Effects of albiglutide on myocardial infarction and ischaemic heart disease outcomes in patients with type 2 diabetes and cardiovascular disease in the Harmony Outcomes trial

Abstract

Aims

Large outcome trials have demonstrated cardiovascular benefits of selected glucagon-like peptide-1 (GLP-1) receptor agonists. We examined coronary disease outcomes in the Harmony Outcomes trial of the GLP-1 receptor agonist albiglutide.

Methods and results

Harmony Outcomes was an event-driven, multicenter, double-blind, and placebo-controlled trial involving 9463 patients >40 years of age with type-2 diabetes and established atherosclerotic cardiovascular disease. It tested the effects of albiglutide on the occurrence of a composite primary endpoint, consisting of cardiovascular death, myocardial infarction (MI), or stroke. Within this post-hoc analysis, the effects of albiglutide on MI subtypes and other ischaemic endpoints were analysed.

During the median-follow up of 1.6 years, a total of 421 patients (4.5%) experienced at least one MI, with 72 patients having more than one event. Treatment with albiglutide reduced both first events [hazard ratio (HR) 0.75 (0.62–0.91)] and overall events [HR 0.75 (0.61–0.91)] as well as first type 1 [HR 0.73 (0.57–0.92)] and type 2 myocardial infarctions [HR 0.65 (0.46–0.92)]. The effect of albiglutide treatment was consistent for ST-segment elevation [HR 0.69 (0.38–1.26)] and non-ST elevation (HR 0.86 (0.66–1.2) MI.

Conclusion

Treatment with the GLP-1 receptor agonist albiglutide resulted in a 25% relative risk reduction in MI that was consistent for type of infarction and presence or absence of ST elevation. Our findings add novel information about the effects of GLP-1 receptor agonists on ischaemic events in patients with type 2 diabetes.

Introduction

Patients with type 2 diabetes mellitus are at increased risk for cardiovascular events.¹ Antihyperglycemic agents of two drug classes, namely sodium/glucose cotransporter 2 (SGLT2)-inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1-receptor agonists), exhibit cardiovascular benefits, as shown in recent cardiovascular outcome trials.² Therefore, current clinical practice guidelines recommend SGLT2-inhibitors and/or GLP-1 receptor agonists as first-line therapy in patients with type 2 diabetes and established cardiovascular disease or at very high or high cardiovascular risk independent of baseline HbA1c.^3,4

Nine cardiovascular outcome trials evaluating seven different GLP-1 receptor agonists using various forms of application have generated inconsistent results with respect to the reduction of combined as well as individual cardiovascular outcomes in patients with type 2 diabetes.^5–13 Across all agents and trials, treatment with GLP1-receptor agonists was associated with a significant 13% relative risk reduction in three-point composite major adverse cardiovascular endpoints (MACEs), consisting of first occurrence of cardiovascular death, myocardial infarction (MI), or stroke.¹⁴

In the Harmony Outcomes trial, treatment with the GLP-1 receptor agonist albiglutide was superior to placebo for the primary outcome, a composite of three-point MACE (cardiovascular death, MI, and stroke) in patients with type 2 diabetes and pre-existing atherosclerotic cardiovascular disease.⁹ Of interest, a 25% relative risk reduction in the secondary outcome of first myocardial infarction (fatal and non-fatal) was observed in patients randomized to albiglutide as compared to placebo.

This substantial reduction of MIs observed with albiglutide deserves a more detailed exploration. The objectives were to evaluate the effects of albiglutide on MI subtypes, recurrent events, and other ischaemic endpoints of interest, as well as to assess the association between a new MI event and subsequent risk of death.

Methods

Study population and trial design

The design and main results of the Harmony Outcomes trial (NCT02465515) have been reported previously.^9,15 In brief, Harmony Outcomes was an event-driven double-blind, randomized controlled trial designed to compare the effects of a once weekly subcutaneous injection of albiglutide (at a dose of either 30 or 50 mg) with a matched placebo on the occurrence of a primary composite three-point MACE endpoint in patients with type 2 diabetes aged 40 years or older with established atherosclerotic cardiovascular disease and an HbA1c level of >7.0%. Pre-existing cardiovascular disease was defined as either coronary, cerebrovascular, or peripheral artery disease. Patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m², severe gastroparesis, a history of or at risk for pancreatitis, or current use of a GLP-1 receptor agonist were excluded (for the full list and detailed inclusion and exclusion criteria definitions, please refer to the supplemental materials of the original publication⁹ and the design manuscript¹⁵).

A total of 9463 patients were randomly assigned to placebo or albiglutide and followed up for a median of 1.6 years. The primary outcome was the first occurrence of death from cardiovascular causes, MI, or stroke. Secondary clinical outcomes included a 4-point composite MACE endpoint consisting of the primary composite with the addition of urgent revascularization for unstable angina, the individual components of the primary endpoint (cardiovascular death, MI, and stroke) as well as the composite of cardiovascular death or hospital admission due to heart failure. All cardiovascular outcomes were adjudicated by an independent clinical events classification (CEC) committee, blinded to treatment allocation. All patients provided written informed consent and the trial protocol was approved by the respective institutional review boards of participating institutions.

Outcomes of interest

Additional centrally adjudicated outcomes that were analysed included type of MI [type 1–5; ST elevation myocardial infarction (STEMI), non-STEMI (NSTEMI)] as well as coronary heart disease death, sudden cardiac death, unstable angina requiring hospitalization, non-elective coronary revascularization, and non-elective percutaneous coronary intervention (PCI). Additional investigator-reported outcomes that were obtained from respective electronic case report form included coronary catheterization resulting in revascularization.

The trial definition for MI was based on the Third Universal Definition of Myocardial Infarction¹⁶ and is illustrated in detail within the Supplementary materials.⁹

Statistical analysis

Harmony Outcomes was designed and powered to investigate the effect of albiglutide compared with placebo on the primary composite outcome. Time-to-event analyses of the primary and secondary cardiovascular outcomes were assessed using the Cox proportional hazards (PH). No adjustment for multiplicity was prespecified for analysis of the secondary and other outcomes.

The secondary analyses reported here were done in the intention-to-treat population, including all randomly assigned patients. For Table 1, we summarized patient characteristics in the overall cohort using counts and percentages and compared the risk of first MI by patient characteristics with hazard ratios (HRs) [95% confidence interval (CI)] from univariable Cox PH models. For this summary, continuous variables were grouped based on clinically meaningful cut points. Risk of first MI, subtypes of MI, as well as other ischaemic endpoints, was also compared between treatment groups using Cox PH models, when sample sizes allowed (number of events >40). For the assessment of risk of recurrent MI between treatment groups, total event rates were calculated, and HRs estimated using the Andersen–Gill recurrent events model with robust standard errors to account for recurrent events within the same patient.

Table 1.

Risk of fatal or non-fatal MI by baseline characteristics

Variable	n/N (%)	Incidence rate (per 100 person-years)	# with event (%)	Univariable HR (95% CI)	P-value
Age					<0.001
<65 years	4714/9463 (49.8%)	2.37	175(3.7%)	Reference
>=65 to < 75 years	3609/9463 (38.1%)	3.15	178(4.9%)	1.33(1.08–1.64)
>=75 years	1140/9463 (12.0%)	3.84	68(6.0%)	1.63(1.23–2.16)
Sex					0.005
Female	2894/9463 (30.6%)	2.25	102(3.5%)	Reference
Male	6569/9463 (69.4%)	3.11	319(4.9%)	1.38(1.10–1.73)
Race or ethnicity					<0.001
Non-hispanic white	6583/9463 (69.6%)	3.16	335(5.1%)	Reference
Non-hispanic black or African–American	225/9463 (2.4%)	3.88	12(5.3%)	1.20(0.67–2.13)
Hispanic	1993/9463 (21.1%)	1.58	46(2.3%)	0.49(0.36–0.67)
Asian	470/9463 (5.0%)	2.99	22(4.7%)	0.94(0.61–1.45)
Other	192/9463 (2.0%)	2.48	6(3.1%)	0.75(0.33–1.68)
Geographic region					<0.001
North America	1945/9463 (20.6%)	5.10	145(7.5%)	Reference
Latin America	1703/9463 (18.0%)	1.13	28(1.6%)	0.22(0.15–0.33)
Asia Pacific	376/9463 (4.0%)	1.78	11(2.9%)	0.35(0.19–0.65)
Eastern Europe	2047/9463 (21.6%)	2.06	70(3.4%)	0.41(0.31–0.55)
Western Europe	3392/9463 (35.8%)	3.05	167(4.9%)	0.61(0.49–0.76)
Coronary artery disease					<0.001
No	2785/9463 (29.4%)	1.15	51(1.8%)	Reference
Yes	6678/9463 (70.6%)	3.57	370(5.5%)	3.12(2.33–4.18)
Prior MI					<0.001
No	5004/9463 (52.9%)	1.82	145(2.9%)	Reference
Yes	4459/9463 (47.1%)	4.03	276(6.2%)	2.21(1.81–2.70)
CABG					<0.001
No	7731/9463 (81.7%)	2.49	303(3.9%)	Reference
Yes	1732/9463 (18.3%)	4.43	118(6.8%)	1.77(1.43–2.19)
PCI					<0.001
No	5300/9463 (56.0%)	1.90	159(3.0%)	Reference
Yes	4163/9463 (44.0%)	4.08	262(6.3%)	2.15(1.77–2.62)
CAD >=50%					<0.001
No	5602/9463 (59.2%)	1.99	175(3.1%)	Reference
Yes	3861/9463 (40.8%)	4.09	246(6.4%)	2.06(1.70–2.50)
Peripheral artery disease					0.565
No	7109/9463 (75.1%)	2.80	312(4.4%)	Reference
Yes	2354/9463 (24.9%)	2.99	109(4.6%)	1.07(0.86–1.33)
Cerebrovascular disease					0.638
No	7121/9463 (75.3%)	2.88	320(4.5%)	Reference
Yes	2342/9463 (24.7%)	2.72	101(4.3%)	0.95(0.76–1.19)
Prior stroke					0.845
No	7782/9463 (82.2%)	2.86	347(4.5%)	Reference
Yes	1681/9463 (17.8%)	2.77	74(4.4%)	0.98(0.76–1.25)
Carotid vascular procedure					0.176
No	9188/9463 (97.1%)	2.81	404(4.4%)	Reference
Yes	275/9463 (2.9%)	3.91	17(6.2%)	1.40(0.86–2.27)
Carotid arterial disease >=50%					0.896
No	8664/9463 (91.6%)	2.85	386(4.5%)	Reference
Yes	799/9463 (8.4%)	2.78	35(4.4%)	0.98(0.69–1.38)
Vascular disease*					<0.001
1	7702/9444 (81.6%)	2.39	289(3.8%)	Reference
2	1554/9444 (16.5%)	4.38	105(6.8%)	1.84(1.47–2.30)
3	188/9444 (2.0%)	9.94	27(14.4%)	4.17(2.81–6.19)
Heart failure					<0.001
No	7541/9463 (79.7%)	2.47	291(3.9%)	Reference
Yes	1922/9463 (20.3%)	4.30	130(6.8%)	1.75(1.42–2.15)
Atrial fibrillation					<0.001
No	8677/9463 (91.7%)	2.66	362(4.2%)	Reference
Yes	786/9463 (8.3%)	4.85	59(7.5%)	1.84(1.39–2.42)
Hypertension					0.063
No	1279/9463 (13.5%)	2.19	43(3.4%)	Reference
Yes	8184/9463 (86.5%)	2.94	378(4.6%)	1.35(0.98–1.85)
Hyperlipidaemia					<0.001
No	1829/9463 (19.3%)	1.82	51(2.8%)	Reference
Yes	7634/9463 (80.7%)	3.08	370(4.8%)	1.70(1.27–2.28)
Family history					0.004
No	6375/9463 (67.4%)	2.65	265(4.2%)	Reference
Unknown	1182/9463 (12.5%)	2.43	46(3.9%)	0.92(0.67–1.26)
Yes	1906/9463 (20.1%)	3.77	110(5.8%)	1.42(1.14–1.77)
Smoking status					0.002
Never	3891/9461 (41.1%)	2.25	137(3.5%)	Reference
Former	4082/9461 (43.1%)	3.29	210(5.1%)	1.46(1.18–1.81)
Current	1488/9461 (15.7%)	3.17	74(5.0%)	1.41(1.06–1.87)
BMI					0.064
<25	703/9413 (7.5%)	1.90	20(2.8%)	Reference
>=25 to < 30	2907/9413 (30.9%)	2.67	121(4.2%)	1.41(0.88–2.27)
>=30 to < 35	3194/9413 (33.9%)	2.78	140(4.4%)	1.47(0.92–2.35)
>=35	2609/9413 (27.7%)	3.32	137(5.3%)	1.76(1.10–2.82)
Systolic blood pressure					0.020
<120	1448/9436 (15.3%)	3.39	74(5.1%)	Reference
>=120 to < 130	1871/9436 (19.8%)	2.49	73(3.9%)	0.74(0.53–1.02)
>=130 to ⇐140	2483/9436 (26.3%)	2.29	90(3.6%)	0.68(0.50–0.93)
>140	3634/9436 (38.5%)	3.18	182(5.0%)	0.94(0.72–1.24)
HbA1c (percent)					0.180
<8	3518/9449 (37.2%)	2.54	142(4.0%)	Reference
>=8 to < 9	2686/9449 (28.4%)	2.81	119(4.4%)	1.10(0.87–1.41)
>=9	3245/9449 (34.3%)	3.16	157(4.8%)	1.24(0.99–1.55)
eGFR (mL/min per 1.73 m^2)					<0.001
>=90	2819/9439 (29.9%)	2.13	94(3.3%)	Reference
>=60 to < 90	4409/9439 (46.7%)	2.70	188(4.3%)	1.27(0.99–1.63)
>=30 to < 60	2211/9439 (23.4%)	4.01	136(6.2%)	1.88(1.45–2.45)
Duration of diabetes (years)					0.001
<10	3355/9447 (35.5%)	2.25	119(3.5%)	Reference
>=10 to < 20	3925/9447 (41.5%)	2.93	180(4.6%)	1.30(1.03–1.64)
>=20	2167/9447 (22.9%)	3.60	121(5.6%)	1.60(1.24–2.06)

*19 subjects had 0 qualifying risk factors for cardiovascular disease. None of the 19 experienced an MI and thus the group was excluded from the analysis because it was unsuitable as a reference group.

HR, hazard ratio; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; CAD, coronary artery disease; BMI, body mass index; eGFR, estimated glomerular filtration rate; NOAC, non-vitamin K antagonist oral anticoagulants; ACE, angiotensin-converting-enzyme; ARB, angiotensin II receptor blocker; DPP IV, dipeptidyl peptidase-4; SGLT-2, sodium glucose cotransporter 2.

In order to assess whether treatment effect differed by estimated risk of MI, a multivariable model was developed in the trial cohort, and patients were divided into tertiles based on predicted risk of MI. Details of the risk model development are provided in the Supplementary appendix. We then estimated HRs for treatment effect within each risk tertile, by fitting a Cox PH model including risk group, treatment, and the interaction of risk group and treatment as covariates and reported the interaction P-values.

Using a similar approach, heterogeneity of the treatment effect with respect to MI was further assessed in a variety of subgroups, including the 19 prespecified subgroups reported for the primary endpoint in the primary manuscript and three non-prespecified subgroups of interest for this analysis, which included history of MI, PCI, and coronary artery bypass grafting (CABG).

Finally, to assess the association between a new MI event and subsequent risk of death, HRs (95% CI) for death were calculated from a Cox PH model with MI as a time-varying covariate that switched from No to Yes on the date of the patient's first MI during the trial. This analysis controlled for prior MI at baseline.

All statistical analyses were generated using SAS V9.4 (SAS Institute, Cary, NC, USA) and R (version 4.2.2). P-values <0.05 were considered nominally statistically significant.

Results

Baseline characteristics and MI incidence

In total, 9463 patients at a mean age of 64.1 years were randomized to either albiglutide (n = 4731) or placebo (n = 4732), of whom 31% were women. Overall, 86.5% had hypertension, 80.7% had a diagnosis of hyperlipidaemia, 15.7% were current smokers, and mean HbA1c was 8.7% (+/−1.5%) at inclusion. Coronary artery disease was present in 70.6%, peripheral artery disease in 24.9%, and 24.7% had cerebrovascular disease at study enrolment. At baseline, 47.1% of the trial population had a history of MI and 44% had undergone revascularization with PCI, and 18.3% with CABG.

During the median follow-up of 1.6 years, a total of 421 first MIs were recorded and adjudicated amongst 9463 total trial participants (4.5%) with an incidence rate of 3.26 per 100 person-years in the placebo group and an incidence rate of 2.43 per 100 person-years in the albiglutide group. Table 1 reports baseline characteristics and the associated incidence rates and HRs for the development of a first adjudicated MI. Baseline characteristics associated with MI were male sex [HR 1.38 (1.10–1.73)], age ≥75 vs. <65 years [HR 1.63 (1.23–2.16)] and worse kidney function [eGFR <60 vs. ≥90 mL/min/1.73 m²; HR 1.88 (1.45–2.45)]. Patients with pre-existing coronary artery disease [HR 3.12 (2.33–4.18)] and a history of MI [HR 2.21 (1.81–2.70)] exhibited a high risk for MI with patients with atherosclerotic disease in all three vascular beds exhibited the highest risk [HR 4.17 (2.81–6.19) for 3 beds vs.1].

Types and consequences of MIs and other ischaemic cardiac events

Amongst the 421 patients with at least 1 reported MI, 72 patients experienced more than 1 MI (513 total MIs). In addition, 44 first MI events were adjudicated as STEMI, 222 as NSTEMI, 270 as type 1, and 136 as type 2 MI events (Figure 1). Other adjudicated myocardial ischaemic events included 148 coronary heart disease deaths, 123 episodes of unstable angina requiring hospitalization, 110 sudden cardiac deaths, 88 non-elective myocardial revascularizations, and 476 (non-adjudicated) coronary catheterizations (Figure 2). A total of 148 patients (1.6%) experienced a death attributed to coronary heart disease and 252 patients (2.7%) died due to cardiovascular causes. After adjusting for prior MI, the hazard of death for a patient who had a MI during the trial was estimated to be 11.54 (95% CI: 8.99, 14.81) times higher than that of a patient who did not have a MI during the trial.

Figure 1.

Effects of albiglutide vs. placebo on time to first MI subtypes. MI, myocardial infarction; NSTEMI, non-ST elevation myocardial infarction; STEMI, ST elevation myocardial infarction; CI, confidence interval. All MI subtypes displayed here were centrally adjudicated.

Figure 2.

Effects of albiglutide vs. placebo on the occurrence of first ischaemic endpoints. MI, myocardial infarction; CHD, coronary heart disease; UA, unstable angina; PCI, percutaneous coronary intervention; CI, confidence interval.

Effects of albiglutide on MI subtypes and other ischaemic cardiac events

Albiglutide treatment reduced both first type 1 and type 2 MIs and was associated with a numerically lower rate of STEMI and NSTEMIs (Figure 1). Treatment with albiglutide was associated with a reduction of both first MIs [n = 421; HR 0.75 (0.62–0.91)] and total MIs [n = 513; HR 0.75 (0.61–0.93)]. Treatment with albiglutide was further associated with a numerically but non-significantly lower rate of the occurrence of unstable angina requiring hospitalization, sudden cardiac death, non-elective coronary revascularization, and overall catheterizations resulting in revascularization (Figure 2).

Effects of albiglutide according to the baseline risk of MI

To assess the effects of albiglutide on the occurrence of MI based on baseline risk, a model incorporating baseline risk factors was built and patients were divided into tertiles of baseline MI. The largest numerical relative risk reductions were seen in the middle risk [HR 0.63 (0.44–0.92)] and the high risk groups [HR 0.77 (0.60–0.99], compared with the low risk group [HR 0.95 (0.55–1.62)], although the interaction was not statistically significant (p_interaction = 0.47) (Figure 3). Thus, the greatest absolute benefit is observed in those with highest absolute risk.

Figure 3.

Kaplan–Meier curves for the occurrence of first MI for patients at low, medium and high risk for MI according to the baseline risk and according to randomized treatment allocation.

Effects of albiglutide on MI occurrence in relevant subgroups

The subgroup analysis incorporating the prespecified subgroups of interest from the primary analysis as well as three additional subgroups of interest for this analysis defined post-hoc (prior MI, prior PCI, and prior CABG) revealed no significant interaction terms except for a nominally significant interaction for baseline use of dipeptidyl peptidase-4 (DPP-IV) inhibitors (P = 0.011) (Figure 4).

Figure 4.

Effects of albiglutide on the occurrence of MI across relevant subgroups. With the exception of prior MI, prior PCI and prior CABG, all subgroups were prespecified for the primary outcome analysis.⁹ CI, confidence interval; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; BMI, body mass index; DPP4, dipeptidyl peptidase.

Discussion

This detailed secondary analysis of the randomized controlled Harmony Outcomes trial, which included 9463 patients with diabetes and established atherosclerotic cardiovascular disease, suggests that the GLP-1 receptor agonist albiglutide reduces a wide array of myocardial ischaemic outcomes, including MI subtypes.

Importantly, the most common MI subtypes that were detected and adjudicated by the CEC were atherothrombotic type 1 MIs, followed by type 2 ‘demand/supply’ mismatch MIs. Treatment with albiglutide was associated with a significant 27% relative risk reduction in type 1 and a 31% relative risk reduction of type 2 MI, as compared with placebo. This is of particular importance, as findings from randomized controlled trials and observational studies have consistently shown a high risk of death following both type 1 and type 2 MIs.¹⁷ In our analysis, patients who have experienced a MI during the trial had an 11.5-fold increased risk of dying as compared to patients without a myocardial infarction, which underscores the importance and high clinical relevance of our observed findings. Furthermore, albiglutide treatment was associated with a consistent, non-significant, trend in reduction of STEMIs and NSTEMIs. In addition, no effect on type 3, 4, or 5 events was noted, with overall low numbers reported. The effect of albiglutide was consistent across a large number of subgroups analysed, except for an interaction with baseline use of DPP-IV inhibitors, likely a finding of chance due to the large number of subgroups analysed. Patients in North America were characterized by a higher incidence rate of MI. Inclusion of a higher risk cohort, ascertainment differences but also the play of chance may explain this phenomenon.

The observed 25% relative risk reduction of MI events associated with albiglutide is the largest, statistically significant effect size seen among the family of GLP-1 receptor agonists^5–13 and also among most other antihyperglycemic medications tested in recent cardiovascular outcome trials.¹⁸ The herein reported risk reduction even exceeds¹⁹ or equals those observed in recent trials evaluating intensive lipid-lowering strategies in patients with atherosclerotic disease.²⁰ The drivers of these effects remain unclear, with several hypotheses deserving further discussion.

In Harmony Outcomes, older age, worse kidney function as well as pre-existing coronary disease, polyvascular atherosclerotic disease, and previous MI were associated with a heightened risk of developing a MI. When evaluating the effects of albiglutide on MI events according to baseline risk factors, patients in the highest risk tertile exhibited the greatest absolute risk reduction, as would be expected given a similar or greater relative risk reduction in the higher risk groups. Harmony Outcomes is the only trial of a total of 9 cardiovascular outcome trials evaluating seven different GLP-1 receptor agonists in patients with type 2 diabetes where a statistically significant and clinically meaningful reduction of MI was observed, suggesting that it is also possible that the results are greater due to the play of chance. Two trials, AMPLITUDE-O, evaluating subcutaneous efpeglenatide and SUSTAIN-6 evaluating subcutaneous semaglutide resulted in a comparable point estimate of the HR for MI, without reaching statistical significance [HR 0.75 (0.54–1.05) and HR 0.81 (0.57–1.16), respectively]. Both trials included a mixed primary and secondary prevention population. The LEADER trial evaluating liraglutide vs. placebo in 9340 patients with type 2 diabetes with approximately two thirds with established cardiovascular disease at baseline resulted in a borderline reduction in MI events with a HR of 0.86 (0.73–1.00).⁷ The incidence ratio for the development of MI in Harmony Outcomes was 3.3/100 patient years in the placebo group, which was among the highest rates reported in GLP-1 receptor agonist trials. Inclusion of a higher risk cohort could serve as another explanation for the greater benefits observed, as exclusively patients with pre-existing atherosclerotic cardiovascular disease were included. The highest MI incidence rate was seen in ELIXA, which enrolled patients with type 2 diabetes and a recent MI but resulted in neutral results with respect to treatment with lixisenatide compared to placebo.⁵

As previously reported in the primary manuscript,⁹ treatment with albiglutide reduced HbA1c by 0.6% at month 8 and by 0.52% at month 16 as compared with placebo, which is similar to other GLP1-receptor agonists and other antihyperglycemic medications. Further, mean body weight reduction was 0.7 kg as compared with placebo, which is among the smallest reduction of body weight of any GLP-1 receptor agonist seen. Similar trends can be observed for effects on systolic blood pressure and eGFR, with minimal effects of −1.11 mL/min per 1.73 m² (95% CI −1.84 to −0.39) at 8 months and −0.43 per 1.73 m² (−1.26 to 0.41) at 16 months which again are in line with results from other GLP-1 receptor agonists and unlikely to explain the observed findings.

Whether albiglutide exhibits biologic effects different from other GLP-1 receptor agonists is not known. Lipid biomarkers were not routinely collected in Harmony Outcomes and the lack of a biobank precludes any further analysis into potential anti-inflammatory effects.²¹ The early and clear separation of cardiovascular endpoint curves after just 12–18 months of therapy observed in Harmony Outcomes and other cardiovascular outcome trials suggests that the beneficial effects are driven by antiatherogenic effects as opposed to glucose-lowering effects.^22,23 Intensive blood glucose control is primarily associated with reductions in microvascular events,²⁴ whereas control of traditional cardiovascular risk factors represents the best opportunity to prevent macrovascular complications.²³ The combination of beneficial effects on a variety of cardiovascular risk factors, including body weight, blood pressure, kidney function, and potentially inflammation, render this drug class interesting for cardiovascular disease prevention even for patients without diabetes.^22,25 Together with a favourable adverse effect profile, especially the low risk of hypoglycaemia, GLP-1 receptor agonists could play a role in cardiovascular disease secondary prevention, especially in patients with another indication for treatment, such as obesity. The SELECT trial randomized 17 604 patients aged 45 or above with pre-existing cardiovascular disease and a body mass index of 27 or above without a history of diabetes to either placebo or once-weekly s.c. semaglutide.²⁶ After a mean exposure of 34 months, semaglutide resulted in a 20% relative risk reduction in the primary outcome of cardiovascular death, MI, or stroke. The HR for the occurrence of non-fatal MI was 0.72 with a 95% CI of 0.61–0.85. The striking effect of semaglutide on reducing MI in SELECT further underscores the potent cardiovascular benefits of GLP-1 receptor agonists in patients with established cardiovascular disease, even in those without diabetes. Of interest, and relevant to the question of whether and how much of the effect of reducing MI is due to weight loss, in HARMONY Outcomes there was only 0.83 kg weight loss with albiglutide vs. placebo. This suggests much of the benefit on reducing MI, at least in those with diabetes, is not mediated by weight loss itself. Additional trials investigating GLP-1 receptor agonists in patients with established atherosclerotic cardiovascular disease but without diabetes or obesity may be warranted.

Limitations

All analyses beyond the prespecified secondary endpoint of first adjudicated MI events are exploratory. Inclusion of a high risk population with prior atherosclerotic cardiovascular disease does not allow to draw conclusions to patients with type 2 diabetes overall or at heightened cardiovascular risk.

Conclusions

Treatment with the GLP-1 receptor agonist albiglutide in a high risk patient population with type 2 diabetes and established atherosclerotic cardiovascular disease resulted in a 25% relative risk reduction in MI that was consistent across MI subtypes and presence or absence of ST elevation. The observed, potent effects call for understanding which patients will derive absolute benefits that warrant prioritizing the addition of GLP-1 receptor agonists. Current guidelines on the use of glucose-lowering drugs recommend SGLT-2 inhibitors or GLP-1 receptor agonists in patients with diabetes and established cardiovascular disease as critical components of care.^3,27 These findings add evidence to support the use of GLP-1 receptor agonists with proven cardiovascular benefits in patients at high risk for ischaemic outcomes.

Funding

K.A.K. is supported by the Max Kade Foundation. The main trial was sponsored by GSK. The sponsor was not involved in the conduct of this secondary analysis. K.A.K. was further supported by the Executive Director's Pathway for Supplemental Funding by the Duke Clinical Research Institute for this project.

Conflict of interest: K.A.K.: Speaker fees: Zoll Medical; Daiichi Sankyo Travel Support: Amgen; Speaker fees: Novartis. G.M.-G.: Consulting fees: Novartis, JAMP Pharma, Boston Scientific, KYE, Pendopharm, HLS; speaker fees: Novartis, Bayer, Boston Scientific, JAMP Pharma, Pendopharm, HLS, KYE, CIS. S.M.: None. K.A.: None. K.C.: None. J.B.G.: Grants/Contracts: Merck, Roche, Boehringer Ingelheim, Lilly, Sanofi/Lexicon; consulting fees: Astra Zeneca, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, Pfizer, Anji, Valo, Vertex; lecture fees Boehringer Ingelheim. L.A.L.: Grants/Contracts: Lexicon; consulting fees: Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, Sanofi; lecture fees: Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Servier. R.L.: Grants/Contracts: BMS, GSK, Medtronic, Pfizer, Sanofi; consulting fees: Bayer, Boehringer Ingelheim, Bristol–Myers Squibb, Daiichi Sankyo, Portola, Glaxo Smith Kline, Medtronic, Merck, Pfizer, Sanofi; travel support: BMS, GSK. S.D.P.: Grants/Contracts: Astra Zeneca, Boehringer Ingelheim; consulting fees: Abbott; Amarin Corporation; Applied Therapeutics; Eli Lilly & Co; Hengrui Pharmaceuticals; Menarinii International; Novo Nordisk; Sun Pharmaceuticals; Evaharma; lecture fees: AstraZeneca; Boehringer Ingelheim; Eli Lilly & Co; Merck Sharpe & Dohme; Novartis Pharmaceuticals; Novo Nordisk; Sanofi; Laboratori Guidotti. W.S.J.: None. J.J.V.M.: Grants: British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; fees for consulting and other activities: Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; personal lecture fees: Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). A.F.H.: Research grants: Merck, Astra Zeneca, Novartis, Verily; Honoraria: Merck, Bayer, Amgen, Astra Zeneca, Novartis. C.B.G.: Consulting fees: Abbvie, Abiomed, Alnylam, Anthos, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol–Myers Squibb, Cardionomic, Celecor Therapeutics, Hengrui USA, Janssen, Medscape, Medtronic, Merck, NephroSynergy, Novo Nordisk, NIH, Novartis, Pfizer, Philips, REATA; Grants/Contracts: Boehringer Ingelheim, Bristol–Myers Squibb, FDA, Janssen, Lilly, Novartis, Pfizer, Philips; Equity: Tenac.io. He is an Editor of European Heart Journal—Cardiovascular Pharmacotherapy and was not involved in the peer review process or publication decision.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.