Why Mounjaro (Tirzepatide) Causes Hypoglycemia When Combined With Insulin or Sulfonylureas

What the Mounjaro label warns about

The Mounjaro label has a dedicated section titled Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin. It states that patients receiving Mounjaro with an insulin secretagogue (for example a sulfonylurea) or with insulin may have an increased risk of hypoglycemia, including severe hypoglycemia, and that the risk may be lowered by a reduction in the dose of the sulfonylurea, other insulin secretagogue, or insulin [1]. The drug interactions section repeats the point: when initiating Mounjaro, consider reducing the dose of the concomitant insulin secretagogue or insulin [1]. The label frames dose reduction as something to consider at initiation and does not name a set percentage.

The label also says to inform patients using these medications of the hypoglycemia risk and to educate them on the signs and symptoms of hypoglycemia. The dose it names for lowering the risk is that of the sulfonylurea or insulin, not the tirzepatide dose [1].

How tirzepatide lowers glucose

Tirzepatide binds and activates both the GIP and GLP-1 receptors. Its glucose-lowering actions include glucose-dependent insulin secretion, reduced glucagon and increased insulin sensitivity [1]. Incretin hormones regulate islet hormone secretion and glucose concentrations, which is the scientific basis for this drug class [3].

A 2024 review of GLP-1-based therapies adds that these drugs slow gastric emptying, which has the benefit of lowering postprandial glucose, but also a potential risk of hypoglycemia in people taking insulin or a sulfonylurea [4]. The Mounjaro label confirms that tirzepatide delays gastric emptying [1].

What the trials measured

SURPASS-6 is the trial closest to the situation the label describes. It randomized 1,428 adults with type 2 diabetes who were taking basal insulin to once-weekly tirzepatide (5, 10 or 15 mg) or thrice-daily insulin lispro, both added to insulin glargine, for 52 weeks. Hypoglycemia events (blood glucose below 54 mg/dL or severe hypoglycemia) occurred at 0.4 events per patient-year with pooled tirzepatide and 4.4 with insulin lispro. HbA1c fell 2.1 percentage points with tirzepatide and 1.1 points with insulin lispro, and body weight changed by -9.0 kg with tirzepatide versus +3.2 kg with lispro [2].

One small study looked at tirzepatide in people who use insulin for type 1 diabetes, an off-label use. A retrospective single-center study followed 62 adults with type 1 diabetes who were prescribed tirzepatide and compared them with 37 matched controls; insulin dose decreased at 3 months and stayed lower through the year, and the authors reported no hospitalizations for severe hypoglycemia or diabetic ketoacidosis [5]. It is a small, retrospective study, so it describes what happened in one center rather than proving a safety profile.

The dose schedule and the partner drug

Mounjaro starts at 2.5 mg once weekly. The dose goes up by 2.5 mg after at least 4 weeks on the current dose if more glycemic control is needed, to a maximum of 15 mg weekly in adults and 10 mg weekly in children 10 and older [1]. The label attaches its statement about the sulfonylurea or insulin to the start of treatment [1].