Management of Hypoglycemia Using Continuous Glucose Monitoring During Tirzepatide Initiation or Uptitration When Used in Addition to Other Glucose-Lowering Agents

The use of injectable incretin-based therapies is becoming more common. Diabetes and obesity are prevalent disease states that can lead to mortality and further health complications. Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide 1 (GLP-1) receptor agonist used in the management of type 2 diabetes, obesity, and overweight (with at least one weight-related complication). Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, which are the targets for native GIP and GLP-1. Tirzepatide enhances first- and second-phase insulin secretion and reduces glucagon levels in a glucose-dependent manner (1). The mechanism of dual agonism results in reductions in blood glucose and body weight. Administered as a once-weekly subcutaneous injection, tirzepatide was approved by the U.S. Food and Drug Administration in May 2022 for the management of type 2 diabetes, in November 2023 for weight management in adults with obesity (BMI >30 kg/m²) or overweight (BMI >27 kg/m²) with at least one weight-related condition, and in December 2024 for the treatment of obstructive sleep apnea (OSA) (2,3).

Tirzepatide has demonstrated a dose-dependent effect in reducing both A1C and body weight. Typically, initial dosing is 2.5 mg subcutaneously once weekly for 4 weeks. Dosing then may be increased in 2.5-mg increments every 4 weeks to a maximum dose of 15 mg weekly. Titration depends on tolerability of side effects, as well as treatment goals, based on patient needs (4).

The typical side effect profile of tirzepatide includes gastrointestinal discomfort, bloating, diarrhea, nausea, and vomiting (5). Clinical trials of tirzepatide demonstrated risk of hypoglycemia, defined as a blood glucose of <70 mg/dL, or severe hypoglycemia, defined as blood glucose <54 mg/dL, with the concomitant use of insulin or sulfonylureas (6). Monotherapy treatment with tirzepatide was not found to increase the risk of hypoglycemia in the SURPASS-1 trial (7). Hypoglycemia was reported infrequently with tirzepatide in the SURPASS-2 trial as an add-on therapy to metformin, as well as in the SURPASS-3 trial when added to metformin with or without a sodium–glucose cotransporter 2 (SGLT2) inhibitor (8,9).

Here, we present a series of case reports demonstrating the use of continuous glucose monitoring (CGM) as a useful tool in the management of hypoglycemia in patients with type 2 diabetes after initiation or uptitration of tirzepatide in addition to other glucose-lowering agents. Our objective is to document management of hypoglycemic adverse reactions to tirzepatide noted through CGM in the real-world setting by providing examples of adjustments made to other glucose-lowering medications to prevent further hypoglycemia. We also provide potential implications of hypoglycemic events with the increasing use of tirzepatide monotherapy for management of type 2 diabetes.

All patients in the cases below were referred to a medication therapy management pharmacist by their primary care provider (PCP) for diabetes management. The pharmacist conducted routine telephone calls with the patients to monitor their medications and blood glucose levels and to make dose adjustments as needed under a collaborative practice agreement.

Cases Reports

Table 1 summarizes glucose metrics reported on standardized CGM ambulatory glucose profile (AGP) reports and referred to in the case reports below (10).

Table 1.

Key Glucose Metrics Reported on Standardized CGM AGP Reports (10)

Metric	Definition	Recommendation
TAR (level 2)	>250 mg/dL	<5% (most adults); <10% (older adults)
TAR (level 1)	181–250 mg/dL	<25% (most adults); <50% (older adults)
TIR	70–180 mg/dL	>70% (most adults); >50% (older adults)
TBR (level 1)	54–69 mg/dL	<4% (most adults); <1% (older adults)
TBR (level 2)	<54 mg/dL	<1%
GMI	An estimate of A1C based on the average glucose level from CGM readings over ≥14 days	Goal for this value is not standardized

Case 1

Patient 1 was a 51-year-old woman with type 2 diabetes. Before starting tirzepatide, her diabetes medications included dulaglutide 4.5 mg weekly, empagliflozin 25 mg daily, insulin aspart 6 units three times daily with meals, and insulin glargine 36 units daily. Her A1C before starting tirzepatide was 9.8%, and her BMI was 37.61 kg/m².

In January 2023, Dulaglutide was discontinued, and tirzepatide 5 mg weekly was initiated to improve glycemic control and facilitate weight loss. Her tirzepatide dose was then increased every 4 weeks in 2.5-mg increments. Once she reached the 12.5-mg weekly dose in April 2023, she started experiencing hypoglycemia, with low alarms on her CGM system. This prompted her to contact her PCP, who decreased her insulin glargine dose to 32 units daily. The next week, when the pharmacist called for a blood glucose review, the patient reported self-discontinuing her insulin aspart and insulin glargine given concerns about hypoglycemia, and the tirzepatide was continued at 12.5 mg weekly. After 1 month, her tirzepatide dose was further increased to 15 mg weekly.

Her blood glucose levels remained stable at this dose of tirzepatide, along with the empagliflozin 25 mg daily, for ∼4 months, until September 2023, when she contacted the pharmacist with concerns about hypoglycemia. Review of her CGM AGP report from the previous 2 weeks showed 2% time below range (TBR) level 2, 14% TBR level 1, 80% time in range (TIR), 3% time above range (TAR) level 1, and 1% TAR level 2. Her average glucose was 107 mg/dL, and her glucose management indicator (GMI) was 5.9%. At that time, the patient confirmed she was not taking any insulin and had self-discontinued empagliflozin.

Her tirzepatide dose was decreased to 12.5 mg weekly, and review of her AGP report 2 weeks later showed 0% TBR (both levels), 90% TIR, 9% TAR level 1, and 1% TAR level 2. Her average glucose was 138 mg/dL, and her GMI was 6.6%.

In November 2023, the patient’s A1C had decreased to 6.7%, and her BMI was 34.78 kg/m². By October 2024, her A1C was 6.0%, and her BMI was 31.02 kg/m² on a stable tirzepatide dose of 12.5 mg weekly.

Case 2

Patient 2 was a 58-year-old man with type 2 diabetes. Before starting tirzepatide, his diabetes medications included insulin glargine 50 units daily, insulin lispro 32 units at lunch and 28 units at supper, semaglutide 2 mg weekly, and empagliflozin 25 mg daily. His A1C was 10.7%, and his BMI was 45.93 kg/m².

In April 2023, his semaglutide was discontinued, and he was initiated on tirzepatide 5 mg weekly to improve glycemic control and facilitate weight loss. His tirzepatide dose was increased every 4 weeks in 2.5-mg weekly increments. After starting the initial 5-mg weekly dose of tirzepatide, his insulin glargine dose was decreased to 45 units daily. Once he reached a tirzepatide dose of 10 mg weekly in May 2023, he was able to discontinue insulin lispro. After attaining a tirzepatide dose of 12.5 mg weekly in June 2023, the patient self-discontinued insulin glargine. Tirzepatide was increased to the maximum dose of 15 mg weekly in September 2023.

In January 2024, ∼4 months after reaching the maximum dose of tirzepatide, he started to experience hypoglycemia, as shown in his CGM data. Review of his AGP report at that time showed 1% TBR level 2, 4% TBR level 1, 69% TIR, 22% TAR level 1, and 4% TAR level 2, with an average glucose of 157 mg/dL. Six months later, in July 2024, his CGM metrics were 1% TBR level 2, 6% TBR level 1, 90% TIR, 3% TAR level 1, and 0% TAR level 2, with an average glucose of 115 mg/dL and a GMI of 6.1%. His empagliflozin was decreased to 12.5 mg daily, which initially resolved the hypoglycemia until September 2024 (∼2 months later) when it started to occur again, and tirzepatide was decreased from 15 to 12.5 mg weekly. His A1C was 7.9% in August 2024, and his BMI was 43.65 kg/m² in October 2024. A repeat A1C test was scheduled for his next follow-up appointment with his PCP in November 2024.

Case 3

Patient 3 was a 77-year-old woman with type 2 diabetes. She was taking tirzepatide 2.5 mg weekly and insulin degludec 30 units daily. She originally started tirzepatide in September 2023. At that time, her A1C was 6.0%, and her BMI was 38.34 kg/m². She previously was unable to tolerate semaglutide because of gastrointestinal side effects.

By June 2024, her A1C was 5.4%, and her BMI was 33.76 kg/m². She did not routinely check her blood glucose levels, but after starting to experience hypoglycemic symptoms in July 2024, she started on CGM and was instructed to discontinue her insulin degludec because of the hypoglycemia. The daily glucose graphs from her AGP report at that time showed frequent glucose readings in the hypoglycemic range.

Her last dose of tirzepatide 2.5 mg was on 13 July 2024. Tirzepatide was discontinued thereafter because of her hypoglycemia. By 4 days later, her hypoglycemia resolved. She started dulaglutide 0.75 mg weekly as a replacement for the tirzepatide on 26 July 2024.

Case 4

Patient 4 was a 64-year-old woman with type 2 diabetes, with an A1C of 7.2% and a BMI of 42.89 kg/m². She started tirzepatide 2.5 mg weekly in August 2023, having been unable to tolerate semaglutide previously. In addition to tirzepatide, she took dapagliflozin 5 mg daily.

Her tirzepatide dose was eventually uptitrated to 10 mg weekly. At that time, her CGM metrics were 1% TBR level 2, 7% TBR level 1, 92% TIR, and 0% TAR (both levels). Her average glucose was 92 mg/dL, and her GMI was 5.5%.

The patient thought perhaps a faulty CGM sensor was contributing to her low blood glucose data, and tirzepatide 10 mg was on backorder at that time, so her dose was decreased to 7.5 mg weekly. Review of her AGP report the next month showed 0% TBR (both levels), 100% TIR, and 0% TAR (both levels), with an average glucose of 95 mg/dL. In September 2024, 1 year after starting tirzepatide, her BMI decreased to 31.97 kg/m², and her A1C was 5.0%.

Case 5

Patient 5 was a 54-year-old woman with type 2 diabetes. Before initiating tirzepatide 5 mg weekly in August 2023, she was taking glimepiride 4 mg twice daily, metformin 1,000 mg twice daily, insulin glargine 13 units daily, insulin aspart 5 units with breakfast and lunch and 6 units with supper, and semaglutide 2 mg weekly. Her A1C before switching from semaglutide to tirzepatide was 11.2%, and her BMI was 36.39 kg/m².

Her glimepiride and insulin aspart were discontinued before starting tirzepatide 5 mg weekly. The tirzepatide dose was then increased every 4 weeks, and once she reached a tirzepatide dose of 7.5 mg weekly, she was able to discontinue insulin glargine. In November 2023, she reached a tirzepatide dose of 15 mg weekly and was able to discontinue metformin.

Six months later, in May 2024, hypoglycemia was noted on her AGP report, with CGM metrics of <1% TBR level 2, 3% TBR level 1, 96% TIR, 1% TAR level 1, and 0% TAR level 2, with an average glucose of 100 mg/dL and a GMI of 5.7%. Her tirzepatide dose was decreased to 12.5 mg weekly. Two weeks later, her AGP report showed <1% TBR level 2, 1% TBR level 1, 98% TIR, <1% TAR level 1, and 0% TAR level 2. Her average glucose was 108 mg/dL, and her GMI was 5.9%. By July 2024, her A1C was 5.5% and her BMI was 29.87 kg/m².

All of the patients in these cases were able to self-manage hypoglycemia with the help of CGM. None required assistance from another person, administration of glucagon, urgent care, an emergency room visit, or hospitalization.

Discussion

These cases illustrate the usefulness of CGM in the management of hypoglycemia with tirzepatide when used in addition to other glucose-lowering agents. Four of the five patients were on insulin or a sulfonylurea before starting tirzepatide, both of which are agents with known risks of hypoglycemia. Therefore, close monitoring of glucose levels was crucial to prevent hypoglycemia. Although the mechanism of action for tirzepatide with regard to agonism of GIP and GLP-1 is thought to be glucose dependent, episodes of hypoglycemia were still noted in four of the five patients, even after discontinuation of insulin or sulfonylurea. This hypoglycemia prompted dose reductions in tirzepatide for four of the five patients and transition from tirzepatide to dulaglutide, a GLP-1 agonist, for one patient.

Although rare, hypoglycemia was reported in 0.6% of the 5-mg dose group, 0.2% of the 10-mg dose group, and 1.7% of the 15-mg dose group receiving tirzepatide with metformin in the SURPASS-2 trial (8). Hypoglycemia also occurred in 1% of the 5-mg group, 1% of the 10-mg group, and 2% of the 15-mg group when tirzepatide was used in addition to metformin with or without an SGLT2 inhibitor in the SURPASS-3 trial (9).

One limitation with these case reports is that the hypoglycemic events were noted from CGM data rather than from capillary blood glucose monitoring with a glucose meter. CGM measures interstitial glucose, which correlates well with plasma glucose but at times can lag if glucose levels are rising or falling rapidly (11). Given that all of the patients described here had type 2 diabetes, it is unknown whether hypoglycemia could be a potential risk in patients using tirzepatide exclusively for weight management or OSA without diabetes.