Question 1

How does SCALE Maintenance compare with STEP-4 for semaglutide?

Accepted Answer

Both are maintenance-design trials, but they differ in run-in mechanism and magnitude. SCALE Maintenance used a 4-12 week low-calorie diet run-in to produce the initial weight loss, then randomized responders to liraglutide 3.0 mg vs placebo for 56 weeks; the treatment difference at the end of randomized follow-up was 6.1 percentage points. STEP-4 (Rubino 2021 JAMA, PMID 33755728) used a 20-week open-label semaglutide 2.4 mg run-in, then randomized responders to continued semaglutide vs placebo for 48 weeks; the treatment difference was 14.8 percentage points. The trials are not head-to-head and the run-in mechanisms are different, but they support the same conclusion: continued GLP-1 therapy maintains and extends loss; comparator participants plateau (placebo on top of diet, SCALE) or regain (placebo after drug withdrawal, STEP-4). The magnitude difference reflects both drug potency and the larger run-in losses produced by a 20-week drug run-in vs a 4-12 week diet run-in.

Question 2

Does Saxenda maintain weight loss as well as Wegovy?

Accepted Answer

No, head-to-head data are limited but the loss-and-maintenance magnitudes consistently favor semaglutide. SUSTAIN-FORTE for diabetes and the indirect comparisons in obesity (STEP-8, Rubino 2022 JAMA, PMID 35015037, randomized 338 adults with obesity 3:1 to semaglutide 2.4 mg vs liraglutide 3.0 mg and reported a 15.8% vs 6.4% mean weight loss at 68 weeks) showed semaglutide produced roughly 2-3× the absolute loss of liraglutide. For maintenance specifically, SCALE Maintenance reported a 6.1 percentage-point treatment difference over 56 weeks while STEP-4 reported a 14.8-point difference over 48 weeks. The two drugs are in the same class and work by the same receptor, but the longer half-life and higher receptor occupancy of semaglutide translate to larger and more durable effects.

Question 3

What happens after stopping Saxenda?

Accepted Answer

SCALE Maintenance included a 12-week off-drug follow-up phase after the 56-week treatment period. Participants in both arms experienced partial weight regain during the off-drug window, with the liraglutide group still ending below randomization weight on average. Wadden and colleagues reported regain in the liraglutide arm during the off-drug follow-up that brought the net advantage closer to the placebo arm by week 68, although liraglutide participants remained below placebo in absolute terms. The broader pattern is consistent with what STEP-1 extension (Wilding 2022, PMID 35441470) showed for semaglutide — roughly two-thirds of the on-drug loss is regained within a year of stopping. Counseling patients to expect regain after discontinuation is standard practice across the class.

Question 4

Is the run-in design clinically realistic?

Accepted Answer

The diet-first, drug-second design is closer to standard obesity-medicine practice than the all-on-drug pivotal trials. Clinicians routinely ask patients to attempt a structured lifestyle intervention before starting a GLP-1 agonist, both for clinical reasons (a meaningful initial loss predicts longer-term success) and for payer reasons (commercial prior-authorization criteria often require documented 3-6 months of lifestyle intervention). SCALE Maintenance baked that pathway into the protocol: 4-12 weeks of a 1,200-1,400 kcal/day diet with monthly visits, then drug initiation for those who hit a 5% loss. The 77% run-in completion rate (422 of 547) is consistent with clinic-level experience that most motivated patients can produce an initial 5% loss with intensive dietary support. Where the design diverges from practice is the 1,200-1,400 kcal/day target, which is more restrictive than the gradual deficits most clinicians recommend today.

Question 5

Does Saxenda work for maintenance only, or also for initial loss?

Accepted Answer

Both. SCALE Obesity and Prediabetes (Pi-Sunyer 2015 NEJM, PMID 26132939) tested liraglutide 3.0 mg as the primary loss agent in 3,731 adults with overweight or obesity and reported an 8.4 kg mean loss vs 2.8 kg on placebo at 56 weeks — that trial supported the original Saxenda approval for chronic weight management. SCALE Maintenance answered the separate question of whether the drug also holds a loss produced by diet, which is a different clinical scenario. The Saxenda label covers both indications because the drug is approved for chronic weight management broadly rather than for a single phase of therapy. In practice clinicians use liraglutide 3.0 mg the same way they use other GLP-1 agonists: start, titrate, continue as long as the patient is benefiting, and accept that discontinuation typically reverses much of the loss.

Question 6

What were the main tolerability issues in SCALE Maintenance?

Accepted Answer

Gastrointestinal events dominated, as expected for the class. Among the 212 liraglutide participants, 74.1% reported any GI event vs 43.8% on placebo, with nausea (47.2% vs 17.1%) leading the list. Most events were mild-to-moderate and clustered during the 4-week dose-escalation phase from 0.6 mg up to 3.0 mg. Permanent treatment discontinuation for adverse events was 9.9% on liraglutide vs 3.8% on placebo — higher than the maintenance-phase discontinuation rate in STEP-4 (2.4%) but in line with the SCALE Obesity initial-loss trial because the run-in in SCALE Maintenance was diet-only, so participants encountered liraglutide titration for the first time post-randomization. Gallbladder-related events were 2.4% on liraglutide vs 0% on placebo, consistent with the gallstone signal observed across rapid weight-loss interventions.

Endpoint	Treatment	Comparator	Difference
Proportion achieving ≥5% additional weight loss from randomization to week 56 Half of liraglutide-treated participants achieved a further 5% loss on top of the run-in loss, more than double the placebo rate.	50.5% (107/212)	21.8% (45/206)	Estimated odds ratio 3.8 (95% CI 2.4 to 5.9; P<0.0001)
Proportion achieving ≥10% additional weight loss from randomization to week 56 Roughly 4× more liraglutide participants achieved a further ≥10% loss after the run-in.	26.1% (55/212)	6.3% (13/206)	Estimated odds ratio 5.4 (95% CI 2.8 to 10.5; P<0.0001)
Proportion maintaining the run-in weight loss (no regain) at week 56 About four out of five liraglutide participants held or extended their run-in loss; fewer than half of placebo participants did. The headline maintenance signal.	81.4%	48.9%	P<0.0001
Absolute body-weight change from randomization to week 56 (kg)	−6.3 kg	−0.2 kg	Estimated treatment difference −6.1 kg (95% CI −7.5 to −4.6; P<0.0001)
Change in waist circumference from randomization to week 56 (cm) Central adiposity continued to fall on liraglutide while flattening on placebo.	−6.5 cm	−3.6 cm	Estimated treatment difference −2.9 cm (95% CI −4.0 to −1.8; P<0.0001)
Change in systolic blood pressure from randomization to week 56 (mmHg) Small but statistically significant additional reduction; the larger blood-pressure drop happened during the run-in.	−2.8 mmHg	−0.9 mmHg	Estimated treatment difference −2.0 mmHg (95% CI −3.9 to 0.0; P=0.046)
Change in fasting lipid profile from randomization to week 56 — total cholesterol Lipid markers were broadly similar between arms over the maintenance phase; the run-in had already produced most of the lipid improvement.	+1.6%	+2.4%	Estimated treatment difference −0.8% (not statistically significant)
Change in HbA1c from randomization to week 56 (percentage points) Participants were non-diabetic at entry, so changes occur within the normoglycemic/prediabetic range. Direction was consistent with the later STEP and SURMOUNT trials in non-diabetic populations.	−0.16	−0.07	Estimated treatment difference −0.09 percentage points (95% CI −0.18 to −0.01; P=0.034)
Body composition: change in total fat mass at week 56 (DXA substudy, % of baseline) DXA substudy demonstrated that the additional weight loss on liraglutide was predominantly fat mass, with preserved lean-to-fat ratios.	−15.4%	−4.5%	Estimated treatment difference favoring liraglutide; P<0.0001
Progression to type 2 diabetes by week 56 Hint of diabetes-prevention signal that was confirmed in the larger SCALE Diabetes Prevention trial (Le Roux 2017, PMID 28237263).	0.9% (2/212)	1.9% (4/210)	Numerically lower on liraglutide; underpowered for formal inference in this trial.

Event	Treatment rate	Comparator rate
Any gastrointestinal disorder GI events clustered during the 4-week dose-escalation phase (0.6 mg → 3.0 mg). Most were mild-to-moderate and transient.	74.1% (157/212)	43.8% (92/210)
Nausea Most common GI event; peaked during titration and attenuated over weeks.	47.2% (100/212)	17.1% (36/210)
Diarrhea	22.6% (48/212)	13.3% (28/210)
Constipation	22.2% (47/212)	11.4% (24/210)
Vomiting	17.9% (38/212)	3.8% (8/210)
Headache	16.5% (35/212)	11.9% (25/210)
Injection-site reaction	13.7% (29/212)	10.5% (22/210)
Hypoglycemia (symptomatic, non-diabetic population) All events were minor; no severe hypoglycemia in either arm.	2.4% (5/212)	0.0% (0/210)
Gallbladder-related events (cholelithiasis, cholecystitis) Consistent with the gallstone signal observed across rapid weight-loss interventions and in later GLP-1 trials.	2.4% (5/212)	0.0% (0/210)
Permanent treatment discontinuation due to adverse events Most discontinuations were for gastrointestinal intolerance during or shortly after the dose-escalation phase.	9.9% (21/212)	3.8% (8/210)
Any serious adverse event No specific SAE class was concentrated in the liraglutide arm beyond the gallbladder signal.	6.1% (13/212)	1.9% (4/210)

SCALE Maintenance deep-dive: liraglutide 3.0 mg after diet-induced weight loss (Wadden 2013)

Primary endpoint

Secondary endpoints

Adverse events

Subgroup analyses

Clinical significance

Frequently Asked Questions

References

Related trial deep-dives