First Data on GLP-1 Agonist/SGLT2 Inhibitor Combo in Diabetes

Becky McCall

September 19, 2016

MUNICH — Combining exenatide (Bydureon, AstraZeneca) with dapagliflozin (Farxiga/Forxiga, AstraZeneca) improved glycemic measures and cardiovascular risk factors more so than each drug alone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.

The study provides the first evidence of efficacy of coadministration of a combination of a glucagonlike-peptide 1 (GLP-1) receptor agonist, exenatide, and a sodium glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, said Cristian Guja, MD, from the Carol Davila University of Medicine and Pharmacy, Bucharest, Romania, presenting the results of the DURATION-8 trial here at the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting. Dr Guja said that the dual treatment regimen was well tolerated, with the expected safety profile for this combination.

The results were published simultaneously September 16 in Lancet Diabetes and Endocrinology by Juan P Frias, MD, of National Research Institute, Los Angeles, California. Dr Guja is the second author.

The combination of once-weekly exenatide injections plus once-daily oral dapagliflozin reduced HbA1c by 2%, showing greater benefit than either drug alone. All patients were on background metformin (at least 1500 mg/day).

"These results show that the combination of exenatide and dapagliflozin was associated with significantly greater reductions than either individual therapy in glycemic parameters, weight, and systolic blood pressure…supporting the efficacy and safety of coinitiating exenatide and dapagliflozin in patients with type 2 diabetes inadequately controlled on metformin monotherapy," reported Dr Guja to a packed hall, for the last talk of the conference.

Furthermore, these improvements occurred without any protocol-defined hypoglycemic events and with no unexpected safety findings.

Interest in the combination of GLP-1 agonist and SGLT2 inhibitor therapy is high, given that recently reported cardiovascular-outcomes studies of such agents are proving that they are cardioprotective and probably work via different mechanisms of action, with doctors now saying the logical next step is to combine these two classes of agent.

However, in an editorial accompanying the paper on exenatide and dapagliflozin, Michael A Nauck, MD, and Juris J Meier, MD, of St Josef Hospital, Bochum, Germany, note that these two agents "are not the ones that have shown significant cardiac benefit (ie, liraglutide [Victoza, Novo Nordisk] [in LEADER] and empagliflozin [Jardiance, Boehringer Ingelheim/Lilly] [in EMPA-REG])."

"The results of the cardiovascular-outcomes trials for exenatide (EXSCEL) and dapagliflozin (DECLARE-TIMI 58) are not expected until 2018 and 2019 respectively, they note.

Whether the cardiovascular benefit of the combination of GLP-1 receptor agonists and SGLT2 inhibitors will be over and above what the individual drugs can provide remains to be demonstrated, they observe.

Combination Enhances Weight Loss, BP Reduction

DURATION-8 was a 28-week, multicenter, double-blind, phase 3, randomized controlled trial carried out over 109 sites internationally. Despite being on metformin therapy, the patients with type 2 diabetes had inadequate glycemic control (mean HbA1c 9.3%), and high mean fasting plasma glucose at 11 mmol/L. Mean age was 54 years and body mass index ranged from 32 to 33 kg/m2.

Altogether, 695 patients were randomly assigned (1:1:1) to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10-mg oral tablets; exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections. Patients were stratified by baseline HbA1c (< 9.0% vs ≥ 9.0%). The study ran for 28 weeks but has a 2-year extension. All analyses were intention to treat.

The primary end point was change in HbA1c from baseline to week 28, and patients on the combination of drugs showed the highest drop in HbA1c, at 2%.

"This was significantly better than patients treated with dapagliflozin alone (1.4%), or exenatide alone (1.6%) (P < .004)," reported Dr Guja.

The exenatide and dapagliflozin combination was found to be significantly superior to either drug alone for all secondary end points, too.

For example, "by week 2, [those on combination therapy] had significantly lower fasting plasma glucose and after 28 weeks of follow-up the mean decrease was 3.6 mmol/L, significantly lower than either of the drugs alone, each of which were around 2.5 mmol/L (< .001)," Dr Guja added.

All patients experienced weight loss, as expected, with the combination arm shedding the most, reported Dr Guja.

After 28 weeks, those taking the combination had lost 3.4 kg, on average, compared with 2.2 kg and 1.5 kg for the dapagliflozin and exenatide arms alone.

"Again, these were highly significant differences," said Dr Guja, adding, "It seems that the weight loss is additive and it continues this way in the combination arm."

However, he noted that "a clearer picture will be available at 52 weeks." Patients with higher HbA1c at baseline showed less weight loss, possibly explained by their catabolic state," Dr Guja suggested.

Specifically, those with HbA1c of between 8% and 9% at baseline showed a drop of 4.5 kg on the combination, compared with losses of 1.9 kg and 2.2 kg on exenatide and dapagliflozin alone, respectively. Patients with higher baseline HbA1c (> 9%) had respective weight losses of 2.6 kg, 1.2 kg, and 2.0 kg in the respective groups.

Systolic blood pressure dropped by 4.2 mm Hg, 1.3 mm Hg, and 1.8 mm Hg in patients on the combination, exenatide alone, and dapagliflozin alone, respectively.

The proportion of patients achieving an HbA1c of less than 7% was approximately 45% in the combination arm, 27% in the exenatide group, and 19% in patients on dapagliflozin.

There were also few, if any, differences in any adverse events, including any serious side effects and any adverse events leading to treatment discontinuation between groups," reported Dr Guja.

The most frequent adverse events were injection-site nodules. Gastrointestinal and nausea were more frequent in exenatide-treated patients, and events suggestive of genital infections were more common in the dapagliflozin group.

No episodes of hypoglycemia were reported.

Less Than Half of Patients Achieving HbA1c < 7% Is "Disappointing"

The authors note in their Lancet paper that reductions in weight, systolic blood pressure, and triglycerides observed in the combination arm seemed to be additive, suggesting independent mechanisms, resulting in changes that did not trigger compensatory counteracting responses.

"The additive effect on systolic blood pressure might have clinical significance and can probably be explained by different mechanisms of blood-pressure lowering," they note.

But effects on glycemic end points were less than additive, and this was true for reductions in HbA1c, fasting plasma glucose, and two-hour postprandial glucose.

In their editorial, Drs Nauck and Meier note that it was expected that "the combination would lower HbA1c and body weight more than either component alone," but the less-than-additive effect on HbA1c was likely due to the fact that the glucose-lowering efficacy of any one drug diminishes with lower baseline HbA1c.

"In the present study, the exenatide and dapagliflozin combination was initiated at the same time, not sequentially, as will probably happen in most clinical cases."

They add that the finding that only 45% of patients in the combination-therapy group achieved an HbA1c of less than 7.0% (<53 mmol/mol) after 28 weeks is "disappointing."

And there is still a long way to go to assess combinations of these two classes, which could also produce potentially deleterious effects (eg, formation of ketone bodies), they stress.

The study was funded by AstraZeneca. Dr Guja has served on scientific advisory boards and received consulting fees from Alfa Wasserman, AstraZeneca, Bayer, Berlin Chemie Menarini, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Servier Pharma, and Worwag Pharma. Dr Zinman declared that he was a consultant for Merck, AstraZeneca, Lilly, and Novo Nordisk. Disclosures for the coauthors are listed in the article. Dr Nauck has received personal fees, nonfinancial support, and compensation for travel costs associated with scientific meetings from Berlin Chemie; personal fees and nonfinancial support from Boehringer Ingelheim, Sanofi, Versartis, Intarcia Therapeuticals, AstraZeneca, Hoffmann-La Roche, Janssen Global Services, and Medscape; and grants, personal fees, and nonfinancial support from Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novo Nordisk, and Novartis. Dr Meier has received grants and personal fees from Novo Nordisk, Sanofi, and Merck Sharp & Dohme; personal fees from Servier, AstraZeneca, Eli Lilly, and Berlin Chemie; and grants and personal fees from Boehringer-Ingelheim.

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Lancet Diabetes Endocrinol. Published online September 16, 2016. Abstract, Editorial

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