The trial tables side by side
Both the US label (Table 3) and Canada’s monograph (Table 4) report low blood sugar separately from other reactions, for three placebo-controlled settings [1][3]. “Severe” means an episode where another person had to help. The second measure counts glucose below 54 mg/dL, which Canada writes as below 3.0 mmol/L [1][3]. A dash means that strength was not tested.
| Setting and measure | Placebo | 7 mg | 14 mg |
|---|---|---|---|
| Tablets alone, 26 weeks (Trial 1 / PIONEER 1): severe | 0% / 0% | 1% / 0.6% | 0% / 0% |
| Same trial: below 54 mg/dL | 1% / 1.1% | 0% / 0% | 0% / 0% |
| Moderate kidney impairment, 26 weeks (Trial 5 / PIONEER 5): severe | 0% / 0% | – | 0% / 0% |
| Same trial: below 54 mg/dL | 3% / 2.5% | – | 6% / 5.5% |
| Added to insulin, 52 weeks (Trial 6 / PIONEER 8): severe | 1% / 0.5% | 0% / 0% | 1% / 1.1% |
| Same trial: below 54 mg/dL | 32% / 27.2% | 26% / 25.4% | 30% / 26.5% |
Reading the rows
On its own, the tablet produced almost no low readings, and placebo did no better [1]. In the kidney-impairment trial, where the tablet was added to metformin, a sulfonylurea and/or basal insulin, low readings were roughly twice as frequent on 14 mg as on placebo [1]. In the insulin trial, about a quarter to a third of every group had a low reading, and severe episodes stayed near 1% [1]. Both documents sum it up the same way: lows were more frequent when the tablets were combined with sulfonylureas or insulin [1][3].
The US and Canadian percentages for the insulin trial are not identical, for example 32% versus 27.2% on placebo. Neither document explains the difference; we show both rather than choose one.
What Europe and the outcome trials add
Europe pools its phase 3a trials and finds severe lows mainly with a sulfonylurea (under 0.1% of people) or insulin (1.1%), and in 0.1% with other oral diabetes medicines [2]. It defines a low as below 3.0 mmol/L (54 mg/dL) [2].
People in the four-year SOUL trial, the US label’s Trial 7, were often on medicines that can cause lows: at the start, 51% used insulin and 29% a sulfonylurea [1]. In an analysis of 2,398 FDA reports for the tablets, a fall in blood glucose was one of the reactions that stood out, with 42 reports [4]. Reports cannot give a rate or prove that the tablet was the cause [4].
Why the background medicine matters
Semaglutide raises insulin and lowers glucagon only when blood sugar is high [1]. During an induced low in a study, it did not blunt the body’s glucagon response compared with placebo [1]. The risk comes mainly from medicines that push insulin up regardless of glucose: sulfonylureas, which make the pancreas release it, and insulin itself [1].
The trials built a precaution in: in Trial 6, everyone on insulin cut their dose by 20% at the start, and Trial 5 did the same for basal insulin [1]. The label says prescribers may consider lowering a sulfonylurea or insulin when starting the tablets [1]. Europe adds that blood-glucose self-monitoring is needed to adjust these medicines, that insulin should be reduced stepwise, and that ketoacidosis has occurred when insulin was cut too quickly [2]. Never change these doses yourself.
Knowing the signs, including at night
- Medication Guide: dizziness or light-headedness, blurred vision, anxiety or irritability, sweating, slurred speech, hunger, confusion or drowsiness, shakiness, weakness, headache, a fast heartbeat or feeling jittery [1].
- Canadian leaflet: a cold sweat, cool pale skin, nausea, changes in vision, difficulty concentrating; the signs may come on suddenly [3].
- MedlinePlus: hunger and sweating can appear when sugar is slightly low, while unclear thinking or a seizure tend to come when it is much lower; some people feel nothing until they faint, which it calls hypoglycaemia unawareness [5].
- NIH: lows during sleep may cause nightmares or crying out and can leave you less aware of lows the next day [6].
Daily life: meals, exercise, alcohol and driving
NIH lists skipping or delaying meals, not eating enough carbohydrate, more physical activity than usual and alcohol without food as triggers for people on insulin or a sulfonylurea [6]. The Medication Guide adds that the dose of Rybelsus® and other diabetes medicines may need to change with illness, fever, infection, stress, surgery, more or less exercise, diet changes or weight changes [1]. These are moments to call your care team, not to adjust anything on your own.
Europe says the tablet itself has little effect on driving, but that people on a sulfonylurea or insulin should take care to avoid lows on the road [2]. Canada and the EU leaflet advise not driving or using machines if you notice signs of a low [2][3]. MedlinePlus suggests asking your provider whether a continuous glucose monitor could help if you struggle to notice lows [5].
Rybelsus® and Ozempic® are registered trademarks of Novo Nordisk A/S. PepLabo is not affiliated with or endorsed by Novo Nordisk.
When to get help
The signs and contact information below come from this article’s sourced guidance.
Emergency
- A person with diabetes who becomes less alert, has a seizure or cannot be woken
Contact: Emergency services (911)
MedlinePlus [5]
- Low blood sugar signs that do not improve after a sugary snack
Contact: Emergency room, by ride or ambulance; do not drive yourself
MedlinePlus [5]
- Confusion, fits or passing out while on Rybelsus® with insulin or a sulfonylurea
Contact: Immediate medical help
Rybelsus® PM [3]
Today
- Shakiness, sweating, hunger or a fast heartbeat
Contact: Treat it the way your care team taught you, then let them know
- Lows that keep happening, happen at night, or come without warning signs
Contact: Your prescriber or diabetes team
At your next appointment
- Starting Rybelsus® while on insulin or a sulfonylurea
Contact: Talk with your prescriber about lows before you start
Rybelsus® Medication Guide [1]