Mounjaro (Tirzepatide) Hypoglycemia Severity Grading: When Combined With Insulin or Sulfonylureas

What does the label say about hypoglycemia with insulin or a sulfonylurea?

The warnings section says that concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia, and that reducing the dose of the insulin secretagogue or insulin may be necessary [1]. The interactions section says to consider reducing the dose of a sulfonylurea or insulin when Mounjaro is initiated, to reduce the risk of hypoglycemia [1]. Sulfonylureas are the label's named example of an insulin secretagogue [1].

Neither section gives an amount or a titration schedule for the reduction [1]. The warnings section also directs prescribers to tell patients using these medications about the risk of hypoglycemia and to educate them on its signs and symptoms [1].

How does the label separate mild from severe lows?

The label does not set up severity grades with a different dose action for each. In its trial tables it reports two measures: the share of patients with glucose under 54 mg/dL, and the share with severe hypoglycemia [1]. The 54 mg/dL cutoff is how those trials counted events.

In SURPASS-5, a 40-week trial of Mounjaro added to basal insulin with or without metformin, glucose under 54 mg/dL occurred in 16%, 19% and 14% of patients on 5 mg, 10 mg and 15 mg, versus 13% on placebo [1]. Severe hypoglycemia was reported in none of the placebo or 5 mg patients, 2% on 10 mg and 1% on 15 mg [1]. In SURPASS-1, a 40-week monotherapy trial, no severe hypoglycemia was reported [1].

The label also states that hypoglycemia was more frequent when Mounjaro was used with a sulfonylurea [1]. Zepbound, a different tirzepatide product, has a label that gives a figure from SURMOUNT-2, a trial in adults with type 2 diabetes and obesity or overweight: glucose under 54 mg/dL in 10.3% of patients on a sulfonylurea versus 2.1% of those not on one. That is a Zepbound trial population, not a Mounjaro one.

Is the warning about Mounjaro alone or in combination?

Combination. The warning specifically highlights increased hypoglycemia risk when Mounjaro is used with insulin or an insulin secretagogue [1]. In the label's monotherapy trial (SURPASS-1), glucose under 54 mg/dL occurred in 0% of patients on each Mounjaro dose and 1% on placebo [1].