AMPLITUDE-O, a cardiovascular outcome trial (CVOT) of efpeglenatide (a once-weekly, exendin-based injectable GLP-1 receptor agonist) in those with previous cardiovascular disease (CVD) events or chronic kidney disease (CKD) and CV risk factors, demonstrated significant reduction in 3-point major adverse cardiovascular events (MACE) and a renal composite of CKD progression, compared to placebo over a median 1.8 years of follow-up. There were no differences in outcomes depending on baseline eGFR or co-prescribed metformin or SGLT2 inhibitors. An updated meta-analysis of GLP-1 RA cardiovascular outcome studies, including AMPLITUDE-O, demonstrated consistent benefits on MACE and slowing progression of CKD across the GLP-1 RA class.
The study randomised 4076 participants with type 2 diabetes and HbA1c >7% (53 mmol/mol) who had either:
- a history of established CVD, or
- aged ≥50 years (male) or ≥55 years (female) with CKD (eGFR 25.0–59.9 mL/min/1.73 m2), plus at least one other CV risk factor.
Mean age was 65.4 years, with nearly 50% <65 years; only 33% were female. 89.6% had prior CVD and nearly one third had an eGFR <60 mL/min/1.73 m2. 21.8% had both established CVD and low eGFR. Previous CVOTs with GLP-1 RAs did not include significant numbers co-treated with SGLT2 inhibitors. AMPLITUDE-O, therefore, sought to clarify how combination treatment with the two classes would affect outcomes; 15.2% were using an SGLT2 inhibitor at baseline. Use of other glucose-lowering and cardioprotective drugs were similar between those randomised to placebo and efpeglenatide. By study completion, 21.2% of those in the placebo group were prescribed an SGLT2 inhibitor compared with 17.5% of those receiving efpeglenatide at either dose.
Participants were randomised to receive efpeglenatide 4 mg or 6 mg or placebo, all delivered in identical syringes for subcutaneous injection, and randomisation was stratified according to SGLT2 inhibitor use. Efpeglenatide was initiated at 2 mg weekly, and the dose increased every 4 weeks until the randomised dose was achieved.
The primary outcome was first occurrence of MACE consisting of cardiovascular death or non-fatal myocardial infarction or stroke.
Secondary outcomes, in hierarchical order of testing, included:
- Expanded MACE (including coronary revascularisation and hospitalisation for unstable angina).
- Composite renal outcome: new macroalbuminuria (ACR >300 mg albumen to creatinine in grams [>33.9 ACR measured in mg albumin to mmol creatinine as reported in the UK]); increase in ACR of ≥30% from baseline; sustained decrease in eGFR ≥40% for >30 days; renal replacement therapy for 90 days; or sustained eGFR <15 mL/min/1.73 m2 for ≥30 days.
- MACE or death from non-CV causes.
Other pre-specified secondary endpoints included components of the expanded MACE or renal outcomes, death from any cause or hospitalisation for heart failure. A variety of additional pre-planned composite outcomes were also explored.
There were 3.9 events MACE events per 100 person years in those treated with efpeglenatide compared to 5.3 events per 100 person years in those receiving placebo (27% significant reduction) demonstrating non-inferiority and superiority of efpeglenatide in reducing major adverse cardiovascular events, with a possible greater benefit for the higher dose of efpeglenatide versus the lower dose. 46 similar patients would need to be treated with efpeglenatide for 1.8 years to prevent one major adverse cardiovascular event. There was also a significantly lower incidence of expanded MACE composite event, which included revascularisation and unstable angina.
The composite renal outcome used in AMPLITUDE-O (new macroalbuminuria, increase in ACR of ≥30% from baseline, sustained decrease in eGFR ≥40% for >30 days, renal replacement therapy for 90 days, or sustained eGFR <15 mL/min/1.73 m2 for ≥30 days) was significantly reduced by 32% in those receiving efpeglenatide versus placebo.
Results of the analyses of the other pre-specified secondary endpoints must be seen as exploratory only, due to the hierarchy of statistical testing. Despite attempts to achieve glycaemic equipoise, there was a 1.24% difference in HbA1c between those treated with efpeglenatide compared to placebo, and small differences in blood pressure and weight, which the investigators concluded might contribute a small amount to the identified outcome differences.
As would be anticipated, gastrointestinal adverse events occurred more frequently with efpeglenatide than with placebo, but other pre-specified safety outcomes and adverse events were similar between the treatment and placebo groups. There was no signal for worsening of retinal disease, but those with severe retinal disease were excluded from the study.
Key take-home messages
In those with type 2 diabetes and high prevalence of CV and kidney disease with high HbA1c and moderate use of an SGLT2 inhibitor, efpeglenatide 4 mg or 6 mg injection once-weekly significantly and safely reduced:
- MACE (including death from unknown causes) by 27%.
- Expanded MACE, including coronary revascularisation or unstable angina, by 21%.
- Renal composite by 32%.
- MACE or non-CV death by 27%.
Professor Naveed Sattar, University of Glasgow, presented an updated meta-analysis of outcomes from the eight GLP-1 RA CVOTs, including AMPLITUDE-O. This demonstrated a 24% reduction in 3-component MACE, with no difference between human and exendin-based GLP-1 RA structures. There was a greater effect (17% reduction) in stroke than myocardial infarction. They demonstrated a decrease in all-cause mortality, plus additional evidence of reduced risk of hospitalisation for heart failure and renal dysfunction. They concluded there was no increased risk of severe hypoglycaemia, retinopathy or pancreatic adverse effects.
In her independent commentary on the study, Amanda Adler (Professor of Diabetic Medicine and Health Policy at the University of Oxford) congratulated the investigators on placing the trial in the context of previous CVOTs, demonstrating the safety of efpeglenatide, and that it lowered the risk of CV and renal disease compared with standard care. Those results that were only exploratory in respect of the statistical hierarchy were clearly labelled. She highlighted that this study is primarily a safety trial and, compared to other GLP-1 RA CVOTs, this study recruited those with longer duration of type 2 diabetes (up to 15 years), eGFRs down to 25 mL/min/1.73 m2, highest mean HbA1c (8.9% [74 mmol/mol]) and the highest percentage of people on insulin (72%).
Professor Adler challenged the use of placebo as the comparator in relation to the CV outcome, since she felt the real question is how this drug compares to other drugs in class. However, for the renal outcome, she agreed placebo was the correct comparator, since the drug would be used mainly as add-on to ACE/ARB or sacubitril–valsartan, rather than instead of these. SGLT2 inhibitors are known to have cardioprotective effects and people were stratified by use at baseline into current use, potential future use and neither current nor future use. She concluded that if there was an interaction between SGLT2 inhibitor use and efpeglenatide, then this study did not find it.
Data were presented at the 81st Scientific Sessions of the American Diabetes Association, and the results from the AMPLITUDE-O study simultaneously published in The New England Journal of Medicine.