GLP-1 Clinical Trials Summary

From early diabetes studies like LEADER and SUSTAIN-6 to modern weight-management trials such as STEP and SURMOUNT, GLP-1 drugs have transformed obesity and metabolic-health care.

Across trials, participants lost 10–22 % of body weight on average, with simultaneous improvements in cholesterol, blood pressure, and inflammation markers.

These results confirm that GLP-1 therapies are effective, safe, and durable when combined with lifestyle support.

STEP Programme (Semaglutide)

STEP 1

• Population: Adults with obesity, no diabetes

• Dose: 2.4 mg weekly

• Duration: 68 weeks

• Mean weight loss: −14.9% vs −2.4% with placebo

• Notes: Landmark trial that established Wegovy’s efficacy for weight management.

STEP 2

• Population: Adults with type 2 diabetes

• Dose: 2.4 mg weekly

• Duration: 68 weeks

• Mean weight loss: −9.6% vs −3.4% with placebo

• Notes: Demonstrated significant benefit in people with diabetes.

STEP 3

• Population: Participants receiving intensive lifestyle intervention plus medication

• Dose: 2.4 mg weekly

• Duration: 68 weeks

• Mean weight loss: −16%

• Notes: Greatest average weight reduction observed when semaglutide was combined with structured behavioural support.

STEP 4

• Population: Participants entering a withdrawal phase after semaglutide treatment

• Dose: 2.4 mg weekly (then discontinued)

• Duration: 68 weeks plus an off-treatment period

• Mean weight loss: Regained about two-thirds of lost weight after stopping

• Notes: Demonstrated that ongoing therapy is required to maintain results.

SURMOUNT-1

• Population: Adults with obesity (no diabetes)

• Dose: 5–15 mg weekly

• Duration: 72 weeks

• Mean weight loss: −15–22%

• Notes: Dual GIP/GLP-1 mechanism; achieved record average weight reduction.

SURMOUNT-2

• Population: Adults with type 2 diabetes

• Dose: 10–15 mg weekly

• Duration: 72 weeks

• Mean weight loss: −3–15%

• Notes: Demonstrated significant glycaemic and metabolic benefits alongside weight reduction.

SURMOUNT-3 / SURMOUNT-4

• Population: Participants following lifestyle lead-in or withdrawal phase

• Dose: 10–15 mg weekly

• Duration: 72 weeks

• Mean weight loss: −21% sustained

• Notes: Showed additive effect of behavioural support and the importance of ongoing therapy for maintenance.

SCALE Obesity

• Population: Adults with obesity (no diabetes)

• Dose: 3 mg daily

• Duration: 56 weeks

• Mean weight loss: −6.2% vs −0.2% with placebo

• Notes: First GLP-1 medication approved for weight management; established liraglutide’s role in obesity treatment.

SCALE Diabetes

• Population: Adults with type 2 diabetes

• Dose: 3 mg daily

• Duration: 56 weeks

• Mean weight loss: −6.0% vs −2.0% with placebo

• Notes: Confirmed liraglutide’s weight-management efficacy in people with diabetes.

SCALE Maintenance

• Population: Participants following an initial diet phase

• Dose: 3 mg daily

• Duration: 56 weeks

• Mean weight loss: Maintained −6–8%

• Notes: Demonstrated liraglutide’s ability to support long-term weight stability after initial loss.

LEADER

• Drug: Liraglutide

• Participants: 9,340

• MACE reduction: 8.2% decrease in cardiovascular death, stroke, or myocardial infarction

• Key finding: Demonstrated a significant survival benefit and established liraglutide’s cardiovascular safety.

SUSTAIN-6

• Drug: Semaglutide

• Participants: 3,297

• MACE reduction: 3–22% reduction in major adverse cardiovascular events (MACE)

• Key finding: Confirmed cardiovascular safety and showed fewer strokes among participants.

REWIND

• Drug: Dulaglutide

• Participants: 9,901

• MACE reduction: 12% reduction in major cardiovascular events

• Key finding: Demonstrated benefit even in people with lower baseline cardiovascular risk.

SURPASS-CVOT

• Drug: Tirzepatide (compared with insulin glargine)

• Participants: ~13,000 (ongoing)

• MACE reduction: Interim results show a favourable trend for tirzepatide

• Key finding: Early data suggest superior cardiometabolic protection compared with standard therapy.

PIONEER

• Agent: Oral semaglutide (Rybelsus)

• Highlight: Achieved comparable HbA1c reductions to injectable GLP-1 therapies with an average weight loss of about 2.4 kg.

AWARD

• Agent: Dulaglutide

• Highlight: Demonstrated sustained glycaemic control and a low risk of hypoglycaemia over long-term follow-up.

SURPASS

• Agent: Tirzepatide

• Highlight: Produced HbA1c reductions of −12% to −27%, outperforming both semaglutide 1 mg and insulin degludec in head-to-head trials.

GLP-1 and dual GIP/GLP-1 therapies are being studied for conditions beyond obesity and diabetes.

• Heart failure: Ongoing SELECT HF and SUMMIT trials exploring cardioprotective effects in preserved ejection-fraction HF.
• Liver disease: Phase III semaglutide and tirzepatide trials in NASH underway.
• Addiction and cognition: EVOKE (Alzheimer’s) and small trials for alcohol-use disorder suggest neuroprotective benefits.
• Next generation: Triple-agonists (GLP-1/GIP/glucagon) such as retatrutide show >24 % mean loss in early studies.

Side effects were usually mild and temporary. The main symptoms were nausea, constipation, and fatigue during dose escalation.

Serious adverse events were rare. No increased risk of cancer, pancreatitis, or thyroid tumours in humans has been confirmed to date, though caution remains for those with MEN2 or MTC history.

Dr Abby Hyams completed her medical training in Bristol and has been a GP for 19 years, spending many of those as a partner in an NHS practice in Hemel Hempstead. She has a particular passion for supporting patients with weight loss and promoting positive behaviour change, helping individuals build sustainable habits that improve their long-term health and wellbeing.

• Wilding JPH et al. N Engl J Med 2021 (STEP 1)
• Jastreboff AM et al. N Engl J Med 2022 (SURMOUNT-1)
• Pi-Sunyer X et al. N Engl J Med 2015 (SCALE)
• Marso SP et al. N Engl J Med 2016 (SUSTAIN-6; LEADER)
• Gerstein HC et al. Lancet 2019 (REWIND)
• Davies M et al. Diabetes Care 2019 (PIONEER-4)
• Frias JP et al. NEJM 2021 (SURPASS-2)
• NICE NG248 (2023); TA875 (2023)

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