September 16, 2016

MUNICH — A second glucagonlike-peptide 1 (GLP-1) agonist has shown positive results in a major cardiovascular-outcomes trial in type 2 diabetes patients at high risk of cardiovascular disease.

Patients treated with one of two doses of the investigational agent semaglutide (Novo Nordisk), which has a long half-life and only needs to be injected subcutaneously once a week, had a significant 26% lower risk of the primary composite outcome of first occurrence of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke over 2 years compared with those receiving placebo in the SUSTAIN-6 trial, reported here at the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting today.

Semaglutide was also a potent glucose-lowering agent, with significant and sustained reductions in HbA1c levels seen with the agent, as compared with placebo, and similar rates of hypoglycemia, although glucose lowering was not the main point of the trial.

The lower cardiovascular risk was principally driven by a significant 39% decrease in nonfatal stroke and a 26% reduction in nonfatal MI (nonsignificant); there was no difference in cardiovascular deaths between the different arms of the trial — 0.5 mg of semaglutide once weekly, 1.0 mg of semaglutide once weekly, and corresponding placebo groups.

And the number of patients who would need to be treated to prevent one event of the primary outcome over 2 years was 45.

The main results of the 3200-patient trial conducted in 22 countries were reported by the principal investigator, cardiologist Steven P Marso, MD, of the Research Medical Center, Kansas City, Missouri, to applause from a packed convention hall and were simultaneously published online in the New England Journal of Medicine.

Cardiologist Dr Lars Rydén, from Karolinska University Hospital, Stockholm, Sweden, who was not involved in the SUSTAIN-6 trial but was the designated discussant at the meeting, said the reduction in cardiovascular events seen with semaglutide in the trial "is quite substantial and better than" is seen in some studies of cardiology agents — for example, platelet-stabilizing drugs.

However, he noted that the separation of curves "takes some time, around a year and a half, but from then on [the benefit] expands." Given that the primary end point was driven by nonfatal stroke and to a lesser extent MI, but not by death, and that hospitalization for heart failure was not affected, the effect of semaglutide is likely on atherosclerosis, he noted.

Regarding the lack of a reduction in cardiovascular deaths with semaglutide in the study, Dr Rydén told Medscape Medical News: "It takes time for cardiovascular benefits to translate into mortality — it's only 2.1 years [trial duration]. They had enough events to show what they wanted, but it's still a very short period in the life of people with diabetes."

There was a concern about higher rates of retinopathy complications in those receiving semaglutide. Vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation were significantly higher among those receiving semaglutide, occurring in 3% of patients on the active drug compared with 1.8% of the placebo group, a 76% increase (= .02).

Presenting this finding as part of the clinical and metabolic outcomes of the study, endocrinologist Tina Vilsbøll, MD, DMSc, of the Center for Diabetes Research, Gentofte Hospital, Copenhagen, Denmark, said: "This is the only forest plot that goes in the wrong direction."

However, she pointed out, "The signals we saw were mostly only in patients with retinopathy at baseline." Nevertheless, she noted that there is an association between rapid glucose lowering and retinopathy — as seen in the DCCT trial—and this observation requires further investigation.

Asked to comment on the findings for Medscape Medical News, endocrinologist Bernie Zinman, MDCM, FRCPC, FACP, from Mount Sinai Hospital, Toronto, Ontario, stressed that "the retinal outcomes [in SUSTAIN-6] can't be ignored; it's a small number of events, but [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation] LEADER also had it going in that direction, so I think that has to be further evaluated to determine whether it's real or not."

"Is it just a worsening of retinopathy when you have rapid improvement and control [of glucose]? Or is there a biological effect on the eye? It remains to be seen."

Wonderful Era for Diabetes — GLP-1 Agonist/SGLT-2 Inhibitor Combos?

Semaglutide joins another Novo Nordisk GLP-1 agonist, liraglutide (Victoza), which in June demonstrated cardiovascular benefit when added to standard of care in type 2 diabetes patients at high cardiovascular risk in the LEADER trial.

LEADER was the second such mandated FDA cardiovascular safety study for a diabetes drug to show cardiovascular benefit, rather than just lack of harm, on top of standard therapy in type 2 diabetes patients at high cardiovascular risk, after the EMPA-REG trial, and the first with an agent from the GLP-1 receptor agonist class.

EMPA-REG was the first trial to show a reduction in cardiovascular death with a glucose-lowering drug, the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance/Boehringer Ingelheim/Lilly), a different class of contemporary diabetes agent, and this study was reported a year ago, at the EASD meeting in 2015.

Importantly, these two classes of glucose-lowering agents, GLP-1 agonists and SGLT2 inhibitors, seem to be reducing cardiovascular events via different mechanisms — the GLP-1 agonists via a delay in the progression of atherosclerosis while the SGLT2 inhibitors appear to be preventing heart failure and associated deaths.

Commenting on how the landscape now looks for contemporary diabetes drugs, Dr Zinman — who was an investigator for the EMPA-REG trial — told Medscape Medical News: "We are in a wonderful era of diabetes. We have drugs that don't cause hypoglycemia or weight gain, and they work very effectively. They can be used in combination — and I think they should be — and one has to study whether together they will be even better."

Regarding SUSTAIN-6 specifically, Dr Zinman said: "It's exciting to have another positive trial with respect to cardiovascular outcomes. What was prominent was the very robust effect in reducing the primary outcome in a small number of patients over a short period of time. And despite everybody treating to target, the HbA1c difference was substantial [between semaglutide and placebo], so this is a very potent drug that lowers A1c very well."

"Endocrinologists and primary-care physicians are going to be happy that we now have opportunities to use agents that can reduce cardiovascular outcomes," he observed.

But, "as with all trials, new questions are raised," Dr Zinman pointed out. "It's a little bit of a disappointment that there was no change in cardiovascular death, whereas with LEADER there was," and he reiterated the further work required to determine whether the retinopathy signal should be of concern or not.

Dr Rydén told Medscape Medical News: "GLP-1 receptor agonists are now shown in two major trials to be not only safe but efficient for glucose lowering, avoiding hypoglycemia, and reducing weight, so they are an ideal drug to use, for instance, with insulin."

"Meanwhile, we have to see whether the heart-failure protecting drug, empagliflozin, and [GLP-1 agonist] together will be something even better," he added.

And he has another message for endocrinologists: "Why should we ever use a sulfonylurea anymore? There are many observational and registry studies showing that sulfonylurea as an addition to metformin is perhaps not a very good choice."

SUSTAIN-6 Cardiovascular Outcomes

In SUSTAIN-6, 3297 patients with type 2 diabetes and an HbA1c of 7% or more aged at least 50 were randomized. Of them, 2735 had established cardiovascular disease, chronic kidney disease, or both; the remainder were aged at least 60 with at least one cardiovascular risk factor. Mean duration of diabetes was 13.9 years and mean HbA1c was 8.7%.

Most patients (93.5%) were taking antihypertensive medication, 76.5% were receiving lipid-lowering drugs, and 76.3% were receiving antithrombotic medications.

The trial is the first preapproval study to demonstrate cardiovascular safety of a potential agent for diabetes, as per the FDA requirement of 2008, and was conducted between February 2013 and December 2013.

A fixed-dose escalation procedure was used, with a starting dose of 0.25 mg of semaglutide (or corresponding placebo) for 4 weeks that escalated to 0.5 mg for 4 weeks until the maintenance dose (0.5 mg or 1.0 mg) was reached. No change in the maintenance dose of either semaglutide or placebo was permitted for the duration of the trial.

Dr Marso noted the cardiovascular risk reduction seen with semaglutide occurred early "and extended and diverged over time," despite the fact an increase in pulse rate of 2 beats per minute was seen with the active drug compared with placebo.

Similar risk reductions were observed with both doses of semaglutide, so they were combined for analysis purposes.

Throughout the trial, a greater proportion of patients in the placebo group than the semaglutide group received additional cardiovascular medications, Dr Marso noted.

"The reduction in CV events observed with semaglutide in SUSTAIN-6 is notable, given the small study population and the short duration," he concluded.

"These findings are clinically relevant, as CVD is the leading cause of death in people with type 2 diabetes, and new treatment options that can also reduce the risk of CV events are needed."

Primary and Secondary Cardiovascular and Microvascular Outcomes

Outcome Semaglutide, n=1648 (%) Placebo, n=1649 (%) Hazard ratio P
Primary composite outcome* 6.6 8.9 0.74 < .001 for noninferiority; 0.02 for superiority
Death from any cause 3.8 3.6 1.05 0.79
CV death 2.7 2.8 0.98 0.92
Nonfatal MI 2.9 3.9 0.74 0.12
Nonfatal stroke 1.6 2.7 0.61 0.04
Revascularization 5.0 7.6 0.65 0.003
Hospitalization for HF 3.6 3.3 1.11 0.57
Retinopathy complications 3.0 1.8 1.76 0.02
New or worsening nephropathy 3.8 6.1 0.64 0.005

Glucose Lowering, Other Clinical Outcomes, and Safety

Dr Vilsbøll documented the "sustained effect" of semaglutide, with respect to HbA1c and fasting plasma glucose. From an overall baseline of 8.7%, semaglutide significantly reduced HbA1c by 1.4% and 1.1% (for the two doses) vs 0.4% for placebo.

"So 39% of patients on the 0.5-mg dose of semaglutide and 49% of those on 1.0-mg dose achieved the ADA target of HbA1c < 7.0%," she noted, and a higher proportion of patients receiving placebo had to intensify their [other] antihyperglycemic treatment.

Rates of hypoglycemia didn't differ between the active and placebo groups, either, she noted.

Body weight "decreased by almost 5 kg with the 1.0-mg dose of semaglutide, from a mean of 92.1 kg," compared with weight loss of 3.6 kg, on average, in the 0.5-mg group and 0.5 to 0.7 kg in the placebo recipients.

Meanwhile, Lawrence Leiter, MD, FRCP, director of the lipid clinic at St Michael's Hospital, Toronto, Ontario, presented the safety findings from SUSTAIN-6 and noted that the total number of adverse events was comparable between all groups, and few serious adverse events were seen with semaglutide. As would be expected, the most common side effects with the active drug were gastrointestinal in nature; nausea, vomiting, and diarrhea, and treatment discontinuation for these reasons was more frequent with semaglutide. Pancreatitis occurred in low and similar numbers in both active-drug and placebo groups, and the frequency and rate of malignant neoplasms was also similar between all arms.

Dr Vilsbøll discussed the retinopathy outcomes in more detail — the majority of subjects who developed diabetic retinopathy complications (> 80%) had preexisting retinopathy at baseline, she stressed.

Specifically, 38 patients taking semaglutide needed retinal photocoagulation vs 20 on placebo; 16 had a vitreous hemorrhage vs seven; while 16 required treatment with intravitreal agents compared with 13 on placebo; and five of those taking semaglutide experienced the onset of diabetes-related blindness, compared with one in the placebo group.

"We have to look into this more; I don't have the exact explanation of why that is, but the numbers were overall small," Dr Vilsbøll told Medscape Medical News.

In contrast, there was a "very nice effect" of semaglutide on nephropathy, she noted.

In conclusion, she said: "It's great to see another trial with a GLP-1 agonist being positive. It is in a high-risk population, and we are not completely sure whether we'll see the same results in a broader population.

"But a risk reduction of 26% overall is really important for me as a diabetologist with this class. It might take a couple of years until we have this agent on the market, but it's good for the class, and it's good for the patient."

Dr Marso reports personal fees from Novo Nordisk during the conduct of the study; grant support and personal fees from Novo Nordisk, and personal fees from Abbott Vascular and AstraZeneca outside the submitted work. Dr Vilsbøll reports being an advisory board member for Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, and Sanofi and consulting or being a speaker for or receiving research support from AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen Cilag, MSD, Novo Nordisk, Sanofi, and Zealand Pharma. Dr Leiter is on the advisory panel and the speaker's bureau for and has received research support from AstraZeneca, as well as from other pharmaceutical companies. Disclosures for the coauthors are listed on the journal website. Dr Rydén has no relevant financial relationships. Dr Zinman reports having served as a director, officer, partner, employee, advisor, consultant, or trustee for Eli Lilly, Boehringer Ingelheim, AstraZeneca, Merck, and Novo Nordisk and receiving research grants from Boehringer Ingelheim and Merck, and AstraZeneca.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

N Engl J Med. Published online September 16, 2016. Article

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