Semaglutide, a glucagon-like peptide (GLP)-1 agonist developed by Novo Nordisk, has demonstrated non-inferiority in cardiovascular (CV) risk, in fact, a 26% reduced composite risk of CV death, non-fatal myocardial infarction and non-fatal stroke, as compared to placebo in a cohort of >3,000 patients with type 2 diabetes (T2DM) at high CV risk. Semaglutide is the third anti-diabetic, and the second GLP-1 agonist that demonstrated a CV benefit, even though the trial, SUSTAIN-6, short for Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes, was not powered to demonstrate the superiority. The CV outcomes from SUSTAIN-6 were presented by Dr Steven Marso, MD, Professor of Medicine at the University of Texas Southwestern Medical Center and Medical Director of Interventional Cardiology, at the 52nd Annual Meeting of the European Association for the Study of Diabetes (EASD)1, with simultaneous publication in the New England Journal of Medicine.2
SUSTAIN is a clinical program for semaglutide comprising of six phase 3a global clinical trials encompassing more than 7,000 adults with T2DM. SUSTAIN-6, along with other CV outcome trials (CVOT) with diabetic medications, was designed to meet the requirements set out by the US Food and Drug Administration following revelations the thiazolidinedione (TZD) rosiglitazone raised the risk of myocardial infarction. Based on the industry guidance issued in 2008, drug companies are required to show that their medications do not result in an unacceptable increase in CV risk.
SUSTAIN-6: a CVOT powered for non-inferiority in T2DM with high CV risk
From February 2013 to March 2016, 3,297 adults with T2DM at high CV risk from 20 countries were enrolled and evaluated in the trial. Patients were randomized in a 1:1:1:1 ratio to receive either 0.5 mg (n=826) or 1.0 mg (n=822) of once-weekly subcutaneous semaglutide or volume-matched placebo (0.5 mg, n=824; 1 mg, n=825) in addition to the standard of care, i.e., lifestyle modifications, glucose-lowering treatments and CV medications. Patients were treated for 104 weeks, including those who had prematurely discontinued a study treatment, followed by a 5-week follow-up period. Patients who were less than 50 years of age, currently using anti-diabetic drugs that complements with semaglutide’s mechanism of action, having a current vascular event or planning a revascularization, were excluded.2
The mean age across groups was similar, ranging from 64.4 to 64.8 years. Baseline data indicated that 83% of patients had established CV disease (CVD), chronic kidney disease, or both. The overall mean duration of T2DM was 13.9 years, and the mean glycated hemoglobin level was 8.7%.2
The primary composite outcome was the first occurrence of a CV outcome comprising CV death, non-fatal myocardial infarction or non-fatal stroke. The trial was designed to assess non-inferiority, with a margin of 1.8 for the upper boundary of 95% CI of the hazard ratio.
Semaglutide demonstrated improved macrovascular outcomes
After a median observation time of 2.1 years, there was significant reduction in the primary composite CV outcome in the semaglutide arm (6.6% vs. 8.9% in placebo arm; HR=0.74; 95%CI: 0.58-0.95; p<0.001 for non-inferiority; p=0.02 for superiority).
“This was driven by 108 events in the semaglutide group compared with 146 events in the placebo group. We needed to accrue 122 events with the truth being the hazard of 1.0. In fact, we accrued twice as many events as predicted because there was a higher-risk cohort of 80% of patients with known [CVD], which, coupled with the 26% relative risk reduction, drove these findings,” said Marso during his presentation.
The non-inferiority, in fact superiority, in CV outcome was driven by significant reduction in nonfatal stroke (1.6% in semaglutide arm vs. 2.7% in placebo; HR=0.61; 95%CI: 0.38-0.99; p=0.04), and a non-significant trend towards reduction in nonfatal myocardial infarction (2.9% in semaglutide arm vs. and 3.9% in placebo arm; HR=0.74; 95%CI: 0.51-1.08; p=0.12), and a neutral outcome in risk of CV death (2.7% in semaglutide arm vs. 2.8% in placebo; HR=0.98; 95%CI: 0.65-1.48; p=0.92).
Revascularization, one of the secondary CV outcomes, was reduced by 35% vs. placebo (p=0.003), suggesting that the beneficial effect of semaglutide may be related to modification of the progression of atherosclerosis. No differences were found in other secondary CV outcomes, including all-cause death, and hospitalization for heart failure and unstable angina pectoris.
Semaglutide was associated with significant and sustained reductions in glycated hemoglobin levels over 2 years (- 1.1% at low dose and -1.4% at high dose vs. -0.4% in placebo; p<0.001for both comparisons). Clinically meaningful weight loss and a reduction in systolic blood pressure at high dose (p<0.001 for both parameters) in the semaglutide arm might have also contributed to the lowering of CV risks.
However, microvascular outcomes were less clear cut as compared to macrovascular outcomes. While significantly fewer number of people treated with semaglutide had new onset or worsening nephropathy (3.8% vs. 6.1 % placebo, HR=0.64; p=0.005), there was an “unexpected higher rate” of retinopathy complications including blindness in semaglutide-treated patients (3% vs. 1.8% in placebo; HR=1.76; p=0.02).
Though the rates of serious adverse events were lower in the semaglutide arm, the drug was associated with higher rates of treatment discontinuation due to adverse events, mainly related to gastrointestinal disorders.
“The reduction in cardiovascular events observed with semaglutide in SUSTAIN-6 is notable given the small study population and the short trial duration,” said Dr Marso. “These findings are clinically relevant as cardiovascular disease is the leading cause of death in people with T2DM, new treatment options that can also reduce the risk of cardiovascular events are needed.”3
A new ‘era’ of anti-hyperglycermic agent?
In fact, semaglutide from SUSTAIN-6 is the third anti-hyperglycemic agent, following empagliflozin in the EMPA-REG OUTCOME Study and liraglutide in the LEADER Study that have demonstrated a favorable CV outcome in T2DM. Though all three trials showed a reduction in the composite primary endpoint, relative contributions of the components to the primary outcome were different, with SUSTAIN-6 showing statistically significant reductions in non-fatal stroke, whereas in LEADER and EMPA-REG OUTCOME, there were differences in cardiovascular death and total mortality that were not observed in SUSTAIN-6.
With both semaglutide and liraglutide being a GLP-1 agonist, the lack of an observed reduction in CV death in SUSTAIN trial inevitably leads to questions about the comparability of the data to LEADER trial. Since more patients in the placebo group received intensification of their anti-diabetic treatment than in the semaglutide group in SUSTAIN-6, doubts were raised whether the observed benefit can be entirely attributable to semaglutide itself or to adverse effects of the other therapies that were used in the placebo groups.
The responses to this question are mixed. The SUSTAIN-6 trial investigators are keen to point out that this difference may be due to the normal variability between trials, or due to differences in the trial duration.4 However, Benjamin Morgan Scirica, MD, Associate Professor of Medicine of the Harvard Medical School is cautious in interpreting the results. “These differences, combined with the lack of benefit with the GLP-1 analogue lixisenatide in the ELIXA study, highlighted the fact that there is still much to learn about the role of GLP1 in cardioprotection,” he wrote in the commentary.5
Nonetheless, study discussant Lars Rydén, MD, PhD, of the Karolinska Institutet, Stockholm, Sweden, hold positive views with the use of GLP-1. “Having looked at the paper and the presentation, I must say it’s a well conducted and well presented study, so there are actually no serious concerns for the quality of data,” he said during the interview made by AACE Video Conference Reporter at the EASD meeting.6 “Importance was also the revascularization which, driven by the process of atherosclerosis, was significantly reduced by this drug in this particular study. It means that following the LEADER study, this one is the second showing a good effect of this compound. We have another one, ELIXA, a short acting GLP, which did not show anything else but non-inferiority, [which means it] didn’t cause harm, didn’t cause benefit. So now we have drugs in our hands which we can use in patients with diabetes, threaten by CV disease, which will be saving them from huge morbidity and mortality,” he said.6
Prof Rydén also noted there is difference in the mechanism of benefit between empagliflozin and the two GLP-1 agonists, with the reductions in heart failure observed in EMPA-REG OUTCOME and the retardation of atheroma observed in LEADER and SUSTAIN-6. “Imagine now the possibility that combining them which I think is the most fascinating thought for a new trial in all time,” he said in the interview.6
The addition of a third major trial reporting the reductions in CV outcomes seems to ratify the FDA mandate for CV safety as a crucial and timely requirement, however, there are concerns regarding the relevancy of these CVOTs to the whole T2DM population.
“The trials generally aim to enroll patients at very high cardiovascular risk (typically acute myocardial infarction survivors or patients with established cardiovascular disease) to accrue a sufficient number of events within a short time horizon”, Steg and colleagues wrote in a commentary published in Circulation.7 “The pathophysiology of recurrent cardiovascular events in these survivors of myocardial infarction with long-standing diabetes mellitus treated for few months may be very different from that of inaugural events in patients with recently diagnosed diabetes mellitus without overt cardiovascular disease treated for many years. Soon after myocardial infarction, thrombosis, particularly stent thrombosis, plays a relatively greater role in the genesis of cardiovascular events than does atherosclerotic disease progression, whereas the converse is true in patients without established cardiovascular disease.” 7
They further stressed that despite most CVOTs of novel drugs had neutral outcomes, which fulfilled their intention of showing CV safety, these trials are often misinterpreted as demonstrating lack of efficacy and generated skepticism about the value of glucose control in T2DM. “This is truly a misinterpretation,” they wrote.7
As a non-inferiority trial with a positive benefit, it seems likely that semaglutide will be approved by the FDA on the grounds of cardiovascular safety, but, for a definitive conclusion on the macrovascular endpoints described above, a larger, longer dedicated cardiovascular outcome trial will be required. It is the stated intention of Novo Nordisk to perform such a study after approval in order to obtain endorsement of cardiovascular risk reduction in the license.
As with all novel agents and class as a whole, the position within the guidelines for T2DM management will remain to be a subject for debate. This issue will only be resolved with further studies. The data from SUSTAIN-6, together with the two other trials published last year, are nevertheless encouraging for the entire field of T2DM management.