As described in module 1, since 2008, the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in Europe have required new drugs for the treatment of diabetes to demonstrate cardiovascular safety, usually including a double-blind placebo-controlled cardiovascular outcome trial (CVOT).1,2 The focus on safety has been particularly on atherosclerotic outcomes, so the primary end point required for the FDA was either the composite end point of major cardiovascular events (MACE), a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, or MACE plus, with the addition of hospitalisation for unstable angina. Hospitalisation for heart failure (HFH) could be included as a secondary outcome but was not part of the primary composite end point. A small number of other investigator-initiated studies have been completed with older antidiabetic drugs using similar methodology and study design to the FDA mandated trials.
The inclusion criteria for the safety trials have been patients with type 2 diabetes and either established atherosclerotic cardiovascular disease or patients with type 2 diabetes at increased risk of cardiovascular disease (CVD) due to the presence of other risk factors, including chronic kidney disease, microalbuminuria or proteinuria. Baseline heart failure was recorded in these trials by the local clinical investigator who recruited the subject to the trial but generally the diagnosis of heart failure was not well characterised.
We now have multiple completed CVOTs for the new drug classes of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter (SGLT2) inhibitors. In this module, we describe CVOTs with the incretin-based therapies of DPP-4 inhibitors (table 1) and GLP-1 receptor agonists (table 2). SGLT1 inhibitor trials are described in detail in module 4.
DPP-4 inhibitor CVOTs
The first two CVOTs to be completed and published were the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus [SAVOR]–Thrombolysis in Myocardial Infarction [TIMI] 53) trial with saxagliptin versus placebo and EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of care) with alogliptin versus placebo.3,4 These were simultaneously published in the New England Journal of Medicine in 2013.
SAVOR-TIMI 53 involved 16,492 patients with type 2 diabetes and established atherosclerotic CVD or multiple risk factors for vascular disease who were followed for a median of 2.1 years (table 1). Baseline CVD included investigator-diagnosed heart failure in 2,105 patients (13%). The results of SAVOR-TIMI 53 were:
- No significant difference in MACE comparing saxagliptin and placebo.3
- An unexpected statistically significant increase in HFH in the saxagliptin group with 289 (3.5%) events compared with 228 (2.8%) events in the placebo group (hazard ratio [HR] 1.27; 95% confidence interval [CI] 1.07 to 1.51; p=0.007).
- Post-hoc analysis showed the increase in HFH occurred in patients taking saxagliptin with no previous history of heart failure; no significant difference in HFH was seen in patients with heart failure at baseline.5
EXAMINE involved 5,380 patients with type 2 diabetes and an acute coronary syndrome (acute myocardial infarction [MI] or unstable angina requiring hospitalisation). Treatment was commenced within 15 to 90 days of the acute coronary syndrome (ACS) for a median duration of 18 months. The results of EXAMINE were:
- No significant difference in MACE comparing alogliptin and placebo.4
- EXAMINE did not report on heart failure outcomes in the primary publication! In post-hoc analysis, HFH occurred in similar numbers in the alogliptin and placebo groups with 106 and 89 events, respectively (HR, 1.19; 95%CI, 0.90 to 1.58; p=0.220).6
- Subgroup analysis of patients with no history of heart failure at baseline showed alogliptin was associated with an increased risk of HFH with 43 (2.2%) events in the alogliptin group compared with 24 (1.3%) events in the placebo group (HR 1.76; 95% CI 1.07 to 2.90; p=0.026). No significant difference was seen for patients with heart failure at baseline.6
The three subsequent CVOTs with DPP-4 inhibitors are described in table 1. TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) was an investigator-initiated trial comparing sitagliptin and placebo in 14,671 subjects with a median follow-up of three years using similar methodology to the FDA-mandated CVOTs.7 In TECOS:
- There was no difference in the primary outcome, which was MACE plus hospitalisation for unstable angina, or in MACE which was a secondary outcome.
- HFH occurred in similar numbers in sitagliptin and placebo groups, and a composite outcome of HFH and cardiovascular death did not differ significantly between groups.
Linagliptin was studied in two cardiovascular outcome trials. CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin) was designed to assess the impact of linagliptin versus placebo on cardiac and renal outcomes and included 6,991 patients with established atherosclerotic CVD plus macroalbuminuria, or patients with impaired renal function and/or albuminuria.8 CAROLINA (Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Type 2 Diabetes) compared linagliptin with the sulfonylurea glimepiride in 6,042 patients with established atherosclerotic CVD or increased cardiovascular risk.9
In CARMELINA and CAROLINA:
- There was no significant difference in MACE, MACE plus or HFH comparing linagliptin and placebo, and linagliptin and glimepiride.8,9
- In CARMELINA, there was no difference in a renal composite outcome of death due to renal failure, end stage renal disease or a decrease in eGFR of 40% or more comparing linagliptin and placebo.8
- In CAROLINA, as expected, there was more weight gain and hypoglycaemia in the group treated with the sulfonylurea glimepiride compared to linagliptin.9
Thus, CVOTS with DPP-4 inhibitors have satisfied the criteria for cardiovascular safety, with no increase in atherosclerotic events, but no cardiovascular benefits – there was no reduction in MACE, HFH, or renal composite events, and a possible increase in HFH with saxagliptin and alogliptin. On the plus side, no other safety issues became evident during these trials.
Table 1. Cardiovascular outcome trials with DPP-4 inhibitors
|Drug||Trial||Key patient features||End point||Key results|
|Saxagliptin||SAVOR-TIMI 533||78% ASCVD
22% CV risk
Increase in HFH
|Alogliptin||EXAMINE4,6||100% recent ACS
Increase in HFH in a subgroup
||MACE plus||MACE, MACE plus non-inferior
HFH no difference
(linagliptin vs placebo)
|90% ASCVD and albuminuria
74% prevalent kidney disease
|MACE||MACE, MACE plus non-inferior
HFH no difference
Renal composite no difference
(linagliptin vs glimepiride)
58% CV risk
|MACE||MACE, MACE plus non-inferior
HFH no difference
|Key: ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin); CAROLINA = Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes; CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; HFH = heart failure hospitalisation; EXAMINE = Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; MACE = major adverse cardiovascular events; MACE plus = major adverse cardiovascular events plus hospitalisation for unstable angina; MI = myocardial infarction; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus –Thrombolysis in Myocardial Infarction 53; TECOS = Trial Evaluating Cardiovascular Outcomes with Sitagliptin|
GLP-1 receptor agonist CVOTs
The first completed and published CVOT with a GLP-1 receptor agonist was ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) with lixisenatide.10 ELIXA assessed the safety of lixisenatide versus placebo in 6,068 patients with type 2 diabetes and a recent ACS with a median follow-up period of 25 months (table 2). Participants were diagnosed with ACS, defined as MI (ST elevation or non-ST elevation) or hospitalisation for unstable angina, in the 180 days preceding randomisation. ELIXA showed:
- No significant difference in MACE comparing lixisenatide and placebo, demonstrating non-inferiority but not superiority (HR 1.02; 95% CI 0.89 to 1.17; p<0.001 for noninferiority, p=0.81 for superiority).10
- There were no significant group differences for HFH.
One year later, LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was the first of several CVOTs with GLP-1 receptor agonists to demonstrate significant reductions in MACE comparing GLP-1 receptor agonists and placebo injection.11 LEADER included 9,340 patients with established CVD or cardiovascular risk who were randomised to receive liraglutide (1.8 mg once daily or maximum tolerated dose) or placebo with median follow-up of 3.8 years. In LEADER:
- The primary MACE end point occurred in significantly fewer patients in the liraglutide group than in the placebo group (13% vs. 14.9%; HR 0.87; 95% CI 0.78 to 0.97; p<0.001 for noninferiority, p=0.01 for superiority).11
- Cardiovascular death was significantly reduced with 219 (4.7%) events in the liraglutide group and 278 (6.0%) events in the placebo group (HR 0.78; 95% CI 0.66 to 0.93; p=0.007). Death from any cause was also significantly reduced in the liraglutide group compared with the placebo group (8.2% vs. 9.6%; HR 0.85; 95% CI 0.74 to 0.97; p=0.02).
- There was no significant difference in the rates of nonfatal MI, nonfatal stroke or HFH between groups.
- A prespecified secondary renal composite outcome of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease occurred in significantly fewer participants in the liraglutide group.12 The result was driven primarily by a reduction in the new onset of persistent macroalbuminuria, with no significant effect on doubling of serum creatinine or the need for renal replacement therapy.
Five subsequent trials with subcutaneous GLP-1 receptor agonists have shown varying results (table 2).13-17 SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) was the first completed CVOT with a once-weekly GLP-1 receptor agonist.13 3,297 patients with type 2 diabetes were randomised to receive once weekly semaglutide (0.5 mg or 1 mg) or placebo in a 1:1:1 ratio for 104 weeks. Patients had established CVD, chronic kidney disease, or both, or raised cardiovascular risk. SUSTAIN-6 was performed as a pre-licensing safety study so non-inferiority for MACE was the primary outcome and testing for superiority for the primary outcome was not prespecified or adjusted for multiplicity. In SUSTAIN-6:
- The primary MACE outcome occurred in 108 (6.6%) patients treated with semaglutide compared with 146 (8.9%) patients treated with placebo (HR 0.74; 95% CI 0.58 to 0.95; p<0.001 for noninferiority, p=0.02 for superiority).13
- The risk of nonfatal stroke was significantly reduced in the semaglutide group compared with placebo (1.6% vs. 2.7%; HR 0.61; 95% CI, 0.38 to 0.99; p=0.04).
- There was no significant difference in nonfatal MI, cardiovascular death, all-cause mortality or HFH between the groups.
- Rates of new or worsening nephropathy were lower in the semaglutide group (p=0.005), but rates of retinopathy complications were unexpectedly significantly higher with semaglutide (p=0.02).
The twice-daily formulation of exenatide was approved by the FDA before the new safety requirements were in place. EXSCEL (Exenatide Study of Cardiovascular Event Lowering Trial) was a large study, which randomised 14,752 patients to receive extended-release exenatide or placebo once weekly with a median of 3.2 years follow-up.14 EXSCEL was designed with elements of a ‘pragmatic’ trial and subjects were seen every six months by the investigators. A major deficiency of EXSCEL is a very high rate of discontinuation (45% in the placebo group, 43% in the exenatide group). Consequently, there was a lower than expected exposure to the intervention. In EXSCEL:
- The primary outcome of MACE occurred in similar numbers of patients in the exenatide and placebo groups (11.4% vs. 12.2%; HR 0.91; 95% CI 0.83 to 1.00; p<0.001 for non-inferiority, p=0.061 for superiority).
- HFH rates were similar between groups (3% vs. 3.1%).
- There was a reduction in all-cause mortality as a secondary outcome, with a nominal p value of 0.016.
Albiglutide was withdrawn from the international market in 2017 for commercial reasons, but fortunately the Harmony Outcomes CVOT with albiglutide was completed.15 Harmony Outcomes included 9,463 patients with type 2 diabetes and established CVD, who were followed for a median of 1.6 years. In Harmony Outcomes:
- The primary MACE outcome occurred in significantly fewer patients in the albiglutide group than the placebo group (7% vs. 9%; HR 0.78; 95% CI 0.68-0.90; p=0.0006).
- The risk of fatal or nonfatal MI was significantly reduced in the albiglutide group compared with placebo (4% vs 5%; HR 0.75; 95% CI 0.61 to 0.90; p=0.003).
- There was no significant between group difference in cardiovascular death, fatal or nonfatal stroke, or death from any cause.
- HFH results were included in a meta-analysis and this was the only CVOT with a GLP-1 receptor agonist to show a significant reduction (HR 0.751; 95% CI 0.53 to 0.94; p<0.0001).18
REWIND (Researching Cardiovascular Outcomes with a Weekly Incretin in Diabetes) was different from earlier CVOTs with GLP-1 receptor agonists as the majority of subjects were recruited because of increased cardiovascular risk (69%) and the minority (31%) had a history of CVD.16 In REWIND:
- MACE was significantly reduced in the dulaglutide group (HR 0.88; 95% CI 0.79 to 0.99; p=0.026). The result was driven primarily by a reduction in nonfatal stokes.
- The hazard ratio of the intervention was similar in patients with and without previous CVD.
- An exporatory secondary renal composite outcome of new-onset macroalbuminuria, sustained decline in eGFR of >30%, or the need for chronic renal replacement therapy was significantly reduced in the dulaglutide group. This was driven primarily by a reduction in the new macroalbuminuria.19
The most recent CVOT with a GLP-1 receptor agonist was the preapproval PIONEER (Peptide Innovation for Early Diabetes Treatment) 6 trial with the oral formulation of semaglutide.17 This included 3,183 subjects with established CVD, chronic kidney disease, or cardiovascular risk factors, with a median time in the trial of 16 months. In PIONEER 6:
- MACE occurred in 61 patients (3.8%) in the oral semaglutide group and 76 patients (4.8%) in the placebo group (HR 0.79; 95% CI 0.57 to 1.11; p<0.001 for noninferiority, p=0.17 for superiority).17
- There were 23 deaths for any cause in the semaglutide and 45 in the placebo group (HR 0.51; 85% CI 0.31-0.84), with 15 and 30 deaths in each group respectively from cardiovascular causes (HR 0.49; 95% CI 0.27-0.92). These outcomes were not controlled for multiple comparisons and should be interpreted as exploratory.
- There were no differences in retinopathy or related complications.
The seven CVOTs described above have been included in a meta-analysis, which demonstrated significant reductions in MACE, cardiovascular death, MI and stroke.18 The benefits were most evident in patients with established atherosclerotic CVD. There were also reductions in all-cause mortality, and renal composites mainly due to reductions in urinary albumin excretion. A significant 9% reduction was seen in HFH in the meta-analysis, driven by the HFH events in the Harmony Outcomes trial, with little effects on HFH in the other trials.
Thus, several GLP-1 receptor agonists have demonstrated reductions in atherosclerotic cardiovascular events and in proteinuria, with minimal if any reductions in hospitalisation for heart failure.
Table 2. Cardiovascular outcome trials with GLP-1 receptor agonists
|Drug||Trial||Key patient features||End point||Key results|
|Lixisenatide||ELIXA10||100% recent ACS
HFH no difference
19% CV risk
|MACE||MACE liraglutide superior
CV and all-cause mortality reduced
HFH no difference
|Semaglutide||SUSTAIN-613||83% ASCVD or CKD
17% CV risk
HFH no difference
|Exenatide once weekly||EXSCEL13||73% ASCVD
27% CV risk
All-cause mortality reduced†
HFH no difference
|Albiglutide||Harmony Outcomes15||100% ASCVD
||MACE||MACE albiglutide superior
69% CV risk
|MACE||MACE dulaglutide superior
HFH no difference
|Oral semaglutide||PIONEER 617||85% ASCVD or CKD
15% CV risk
CV and all-cause mortality reduced‡
HFH no difference
|Key: ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CV = cardiovascular; ELIXA = Evaluation of Lixisenatide in Acute Coronary Syndrome; GLP-1 = glucagon-like peptide 1; EXSCEL = Exenatide Study of Cardiovascular Event Lowering Trial; HFH = heart failure hospitalisation; LEADER = Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE = major adverse cardiovascular events; MI = myocardial infarction; PIONEER = Peptide Innovation for Early Diabetes Treatment; REWIND = Researching Cardiovascular Outcomes with a Weekly Incretin in Diabetes; SUSTAIN-6 = Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes
* In SUSTAIN-6 non-inferiority for MACE was the primary outcome and testing for superiority for the primary outcome was not prespecified or adjusted for multiplicity
† In EXSCEL non-inferiority for MACE was demonstrated (safety), but not superiority (efficacy). Because of conditional hierarchical analyses the all-cause mortality outcome should be considered exploratory.
‡ In PIONEER 6 these outcomes were not controlled for multiple comparisons and should be interpreted as exploratory.
DPP-4 inhibitors are currently widely used as a treatment for type 2 diabetes and in the UK have surpassed sulfonylureas as the drug class which is most commonly initiated after metformin. They have few side effects and are of low to moderate efficacy. However, the lack of any cardiovascular benefit means that these drugs should now be reserved for a small group of patients where avoidance of weight gain or avoidance of hypoglycaemia is the main clinical issue.
By contrast, GLP-1 receptor agonists are highly efficacious but are rarely used as a second-line drug and, at this point in time, are often relegated to third- or fourth-line despite the clear cardiovascular and renal benefits, which have been demonstrated in multiple CVOTs and meta-analysis, and their inclusion in most guidelines on the management of type 2 diabetes. The availability of the oral formulation of semaglutide may facilitate the earlier use of this class than the subcutaneous GLP-1 receptor agonists.
The pattern of cardiovascular benefits seen with GLP-1 receptor agonists is different to the benefits that have been seen with SGLT2 inhibitors (see module 4) with a slower separation in MACE, and minimal effect on HFH. In addition, the renal benefits are mostly in reductions in albuminuria, with minimal if any effect on eGFR. The updated consensus report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends the use of GLP-1 receptor agonists to reduce the risk of MACE in patients with type 2 diabetes and established atherosclerotic CVD (such as prior MI, unstable angina, coronary revascularisation) as the level of evidence for MACE benefit is greater than for SGLT2 inhibitors.20 Cardiologists should consider the initiation of a GLP-1 receptor agonist when these patients are consulted in outpatients, admitted to hospital, or attend for cardiac rehabilitation.
Within the GLP-1 receptor class, clear cardiovascular benefits have been demonstrated with liraglutide, subcutaneous semaglutide and dulaglutide, with less certain benefit from oral semaglutide and once-weekly exenatide, and no demonstrable benefit from lixisenatide. Several mechanisms of benefit have been suggested for GLP-1 receptor agonists (figure 1) and the effects of different GLP-1 receptor agonists on these factors may be different.21 Lixisenatide and exenatide are based on the exendin 4 peptide which differs considerably from native GLP-1 whereas liraglutide, semaglutide and dulaglutide are GLP-1 analogues, and this may be a possible explanation for the differing results.
It should be noted that the PIONEER 6 CVOT with oral semaglutide was a preapproval trial and that a larger post-licensing CVOT is currently underway (table 3). There are also CVOTs with the GLP-1 receptor agonist efpeglenatide in people with diabetes and weekly semaglutide in people with obesity. Further trials are also underway with weekly semaglutide in people with diabetes looking at renal and retinal outcomes (table 3). Dual agonists are now in development which combine GLP-1 receptor agonist effects with other agonist effects like glucagon receptor agonists and GIP (glucose-dependent insulinotropic polypeptide) agonists. Tirzepatide is a dual GIP and GLP-1 receptor agonist and is being compared with dulaglutide in a large CVOT that is estimated to complete in 2024.
Table 3. Future trials with GLP-1 receptor agonists
|Drug||Trial||Key patient features||End point|
|Oral semaglutide||SOUL||T2D and ASCVD||MACE|
|Subcutaneous semaglutide||SELECT||Overweight/obesity and ASCVD||MACE|
|Subcutaneous semaglutide||FLOW||T2D and DKD||Renal composite outcome|
|Subcutaneous semaglutide||FOCUS||T2D and diabetic retinopathy||Progression of retinopathy|
|Efpeglenatide||AMPLITUDE-O||T2D and ASCVD or DKD||MACE|
|Tirzepatide (vs dulaglutide)||SURPASS-CVOT||T2D and ASCVD||MACE|
|Key: AMPLITUDE-O = Effect of Efpeglenatide on Cardiovascular Outcomes; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; DKD = diabetic kidney disease; FLOW = Semaglutide diabetic kidney outcomes trial; FOCUS = A research study to look at how semaglutide compared to placebo affects diabetic eye disease in people with type 2 diabetes; MACE = major adverse cardiovascular events; SELECT = CVOT with semaglutide once weekly in patients that are overweight or obese; SOUL = Oral semaglutide CVOT in patients with type 2 diabetes; SURPASS-CVOT = Study of tirzepatide (LY3298176) compared to dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes; T2D = type 2 diabetes|
- DPP-4 inhibitors should be avoided in patients with atherosclerotic cardiovascular disease or heart failure.
- GLP-1 receptor agonists reduce major adverse cardiovascular events in people with diabetes and atherosclerotic disease, including prior myocardial infarction.
- Clinicians should select from daily liraglutide, weekly semaglutide, or weekly dulaglutide in these patients as these are of proven cardiovascular benefit.
- GLP-1 receptor agonists should be introduced early in the treatment pathway for these patients.
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2. European Medicines Agency (EMA). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London: EMA, 2012. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf
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16. Gertsein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardio- vascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised, placebo-controlled trial. Lancet 2019;394:121–30. https://doi.org/10.1016/S0140-6736(19)31149-3
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18. Kristensen SL, Rorth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776-85. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(19)30249-9/fulltext
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20. Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020;63:221-8. https://link.springer.com/article/10.1007/s00125-019-05039-w
21. Drucker DJ. The ascending GLP-1 road from clinical safety to reduction of cardiovascular complications. Diabetes 2018;67:1710-19. https://diabetes.diabetesjournals.org/content/67/9/1710.long