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Good news for glucose metabolism in new STEP 2 analysis


A further analysis of the STEP 2 trial results presented at last week’s 57th EASD Annual Meeting showed promising glucose metabolism results for the GLP-1 receptor agonist, with two thirds of participants assigned semaglutide (2.4 mg) in the trial attaining HbA1c of <6.5%.


STEP trials 1 and 2 showed semaglutide 2.4 mg as a promising obesity treatment and it is now FDA-approved for weight management in people with overweight/obesity.


STEP 2 included people with people with overweight or obesity and type 2 diabetes. As a recap, participants had a body mass index (BMI) of at least 27 kg/m², an HbA1c of 7-10% (53-56 mmol/mol) and had been diagnosed with type 2 diabetes for at least 180 days. Participants were assigned to either semaglutide 2.4 mg, semaglutide 1.0 mg or placebo. It found that 2.4 mg of subcutaneous semaglutide once weekly achieved a clinically meaningful decrease in bodyweight compared with placebo. From baseline to week 68, it showed that the mean change in bodyweight was:

  • 2.4 mg: –9.6%
  • 1.0 mg: –7.0%
  • Placebo: –3.4%

More patients in the semaglutide 2.4 mg group achieved at least 5% weight reduction (68.8%), than with 1.0 mg (57%) or placebo (28.5%). The weight loss was also accompanied by an HbA1c reduction of 1.6% with 2.4 mg, 1.5% with 1.0 mg and 0.4% with placebo.


In this presentation, Dr Sue Pedersen, an endocrinologist at C-ENDO Diabetes and Endocrinology Clinic in Calgary, discussed a post-hoc analysis of STEP 2 focusing on glucose metabolism outcomes.


Assessed endpoints were:

  • Proportions achieving HbA1c of ≤6.5% and <7%
  • Proportions achieving those targets with metformin only or no oral antidiabetic drug (OAD) treatment at randomisation
  • Proportions achieving composite endpoints of HbA1c <7% and weight loss ≥10% or ≥15%
  • Change in OAD medication from baseline to week 68 for patients achieving HbA1c <7% and weight loss ≥15%
  • Change in fasting plasma glucose, fasting serum insulin, HOMA-IR (homeostatic model assessment of insulin resistance) and HOMA-β (HOMA of beta cell function)

Key findings included that two thirds of patients on semaglutide 2.4 mg were able to reach an HbA1c of ≤6.5% and over three quarters were able to reach <7%. Among those on metformin or no OAD at baseline, even more patients were able to achieve an HbA1c of ≤6.5% (77%) and <7% (85%) – this was significantly more than with semaglutide 1.0 mg.


In conclusion:

  • With semaglutide 2.4 mg, more patients achieved the composite endpoints of HbA1c of <7% with weight loss ≥10% or ≥15% versus semaglutide 1.0 mg or placebo, which was more pronounced in patients who were not on OADs, or on metformin only, at baseline
  • More patients reduced OAD use during treatment with semaglutide 2.4 mg versus semaglutide 1.0 mg or placebo
  • Treatment with semaglutide resulted in improvements in insulin resistance and β-cell function, two key mechanistic drivers of type 2 diabetes and diabetes progression
  • Treatment with semaglutide was consistent with the GLP-1 receptor agonist class in general and with that reported in the once-weekly subcutaneous semaglutide type 2 diabetes trials

A short discussion followed with Professor Melanie Davis, in which she highlighted that the magnitude of weight loss was greater in STEP 2 than in the SCALE diabetes trial with daily liraglutide 3 mg and the percentage of patients able to achieve 5% and 10% weight loss was also much greater (although these were not head-to-head trials).


With regard to long-term side-effects, the study - which spanned 68 weeks- saw the gastrointestinal side-effects that would be expected for this drug class. The two doses saw similar effects, with slightly more vomiting reported in the 2.4 mg group (20% versus 13%). There were only a very few cases of pancreatitis and no other unexpected adverse events.


The opinions expressed in this article are those of the author, Dr Eleanor D Kennedy.


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