Clinical Context
When patients are newly diagnosed with type 2 diabetes, treatment traditionally begins with lifestyle modification followed by metformin. However, many patients cannot tolerate metformin (gastrointestinal intolerance, contraindications with kidney disease) or prefer not to take daily oral medications. For these patients, alternative first-line options are needed that provide effective glucose lowering without the burden of daily administration.
The SUSTAIN 1 trial evaluated semaglutide as monotherapy in treatment-naive patients—those managed only with diet and exercise. This represents the earliest stage of pharmacological intervention in type 2 diabetes. Demonstrating efficacy as monotherapy establishes semaglutide as a potential first-line option, not just an add-on therapy for patients failing other treatments.
For patients who prioritize weight management alongside glucose control—which includes most patients with type 2 diabetes—the prospect of starting treatment with an agent that produces both glycemic improvement and weight loss is appealing. SUSTAIN 1 addressed whether semaglutide could fill this role from the beginning of therapy.
PICO Summary
Population: Treatment-naive adults with type 2 diabetes (n=388), HbA1c 7.0-10.0%, managed only with diet and exercise.
Intervention: Once-weekly subcutaneous semaglutide at 0.5 mg or 1.0 mg for 30 weeks.
Comparison: Matching placebo administered weekly.
Outcome: Semaglutide 0.5 mg reduced HbA1c by 1.45% and semaglutide 1.0 mg by 1.55%, compared to 0.02% with placebo. Body weight decreased by 3.73 kg (0.5 mg) and 4.53 kg (1.0 mg) versus 1.02 kg with placebo. The majority of semaglutide patients achieved HbA1c <7.0% (74% with 1.0 mg). Gastrointestinal adverse events (nausea, vomiting, diarrhea) were the most common side effects but led to few discontinuations.
Clinical Pearls
1. Robust Efficacy as First-Line Monotherapy: The 1.55% HbA1c reduction with semaglutide 1.0 mg monotherapy exceeds what is typically achieved with metformin (approximately 1.0-1.2%). This establishes semaglutide as a highly effective first-line option, not just a therapy for treatment failures.
2. High Target Achievement Rates: Nearly three-quarters of patients on semaglutide 1.0 mg achieved HbA1c <7.0%—the ADA target for most adults with diabetes. Starting treatment with an agent capable of achieving targets in most patients reduces the need for early treatment escalation.
3. Meaningful Weight Loss From Treatment Initiation: The 4.5 kg weight loss over 30 weeks addresses a key patient concern from the outset of therapy. Unlike many first-line diabetes medications (sulfonylureas, insulin), semaglutide doesn’t require patients to accept weight gain as the price of glucose control.
4. Once-Weekly Convenience for Treatment-Naive Patients: Starting with a once-weekly injectable may seem aggressive, but the convenience of weekly dosing compared to daily oral medication appeals to many patients. Establishing this regimen from the beginning normalizes injectable therapy early in the treatment journey.
Practical Application
Consider semaglutide as first-line therapy for patients who: cannot tolerate or have contraindications to metformin, strongly prioritize weight loss, prefer injectable over daily oral medication, or present with HbA1c levels where monotherapy with less potent agents is unlikely to achieve targets.
Cost remains a barrier to first-line GLP-1 RA use in many healthcare systems. Where cost is prohibitive, metformin remains the appropriate first-line choice. However, when access is available, semaglutide’s superior efficacy and weight benefits support its consideration as initial therapy.
Counsel treatment-naive patients that gastrointestinal side effects (nausea, vomiting, diarrhea) are common during the initial weeks but typically improve with continued treatment. Start at 0.25 mg weekly and titrate gradually to minimize GI effects. The 30-week trial duration confirms that efficacy is maintained beyond the initial treatment period.
Broader Evidence Context
SUSTAIN 1 established semaglutide’s efficacy as monotherapy, complementing subsequent trials that demonstrated superiority over other diabetes medications (SUSTAIN 2-4) and cardiovascular benefits (SUSTAIN-6). The complete SUSTAIN program positioned semaglutide across the entire treatment spectrum from first-line to advanced combination therapy.
Current ADA/EASD guidelines support GLP-1 RAs as first-line alternatives to metformin when compelling indications exist (cardiovascular disease, obesity with weight prioritization). SUSTAIN 1 provides the efficacy evidence supporting this recommendation.
Study Limitations
The 30-week duration doesn’t address long-term durability of glycemic effects or weight loss. The placebo comparison, while appropriate for establishing efficacy, doesn’t directly compare to metformin—the usual first-line alternative. The treatment-naive population may not reflect real-world patients who often have comorbidities and prior treatment experience.
Bottom Line
Once-weekly semaglutide monotherapy produces substantial glycemic improvement (1.55% HbA1c reduction) and meaningful weight loss (4.5 kg) in treatment-naive patients with type 2 diabetes. These findings support semaglutide as an effective first-line therapy option when metformin is contraindicated, not tolerated, or when patients prioritize weight management from the outset.
Source: Sorli C, et al. “Efficacy and Safety of Once-Weekly Semaglutide Monotherapy Versus Placebo in Patients with Type 2 Diabetes (SUSTAIN 1): A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group, Multinational, Multicentre Phase 3a Trial.” Lancet Diabetes & Endocrinology, 2017. Read article
