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SUSTAIN 1–5 demonstrate semaglutide’s efficacy in reducing blood glucose, body weight

Roshini Claire Anthony
17 Jan 2018

Semaglutide has superior efficacy in reducing glucose levels and body weight over a range of comparator treatments, according to findings from the phase 3 SUSTAIN 1–5* trials.

Study participants were 3,918 adults with type 2 diabetes (T2D; HbA1c 7.0–10.0 percent for SUSTAIN 1, 4, and 5 and 7.0–10.5 percent for SUSTAIN 2 and 3) who were randomized to receive subcutaneous semaglutide 0.5 mg or 1.0 mg QW, or comparators (placebo [SUSTAIN 1], sitagliptin [SUSTAIN 2], extended-release exenatide [SUSTAIN 3], insulin glargine [SUSTAIN 4]), or in addition to basal insulin with or without metformin vs placebo (SUSTAIN 5) for 30 or 56 weeks.

The efficacy of semaglutide vs comparators on multiple endpoints was presented as several posters at the recent IDF 2017 conference.

 

Superior glucose-lowering effect

Semaglutide reduced mean fasting plasma glucose (FPG) levels across all trials, with a significantly better FPG level reduction with semaglutide 1.0 mg compared with all comparators (difference, -1.79, -1.49, -0.84, -0.61, and -1.88 mmol/L for SUSTAIN 1–5, respectively; p≤0.0002 for all comparisons). [IDF 2017, abstract OP-0011]

Semaglutide 0.5 mg also induced significant reductions in FPG compared with placebo in SUSTAIN 1 (difference, -1.96; p<0.0001), compared with sitagliptin in SUSTAIN 2 (difference, -0.97 mmol/L; p<0.0001) and when added to basal insulin (compared with placebo) in SUSTAIN 5 (difference, -1.14 mmol/L; p=0.0002).

Semaglutide also reduced mean postprandial glucose (PPG) levels across all trials, again with significantly better improvements noted with semaglutide 1.0 mg (difference, -0.74, -0.38, -0.24, -0.65, and -1.01 mmol/L for SUSTAIN 1–5, respectively; p<0.02 for all comparisons), and semaglutide 0.5 mg demonstrating significant reductions when compared with insulin glargine and in addition to basal insulin in SUSTAIN 4 and 5, respectively (difference, -0.39 and -0.66 mmol/L, respectively; p<0.005 each).

“Semaglutide consistently reduced FPG and PPG across SUSTAIN 1–5, suggesting that both components contribute to significantly better glycaemic control vs comparators … [and] that semaglutide is effective across different background therapies, duration of diabetes, and stages in the treatment continuum,” said the authors, led by Dr Esteban Jodar from the Hospital Universitario Quirónsalud Madrid in Spain.

 

Achieving target HbA1c levels

More patients on semaglutide achieved HbA1c levels <7 percent compared with those on comparators (p<0.0001 for each comparison). [IDF 2017, abstract OP-0012]

“[S]ignificantly more subjects achieved HbA1c <7.0 percent with semaglutide vs comparators without weight gain or hypoglycaemia. Moreover, semaglutide remained favourable vs comparators when the composite endpoint included the component of no moderate/severe gastrointestinal adverse events [AEs; p<0.0001 for each comparison],” said study author Dr Vincent Woo from the University of Manitoba, Winnipeg, Manitoba, Canada, and co-authors.

 

Significant reductions in body weight

Semaglutide also induced significant loss in body weight across all trials (p<0.0001), with greater absolute weight reductions (vs baseline) noted with semaglutide 1.0 mg compared with all comparators (-4.5 vs -1.0 kg [SUSTAIN 1], -6.1 vs -1.9 kg [SUSTAIN 2], -5.6 vs -1.9 kg [SUSTAIN 3], -5.2 vs +1.2 kg [SUSTAIN 4], and -6.4 vs -1.4 kg [SUSTAIN 5]). [IDF 2017, abstract P-0526]

More patients on semaglutide 0.5 and 1.0 mg achieved ≥5 or ≥10 percent weight loss compared with comparators.

“Despite diet and exercise modification, weight management remains a challenge for patients with T2D. The effect of semaglutide on body weight is an added benefit to the improved glycaemic control for patients with T2D,” said Woo and co-authors.

 

Comparable safety profile

“Overall, semaglutide had a similar safety profile to that of other [glucagon-like peptide-1 receptor agonists],” said Jodar and co-authors.

The incidence of AEs was comparable between patients on all treatments. However, treatment discontinuation was higher among patients on semaglutide, ranging from 10.6–13.5 percent with semaglutide 0.5 mg and 12.2–20.3 percent with semaglutide 1.0 mg compared with comparators (7.2–21.0 percent).

The higher discontinuation rate was driven primarily by gastrointestinal AEs, said the researchers. The gastrointestinal AEs were also not the cause of weight loss, said Woo and co-authors.

The overall rates of severe and blood glucose-confirmed hypoglycaemia were low among patients on semaglutide, with higher rates only noted among patients with baseline background treatment of sulphonyureas and/or insulin.

 

Conclusion

“T2D is a complex disease and treatment goals should focus beyond reducing HbA1c. It is clinically relevant to achieve HbA1c targets, as well as to avoid weight gain, the risk of hypoglycaemia, and other short- and long-term side effects,” said Woo and colleagues.

 

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