Another Positive GLP-1 RA CVOT: The AMPLITUDE-O Trial

Quick Takes

  • Both established cardiovascular and renal diseases predict future adverse events resulting from diabetes.
  • GLP-1 receptor agonists have emerged not only as powerful medications for type 2 diabetes management and weight reduction but now have been shown to provide strong cardiovascular and renal risk reduction.
  • Efpeglenatide, a new potent, exendin-4-based weekly subcutaneous GLP-1 receptor agonist, has been shown to reduce cardiovascular and renal events by 27% and 32%, respectively, in people with type 2 diabetes and a history of cardiovascular or renal disease.

Type 2 diabetes mellitus (T2DM) is a well-established, independent risk factor for cardiovascular disease (CVD).1 People with diabetes have more than double the risk for future CVD events.1 The presence of diabetic kidney disease (DKD) – characterized by declined estimated glomerular filtration rate (eGFR)2 or elevated urinary albumin-to-creatinine ratio (UACR)3 – increases the incidence of CVD events and has become a significant additional risk factor for CVD.4 The presence of diabetes and CVD more than doubles the risk of mortality.5 CVD is a leading cause of death in people with diabetes and diabetic kidney disease.6 Early and evidence-based interventions aimed at reducing these events are much needed.

Numerous cardiovascular outcome trials (CVOTs) have shown not only the safety of GLP-1 receptor agonists (GLP-1 RAs) in the management of people with T2DM with or at risk for CVD, but a growing number of trials have shown proven benefit to reduce such risks.7-10 Efpeglenatide, a novel, exendin-4-based weekly GLP-1 RA to be administered subcutaneously, effectively lowers glucose levels in people with T2DM.11 In a new large CVOT, Gerstein et al. evaluated the effect of efpeglenatide on cardiovascular and renal outcomes in adults with T2DM.12

The AMPLITUDE-O Trial enrolled 4,076 adults with T2DM who had an HbA1c >7.0% and either a baseline history of CVD (89.6%) or diabetic kidney disease (DKD) with an eGFR <60 ml/min (31.6%).12 Baseline CVD was defined as a history of coronary artery disease (CAD), stroke, peripheral artery disease (PAD), or if they had at least one CVD risk factor and an eGFR between 25 to 59.9 ml/min per 1.73 m2 of body surface area in adults, men age ≥50 or women ≥55.12 Notably, 21.8% of the participants had both CVD and DKD.12 All participants were already treated with standard of care, and they were also stratified based on the use of an SGLT-2 inhibitor (15.2%).12

The primary composite outcome was the first occurrence of a 3-point major adverse cardiovascular event (MACE), including nonfatal myocardial infarction, nonfatal stroke, or death from CV-related or undetermined causes.12 This trial's key secondary outcomes were an expanded MACE composite outcome to include coronary revascularization or hospitalization for unstable angina and a composite renal outcome defined as a new onset of proteinuria (UACR > 300 mg/g) and an increase in UACR ≥ 30% from baseline, a sustained decrease of eGFR ≥ 40% for at least 30 days, a sustained eGFR < 15 ml/min per 1.73 m2 for at least 30 days, or any need for renal replacement therapy for at least 90 days.12

The investigational team aimed to achieve a power of 90% in the trial for demonstrating the US Food and Drug Administration (FDA)-mandated noninferiority between results from the efpeglenatide group and the placebo group.12 In addition, the research team used Cox proportional hazards models with adjustments on geographical regions and SGLT2 inhibitor use stratification factor from randomization to estimate hazard ratios (HR) for the pre-identified primary and secondary outcomes with 95% confidence intervals (CI).12 Due to the sponsor's decision to end funding, CVOT was closed after the accrual of 314 primary events rather than the planned 330; still it showed positive result.

In this pivotal CVOT, there was a 27% reduction in the primary composite outcome in participants on efpeglenatide (4 or 6 mg weekly) (HR, 0.73; 95% CI, 0.58 - 0.92; p < 0.007 for superiority) compared to placebo among persons with T2DM with CVD history or existing kidney disease.12 This resulted in a number needed to treat (NNT) of 46 participants to prevent one MACE event over 1.8 years, and the NNT for the composite renal outcome was 19.12 The significant benefits were also observed in the expanded MACE composite outcome (HR 0.79; 95% CI, 0.65 - 0.96; p = 0.02 for superiority), a MACE or death from non-cardiovascular causes (HR 0.73; 95% CI, 0.59-0.91; p < 0.004 for superiority) and composite renal outcome (HR 0.68; 95% CI, 0.57 - 0.79; p < 0.001 for superiority).12 Benefits were greater in those who had baseline CVD (HR 0.71; 95% CI, 0.57 - 0.90; p < 0.05), were on baseline metformin (HR 0.70; 95% CI, 0.53 - 0.92; p < 0.05), were obese with body mass index (BMI) > 31.9 kg/m2 (HR 0.61; 95% CI, 0.45 – 0.83) and had a baseline eGFR < 71.5 ml/min per 1.73 m2  (HR 0.67; 95% CI, 0.50 - 0.93; p < 0.05).12 Those without baseline CVD had a hazard ratio of 1.71 (95% CI, 0.48 - 6.07; p > 0.05) for the new onset of MACE.12 Those who were not on a baseline SGLT2 inhibitor exhibited a significant relative risk reduction (RRR) on new onsets of MACE (HR 0.74; 95% CI, 0.58 – 0.94) compared to those who were on this class of agents at baseline without a significant RRR (HR 0.70; 95% CI, 0.37 – 1.30). However, this difference in obtaining significant results between these two subgroups could have been due to fewer participants meeting the primary composite endpoint in both groups with a baseline SGLT2 inhibitor, as the SGLT2 inhibitor might have prevented the new onset of MACE in this subgroup of participants. With fewer occurrences of MACE in the subgroup with a baseline SGLT2 inhibitor, the statistical power was not robust enough.

Compared to the previous CVOTs of GLP-1 RAs, the AMPLITUDE-O Trial included participants who were at a higher risk for CVD and had more cases of kidney disease.12 This trial, with an exendin-4-based, weekly GLP-1 RA, further reinforces the expanding and robust database beyond the GLP-1 RAs that have a similar structure to human GLP-1 as powerful glycemic-lowering and weight-loss agents as well as effective in reducing CV and renal adverse event risks. Recent guidelines have placed this class of agents as first-line glycemic-lowering therapy in people with baseline CVD, high risk for CVD, or chronic kidney disease (CKD).13-15

There is indeed ample evidence for all healthcare professionals (including at least primary care, endocrinologists, and cardiologists) to add a GLP-1 RA with proven CV benefits in patients' pharmacotherapeutic regimens for those with T2DM and CVD; select findings from all GLP-1RA CVOTs are summarized in Table 1.

Table 1

GLP-1 RA Mean Follow-Up Duration (Years) Name of the CVOT Number of Participants Composite MACE Outcome
HR; 95% CI
Composite Renal Endpoint
HR; 95% CI
lixisenatide 2.1 ELIXA16 6,068 1.02; 0.89 - 1.17  
liraglutide 3.8 LEADER7 9,340 0.87; 0.78 - 0.97  
3.1 SUSTAIN-68 3,297 0.74; 0.58 - 0.95 0.64; 0.46 - 0.88*
3.2 EXSCEL17 14,752 0.91; 0.83 - 1.00  
albiglutide 1.6 HARMONY10 9,463 0.78; 0.68 - 0.90  
dulaglutide 5.4 REWIND9 9,901 0.88; 0.79 - 0.99 0.85; 0.77 - 0.93**
1.3 PIONEER 618 3,183 0.79; 0.57 - 1.11  
efpeglenatide 1.8 AMPLITUDE-O12 4,076 0.73; 0.58 - 0.92 0.68; 0.57 - 0.79***
Table 1. Summary of CVOTs assessing composite MACE outcome and renal endpoint. Courtesy of Shubrook JH, Young CF.
* Persistent macroalbuminuria, persistent doubling of the serum creatinine (SCr) level and a creatinine clearance (CrCl) of < 45 ml/min per 1.73 m2 of body-surface area, or renal-replacement therapy.
** New onset of macroalbuminuria/proteinuria, a sustained decline in eGFR of ≥ 30% from baseline, or chronic renal replacement therapy.
*** New onset of macroalbuminuria/proteinuria plus an increase in urinary albumin-to-creatinine ratio of ≥ 30% from baseline, a sustained decline in eGFR of ≥ 40% for 30 days or more, renal-replacement therapy for 90 days or more, or a sustained eGFR of < 15 ml/min per 1.73 m2 for 30 days or more.


  1. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol 2015;3:105-13.
  2. Cherney DZI, Repetto E, Wheeler DC, et al. Impact of cardio-renal-metabolic comorbidities on cardiovascular outcomes and mortality in type 2 diabetes mellitus. Am J Nephrol 2020;51:74-82.
  3. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286:421-26.
  4. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009;20:1813-21.
  5. Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA 2015;314:52-60.
  6. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol 2018;17:83.
  7. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
  8. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
  9. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-30.
  10. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519-29.
  11. Rosenstock J, Sorli CH, Trautmann ME, et al. Once-weekly efpeglenatide dose range effects on glycemic control and body weight in patients with type 2 diabetes on metformin or drug naive, referenced to liraglutide. Diabetes Care 2019;42:1733-41.
  12. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021;385:896-907.
  13. American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022;45 (Supplement 1):S125 – S143.
  14. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255-323.
  15. Das SR, Everett BM, Birtcher KK, et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes. J Am Coll Cardiol 2020;76:1117-45.
  16. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.
  17. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.
  18. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841-51.

Clinical Topics: Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Diabetes and Cardiometabolic Disease

Keywords: Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor, Body Mass Index, Creatinine, Exenatide, Glycated Hemoglobin A, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Diabetic Nephropathies, Glomerular Filtration Rate, Proportional Hazards Models, Body Surface Area, Confidence Intervals, Coronary Artery Disease, Endocrinologists, Standard of Care, United States Food and Drug Administration, Risk Factors, Renal Insufficiency, Chronic, Stroke, Evidence-Based Medicine, Peripheral Arterial Disease, Renal Replacement Therapy, Myocardial Infarction, Anti-Obesity Agents, Angina, Unstable, Primary Health Care, Delivery of Health Care, Proteinuria, Metformin, Albumins, Glucose, Glucagon-Like Peptide 1, Obesity

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