What each document reports
All three regulators use the same threshold for a clinically important low: plasma glucose under 54 mg/dL, which Canada writes as 3.0 mmol/L. [1][3][4] The figures come mainly from SURMOUNT-2, the 72-week Zepbound® trial in adults with type 2 diabetes. [1]
| Source and population | Zepbound® or tirzepatide | Comparison |
|---|---|---|
| US label: SURMOUNT-2, type 2 diabetes, below 54 mg/dL [1] | 4.2% | Placebo 1.3% |
| US label: SURMOUNT-2, Zepbound® with a sulfonylurea [1] | 10.3% | Zepbound® without one 2.1% |
| US label: SURMOUNT-1, no diabetes, not systematically collected [1] | 0.3% | Placebo 0% |
| Canada: SURMOUNT-2, below 3.0 mmol/L [3] | 4.2% (10.3% with a sulfonylurea) | Placebo 1.3% |
| EU, tirzepatide weight trial in type 2 diabetes [4] | 4.2%; no severe episodes | Placebo 1.3% |
Inside SURMOUNT-2
SURMOUNT-2 enrolled 938 adults with a BMI of 27 or more and type 2 diabetes with an HbA1c of 7% to 10%. They were managed with diet and exercise or with diabetes tablets, but not DPP-4 inhibitors or GLP-1 receptor agonists; people using insulin or injectable GLP-1 medicines were excluded. [1][5] The trial was funded by Eli Lilly, and its published report described the most frequent adverse events as stomach-related and mostly mild to moderate. [5]
Blood sugar control changed a lot. Average HbA1c started at 8.0% and fell by 2.1 points on both Zepbound® doses, against 0.5 on placebo. [1] Without a sulfonylurea, 2.1% of people on Zepbound® had a reading below 54 mg/dL; with one, the figure rose to 10.3%. [1] The label adds that tirzepatide with insulin also increases the risk, a statement drawn from beyond this trial since insulin users were not enrolled. [1]
Without diabetes: thin data, one clear sentence
Most people take Zepbound® without diabetes. SURMOUNT-1 did not collect low blood sugar systematically; the 0.3% figure is a count of readings that happened to be recorded. [1] Canada says the same and gives no rate. [3] The two sleep apnea trials excluded people with type 2 diabetes and report nothing separate. [1] Even so, section 5.7 states that hypoglycemia has been associated with Zepbound® and with GLP-1 receptor agonists in adults without type 2 diabetes. [1]
A published case report gives an example rather than a rate: six days after a first tirzepatide injection, a non-diabetic woman with obesity reached the emergency department vomiting persistently; her blood tests showed ketoacidosis alongside a mildly low glucose, and she was well again within two days. [9] One patient cannot tell us how often this happens or whether the medicine caused it.
A post hoc analysis of SURMOUNT-1 and -2, written largely by Lilly authors, grouped people by whether they lost at least 5% of their weight by week 8 and listed hypoglycaemia among the outcomes it assessed, but its abstract does not report a hypoglycaemia result. [6] Outside the medicine, MedlinePlus lists causes of low blood sugar in people without diabetes: alcohol, a rare insulin-making tumour, a lack of cortisol, growth or thyroid hormone, severe heart, kidney or liver failure, sepsis, some types of weight-loss surgery (usually years later) and certain non-diabetes medicines. [7]
Why the medicines you combine matter
- Supported by the label: Zepbound® lowers blood glucose, and tirzepatide stimulates insulin release in a glucose-dependent way. [1] The warning is therefore framed around combinations: the risk rises with a sulfonylurea or insulin, and section 7.1 asks prescribers to consider lowering those doses when Zepbound® starts. [1] Canada adds that glucose should be monitored at the start for people on a sulfonylurea or insulin. [3]
- From the European patient leaflet: low blood sugar is described as very common when tirzepatide is used with a sulfonylurea and/or insulin, and the leaflet says those doses may need lowering. [4]
- From NIDDK: the diabetes medicines that can cause lows are insulin and two types of tablet, sulfonylureas, which raise insulin over several hours, and meglitinides, taken before meals. [8]
- Proposed but not measured for Zepbound®: tirzepatide decreases calorie intake, [1] and NIDDK lists too few carbohydrates, fasting, more activity than usual, alcohol without food and being sick as triggers for people on these medicines. [8] No Zepbound® study has linked eating less to lows.
- Not for combining: the label advises against using Zepbound® with other tirzepatide products or any GLP-1 receptor agonist, and Canada names Mounjaro® and DPP-4 inhibitors as well. [1][3]
Signs to know
The Medication Guide’s list covers dizziness or light-headedness, blurred vision, anxiety, irritability or mood changes, sweating, slurred speech, hunger, confusion or drowsiness, shakiness, weakness, headache, a fast heartbeat and feeling jittery. [2] MedlinePlus notes that many people with diabetes get much the same symptoms each time, and that a low can occur without any warning symptoms, which is called hypoglycemic unawareness. [7]
NIDDK describes how a low during sleep can show: crying out or nightmares, sweat-dampened sheets, and waking tired, irritable or confused. [8] For people using Zepbound® for sleep apnea who also have diabetes, those night-time signs are worth separating from the sleep apnea itself. Canada places severe low blood sugar, with disorientation, loss of consciousness or seizure, in its table of serious side effects. [3]
Eyes, driving and planning ahead
Quick improvements in blood sugar can bring their own warning: section 5.8 reports a temporary worsening of diabetic retinopathy with rapid improvement in glucose control, so people with a history of retinopathy are monitored, and the Medication Guide asks people with type 2 diabetes to report changes in vision. [1][2]
Canada advises against driving or using machines if you have any signs of low blood sugar, because it can affect concentration, and asks that people on a sulfonylurea or insulin take precautions at the wheel. [3]
The Medication Guide asks you to talk about low blood sugar and how to handle it before starting Zepbound®, and to name any insulin or sulfonylurea you take. [2] MedlinePlus describes the kinds of treatment a provider may teach, such as a sugary drink, food, glucose tablets or glucagon, [7] and NIDDK suggests discussing a glucagon kit, teaching family or coworkers when to use it, and wearing medical ID. [8] The details of your own plan come from your clinician, not from this page.
Zepbound® and Mounjaro® are registered trademarks of Eli Lilly and Company. PepLabo is not affiliated with or endorsed by Eli Lilly and Company.
When to get help
The signs and contact information below come from this article’s sourced guidance.
Emergency
- Someone who cannot be woken, is losing consciousness or is having a seizure
Contact: Emergency services (911 or local number); glucagon from someone trained to give it
- Low blood sugar signs that do not improve after a sugary snack
Contact: Emergency room or emergency services; do not drive yourself
MedlinePlus [7]
Today
- An episode with disorientation or confusion, even after it has passed
Contact: Your healthcare professional, in all cases
Canadian patient information [3]
- Shakiness, sweating, hunger or a fast heartbeat while also on insulin or a sulfonylurea
Contact: Treat as your plan says, then tell your prescriber
- Vomiting or eating very little while on insulin or a sulfonylurea
Contact: Your diabetes team, for sick-day advice
NIDDK [8]