SUSTAIN-8: Semaglutide vs Canagliflozin After Metformin in T2D

Becky McCall

September 23, 2019

BARCELONA — Only the second head-to-head trial to directly compare two new classes of type 2 diabetes drugs, a GLP-1 agonist with an SGLT2 inhibitor, shows the former, in this case once-weekly subcutaneous semaglutide (Ozempic, Novo Nordisk) was superior to the latter, daily canagliflozin (Invokana, Janssen) in reducing HbA1c and body weight in patients with type 2 diabetes uncontrolled on metformin.

"There are very few head-to-head comparator trials with one [type 2 diabetes] drug class versus the other," said Ildiko Lingvay, MD, from UT Southwestern Medical Center, University of Texas, Dallas, who presented the findings of the SUSTAIN-8 trial here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting.

In the study — funded by Novo Nordisk, the maker of semaglutide — subcutaneous semaglutide led to a reduction in mean HbA1c of 1.5% compared to 1.0% with canagliflozin from a baseline of 8.3% over the 1-year study. Participants treated with subcutaneous semaglutide also lost more weight compared with canagliflozin, on average 5.3 kg versus 4.2 kg, from a mean baseline of 90.2 kg.

The trial was simultaneously published in Lancet Diabetes & Endocrinology.

"SUSTAIN-8 provides clinically relevant information regarding the head-to-head comparison of these two commonly used glucose-lowering classes as second-line therapy in patients with type 2 diabetes," Lingvay told delegates.

Other physicians stressed the need to take into account a wide range of factors before deciding which type 2 diabetes drug to use as add-on therapy to metformin for any one particular patient.

These include André Scheen, MD, from the University of Liège, Belgium, who penned an editorial accompanying, also published in Lancet Diabetes & Endocrinology.

"Beyond effects on HbA1c and bodyweight, consideration should also be given to patient preference, individual tolerance profile, and cost," he said.

In an interview with Medscape Medical News at EASD, Hertzel Gerstein, MD, McMaster University and Hamilton Health Sciences, Ontario, Canada, agreed.

"In isolation, the trial will not drive therapy towards one agent or the other, but it will inform judgement when a clinician interacts with a patient and is really practicing personalized care," he commented. 

The decision regarding therapy "depends on many things...including the jurisdiction one is in, which incorporates the cost, and whether [that]...is covered by a third party; the side effect profile; and what the patient wants to take," Gerstein added.

SUSTAIN-8 Phase 3 Trial Fills Evidence Gap

"Studies show that achieving a target HbA1c of 7.0% or lower is crucial for reducing the development and progression of microvascular complications in type 2 diabetes," said Lingvay.

And because data show that GLP-1 agonists and SGLT2 inhibitors cause weight loss and lead to improvements in cardiovascular outcomes, as well as lower HbA1c, the two drug classes are increasingly being used as preferred second-line agents after metformin.

But data comparing the two drugs classes head-to-head in patients inadequately controlled with metformin are lacking, with just one prior study comparing the new oral formulation of semaglutide — just approved by the FDA — with the SGLT2 inhibitor empagliflozin (Jardiance, Lilly/Boehringer Ingelheim).

Lingvay reported that SUSTAIN-8 was a 52-week, double-blind, parallel-group, randomized controlled phase 3 trial conducted across 11 countries investigating the efficacy and safety of once-weekly subcutaneous semaglutide (1.0 mg) versus canagliflozin (300 mg daily) as add-on to metformin in people with type 2 diabetes. The first 8 weeks was a dose-titration phase, followed by 44 weeks of treatment maintenance and 5 weeks of follow-up.

The primary endpoint was change in HbA1c from baseline to week 52, and key secondary endpoints included change in body weight and total fat mass, as well as the proportion of patients achieving HbA1c < 7.0%.

As well as the significantly greater reduction in HbA1c with semaglutide compared with canagliflozin — a treatment difference of 0.5 percentage points (P < .0001) — 66.1% versus 45.1% achieved an HbA1c < 7%.

Also, significantly more patients treated with semaglutide achieved a 10% or greater reduction in body weight versus canagliflozin (22.3% vs 8.9%).

Although serious adverse events were rare for both drugs, almost double the number of patients taking semaglutide versus canagliflozin discontinued treatment, primarily because of gastrointestinal side effects.

Comorbidities Should Direct Choice of Second-Line Therapy

Scheen emphasizes in his editorial that, according to current recommendations (American Diabetes Association and EASD), the presence of comorbidities such as heart failure and renal disease should help steer physicians towards prescribing an SGLT2 inhibitor rather than a GLP-1 receptor agonist as second-line therapy in type 2 diabetes.

Gerstein agrees: "Renal disease, glomerular filtration rate, and history of other medical events, for example, whether they've had heart failure or not, might push towards an SGLT2 inhibitor."

"As a clinician, one usually makes a choice based on the personal story of the patient, combined with history and physical examination, to provide personalized medicine," he observed.

But for those with atherosclerotic heart disease, a GLP-1 receptor agonist should be the preferred choice, says Scheen.

However, the cost of subcutaneous semaglutide is higher than the cost of canagliflozin, which might be a concern in many countries, he writes. 

"Presumably, this difference in cost will remain with the oral formulation of semaglutide?" he wondered.   

Nevertheless, there may even be a place for using both together in patients at high risk of cardiovascular and renal disease.

"We might speculate about the add-on value of a combination therapy instead of the dilemma of choosing between a GLP-1 receptor agonist and an SGLT2 inhibitor," Scheen concludes.

EASD 2019 Annual Meeting. Presented September 17, 2019. Abstract 52.

Lancet. Published online September 17, 2019. Abstract, Editorial

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