiazolidinedione pioglitazone can cause fluid retention and should be avoided in patients with (or at risk of) heart failure.

Practical considerations when prescribing SGLT2 inhibitors
At the time of writing, marketing authorisations for available SGLT2 inhibitors do not recommended initiation in patients with eGFR<60mL/min/1.73m². However, SGLT2 inhibitors were safely used in patients with lower eGFR in clinical trials and are known to protect against future renal dysfunction. Renal thresholds for initiation are likely to change and the SPC and Leeds Formulary should be consulted for current recommendations.

Rarely, diabetic ketoacidosis can occur with SGLT2 inhibitors in the absence of marked hyperglycaemia. Clinicians should be aware of this possibility in patients who are unwell despite the absence of hyperglycaemia. Inform patients of the signs and symptoms of DKA, (including rapid weight loss, nausea or vomiting, abdominal pain, fast and deep breathing, sleepiness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odour to urine or sweat), and advise them to seek immediate medical advice if they develop any of these. Test for raised ketones in patients with signs and symptoms of DKA, even if plasma glucose levels are near-normal. SGLT2 inhibitors should be avoided in patients with a history of diabetic ketoacidosis. SGLT2 inhibitors should be used with caution in patients with risk factors for DKA, (including a low beta cell reserve, conditions leading to restricted food intake or severe dehydration, sudden reduction in insulin, increased insulin requirements due to acute illness, surgery or alcohol abuse), and discuss these risk factors with patients.

SGLT2 inhibitors increase the risk of genital infections – predominantly fungal infections, in men and women. Patients should be counselled on the importance of good hygiene.

Fournier’s gangrene, a rare but serious and potentially life-threatening infection, has been associated with the use of SGLT2 inhibitors. Patients should be advised to seek urgent medical attention if they experience severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise—urogenital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, stop the SGLT2 inhibitor and urgently start treatment (including antibiotics and surgical debridement).

Initiation in patients immediately after acute coronary syndrome has not been studied in clinical trials. However, review and adjustment of therapy in this setting is likely to optimise risk reduction in this group of patients. Avoid initiation in patients who are clinically unstable or hypotensive. Consider reducing diuretic dose when initiating SGLT2 inhibitors to patients stabilised on diuretic therapy.
Tables 6 and 7 provide practical advice for prescribing SGLT2 inhibitors and GLP1 receptor agonists, respectively.

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Table 6 -  Initiation and monitoring of SGLT2 inhibitor therapy

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Table 7 -  Initiation and monitoring of GLP1 receptor agonist therapy

Patient-centred care & shared decision-making

When acting on these guidelines, healthcare professionals should consider the patient’s broader health and social care needs. Adopt an individualised approach to diabetes care that is tailored to the needs and circumstances of adults with type 2 diabetes. Take into account the patient’s personal preferences, comorbidities, risks from polypharmacy, and their ability to benefit from long‑term interventions because of reduced life expectancy.  Review and stop any medicines that are not effective. Refer to Leeds Guideline ‘Glycaemic Control for Older People with Type 2 Diabetes and Frailty and/or Multi-morbidity’. Patients should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals. Discuss with patients the benefits and risks of drug treatment, and the options available. Agree with patients a care plan that meets their individual clinical circumstances and individual preferences and needs.

Follow-up

Ensure all changes to therapy are communicated to primary care on the discharge notification or clinic letter. Changes made to therapy during hospital admission should be reviewed at follow-up appointments in cardiology or cardiometabolic out-patient clinics.

Clinic letters should provide a clear summary of the reasons for treatment choices and recommendations for ongoing management in primary care. Patients should be stable with optimum achievable risk factor control (including HbA1c) before discharge to primary care. Patients who do not attend their planned review appointment should be contacted and offered a further appointment. Failure to addend a second appointment should trigger a letter to primary care with advice on further management.

This guidance is intended to optimise therapy in patients with type 2 diabetes and cardiovascular disease assessed by the cardiology multidisciplinary team by prioritising SGLT2 inhibitors and GLP-1 receptor agonists with cardiovascular benefit. Management of long-term glycaemic control remains in primary care, with specialist advice from the Leeds Community Healthcare Diabetes Service available to patients fulfilling the referral criteria.

Conclusions

Patients with type 2 diabetes and cardiovascular disease are at high risk of cardiovascular events and mortality. Initiation of SGLT2 inhibitor therapy offers valuable opportunity to reduce the risk of major cardiovascular events, heart failure hospitalisation, renal events and cardiovascular mortality independent of glycaemic control. GLP1 receptor agonist therapy should be considered for cardiovascular risk reduction in patients for whom SGLT2 inhibitor therapy is inappropriate or for whom weight loss is a priority.

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Declarations of Interest

SBW has received honoraria from Bayer, AstraZeneca, Servier and Boehringer Ingelheim.
RA received honoraria, education or research support from Eli Lilly, Boehringer Ingelheim, AztraZeneca and NovoNordisk.
RK received one or more of the following: educational & research grants and speaker fees from AstraZeneca, Boehringer Ingelheim, NovoNordisk and MSD.