Cardiovascular Disease and Diabetes: Thinking Beyond Glucose Control

Dr Kevin Fernando Examines the 2023 Update to European Society of Cardiology Guidance on the Management of Cardiovascular Disease in Patients with Diabetes

A significant mortality gap exists between patients with type 2 diabetes and cardiovascular disease (CVD) and people of a similar age with neither condition. Data from the Emerging Risk Factors Collaboration show that, on average, a 60-year-old woman living in the UK with type 2 diabetes and one risk factor for CVD will die around 13 years earlier than a similarly aged woman with neither of these conditions.¹ The corresponding average decrease in life expectancy for a 60-year-old man living with type 2 diabetes and one cardiovascular risk factor in the UK is 12 years.¹

The reduction in life expectancy associated with multiple cardiometabolic risk factors highlights the need to improve the primary and secondary prevention of CVD in people living with diabetes in the UK.¹ This article will explore key new recommendations from the European Society of Cardiology (ESC) on the management of CVD in patients with diabetes,² which were presented at the ESC Congress 2023 in Amsterdam.³

Going Beyond a Glucocentric Approach

The updated ESC guideline emphasises that, rather than adopting a glucocentric approach that focuses on treating hyperglycaemia, the primary goal of management in patients with CVD and diabetes should be a reduction in cardiovascular events and mortality, to improve both prognosis and quality of life.² Of course, good glycaemic control remains important in this population to prevent microvascular complications of diabetes, but the impact of glycaemic control on macrovascular complications such as CVD is less clear.²

Screening for CVD

People with type 2 diabetes are two to four times more likely to develop CVD during their lifetime than those without type 2 diabetes; hence, the ESC recommends that all patients with diabetes are evaluated for the presence of atherosclerotic cardiovascular disease (ASCVD) and severe target organ damage, and that patients with type 2 diabetes but without symptomatic ASCVD or severe target organ damage are screened using a new 10-year CVD risk calculator called SCORE2-Diabetes.² This algorithm extends the established SCORE2 CVD risk prediction tool⁴ by adding predictors specifically related to type 2 diabetes.² It also takes account of variation in risk across Europe;² for example, Eastern Europe has a higher cardiovascular risk profile than Western Europe.⁵

The thresholds used by the SCORE2-Diabetes algorithm are intended to inform joint decision-making conversations with patients aged 40 years or older about treatment options and intensity, and are as follows:²

• less than 5%—low 10-year risk of CVD
• 5–10%—moderate risk
• 10–20%–high risk
• 20% or higher—very high risk.

Using SCORE2-Diabetes will be a change in practice for some primary care practitioners, who will likely use the CVD risk calculator QRISK3^®,⁶ even though it has been less extensively validated in patients with type 2 diabetes.^7,8 Helpfully, a CVD Risk Calculation App is available from the ESC,⁹ through which the calculation of a SCORE2-Diabetes risk score can be tailored to a specific geographical region.

Adopting Revised Risk Categories

In the updated guideline, cardiovascular risk categories are now defined on the basis of the presence of ASCVD, severe target organ damage, or 10-year cardiovascular risk calculated using SCORE2-Diabetes.² These categories are defined as follows:²

• patients are considered to be at very high cardiovascular risk if they have type 2 diabetes and clinically established ASCVD, target organ damage, or a SCORE2-Diabetes result of 20% or more
• those with type 2 diabetes without clinically established ASCVD or target organ damage and with a SCORE2-Diabetes result of less than 20% are considered to be at high cardiovascular risk
• individuals are considered to be at moderate cardiovascular risk if they have type 2 diabetes without clinically established ASCVD or target organ damage and with a SCORE2-Diabetes result of 5–10%
• patients are considered to be at low cardiovascular risk if they have type 2 diabetes without clinically established ASCVD or target organ damage and with a SCORE2-Diabetes result of less than 5%.

These thresholds are intended for use with the SCORE2-Diabetes algorithm to help guide clinicians and patients in joint decision-making discussions.² 

Identifying Comorbidities

The updated ESC guidance also explicitly reminds healthcare professionals to look for significant comorbidities, such as heart failure (HF) of all subtypes and chronic kidney disease (CKD).² This is because early identification and management of comorbidities can have a major impact on prognosis.²

In all patients with type 2 diabetes, the guidance recommends a systematic survey for signs and symptoms of HF at each clinical encounter.² Although HF is underdiagnosed in this population, in my opinion this recommendation will be challenging to implement and has significant workload implications as, in my experience, HF often presents in insidious, nonspecific ways in primary care.

Nonpharmacological Interventions

The ESC advocates a multifactorial approach to risk factor and lifestyle management as a basic measure to prevent cardiovascular complications, events, and mortality in people with CVD and type 2 diabetes.² The guidance discusses evidence on the benefits of interventions such as weight reduction, improved diet, smoking cessation, and increased physical activity on metabolic control and cardiovascular risk.² Weight reduction is a major focus of lifestyle recommendations: in addition to improving glycaemic control, lipid levels, and blood pressure, weight loss has the potential to bring about remission of diabetes.² However, each risk factor optimised has a positive effect on outcomes and life expectancy.²

Supporting Adherence

Adherence to lifestyle changes tends to fall over time; hence, the guideline recommends the provision of person-centred information on the importance of adherence that is tailored to patients’ health status and literacy and that takes into account patients' individual characteristics and preferences as part of shared decision making.² The guidance notes that emerging technologies, such as mobile phone apps, may also support adherence.²

A Stepwise Approach

The 2021 publication ESC guidelines on cardiovascular disease prevention in clinical practice introduced a stepwise approach to risk factor management and treatment intensification intended to overcome poor adherence by providing risk factor targets for healthcare professionals and patients to aim for.^2,10 The approach takes risk factors, comorbidities, characteristics such as age and sex, and individual preferences into consideration, and may be useful when discussing adherence and escalating treatment in patients with CVD and type 2 diabetes.^2,10

Pharmacological Treatments

The pharmacotherapeutic options recommended by the ESC for the management of diabetes and CVD prioritise the use of agents with proven cardiovascular benefit and a low risk of hypoglycaemia.² The aim of pharmacotherapy in this population is to improve cardiovascular risk independent of glycaemic control.² The full guideline features a useful algorithm summarising the ESC-recommended treatment options for type 2 diabetes and CVD, which can be accessed here.² 

Type 2 Diabetes and ASCVD

Glucagon-like Peptide-1 Receptor Agonists

The evidence on the association between glucagon-like peptide-1 receptor agonist (GLP-1 RA) use and the reduction of ASCVD risk in people with type 2 diabetes is compelling, perhaps even more so than the evidence for sodium–glucose co-transporter-2 (SGLT2) inhibitor use.² However, the ESC’s recommendation of GLP-1 RAs as a standard glucose-lowering therapy for people with type 2 diabetes and ASCVD, alongside SGLT2 inhibitors, will be challenging to implement in the UK given current issues with the supply of GLP-1 RAs, which are being driven by off-label use of these medications for the management of obesity.¹¹ Despite calls from the DHSC and Medicines and Healthcare products Regulatory Agency for stocks of GLP-1 RAs to be reserved for the treatment of diabetes, GLP-1 RA supplies are not expected to stabilise until mid-2024.¹¹

Metformin

Controversially, the updated ESC guidance recommends that metformin—when not being used already—is only used in patients with type 2 diabetes and ASCVD who require additional glucose control.² This is a misstep, in my opinion, because insulin resistance is a key pathology in patients with type 2 diabetes.¹² One of the key benefits of metformin use is a reduction in insulin resistance.¹² Therefore, this recommendation will not change my practice—I will continue to prescribe metformin alongside GLP-1 RAs or SGLT2 inhibitors for patients with the highest cardiovascular risk.

Type 2 Diabetes and HF

SGLT2 Inhibitors 

For patients with type 2 diabetes and HF with reduced ejection fraction, use of SGLT2 inhibitors is recommended by the ESC to reduce the risk of hospitalisation for HF and cardiovascular death.² In addition, for patients with type 2 diabetes and HF with mid-range or preserved ejection fraction (for instance, a left-ventricular ejection fraction >40%), SGLT2 inhibitors are also recommended by the ESC, independent of glycaemic control, to reduce the risk of hospitalisation for HF or death from a cardiovascular cause.² 

The ESC’s recommendations for patients with type 2 diabetes and HF are consistent with other global guidance on HF.¹³ Increasingly, the pillars of HF therapy are being challenged with the early initiation of SGLT2 inhibitors, as a result of their compelling evidence base, early symptomatic benefit, and ease of use.²

Very High Cardiovascular Risk

Dual Therapy

For patients at very high cardiovascular risk (for example, those with type 2 diabetes and established ASCVD), the ESC guidance recommends therapy with a GLP-1 RA and/or an SGLT2 inhibitor to reduce cardiovascular risk, independent of glucose control.² Dual therapy with a GLP-1 RA and an SGLT2 inhibitor can therefore be considered.² This dual therapy is recommended in addition to standard-of-care antiplatelet, antihypertensive, and lipid-lowering therapies.²

CKD in Diabetes

Finerenone

In patients with type 2 diabetes and CKD, SGLT2 inhibitors and finerenone are now both recommended by the ESC to reduce the risks of kidney failure and CVD, independent of glycaemic control and in addition to standard of care (for example, statins-based therapies, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers).² Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) with quite different pharmacokinetics and clinical effects to those of the steroidal MRAs spironolactone and eplerenone.¹⁴ Specifically, finerenone does not significantly lower blood pressure,^15,16 and has fewer steroid-induced adverse effects such as gynaecomastia, impotence, and menstrual abnormalities.¹⁴ However, like steroidal MRAs, finerenone can cause hyperkalemia.¹⁴

Finerenone has demonstrated significant kidney and cardiovascular benefits across the spectrum of CKD in patients with type 2 diabetes.¹⁷ This reinforces the importance of measuring urinary albumin–creatinine ratio in patients with type 2 diabetes and preserved kidney function.

Summary

The 2023 ESC guideline on the management of cardiovascular disease in patients with diabetes features forward-thinking recommendations. These look beyond glycaemia, and reflect the current evidence on newer glucose-lowering therapies with proven cardiorenal benefits. Nevertheless, the implementation of these recommendations will be challenging, given their workload implications, the unstable supply of GLP-1 RAs, and a persistent glucocentric approach to type 2 diabetes care in some areas. Uptake of the ESC guidance will require ongoing education for healthcare professionals about the risk–benefit ratios of SGLT2 inhibitors and GLP-1 RAs. It also will require a re-evaluation of the workforce strategy to support the development of a skilled and sustainable workforce.