Weekly GLP-1 Analog Improves Glycemic Control vs Glargine in T2D Inadequately Controlled on Metformin

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Once weekly semaglutide improves glycemic control and increases weight loss in patients with type 2 diabetes whose disease is inadequately controlled on metformin with or without sulfonylureas.
Once weekly semaglutide improves glycemic control and increases weight loss in patients with type 2 diabetes whose disease is inadequately controlled on metformin with or without sulfonylureas.

Patients with type 2 diabetes that is inadequately controlled with metformin who are taking the novel glucagon-like peptide-1 (GLP-1) analog semaglutide had greater reductions in hemoglobin A1c (HbA1c)  and weight compared with patients taking insulin glargine, according to recent research published in The Lancet Diabetes & Endocrinology.

“[S]emaglutide was associated with superior glyc[a]emic control and reduced bodyweight, with few episodes of hypoglyc[a]emia, compared with insulin glargine in patients with type 2 diabetes receiving metformin with or without a sulfonylurea,” Vanita R. Aroda, MD, from the MedStar Health Research Institute in Hyattsville, Maryland, and colleagues wrote.

“However, insulin glargine did not achieve titration targets, reflecting a potential limitation of titration often seen in clinical practice.”

In a randomized, open-label, parallel-group, noninferiority, multicenter international trial, researchers from 196 sites in 14 different countries enrolled 1089 participants in the SUSTAIN 4 study (ClinicalTrials.gov Identifier: NCT02128932).  

SUSTAIN 4 aimed to compare the effect of 2 doses of once-weekly semaglutide with the effect of once-daily insulin glargine with or without sulphonylurea on glycemic control in insulin-naïve subjects with type 2 diabetes after 30 weeks of treatment.

Participants were >18 years old with type 2 diabetes, HbA1c levels between 7% and 10% (53-86 mmol/mol), and persistent poor glycemic control after taking metformin or combination metformin and sulfonylurea.

Study participants continued their metformin and sulfonylurea regimens and were randomly assigned to receive weekly semaglutide (0.5 mg or 1.0 mg) subcutaneously in a fixed-dose escalation regimen, or daily insulin glargine with a starting dose of 10 IU followed by a titrated weekly dose based on a plasma glucose of 4.0 to 5.5 mmol/L (72-99 mg/dL) over 30 weeks.

At 30 weeks, there were reductions in HbA1c of 1.21% (95% CI, 1.10%-1.31%) in the 0.5 mg semaglutide group and 1.64% (95% CI, 1.54% – 1.74%) in the 1.0 mg semaglutide group compared with a baseline HbA1c level of 8.17%.

The insulin glargine group had a reduction of 0.83% (95% CI, 0.73%-0.93%) compared with baseline HbA1c levels, and a −0.38% (95% CI, −0.52% to −0.24%; P <.0001) difference between treatment groups for the 0.5 mg semaglutide group and a −0.81% (95% CI, −0.96% to −0.67%; P <.0001) in the 1.0 mg semaglutide group.

Regarding weight loss, participants in the 0.5 mg semaglutide group lost 3.47 kg (95% CI, 3.00 kg-3.93 kg), while participants in the 1.0 mg semaglutide group lost 5.17 kg (95% CI, 4.71 kg-5.66 kg) at 30 weeks from mean 93.45 kg at baseline.

Participants in the insulin glargine group gained 1.15 kg at 30 weeks compared with baseline weight, with a treatment group difference of −4.62 kg (95% CI, −5.27 kg to −3.96 kg; P <.0001) in the 0.5 semaglutide group and −6.33 kg (95% CI, −6.99 kg to −5.67 kg; P <.0001) in the 1.0 mg semaglutide group.

Of the participants who started treatment at baseline, 14% (n=49) in the 0.5 mg semaglutide group, 15% (n=49) in the 1.0 mg semaglutide group, and 7% (n=26) in the insulin glargine group discontinued treatment.

The most common adverse event was nausea, which occurred in 21% of cases (n=77) in the 0.5 mg semaglutide group, 22% of cases (n=80) in the 1.0 mg semaglutide group, and 12% of cases (n=44) in the insulin glargine group.

“Numerically, more participants discontinued treatment prematurely in the semaglutide groups compared with the insulin glargine group; most discontinuations were due to adverse events (mostly gastrointestinal with semaglutide and from other causes with insulin glargine, including skin and subcutaneous tissue disorders such as rash, pruritus, and urticaria),” Dr Aroda and colleagues wrote.

The researchers noted hypoglycemia occurred in 4% of cases (n=16; P =.0021) in the 0.5 mg semaglutide group, and 6% of cases (n=20; P =.0202) in the 1.0 mg semaglutide group compared with 11% of cases (n=38) in the insulin glargine group.

There were severe cases of hypoglycemia in 2 participants in the 0.5 mg semaglutide group, 5 participants in the 1.0 mg semaglutide group, and 5 participants in in the insulin glargine group.

The researchers reported 6 deaths during the trial; 2 cases occurred in the 0.5 mg semaglutide group and 4 cases occurred in the insulin glargine group.

Dr Arola and colleagues noted that the combination of weight loss and glycemic control seen in participants in the semaglutide groups is promising for the use of the treatment in clinical practice.

“The combination of glycaemic control and bodyweight reduction with a low potential for hypoglycaemia, delivered with a once-weekly injection of semaglutide, is a promising finding given that a high proportion of patients with type 2 diabetes are overweight or obese and many other treatments either do not affect weight or are associated with weight gain accompanied by hypoglycaemia or the need to be injected daily,” Dr Arola and colleagues wrote.

Disclosures: This study was funded by Novo Nordisk A/S, the manufacturer of semaglutide. The researchers report multiple financial disclosures. Please see the full study for a complete list of disclosures.

Reference

Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial [published March 23, 2017]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(17)30085-2

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