What are the main results of the STEP 2 trial with 2.4 mg semaglutide (glucagon-like peptide-1 receptor agonist) for obese patients with diabetes mellitus?

STEP 2 Trial Main Results: Semaglutide 2.4 mg for Obese Diabetic Patients

Semaglutide 2.4 mg once weekly achieved a clinically superior mean weight loss of 9.6% compared to 3.4% with placebo at 68 weeks in adults with type 2 diabetes and overweight or obesity, with 68.8% of patients achieving at least 5% weight loss versus only 28.5% with placebo. 1

Primary Efficacy Outcomes

Weight Loss Results:

• The estimated treatment difference between semaglutide 2.4 mg and placebo was -6.2 percentage points (95% CI -7.3 to -5.2; p<0.0001), demonstrating highly significant superiority 1
• Patients on semaglutide 2.4 mg were nearly 5 times more likely to achieve ≥5% weight reduction compared to placebo (odds ratio 4.88,95% CI 3.58 to 6.64; p<0.0001) 1

Comparison with Approved Diabetes Dose:

• Semaglutide 2.4 mg demonstrated superior weight loss compared to the 1.0 mg dose approved for diabetes treatment, though the trial was primarily designed to compare against placebo 1
• This establishes that the higher 2.4 mg dose provides additional weight loss benefit beyond glycemic control alone 1

Study Population and Design

Patient Characteristics:

• The trial enrolled 1,210 adults with BMI ≥27 kg/m² and HbA1c 7-10% (53-86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening 1
• Patients were recruited from 149 outpatient clinics across 12 countries in Europe, North America, South America, the Middle East, South Africa, and Asia 1
• All patients received lifestyle intervention in addition to medication 1

Trial Design:

• This was a 68-week, double-blind, double-dummy, phase 3 superiority study with patients randomized 1:1:1 to semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo 1
• Randomization was stratified by background glucose-lowering medication and glycated hemoglobin 1

Safety Profile

Adverse Event Frequency:

• Adverse events occurred more frequently with semaglutide 2.4 mg (87.6% of patients) compared to placebo (76.9%) 1
• Gastrointestinal adverse events were reported in 63.5% of patients on semaglutide 2.4 mg versus 34.3% with placebo 1
• Most gastrointestinal side effects were mild to moderate in severity 1

Common Side Effects:

• The usual adverse effects observed included nausea, vomiting, diarrhea, constipation, and abdominal cramps 2
• These gastrointestinal effects are consistent with the known mechanism of GLP-1 receptor agonists, which delay gastric emptying and affect appetite regulation 2

Clinical Significance for Diabetic Obesity

Dual Benefits:

• Weight loss appears to be lower in individuals with type 2 diabetes compared to those without diabetes, making the 9.6% weight loss in this diabetic population particularly meaningful 3
• Semaglutide provides both improved glycemic control and weight loss in patients with type 2 diabetes, addressing two critical therapeutic targets simultaneously 3

Mechanism of Action:

• Semaglutide promotes weight loss via appetite and hunger suppression, decreases energy intake, controls eating, and reduces preference for fatty, energy-dense foods 2
• The pharmacokinetics show a drop in both HbA1c and total body weight 2

Important Clinical Context

Comparison with Non-Diabetic Population:

• In the STEP 1 trial of non-diabetic patients with obesity, semaglutide 2.4 mg achieved 14.9% weight loss at 68 weeks, demonstrating that diabetic patients experience somewhat attenuated weight loss responses 3
• This difference underscores the importance of the STEP 2 trial specifically evaluating the diabetic population 3

Long-Term Considerations:

• After cessation of semaglutide, significant weight regain occurs (11.6% of lost weight regained after 52 weeks), highlighting the need for long-term use 3
• Patients should be counseled that semaglutide must be used in conjunction with lifestyle changes and may need to be used lifelong 3