ADA/EASD 2019: New recommendations aim to reduce cardiovascular and renal risk in type 2 diabetes

The latest update to international guidance for the management of type 2 diabetes recommends the use of GLP-1 receptor agonists or SGLT2 inhibitors to reduce the risk of cardiovascular events and chronic kidney disease, irrespective of baseline glucose levels

The American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD) have updated their 2018 consensus report based on findings from large cardiovascular outcome trials published during 2019.¹ The overall principles of management set out in the 2018 report remain valid so this update should be read in conjunction with the previous report.² See New guideline transforms approach to therapy in T2D.

New recommendations

• The decision to treat high-risk patients with a GLP-1 RA or SGLT2 inhibitor to reduce major cardiovascular events (MACE), hospitalisation for heart failure (hHF), cardiovascular death, or chronic kidney disease (CKD) progression should be considered irrespective of baseline HbA1c or individual HbA1c target.
• GLP-1 RAs can also be considered in patients with type 2 diabetes without established CVD but with indicators of high risk.
• SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction, to reduce hHF, MACE and CVD death, as well as in patients with type 2 diabetes with CKD (eGFR rate 30 to ≤60 ml/min/1.73m2 or urinary albumin-to-creatinine ratio >3 mg/mmol, and particularly >30 mg/mmol) to prevent the progression of CKD, hHF, MACE and cardiovascular death.*¹

Based on studies published to date, the ADA/EASD considers that for patients with type 2 diabetes and established atherosclerotic CVD (prior myocardial infarction, ischaemic stroke, unstable angina with ECG changes etc) where MACE is the gravest threat, the level of evidence for MACE benefit is greatest for GLP-1 RAs.¹

For patients with or without established atherosclerotic CVD, but with heart failure with reduced ejection fraction (HFrEF) or CKD, defined above, the level of evidence is greatest for SGLT2 inhibitors.¹

The new recommendations are based on a number of CVOTs that reported in 2019.

REWIND

The Researching cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial of the glucagon-like peptide receptor agonist (GLP-1 RA) dulaglutide included a high proportion of people with type 2 diabetes with high cardiovascular risk but without prior established CVD (68.5%). The trial involved 9,901 subjects, followed for an average of 5.4 years. Major adverse cardiovascular events (MACE) occurred in 12% in the dulaglutide group compared with 13.4% in the plaebo group. (2.4 versus 2.7 per 100 person-years, respectively).³

Recommendation

To reduce the risk of MACE, GLP-1 RAs can be considered in patient with type 2 diabetes without established CVD with indicators of high risk, specifically, patients aged ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy (LVH), eGFR <60ml/min/1.73m2 or albuminuria (≥3mg/mmol).¹

DECLARE-TIMI 58

The Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial compared the SGLT2 inhibitor dapagliflozin with placebo, and enrolled a greater proportion of subjects with type 2 diabetes without prior established CVD but with multiple risk factors (59.4%). The study evaluated 17,160 patients including 10,186 without ASCVD, and followed them over an average of 4.2 years. Dapagliflozin did not result in lower incidence of MACE, but did show reductions in the incidence of cardiovascular death and hospitalisation for heart failure (hHF), and renal events occurred less frequently in the dapagliflozin group than with placebo (4.3% versus 5.6%, respectively).⁴

Meta-analysis of the SGLT2 inhibitor CVOTs suggests a class effect to reduce hHF and CKD progression across both high and low risk CVD groups but with no effect on MACE in people without established ASCVD.⁵

Recommendation

SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with HFrEF to reduce hHF, MACE and cardiovascular death.¹

HbA1c eligibility

The REWIND trial of dulaglutide had no lower limit to HbA1c for eligibility and showed equal efficacy for reduction of MACE above and below the median HbA1c of 55 mmol/mol. None of the CVOTs of SGLT2 inhibitors with primary MACE endpoints have recruited patients with an HbA1c of <48 mmol/mol and there is little evidence to inform clinical decisions in patients with an HbA1c <53 mmol/mol. But the benefits observed in the CVOTs do not appear to be restricted to patients with a raised HbA1c. The DAPA-HF trial recruited patients with HFrEF with and without diabetes, and the evidence for reduction of mortality rate and HF events was significant for both groups of patients, suggesting that the effect of dapagliflozin on these outcomes is independent of HbA1c.⁶

Recommendation

In appropriate high-risk individuals with established type 2 diabetes, the decision to treat with a GLP-1 RA or SGLT2 inhibitor to reduce MACE, hHF, cardiovascular death or CKD progression should be considered independently of baseline HbA1c or individualised HbA1c target.¹

Recommendation

It is reasonable to prescribe a drug with known CVD, CKD, and hHF benefit as a substitute for one without known benefit in high-risk patients is reasonable when patients are at individualised glycaemic targets.¹

RENAL OUTCOMES

CREDENCE

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial of the SGLT2 inhibitor canagliflozin was the first renal outcome trial of a diabetes medication with the primary composite endpoint of end-stage kidney disease (dialysis, transplantation or sustained eFGR of <15 ml/min/1.73m2), a doubling of serum creatinine level, or death from renal or cardiovascular causes.⁷

This trial demonstrated a clear benefit of canagliflozin on multiple renal end points, including progression to end-stage kidney disease, and on cardiovascular mortality, MACE, and hHF. Results were similar regardless of baseline cardiovascular status or CKD grade 2-3.

Recommendation

SGLT2 inhibitors should be used to prevent hHF, MACE, CV death and the progression of CKD in patients with type 2 diabetes and CKD.¹

Patients with foot ulcers or at high risk for amputation should only be treated with SGLT2 inhibitors after careful shared decision making around the risk and benefits, with comprehensive education on foot care and amputation prevention.

Initial combination therapy

In the 2018 report, the ADA/EASD said it had found no evidence of advantage for using initial combination therapy for newly diagnosed patients, but a recent study of vildagliptin in combination with metformin for the early treatment of type 2 diabetes (VERIFY) showed that using this combination of a DPP-4 inhibitor and metformin resulted in a lower rate of failure of glycaemic control than using these drugs sequentially.⁸

Recommendation

Consider initial combination therapy (with the DPP-4 inhibitor vildapliptin and metformin) in new onset cases of type 2 diabetes.¹

The report concludes that while the way that GLP-1 RAs and SGLT2 inhibitors confer cardiovascular and renal benefits is not yet understood, there is now clear potential of drugs for diabetes to reduce the cardiovascular and renal complications of the disease.¹

Definitions

• Proven CVD benefit means the drug has a licensed indication for reducing CVD events
• Adequate eGFR for SGLT2 inhibitors: be aware that SGLT2 inhibitor licenses vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use
• Empagliflozin, canagliflozin and dapagliflozin have shown reduction in HF and to reduce CKD progression in CVOTs. Canagliflozin has primary renal outcome data from CREDENCE.⁷ Dapagliflozin has primary heart failure outcome data from DAPA-HF.⁶

*Many of these recommendations are outside the current product licenses for GLP-1 RAs and/or SGLT2 inhibitors. Clinicians should consult the summary of product characteristics before prescribing, or follow the advice on off-label prescribing at https://www.gov.uk/drug-safety-update/off-label-or-unlicensed-use-of-medicines-prescribers-responsibilities

References

1. Buse JB, et al. Diabetes Care 2019 Dec; dci190066. https://care.diabetesjournals.org/content/early/2019/12/18/dci19-0066

2. Davies MJ, et al. Diabetes Care 2018;41:2669-2701

3. Gerstein HC, et al. Lancet 2019;394:121-130

4. Wiviott SD, et al. N Engl J Med 2019;380:347-357

5. Zelniker TA, et al. Circulation 2019;139:2022-2031

6. McMurray JJV, et al. N Engl J Med 2019:381:1995-2008

7. Perkovic V, et al. N Engl J Med 2019;380:2295-2306

8. Matthews DR, et al. Lancet 2019;394:1519-2529