Should a patient who has been off their weekly GLP‑1 receptor agonist (e.g., semaglutide or dulaglutide) for a few weeks restart at the same dose if it was previously well tolerated and there are no new contraindications?

Resuming GLP-1 Weekly Injection After a Few Weeks Off

If a patient has missed only 1–2 consecutive weekly doses and previously tolerated the medication well, resume at the same dose; if 3 or more consecutive doses have been missed, restart the titration schedule from a lower dose to minimize gastrointestinal adverse effects. 1

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Algorithmic Approach to Dose Resumption

1–2 Missed Doses (≤2 weeks off therapy)

• Resume at the previous dose if the patient tolerated the medication well and experienced no significant gastrointestinal side effects (nausea, vomiting, diarrhea) during prior treatment 1, 2
• Consider lowering the next dose if the patient had previously experienced significant gastrointestinal side effects, even if they completed the titration schedule 1
• Administer the missed dose as soon as possible if fewer than 3 days (72 hours) remain until the next scheduled dose for dulaglutide 3, or within 5 days for semaglutide 4
• If the next regularly scheduled dose is due in 1–2 days, skip the missed dose and resume with the next regularly scheduled dose 3, 4

3 or More Missed Doses (≥3 weeks off therapy)

• Restart the titration schedule from a lower dose to minimize the risk of gastrointestinal adverse effects, which are dose-dependent and most common during dose escalation 1, 5, 2
• For semaglutide, restart at 0.25 mg weekly for 4 weeks, then titrate to 0.5 mg weekly, regardless of the patient's previous maintenance dose 5
• For dulaglutide, restart at 0.75 mg weekly, then increase to 1.5 mg weekly after 4 weeks if additional glycemic control is needed 3
• Clinical judgment is required to determine subsequent dosing, considering factors such as previous tolerance and gastrointestinal side effects 1

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Key Clinical Considerations

Gastrointestinal Tolerability

• Gastrointestinal effects (nausea, vomiting, diarrhea, constipation) are the most frequently reported adverse events with GLP-1 receptor agonists, occurring in a dose-dependent manner and most commonly during dose escalation 6, 7, 8, 9
• These effects are typically mild-to-moderate and transient, decreasing over time with continued exposure 6, 7, 8, 9
• Slow titration with gradual dose escalation every 4 weeks minimizes gastrointestinal side effects and improves overall tolerability 6, 7

Hypoglycemia Risk

• When resuming GLP-1 receptor agonist therapy, monitor blood glucose more frequently, especially if the patient is also taking insulin or insulin secretagogues (sulfonylureas), as recommended by the American Diabetes Association 1
• Consider reducing basal insulin by approximately 20% or discontinuing/reducing sulfonylurea doses by 50% when reinitiating GLP-1 therapy to prevent hypoglycemia 3, 4

Perioperative Aspiration Risk

• For patients on GLP-1 receptor agonists who are scheduled for surgical procedures, be aware of the potential for delayed gastric emptying, which may increase aspiration risk, according to the American Society of Anesthesiologists 1
• Retained gastric contents are documented even after extended fasting periods (10–14 days discontinuation and 12-hour fasting), with 24.2% of semaglutide users showing increased residual gastric content versus 5.1% of controls 10

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Common Pitfalls to Avoid

• Do not resume at the previous high dose after ≥3 missed doses – this markedly increases the incidence of gastrointestinal adverse events (nausea, vomiting, diarrhea) and leads to higher discontinuation rates 1, 2
• Do not ignore prior gastrointestinal intolerance – if the patient experienced significant nausea or vomiting during initial titration, consider restarting at an even lower dose or extending the titration interval 1, 2
• Do not forget to adjust concomitant diabetes medications – failure to reduce insulin or sulfonylurea doses when resuming GLP-1 therapy increases hypoglycemia risk 1, 3, 4
• Do not delay restarting therapy indefinitely – prolonged lapses in GLP-1 receptor agonist therapy may result in loss of glycemic control and weight regain, so resume as soon as feasible 2

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Special Populations

Patients with Chronic Kidney Disease

• No dose adjustment is required for dulaglutide, liraglutide, or semaglutide across all stages of CKD, including patients with eGFR <30 mL/min/1.73 m² 6
• Resume at the same dose (if 1–2 missed doses) or restart titration (if ≥3 missed doses) without renal dose modification 6

Patients with Cardiovascular Disease

• GLP-1 receptor agonists provide sustained cardiovascular protection beyond glycemic control and weight loss, with a 26% reduction in composite cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.74,95% CI 0.58–0.95) for semaglutide 4, 6
• Resuming therapy promptly after a lapse is particularly important in this population to maintain cardiovascular benefit 6

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Practical Implementation

• Assess the duration of the therapy lapse – count the number of missed weekly doses to determine whether to resume at the previous dose (1–2 missed) or restart titration (≥3 missed) 1, 2
• Review prior gastrointestinal tolerability – if the patient experienced significant nausea, vomiting, or diarrhea during initial titration, consider restarting at a lower dose even if only 1–2 doses were missed 1, 2
• Adjust concomitant medications – reduce insulin by 20% or discontinue/reduce sulfonylureas by 50% when resuming GLP-1 therapy to prevent hypoglycemia 1, 3, 4
• Monitor closely during the first 2–4 weeks – assess for gastrointestinal side effects, hypoglycemia, and glycemic control 1, 6