29th January 2020, Dr Chee L Khoo
The major difference between the 2018 American Diabetes Association/ European Association for the Study of Diabetes (ADA/EASD) consensus guidelines compared to previous guidelines were that they were less glucose centric in determining which agent to use after metformin. We used to use the most potent agent to get the sugars to target but increasingly, we are now looking at what other benefits the next agent has in addition to lowering glucose. Many of the newer agents have been shown in numerous cardiovascular outcome trials (CVOTs) to improve major adverse cardiovascular events (MACE), hospitalisation for heart failure (hHF), cardiovascular death and progression of chronic kidney disease (CKD). There has been an update to those guidelines. Let’s have a look at what’s new.
Step one in the 2018 guidelines in a patient whose HbA1c is not on target, was to consider whether the patient have significant CVD or renal disease. If they have, then we should consider either an SGLT2 inhibitor (SGLT2i) or a GLP1 agonist as the next agent. The guidelines were not that specific as to which of the two classes we should choose and they seem to lump cardiac disease with renal disease. The reasons for that approach is 1) we don’t have data to dissect out which cardiovascular component improved and 2) there were no direct and specific data on the impact on renal endpoints.
ADA/EASD – the 2019 update
Recommendation 1 – T2D with atherosclerotic CV disease (ASCVD)
In the REWIND study involving GLP1 agonist, dulaglutide (Trulicity), half the trial population had established cardiovascular disease while the other half had high cardiovascular risks (1). Overall, dulaglutide was found to reduce MACE by 12%. When the populations were considered separately the reduction in MACE was not significant. Thus, for patients with type 2 diabetes and established atherosclerotic CV disease (such as those with prior myocardial infarction, ischaemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging or stress test, or revascularisation of coronary, carotid, or peripheral arteries) where MACE is the gravest threat, the level of evidence for MACE benefit is greatest for GLP-1 receptor agonists.
A GLP1 agonist should also be considered in patients with T2D and established CV disease or at high risk of CV disease including patients aged 55 years or older with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR = 60 mL/min/1.73m2, or albuminuria.
Recommendation 2 – T2D with hospitalisation for heart failure (hHF)
Meta-analysis of the SGLT2i CVOTs suggests a class effect to reduce hHF and CKD progression across high and lower CVD risk subgroups. Interestingly, SGLT2i had with no effect on MACE in patients with no established ASCVD (2). Further, analysis of two SGLT2i CVOTs, DECLARE–TIMI 58 (3) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (4), suggests that the benefits of SGLT2i for hHF, MACE, and CV death are greatest for those individuals with pre-existing heart failure with reduced ejection fraction (HFrEF) compared with those without HFrEF.
The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial of dapagliflozin was the first dedicated heart failure outcome trial of a diabetes medication (5). Dapagliflozin reduce the primary composite end point of CV death, hHF, and urgent HF visits, as well as for HF events and mortality (CV and total) in patients with or without diabetes.
SGLT2i are now recommended in patients with type 2 diabetes and HF, particularly those with HFrEF, to reduce hHF, MACE, and CV death.
Recommendations 3 – T2D with CKD
Due to its mechanism of action, the glucose lowering efficacy of SGLT2i decreases with decreasing renal function. SGLT2i can only be used if the eGFR is >45 for both empagliflozin and dapagliflozin. Fortunately, the cardiovascular benefits of SGLT2i are not dependent on eGFR. Further, in the SGLT2i CVOTs, the small subgroup of patients with renal impairment, there was a suggestion that SGLT2 inhibitors may reduce the progression of renal disease. But the numbers were small and renal endpoints were not in the primary outcomes.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial of the SGLT2i canagliflozin was the first specific renal outcome trial of a diabetes medication (6) with a primary composite end point of end-stage kidney disease (dialysis, transplantation, or a sustained eGFR = 15-60 mL/min/1.73m2, a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Canagliflozin (which is no longer available in Australia) demonstrated reduction in MACE, hHF, cardiovascular mortality, and renal end points regardless of baseline status for cardiovascular or CKD grade 2–3. The benefits are clear-cut for those with urinary ACR (uACR) ≥ 300 mg/g and eGFR = 30 – 90 mL/min/1.73m2and less well established for lesser grades of CKD.
Thus, SGLT2 inhibitors should be used to prevent hHF, MACE, and CV death and the progression of CKD in patients with type 2 diabetes with CKD. You may hesitate to use a SGLT2i in patients with CKD but to the contrary, these are the patients you should use an SGLT2i.
Recommendations 4 – high risk lower limb amputation
In the CANVAS trial, there was an increased risk of lower limb amputation with canagliflozin compared with placebo (4). This increase was not seen in CREDENCE (also involving canagliflozin) or the other SGLT2i CVOTs. Nonetheless, there is a recommendation that in patients with foot ulcers or at high risk of amputation, use of SGLT2i should taken with care and with foot education with the patient.
Recommendation 5 – early use of combination therapy
In newly diagnosed patient, we generally think about metformin and lifestyle measures first. If the HbA1c after 3-6 months is still suboptimal, then we consider adding a second agent. There is limited evidence of initial combination therapy, well, until VERIFY study. The Vildagliptin Efficacy in Combination with Metformin for Early Treatment of Type 2 Diabetes (VERIFY) looked at newly diagnosed (<2 years) T2D and compared metformin monotherapy to metformin plus vildagliptin (7). Over a 5 year follow up period, metformin/vildagliptin combination in newly diagnosed T2D reduced median time to treatment failure compared with metformin monotherapy (61.9 months vs 36.1 months)
Summary of the summary of the 2019 guidelines
In patients with T2D on metformin and attended to lifestyle issues and the HbA1c is still not on target:
- If there is established CVD or at high risk of CVD, consider a GLP1 agonist with proven cardiovascular benefits
- If there is heart failure especially heart failure with reduced ejection fraction (HFrEF), the consider a SGLT2i
- If there is CKD, especially if eGFR between 30-60 ml/min/1.73 m2, or uACR > 300g/mg, then consider a SGLT2i
- If there are foot ulcers or at high risk of lower limb amputation, take care when using SGLT2i. Use after full foot assessment, discussion with patient and foot education
In newly diagnosed T2D, initial combination therapy may be considered.
- Gerstein HC, Colhoun HM, Dagenais GR, et al.; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394: 121–130
- Zelniker TA,Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascularand renal outcomes in type 2 diabetes mellitus. Circulation 2019;139:2022–2031
- Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019;139:2528–2536
- Figtree GA, R°adholm K, Barrett TD, et al. Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes mellitus. Circulation 2019;139:2591–2593
- McMurray JJV, Solomon SD, Inzucchi SE, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 21 November 2019 [Epub ahead of print]. DOI:10.1056/NEJMoa1911303
- Perkovic V, Jardine MJ, Neal B, et al.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306
- Matthews DR, Pald´anius PM, Proot P, Chiang Y, Stumvoll M, Del Prato S; VERIFY study group. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 2019;394:1519–1529