Karen Bartha Discusses the Association of British Clinical Diabetologists Position Statement on the Use of Newer Antidiabetic Drugs in Patients with Cardiovascular Disease
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The association between diabetes and cardiovascular disease (CVD) is well documented, and CVD is a major cause of death and disability among people with diabetes.1 The term CVD encompasses all forms of coronary artery disease, cerebrovascular disease (including stroke), and peripheral arterial disease.2 The prevalence of heart failure (HF) is also higher in people with diabetes compared with those without diabetes;3 thus, the National Diabetes Audit includes HF as a cardiovascular (CV) complication of diabetes.4
With this in mind, reducing CV risk is a significant goal in the treatment of diabetes. The risk of CVD in people with diabetes can be reduced by lowering high blood pressure (BP) and high glucose levels, and through the use of lipid-lowering medications.2 The focus of this article is the impact on CVD in type 2 diabetes, of newer antidiabetic agents that are available in the UK , and any challenges associated with tailoring antidiabetic treatment for patients with diabetes and CVD in primary care.
Understanding the Background of CV Safety Data
The increased risk of CVD in type 2 diabetes is multifactorial. The impact of improved glycaemic control on microvascular end points is well recognised,5,6 but evidence supporting the potential of improved glycaemic control to reduce CV events is less strong than that supporting the CV benefits of lowering of BP and lipids.5,7,8 Hypertension is a significant risk factor for both atherosclerotic cardiovascular disease (ASCVD) and microvascular disease;7 conversely, microvascular changes within the kidney can influence BP as well as independently increasing CV risk.9
The Requirement for Newer Antidiabetic Agents to Demonstrate CV Safety
Following safety concerns associated with the use of rosiglitazone,10 the US Food and Drug Administration instructed the pharmaceutical industry that new antidiabetic therapies for type 2 diabetes should not result in an unacceptable increase in CV risk, to be demonstrated by the recording of CV events during all phase 2 and 3 trials.11 These events were to include, as a minimum, CV mortality, non-fatal myocardial infarction, and non-fatal stroke (a composite end point termed ‘three-point major adverse cardiac events’ [MACE]). Although the purpose of these studies was to demonstrate non-inferiority for CV safety, what began to emerge was superiority in some of the CV primary end points and, subsequently, the renal secondary end points.9
Although older antidiabetic treatments were not subjected to the same scrutiny, the available CV safety data has been summarised by Basu et al. as a position statement for the Association of British Clinical Diabetologists (ABCD).9
The effects on CV outcomes of newer and older antidiabetic medications as summarised by the ABCD are presented in Table 1.9
Table 1: Summary of the Results of CV Outcomes Trials9
| Class/Drug | CV Outcomes |
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| Metformin | The UKPDS demonstrated risk reduction for myocardial infarction in overweight individuals, which was maintained over the post-interventional 10-year follow-up period.12,13 |
Sulfonylureas | In the absence of properly designed CV outcome trials, the CV effects of sulfonylureas have previously been questioned. Gliclazide and glimepiride have been shown to carry a low risk of all-cause and CV mortality compared with glibenclamide.14 The ADVANCE trial saw no evidence of excess mortality or adverse CV outcomes for gliclazide.15 People receiving 1–4 mg glimepiride did not demonstrate excess CV mortality or any significant increase in all-cause mortality compared with linagliptin (CAROLINA trial).16 |
| Meglitinides | There are no long-term studies of repaglinide or nateglinide to assess CV outcomes or mortality in patients with type 2 diabetes. |
| Pioglitazone | The accumulated evidence from clinical trials favours pioglitazone as a drug with CV benefit. Pioglitazone should not be used in patients with HF or a history of HF.17 |
| DPP-4is | Alogliptin: the EXAMINE trial demonstrated safety in patients after an acute coronary event.18 Caution is advised in patients with NYHA stages III and IV HF, in whom the drug is best avoided.19 Linagliptin: the CARMELINA trial demonstrated non-inferiority in three-point MACE and no increased risk of HHF. Linagliptin was also associated with a statistically significant reduction in progression of albuminuria.20 Saxagliptin: the SAVOR-TIMI 53 trial saw an increase in HHF—therefore, cautious use is recommended in individuals with HF or at increased risk of HF.21 Sitagliptin: the TECOS trial showed non-inferiority across all primary and secondary CVD outcome measures and no increase in HHF.22 Vildagliptin: no specific CVD outcome studies have been conducted for vildagliptin. |
| GLP-1 RAs | Lixisenatide: non-inferiority for four-point MACE, which in this study included hospitalisation for unstable angina, in the ELIXA trial. There was no increase in HHF. Safety demonstrated following acute coronary syndrome.23 Liraglutide: a significant reduction in three-point MACE was demonstrated for liraglutide 1.8 mg in patients at high CVD risk or with pre-existing CVD in the LEADER trial. Although a reduction was seen in HHF, this did not reach statistical significance.24 Exenatide extended-release: in the EXSCEL trial, there was no significant difference in three-point MACE between exenatide extended-release versus placebo. Similarly, HHF was not significantly different between exenatide extended-release versus placebo.25 Semaglutide: in the SUSTAIN-6 trial, there was a significantly lower rate of three-point MACE in patients who were at high CV risk with once-weekly subcutaneous semaglutide.26 In the PIONEER 6 trial, non-inferiority was demonstrated for three-point MACE in those taking once-daily oral semaglutide.27 HHF was not significantly different in either trial versus placebo.26,27 Dulaglutide: the REWIND trial demonstrated a reduction in three-point MACE versus placebo in those with type 2 diabetes and pre-existing ASCVD or at high risk of CVD, with a significant reduction in non-fatal stroke. There was no difference in HHF, hospitalisation for unstable angina, or all-cause mortality.28 |
| SGLT2is | Canagliflozin: the CANVAS series of clinical trials showed CV protection for canagliflozin versus placebo, with a reduction in three-point MACE, a more marked reduction in HHF, and regression of albuminuria. However, there was no difference in all-cause mortality.29 The CREDENCE trial was designed to consider renal outcomes, and found significant reductions in decline in glomerular filtration rate, progression to end-stage renal disease, and death from renal or CV causes in patients with established CKD.30 Empagliflozin: all patients had established ASCVD in the EMPA-REG trial, which showed not only a reduction in three-point MACE, but also a significant reduction in CV death for empagliflozin, plus significant reductions for HHF and all-cause mortality.31 Further analysis of renal outcomes in the EMPA-REG trial demonstrated a reduction in incident or worsening nephropathy, progression to macroalbuminuria, or initiation of renal replacement therapy.32 The EMPEROR-Reduced trial saw a reduction in CV death or hospitalisation for worsening HF when empagliflozin was used in patients with chronic HF, independent of the presence of diabetes.33 Dapagliflozin: in the DECLARE trial, there was no significant reduction in three-point MACE for dapagliflozin versus placebo (although non-inferiority was shown), and there was a more marked reduction in HHF.34 The DAPA-HF study examined worsening of HF or death from CV causes, and showed a significant reduction versus placebo independent of the presence of diabetes.35 Dapagliflozin demonstrated reno-protection in CKD by significantly reducing decline in eGFR, end-stage kidney disease, or renal death. In the DAPA-CKD trial, a reduction in death from CV causes and HHF was also demonstrated in this group with dapagliflozin.36 Ertugliflozin: in the VERTIS CV trial, no reduction was demonstrated in three-point MACE for ertugliflozin (although non-inferiority was shown), but a more marked reduction was shown in reduction of HHF. No significant difference was seen in renal end points.37 |
| For more information regarding a specific drug, refer to the individual Summary of Product Characteristics |
| CV=cardiovascular; UKPDS=UK Prospective Diabetes Study; HF=heart failure; DPP-4i=dipeptidyl peptidase 4 inhibitor; NYHA=New York Heart Association; MACE=major adverse cardiac events; HHF=hospitalisation for heart failure; CVD=cardiovascular disease; GLP-1 RA=glucagon-like peptide-1 receptor agonist; ASCVD=atherosclerotic cardiovascular disease; SGLT2i=sodium–glucose co-transporter-2 inhibitor; CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate |
| Basu A, Patel D, Winocour P, Ryder R. Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement. Br J Diabetes 2021; 21: 132–148. |
Applying Up-to-date Guidance
Although clinicians endeavour to keep up to date with emerging clinical data and aspire to practise evidence-based medicine, prescribing is often done within the constraints of national and local guidance. Current NICE guidance on the management of CVD in people with type 2 diabetes promotes treatment of CV risk factors with atorvastatin for the primary prevention of CVD.38 NICE guidance on the management of type 2 diabetes in adults predates many of the CV outcome trials in which the CV benefits of newer antidiabetic agents such as sodium–glucose co-transporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were demonstrated, and so does not offer any specific recommendations for clinicians around tailoring treatment based on CV risk.39 Thus, updated NICE guidance that takes into account data from CV outcome trials is overdue.
ADA/EASD Consensus Report
The 2018 American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus report offers more specific advice based on the most recent evidence, and recommends the use of SGLT2is or GLP-1 RAs with proven CVD benefit as second-line agents to metformin in established ASCVD.40 If treatment intensification is indicated by glycated haemoglobin (HbA1c) level, then addition of the other class (SGLT2i/GLP-1 RA) is recommended.40 The use of an SGLT2i with evidence of reducing HF is advocated for patients in whom HF is a particular concern.40
ESC/EASD Guidelines
In 2019, the European Society of Cardiology (ESC) recognised the benefits of SGLT2is and GLP-1 RAs in patients with CVD or high CV risk in their guidelines developed in collaboration with the EASD. The ESC/EASD guidelines recommend that liraglutide should be used in patients with prevalent CVD, and that empagliflozin should be used in patients with prevalent CVD or high CV risk, to reduce the risk of death. The guidelines also suggest the use of SGLT2is or GLP-1 RAs as monotherapy in treatment-naïve patients with established ASCVD or high CV risk.41
CaReMeUK Consensus Guidance
In May 2021, in response to the often fragmented care provided to patients with type 2 diabetes and co-morbidities such as CVD, the Cardio–Renal–Metabolic (CaReMeUK) Partnership—a collaboration between the British Cardiovascular Society, the Renal Association, the Association of British Clinical Diabetologists, the Primary Care Cardiovascular Society, and the Primary Care Diabetes Society—issued consensus guidance calling for a more joined-up approach. The guidance takes recent evidence from CV outcome trials into account, and recommends an SGLT2i or GLP-1 RA with proven CV and renal benefits second line after metformin, with the addition of the other class (SGLT2i/GLP-1 RA) if HbA1c remains insufficiently controlled.42
Local Guidance
Some local medicines management groups have also provided guidance for primary care, with the recommendation to use an SGLT2i after metformin in established CVD.43,44 However, the use of GLP-1 RAs is restricted to use in combination with metformin and a sulfonylurea in individuals with a body mass index (BMI) ≥35 kg/m² or for whom insulin therapy would have significant occupational implications, in line with NICE guidance.39 Furthermore, some local guidance recommends that co-prescribing an SGLT2i and a GLP-1 RA should be avoided to reduce prescribing costs.44
What is the ABCD Position?
The ABCD recommends the use of a long-acting GLP-1 RA in patients with established CVD or CVD risk, and an SGLT2i in patients with established HF. For the full ABCD recommendations on the use of newer antidiabetic agents, see Box 1.9
| Box 1: The ABCD Position Statement on the CV Impact of New Antidiabetic Drugs9 |
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DPP-4is The ABCD position is to exercise caution [when using DPP-4is] in patients with HF as other therapeutic agents such as SGLT2is have clearly demonstrated benefit. Sitagliptin, alogliptin and linagliptin are all safe in patients with pre-existing CVD—alogliptin particularly so in patients after acute coronary syndrome, and linagliptin in patients with renal impairment. GLP-1 RAs The ABCD position based on existing data is to consider the use of a long-acting GLP-1 RA—in particular, semaglutide 1 mg once weekly, dulaglutide 1.5 mg once weekly or liraglutide 1.8 mg daily—in patients with pre-existing CVD or CVD risk, if tolerated by the patient. Lixisenatide and prolonged-release exenatide are both safe in patients with pre-existing CVD, and lixisenatide in patients following acute coronary syndrome. These two drugs will help lower HbA1c and promote weight loss but may not confer additional CVD benefits. SGLT2is The ABCD position is to use canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin in patients with pre-existing CVD and type 2 diabetes:
ABCD=Association of British Clinical Diabetologists; CV=cardiovascular; DPP-4i=dipeptidyl peptidase-4 inhibitor; HF=heart failure; SGLT2i=sodium–glucose co-transporter-2 inhibitor; CVD=cardiovascular disease; GLP-1 RA=glucagon-like peptide-1 receptor agonist; HbA1c =glycated haemoglobin; HFrEF=heart failure with reduced ejection fraction; NYHA=New York Heart Association Basu A, Patel D, Winocour P, Ryder R. Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement. Br J Diabetes 2021; 21: 132–148. |
Additional Considerations for Primary Care when Prescribing Newer Antidiabetic Agents in Patients with CVD
Although NICE has yet to update its guidance to reflect the CVD benefits of tailoring treatment for type 2 diabetes, it does provide some recommendations on treatment selection (see Box 2).39
| Box 2: NICE Recommendations on Choice of Treatment for Type 2 Diabetes39 |
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For adults with type 2 diabetes, discuss the benefits and risks of drug treatment, and the options available. Base the choice of drug treatment(s) on:
© NICE 2015. Type 2 diabetes in adults: management. Available from: www.nice.org.uk/guidance/ng28 All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication. See www.nice.org.uk/re-using-our-content/uk-open-content-licence for further details. |
Clinicians are allowed the freedom to select the most appropriate therapy for the individual, within the parameters of their local drug formulary and individual drug licences. Care should be person centred,39,40 so algorithms cannot be applied. The use of metformin as the first-line agent in the management of type 2 diabetes is not disputed;39,40 we will now examine other considerations when escalating antidiabetic treatment.
DPP-4i Therapy
The DPP-4is sitagliptin, alogliptin, and linagliptin have demonstrated safety in terms of three-point MACE end points, but do not appear to have any effect on overall mortality.9 These agents are particularly useful because they are generally well tolerated and carry a lower risk of hypoglycaemia than some other therapies, including metformin, thiazolidinediones, and SGLT2is.45 According to NICE guidance, therapy with sitagliptin or vildagliptin should only be continued if the person has had a beneficial metabolic response (a reduction of at least 0.5 percentage points [5.5 mmol/mol] in HbA1c in 6 months).46 Caution should be exercised when using saxagliptin in patients known to have HF.21
GLP-1 RAs
Although the ADA/EASD may endorse the use of GLP-1 RAs as a second- or third-line agent in the management of type 2 diabetes,40 the cost constraints of prescribing within the NHS are likely to prohibit such widespread use. However, to withhold a drug with proven CV benefits in someone with a BMI <35 kg/m² presents a moral dilemma for clinicians and stakeholders alike. Whether a caveat will be added to future guidance that explains when GLP-1 RAs should be used outside of obesity remains to be seen. In the absence of such guidance, clinicians should use their clinical judgement, and may choose to consider using semaglutide, dulaglutide, or liraglutide as a second-line agent in people with pre-existing CVD, if SGLT2is are contraindicated or not tolerated, and based on medical evidence.
A significantly higher incidence of retinopathy complications is seen with semaglutide versus placebo; these are attributed to a rapid reduction in HbA1c in patients with pre-existing diabetic retinopathy and poor glycaemic control and in those treated with insulin.9 Rapid improvement in HbA1c is known to increase the risk of worsening diabetic retinopathy,47 and caution should be exercised when using semaglutide in patients with diabetic retinopathy who are taking insulin.48
SGLT2is
SGLT2is are the newest class of antidiabetic agents, and offer additional benefits across the class, aside from glucose lowering.49 With a wealth of clinical evidence supporting their use and national guidance pending, the use of empagliflozin, dapagliflozin, or canagliflozin as the second-line drug of choice in patients with type 2 diabetes and established CVD seems wholly appropriate. Basu et al. advocate the use of SGLT2is in HF,9 although dapagliflozin is currently the only drug with a licence for use in HF with reduced ejection fraction, irrespective of the presence of type 2 diabetes.50 Dapagliflozin is not licensed for the treatment of HF in type 1 diabetes.50
Although there is evidence supporting the reno-protective benefits of canagliflozin and dapagliflozin,9 drug licences are yet to be amended. SGLT2is should only be initiated for the treatment of type 2 diabetes if glomerular filtration rate (GFR) is >60 ml/min/1.73 m2, and should be discontinued if GFR is persistently <45 ml/min/1.73 m2.51 However, no dose adjustment based on renal function is required if dapagliflozin is initiated for HF, which is confusing for clinicians, and there is limited experience of the use of dapagliflozin for HF in patients with severe renal impairment (GFR <30 ml/min/1.73 m2).50
Based on the available evidence, prescribing of SGLT2is by both cardiologists and nephrologists is extremely likely to increase. Changes to drug licences to capitalise upon the CV and renal benefits of SGLT2is will come, and clinicians must remain abreast of these updates; however, consideration needs to be given to safety, as well as the benefits of these agents.
Side-effects of Newer Antidiabetic Agents
Diabetic ketoacidosis (DKA) is a potential rare adverse effect following treatment with SGLT2is, which sometimes presents atypically without elevated blood glucose.52 The European Medical Agency recommends that patients are made aware of the symptoms of DKA, and instructed to seek advice if the symptoms present.53 Treatment with SGLT2is should be stopped immediately if DKA is suspected or confirmed, and should not be restarted unless another cause for the DKA is identified and resolved.52 To minimise the risk of DKA, patients should be reminded to stop their treatment temporarily when undergoing major surgery or during acute serious illnesses.52
A possible increased risk of lower-limb amputation (mainly toes) has been seen in clinical trials with canagliflozin, but it is unclear if this is a class effect.54 Patients with poor glycaemic control and pre-existing CVD are at increased risk of ulceration and infection, and should be counselled with regard to routine preventative foot care and adequate hydration.54
Fournier’s gangrene is also infrequently associated with the use of SGLT2is and, if suspected, the SGLT2i should be stopped and treatment commenced urgently.55 Patients should be counselled 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.55
Summary
Differences in study populations and design make direct comparisons of CV outcome trials data more difficult. Although national and local guidance remains invaluable to those with less clinical experience, there should always be scope to prescribe outside of guidance at a clinician’s discretion, based on the evidence available to them.
| Key Points |
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CV=cardiovascular; SGLT2i=sodium–glucose co-transporter-2 inhibitor; HF=heart failure; GLP-1 RA=glucagon-like peptide-1 receptor agonist; CVD=cardiovascular disease; CKD=chronic kidney disease |
Karen Bartha
Diabetes Clinical Nurse Specialist, University Hospitals Birmingham NHS Foundation Trust
| Implementation Actions for Clinical Pharmacists in General Practice |
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Written by Shailen Rao, Managing Director, Soar Beyond Ltd The following implementation actions are designed to support clinical pharmacists in general practice with implementing the guidance at a practice level. Every GP clinical pharmacist has a role to play in the optimisation of treatments for patients with diabetes and CVD. Many GP clinical pharmacists are already specialising and running proactive diabetes clinics and as their remit expands, pharmacists are taking on more complex patients with co-morbidities.
Soar Beyond’s i2i Network has three programmes designed to support GP clinical pharmacists at various points in their development journey in managing type 2 diabetes, available free to pharmacists. www.i2ipharmacists.co.uk [A] PCDS. How to prioritise primary care diabetes services during and post COVID-19 pandemic. PCDS, 2020. Available at: www.pcdsociety.org/resources/details/howprioritise- primary-care-diabetes-services-during-and-post-covid-19-pandemic CVD=cardiovascular disease; BMI=body mass index; PCDS=Primary Care Diabetes Society; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; SGLT2i=sodium–glucose co-transporter-2 inhibitor; GLP‑1 RA=glucagon-like peptide-1 receptor agonist; MDT=multidisciplinary team |