What are the key findings and implications of the SUSTAIN 1 trial for the management of type 2 diabetes, particularly regarding the use of semaglutide (Glucagon-Like Peptide-1 (GLP-1) receptor agonist)?

SUSTAIN 1 Trial: Comprehensive Overview

Trial Design and Population

SUSTAIN 1 was a 30-week, double-blind, randomized, placebo-controlled phase 3a trial that established semaglutide's efficacy as monotherapy in treatment-naive patients with type 2 diabetes inadequately controlled by diet and exercise alone. 1

The trial enrolled 388 participants across 72 sites in 8 countries (Canada, Italy, Japan, Mexico, Russia, South Africa, UK, and USA), with 387 receiving at least one dose of study medication 1. Key inclusion criteria included:

• Treatment-naive adults ≥18 years with type 2 diabetes managed only with diet and exercise for ≥30 days before screening 1
• Baseline HbA1c of 7.0%-10.0% (53-86 mmol/mol) 1
• Mean baseline HbA1c was 8.05% (SD 0.85) and mean bodyweight was 91.93 kg (SD 23.83) 1

Participants were randomized 2:2:1:1 to once-weekly subcutaneous semaglutide 0.5 mg, semaglutide 1.0 mg, or volume-matched placebo (0.5 mg or 1.0 mg dose volumes) 1.

Primary Efficacy Outcomes: Glycemic Control

Semaglutide demonstrated superior glycemic control compared to placebo, with both doses achieving statistically significant and clinically meaningful HbA1c reductions. 1

At week 30, the primary endpoint results were:

• Semaglutide 0.5 mg: HbA1c decreased by 1.45% (95% CI -1.65 to -1.26), with an estimated treatment difference vs placebo of -1.43% (95% CI -1.71 to -1.15; p<0.0001) 1
• Semaglutide 1.0 mg: HbA1c decreased by 1.55% (95% CI -1.74 to -1.36), with an estimated treatment difference vs placebo of -1.53% (95% CI -1.81 to -1.25; p<0.0001) 1
• Placebo: HbA1c decreased by only 0.02% (95% CI -0.23 to 0.18), which was not statistically significant 1

This represents one of the most robust glycemic improvements seen in monotherapy trials for type 2 diabetes 2, 3.

Secondary Efficacy Outcomes: Weight Loss

The confirmatory secondary endpoint of bodyweight reduction was also significantly superior with semaglutide compared to placebo, establishing its dual benefit for both glycemic control and weight management. 1

At week 30:

• Semaglutide 0.5 mg: Bodyweight decreased by 3.73 kg (95% CI -4.54 to -2.91), with an estimated treatment difference vs placebo of -2.75 kg (95% CI -3.92 to -1.58; p<0.0001) 1
• Semaglutide 1.0 mg: Bodyweight decreased by 4.53 kg (95% CI -5.34 to -3.72), with an estimated treatment difference vs placebo of -3.56 kg (95% CI -4.74 to -2.38; p<0.0001) 1
• Placebo: Bodyweight decreased by only 0.98 kg (95% CI -1.82 to -0.13) 1

The weight loss observed was dose-dependent and sustained throughout the 30-week treatment period 1.

Mechanism of Action

Semaglutide achieves its therapeutic effects through multiple mechanisms as a GLP-1 receptor agonist 4, 2:

• Glucose-dependent insulin secretion: Stimulates both first- and second-phase insulin secretion from pancreatic beta cells when blood glucose is elevated 4
• Glucagon suppression: Lowers fasting and postprandial glucagon concentrations in a glucose-dependent manner (8% reduction in fasting glucagon, 14-15% reduction in postprandial glucagon) 4
• Gastric emptying delay: Causes early postprandial gastric emptying delay, reducing the rate of glucose appearance in circulation 4
• Appetite reduction: Decreases energy intake by reducing appetite, food cravings, and preference for fatty, energy-dense foods 2
• Albumin binding: The primary protraction mechanism is albumin binding (>99% bound to plasma albumin), which results in decreased renal clearance and protection from metabolic degradation, enabling once-weekly dosing 4

Safety Profile

The safety profile of semaglutide in SUSTAIN 1 was consistent with the GLP-1 receptor agonist class, with gastrointestinal adverse events being the most common. 1

Adverse Events

• No deaths were reported in any study group 1
• Most adverse events were mild or moderate in severity 1
• Discontinuation rates: 13% with 0.5 mg semaglutide, 12% with 1.0 mg semaglutide, and 11% with placebo, with gastrointestinal adverse events being the main reason 1

Gastrointestinal Effects

The most frequently reported adverse events were gastrointestinal 1:

• Nausea: 20% (0.5 mg), 24% (1.0 mg), 8% (placebo) 1
• Diarrhea: 13% (0.5 mg), 11% (1.0 mg), 2% (placebo) 1

Meta-analysis data from the broader SUSTAIN program confirmed that semaglutide induced a higher risk of gastrointestinal disorders compared to other therapies (RR: 1.98,95% CI: 1.49 to 2.62, P < 0.001) 3.

Hypoglycemia Risk

In monotherapy, semaglutide demonstrated an extremely low risk of hypoglycemia due to its glucose-dependent mechanism of action. 4

• Severe hypoglycemia: 0% in all groups 4
• Documented symptomatic hypoglycemia (≤70 mg/dL): 0% (0.5 mg), 1.6% (1.0 mg), 3.8% (placebo) 4
• During induced hypoglycemia testing, semaglutide did not alter counter-regulatory glucagon responses or impair C-peptide decrease 4

Other Safety Considerations

• Cardiac effects: Mean increase in heart rate of 2-3 beats per minute with semaglutide vs 0.3 bpm decrease with placebo 4
• Pancreatic enzymes: Mean increase from baseline in amylase of 13% and lipase of 22% (not observed in placebo) 4
• Cholelithiasis: Reported in 1.5% (0.5 mg) and 0.4% (1.0 mg) vs 0% with placebo 4
• QTc interval: At 1.5 times the maximum recommended dose, semaglutide does not prolong QTc intervals to any clinically relevant extent 4

Clinical Implications and Context Within SUSTAIN Program

SUSTAIN 1 established semaglutide as a highly effective first-line monotherapy option for treatment-naive patients with type 2 diabetes, setting the foundation for the broader SUSTAIN clinical program. 2, 1

Position in Treatment Algorithm

The American Diabetes Association guidelines recognize semaglutide's efficacy demonstrated in SUSTAIN 1 and subsequent trials 5. The trial supports semaglutide as:

• An appropriate monotherapy option when metformin is contraindicated or not tolerated 1
• A treatment choice for patients requiring both glycemic control and weight reduction 1
• Part of a comprehensive approach to cardiovascular risk reduction, as later demonstrated in SUSTAIN 6 5

Comparative Effectiveness

Across the SUSTAIN 1-7 trials, semaglutide consistently demonstrated superior glycemic control and weight loss versus all comparators evaluated, including other GLP-1 receptor agonists 2, 3. Direct and indirect comparative analyses showed that subcutaneous semaglutide (0.5 or 1.0 mg once weekly) exerts better glucose-lowering activity and greater weight loss than other GLP-1 receptor agonists such as exenatide extended-release and dulaglutide 6, 3.

Cardiovascular Context

While SUSTAIN 1 focused on glycemic efficacy and safety, the subsequent SUSTAIN 6 trial demonstrated cardiovascular benefits 5. In SUSTAIN 6, the primary composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke occurred in 6.6% of the semaglutide group vs 8.9% of the placebo group (HR 0.74,95% CI 0.58-0.95; P<0.001) 5. This cardiovascular benefit extends to patients with peripheral artery disease, where 13.7% of SUSTAIN 6 participants had PAD at baseline 5.

Pharmacokinetic Properties Supporting Once-Weekly Dosing

The pharmacokinetic profile established in SUSTAIN 1 supports convenient once-weekly administration with predictable steady-state concentrations. 4

• Bioavailability: 89% absolute bioavailability 4
• Time to maximum concentration: 1-3 days post-dose 4
• Steady-state: Achieved after 4-5 weeks of once-weekly administration 4
• Half-life: Approximately 1 week, meaning semaglutide remains in circulation for about 5 weeks after the last dose 4
• Steady-state concentrations: Approximately 65.0 ng/mL (0.5 mg dose) and 123.0 ng/mL (1.0 mg dose) 4
• Dose proportionality: Exposure increases proportionally for once-weekly doses of 0.5 mg and 1.0 mg 4

Practical Prescribing Considerations from SUSTAIN 1

Initiation should begin with the 0.25 mg dose for 4 weeks to minimize gastrointestinal adverse events, then escalate to the 0.5 mg maintenance dose, with optional further escalation to 1.0 mg if additional glycemic control is needed. 4, 1

Administration Details

• Subcutaneous injection in abdomen, thigh, or upper arm (similar exposure across sites) 4
• Can be administered at any time of day, with or without meals 4
• Patients should be encouraged to inject on the same day each week 1
• No dose adjustment needed for renal or hepatic impairment 4

Managing Gastrointestinal Adverse Events

To optimize tolerability based on SUSTAIN 1 experience 1:

• Start at low dose (0.25 mg) and titrate slowly 5
• Reduce meal size 5
• Limit alcohol and carbonated drinks 5
• Avoid high-fat diet 5
• Recognize that gastrointestinal symptoms typically improve over time with continued use 1

Drug Interactions

Semaglutide causes delayed gastric emptying, which has potential to impact absorption of concomitantly administered oral medications 4. However, clinical pharmacology trials showed semaglutide did not affect absorption of orally administered medications to any clinically relevant degree 4. Nonetheless, caution should be exercised when oral medications are concomitantly administered 4.