Insulin Deprescribing Utilizing Continuous Glucose Monitoring With Low-Dose Tirzepatide

Introduction

Tirzepatide (Mounjaro; Eli Lilly), a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist (GLP-1 RA), is recommended as a preferred pharmacotherapy option for the management of type 2 diabetes (T2D), particularly for patients whose weight reduction and sustained glycemic control are key therapeutic priorities, typically at maintenance doses of 5 mg weekly or higher.¹ Despite this, real-world clinical experience suggests that a subset of patients may exhibit marked glycemic improvement at lower doses. This case describes rapid insulin de-escalation and discontinuation following initiation of tirzepatide 2.5 mg weekly, monitored using continuous glucose monitoring (CGM), and explores potential clinical and pharmacogenomic considerations relevant to pharmacists.

Case Report

A 67-year-old man with long-standing T2D (> 10 years), stage IIIA chronic kidney disease (CKD), and peripheral arterial disease was referred for pharmacist medication management due to suboptimal glycemic control and regimen complexity. Baseline therapy included metformin immediate release (IR) 1000 mg twice daily and premixed insulin aspart protamine/aspart 70/30 (NovoLog Mix 70/30; Novo Nordisk) at 38 units twice daily with breakfast and dinner. The most recent hemoglobin A_1c (HbA_1c), obtained approximately 6 weeks prior to CGM review, was approximately 8.1%.

CGM data with 15 days of wear demonstrated an average glucose of 171 mg/dL, glucose management indicator (GMI) 7.4%, time in range (TIR; 70-180 mg/dL) 60%, time above range (TAR) 36% high (181-250 mg/dL), 4% very high (> 250 mg/dL), and no low (< 70 mg/dL) readings. The coefficient of variation (%CV) was 25.8%. The patient reported adherence to his insulin regimen but described waiting to go to bed until his blood glucose decreased to 125 mg/dL and consuming orange juice to treat nocturnal hypoglycemia. He would sometimes miss metformin doses.

He had previous trials with semaglutide (Ozempic; Novo Nordisk) but could not tolerate it due to gastrointestinal (GI) adverse effects (AEs). Although he tolerated dulaglutide (Trulicity; Eli Lilly and Company), treatment was discontinued due to availability issues. 

At the first pharmacy visit, metformin IR was changed to the extended-release (ER) formulation, four 500-mg tablets once a day with breakfast. His mixed insulin 38 units twice a day was discontinued, and basal insulin degludec 200 units/mL (Tresiba; Novo Nordisk) was initiated at 20 units once a day with instructions to titrate up by 2 units every 4 days to target a fasting blood glucose of 80 to 130 mg/dL. A prescription of ready-to-use glucagon was given, and education on the identification, prevention, and management of hypoglycemia was provided. Tirzepatide 2.5 mg weekly was initiated.

After 2 weeks, the patient’s 14-day CGM data showed significant improvement, with a TIR of approximately 87%, TAR reduced to 12% high, and 1% very high, and no hypoglycemia. His average glucose was 139 mg/dL, GMI 6.6%, and %CV 26%. He reported feeling significantly better. His basal insulin dose was then reduced to 10 units daily, and a new prescription and prior authorization for tirzepatide 5 mg weekly were initiated.

Two weeks later, despite the insulin dose reduction, his TIR improved to 99%, with TAR at 1% and no hypoglycemia. His average glucose was 120 mg/dL, GMI 6.2%, and %CV was 17.7%. Basal insulin was discontinued. The prior authorization was not approved, and another 4 weeks of samples of tirzepatide 2.5 mg weekly were provided. About one month later, it was approved.

At his 3-month follow-up visit, his TIR was 97%, TAR was 1%, and time below range was 2%. During this visit, tirzepatide 5 mg weekly was continued, metformin ER was reduced to 1000 mg once a day, and empagliflozin 10 mg (Jardiance; Boehringer Ingelheim and Eli Lilly and Company) daily was initiated due to his history of CKD. He reported feeling better than he has in many years and had no reported GI AEs or symptomatic hypoglycemia.

Alternative Explanations and Limitations

Although the temporal association suggests a robust response to low-dose tirzepatide, several alternative explanations must be considered. Simplification from premixed to basal insulin may have reduced dosing errors and hypoglycemia-driven compensatory eating. Improved adherence with once-a-day metformin ER and increased engagement during CGM review may also have contributed. Importantly, this is a single-patient observation without pharmacogenomic testing, limiting causal inference and generalizability.

Pharmacogenomic Considerations and Pharmacist Implications

Interindividual variability in response to incretin-based therapies has been associated with genetic variants affecting GLP-1 receptor signaling, insulin secretion, and incretin metabolism. While specific variants (eg, GLP1R polymorphisms) have been linked to differential glycemic response in population studies, pharmacogenomic testing was not performed in this case. Any genetic contribution remains speculative and hypothesis-driving.

For pharmacists, the key takeaway is not routine pharmacogenomic testing but recognition of a potential low-dose responder phenotype. CGM-guided titration and cautious insulin de-escalation may be appropriate in select patients demonstrating rapid glycemic improvement, even at initiation doses traditionally considered subtherapeutic. Further research is needed to determine which genetic variants are actionable and whether they should guide dose adjustments or individualized treatment strategies. The ability to individualize therapy based on observed response and, in the future, potentially genotype, highlights an emerging precision-medicine opportunity in diabetes care. As incretin-based therapies become increasingly integrated into treatment algorithms, pharmacist involvement in therapeutic decision-making, dose optimization, and patient education remains essential to improving glycemic outcomes, minimizing polypharmacy, and enhancing quality of life. Detailed pharmacogenomic associations are summarized in the Table for reference.

Discussion and Conclusion

This case highlights the role of a pharmacist in individualized diabetes management, particularly in identifying opportunities for insulin deprescribing using CGM data. While tirzepatide 2.5 mg is not intended as a maintenance dose, select patients may achieve clinically meaningful glycemic control at lower doses, emphasizing the importance of patient-specific assessment rather than rigid adherence to population-level dosing assumptions. Further studies are needed to characterize predictors of low-dose responsiveness, including clinical phenotypes and genetic factors, and to determine the durability of response over a longer follow-up period.

Insulin discontinuation following initiation of tirzepatide 2.5 mg is uncommon but clinically plausible in select patients. Pharmacists should leverage CGM data to guide safe insulin de-escalation, remain vigilant for alternative explanations, and view pharmacogenomic hypotheses as exploratory.

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Disclosures/Conflicts of Interest:

Youngseon Kim reports no conflicts of interest.

Hailey Choi reports serving as a speaker for Novo Nordisk.

Jennifer Goldman reports serving as a speaker for Novo Nordisk, Eli Lilly and Company, Abbott Diabetes Care, Xeris Pharmaceuticals, CeQur, and Amgen.

No external funding was received.